The objective of this paper is to evaluate the influence of patient risk status on the incidence of and indications for cesarean delivery. All live births > or = 23 weeks at the University of Vermont in 1995 (n = 2395) were retrospectively analyzed for delivery route, indication for cesarean, gestational age, parity, and practice group (to reflect risk status). The total cesarean rate was 14.4% (344 of 2395), and the primary rate was 11.4% (244 of 2144). Abnormal presentation was the most common indication (25.6%, 88 of 344). The "corrected" cesarean rate (maternal-fetal medicine and transported patients excluded) was 12.4% (273 of 2194), and the "corrected" primary rate was 9.6% (190 of 1975). Furthermore, when all deliveries were analyzed, regardless of risk status but limited to gestational age > or = 36 weeks, the rates did not change (12.6%, 280 of 2214; primary 9.2%, 183 of 1994). Arrest of dilation was the most common indication in both "corrected" subgroups (23.4 and 24.6%, respectively). Cesarean rates at tertiary care hospitals should be compared with rates at community hospitals only after correcting for dissimilar patient groups or gestational age. In the third trimester, the amniotic fluid index (AFI) may be affected by maternal fluid status. As the ambient temperature increases, there is an increase in insensible fluid loss and the potential for dehydration. We hypothesize that as temperature increases there would be a concomitant decrease in AFI. From June 11 to August 16, 1993, during a period of unusual high heat, 42 women with singleton pregnancies between 27 and 40 weeks' gestation undergoing serial antenatal testing had AFI determinations recorded at least weekly. The daily high ambient temperature in our urban area was subsequently obtained. A 2-, 3-, and 4-day mean temperature prior to the test date was compared to AFI using a Spearman-rank Correlation. The daily high temperature ranged from 71 to 104 degrees F and AFI values ranged from 1.7 to 24.7 cm during the study period. There was a significant correlation between the 2-, 3-, and 4-day mean temperature and AFI, with the 4-day mean being the most significant (r = 0.31, p < 0.001). Fluctuations in ambient temperature are inversely correlated to changes in AFI. This relationship should be taken into account when interpreting the AFI as a measure of fetal well-being. This study tested the hypothesis that to reduce the rate of macrosomic infants in gestational diabetes cases, good glycemic control should be initiated before 34 completed gestational weeks. The study population included 84 women with gestational diabetes, ascertained by universal screening of all women attending the antenatal clinic of the Hadassah Medical Center, over a 2-year period. The 60 women (71%), who initiated treatment before 34 completed weeks, composed the "early" group. The 24 women (29%), who initiated treatment after the 34th week, composed the "late" group. All patients were managed by an intensified protocol, including stringent glycemic control. In the "early" and "late" groups, mean gestational age at the beginning of treatment was 30.0 +/- 3.8 and 36.2 +/- 1.2 weeks, and duration of treatment was 9.6 +/- 4.1 and 3.7 +/- 1.8 weeks, respectively. Maternal characteristics were similar in the two groups. The rate of macrosomic and large-for-gestational-age infants were 5 and 11%, respectively, in the early group as compared to 25 and 29% in the "late" group (p < 0.05). No significant differences were found between the two groups in the mode of delivery or Apgar scores. We conclude that to reduce the rate of macrosomic infants in gestational diabetes cases , good glycemic control should be initiated before 34 completed gestational weeks. Our aim was to investigate the contribution of certain antenatally detectable markers leading to the diagnosis of trisomic fetuses we observed over a period of 6 years. In our study, we specifically analyzed the role played by advanced maternal age and sonographically discovered abnormalities in the detection of autosomal trisomies. All together, 27 fetuses had this disorder, representing 28.7% (27 of 94) of all cytogenetic aberrations detected at our center over the same period. Down syndrome (12 cases) and Edward syndrome (11 cases) were the most common trisomies, while 4 cases of Patau syndrome were also diagnosed. The most common indication leading to diagnosis was abnormal ultrasound finding (48.2%), followed by advanced maternal age (44.4%). However, 63% of the trisomic fetuses belonged to mothers aged 35 years and above. Down syndrome fetuses (41.7%) had prenatally detected sonographic anomalies, 63.6% for Edward syndrome, and all fetuses with Patau syndrome (4 of 4) showed abnormal sonographic signs. Trisomy 21 presented with the following features: hydramnios, complex malformations, pyelectasis, and duodenal atresia. Trisomy 18 fetuses showed hydramnios, intrauterine growth retardation, microcephaly, spina bifida, and nonimmune hydrops fetalis. Signs observed in fetuses with trisomy 13 were: hydrocephalus, intrauterine growth retardation, oligoanhydramnios, complex malformations, severe fetal bradycardia and hydronephrosis. The objective of this study was to determine if the rate of preeclampsia is increased in triplet as compared to twin gestations. Fifty-three triplet pregnancies between 1986 and 1993 at The New York Hospital-Cornell Medical Center were reviewed. These were matched for maternal age, parity, and race to twin gestations (N = 53) from the same population. Severe preeclampsia was defined by standard criteria. Student's t-test, Fisher exact test, and Chi-square were used for statistical analysis. The rate of severe preeclampsia was increased significantly in the triplet group 12 of 53 (22.6%) as compared with the twin group 3 of 53 (5.7%) (OR = 4.9, 95% CI 1.2-23.5, p = 0.02). The rate of overall preeclampsia was not significantly different in the triplet 18 of 53 (33.96%) or twin 12 of 53 (22.6%) groups. In this retrospective, case-controlled study, the rate of severe pre-eclampsia was significantly increased in triplet gestations as compared to twins although the overall rate of preeclampsia was not. This information may be useful in counseling patients with high order multifetal gestations. We conducted a survey and audit of thermal equipment use in very low-birth-weight infants in five Ohio neonatal intensive care units (NICUs) to document regional practice. The survey indicated a variety of thermal care styles. Two NICUs preferred to admit infants to incubators, the other three favoring radiant warmers. These three NICUs moved infants from radiant warmers into incubators at significantly different mean ages. The audit demonstrated inconsistent use of plastic covers, warming mattresses, and added humidity under radiant warmers, and discrepancies between survey responses and actual use within NICUs. Inter-NICU variability of thermal equipment use may complicate fluid management. This report describes a full-term newborn with massive fetomaternal hemorrhage. Fetal movements were decreased 48 hr prior to delivery. On the day of delivery, they were absent. The nonstress test was abnormal with low biophysical profile and decreased beat-to-beat variability. The infant presented with extreme pallor, hypotonia, hepatosplenomegaly, and ascites. The initial hemoglobin was 2.2 g/dL, the Kleihauer-Betke stain was 27.6% (highest level ever reported). Right temporal and cerebellar hemorrhages were present. Sequelae include severe developmental delay and asymmetric double hemiplegia. Omphalocele-Exstrophy-Imperforate anus-Spinal defects (OEIS complex) , a combination of omphalocele, exstrophy of the bladder, an imperforate anus and spinal defects, arises from a single localized defect in the early development of the mesoderm that will later contribute to infraumbilical mesenchyme, cloacal septum, and caudal vertebrae. In this report, we document the perinatal features of two cases of OEIS complex associated with meningomyeloceles and severe lower limb defects, and discuss the prenatal diagnosis, inheritance, and differential diagnosis of this association of malformations. Although long-term survival can be achieved by successful corrective surgery, the associated structural defects such as large meningomyelocele and severe limb aplasia or hypoplasia, as seen in our patient, can influence the patient's quality of life. We would like to emphasize that an accurate prenatal diagnosis of OEIS complex and associated malformations is important for the detailed counseling of the family as well as appropriate perinatal management by the obstetricians, pediatric surgeons, urologists, neurosurgeons, and neonatologists. Nonimmune hydrops fetails diagnosed at 21 weeks' gestation with profound ascites, hydrothorax, and pericardial effusion receded gradually with regression of a subchorial placental lucencies immediately below the umbilical cord insertion. Careful inspection of the delivered placenta revealed that there was a yellowish lesion of fibrin deposits below the cord insertion site, which resulted from the absorption of hematoma. A subchorial placental hematoma, which detected as a subchorial placental lucencies by ultrasonography, can be a cause of reversible nonimmune hydrops fetalis. The mitochondrial diseases are uncommon multisystem disorders characterized by the presence of functionally and/or structurally abnormal mitochondria. As there have been few reports of the obstetrical care of affected patients, we wish to document two pregnancies in a woman with a Chronic Progressive External Ophthalmoplegia (Kearns-Sayre-like syndrome) . Both pregnancies were complicated by preterm labor and hypertension. CONTEXT: Four genetic loci have been identified as contributing to Alzheimer disease (AD) , including the amyloid precursor protein gene, the presenilin 1 gene, the presenilin 2 gene, and the apolipoprotein E gene, but do not account for all the genetic risk for AD. OBJECTIVE: To identify additional genetic risk factors for late-onset AD. DESIGN: A complete genomic screen was performed (N=280 markers). Critical values for chromosomal regional follow-up were a P value of .05 or less for affected relative pair analysis or sibpair analysis, a parametric lod score of 1.0 or greater, or both. Regional follow-up included analysis of additional markers and a second data set. SETTING: Clinic populations in the continental United States. PATIENTS: >From a series of multiplex families affected with late-onset (> or =60 years) AD ascertained during the last 14 years (National Insititute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria) and for which DNA has been obtained, a subset of 16 families (135 total family members, 52 of whom were patients with AD) was used for the genomic screen. A second subset of 38 families (216 total family members, 89 of whom were patients with AD) was used for the follow-up analysis. MAIN OUTCOME MEASURES: Linkage analysis results generated using both genetic model-dependent (lod score) and model-independent methods. RESULTS: Fifteen chromosomal regions warranted initial follow-up. Follow-up analyses revealed 4 regions of continued interest on chromosomes 4, 6, 12, and 20, with the strongest results observed forchromosome 12. Peak 2-point affecteds-only lod scores (n=54) were 1.3, 1.6, 2.7, and 2.2 and affected relative pairs P values (n=54) were .04, .03, .14, and .04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. Sibpair analysis (n=54) resulted in maximum lod scores (MLSs) of 1.5, 2.6, 3.2, and 2.3 for these markers, with a peak multipoint MLS of 3.5. A priori stratification by APOE genotype identified 27 families that had at least 1 member with AD whose genotype did not contain an APOE*4 allele. Analysis of these 27 families resulted in MLSs of 1.0, 2.4, 3.7, and 3.3 and a peak multipoint MLS of 3.9. CONCLUSIONS: A complete genomic screen in families affected with late-onset AD identified 4 regions of interest after follow-up. Chromosome 12 gave the strongest and most consistent results with a peak multipoint MLS of 3.5, suggesting that this region contains a new susceptibility gene for AD. Additional analyses are necessary to identify the chromosome 12 susceptibility gene for AD and to follow up the regions of interest on chromosomes 4, 6, and 20. CONTEXT: A mutation in the BRCA1 gene may confer substantial risk for breast and/or ovarian cancer. However, knowledge regarding all possible mutations and the relationship between risk factors and mutations is incomplete. OBJECTIVES: To identify BRCA1 mutations and to determine factors that best predict presence of a deleterious BRCA1 mutation in patients with breast and/or ovarian cancer. DESIGN: A complete sequence analysis of the BRCA1 coding sequence and flanking intronic regions was performed in 798 women in a collaborative effort involving institutions from the United States, Italy, Germany, Finland, and Switzerland. PARTICIPANTS: Institutions selected 798 persons representing families (1 person for each family) thought to be at elevated a priori risk of BRCA1 mutation due to potential risk factors, such as multiple cases of breast cancer, early age of breast cancer diagnosis, and cases of ovarian cancer. No participant was from a family in which genetic markers showed linkage to the BRCA1 locus. MAJOR OUTCOME MEASURES: Sequence variants detected in this sample are presented along with analyses designed to determine predictive characteristics of those testing positive for BRCA1 mutations. RESULTS: In 102 women (12.8%), clearly deleterious mutations were detected. Fifty new genetic alterations were found including 24 deleterious mutations, 24 variants of unknown significance, and 2 rare polymorphisms. In a subset of 71 Ashkenazi Jewish women, only 2 distinct deleterious mutations were found: 185delAG in 17 cases and 5382insC in 7 cases. A bias in prior reports for mutations in exon 11 was revealed. Characteristics of a patient's specific diagnosis (unilateral or bilateral breast cancer, with or without ovarian cancer), early age at diagnosis, Ashkenazi Jewish ethnicity, and family history of cancer were positively associated with the probability of her carrying a deleterious BRCA1 mutation. CONCLUSIONS: Using logistic regression analysis, we provide a method for evaluating the probability of a woman's carrying a deleterious BRCA1 mutation for a wide range of cases, which can be an important tool for clinicians as they incorporate genetic susceptibility testing into their medical practice. CONTEXT: Approximately 9% of prostate cancer cases have been estimated to result from inheritance of mutated prostate cancer susceptibility genes. Few data exist as to whether there are clinical differences between prostate cancers that are inherited and those that occur in the general population. OBJECTIVE: To investigate phenotypic characteristics of families potentially linked to the hereditary prostate cancer 1 (HPC1) locus on chromosome 1q24-25. DESIGN: Retrospective case study in which clinical data were extracted from medical and pathological records. FAMILIES: A total of 74 North American families with hereditary prostate cancer. Prostate cancer cases from the National Cancer Data Base were used as a reference population for comparison. MAIN OUTCOME MEASURES: The families were divided into 2 groups: either potentially linked (33 families with 133 men with prostate cancer), and thus likely to be carrying an altered HPC1 gene, or potentially unlinked (41 families with 172 men with prostate cancer), on the basis of haplotype analysis in the region of HPC1. The age at diagnosis of prostate cancer, serum prostate-specific antigen levels, digital rectal examination status, stage, grade, primary treatment of prostate cancers, and occurrence of other cancers were compared between the groups. RESULTS: The mean age at diagnosis of prostate cancer for men in potentially linked families was significantly lower than for men in potentially unlinked families (63.7 vs 65.9 years, respectively, P=.01; mean age at diagnosis in the reference population was 71.6 years). Higher-grade cancers (grade 3) were more common in potentially linked families, and advanced-stage disease was found in 41% of the case patients in potentially linked families compared with 31% in both the potentially unlinked families and the reference groups (P=.03 for the latter comparison). In the other clinical parameters, we found no significant differences between the groups. A modest excess of breast cancer and colon cancer was found in potentially linked families in comparison with potentially unlinked families, but this difference was not statistically significant. CONCLUSIONS: Families that provide evidence for segregation of an altered HPC1 gene are characterized by multiple cases of prostate cancer that, in most respects, are indistinguishable from nonhereditary cases. However, 3 characteristics were observed: younger age at diagnosis, higher-grade tumors, and more advanced-stage disease. Our study shows that a significant fraction of hereditary prostate cancers are diagnosed in advanced stages, emphasizing the clinical importance of early detection in men potentially carrying prostate cancer susceptibility genes. These findings support the current recommendations to screen men with a positive family history of prostate cancer beginning at age 40 years. CONTEXT: Susceptibility to multiple sclerosis (MS) involves a genetically complex autoimmune component. However, except for genes in the HLA system, specific susceptibility loci are unknown or unconfirmed. OBJECTIVE: To investigate several loci spanning 3 candidate regions for a role in multiple sclerosis (MS) susceptibility in 2 ethnic groups using both single-locus and haplotype analyses. The 3 regions include HLA on chromosome 6p21.3, APOE on chromosome 19ql 3.2, and MBP(myelin basic protein) on chromosome 18q23. DESIGN: Case-control association testing. SUBJECTS: A total of 120 Caucasian patients with MS and 107 unrelated control individuals from California, and 32 patients and 32 unrelated control individuals from Beijing, China. All patients with MS were diagnosed as having clinically definite disease according to published criteria. MAIN OUTCOME MEASURES: Chi2 Testing of loci and individual alleles and haplotypes. Haplotype frequencies were estimated with standard maximum likelihood methods. RESULTS: The HLA effect is due to the class II DR2 haplotype, DRB1*1501-DQA1*0102-DRB1*0602; contributions to MS susceptibility from additional DRB1-DQB1 alleles or other HLA region loci were not observed. Variation within the MBP locus on chromosome 18q23 showed no effect in MS. The distribution of haplotypes from 5 loci within the chromosome 19q13.2 region, including D19S178, D19S574, APOE, APOC2, and D19S219, differed between patient and control samples. D19S574 showed a significant effect (P=.015) in Caucasian patients with MS due to the increased frequency of a single allele (P=.002). The APOE variation, prominent in other neurological diseases, showed no influence on MS susceptibility, despite its location within the chromosome 19q13.2 region. Interaction effects between DR2 and chromosome 19q13.2 or MBP in MS susceptibility were not apparent. CONCLUSIONS: The significant chromosome 19q13.2 single-locus and multilocus haplotype associations with MS in Caucasian and Chinese patient samples indicate an effect from a nearby disease susceptibility locus. These initial observations are an encouraging step toward the description of non-HLA genetic susceptibility to MS. CONTEXT: There is a substantial risk of a second cancer for persons with hereditary retinoblastoma, which is enhanced by radiotherapy. OBJECTIVE: To examine long-term risk of new primary cancers in survivors of childhood retinoblastoma and quantify the role of radiotherapy in sarcoma development. DESIGN: Cohort incidence study of patients with retinoblastoma followed for a median of 20 years, and nested case-control study of a radiation dose-response relationship for bone and soft tissue sarcomas. SETTING/PARTICIPANTS: A total of 1604 patients with retinoblastoma who survived at least 1 year after diagnosis, identified from hospital records in Massachusetts and New York during 1914 to 1984. RESULTS: Incidence of subsequent cancers was statistically significantly elevated only in the 961 patients with hereditary retinoblastoma, in whom 190 cancers were diagnosed, vs 6.3 expected in the general population (relative risk [RR], 30 [95% confidence interval, 26-47]). Cumulative incidence (+/-SE) of a second cancer at 50 years after diagnosis was 51.0% (+/-6.2%) for hereditary retinoblastoma, and 5.0% (+/-3.0%) for nonhereditary retinoblastoma. All 114 sarcomas of diverse histologic types occurred in patients with hereditary retinoblastoma. For soft tissue sarcomas, the RRs showed a stepwise increase at all dose categories, and were statistically significant at 10 to 29.9 Gy and 30 to 59.9 Gy. A radiation risk for all sarcomas combined was evident at doses above 5 Gy, rising to 10.7-fold at doses of 60 Gy or greater (P<.05). CONCLUSIONS: Genetic predisposition has a substantial impact on risk of subsequent cancers in retinoblastoma patients, which is further increased by radiation treatment . A radiation dose-response relationship is demonstrated for all sarcomas and, for the first time in humans, for soft tissue sarcomas. Retinoblastoma patients should be examined for new cancers and followed into later life to determine whether their extraordinary cancer risk extends to common cancers of adulthood. The objective of this study was to determine the rate of recent cocaine use among a metropolitan population of predominantly Hispanic and African-American women with preterm premature rupture of the membranes (PROM) and to ascertain the impact of cocaine on the latency period between rupture of membranes and delivery. Urine toxicology screens were prospectively obtained on 147 women with preterm PROM. The urine screen did not influence management decisions. All women were expectantly managed without tocolytics until 37 weeks' gestation unless they developed clinical chorioamnionitis, or nonreassuring fetal heart rate tracing or biophysical profile. Demographic information, hours from rupture of membranes to delivery, gestational age, and birth weight at delivery were compared using Fisher's exact, Mann-Whitney U, and randomization tests where appropriate. The rate of positive urine drug screens for cocaine was 8.2%. Women in the cocaine positive group were of higher parity (3, [0-7]vs. 1, [0-6], p = 0.001) and tended to be older (27, [23-42]vs. 25, [14-40]). There was a higher rate of recent cocaine use among African-American women (20.4%) as compared to non-African-Americans (1.2%, p = 0.0001). Cocaine-positive women presented at an earlier gestational age (32 weeks', [24-34]vs. 33 weeks', [23-36], p = 0.02) and had a significantly longer membrane rupture to delivery interval than women with a negative urine drug screen (174 hr, [6-475]vs. 33 hours [1-833], p = 0.01). There was no significant difference in the reason for delivery between the two groups of patients. Recent cocaine use among women with preterm PROM is common in only some segments of an urban population. Women with recent cocaine use present with ruptured membranes at an earlier gestational age and may actually have a longer latency period than women who do not use cocaine. The objective of this article is to explore attitudes of an inner-city, pregnant cohort about general and HIV-related prenatal care. Responses to an interview at initial prenatal care enrollment were compared using Chi-square and Fisher's exact tests. Of 75 women, drug users (51%) were more likely to say that they would defer initiating prenatal care (P = 0.03) and to minimize the risk of drug or alcohol use to the fetus (P = 0.04). Most (85%) viewed pregnancy as inappropriate for HIV infected women and primarily drug users (P = 0.06) would abort if HIV infected. Over half thought HIV transmission occurred most times or always. Only 20% had heard of