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Examines the relationship among the expression of human sperm surface progesterone receptors, the ability to undergo a mannose-stimulated acrosome reaction and the rate of fertilization in vitro in a prospective blind study. Surface labelling of aliquots of motile spermatozoa with progesterone and/or mannose-fluoroceinated ligands.

Background: Response to antidepressants in major depressive disorder is variable and determinants are not well understood or used to design clinical trials. We aimed to understand these determinants., Methods: Supported by Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from industry sponsored randomized placebo-controlled trials of antidepressant drugs in adults with MDD. We examined patient and trial-design-related determinants of outcome as measured by change on Hamilton Depression Scale or Montgomery-Asberg Depression Rating Scale in 34 placebo-controlled trials (drug, n = 8260; placebo, n = 3957)., Results: While it is conventional for trials to be 6-8 weeks long, drug-placebo differences were nearly the same at week 4 as at week 6 and with lower dropout rates. At the multivariate level, having any of these attributes was significantly associated with greater drug vs. placebo differences on symptom improvement: female, increasing proportion of patients on placebo, centers located outside of North America, centers with low placebo response (regardless of active treatment response) and using randomized withdrawal designs., Limitations: Data on compounds that failed were not available to us. Findings may not be relevant for new mechanisms of action., Conclusions: Proof of concept trials can be shorter and efficiency improved by selecting enriched populations based on clinical and demographic variables, ensuring adequate balance of placebo patients, and carefully selecting and monitoring centers. In addition to improving drug discovery, patient exposure to placebo and experimental treatments can be reduced., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Several often-cited meta-analyses have reported that the efficacy of antidepressant medications depends on the severity of depression. They found that drug-placebo differences increased as a function of initial severity, which was attributed to decreased responsiveness to placebo among patients with severe depression rather than to increased responsiveness to medication. We retested this using patient-level data and also undertaking a meta-analysis of trial-level data from 34 randomised placebo controlled trials (n = 10 737) from the NEWMEDS registry. Although our trial-level data support prevous findings, patient-level data did not show any significant effect of initial depression severity on drug v. placebo difference., (© The Royal College of Psychiatrists 2016.)

Introduction: Gastrointestinal symptoms are common among patients with transthyretin familial amyloid polyneuropathy (TTR-FAP). This post hoc analysis evaluated the nutritional status of TTR-FAP patients treated with tafamidis while enrolled in clinical trials., Methods: Nutritional status was measured by the modified body mass index (mBMI = BMI × albumin level). Treatment-related changes in mBMI were reported for 71 Val30Met TTR-FAP patients who completed an 18-month, randomized, double-blind, placebo-controlled trial and who continued into its open-label, 12-month extension., Results: At month 18, mBMI worsened in the placebo group (n = 33) (-33 ± 16 kg/m(2) g/l, P = 0.04 versus baseline) but improved in the tafamidis group (n = 38) (+37 ± 14 kg/m(2) g/l, P = 0.01 versus baseline) such that the effect size between the groups was statistically significant (P = 0.001). By month 30 (completion of the open-label extension), placebo patients with 12 months of tafamidis treatment and tafamidis-treated patients with 30 months of treatment both tended to increase their mBMI (28 ± 19 kg/m(2) g/l and 16 ± 18 kg/m(2) g/l, respectively). Increase in BMI was most pronounced in patients with low BMI at entry into the studies., Conclusions: mBMI is well suited to monitor disease progression in TTR-FAP patients. The delay in neurological deterioration brought about by tafamidis treatment in clinical trials is associated with improvements in, or maintenance of, mBMI., Funding: This study was sponsored by Pfizer Inc., New York, USA.

Objective: Metabolic syndrome (MetS) is prevalent in subjects with schizophrenia-related psychotic disorders and contributes to increased rates of premature death due to cardiovascular disease. This study examined the impact of switching from another antipsychotic to ziprasidone on the distribution of the number of risk factors for MetS in subjects with schizophrenia or related psychotic disorders., Research Design and Methods: In this 1 year, open-label, prospective study, all subjects received ziprasidone 40-160 mg/day. Standard exclusion criteria included treatment resistance, physical health disorders, and substance abuse. The primary end point was the percentage of subjects achieving a reduction from baseline of at least one risk factor for MetS at end point (week 52 or premature discontinuation) in the per-protocol population (treated for at least 16 weeks). Secondary end points included the mean change from baseline in number of MetS risk factors, the prevalence of MetS, individual MetS risk factors (waist circumference, blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, and glucose), and 10 year coronary heart disease (Framingham score) risk., Clinical Trial Registration: www.clinicaltrials.gov: NCT00748566., Main Outcome Measures: Of 114 evaluable subjects, 58.77% demonstrated one less MetS risk factor at week 52 (last observation carried forward) compared with baseline. Secondary end points also improved, with reductions in other metabolic parameters (fasting low-density lipoprotein cholesterol, total cholesterol and serum insulin, weight, body mass index and glycosylated hemoglobin [HbA1c]). The 10 year coronary heart disease risk decreased continually over time. The open-label and uncontrolled design is a limitation of the study., Conclusions: Ziprasidone treatment reduced both the rate of MetS and its individual risk factors in subjects with schizophrenia and related psychotic disorders. The results have implications for the selection of first-line treatments in schizophrenia and related psychotic disorders, and provide treatment options for subjects who have developed MetS as a result of other antipsychotics.