a drug to reduce this risk, but 95% would take such a therapy. These inner-city, pregnant women disapproved of pregnancy if HIV infected and thought the risk of transmission was high. They knew little of how to reduce this risk but nearly all would accept a drug to prevent transmission. The association of parvovirus B19 infection and hydrops fetalis is well known. However, the association of parvovirus and fetal pleural or pericardial effusions has not been reported. We present five cases of isolated pleural or pericardial effusion with documented maternal parvovirus infection in four of these pregnancies. In the absence of structural or karyotypic abnormalities, spontaneous resolution of the effusion portends for a successful pregnancy outcome. BACKGROUND: Cochlear implantation is nowadays a reliable and well-accepted method of auditory rehabilitation in selected adults and children. METHODS: We present rehabilitation data on 21 adult patients provided with the Nucleus CI22 M cochlear implant using the SPEAK strategy. RESULTS: Results of first tune-up show an open set speech understanding in approximately 50% of patients. Long-term results also reveal further improvement in patients who had no open set speech understanding. Our data seem to indicate similar results in comparison to other groups using the CIS strategy. CONCLUSIONS: In adults, open set speech understanding can be achieved even at the first tune-up. Results of early rehabilitation seem to be influenced by duration and etiology of deafness, experience with hearing aids, and other factors. Adverse drug effects are manifold and heterogenous. Many situations may hamper the signalling (i.e. the detection of early warning signs) of adverse effects and new signals often differ from previous experiences. Signals have qualitative and quantitative aspects. Different categories of adverse effects need different methods for detection. Current pharmacovigilance is predominantly based on spontaneous reporting and is mainly helpful in detecting type B effects (those effects that are often allergic or idiosyncratic reactions, characteristically occurring in only a minority of patients and usually unrelated to dosage and that are serious, unexpected and unpredictable) and unusual type A effects (those effects that are related to the pharmacological effects of the drug and are dosage-related). Examples of other sources of signals are prescription event monitoring, large automated data resources on morbidity and drug use (including record linkage), case-control surveillance and follow-up studies. Type C effects (those effects related to an increased frequency of 'spontaneous' disease) are difficult to study, however, and continue to pose a pharmacoepidemiological challenge. Seven basic considerations can be identified that determine the evidence contained in a signal: quantitative strength of the association, consistency of the data, exposure response relationship, biological plausibility, experimental findings, possible analogies and the nature and quality of the data. A proposal is made for a standard signal management procedure at pharmacovigilance centres, including the following steps: signal delineation, literature search, preliminary inventory of data, collection of additional information, consultation with the World Health Organization Centre for International Drug Monitoring and the relevant drug companies, aggregated data assessment and a report in writing. A better understanding of the conditions and mechanisms involved in the detection of adverse drug effects may further improve strategies for pharmacovigilance. OBJECTIVE: To study the safety and efficacy of methylphenidate in children with the dual diagnosis of epilepsy and attention deficit hyperactivity disorder (ADHD) . STUDY DESIGN: Thirty children, aged 6.4 to 16.4 years, with epilepsy and ADHD were studied during a 4-month period. During the initial 2 months of the study, the children were treated with antiepileptic drugs (AEDs) only, and for the remaining 2 months, methylphenidate was added at a morning dose of 0.3 mg/kg. They underwent neurologic assessment, brain computed tomography, IQ testing, and assessment with the Childhood Behavior Checklist at baseline before methylphenidate therapy. Electroencephalography, AED determinations, and the continuous-performance task (CPT) test were done at baseline and after 2 months of methylphenidate therapy. A double-blind, crossover design was used to compare the effects of methylphenidate versus placebo on an electroencephalogram, AED levels, and the CPT. On the 2 days of testing, the child received AEDs and a capsule containing either placebo or methylphenidate. RESULTS: None of the 25 children of this sample who were seizure free had attacks while taking methylphenidate. Of the 5 children with seizures, 3 had an increase in attacks, whereas the other 2 showed no change or a reduction. There were no significant changes in AED levels or electroencephalographic findings. Methylphenidate benefited 70% of children according to parental report; methylphenidate also enhanced performance on the CPT. Side effects of methylphenidate were mild and transient. CONCLUSION: Methylphenidate is effective in treating children with epilepsy and ADHD and safe in children who are seizure free. Caution is warranted for those still having seizures while receiving AED therapy. The temporal properties of semantic and phonological processes in speech production were investigated in a new experimental paradigm using movement-related brain potentials. The main experimental task was picture naming. In addition, a 2-choice reaction go/no-go procedure was included, involving a semantic and a phonological categorization of the picture name. Lateralized readiness potentials (LRPs) were derived to test whether semantic and phonological information activated motor processes at separate moments in time. An LRP was only observed on no-go trials when the semantic (not the phonological) decision determined the response hand. Varying the position of the critical phoneme in the picture name did not affect the onset of the LRP but rather influenced when the LRP began to differ on go and no-go trials and allowed the duration of phonological encoding of a word to be estimated. These results provide electrophysiological evidence for early semantic activation and later phonological encoding. The effects of alanine and glycine substitution for tryptophan upon the species heterogeneity of gramicidin A analogs incorporated into SDS micelles have been investigated. The sequential replacement of the four tryptophan residues in gramicidin A at positions 15, 13, 11, and 9 with glycine showed that there was no detectable effect at position 15 but increasing heterogeneity of species in the micelles proceeding toward the interior of the micelle at position 9. The replacement of tryptophan at positions 15 and 9 with alanine was found to produce more species heterogeneity than found with glycine substitution at the same positions. An increase in the SDS concentration reduces the number of different species present in micelles. With the Gly-11, Gly-13, and Gly-15 analogs, the increase in SDS concentration results in the formation of a single species; however, for the Gly-9, Ala-9, and Ala-15 analogs, heterogeneity remains. Molecular dynamics in torsion-angle space was applied to nuclear magnetic resonance structure calculation using nuclear Overhauser effect-derived distances and J-coupling-constant-derived dihedral angle restraints. Compared to two other commonly used algorithms, molecular dynamics in Cartesian space and metric-matrix geometry combined with Cartesian molecular dynamics, the method shows increased computational efficiency and success rate for large proteins, and it shows a dramatically increased radius of convergence for DNA. The torsion-angle molecular dynamics algorithm starts from an extended strand conformation and proceeds in four stages: high-temperature torsion-angle molecular dynamics, slow-cooling torsion-angle molecular dynamics, Cartesian molecular dynamics, and minimization. Tests were carried out using experimental NMR data for protein G, interleukin-8, villin 14T, and a 12 base-pair duplex of DNA, and simulated NMR data for bovine pancreatic trypsin inhibitor. For villin 14T , a monomer consisting of 126 residues, structure determination by torsion-angle molecular dynamics has a success rate of 85%, a more than twofold improvement over other methods. In the case of the 12 base-pair DNA duplex, torsion-angle molecular dynamics had a success rate of 52% while Cartesian molecular dynamics and metric-matrix distance geometry always failed. The wavelet-transform method is used to quantify the magnetic resonance spectroscopy (MRS) parameters: chemical shift, apparent relaxation time T2, resonance amplitude, and phase. Wavelet transformation is a time-frequency representation which separates each component from the FID, then successively quantifies it and subtracts it from the raw signal. Two iterative procedures have been developed. They have been combined with a nonlinear regression analysis method and tested on both simulated and real sets of biomedical MRS data selected with respect to the main problems usually encountered in quantifying biomedical MRS, specifically "chemical noise," resulting from overlapping resonances, and baseline distortion. The results indicate that the wavelet-transform method can provide efficient and accurate quantification of MRS data. BACKGROUND: Antiplatelet therapy with aspirin and systematic anticoagulation with warfarin reduce cardiovascular morbidity and mortality after myocardial infarction when given alone. In the Coumadin Aspirin Reinfarction Study (CARS), we aimed to find out whether a combination of low-dose warfarin and low-dose aspirin would give superior results to standard aspirin monotherapy without excessive bleeding risk. METHODS: We used a randomised double-blind study design. At 293 sites, we randomly assigned 8803 patients who had had myocardial infarction , treatment with 160 mg aspirin , 3 mg warfarin with 80 mg aspirin, or 1 mg warfarin with 80 mg aspirin . Patients took a single tablet daily, and attended for prothrombin time (PT) measurements at weeks 1, 2, 3, 4, 6, and 12, and then every 3 months. Patients were followed up for a maximum of 33 months (median 14 months). FINDINGS: The primary event was first occurrence of reinfarction, non-fatal ischaemic stroke, or cardiovascular death. 1-year life-table estimates for the primary event were 8.6% (95% CI 7.6-9.6) for 160 mg aspirin, 8.4% (7.4-9.4) for 3 mg warfarin with 80 mg aspirin, and 8.8% (7.6-10) for 1 mg warfarin with 80 mg aspirin. Primary comparisons were done with all follow-up data. The relative risk of the primary event for the 160 mg aspirin group compared with the 3 mg warfarin with 80 mg aspirin group was 0.95 (0.81-1.12, p = 0.57). For spontaneous major haemorrhage (not procedure related), 1-year life-table estimates were 0.74% (0.43-1.1) in the 160 mg aspirin group and 1.4% (0.94-1.8) in the 3 mg warfarin with 80 mg aspirin group (p = 0.014 log rank on follow-up). For the 3382 patients assigned 3 mg warfarin with 80 mg aspirin, the INR results were: at week 1 (n = 2985) median 1.51 (IQR 1.23-2.13); at week 4 (n = 2701) 1.27 (1.13-1.64); at month 6 (n = 2145) 1.19 (1.08-1.44). INTERPRETATION: Low, fixed-dose warfarin (1 mg or 3 mg) combined with low-dose aspirin (80 mg) in patients who have had myocardial infarction does not provide clinical benefit beyond that achievable with 160 mg aspirin monotherapy. BACKGROUND: There is serological evidence for an association between Chlamydia pneumoniae and coronary heart disease. We investigated the hypothesis that an antichlamydial macrolide antibiotic, roxithromycin , can prevent or reduce recurrent major ischaemic events in patients with unstable angina . METHODS: The effect of roxithromycin was assessed in a double-blind, randomised, prospective, multicentre, parallel-group, placebo-controlled pilot study of 202 patients with unstable angina or non-Q-wave myocardial infarction . Patients were randomly assigned either roxithromycin 150 mg orally twice a day (n = 102) or placebo orally twice a day (n = 100). The treatment was for 30 days. Patients were followed up for 6 months. We report the primary clinical endpoints (cardiac ischaemic death, myocardial infarction, and severe recurrent ischaemia), assessed at day 31, in 202 patients on an intention-to-treat basis. FINDINGS: A statistically significant reduction in the primary composite triple endpoint rates was observed in the roxithromycin group: p = 0.032. The rate of severe recurrent ischaemia, myocardial infarction, and ischaemic death was 5.4%, 2.2%, and 2.2% in the placebo group and 1.1%, 0%, and 0%, in the roxithromycin group, respectively. No major drug-related adverse effects were observed. INTERPRETATION: Antichlamydial antibiotics may be useful in therapeutic intervention in addition to standard medication in patients with coronary-artery disease . Large-scale trials are needed to confirm these preliminary observations. BACKGROUND: Stage Ib and IIa cervical carcinoma can be cured by radical surgery or radiotherapy . These two procedures are equally effective, but differ in associated morbidity and type of complications. In this prospective randomised trial of radiotherapy versus surgery, our aim was to assess the 5-year survival and the rate and pattern of complications and recurrences associated with each treatment. METHODS: Between September, 1986, and December, 1991, 469 women with newly diagnosed stage Ib and IIa cervical carcinoma were referred to our institute. 343 eligible patients were randomised: 172 to surgery and 171 to radical radiotherapy. Adjuvant radiotherapy was delivered after surgery for women with surgical stage pT2b or greater, less than 3 mm of safe cervical stroma, cut-through, or positive nodes. The primary outcome measures were 5-year survival and the rate of complications. The analysis of survival and recurrence was by intention to treat and analysis of complications was by treatment delivered. FINDINGS: 170 patients in the surgery group and 167 in the radiotherapy group were included in the intention-to-treat analysis; scheduled treatment was delivered to 169 and 158 women, respectively, 62 of 114 women with cervical diameters of 4 cm or smaller and 46 of 55 with diameters larger than 4 cm received adjuvant therapy. After a median follow-up of 87 (range 57-120) months, 5-year overall and disease-free survival were identical in the surgery and radiotherapy groups (83% and 74%, respectively, for both groups), 86 women developed recurrent disease: 42 (25%) in the surgery group and 44 (26%) in the radiotherapy group. Significant factors for survival in univariate and multivariate analyses were: cervical diameter, positive lymphangiography, and adeno-carcinomatous histotype. 48 (28%) surgery-group patients had severe morbidity compared with 19 (12%) radiotherapy-group patients (p = 0.0004). INTERPRETATION: There is no treatment of choice for early-stage cervical carcinoma in terms of overall or disease-free survival. The combination of surgery and radiotherapy has the worst morbidity, especially urological complications. The optimum therapy for each patient should take account of clinical factors such as menopausal status, age, medical illness, histological type, and cervical diameter to yield the best cure with minimum complications. Today's technology links health care providers and patients across town, in the next state or even another country. Nursing across state lines poses complications: state-bound regulatory and licensure issues. This article discusses many of the nutritional topics important to the intensivist. Nutritional assessment, substrate immunonutrition, and disease specific issues are presented. Early introduction of enteral feeds and the use of nutritional modulation are emphasized. PROBLEM: To compare the expression by T-lymphocytes of an immunomodulatory protein known as progesterone-induced blocking factor (PIBF) in conception versus non-conception cycles even when there has been definite fertilization and embryo formation. METHOD: PIBF expression on T lymphocytes was measured using an immunohistochemical method with a PIBF-specific polyclonal antibody. These levels were determined in patients undergoing three types of therapy: non-in vitro fertilization (IVF), IVF-embryo transfer (ET), and frozen ET. Sera were drawn 12 days from ovulation in non-IVF cycles or 9 days after ET and were assayed for PIBF and beta human chorionic gondotropin. Comparison of the frequency of lymphocyte expression of PIBF in pregnant versus non-pregnant women were made. RESULTS: PIBF was detected in 29.5% of non-pregnant women and 52.5% of pregnant women. There were no differences in PIBF levels by therapy used in non-pregnant cases or in the pregnant group. CONCLUSION: These data are consistent with the hypothesis that maternal expression of PIBF in T-lymphocytes soon after trophoblast invasion may depend on successful implantation. Many amino acids contain an asymmetric centre, occurring as laevorotatory, L, or dextrorotatory, D, compounds. It is generally assumed that abiotic synthesis of amino acids on the early Earth resulted in racemic mixtures (L- and D-enantiomers in equal abundance). But the origin of life required, owing to conformational constraints, the almost exclusive selection of either L- or D-enantiomers, and the question of why living systems on the Earth consist of L-enantiomers rather than D-enantiomers is unresolved. A substantial fraction of the organic compounds on the early Earth may have been derived from comet and meteorite impacts. It has been reported previously that amino acids in the Murchison meteorite exhibit an excess of L-enantiomers, raising the possibility that a similar excess was present in the initial inventory of organic compounds on the Earth. The stable carbon isotope compositions of individual amino acids in Murchison support an extraterrestrial origin -- rather than a terrestrial overprint of biological amino acids-although reservations have persisted. Here we show that individual amino-acid enantiomers from Murchison are enriched in 15N relative to their terrestrial counterparts, so confirming an extraterrestrial source for an L-enantiomer excess in the Solar System that may predate the origin of life on the Earth. Home care workers face an increasing risk for workplace violence. A proactive preventive approach is presented that suggests strategies to use during the previsit phase, the visit experience, and on an ongoing basis. The miracidia of Fasciola hepatica and Trichobilharzia ocellata approach their host snails Lymnaea truncatula and L. stagnalis by increasing their rate of change of direction (RCD) in increasing gradients of snail-conditioned water (SCW), and they perform a turnback swimming in decreasing gradients. Both hostfinding responses in both species were induced by glycoconjugates with a molecular weight of > 30 kDa that were sensitive to hydrolysis with pronase E and oxidation with NaIO4. Alkaline cleavage revealed that they contained carbohydrates linked O-glycosidically via serine and N-acetylgalactosamine. Miracidia clearly preferred SCW from their specific host snail versus other sympatric snail species and did not respond to water conditioned with fish, tadpoles, or leeches. Differences in the chemical characteristics of SCW from the intermediate hosts L. truncatula and L. stagnalis could be shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, blotting, and subsequent carbohydrate detection. The first step of purification of the effective signaling SCW components from both snail species was achieved by ion-exchange chromatography. Black patients with colon cancer in the Black/White Cancer Survival Study were found to have a poorer survival than white patients. More advanced-stage disease at diagnosis was the primary determinant, accounting for 60% of the excess mortality. After adjusting for stage, factors such as poverty, other socioeconomic conditions, and treatment did not further explain the remaining survival deficit. This study examined the aggressiveness of colon tumors in blacks and whites to explore its role in the racial survival differences. Tumor characteristics of 703 cases of newly diagnosed invasive colon adenocarcinoma were centrally evaluated by a gastrointestinal pathologist, blinded in regard to the age, race, and sex of the patients. Blacks were less likely to have poorly differentiated (grade 3) tumors [odds ratio (OR), 0.44; 95% confidence interval, 0.22-0.88] and lymphoid reaction (OR, 0.49; 95% confidence interval, 0.26-0.90) when compared with whites. These black/white (B/W) differences remained statistically significant after adjusting for age, sex, metropolitan area, summary stage, socioeconomic status, body mass index, and health care access and utilization. In addition, blacks were less likely to have high-grade (grade 3) nuclear atypia, mitotic activity, and tubule formation, although these ORs did not reach a statistical significance level of 0.05. Similar B/W differences were observed for patients with advanced disease but not with early stage. Comparison by anatomical subsite showed that blacks had statistically significantly better differentiated tumors for cancers of the proximal and transverse colon but not for the distal. No racial differences were found for blood vessel and lymphatic invasion, necrosis, fibrosis, and mucinous type of histology. The findings, therefore, are the opposite of those hypothesized. After adjusting for stage, more aggressive tumor characteristics do not explain the adverse survival differential in blacks. This suggests that there may be racial differences in environmental exposure, and that the intensity and mode of delivery of carcinogen insult as well as host susceptibility may differ by race and anatomical subsite. Future studies should explore the B/W differences in tumor biology using molecular markers that precede the conventional histological parameters evaluated here. A new method is described for detection of mutations in the lysosomal alpha-glucosidase gene (GAA) leading to Glycogen Storage Disease type II (GSDII) . A key feature of the method is isolation and reverse transcription of mRNA followed by PCR amplification of lysosomal alpha-glucosidase cDNA with M13-extended primers. Dye labeled primers are used for cycle sequencing and an ABI PRISM 377 DNA sequencing system for analysis. The method is rapid and complementary to the automated sequencing of all the 19, PCR amplified, coding exons of the GAA gene. The advantages and pitfalls of this new method are discussed in the light of the results obtained with an infantile GSDII patient. A new splice site mutation in the GAA gene of this patient was identified, IVS16(+2T-->C), resulting in the deletion of 16 base pairs of exon 16. The presence of clinical autonomic dysfunction in patients with neurologic diseases, such as multiple sclerosis, Parkinson's disease, and cerebrovascular accident, has become increasingly recognized in the past decade. Very few autonomic tests have been done on pediatric patients thus far. The purpose of this study was to investigate the autonomic function in patients with cerebral palsy using two noninvasive tests: sympathetic skin response (SSR) and R-R interval variation (RRIV). Twenty-four patients with cerebral palsy and 24 control subjects between the ages of 4 and 12 yr were enrolled in this study. There was no significant difference of mean latency, amplitude, or amplitude ratio of SSR between the two groups under electric stimulus, startling stimulus, and deep breathing conditions. No significant difference in frequency of absent response and asymmetric response was also noted. Mean heart rate under relaxed sitting condition was significantly higher in the study group. Significant negative correlation between heart rate and age was noted in the control group but was not present in the study group. Also, there was no statistical difference of mean RRIV between the two groups. No objective evidence of autonomic disturbance in patients with cerebral palsy was found in this study. A two-credits per semester clinical medicine course was established in the Department of Physical Medicine and Rehabilitation (PM&R) in cooperation with the Johns Hopkins University undergraduate Human Biology faculty to present the variety of inpatient consultation personnel, units, patient diagnostic groups, and functional problems. College students spend 4 hr weekly on the PM&R consultation service as team members under resident supervision. The curriculum emphasizes student understanding of the roles of rehabilitation team members. Objectives include demonstration of working knowledge of the Biopsychosocial Model, the World Health Organization Model of disablement and interdisciplinary rehabilitation intervention. The course includes simulations of physical impairments, demonstrations of adaptive equipment, interactive chart reviews, readings, and audio lectures. A retrospective sequential review was made of the last 100 physical medicine and rehabilitation consultations with student attendance. The results confirm student exposure to many ward settings (surgery, 30%; neurology/neurosurgery, 28%; medicine, 24%; intensive care, 15%; oncology, 2%; and psychiatry, 1%), patient complexity (averaging 10 problems), and multiple ICD-9 diagnosis categories (circulatory, 36%; neurologic, 22%; musculoskeletal, 17%; neoplasms, 10%; injury, 5%; endocrine, 4%; infections, 3%; and others, 3%). The rehabilitation consultation service is particularly effective as an introduction to hospital-based medical practice due to the diagnostic variety of the patients, the functional approach of rehabilitation, and student exposure to multiple hospital settings. The Biopsychosocial Model of medical practice is demonstrated through multiple interdisciplinary perspectives of needs and interventions for patients with obvious functional deficits. This process develops a rudimentary understanding of the effect of illness on the person and the variety of medically effective therapeutic modalities. This study is designed to investigate the immediate effectiveness of electrotherapy on myofascial trigger points of upper trapezius muscle . Sixty patients (25 males and 35 females) who had myofascial trigger points in one side of the upper trapezius muscles were studied. The involved upper trapezius muscles were treated with three different methods according to a random assignment: group A muscles (n = 18) were given placebo treatment (control group); group B muscles (n = 20) were treated with electrical nerve stimulation (ENS) therapy; and group C muscles (n = 22) were given electrical muscle stimulation (EMS) therapy. The effectiveness of treatment was assessed by conducting three measurements on each muscle before and immediately after treatment: subjective pain intensity [(PI) with a visual analog scale], pressure pain threshold [(PT) with algometry], and range of motion [(ROM) with a goniometer] of upper trapezius muscle (lateral bending of cervical spine to the opposite side). When the effectiveness of treatment was compared with that of the placebo group (group A), there was significant improvement in PI and PT in group B (P < 0.01) but not in group C (P > 0.05). The improvement of ROM was significantly more in group C (P < 0.01) as compared with that in group A or group B. When each group was divided into two additional subgroups based on the initial PI, it was found that ENS could reduce PI and increase PT significantly (P < 0.05), but did not significantly (P > 0.05) improve ROM, as compared with the placebo group for both subgroups. EMS could significantly (P < 0.05) improve ROM, but not PT, better than the placebo groups, for either subgroup. It could reduce PI significantly more (P < 0.05) than placebo controls only for the subgroup with mild to moderate pain, but not with severe pain. For pain relief, ENS was significantly better (P < 0.05) than EMS; but for the improvement of ROM, EMS was significantly better (P < 0.05) than ENS. It is concluded that ENS is more effective for immediate relief of myofascial trigger point pain than EMS, and EMS has a better effect on immediate release of muscle tightness than ENS. Because activity and regular exercise are important factors to maintain general good health in senior citizens, we investigated whether senior dancing has any effect on peripheral or lumbar bone density. We performed a prospective study over a12-mo period on bone density at a spinal and peripheral measuring site in 28 female senior members (mean age: 67 +/- 2 yr) of a dancing group in Vienna. Lumbar bone mineral density was assessed by quantitative computed tomography (qCT) and radial bone density by single photon absorptiometry of the distal forearm. The mean training time per week was 3.2 +/- 0.8 h. In the entire group of female dancers, no significant effects of dancing on radial or lumbar bone density could be observed. Linear regression analysis showed that the lower the qCT at the beginning of the observation period, the higher was the percentage increase of spinal qCT in the entire group during 12 mo of dancing (r = 0.52, P < 0.0001). For additional evaluation, females were divided into two subgroups, osteoporotic or nonosteoporotic, based on x-rays and lumbar bone mineral density (BMD) as measured by qCT. The group classified as dancers with osteoporosis (group I) showed a significant increase in lumbar bone density, whereas in the group of dancers without signs of osteoporosis (group II), BMD remained unchanged. Additionally, radial bone density did not show any changes in either group. Group I showed a significant correlation between basal spinal BMD and the percentage change of BMD during the observation period (r = 0.7, P < 0.001). Changes of the biochemical parameters were observed in the bone-specific isoenzyme of alkaline phosphatase, a marker of osteoblastic activity, in group I giving additional evidence of increased bone formation. OBJECTIVES: To estimate the prevalence of Chlamydia trachomatis in asymptomatic women attending general practice: to assess the potential of the ligase chain reaction as a screening tool; and to evaluate selective screening criteria. DESIGN: Cross sectional survey. SETTING: Four general practices in northeast London. SUBJECTS: 890 women aged 18-35 years attending general practice for a cervical smear or a "young well woman" check between October 1994 and January 1996. The women were tested for C trachomatis with confirmed enzyme immunoassay (endocervical specimens) and ligase chain reaction assay on urine specimens. MAIN OUTCOME MEASURES: Prevalence of C trachomatis infection in women aged 18-35 on the basis of each test; sensitivity and specificity of both tests in this population. RESULTS: Prevalence of confirmed infection was 2.6% (95% confidence interval 1.6% to 3.6%) in all women. Prevalence on the basis of enzyme immunoassay was 1.6% (0.8% to 2.7%), with a sensitivity of 60% and a specificity of 100%. Prevalence on the basis of ligase chain reaction was 2.5% (1.5% to 3.9%), with 90% sensitivity and 99.8% specificity. Screening all women aged < or = 25 and all women who had had two or more partners in the past year would have detected 87% (20/23) of infections. CONCLUSION: Ligase chain reaction on urine samples performs at least as well as enzyme immunoassay on cervical specimens in this low prevalence population. It offers potential as a non-invasive screening tool. A simple selective screening strategy might be appropriate and would be able to detect most cases of infection. However, a rigorous economic evaluation of possible screening strategies is needed first. Recently, many advances have been made in the study of sexual differentiation, including the discoveries of the gene for antimÃ1/4llerian hormone as well as the gene for its receptor. However, the etiology of the clinical syndrome of mÃ1/4llerian agenesis remains elusive. We hypothesize that activating mutations of either the antimÃ1/4llerian hormone gene or its receptor gene may cause mÃ1/4llerian duct regression in a genetic female during embryogenesis. This clinical commentary discusses the current management of the syndrome including the Abbe-McIndoe procedure, the most commonly used method of surgical correction, and the Frank vaginal dilation method, the most common nonsurgical method of correction. OBJECTIVES: Obesity is an important clinical problem, and the use of dexfenfluramine hydrochloride for weight reduction has been widely publicized since its approval by the Food and Drug Administration. However, animal and human studies have demonstrated toxic effects of fenfluramines that clinicians should be aware of when considering prescribing the drugs. Our purpose was to systematically review data on brain serotonin neurotoxicity in animals treated with fenfluramines and the evidence linking fenfluramines to primary pulmonary hypertension (PPH). DATA SOURCES: Archival articles and reviews identified through a computerized search of MEDLINE from 1966 to April 1997 using "fenfluramine(s)," "serotonin," "neurotoxicity," "behavior," "anorexigens," "weight loss," and "primary pulmonary hypertension" as index terms. STUDY SELECTION: Reports dealing with long-term effects of fenfluramines on brain serotonin neurons, body weight, and pulmonary function in animals and humans. DATA EXTRACTION: Reports were reviewed by individuals with expertise in serotonin neurobiology, neurotoxicity, neuropsychiatry, and pulmonary medicine and evaluated for appropriateness for inclusion in this review. DATA SYNTHESIS: Fenfluramines cause dose-related, long-lasting reductions in serotonin axonal markers in all the animal species tested and with all the routes of drug administration used. Doses of fenfluramines that produce signs of brain serotonin neurotoxicity in animals are on the same order as those used to treat humans for weight loss when one takes into account known relations between body mass and drug clearance. However, no human studies have been conducted, and the pathological and clinical potential for neurotoxicity in humans is unknown. Appetite suppressants-most commonly fenfluramines -increase the risk of developing PPH (odds ratio, 6.3), particularly when used for more than 3 months (odds ratio, >20). CONCLUSIONS: Fenfluramine and dexfenfluramine have been demonstrated to damage brain serotonin neurons in animal studies. It is not known if such damage occurs in humans or if there are clinical consequences. Use of fenfluramines is associated with an increased risk of PPH. Future studies should address the long-term consequences of prolonged use of fenfluramines. Moxonidine (Physiotens-Solvay) was introduced last year as the first of a new class of centrally-acting antihypertensive agents, the selective imidazoline receptor agonists. The manufacturer claims that moxonidine "accurately targets imidazoline receptors at the cardiovascular control centre in the brainstem" and is "as effective as current first-line therapies for essential hypertension ". Other claims suggest that it causes fewer unwanted effects than older centrally-acting antihypertensive drugs such as clonidine and methyldopa. Is moxonidine a useful addition to the growing number of antihypertensives on the market? This article discusses dental anxiety and phobia. The author presents background information, including incidence and etiology. A discussion of evaluative techniques for assessing anxiety levels follows. Examination and treatment planning are considered in relation to this patient's special needs. The article stresses behavioral treatment modalities that eliminate the debilitating phobia. In closing, the author presents practical information regarding prevention of dental phobia and the merits of incorporating this type of patient into a dental practice. In order to evaluate the applicability of anthelminthic treatment of wild foxes (Vulpes vulpes) to limit their infection with Echinococcus multilocularis , bait pellets, each containing 50 mg praziquantel , were repeatedly distributed in an area of 566 km2 where many foxes are infected, in southern Germany. After six baiting campaigns (15-20 baits/km2) over a period of 14 months, the prevalence of the cestode in foxes, initially 32%, had fallen to 4%. The effect was most pronounced in the central part of the treated area, where no positive fox was found in the 2 months before the end of the trial. The study was controlled for other factors that could influence the parasite's prevalence, such as the availability of intermediate hosts. While the potential of this baiting method to remove E. multilocularis from wild hosts has been demonstrated, the question of its long-term efficacy and other unresolved problems have to be addressed by consecutive studies before routine application can be recommended. In patients with chronic myeloid leukemia (CML) , the neoplastic (BCR-ABL+) progenitor cells are characterized by an increased proliferative activity. Whether these cells are also resistant to apoptosis and if so, under what conditions remains controversial. We now show that highly purified populations of very primitive neoplastic progenitor cells obtained directly from CML patients survive and proliferate in vitro for several weeks in the absence of any added growth factors (except insulin). In contrast, purified primary normal progenitors maintained under the same conditions die rapidly. Nevertheless, both primary CML cells and BCR-ABL+ BAF3 cells show the same dose-dependent sensitivity to TNF-alpha or ceramide-induced apoptosis as their respective normal counterparts. In fact, time course studies demonstrated an even faster onset of apoptosis in ceramide-treated BCR-ABL+ BAF3 cells as compared to normal controls. BCR-ABL+ cells treated with ceramide also showed a rapid and sequential increase in the tyrosine phosphorylation of p210(BCR-ABL), p46-56SHC and p120Cbl. These findings suggest growth factor deprivation and treatment with TNF-alpha or ceramide trigger different initial events both of which can lead to apoptosis in factor-dependent hematopoietic cells. However, in the first case, activation of apoptosis is blocked by the basal activity of p210(BCR-ABL), whereas in the second, the presence of p210(BCR-ABL) appears to accelerate the onset of apoptosis by a mechanism that may involve an activation of its kinase function. Clinically, the hallmark of the human amnesic syndrome is an impaired ability to consciously recollect or remember daily events. If the medial region of the temporal lobes, including the hippocampus and related structures, is critical for establishing these new memories, then this brain region should be active whenever events are experienced, regardless of whether subjects are asked explicitly to learn and remember. Here we show that the medial temporal region is active during encoding and that the hemisphere activated and the amount of activation depend on the type of stimulus presented (objects or words), whether the stimulus can be encoded for meaning (real objects and words versus nonsense objects and words), and task experience (first versus the second time a task is performed). These findings demonstrate that the medial temporal lobe memory system is engaged automatically when we attend to a perceptual event and that the location and amount of activation depend on stimulus characteristics (physical form, meaning) and experience. The involvement of structures in the medial temporal lobe during the encoding of visual associations was studied with functional magnetic resonance imaging. In 11 out of 12 normal healthy volunteers this task resulted in activation in posterior portions of the parahippocampal region, close to the collateral sulcus. In seven subjects activation was encountered in the hippocampal formation. The visual association task as adapted for this study may provide a sensitive measure to study anterograde amnesia prevalent in Alzheimer's disease. Therefore, the present paradigm enables the study of individual changes in learning and memory capacities over time. Altered calcium (Ca2+) homeostasis is thought to play a key role in aging and neuropathology resulting in memory deficits. Several forms of hippocampal synaptic plasticity are dependent on Ca2+, providing a potential link between altered Ca2+ homeostasis and memory deficits associated with aging. The current study reviews evidence for Ca2+ dysregulation during aging which could interact with Ca(2+)-dependent synaptic plasticity. The authors suggest that changes in Ca2+ regulation could adjust the thresholds for synaptic modification, favoring processes for depression of synaptic strength during aging. Transiently evolked otoacoustic emissions (TEOAE) have been reported in several studies as absent in a small minority of normal ears. Other studies have reported TEOAEs in all normal ears. Differences between studies may arise directly from criteria for TEOAE identification, criteria for selection of normals, or statistically due to limited sample sizes. In order to understand and model cochlear processes involved in TEOAE generation, it needs to be known whether the presence of normal hearing leads automatically to generation of TEOAEs. The present study set out to establish in a large sample if any ears could be found that lacked TEOAEs despite normal hearing threshold levels (HTL). A total of 397 ears from highly cooperative adult subjects were examined under laboratory conditions. Using cross correlation between replicate nonlinear waveforms as the criterion, TEOAEs were present in 99.2% of the sample (lower CI 98.1%). However, careful visual assessment of the recorded waveforms for the remaining ears did not unequivocally show absence of TEOAE characteristics in any ear with normal HTLs. While TEOAE strength varies widely among ears, no clear evidence was found to show that TEOAEs can be absent when HTLs are normal. In addition to a long form of 591 amino acids (aa), two other forms of PRL receptor (PRLR), differing in the length of their cytoplasmic domains, have been identified in the rat. The Nb2 form, lacking 198 aa in the cytoplasmic domain, is able to transmit a lactogenic signal similar to the long form, whereas the short form of 291 aa is inactive. The ability of PRL to activate the promoter of the beta-casein gene or the lactogenic hormone responsive element fused to the luciferase reporter was assessed in Chinese hamster ovary cells or 293 fibroblasts transiently transfected with PRLR cDNAs. The function of the short form was examined after cotransfection of both the long and short forms. These results clearly show that the short form acts as a dominant negative inhibitor through the formation of inactive heterodimers, resulting in an inhibition of Janus kinase 2 (JAK2) activation. The present study also investigates the possible participation of cytoplasmic receptors in the signal transduction pathway, using cotransfection experiments and a new approach that selectively determines the contribution of cytoplasmic receptors in the process of signal transduction. We cotransfected Chinese hamster ovary cells with two cDNA constructs: a cytoplasmic (soluble) form of the receptor with a deleted signal peptide (delta-19), which is unable to bind PRL, and a functionally inactive receptor mutant (lacking box 1), which is anchored in the plasma membrane and able to bind PRL. This approach has allowed us to show that delta-19, lacking expression at the plasma membrane, can transduce the hormonal message, at least to a limited extent (up to 30% of wild type efficiency), providing that association/activation occurs with a PRL-PRLR complex initiated at the cell surface level; box 1 of the cytoplasmic form is necessary to rescue this partial transcriptional activity of the inactive mutant. This partial recovery is also parallel to the partial activation of JAK2, indicating that the signal transduction pathway implicated JAK2. Our results provide evidence that heterodimerization of receptors can be implicated either in the positive or in negative activation of gene transcription. BACKGROUND: Inadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons. METHODS: We studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records. RESULTS: The mean (+/-SD) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows: femoral neck, +0.50+/-4.80 and -0.70+/-5.03 percent, respectively (P=0.02); spine,+2.12+/-4.06 and +1.22+/-4.25 percent (P=0.04); and total body, +0.06+/-1.83 and -1.09+/-1.71 percent (P<0.001). The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year, but it was significant only for total-body bone mineral density in the second and third years. Of 37 subjects who had nonvertebral fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D group (P=0.02). CONCLUSIONS: In men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures. The sterilization and contaminated waste disposal practices in all 14 dental clinics operated by the Southern Sydney Area Health Service were surveyed. All of the clinics used autoclaves for sterilization. All hand instruments, handpieces and triplex syringes were autoclaved between patients. Chemical disinfection solutions were used in 12 of the 14 dental clinics, mainly for surface decontamination. Five dental clinics had separate storage areas for contaminated waste which compiled with contaminated waste separation and disposal guidelines. The practice of recapping needles with fingers and some inadequate washing facilities are areas that require particular attention. Safety and efficacy are crucial but separate issues for vitamin and mineral supplements. Misinterpretation of "safe and adequate" to mean "safety limit" would impose restrictions on vitamin and mineral intakes that are not needed to ensure safety. Substantial evidence indicates that intakes greater than the recommended dietary allowances (RDAs) of certain vitamins and minerals such as calcium, folic acid, vitamin E, selenium, and chromium reduce the risk of certain diseases for some people. Limitation of intakes to the RDAs would preclude reductions in disease risk from these nutrients. The margin of safety between the usual dietary intake and the intake that would produce adverse effects varies greatly among the different nutrients. Very high intakes of vitamins A and D, niacin, pyridoxine, and selenium have produced adverse effects. Many widely discussed putative adverse effects of vitamin C, vitamin E, and trivalent chromium have little factual basis. There is no evidence of adverse effects from beta-carotene supplements except in current heavy smokers. The mutator hypothesis of tumorigenesis suggests that loss of chromosomal stability or maintenance functions results in elevated mutation rates, leading to the accumulation of the numerous mutations required for multistep carcinogenesis. The human DNA mismatch repair (MMR) genes are highly conserved homologues of the Escherichia coli MutHLS system, which contribute to genomic stability by surveillance and repair of replication misincorporation errors and exogenous DNA damage. Mutations in one of these MMR genes, hMSH2, account for about half of all cases of genetically linked hereditary non-polyposis colorectal cancer. Loss of function of p53 has also been proposed to increase cellular hypermutability, thereby accelerating carcinogenesis, although a clear role for p53 in genomic instability remains controversial. p53 is mutated frequently in a wide range of human cancers, including colonic tumours. Both Msh2- and p53-targeted knockout mice are viable and susceptible to cancer. Here we demonstrate that combined Msh2 and p53 ablation (Msh2-/-p53-/-) results in developmental arrest of all female embryos at 9.5 days. In contrast, male Msh2-/-p53-/- mice are viable, but succumb to tumours significantly earlier (t1-2 is 73 days) than either Msh2-/- or p53-/- littermates. Furthermore, the frequency of microsatellite instability (MSI) in tumours from Msh2-/-p53-/- mice is not significantly