Background: Response to antipsychotics in schizophrenia is highly variable, and determinants are not well understood or used to design clinical trials., Objective: We aimed to understand determinants of response to antipsychotic treatment., Method: Supported by the Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from randomized placebo-controlled trials of second-generation antipsychotics conducted in adult schizophrenia patients by 5 large pharmaceutical companies. The dataset included all placebo-controlled trials of risperidone, paliperidone, ziprasidone, sertindole, olanzapine, and quetiapine. We examined patient and trial-design-related determinants of outcome as measured by change on the Positive and Negative Syndrome Scale in 29 placebo-controlled trials (drug, n =6,971; placebo, n = 2,200) and initial findings confirmed in additional data from 5 separate trials (drug, n =1,699; placebo, n = 580)., Results: While it is conventional for trials to be 6 weeks long, drug-placebo differences were observable at week 4 with nearly the same sensitivity, and dropout rates were lower. Having any of these attributes was associated with significantly greater drug versus placebo differences in symptom improvement and rates of study completion: being female (P ≤ .04), being a young adult patient who is a few years beyond the first episode (P ≤ .03), having prominent positive and negative symptoms (P ≤ .03), and living in Eastern Europe versus North America (P ≤ .04). Contrary to prevalent clinical opinion, age at onset and use of benzodiazepines did not show a differential treatment response, and patients just above PANSS inclusion threshold were not overrepresented., Conclusions: Proof-of-concept trials can be shorter and efficiency improved by including an even distribution of sexes and of patients with prominent symptomatology, thus reducing patient exposure to placebo and experimental treatments., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Outcomes in RCT's of antipsychotic medications are often examined using last observation carried forward (LOCF) and mixed effect models (MMRM), these ignore meaning of non-completion and thus rely on questionable assumptions. We tested an approach that combines into a single statistic, the drug effect in those who complete trial and proportion of patients in each treatment group who complete trial. This approach offers a conceptually and clinically meaningful endpoint. Composite approach was compared to LOCF (ANCOVA) and MMRM in 59 industry sponsored RCT's. For within study comparisons we computed effect size (z-score) and p values for (a) rates of completion, (b) symptom change for complete cases, which were combined into composite statistic, and (c) symptom change for all cases using last observation forward (LOCF). In the 30 active comparator studies, composite approach detected larger differences in effect size than LOCF (ES=.05) and MMRM (ES=.076). In 10 of the 49 comparisons composite lead to significant differences (p ≤ .05) where LOCF and MMRM did not. In 3 comparisons LOCF was significant, in 2 MMRM lead to significant differences whereas composite did not. In placebo controlled trials, there was no meaningful difference in effect size between composite and LOCF and MMRM when comparing placebo to active treatment, however composite detected greater differences than other approaches when comparing between active treatments. Composite was more sensitive to effects of experimental treatment vs. active controls (but not placebo) than LOCF and MMRM thereby increasing study power while answering a more relevant question., (© 2013 Published by Elsevier B.V. and ECNP.)