different than in Msh2-/- mice. Synergism in tumorigenesis and independent segregation of the MSI phenotype suggest that Msh2 and p53 are not genetically epistatic. Our data (Reddy et al., Radiat. Res. 141, 252-258, 1995) on the kinetics of the repair of potentially lethal damage in log-phase Chinese hamster V79 cells are used to test some predictions which arise from the different assumptions of the repair-misrepair (RMR) (C. A. Tobias, Radiat. Res. 104, S77-S95, 1985), lethal-potentially lethal (LPL) (S. B. Curtis, Radiat. Res. 106, 252-270, 1986) and double-strand break (DSB) (J. Y. Ostashevsky, Radiat. Res. 118, 437-466, 1989) models. The LPL model defines the time available for repair of PLD (t(rep)) as the time taken to reach maximal survival in a delayed-plating recovery experiment. Those data show that after this time has elapsed, contrary to the expectation of the LPL model, survival can be increased by changing the medium used for delayed plating from fresh growth medium to conditioned medium. According to the RMR model, all potentially lethal lesions should also be committed by that time and be unavailable for repair in the new medium. Only the DSB model correctly predicted that PLD (= DSBs) would still be available for repair after that time. Second, data for split-dose recovery are used to predict the first-order kinetics time constant for DSB repair (tau(DSBR)) using the DSB model (24 +/- 1.5 min). This value is nearly identical to the value of 27 +/- 1 min determined from the data obtained by Cheong et al. using pulsed-field gel electrophoresis (PFGE) (Mutat. Res. 274, 111-122, 1992). The value based on PFGE is used to calculate the value of t(rep) predicted by the DSB model (2.6 +/- 0.1 h), which agrees with the value determined experimentally as the time when changing the delayed-plating medium from growth medium to conditioned medium no longer gives the full recovery seen with delayed plating in conditioned medium (2.5 h). However, some recovery was seen for a change in the medium (growth medium to conditioned medium) up to 5-6 h postirradiation. Reanalysis of the original data on DSB repair shows that they are consistent with two first-order repair rates (18 +/- 7 min and about 52 min). These results are consistent with two pools of DSBs (or cells), each with their own t(rep). The early t(rep), associated with tau(fast), is predicted to be 1.7 +/- 0.7 h, and the late t(rep), associated with tau(slow), is predicted to be about 5 h. Both values are in excellent agreement with the times at which changing from growth medium to conditioned medium no longer gives the full recovery seen in conditioned medium only (the early t(rep)), and the time when changing from growth medium to conditioned medium produces no further increase in survival (the late t(rep)), respectively. It is noted that attempts to correlate radiosensitivity with the rates of DSB repair, rather than using an explicit model such as the DSB model, are unlikely to be productive since survival depends on both tau(DSBR) and t(rep) (as defined in the DSB model) and the latter may be the more important determinant of radiosensitivity (as it appears to be for ataxia telangiectasia cells compared to normal fibroblasts and for irs compared to V79 cells). CONTEXT: Adolescents' concerns about privacy in clinical settings decrease their willingness to seek health care for sensitive problems and may inhibit their communication with physicians. OBJECTIVE: To investigate the influence of physicians' assurances of confidentiality on adolescents' willingness to disclose information and seek future health care. DESIGN: Randomized controlled trial. SETTING: Three suburban public high schools in California. PARTICIPANTS: The 562 participating adolescents represented 92% of students in mandatory classes. INTERVENTION: After random assignment to 1 of 3 groups, the adolescents listened to a standardized audiotape depiction of an office visit during which they heard a physician who assured unconditional confidentiality, a physician who assured conditional confidentiality, or a physician who did not mention confidentiality. MAIN OUTCOME MEASURES: Adolescents' willingness to disclose general information, willingness to disclose information about sensitive topics, intended honesty, and likelihood of return visits to the physician depicted in the scenario were assessed by anonymous written questionnaire. RESULTS: Assurances of confidentiality increased the number of adolescents willing to disclose sensitive information about sexuality, substance use, and mental health from 39% (68/175) to 46.5% (178/383) (beta=.10, P=.02) and increased the number willing to seek future health care from 53% (93/175) to 67% (259/386) (beta=.17, P<.001). When comparing the unconditional with the conditional groups, assurances of unconditional confidentiality increased the number of adolescents willing to return for a future visit by 10 percentage points, from 62% (122/196) to 72% (137/190) (beta=.14, P=.001). CONCLUSIONS: Adolescents are more willing to communicate with and seek health care from physicians who assure confidentiality. Further investigation is needed to identify a confidentiality assurance statement that explains the legal and ethical limitations of confidentiality without decreasing adolescents' likelihood of seeking future health care for routine and nonreportable sensitive health concerns. BACKGROUND: Diabetic foot infections cause substantial morbidity and mortality. Neutrophil superoxide generation, a crucial part of neutrophil bactericidal activity, is impaired in diabetes. Granulocyte-colony stimulating factor (G-CSF) increases the release of neutrophils from the bone marrow and improves neutrophil function. We assessed G-CSF as adjuvant therapy for the treatment of severe foot infections in diabetic patients . METHODS: 40 diabetic patients with foot infections were enrolled in a double-blind placebo-controlled study. On admission, patients were randomly assigned G-CSF (filgrastim) therapy (n = 20) or placebo (n = 20) for 7 days. Both groups received similar antibiotic and insulin treatment. Neutrophils from the peripheral blood of these participants and from healthy controls were stimulated with opsonised zymosan, and superoxide production was measured by a spectrophotometric assay (reduction of ferricytochrome C). FINDINGS: G-CSF therapy was associated with earlier eradication of pathogens from the infected ulcer (median 4 [range 2-10] vs 8 [2-79] days in the placebo group; p = 0.02), quicker resolution of cellulitis< (7 [5-20] vs 12 [5-93] days; p = 0.03), shorter hospital stay (10 [7-31] vs 17.5 [9-100] days; p = 0.02), and a shorter duration of intravenous antibiotic treatment (8.5 [5-30] vs 14.5 [8-63] days; p = 0.02). No G-CSF-treated patient needed surgery, whereas two placebo recipients underwent to amputation and two had extensive debridement under anaesthesia. After 7 days' treatment, neutrophil superoxide production was significantly higher in the G-CSF group than in the placebo group (16.1 [4.2-24.2] vs 7.3 [2.1-11.5] nmol per 10(6) neutrophils in 30 min; p < 0.0001). G-CSF therapy was generally well tolerated. INTERPRETATION: G-CSF treatment was associated with improved clinical outcome of foot infection in diabetic patients . This improvement may be related to an increase in neutrophil superoxide production. BACKGROUND: Accelerated infusion of alteplase (tissue plasminogen activator) over a period of 90 minutes induces more rapid lysis of coronary-artery thrombi than a 3-hour infusion. With two bolus doses of alteplase, further shortening the duration of administration, complete reperfusion was achieved in more than 85 percent of the patients in initial angiographic studies. We tested the hypothesis that double-bolus alteplase is at least as effective as accelerated infusion. METHODS: In 398 hospitals, 7169 patients with acute myocardial infarction were randomly assigned to weight-adjusted, accelerated infusion of 100 mg of alteplase or to a bolus of 50 mg of alteplase over a period of 1 to 3 minutes followed 30 minutes later by a second bolus of 50 mg (or 40 mg for patients who weighed less than 60 kg). The primary end point was death from any cause at 30 days. The trial was stopped prematurely because of concern about the safety of the double-bolus injection. RESULTS: Thirty-day mortality was higher in the double-bolus group than in the accelerated-infusion group: 7.98 percent as compared with 7.53 percent. The absolute difference was 0.44 percent, with a one-sided 95 percent upper boundary of 1.49 percent, which exceeded the prespecified upper limit of 0.40 percent to indicate equivalence in 30-day mortality between the two regimens. The respective rates of any stroke and of hemorrhagic stroke were 1.92 and 1.12 percent after double-bolus alteplase, as compared with 1.53 and 0.81 percent after an accelerated infusion of alteplase (P=0.24 and P=0.23, respectively). CONCLUSIONS: Double-bolus alteplase was not shown to be equivalent, according to the prespecified criteria, to accelerated infusion with regard to 30-day mortality. There was also a slightly higher rate of intracranial hemorrhage with the double-bolus method. Therefore, accelerated infusion of alteplase over a period of 90 minutes remains the preferred regimen. BACKGROUND: Fenfluramine and phentermine have been individually approved as anorectic agents by the Food and Drug Administration (FDA). When used in combination the drugs may be just as effective as either drug alone, with the added advantages of the need for lower doses of each agent and perhaps fewer side effects. Although the combination has not been approved by the FDA, in 1996 the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million. METHODS: We identified valvular heart diseasein 24 women treated with fenfluramine-phentermine who had no history of cardiac disease. The women presented with cardiovascular symptoms or a heart murmur. As increasing numbers of these patients with similar clinical features were identified, there appeared to be an association between these features and fenfluramine-phentermine therapy. RESULTS: Twenty-four women (mean [+/-SD] age, 44+/-8 years) were evaluated 12.3+/-7.1 months after the initiation of fenfluramine-phentermine therapy. Echocardiography demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved. Eight women also had newly documented pulmonary hypertension. To date, cardiac surgical intervention has been required in five patients. The heart valves had a glistening white appearance. Histopathological findings included plaque-like encasement of the leaflets and chordal structures with intact valve architecture. The histopathological features were identical to those seen in carcinoid or ergotamine-induced valve disease. CONCLUSIONS: These cases arouse concern that fenfluramine-phentermine therapy may be associated with valvular heart disease. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease. Between 1987 and 1992, all patients presenting to the senior author with a symptomatic failed silicone implant arthroplasty refractory to conservative treatment were converted to a metatarsophalangeal joint arthrodesis. Internal fixation was achieved with either dual intrameduilary threaded Steinmann pins or an obliquely placed AO compression screw and a three- or four-hole one-third tubular dorsal neutralization plate. Bone grafting was used to maintain hallux length. Successful arthrodesis was achieved in all five feet in patients with rheumatoid arthritis. Subjectively, patients improved from an average of 0.69 before arthrodesis to 4.89 after arthrodesis. The average walking tolerance improved from 1.11 to 4.80, and the overall level of satisfaction improved from 0.0 to 4.79. The patient's ability to wear shoes improved from 0.87 to 3.1. Successful arthrodesis produces a foot that is more functional and durable than excisional arthroplasty. Subjectively, these patients stated that their level of pain, walking tolerance, and overall satisfaction improved significantly after the arthrodesis. Clinically, there was no evidence of transfer lesions, tenderness, or hallux subluxation. Hallux length was well maintained after surgery with bone grafting, but it was more difficult to obtain the alignment goals. The average postoperative metatarsophalangeal dorsiflexion angle was 15.6 degrees and the first metatarsophalangeal angle was 3.1 degrees. Despite this, patient satisfaction was high. Arthrodesis of the first metatarsophalangeal joint using a bone graft to salvage failed silicone implant arthroplasty produces acceptable subjective and radiographic results. Although technically demanding, it provides long-term stability to the hallux, restores weightbearing, and allows for maintenance of a propulsive gait. We recommend this procedure instead of an excisional arthroplasty to maintain high level of function and overall patient satisfaction. OBJECTIVE: To estimate the crude incidence rates of cerebrovascular accidents among the black residents of Harare. DESIGN: Prospective community-based study. SETTING: Black residents of Harare, Zimbabwe. PARTICIPANTS: Two hundred and seventy-three 'first-ever' strokes prospectively identified over a 12-month period. MAIN OUTCOME STUDY FACTORS: Cerebrovascular accident first-week fatality rate; age- and sex-related incidence. RESULTS: The crude incidence rate was estimated to be 30.7 per 100000 (95% confidence interval 27.1-34.4) and the standardised rate was 68 per 100000. Fifty-one per cent of stroke victims were below the age of 54 years. Thirty-five per cent of patients died within 1 week of the stroke. Overall, the age-specific rates for both sexes rose with age, with the rates for women being higher at all age strata except for the group 45-54 years. CONCLUSION: With a standardised rate of 68 per 100000 and a first-week mortality rate of 35%, stroke must now be considered an important cause of morbidity and mortality in the population. OBJECTIVE: To explore the long-term effect of calcium supplementation during pregnancy on the offspring's blood pressure during childhood. DESIGN: Follow up of a population enrolled in a double blind, randomised, placebo controlled trial. SETTING: Perinatal research unit, World Health Organisation's collaborative research centre. SUBJECTS: 591 children at a mean age of 7 years whose mothers were randomly assigned during pregnancy to receive 2 g/day of elemental calcium (n = 298) or placebo (n = 293). MAIN OUTCOME MEASURES: Mean blood pressure and rate of high blood pressure of children. RESULTS: Overall, systolic blood pressure was lower in the calcium group (mean difference -1.4 mm Hg; 95% confidence interval -3.2 to 0.5) than in the placebo group. The effect was found predominantly among children whose body mass index at assessment was above the median for this population (mean difference in systolic blood pressure -5.8 mm Hg (-9.8 mm Hg to -1.7 mm Hg) for children with an index > 17.5 and -3.2 mm Hg (-6.3 mm Hg to -0.1 mm Hg) for those with an index of > 15.7 to 17.5). The risk of high systolic blood pressure was also lower in the calcium group than in the placebo group (relative risk 0.59; 0.39 to 0.90) and particularly among children in the highest fourth of body mass index (0.43; 0.26 to 0.71). CONCLUSION: Calcium supplementation during pregnancy is associated with lower systolic blood pressure in the offspring, particularly among overweight children. The fast reaction of peroxynitrite with CO2 and the high concentration of dissolved CO2 in vivo (ca. 1 mM) suggest that CO2 modulates most of the reactions of peroxynitrite in biological systems. The addition of peroxynitrite to CO2 produces of the adduct ONOO-CO2- (1). The production of 1 greatly accelerates the decomposition of peroxynitrite to give nitrate. We now show that the formation of 1 is followed by reformation of CO2 (rather than another carbonate species such as CO3 = or HCO3-). To show this, it is necessary to study systems with limiting concentrations of CO2. (When CO2 is present in excess, its concentration remains nearly constant during the decomposition of peroxynitrite, and the recycling of CO2, although it occurs, can not be detected kinetically). We find that CO2 is a true catalyst of the decomposition of peroxynitrite, and this fundamental insight into its action must be rationalized by any in vivo or in vitro reaction mechanism that is proposed. When the concentration of CO2 is lower than that of peroxynitrite, the reformation of CO2 amplifies the fraction of peroxynitrite that reacts with CO2. Even low concentrations of CO2 that result from the dissolution of ambient CO2 can have pronounced catalytic effects. These effects can cause deviations from predicted kinetic behavior in studies of peroxynitrite in noncarbonate buffers in vitro, and since 1 and other intermediates derived from it are oxidants and/or nitrating agents, some of the reactions attributed to peroxynitrite may depend on the availability of CO2. A prospective, randomized, placebo-controlled, double-blind, parallel-group, 6-month study assessed the efficacy and safety of ropinirole, a nonergoline D2-dopamine agonist , in patients with early Parkinson's disease (n = 241; Hoehn & Yahr stages I to III) with limited or no prior dopaminergic therapy. Patients (mean age, 62.8 years), stratified by concomitant use of selegiline, were randomized to ropinirole (n = 116) or placebo (n = 125). The starting dose of ropinirole was 0.25 mg tid with titration to at least 1.5 mg tid (maximum dose, 8 mg tid). Primary efficacy endpoint was the percentage improvement in Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Ropinirole-treated patients had a significantly greater percentage improvement in UPDRS motor score than patients who received placebo (+24% vs -3%; p < 0.001). Ropinirole was well tolerated and patient withdrawals were infrequent. Most adverse experiences were related to peripheral dopaminergic activity. Ropinirole monotherapy is an effective and well-tolerated therapeutic option for treatment of early Parkinson's disease . Starfish oocytes can be fertilized after germinal vesicle breakdown (GVBD) and artificial parthenogenesis can be induced by activating the oocytes after GVBD (post-GVBD activation). In the present study, parthenogenotes were obtained by the activation of immature oocytes with caffeine before treatment with 1-methyladenine (1-MeAde) to induce oocyte maturation. Most of the caffeine-treated eggs developed as tetraploids, as parthenogenotes produced by the post-GVBD activation. The parthengenotes were derived only from eggs that failed to extrude polar bodies, mostly from eggs failing to extrude a second polar body. Eggs derived from immature oocytes activated by A23187, treated with 1-MeAde and post-treated with cytochalasin B failed to extrude polar bodies, and eventually developed into parthenogenetic embryos. These results indicate that the present parthenogenesis mechanism shares the same characteristics as that achieved by post-GVBD activation in the suppression of polar body formation as a key means for successful starfish parthenogenesis. We hypothesized that fluoride partly acts by changing the levels of circulating calcium-regulating hormones and skeletal growth factors. The effects of oral fluoride on 24 female, Dutch-Belted, young adult rabbits were studied. The rabbits were divided into two study groups, one control and the other receiving about 16 mg fluoride/rabbit/day in their drinking water. After 6 months of fluoride dosing, all rabbits were euthanized and bone and blood samples were taken for analyses. Fluoride treatment increased serum and bone fluoride levels by over an order of magnitude (P < 0.001), but did not affect body weight or the following serum biochemical variables: urea, creatinine, phosphorus, total protein, albumin, bilirubin, SGOT, or total alkaline phosphatase. No skeletal fluorosis or osteomalacia was observed histologically, nor did fluoride affect serum PTH or Vitamin D metabolites (P > 0.4). BAP was increased 37% (P < 0.05) by fluoride; serum TRAP was increased 42% (P < 0.05); serum IGF-1 was increased 40% (P < 0.05). Fluoride increased the vertebral BV/TV by 35% (P < 0.05) and tibial ash weight by 10% (P < 0.05). However, the increases in bone mass and bone formation were not reflected in improved bone strength. Fluoride decreased bone strength by about 19% in the L5 vertebra (P < 0.01) and 25% in the femoral neck (P < 0. 05). X-ray diffraction showed altered mineral crystal thickness in fluoride-treated bones (P < 0.001), and there was a negative association between crystal width and fracture stress of the femur (P < 0.02). In conclusion, fluoride's effects on bone mass and bone turnover were not mediated by PTH. IGF-1 was increased by fluoride and was associated with increased bone turnover, but was not correlated with bone formation markers. High-dose fluoride treatment did not improve, but decreased, bone strength in rabbits, even in the absence of impaired mineralization. PURPOSE: To determine the effect of various methods of managing the posterior capsule and anterior vitreous on the rate of posterior capsule opacification in pediatric eyes implanted with posterior chamber intraocular lenses (PC IOLs). SETTING: Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA. METHODS: We reviewed the charts of 20 eyes of 15 children (aged 1.5 to 2 years) who had primary cataract surgery with PC IOL implantation during the past 5 years. The posterior capsule and anterior vitreous were managed in a variety of ways: In 5 eyes, the posterior capsule was left intact; in 15 eyes, a posterior continuous curvilinear capsulorhexis (PCCC) was performed - 6 with and 9 without anterior vitrectomy; in 8 eyes, posterior optic capture was performed - 3 with and 5 without vitrectomy. The follow-up ranged from 1 to 4.5 years (mean 2 years). RESULTS: Visually significant secondary cataract developed in the five eyes with intact posterior capsules and in the four eyes that had PCCC without vitrectomy and without posterior optic capture (i.e., the optic was left in the capsular bag). The optical axis remained clear in the six eyes that had PC IOL implantation with vitrectomy (with or without posterior optic capture). Initially, all eyes that had optic capture without vitrectomy also remained clear, but after 6 months, four of five developed opacification. CONCLUSION: In this series, PCCC with anterior vitrectomy was the only effective method of preventing or delaying secondary cataract formation in infants and children. Evidence for the presence of a serotonin1A (5-HT1A) receptor subtype in the salmonid fish brain has recently been presented. In the present study the potent 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) was tested for its effect on plasma cortisol concentrations in rainbow trout (Oncorhynchus mykiss). Blood was sampled and 8-OH-DPAT administered through a catheter in the dorsal aorta. Thirty minutes after the injection of 40 microg of 8-OH-DPAT/kg, plasma cortisol levels had increased from 12 to 149 ng/ml, whereupon they fell, reaching baseline levels after 4 h. The effect of 1-40 microg 8-OH-DPAT/kg on plasma cortisol concentrations was dose-dependent. The results lends further support to the hypothesis that the brain serotonergic system plays a key role in integrating autonomic, behavioral and neuroendocrine stress-responses in fish as well as mammals, suggesting that not only the structural and biochemical organization, but also the function of the serotonergic system has been conserved during vertebrate evolution. OBJECTIVE: To assess the medicalising effect of prescribing antibiotics for sore throat . SETTING: 11 general practices in England. DESIGN: Randomised trial of three approaches to sore throat: a 10 day prescription of antibiotics, no antibiotics, or a delayed prescription if the sore throat had not started to settle after three days. PATIENTS: 716 patients aged 4 and over with sore throat and an abnormal physical sign: 84% had tonsillitis or pharyngitis. OUTCOME MEASURES: Number and rate of patients making a first return with sore throat, pharyngitis, or tonsillitis. Early returns (within two weeks) and complications (otitis media, sinusitis, quinsy). Outcomes were documented in 675 subjects (94%). RESULTS: Mean follow up time was similar (antibiotic group 1.07 years, other two groups 1.03 years). More of those initially prescribed antibiotics initially returned to the surgery with sore throat (38% v 27%, adjusted hazard ratio for return 1.39%, 95% confidence interval 1.03 to 1.89). Antibiotics prescribed for sore throat during the previous year had an additional effect (hazard ratio 1.69, 1.20 to 2.37). Longer duration of illness (> 5 days) was associated with increased return within six weeks (hazard ratio 2.90, 1.70 to 4.92). Prior attendance with upper respiratory conditions was also associated with increased reattendance. There was no difference between groups in early return (13/238 (5.5%) v 27/437 (6%)), or complications (2/236 (0.8%) v 3/434 (0.7%)). CONCLUSIONS: Complications and early return resulting from no or delayed prescribing of antibiotics for sore throat are rare. Both current and previous prescribing for sore throat increase reattendance. To avoid medicalising a self limiting illness doctors should avoid antibiotics or offer a delayed prescription for most patients with sore throat. This study was designed to determine and compare the dose-response characteristics, speed of onset, and relative potency of single-dose epidural fentanyl (F) and sufentanil (S) for postoperative pain relief . Eighty women undergoing cesarean section (C/S) with epidural 2% lidocaine with epinephrine (1:200,000) were randomly assigned to receive double-blind epidural administration of F (25, 50, 100, or 200 microg) or S (5, 10, 20, or 30 microg) (n = 10 per group) upon complaint of pain postoperatively. Visual analog scales (VAS, 0-100 mm) were used to assess pain and sedation at baseline; at 3, 6, 9, 12, 15, 20, 25, 30, 45, and 60 min; and every 30 min until further analgesia was requested. The study was terminated at 30 min if satisfactory analgesia was not achieved. Side effects were recorded. A dose-response was demonstrated for both opioids. F 25 microg and S 5 microg were ineffective, with significantly fewer women achieving VAS scores <10 mm (P < 0.05 compared with F 100 or 200 microg and S 20 or 30 microg). F 100 and 200 microg and S 20 and 30 microg all achieved VAS scores <10 mm in all women with no differences in time to 50% reduction in VAS (mean 11-16 min) and no differences in duration of analgesia (mean 117-138 min). The 50% and 95% effective dose values for each opioid to achieve a VAS score <10 mm were F 33 microg and 92 microg and S 6.7 microg and 17.5 microg. There were no differences among groups in sedation scores or side effects. Our data suggest that the relative analgesic potency of epidural S:F is approximately 5 and that there are no differences between the opioids in the onset, duration, and effectiveness of analgesia when equianalgesic doses are administered postoperatively after lidocaine anesthesia for C/S. We describe 2 cases in which intraoperative transesophageal echocardiography detected complications related to the proximal coronary arteries during homograft aortic valve and root replacement. In both cases, cardiopulmonary bypass could not be discontinued despite the use of large doses of inotropic drugs. Transesophageal echocardiography demonstrated aliasing on color flow mapping in the left main coronary artery in 1 case and proximal right coronary artery in the other, along with severely depressed left ventricular anterior wall and right ventricular function, respectively. Coronary artery bypass grafting was performed in both cases, and the outcome was successful. Granulocyte colony-stimulating factor (G-CSF) has been used to improve granulocyte count in chronic neutropenia and myelodysplasia, to minimize the incidence and duration of neutropenia during conventional chemotherapy, and to mobilize peripheral blood stem cells prior to leukapheresis for use in autologous and allogeneic marrow transplantation. The most common toxicity is bone pain, and other reactions such as inflammation at the site of injection have also occurred. In patients with chronic neutropenia, splenomegaly has been described with long-term use, and extramedullary hematopoiesis has also been reported. However, thus far, no life-threatening sequelae of these effects are found in the literature. We now describe a case of spontaneous splenic rupture four days following a six-day course of G-CSF therapy in an allogeneic donor of peripheral blood stem cells. Evidence-based medicine (EBM) aids clinical decision making in all fields of medicine, including primary care. General practice is characterized by particular emphasis on the doctor-patient relationship and on biomedical, personal and contextual perspectives in diagnosis. Most evidence available to general practitioners (GPs) addresses only the bio-medical perspective and is often not directly applicable to primary care, as it derives from secondary or tertiary care. Emphasis on the biomedical domain and the randomized controlled trial (RCT) alone reflects a reductionist approach that fails to do justice to the philosophy of general practice. The art of medicine is founded on context, anecdote, patient stories of illness and personal experience, and we should continue to blend this with good quality and appropriate research findings in patient care. Abdominal tuberculosis is not uncommon in the UK, especially in Asian immigrants. It resembles Crohn's disease clinically and radiologically, and it may be difficult to differentiate between them, even at laparotomy or histology. The distinction is important, however, for proper management of the two conditions. Every effort must be made to exclude abdominal tuberculosis before the patient is diagnosed as having Crohn's disease and is treated with steroids . PURPOSE: The American Urological Association convened the Female Stress Urinary Incontinence Clinical Guidelines Panel to analyze the literature regarding surgical procedures for treating stress urinary incontinence in the otherwise healthy female subject and to make practice recommendations based on the treatment outcomes data. MATERIALS AND METHODS: The panel searched the MEDLINE data base for all articles through 1993 on surgical treatment of female stress urinary incontinence. Outcomes data were extracted from articles accepted after panel review. The data were then meta-analyzed to produce outcome estimates for alternative surgical procedures. RESULTS: The data indicate that after 48 months retropubic suspensions and slings appear to be more efficacious than transvaginal suspensions, and also more efficacious than anterior repairs. The literature suggests higher complication rates when synthetic materials are used for slings. CONCLUSIONS: The panel found sufficient acceptable long-term outcomes data (longer than 48 months) to conclude that surgical treatment of female stress urinary incontinence is effective, offering a long-term cure in a significant percentage of women. The evidence supports surgery as initial therapy and as a secondary form of therapy after failure of other treatments for stress urinary incontinence . Retropubic suspensions and slings are the most efficacious procedures for long-term success (based on cure/dry rates). However, in the panel's opinion retropubic suspensions and sling procedures are associated with slightly higher complication rates, including longer convalescence and postoperative voiding dysfunction. A 55-year-old lady underwent repeat aortic valve replacement using a 16-mm Carbomedics prosthesis. She made an uneventful postoperative recovery and now leads an unrestricted life. Doppler echocardiography reveals a 21-mm Hg gradient across the valve at rest. This did not increase with an infusion of 30 mcg/kg per min of dobutamine, which resulted in an increase in the cardiac output from 1.96 to 5.46 l/min. BACKGROUND: For more than 30 years it has been known that gastric acid secretion is inversely related to the extent and severity of corpal gastritis. We therefore evaluated the effect of cure of Helicobacter pylori infection on basal and pentagastrin-stimulated acid secretion. METHODS: Basal acid output (BAO) and maximal acid output (MAO) were assessed in 11 H. pylori-infected dyspeptic patients (8 women and 3 men; mean age, 28 years) before and after successful anti-H. pylori therapy. RESULTS: The gastritis index was significantly lower after therapy and was associated with an increase in both BAO and MAO after cure of the H. pylori infection (BAO from 0.3 mmol/h and MAO from 4.8 mmol/h to 19 mmol/ h). Basal and stimulated acid concentrations also increased (29.1 +/- 36.6 to 54 +/- 31 mmol/l and 72.5 +/- 46 to 120.1 +/- 30 mmol/l, respectively, for basal and stimulated acid concentrations; P < 0.05 for peak and MAO, P = 0.07 for BAO). CONCLUSION: Gastric acid secretion increased into the normal range after successful treatment of H. pylori infection, suggesting that gastric function can recover to normal or almost normal after cure of H. pylori infection. OBJECTIVE: Reports suggest that there is an increased incidence of preeclampsia after a previously normal pregnancy if there is a change in paternity. We hypothesize that there is a higher incidence of preeclampsia (proteinuric hypertension) in women conceiving by intrauterine insemination with donor sperm versus intrauterine insemination with partner sperm. STUDY DESIGN: This was a retrospective cohort study. In women with primary infertility all pregnancies achieved by either partner or donor intrauterine insemination carried to birth of a fetus (> 20 weeks) were identified. The medical records were examined for the maternal and pregnancy outcome data. The relative risk and 95% confidence interval were calculated for the risk of preeclampsia. The baseline data were compared with t tests, chi 2 analysis and Fisher's exact test where appropriate. RESULTS: Forty-four patients in the partner intrauterine insemination group and 37 in the donor insemination group were identified as having primary infertility. Three cases of mild preeclampsia were found in the partner insemination program and nine cases of preeclampsia (five severe, four mild) in the donor insemination program (relative risk 1.85, 95% confidence interval 1.20 to 2.85).CONCLUSIONS: There is a higher incidence of preeclampsia in women conceiving by intrauterine insemination with washed donor sperm compared with intrauterine insemination with washed partner sperm. CONCLUSIONS: There is a higher incidence of preeclampsia in women conceiving by intrauterine insemination with washed donor sperm compared with intrauterine insemination with washed partner sperm. This supports, indirectly, an immunologic basis for preeclampsia. The antigenic factor would appear to be located on the sperm as opposed to the seminal fluid itself. After a rapid examination of a few basic concepts concerning cellular aging and programmed cell death, the aging of the tissues and organs, the authors discuss the principal theories on senescence. They underline that it is necessary to agree in considering the various genetic and epigenetic, endogenous and exogenous mechanisms that lead to the complex aging phenomenon multiple and interrelated. In particular they stress the hypothesis that senescence can be due to a sum of molecular damages caused by free radicals, and to the loss of telomeric DNA. Radical reactions can cause mutations, inactivation or a decrease in the turnover of mitochondrial DNA which is more vulnerable than the nuclear genoma to the attack of mutagenic agents, acting also as a continuous source of initial and/or promoting factors of the carcinogenetic process. The somatic cells become senescent because during cell division, they lose the mechanisms for the lengthening of the telomere. The telomerase prevents the shortening of telomeres in neoplastic cells and therefore renders them immortal. Paradoxically the protection of the telomere is exactly what must be avoided in the case of tumor cells. Recently the demonstration that telomerase is not always involved in the restoration of telomere length shows the complexity of the problems connected to the cause of senescence. Chromosomally integrated retroviral switch (S) substrates have been developed to reveal switch recombinase-like activities (SRLA) in pre-B and mature B cell lines. Switch substrate retrovectors (SSR) contain a long-terminal repeat-driven neomycin (Neo) gene for proviral chromosomal maintenance (pre- and post-S recombination) and a CMV promoter-driven, chimeric hygromycin-thymidine kinase (Hytk) gene (flanked by S mu and S gamma 2b recombination targets) to select for (ganciclovir) and against (hygromycin B) S region recombination. The retro-substrates' strong, constitutive promoters ensure that variations in cellular switch recombinase activities are independent of S region accessibility control. By initially selecting for proviral integrants in hygromycin followed by shifting into neomycin + ganciclovir to select for S sequence-mediated deletions, switch recombinations can be specifically forestalled in B cell lines whilst most switch-incompetent cells do not survive secondary selection. A qualitative, direct PCR assay reveals that SSR recombinations are stochastic in B cell lines generating a product array akin to natural GH class switching. A semi-quantitative DC-PCR assay detects a significant recombinase activity only in a restricted set of late stage pre-B and mature B cell lines. BCL1B1 mature B cells have the highest level of recombinase activity with 25% or more of proviral integrants accumulating S mu/S gamma 2b substrate recombinations within 10-14 cell generations. The SSR recombinase assay can be performed in a transient fashion wherein extensive, B cell-specific recombination can be visualized within only a few cell divisions post proviral integration. We propose that switch recombinase activity becomes activated during B cell ontogeny independent of or prior to the acquisition of CH locus accessibility and that endogenous S segment targeting to pre-existing recombinase requires a level of accessibility beyond transcriptional activation. OBJECTIVE: To determine the prevalence of illicit drug abuse and alcohol use in an obstetric population based in an urban maternity hospital. SETTING: A collaborative study between the Rotunda Hospital, Dublin and the Irish National Drug Advisory & Treatment Centre. DESIGN: A prospective study consisting of anonymous, unlinked urine testing of 504 'first visit' antenatal patients and a separate group of 515 patients six weeks after delivery. METHODS & OUTCOME MEASURES: Toxicological screening using enzyme-linked immunoassay techniques, with all positive samples being reanalysed. Drug histories were taken and samples were tested for alcohol and six of the most commonly abused drugs. The pre- and postnatal prevalence of abuse was matched with demographic data. RESULTS: The prevalence of chemical substance misuse in the antenatal population was 2.8% and 5.6% in the postnatal population. Substances identified included benzodiazepines, cannabis, amphetamines, opiates and cocaine. Less than 2% of samples tested positive for alcohol. None of the women yielding positive samples had been pre-identified on the basis of history. A significant proportion of the women were in the high risk categories with regard to age and socio-economic status. CONCLUSION: The prevalence of drug misuse antenatally was nearly 3% and postnatally almost 6%. Substance abusers in pregnancy are more likely to be single, unemployed, and to have had a previous pregnancy. Schizophrenic illnesses occur with approximately the same incidence in all human populations with a characteristic distribution (slightly earlier in males) of ages of onset. Given that the predisposition (which presumably is genetic) is associated with a procreative disadvantage why do such illnesses persist? Here it is suggested that these conditions are a manifestation of genetic diversity in the evolution of the specifically human characteristic of language, an innovation that has occurred by a process of progressive hemispheric specialization-the establishment of dominance for some critical component of language in one or the other hemisphere. Individuals who develop schizophrenic symptoms show lesser anatomical and functional asymmetries than the population as a whole; such symptoms may reflect 'dominance failure' for language. Cloacal anomalies are extremely rare and have variable presentations. Prenatal diagnosis can be difficult especially if they present in late gestation. Here we present two cases diagnosed in the late third trimester and review the literature regarding prenatal diagnosis of cloacal anomalies. OBJECTIVE: To determine whether patients with myocardial amyloidosis due either to AL (primary) amyloid or familial amyloid have distinguishing echocardiographic or electrocardiographic features; and to compare the prevalence of heart failure and survival in the two types of amyloidosis in relation to echocardiographic findings. DESIGN: Blinded group comparison of randomly selected cases of cardiac amyloidosis. SETTING: International referral centre for amyloid research and treatment. PATIENTS: 36 patients with cardiac amyloid heart disease, of whom 12 had familial and 24 had primary AL amyloidosis. RESULTS: Familial and AL echocardiograms were morphologically indistinguishable, with similar left ventricular wall thickness, mean (SD) 15.4 (2.3) nu 15.8 (2.5) mm, respectively; right ventricular wall thickness was also similar between amyloid types: 9.6 (2.8) nu 9.7 (6.5) mm, respectively. Doppler indices of left and right ventricular function, left ventricular volume, and ejection fraction were also similar. Low voltage electrocardiograms (< 0.5 mV) were more common in the AL (16/24, 67%) than in the familial group (4/12, 25%), P < 0.05. The one year survival for familial and AL forms was 92% (11/12) nu 38% (6/24), respectively, with virtually all deaths due to cardiac causes. CONCLUSIONS: Although cardiac involvement is echocardiographically indistinguishable, cardiac mortality is very different between the two forms of amyloidosis. Preservation of electrocardiographic voltage in familial amyloidosis suggests that the particular biochemical characteristics of distinct types of amyloid fibril have different pathological effects on the myocardium. This distinction becomes critical in the evaluation, treatment, and management of patients who have a diagnosis within the spectrum of the protein deposition diseases. OBJECTIVE: To examine the relationship between plasma plasminogen activator inhibitor 1 (PAI-1) activity and PAI-1 gene (4G/5G) polymorphism and diabetic retinopathy in Pima Indians with type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 171 Pima Indians with type 2 diabetes between the ages of 30-70 years in a population-based epidemiological survey. Plasma PAI-1 activity was measured by a spectrophotometric assay and PAI-1 4G/5G promoter genotype by the polymerase chain reaction (PCR) using allele-specific primers. Retinopathy was assessed by ophthalmoscopy after pupillary dilation and classified as any retinopathy or as nonproliferative and proliferative. RESULTS: Retinopathy was present in 70 (41%) subjects, and 4 (2.3%) subjects had proliferative retinopathy. Plasma PAI-1 activity was not significantly different among subjects with and without retinopathy (17.1 +/- vs. 19.7 +/- 9.1 arbitrary units (AU)/ml, P = 0.09). PAI-1 activity was negatively correlated with duration of diabetes (rs = -0.18, P = 0.02). In a logistic regression analysis controlled for age, sex, BMI, and duration of diabetes, any retinopathy was significantly associated with fasting plasma glucose concentrations (P < 0.05), 2-h postload glucose (P = 0.02), and HbA1c (P = 0.008), but not with PAI-1 activity (P = 0.48). The prevalence of retinopathy in the three genotype groups differed significantly (4G/4G, 4G/5G, and 5G/5G were 44, 49, and 24%, respectively; chi 2 = 8.22, df = 2, P = 0.016) and remained significant after controlling for age, sex, BMI, duration of diabetes, glycated hemoglobin, and urine albumin-to-creatine ratio in a logistic regression analysis. The odds ratios for retinopathy in subjects with 4G/4G and 4G/5G, compared with the 5G/5G genotype, were 2.0 and 3.1, respectively. CONCLUSIONS: Although diabetic retinopathy in Pima Indians with type 2 diabetes is not associated with PAI-1 activity, subjects with the 4G/4G and 4G/5G genotype had a higher prevalence of retinopathy compared with 5G/5G PAI-1genotype. These preliminary findings indicate that in Pima Indians with type 2 diabetes, presence of the 4G allele of the PAI-1 gene was associated with a higher risk of diabetic retinopathy. BACKGROUND: Diagnostic peritoneal lavage (DPL) is used to diagnose intra-abdominal injury in patients with stab wounds and blunt trauma. Because exploratory celiotomy is routinely performed on patients with gunshot wounds to the abdomen , DPL is rarely employed. However, several studies have questioned routine exploration and have drawn attention to the associated morbidity of negative celiotomy. Diagnostic peritoneal lavage is an easily performed and inexpensive test that may be useful in this situation. OBJECTIVE: To evaluate the performance of DPL in the diagnosis of intra-abdominal injury in hemodynamically stable patients with gunshot wounds to the abdomen. DESIGN: A prospective clinical trial. SETTING: Two urban trauma centers. PATIENTS: Patients with gunshot wounds to the abdomen and a systolic blood pressure of at least 90 mm Hg. INTERVENTIONS: Clinical predication of intra-abdominal injury in the emergency department and DPL performed in the operating room before the initiation of celiotomy. Injuries found during the celiotomy were recorded. MAIN OUTCOME MEASURES: The results of the clinical evaluation and DPL were compared with the findings of the celiotomy. RESULTS: Forty-four patients were enrolled into the study. Intra-abdominal injury was present in 32 (73%) of these patients. The senior surgery resident correctly predicted the presence of intra-abdominal injury in 36 (82%) of the patients (sensitivity = 90.0%, specificity = 58.3%, positive predictive value = 85.3%, negative predictive value = 63.6%, phi = 0.52, P < .01) in the emergency department before DPL and celiotomy were performed. Diagnostic peritoneal lavage correctly identified the presence or absence of intra-abdominal injury in 40 (91%) of the patients (positive predictive value = 96.7%, negative predictive value = 78.6%, phi = 0.79, P < .01). CONCLUSIONS: Clinical judgment is highly accurate in separating patients with tangential gunshot wounds to the abdomen from those with intra-abdominal injury but may miss patients with intra-abdominal hemorrhage. Diagnostic peritoneal lavage is highly predictive of the presence of intra-abdominal injury. The return of gross blood on aspiration or a lavage red blood cell count greater than 10 x 10(9)/L should prompt an urgent celiotomy. Missed injuries are rare and most likely to be bowel perforations. Diagnostic peritoneal lavage is an objective test that may augment clinical judgment in selecting hemodynamically stable patients with potential tangential gunshot wounds for observation and is especially useful in identifying intra-abdominal hemorrhage. BACKGROUND: To evaluate the frequency of Blastocystis hominis parasitation and to ascertain its role as an intestinal a prospective study during 18 months pathogen has been carried out. SUBJECTS AND METHODS: The study included 2,039 patients, which were classified in three groups (asymptomatic [group A], with suspicion of parasitosis [group B], with diarrhoea [group C]). In all cases a coproparasitological study was performed. In the group C the presence of non-parasitic enteropathogens was also investigated. In patients with B. hominis in the absence of other pathogens clinical and epidemiological characteristics were evaluated. Also, its was determined the morphology and quantification of parasites. RESULTS: Parasites were identified in 26.2% of population. B. hominis was identified in 336 patients (16.5%). The frequency of parasitation was superior in adults (p < 0.0001), with a slight predominance in the female sex. The rate of asymptomatic carriers was 3.3%. In 21 patients B. hominis (group C) was observed in absence of other enteropathogens. Statistical significant association was found between B. hominis, in absence of other pathogens and the presence of clinical manifestations (p < 0.0001), the most common of which were diarrhoea and abdominal pain. We did not find a statistically significant association between the number of B. hominis present and stool characteristics. The vacuolar form was the predominant morphological type. The ameboid form was observed only in diarrhoeal stools. CONCLUSIONS: B. hominis is the most frequent parasite found in faecal parasitological investigation. In absence of other causes, B. hominis must be considered as a pathogen. BACKGROUND: The cause of severe acquired hyperammonemia, an uncommon but often fatal complication of organ transplantation and chemotherapy for cancer, is obscure. OBJECTIVE: To test the hypothesis that liver glutamine synthetase deficiency may explain hyperammonemia in patients who have had organ transplantation or are receiving chemotherapy. DESIGN: Case report. PATIENTS: Two patients who had fatal hyperammonemia after orthotopic lung transplantation. MEASUREMENTS: Liver tissue was analyzed to determine the activities of two urea cycle enzymes and glutamine synthetase. Western blot assays for hepatic glutamine synthetase were performed to determine whether glutamine synthetase deficiency resulted from reduced enzyme levels. RESULTS: Activities of carbamoyl phosphate synthetase I and ornithine carbamoyltransferase in the liver were normal. The activity of hepatic glutamine synthetase was markedly reduced (in patient 1, 12% of the mean value in controls; in patient 2, 28% of the mean value in controls), and a concomitant reduction in the amount of glutamine synthetase protein was observed. CONCLUSION: Hyperammonemia after transplantation was associated with hepatic glutamine synthetase deficiency in two patients, but the causal relation between these two conditions must be further studied. Postnatal growth was prospectively measured from birth to 1 y in 54 term infants born small for gestational age (SGA), fed either breast milk or a standard term infant formula. Breastfeeding was associated with a 0.36 and 0.64 standard deviation (SD) increase in weight at 2 weeks and 3 months of age, respectively, which persisted beyond the breastfeeding period (0.64 SD at 1 y). Breastfed infants also showed greater catch-up growth in head circumference [SD score (SDS) 0.53 higher at 3 months], and greater body length gain (SDS 0.68 higher at 6 months). This increased growth was independent of potentially confounding obstetric, social and demographic factors. Our findings suggest that breastfeeding may promote faster growth in infants compromised by poor growth in utero. SGA infants may be programmed for a number of adverse outcomes; the possibility that such events are altered by choice of postnatal diet is a key issue for future research. BACKGROUND: Few studies have explored the health practices of critical care nurses. Critical care nurses routinely teach patients about using healthy practices such as low-fat diets, exercise, and routine screening examinations. However, it may be even more important that the nurses themselves have a healthy lifestyle, thus serving as role models for patients. Nurses are selling a product, and that product is health. The best salespersons are those who are genuinely committed to their product and model its benefits. Therefore, critical care nurses' healthful practices can have a profound effect on their patients. OBJECTIVES: The purpose of this descriptive exploratory study was to examine critical care nurses' responses to three questions about health practices in their daily lives: (1) What are critical care nurses doing currently to stay healthy? (2) Do they anticipate making any changes in their lifestyle in the future? (3) Would they recommend their lifestyle to their patients? METHODS: One hundred twenty-seven critical care nurses attending a midwestern critical care conference completed a two-part questionnaire designed to produce a health profile. In a man-on-the-street approach, 23 nurses participated in an interview via video camera. Descriptive statistics were used to analyze the data retrieved from the questionnaires. Interviews were transcribed verbatim and analyzed for themes with a constant comparative method. RESULTS: More than 70% of the critical care nurses who responded engage in exercise and follow a healthy, low-fat diet. Seventy-one percent said that they anticipate making a change in their lifestyle in the future, and 70% said that they would recommend their lifestyle to their patients. Five themes emerged from the videotaped interviews: (1) Heart-healthy practices predominated the responses. (2) Incorporating a healthy lifestyle was easy for some and a struggle for others. (3) Critical care nurses readily listed barriers to healthy living. (4) The nurses had a positive attitude about their healthy lifestyles and felt optimistic about being role models for their patients. (5) Future plans were either singular in focus or limited to maintenance of current health habits. CONCLUSIONS: The majority of the nurses reported practicing a healthy lifestyle and thought that they were good role models for patients. Cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) genetic polymorphisms are involved in the activation and detoxification of chemical carcinogens found in tobacco smoke; thus they may influence host susceptibility to lung cancer. In this study at Massachusetts General Hospital (Boston, MA, USA) of 416 cases and 446 controls (mostly White) we evaluated the association between the CYP1A1 MspI and GSTM1 polymorphisms and lung cancer risk, and their interaction with cigarette smoke. The CYP1A1 MspI heterozygous genotype was present in 18 percent of cases and 16 percent of controls, and one percent of cases and controls were CYP1A1 MspI homozygous variant. The GSTM1 null genotype was detected in 54 percent of cases and 52 percent of controls. After adjusting for age, gender, pack-years of smoking, and years since quitting smoking, while neither the CYP1A1 MspI heterozygous genotype alone nor the GSTM1 null genotype alone were associated with a significant increase in lung cancer risk, having both genetic traits was associated with a twofold increase in risk (95 percent confidence interval [CI] = 1.0-3.4). Our data did not provide enough evidence for a substantial modification of the effect of pack-years on lung cancer risk by the CYP1A1 MspI and GSTM1 genotypes. However, limitations of our study preclude a conclusion about this potential interaction. BACKGROUND: Thrombolytic treatment has been shown to accelerate resolution of major pulmonary embolism and lead to a rapid improvement of right-side hemodynamics. However, the association between these favorable effects and the clinical outcome of patients who have no severe hemodynamic compromise at presentation remains unknown. METHODS AND RESULTS: The present multicenter registry included 719 consecutive patients with major pulmonary embolism according to clinical, echocardiographic, scintigraphic, and cardiac catheterization criteria. Symptom onset was acute (<48 hours) in 63% of patients. All patients were hemodynamically stable (ie, without evidence of cardiogenic shock) at presentation. (within 24 hours of diagnosis) was given to 169 patients (23.5%), whereas the remaining 550 patients were initially treated with heparin alone. Overall 30-day mortality was significantly lower in the patients who received thrombolytic agents (4.7 versus 11.1%, P=.016). Clinical factors associated with a higher death rate were syncope (P=.012), arterial hypotension (P=.021), history of congestive heart failure (P=.013), and chronic pulmonary disease (P=.032). However, only primary thrombolysis was found by multivariate analysis to be an independent predictor of survival (odds ratio for in-hospital death, 0.46; 95% confidence interval, 0.21 to 1.00). Patients who underwent early thrombolytic treatment had a reduced rate of recurrent pulmonary embolism (7.7 versus 18.7%, P<.001) but also a higher frequency of major bleeding episodes (21.9% versus 7.8%, P<.001). Cerebral bleeding occurred in 2 patients in each treatment group, and 1 patient in each group died of a bleeding complication. CONCLUSIONS: The results of our study suggest that thrombolysis may favorably affect the clinical outcome of hemodynamically stable patients with major pulmonary embolism . A 66-year-old male engineer diagnosed with malignant pleural mesothelioma 4 years previously had thoracotomy, radiotherapy, and chemotherapy . He was followed regularly with chest computed tomography (CT) scan and had been asymptomatic. During one of his physical examinations, routine sigmoidoscopy showed incidental colonic polyps which were biopsied. Subsequently, recurrence of pleural mesothelioma and peritoneal involvement by mesothelioma was documented. Two of the polyps showed metastatic malignant mesothelioma in the lamina propia which strongly resembled adenocarcinoma histologically causing difficulty in making definitive diagnosis. Review of the literature disclosed no previously documented similar occurrence. This case shows the importance of clinical history and ancillary laboratory procedures such as immunohistochemistry and electron microscopy to avoid diagnostic pitfalls. The authors report the postoperative magnetic resonance (MR) imaging findings in 36 patients with advanced Parkinson's disease who underwent unilateral microelectrode-guided posteroventral pallidotomy . The lesions were placed within 1 mm of the ventral border of the globus pallidus internus (GPi) to include pallidothalamic outflow pathways. Sequential MR studies were obtained within 1 to 3 days postoperatively and at 6-month follow-up examination. Thirty-four (94%) of the 36 patients enjoyed sustained moderate or marked improvement of their parkinsonian symptoms 6 months postoperatively. Transient side effects occurred in five patients (14%), but there were no persistent complications. The pallidal radiofrequency lesions were prolate spheroid shaped and were composed of three concentric zones in the early postoperative studies. The mean volume of the middle zone, corresponding to the area of hemorrhagic coagulation necrosis, was 44.4 +/- 17.6 mm3; the mean lesion volume as defined by the outer zone, corresponding to perilesional edema, was 262.2 +/- 111.6 mm3. Additional edema spreading to the internal capsule was noted in 32 of 34 cases and to the optic tract in 11 of 34 cases. In two patients small ischemic infarctions involving the corona radiata were found, and in one a venous infarction was detected. Ischemic infarction resulted in mild transient Broca's aphasia in one patient, but there was no detectable neurological deficit in the other two. The mean volume of late-phase (6 months) lesions was 22 +/- 28.8 mm3. In three patients no lesion was identified despite sustained clinical improvement. The lesion was located in the posteroventral GPi in all cases except in one patient in whom it was confined to the GP externus (GPe). This 49-year-old woman did not experience sustained benefit. The authors found no consistent correlations between lesion size and location and clinical outcome as measured by a global outcome score, the Unified Parkinson's Disease Rating Scale motor, activities of daily living, and bradykinesia "off" scores or rating of dyskinesias. Lesioning of pallidal and subpallidal pathways may contribute to the sustained clinical benefit in this series. Magnetic resonance imaging analysis showed that intraoperative microelectrode recording facilitated accurate placement of the lesion in this critical area. A commercially available health food product of cold-pressed hemp seed oil ingested by one volunteer twice a day for 4 1/2 days (135 mL total). Urine specimens collected from the volunteer were subjected to standard workplace urine drug testing procedures, and the following concentrations of 11-nor-delta9- tetrahydrocannabinol carboxylic acid (9-THCA) were detected: 41 ng/mL 9-THCA at 45 h, 49 ng/mL at 69 h, and 55 ng/mL at 93 h. Ingestion was discontinued after 93 h, and the following concentrations were detected: 68 ng/mL at 108 h, 57 ng/mL at 117 h, 31 ng/mL at 126 h, and 20 ng/mL at 142 h. The first specimen that tested negative (50 ng/mL initial immunoassay test, 15 ng/mL confirmatory gas chromatographic-mass spectrometric test) was at 146 h, which was 53 h after the last hemp seed oil ingestion. Four subsequent specimens taken to 177 h were also negative. This study indicates that a workplace urine drug test positive for cannabinoids may arise from the consumption of commercially available cold-pressed hemp seed oil. OBJECTIVE: We determined the sensitivity and specificity of neonatal brain-stem auditory evoked potentials (BAEP) as markers for subsequent hearing impairment and for developmental problems found later in infancy and childhood. METHODS: BAEP studies were performed before discharge in infants treated with extracorporeal membrane oxygenation (ECMO), and two specific abnormalities were analyzed: elevated threshold and delayed central auditory conduction. Behavioral audiometry was repeated during periodic follow-up until reliable responses were obtained for all frequencies, and standardized developmental testing was also conducted. The sensitivity and specificity of an elevated threshold on the neonatal BAEP for detecting subsequent hearing loss, and the relationship of any neonatal BAEP abnormality to language or developmental disorders in infancy, were calculated. RESULTS: Test results for 46 ECMO-treated infants (57.5%) were normal, and those for 34 infants (42.5%) were abnormal, with either elevated wave V threshold, prolonged wave I-V interval, or both on neonatal BAEP recordings. Most significantly, 7 (58%) of the 12 children with subsequent sensorineural hearing loss had left the hospital after showing normal results on threshold tests. There was no significant difference in the frequency of hearing loss between subjects with abnormal (5/21, or 24%) and those with normal BAEP thresholds (7/59, or 12%; Fisher Exact Test, p = 0.28). Therefore the sensitivity of neonatal BAEP testing for predicting subsequent hearing loss was only 42%. Neonatal BAEP specificity for excluding subsequent hearing loss was 76%. In contrast, on language development testing, 19 children demonstrated receptive language delay. Of these children, 12 (63%) had abnormal neonatal BAEP recordings and 7 (37%) had a normal BAEP threshold, normal central auditory conduction test results, or both (p = 0.04). CONCLUSIONS: Neonatal BAEP threshold recordings were of limited value for predicting subsequent hearing loss common in ECMO-treated survivors. However, an abnormal neonatal BAEP significantly increased the probability of finding a receptive language delay during early childhood, even in those with subsequently normal audiometry findings. Because neonatal ECMO is associated with a high risk of hearing and receptive language disorders, parents should be counseled that audiologic and developmental follow-up evaluations in surviving children are essential regardless of the results of neonatal BAEP testing. The Federated Council of Internal Medicine has developed a resource guide to help internal medicine residency programs produce internists who are prepared for today's practice of internal medicine and the challenges of practice in the future. The guide situates general internal medicine as the primary care profession that focuses on preventive, short-term, and long-term care of adult patients. It assumes that a single pathway is sufficient for educating general internists and subspecialty-bound trainees. It identifies the learning experiences that should be part of general internal medicine residency training, lists the clinical competencies that are important for primary care practice, and describes the role of the integrative disciplines that should inform the care of every patient. It also describes a process that program directors and local program committees can use to develop competency-based curricula. BACKGROUND: Darier disease is an uncommon genodermatosis characterized by the symmetrical eruption of keratotic reddish-brown papules occurring in the seborrheic areas of the body. A unilateral, or localized, variant has been identified. We report 4 new cases of localized Darier disease and review the English-language literature. The implications of these cases on future genetic studies are also discussed. OBSERVATIONS: Localized Darier disease occurred with equal frequency in males and females. The average age at onset was 27 years. The most frequent site of involvement was the trunk (40% [16/40]). This condition was aggravated by sunlight, heat, or sweating in 42% (19/40) of reported cases, and 38% (15/40) of the patients responded to treatment with topical tretinoin. CONCLUSIONS: Many of the clinical features of localized Darier disease suggest that it is a genetic mosaic of generalized Darier disease. Further studies of localized Darier disease may therefore prove to be instrumental in the search for the Darier disease gene. UV radiation induces two major DNA damage products, the cyclobutane pyrimidine dimer (CPD) and, at a lower frequency, the pyrimidine (6-4) pyrimidinone dimer (6-4 product). Although Escherichia coli and Saccharomyes cerevisiae produce a CPD-specific photolyase that eliminates only this class of dimer, Arabidopsis thaliana, Drosphila melanogaster, Crotalus atrox, and Xenopus laevis have recently been shown to photoreactivate both CPDs and 6-4 products. We describe the isolation and characterization of two new classes of mutants of Arabidopsis, termed uvr2 and uvr3, that are defective in the photoreactivation of CPDs and 6-4 products, respectively. We demonstrate that the CPD photolyase mutation is genetically linked to a DNA sequence encoding a type II (metazoan) CPD photolyase. In addition, we are able to generate plants in which only CPDs or 6-4 products are photoreactivated in the nuclear genome by exposing these mutants to UV light and then allowing them to repair one or the other class of dimers. This provides us with a unique opportunity to study the biological consequences of each of these two major UV-induced photoproducts in an intact living system. A diffuse macular erythroderma and subsequent desquamation after 1 to 2 weeks are two of the five major diagnostic criteria of toxic shock syndrome (TSS). We present the case of a 15-month-old girl with TSS, but without erythroderma or desquamation. She was admitted with high fever, shock, and multiorgan involvement. Minimal or no cutaneous signs were present. Initially the diagnosis of the syndrome of hemorrhagic shock and encephalopathy was made. After 7 days, a TSS toxin 1-producing strain of Staphylococcus aureus was cultured from an inguinal lymph node, where inflammation had already been noticed on admission. Moreover, the girl had no antibodies against this toxin. The serum cytokine profile during the acute phase of her illness showed high levels of tumor necrosis factor-alpha, interleukin-6 and interferon-gamma, as is seen during activation of the immune system by TSS toxin 1. Other possible causes for the patient's illness were excluded. We conclude that the patient had TSS without rash. Without the evidence implicating a TSS toxin 1-producing strain of S. aureus as the cause of her disease, a diagnosis of syndrome of hemorrhagic shock and encephalopathy would have been made. It is possible that some cases of syndrome of hemorrhagic shock and encephalopathy represent a variant of TSS in small children. BACKGROUND: The growing teratoma syndrome refers to the phenomenon whereby germ cell tumors enlarge after chemotherapy despite complete eradication of malignant cells and normalization of serum tumor markers. This clinical scenario must be differentiated from that in which germ cell tumors maintain their malignant characteristics with elevated levels of serum tumor markers. METHODS: Hospital record review was conducted of 2 cases. RESULTS: Two male patients are presented, 1 with a metastatic germ cell tumor of both the retroperitoneum and mediastinum (with elevated alpha-fetoprotein level) and 1 with a primary germ cell tumor of the mediastinum (with elevated alpha-fetoprotein and beta-human chorionic gonadotropin levels). After completion of chemotherapy and normalization of tumor markers, both patients presented with pulmonary symptoms attributable to their massively enlarging mediastinal teratomas. The clinical and roentgenographic features of patients with thoracic manifestations of the growing teratoma syndrome, as well as its management, are reviewed. CONCLUSIONS: After chemotherapy in patients with primary or metastatic mediastinal germ cell tumors whose tumor markers normalize, a growing mass in the mediastinum may represent the growing teratoma syndrome. The chicken calmodulin I (CaMI) gene has been isolated and characterized on the level of cDNA and genomic DNA. The deduced amino acid (aa) sequence is identical to the one of chicken CaMII which consists of 148 aa. The CaMI gene contains six exons. Its intron/exon organization is identical to that of the chicken CaMII and the CaMI and CaMIII genes of rat and human. Expression of the CaMI gene was detected in all chicken tissues examined, although at varying levels. The gene is transcribed into four mRNAs of 0.8, 1.4, 1.7 and 4.4 kb as determined by Northern blot analysis. Our results demonstrate that the "multigene-one-protein" principle of CaM synthesis is not only applicable to mammals whose CaM is encoded by three different genes, but also to chickens. BACKGROUND: We assessed the accuracy of two electron beam computed tomography (EBCT) protocols for predicting coronary events. METHODS AND RESULTS: In 1994, 24 months after enrollment in a longitudinal study, 326 high-risk adults underwent both 3- and 6-mm image-slice thickness EBCT scanning and were followed up for 32.0+/-4.0 additional months. Events were defined as either coronary death, myocardial infarction, or revascularization. We monitored these subjects for the 32-month postscanning period with yearly phone calls and acquisition of records for all hospital admissions. At the time of scanning, 11 subjects (3%) had already suffered 12 events (5 infarctions and 7 revascularizations) during the 24-month prescanning period. During the postscanning period, 18 subjects (6%) suffered 23 events (5 coronary deaths, 6 infarctions, and 12 revascularizations). Thus, 28 subjects (9%) suffered 35 events. Calcium quantities calculated for both protocols, performed on the same subjects, were sorted in ascending order and divided into equal quartiles. When revascularizations were included, there was a significant trend toward higher frequencies of events with increasing calcium quantity (P<.01). However, coronary death and infarction were not significantly more frequent in higher quartiles. These relationships were preserved in the subjects without prior events at the time of scanning. CONCLUSIONS: Calcium quantities from the 3-mm and the more reproducible 6-mm scanning are equally accurate for predicting events. Coronary calcium amount appears to be a weak predictor of coronary death and infarction. Its predictive accuracy is superior for predicting revascularization. Research into the genetic component of some complex behaviors often causes controversy, depending on the social meaning and significance of the behavior under study. Research into sexual orientation-simplistically referred to as "gay gene" research-is an example of research that provokes intense controversy. This research is worrisome for many reasons, including the fact that it has been used to harm lesbians and gay men. Many homosexual people have been forced to undergo "treatments" to change their sexual orientation. Other chose to undergo them to escape discrimination and social disapprobation. But there are other reasons to worry about such research. The very motivation for seeking an "origin" of homosexuality reveals homophobia. Moreover, such research may lead to prenatal tests that claim to predict for homosexuality. For homosexual people who live in countries with no legal protections these dangers are particularly serious. The efficiency of testicular sperm retrieval by testicular fine needle aspiration (TEFNA) was compared with open biopsy and testicular sperm extraction (TESE), in 37 rigorously selected patients with non-obstructive azoospermia. All patients underwent TEFNA and TESE consecutively. Thus, each patient served as his own control. The case was regarded as successful if at least one testicular spermatozoon was found allowing intracytoplasmic sperm injection (ICSI) of at least one oocyte. The mean age of the male patients was 32.7 years (range 24-47). Whereas by TEFNA spermatozoa enabling performance of ICSI were found in only four patients out of 37 (11%), open biopsy and TESE yielded spermatozoa in 16 cases (43%). The negative predictive value of high serum follicle stimulating hormone (FSH) concentrations (> or =10 IU/l) (predicting failure to find spermatozoa for ICSI) was low (38.4%). The positive predictive value (predicting the chance to find spermatozoa for ICSI) of normal-sized testicle was not different from that of small-sized (<15 ml) testicle (50%). Complications included one case of testicular bleeding following fine needle aspiration, treated locally, and two cases of extratunical haematomata following TESE requiring no intervention. In patients with non-obstructive azoospermia, TEFNA has a significantly lower yield compared to TESE. Performance of ICSI with testicular sperm in these cases resulted in satisfactory fertilization and high embryo transfer rates. The implantation and pregnancy rates per embryo transfer were 13 and 29% respectively. Neither serum FSH values nor testicular size were predictive of the chances to find spermatozoa for ICSI. Some complications may occur even following TEFNA. Cyclin D1, the regulatory subunit of certain protein kinases thought to advance the G1 phase of the cell cycle, is now established as a proto-oncogene, with evidence indicating that its derangement may contribute to the uncontrolled cell growth characteristic of tumors. The chromosomal translocation t(11;14)(q13:q32), involving rearrangement of the BCL-1 locus, is closely associated with human lymphoid neoplasia affecting mantle cell lymphomas (MCL). Recently, the putative BCL-1 proto-oncogene turned out to be none other than the cyclin D1 gene. Although the observed break points in the BCL-1 locus are not tightly clustered, its rearrangement has been documented in 40-70% of cases of mantle cell lymphoma, whereas it only rarely occurs in other B cell lymphomas. Of note, all of the known break points leave the cyclin D1 coding region structurally intact and result in increased protein expression, implying that this may provide a highly sensitive and specific marker for MCL. Recent studies demonstrated that immunohistochemical detection in paraffin-embedded material, using a monoclonal antibody, is very useful for routine diagnosis. Current knowledge of cyclin D1 overexpression in malignant lymphomas, with emphasis on its clinicopathologic significance, is reviewed. In the mammalian central nervous system, a diverse group of basic helix-loop-helix (bHLH) proteins is involved in the determination of progenitor cells and, subsequently, in regulating neuronal differentiation. Here we report the identification of a novel subfamily of bHLH proteins, defined by two mammalian enhancer-of-split- and hairy-related proteins, termed SHARP-1 and SHARP-2. In contrast to known bHLH genes, detectable transcription of SHARP genes begins at the end of embryonic development marking differentiated neurons that have reached a final position, and increases as postnatal development proceeds. In the adult, SHARP genes are expressed in subregions of the CNS that have been associated with adult plasticity. In PC12 cells, a model system to study neurite outgrowth, SHARP genes can be induced by NGF with the kinetics of an immediate-early gene. Similarly, within 1 h after the administration of kainic acid in vivo, SHARP-2 is induced in neurons throughout the rat cerebral cortex. This suggests that neuronal bHLH proteins are also involved in the "adaptive" changes of mature CNS neurons which are coupled to glutamatergic stimulation. The embryonic development of the face has been studied in many reviews, this work purposes only to clear up some points which remain obscure concerning cervico-facial morphogenesis. In the first part of this study only the facial development, properly speaking, is considered, although it cannot be separate of cervical development to which a second study will be reserved. In the present study we recall the particular aspects of the neurulation in the cephalic area, then the establishment of the facial processes. Then we approach among other things the way to consider the maxillary process with regard to the other facial processes. After is considered constitution and natured of the prechordal plate which has been diversely explained. Finally, the modelling of the face is evocated, in which the dissociation between the olfactive and buccal spheres is pointed out, with the disparition of the muzzle, as it is established in the haplorhinae, a class of primates in which the human being is involved. This phenomenon raises different questions, in particular about the relation of this disposition with the nasoseptal center, the medial part of the nasodorsal center. A case-control study was performed in eight pairs of women to determine whether preeclamptic women developed abnormalities in minor hemoglobins, glycolytic enzymes, or other blood components that might provide insight into the pathophysiology of preeclampsia, or that in combination might be used as a marker for the condition. These variables and standard clinical tests were analyzed as discriminators between preeclamptic and control women. The subjects were matched for age, ethnicity, parity, and gestational age. Blood samples were taken at the time of diagnosis of preeclampsia and at comparable gestational ages for matched normal controls. Variables differing significantly between groups included increases in uric acid (UA), low-density lipoproteins (LDL), phosphoglycerate kinase (PGK), and mean platelet volume (MPV), and decreases in glyceraldehyde phosphate dehydrogenase (G3PD) in preeclamptic women compared to normal controls. Discriminant analysis revealed the following function to separate the groups: 0.7764 (UA) + 0.8086 (PGK) -0.7032 (G3PD) + 0.1399 (LDL) -0.2386 (MPV). A discriminant score of > or = 275 indicated a > or = 90% probability of preeclampsia. The results are consistent with perturbations in red cell glycolysis in preeclampsia. Further prospective studies are warranted to test the efficacy of this discriminant function in predicting preeclampsia. A novel technique for patterning immobilized antibody layers based upon photolithography and oxygen plasma exposure has been developed. Mouse monoclonal antibodies specific for thiabendazole (a post-harvest fungicide and veterinary anthelmintic) were covalently linked through free amine groups to aminosilanized silicon dioxide films using glutaraldehyde. Immobilized antibody layers were stabilized with sucrose, dehydrated, and stored refrigerated with desiccant. Photolithographic patterning was performed with a positive photoresist with modified bake temperatures and times, selective UV exposure with a contact mask, and aqueous alkaline solubilization of exposed resist. Exposed regions of immobilized antibody were then removed by exposure to a low power, radio frequency oxygen discharge. Residual resist was stripped with acetone. Successful patterning was demonstrated by challenging surfaces with goat anti-mouse antibody conjugated to tetramethylrhodamine isothiocyanate. Sucrose stabilization was necessary for antibody to undergo photoresist processing without loss of binding activity. Challenge with enzyme linked antigen of oxygen plasma exposed antibody layers demonstrated that plasma treatment completely neutralized antibody capture ability. Ellipsometry measurements of oxygen plasma exposed antibody layers indicated complete removal of immobilized antibodies. Fluorescent imaging demonstrated smallest line widths of 2-3 microns. Immune cells in vivo routinely perform highly selective immunosensing in blood and tissues as part of their normal immune surveillance functions. We have been investigating the potential of exploiting the immunosensing detection abilities of excitable immune cells (i.e. the mast cell) for the development of whole cell immunobiosensors. A key feature is that these immune cells can be selectively engineered to recognize specific antigens in vitro. In the presence of antigen, these cells undergo excitable activation responses which result in increased metabolism and the exocytosis of stored intracellular mediators. We have previously determined that mast cell metabolic responses can be thermally transduced in real time, thus indicating the possibility of whole cell thermoelectric immunobiosensing. In this work we investigated the use of enzyme amplification systems to enhance the direct transduction of immune cell responses to analyte. It was found that with appropriate enzymes, peak outputs occurred within approximately 5 min (4-20 times faster than without enzymes) and peak response magnitudes were up to nine-fold greater than without enzymes. An easy-to-use technique for detection of antibodies specific for the parasite L. donovani in human serum sample has been developed. The method is based on an evanescent wave generated from a tapered configuration of decladded optical fibre and does not require any volumetric measurement. Tapered fibres are immobilized with the purified cell surface protein of L. donovani by covalent bonding. Treated fibres are incubated with the patient serum for 10 min followed by incubation with goat anti human IgG tagged FITC. Fluorescent intensity from the fibre has been shown to be proportional to L. donovani specific antibodies present in the test sera. Direct readings can be obtained after signal enhancement through a photomultiplier tube within 5 min. The system, when tested on 12 positive sera, did not show any false negative result. Also, no false positive result was obtained with serum samples of patients infected with leprosy, tuberculosis, typhoid and malaria, showing the specificity of the sensor and efficacy of the technique. We present an optical biosensor design that expands the utility of enzyme biosensors. These biosensors are fabricated by site-selective photodeposition of analyte-sensitive polymer matrices on optical imaging fibres. These dual-analyte arrays allow for the simultaneous, independent measurement of the analyte of interest and the transducing analyte. The first integrated optical-biosensors using this design have been prepared that allow both the dependent and independent analytes to be measured simultaneously, for example penicillin and pH (Healey & Walt, 1995) or glucose and O2 (Li & Walt, 1995). Independent measurement of the transducing analyte allows penicillin or glucose to be quantitated in the presence of a concurrent pH or O2 change, respectively. Penicillin can be measured in the range 0.25-10.0 mM in the pH range 6.2-7.5. Glucose can be measured in the range 0.6-20.0 mM in the O2 range 20-100%. The utility of the sensor design was demonstrated by using the penicillin-dual-analyte biosensor to quantitate penicillin produced during a Penicillium chrysogenum fermentation. The characterization of low molecular weight ligand interaction with receptor molecules is of importance for the investigation of biological processes and for drug research. We report on the investigation of the binding of low molecular weight ligands to immobilized receptors by label-free detection. Reflectometric interference spectroscopy, an optical transducer which allows the monitoring of a few picograms per square millimetre changes in surface coverage, was used to study two model systems. In both cases detection of the binding event was successful. High affinity binding of biotin to immobilized streptavidin was clearly detectable at receptor surface concentrations as low as 1-2 x 10(10) binding sites/mm2. Linear correlation between the receptor surface concentration and the response to biotin binding was observed. Using immobilized DNA, we investigated the binding of common intercalators with respect to kinetics and thermodynamics by evaluation of the association and the dissociation part of the binding curve. Bi-exponential increase and decrease of intercalator loading was observed, indicating complex interaction kinetics. The four structurally different intercalators showed significant distinction in binding kinetics and equilibrium signals. Improvement of experimental parameters is required to obtain more reliable kinetic data. An amperometric lactate oxidase catheter has been developed for in vivo application to real-time lactate monitoring. The electrochemical behaviour of the 1 x 3 mm Pt-Ag/AgCl thin film electrode is not significantly influenced by lactate oxidase-polyurethane covering. Gamma-irradiation (25 kGy) is suitable for the sterilization procedure. The final lactate catheter is characterized by a linear concentration range between 0.5 and 20 mmol/l lactate with a sensitivity around 2 nA mmol-1 l-1 lactate. The accuracy is demonstrated by the measurement of control sera. Both physiological and pathological materials correlate well with the declared values. The dry stored lactate catheter needs about 10 min for hydration and is characterized by response times t98% of less than 2 min. Ex vivo whole blood measurements using the lactate catheter (y) give a correlation with the BIOSEN Med L (x) of y = (1.010x + 0.513) mmol/l (r = 0.9748). Lactate values obtained by continuous catheter operation ex vivo correlate well with those obtained by BIOSEN Med L. First subcutaneous implantation (dog) underlines the characteristics obtained ex vivo: after 30 min hydration the lactate catheter follows the lactate concentration measured ex vivo with samples from the leg vein by BIOSEN Med L. The diffusion-limited binding kinetics of antigen (or antibody) in solution to antibody (or antigen) immobilized on a biosensor and other surfaces is analyzed within a fractal framework. Often, the binding kinetics may be described by a single-fractal analysis. In some cases, the binding curve exhibits complexities. Then, for these cases, the dual-fractal analysis provides an improved fit when compared with a single-fractal analysis. This indicates a change in the reaction mechanism on the surface. It is of interest to note that the state of disorder (or the fractal dimension) and the binding rate coefficient both increase as the reaction progresses on the biosensor surface. For example, for the binding of 10 nM insulin growth factor-1 in solution to insulin growth factor binding protein-1 immobilized on a biosensor surface, a 64% increase in the fractal dimension from 1.73 (Df1) to 2.85 (Df2) leads to an increase in the binding rate coefficient by a factor of 31.8 from 3.92 (k1) to 125 (k2). Furthermore, as the IGF-1 concentration in solution increases from 10 to 80 nM in solution, k2 and Df2 exhibit a linear increase. k1 and Df1 exhibit a linear increase with the reciprocal of the IGF-1 concentration in solution. The different examples analyzed and presented together provide a means by which the antigen-antibody reactions may be better controlled by noting the magnitude of the changes in the fractal dimension and in the binding rate coefficient as the reaction progresses on the biosensor surface. Also, the magnitude of the changes in the binding rate coefficients (k1 and k2) and in the fractal dimensions (Df1 and Df2) as different parameters are changed for the different biosensor applications are of particular value, since they provide us with a measure or extent of changes in the binding rate coefficient on changing different experimental parameter values. It is of interest to note the effect of different parameters on the extent or heterogeneity that exists on the surface and how this influences the binding rate coefficients. This may be one method to help manipulate or control the binding rate coefficients on the reaction surface. To determine if microscopic urinalysis is needed in all pediatric emergency room patients screened for urinary tract infections (UTI), we compared the dipstick urinalysis and complete urinalysis (dipstick and microscopy) with urine cultures in 236 children, aged 3 weeks to 21 years. The ability to detect UTI by dipstick only and by complete urinalysis was the same, however microscopic evaluation added many false-positive results without detecting additional UTIs. Because the ability to detect UTI (sensitivity) is maintained, we now offer a dipstick only urinalysis to our emergency room for children 2 years of age or older, with a microscopic analysis performed automatically if dipstick results are positive. If no microscopic urinalysis is required, testing turn-around time is reduced by 12.3 min/test and the hospital charge is reduced from U.S. $32 to U.S. $12. Using video-intensified fluorescence microscopy and a pseudocolor display of fluorescence intensity, we analyzed the distribution of microinjected molecules within the nurse-cell/oocyte syncytium of Drosophila ovarian follicles. We varied the composition and the osmolarity of the culture solution as well as the electrical charge and the molecular mass of the microinjected fluorescent probe. As culture solutions, we used four simple salines (IMADS) and a complex tissue-culture medium (R-14) that matched the osmolarity of adult hemolymph. Small amounts of two anionic dyes (Lucifer Yellow CH and Lucifer Yellow dextran) as well as of two cationic dyes (rhodamine 6G and tetramethylrhodamine dextran-lysine) were iontophoretically microinjected either into a nurse cell or into the oocyte of stage-10 follicles. In the tissue-culture medium, within a few seconds following microinjection, all tested dyes passed through the intercellular bridges in both the anterior direction (to the nurse cells) and the posterior direction (to the oocyte), independent of their electrical charge or molecular mass. In all simple salines, irrespective of their osmolarity, Lucifer Yellow CH was found to preferentially migrate in the posterior direction and to accumulate in the oocyte due to progressive binding to yolk spheres. Thus, with this sensitive method, no correlation was detectable between the external osmolarity, the electrical charge and the preferential direction of migration of a microinjected probe. Our results indicate that the electrical gradient described by other authors does not exert significant influence on the migration of charged molecules through intercellular bridges in situ. The AF-4 gene on human chromosome 4q21 is involved in reciprocal translocations to the ALL-1 gene on chromosome 11q23, which are associated with acute lymphoblastic leukaemias. A set of recombinant phage carrying genomic fragments for the coding region and flanking sequences of the AF-4 gene were isolated. Phage inserts were assembled into four contigs with 21 exons, and an intron phase map was produced enabling the interpretation of translocation-generated fusion proteins. The gene contains two alternative first exons, 1a and 1b, both including a translation initiation codon. The translocation breakpoint cluster region is flanked by exons 3 and 6 and two different polyadenylation signals were identified. Polyclonal antisera directed against three different portions of the AF-4 protein were produced and used to detect a 116 kD protein in cellular extracts of human B-lymphoblastoid and proB cell lines. In mitogen-stimulated human peripheral blood mononuclear cells the AF-4 antigen was predominantly located in the nucleus. The AF-4 gene is a member of the AF-4, LAF-4 and FMR-2 gene family. The members of this family encode serine-proline-rich proteins with properties of nuclear transcription factors. Comparison of AF-4 protein coding sequences with the LAF-4 and FMR-2 sequences revealed five highly conserved domains of potential functional relevance. Immunoglobulin superfamily molecules in the brain are involved in distinct aspects of nervous system histogenesis, for example neuronal migration and axonal growth. To identify novel members of this superfamily in the chick nervous system, we developed a polymerase chain reaction-based approach making use of sequence motifs of immunoglobulin-like domains. In the present study, we report the molecular cloning of three isoforms, the biochemical analysis and the immunohistochemical characterization of one of the proteins identified in this screen. This molecule has 91% sequence identity with the limbic system-associated membrane protein (LAMP) characterized in the rat and is therefore referred to as the chicken homologue of the latter (chLAMP). The molecule is a glycosylphosphatidyl-inositol-anchored 60 kDa protein with three immunoglobulin-like domains and contains 40% N-linked carbohydrate. We identify three different mRNA forms of chLAMP and show that two forms with distinct 5'-termini are differentially transcribed in neural development. In addition, we demonstrate using a fusion protein expressed in eukaryotic cells that chLAMP has homophilic binding activity. The protein was found on a subset of axons in the central and peripheral nervous system and is likely to be involved in specific cell-cell interactions in neurohistogenesis. Two novel cDNAs, DNAS1L2 and DNAS1L3, are predicted to encode proteins of 299 and 305 amino acids with 56 and 46% residue identity (71 and 63% similarity), respectively, to deoxyribonuclease I (DNase I). DNAS1L2 is located on a 16p13.3 cosmid, while DNAS1L3 maps to 3p14.3-p21.1 by fluorescence in situ hybridization and by PCR analysis of a radiation hybrid panel. Northern analysis revealed DNAS1L3 expression nearly exclusively in liver, while DNAS1L2 expression was detected in brain by RT-PCR. The previously defined DNL1L or DNAS1L1 is expressed highest in heart and skeletal muscle, while DNase I is expressed in the pancreas, parotid gland, and kidney. Thus, to date, four DNase I-like genes that show different tissue expression patterns are known. A comparison of DNAS1L1, DNAS1L2, and DNAS1L3 with the well-characterized DNase I suggests that the DNAS1L proteins are unlikely to be glycosylated or bind actin; however, catalytic and calcium- and DNA-binding residues are conserved, and potentially cleavable signal peptides are present among all these proteins. This analysis also identifies regions of high conservation among these proteins with no currently assigned function. Two different responses to the therapy were observed in a group of patients receiving the protease inhibitor indinavir. In one, suppression of virus replication occurred and has persisted for 90 weeks (bDNA, < 500 human immunodeficiency virus type 1 [HIV-1] RNA copies/ml). In the second group, a rebound in virus levels in plasma followed the initial sharp decline observed at the start of therapy. This was associated with the emergence of drug-resistant variants. Sequence analysis of the protease gene during the course of therapy revealed that in this second group there was a sequential acquisition of protease mutations at amino acids 46, 82, 54, 71, 89, and 90. In the six patients in this group, there was also an identical mutation in the gag p7/p1 gag protease cleavage site. In three of the patients, this change was seen as early as 6 to 10 weeks after the start of therapy. In one patient, a second mutation occurred at the gag p1/p6 cleavage site, but it appeared 18 weeks after the time of appearance of the p7/p1 mutation. Recombinant HIV-1 variants containing two or three mutations in the protease gene were constructed either with mutations at the p7/p1 cleavage site or with wild-type (WT) gag sequences. When recombinant HIV-1-containing protease mutations at 46 and 82 was grown in MT2 cells, there was a 68% reduction in its rate of replication compared to the WT virus. Introduction of an additional mutation at the gag p7/p1 protease cleavage site compensated for the partially defective protease gene. Similarly, rates of replication of viruses with mutations M46L/I, I54V, and V82A in protease were enhanced both in the presence and in the absence of Indinavir when combined with mutations in the gag p7/p1 and the gag p1/p6 cleavage sites. Optimal rates of virus replication require protease cleavage of precursor polyproteins. A mutation in the cleavage site that enhanced the availability of a protein that was rate limiting for virus maturation would confer on that virus a significant growth advantage and may explain the uniform emergence of viruses with alterations at the p7/p1 cleavage site. This is the first report of the emergence of mutations in the gag p7/p1 protease cleavage sites in patients receiving protease therapy and identifies this change as an important determinant of HIV-1 resistance to protease inhibitors in patient populations. A novel intracellular calcium-binding protein from Echinococcus granulosus is described in this work. A cDNA was isolated from a lambdagt11 protoscolex expression library and the deduced amino acid sequence has at least fifteen sequentially repeated twelve-residue repeats that resemble the calcium-binding loop of EF-hands; however, the dodecamer motif has no flanking helices. The cDNA was expressed in Escherichia coli using the pGEX vector, and a recombinant fusion protein (EgCaBP1-GST) was obtained. The recombinant fusion protein binds calcium when assayed with 45Ca. It is possible that the calcium-binding motifs present a secondary structure similar to the parallel beta roll structure described for an alkaline protease from Pseudomonas aeruginosa. A native protein of more than 300 kDa was recognized by an anti-EgCaBP1 monoclonal antibody by Western-blot analysis. Immunohistochemistry using a pool of anti-EgCaBP1-GST mouse sera demonstrated a strong association of the protein with calcareous corpuscles. The possible role of this protein and that of the calcareous corpuscles in the protoscolex are discussed. The enzyme activity of mitogen-activated protein kinase (MAP kinase) increases in response to agents acting on a variety of cell surface receptors, including receptors linked to heterotrimeric G proteins. In this report, we demonstrated that Raf-1 protein kinase activity in the mouse parotid glands was induced by chronic isoproterenol administration in whole animals. To investigate the molecular nature underlying cellular responses to Raf-1 activation, we have stably transfected rat salivary epithelial Pa-4 cells with human Raf-1-estrogen receptor fusion gene (DeltaRaf-1:ER) and used mRNA differential display in search of messages induced by DeltaRaf-1:ER activation. Through this approach, the gene encoding non-histone chromosomal protein HMGI-C was identified as one of the target genes activated by oncogenic Raf-1 kinase. Activation of Raf-1 kinase resulted in a delayed and sustained increase of HMGI-C expression in the Pa-4 cells. The induction of HMGI-C mRNA level is sensitive to both the protein synthesis inhibitor cycloheximide and transcription inhibitor actinomycin D. The role of the extracellular signal-related kinase (ERK) signaling pathway in the HMGI-C induction was highlighted by the result that the MAP kinase kinase (MEK) inhibitor, PD 98059, blocked DeltaRaf-1:ER- and 12-O-tetradecanoylphorbol-13-acetate-stimulated HMGI-C induction. Altogether, these findings support the notion that the Raf/MEK/ERK signaling module, at least in part, regulates transcriptional activation of the chromosomal architectural protein HMGI-C. Pendred syndrome is a recessively inherited disorder with the hallmark features of congenital deafness and thyroid goitre. By some estimates, the disorder may account for upwards of 10% of hereditary deafness. Previous genetic linkage studies localized the gene to a broad interval on human chromosome 7q22-31.1. Using a positional cloning strategy, we have identified the gene (PDS) mutated in Pendred syndrome and found three apparently deleterious mutations, each segregating with the disease in the respective families in which they occur. PDS produces a transcript of approximately 5 kb that was found to be expressed at significant levels only in the thyroid. The predicted protein, pendrin, is closely related to a number of known sulphate transporters. These studies provide compelling evidence that defects in pendrin cause Pendred syndrome thereby launching a new area of investigation into thyroid physiology, the pathogenesis of congenital deafness and the role of altered sulphate transport in human disease. We report the cDNA cloning, partial genomic organization, and expression pattern of Stra10, a novel retinoic acid-inducible gene in P19 embryonal carcinoma cells. Four murine cDNA isoforms have been isolated, which are likely to result from alternative splicing. The predicted protein sequences exhibit approximately 85% identity with the Pbx-related Meis1 homeobox gene products, which are involved in myeloid leukemia in BXH-2 mice, and one of the Stra10 isoforms corresponds to the recently published Meis2 sequence (Nakamura et al. [1996] Oncogene 13:2235-2242). The Meis2 homeodomain is identical to that of Meis1, and is most closely related to those of the Pbx/TGIF homeobox gene products. By in situ hybridization analysis, we show that the Meis2 gene displays spatially restricted expression patterns in the developing nervous system, limbs, face, and in various viscera. In adult mice, Meis2 is mainly expressed in the brain and female genital tract, with a different distribution of the alternative splice forms in these organs. A methodical strategy for the isolation of microsatellite markers specific for targeted regions of bovine chromosomes is presented. The procedure involves directed microdissection of one defined subchromosomal area, its DOP-PCR-amplification and cloning. With this approach, a library specific to the BTA 6q21-31 chromosomal region was constructed. Eleven unique microsatellite-containing sequences were isolated, converted into sequence-tagged microsatellite sites, and characterized concerning their species-specific origin. Seven primer pairs generated bovine-specific PCR products and provided a set of microsatellite markers that generally revealed high informativity in the HF breed. Linkage analysis assigned six of them to their predefined subchromosomal origin on BTA 6 corresponding to the specific rehybridization signal of the DOP-PCR product generated from the microdissected chromosome area 6q21-31. The results underline the usefulness of the BTA 6q21-31 library for targeted isolation of unique sequences that are specific for the dissected chromosomal region as demonstrated here by the isolation of microsatellite markers. Phylogeographic structure was determined for the yellow mongoose, Cynictis penicillata, using mtDNA RFLPs and control region sequences. The RFLP analysis revealed 13 haplotypes which showed weak geographical patterning consistent with a recent range expansion from a refugial population(s). An analysis of molecular variance (AMOVA) revealed no correspondence between mtDNA phylogeography and subspecies delimitation, nor between matrilines and areas characterized by a high incidence of the viverrid-type rabies, of which the yellow mongoose is the principal vector. The lack of structure was also shown by control region sequences although four of the maternal lineages shared a near-perfect 81 bp repeat. We speculate that regional hot spots of the viverrid rabies biotype reflect population density differences in the yellow mongoose that are not underscored by genetic partitioning, at least at the level of resolution provided by our analyses. The indoor pollution, where the patients pass in general close to 90% of their time, is an important factor to take in consideration if one wants to evaluate suitably the effects of the air pollution on the health. Causes of this kind of pollution are partially linked to the external pollution and the outdoor environment and also are function of human activities and introduced products in the habitat (heating, tabagisme, handywork, products of maintenance, coatings, materials of construction, etc.). The effects on health are as various as the pollutants, going from sharp intoxication to irritations or simply desagreements. In this problem of public health we may not underestimated sensitive persons and risky group as well as long terme effects, and chronic exposition effects. The search of solutions needs multiple competences from the physician, who has to play an essential role. Dioxins are a family of chlorinated aromatic hydrocarbons that are produced during combustion processes in the presence of a chlorine donor and as by-products of the chlorine-processing chemical industries. Several dioxins are extremely stable compounds and persist for years in the environment. Exposure to dioxins occurs mainly via the ingestion of contaminated food. The lipophilic character of dioxins prevents their excretion in the urine and causes their accumulation in body fat. The mechanisms of dioxin action are similar to those of a hormone. Dioxins bind to a specific intracellular receptor and the complex acts as a transcription factor that induces the production of a great number of proteins. Certain dioxins, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin, are very toxic and able to induce numerous clinical conditions. The carcinogenicity of dioxins is well documented in animal models and has been described in humans after professional and accidental exposures. Recent experimental data also indicate that dioxins can cause dysfunction of the sexual and thyroid hormone systems and that the administration of dioxins induces several conditions related to hormonal dysfunction. Chronic exposure of female Rhesus monkeys increases the incidence and severity of endometriosis. The administration of dioxins during pregnancy and nursing causes altered development of the reproductive system, decreased spermatogenesis, hypothyroidism and disturbed psychomotor development in the offspring. The particular sensibility of the fetus and newborn is of concern because the exposition to dioxins is particularly important during those periods of life. In humans a series of conditions related to hormonal dysfunction as undescended testis, decreased spermatogenesis, testicular cancer and endometriosis have increased in incidence during the last decades. The chronological parallelism with the appearance of dioxins in the environment suggests that these might exert biological effects at the prevailing level of exposure. Nevertheless this hypothesis is currently unconfirmed by epidemiological studies. The implications of this scientific incertitude for the implementation of preventive measures are briefly discussed. This presentation summarizes the debate on the suggested progressive impairment of semen quality (the "sperm fall") in the last forty years in the developed countries. The various available data strongly suggesting an environmental toxic origin for the "sperm fall" will be presented as well as the most frequently suspected class of substances, the xenoestrogens. Diabetes mellitus is a still growing disease. New diagnostic criteria lowered the cut off value to 126 mg/dl, in order to detect more rapidly diabetes and its complications. The treatment of diabetes 2 by the classic oral antidiabetic drugs (sulfamides and biguanides) is completed by intestinal glycosidases inhibitors and thiazolidendiones. These last drugs seem very attractive because they decrease insulin resistance in obese, diabetics. Their hepatic side effects must be however under control. Better knowledge of non lipidic effects of statins on the arterial wall and the discovery of the action of fibrates on PPAR (Peroxisome Proliferator Activated Receptors) improved strongly the therapeutic management of hyperlipidemias. Recent intervention studies have demonstrated the necessity to treat vigorously dysipidemias. Despite Beta-blockade therapy has been considered as an absolute contraindication in the treatment of heart failure, it has been shown that they could have a beneficial effect, provided that they were introduced at very low dose, and very progressively in addition of the traditional treatment. The advances in the understanding of the neuro-hormonal mechanisms of heart failure have modified the therapeutic strategy: the deleterious effect of the activation of the sympathetic nervous system on the myocardium has served as the rationale for randomized clinical trials comparing beta-blockade to placebo: the current data are promising, suggesting a beneficial effect on survival as well as on quality of life. However, these results have to be confirmed by larger trials, currently underway, before to consider that beta-blockade should definitely be incorporated in the treatment of heart failure. Calcium antagonists have been used for treatment of cardiovascular diseases for more than 25 years. Several recent retrospective studies have suggested that chronic treatment with short-acting dihydropyridines increased the incidence of cardiac events, cancer and gastrointestinal bleedings. Randomized prospective studies have, however, never been able to confirm these observations. In addition, well-conducted studies using verapamil and diltiazem have suggested that these calcium antagonists may even improve cardiovascular mortality and morbidity of the hypertensive patient. There is therefore no reason to believe that the questionable results derived from retrospective studies of the effects of short-acting calcium antagonists on cardiac and noncardiac events may apply to the newer generation of long-acting calcium antagonists. Sumatriptan and other selective serotonin agonists represent a major breakthrough in acute migraine treatment. These drugs are very efficacious and generally devoided of important side effects, but they are expensive and therefore have to be compared with other, more conventional drugs with established or assumed efficacy. We summarize the pharmacologic characteristics of Sumatriptan and give recommendations about its use in clinical practice. Fiercer competition between athletes and a wider knowledge of optimal training regimens dramatically influence current training methods. A single training bout per day was previously considered sufficient, whereas today athletes regularly train twice a day or more. Consequently, the number of athletes who are overtraining and have insufficient rest is increasing. Positive overtraining can be regarded as a natural process when the end result is adaptation and improved performance: the supercompensation principle--which includes the breakdown process (training) followed by the recovery process (rest)--is well known in sports. However, negative overtraining, causing maladaptation and other negative consequences such as staleness, can occur. Physiological, psychological, biochemical and immunological symptoms must be considered, both independently and together, to fully understand the 'staleness' syndrome. However, psychological testing may reveal early-warning signs more readily than the various physiological or immunological markers. The time frame of training and recovery is also important since the consequences of negative overtraining comprise an overtraining-response continuum from short to long term effects. An athlete failing to recover within 72 hours has presumably negatively overtrained and is in an overreached state. For an elite athlete to refrain from training for > 72 hours is extremely undesirable, highlighting the importance of a carefully monitored recovery process. There are many methods used to measure the training process but few with which to match the recovery process against it. One such framework for this is referred to as the total quality recovery (TQR) process. By using a TQR scale, structured around the scale developed for ratings of perceived exertion (RPE), the recovery process can be monitored and matched against the breakdown (training) process (TQR versus RPE). The TQR scale emphasises both the athlete's perception of recovery and the importance of active measures to improve the recovery process. Furthermore, directing attention to psychophysiological cues serves the same purpose as in RPE, i.e. increasing self-awareness. This article reviews and conceptualises the whole overtraining process. In doing so, it (i) aims to differentiate between the types of stress affecting an athlete's performance: (ii) identifies factors influencing an athlete's ability to adapt to physical training: (iii) structures the recovery process. The TQR method to facilitate monitoring of the recovery process is then suggested and a conceptual model that incorporates all of the important parameters for performance gain (adaptation) and loss (maladaptation). Little attention has been directed toward identifying the changes which occur in salivary composition in response to exercise. To address this, our article first refers to the main aspects of salivary gland physiology. A knowledge of the neural control of salivary secretion is especially important for the understanding of the effects of exertion on salivary secretion. Both salivary output and composition depend on the activity of the autonomic nervous system and any modification of this activity can be observed indirectly by alternations in the salivary excretion. The effects of physical activity (with reference to factors such as exercise intensity and duration, or type of exercise protocol) on salivary composition are then considered. Exercise might indeed induce changes in several salivary components such as immunoglobulins, hormones, lactate, proteins and electrolytes. Saliva composition might therefore be used as an alternative noninvasive indicator of the response of the different body tissues and systems to physical exertion. In this respect, the response of salivary amylase and salivary electrolytes to incremental levels of exercise is of particular interest. Beyond a certain intensity of exercise, and coinciding with the accumulation of blood lactate (anaerobic threshold or AT), a 'saliva threshold' (Tsa) does indeed exist. Tsa is the point during exercise at which the levels of salivary alpha-amylase and electrolytes (especially Na+) also begin to rise above baseline levels. The occurrence of the 2 thresholds (AT and Tsa) might, in turn, be attributable to the same underlying mechanism, that of increased adrenal sympathetic activity at high exercise intensities. Fat is an extremely important substrate for muscle contraction, both at rest and during exercise. Triglycerides (TGs), stored in adipose tissue and within muscle fibres, are considered to be the main source of the free fatty acids (FFAs) oxidised during exercise. It is still unclear, however, how the use of these substrates is regulated during exercise. The regulation seems to be multifactorial and includes: (i) dietary and nutritional status; (ii) hormonal milieu; (iii) exercise mode, intensity and duration; and (iv) training status. On the other hand, the mechanism for FFA transport from its storage as triglycerides in adipose tissue and muscle to its place of utilisation in heart, skeletal muscle, kidney and liver is more clearly understood. It has been determined that the plasma FFA turnover rate is sufficiently rapid to account for most of the fat metabolised during low intensity exercise (25 to 40% VO2max). However, an exercise intensity of 65% VO2max results in a slight decrease in the amount of plasma FFA uptake by muscle tissue. Other studies have found that during prolonged exercise, muscle TGs become the predominant source of energy obtained from fat. Furthermore, it is widely documented that endurance activities increase the energy utilisation from fat while sparing carbohydrate sources. For example, during exercise on a cycle ergometer, nonplasma FFAs and plasma FFAs contribute 40%, and carbohydrates 60%, of the total calculated amount of energy expenditure before exercise and vice versa after exercise (60% nonplasma and plasma FFAs and 40% carbohydrates). Although it was many years before it was fully demonstrated, fat is now known to be transported in the blood as FFA bound to the protein carrier albumin. The mobilisation of FFA is primarily a function of sympathetic nervous activity directed towards the adipocytes, or the 'fat pad'. This nervous activity can be direct or may be an effect of circulating catecholamines such as adrenaline (epinephrine). This article summarises the role of fat metabolism during exercise. As the clinical availability of glycohaemoglobin/GHb measurement increases, so does the need for comparable and accurate values among different laboratories and different methods. At least there should be comparability, i.e., commutability or feasibility of providing comparable results from different assays in different laboratories. A clinical joint study on insulin therapy, a survey of the actual inter-laboratory differences in GHb measurement among 41 institutions and an assessment of 11 assay methods for the determination of GHb were performed using commercial calibrators and fresh blood samples. Data on the actual state of inter-laboratory and inter-assay differences of observed values were useful for comparing results among facilities. The recommendation of the Japan Diabetes Society to measure only the stable GHb component and to correct the GHb percentage by two-point calibration with assigned values, was effective but not sufficient. Even after correction, 8 out of 11 methods still remained of little practical use because of their large relative errors. Inter-method differences among 11 available assay methods were great even after correction and depended on not only the methods but the samples used for the determination. The performance of some methods or instruments used are only poor at distinguishing the stable glycated haemoglobin itself. Some alternative measurement system with comparability, commutability and precision should be established. An urgent and worldwide problem to remove inter-laboratory differences in the measurement of GHb needs to be solved. Users in clinical practice must recognize these problems, and, before supply, the providers should check their method and keep records that are readily traceable. A postal survey was performed to determine the current practices and attitudes of radiologists towards the imaging of suspected lower limb deep vein thrombosis (DVT). One hundred and twenty-seven departments responded to a questionnaire sent in March 1996. The results show that 87% of hospitals possess colour Doppler ultrasound (CDUS) machines and that 46% of departments perform ultrasound as the first line investigation in over 90% of cases. Thirty per cent of departments considered calf vein visualization to be generally adequate and 34% thought that clinicians in their hospitals invariably anticoagulated patients with isolated calf thrombus. In hospitals where venography was routinely used as the first line investigation, the most common reasons were: the perceived inferiority of ultrasound (US) in demonstrating below-knee clot, its time-consuming nature and the limited access to suitable ultrasound machines. The widespread use of ultrasound is encouraging, however, there are clearly diverse views. A significant minority of departments depend principally upon venography in the diagnosis of DVT.