Background: Negative symptoms are an important target for intervention in schizophrenia. There is lack of clarity in defining appropriate patients for negative symptom trials. While regulators, drug developers and academics have expressed positions in this regard, the implications of these definitions are not yet tested in large-scale trials and there is no consensus., Objectives: We examined the extent to which various operational criteria for inclusion in negative symptoms in schizophrenia clinical trials can impact patient selection and examined the effectiveness of second generation antipsychotics (SGAs) in patients with various degrees of negative symptoms., Method: Using anonymized patient data from AstraZeneca, Janssen Pharmaceuticals, Eli Lilly, Lundbeck, and Pfizer from 20 placebo-controlled trials of SGAs in schizophrenia from the NewMeds repository, we applied different criteria for negative symptoms: prominent, predominant, and EMA criteria, which require predominant and core negative symptoms to be present and examined the impact of these on inclusion and outcome., Results: Operational criteria for negative symptoms in trials vary greatly in their inclusion of patients from "typical" trial samples. Of the patients in our studies, 8.1% and 62.3% met criteria for prominent negative symptoms, 10.2% to 50.2% met criteria for predominant negative symptoms and 7.6% to 40.0% met EMA criteria at baseline. After 6weeks of active treatment, 8% and 33.1% of patients met criteria for prominent residual negative symptoms and 14.9% to 65% met criteria for prominent and 12.2% to 45.5% met EMA criteria. Patients with predominant or prominent negative symptoms showed marked improvement on second generation antipsychotics., Conclusions: Applying various operational criteria for selecting patients for negative symptoms trials provides a great variability in percentage of suitable patients calling into question the extent to which some definitions may be overly narrow., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background and Objective: A number of operational definitions have been proposed to describe outcomes in bipolar disorders; the criteria used to define terms such as recurrence, relapse, response, remission and recovery have varied both in observational studies and in clinical trials. We carried out a post hoc analysis of rates of symptomatic point remission and sustained remission using four different remission criteria that had been evaluated in a previously published 24-week, double-blind, placebo-controlled study., Methods: After stabilization for 8 consecutive weeks on open-label ziprasidone plus lithium or valproate, stabilized subjects were randomized to two groups, ziprasidone with lithium or valproate (ziprasidone group), or placebo with lithium or valproate (placebo group) for 16 weeks. Four remission criteria included (i) Mania Rating Scale (MRS) score ≤7, (ii) MRS ≤7 + Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤10, (iii) MRS ≤7 + Clinical Global Impression-Improvement (CGI-I) = 1, (iv) MRS score ≤7 + MADRS score ≤10 + CGI-I score = 1. We examined the percentages of subjects in each treatment group achieving symptomatic point (i.e. at each visit) and sustained (i.e. for ≥8 weeks) remission during the double-blind phase., Results: At week 24, symptomatic point remission based on the above two more stringent criteria was achieved by 48.0 and 24.4% of the ziprasidone group versus 36.9 and 18.0% of placebo recipients, respectively (p = 0.04 and 0.14). Sustained remission rates at 24 weeks were 42.5 and 18.1% for ziprasidone, respectively (vs 33.3 and 14.4% for placebo, p = 0.04 and 0.21, respectively)., Conclusion: This analysis indicates that ziprasidone plus lithium or valproate treatment showed modest to moderate remission rates at week 24 based on four different remission criteria in terms of symptomatic and sustained remission, despite the stringent criteria. Our findings indicate that ziprasidone may be effective in achieving sustained remission in bipolar I disorder and propose that a better understanding regarding the definition of remission in bipolar disorders should be required in clinical practice since our results showed different remission rates with different remission criteria.

Clinical trials today are conducted in multiple countries to enhance patient recruitment and improve efficiency of trials. However, the demographic and cultural diversity may contribute to variations in study outcomes. Here we conducted post-hoc analyses for a placebo-controlled study with ziprasidone and haloperidol for the treatment of acute mania to address the demographic, dosing, and outcome disparities in India, Russia and the USA. We compared the baseline characteristics, outcomes and discontinuations in patients and explored the relationship between the outcome measures across these countries. We found substantial differences in baseline characteristics of subjects, administered dosage and disease severity in India compared to the USA and Russia. Conversely, US subjects had a higher placebo response compared to subjects in Russia and India. These results are probably due to demographic differences in patient populations and psychiatric clinical practice across countries. While we offer initial ideas to address the disparities identified in this analysis, it is clear that further research to improve our understanding of geographical differences is essential to ensure globally applicable results for clinical trials in psychiatry.

Objective: To determine the degree to which a proxy measure of remission in schizophrenia correlates with the criteria identified by the Remission in Schizophrenia Working Group, and how well early treatment response to ziprasidone predicts remission., Methods: Data from 10 ziprasidone studies were analyzed to determine rates of remission achieved with ziprasidone using a remission definition of Clinical Global Impression of Improvement (CGI-I) of 1, and compared with rates of remission achieved using the remission working group criteria. Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) scores were then investigated as predictors of remission., Results: A CGI-I score of 1 correlated with the remission criteria developed by the remission working group. In the combined ziprasidone arms, BPRS scores at Weeks 1, 3, and 4 successfully predicted PANSS remission (p<0.01) and BPRS remission (p<0.0001) at study endpoint (44-196weeks). PANSS scores (at Weeks 1, 3, and 4) successfully predicted PANSS remission (p<0.01) at study endpoint. PANSS scores at Week 3 successfully predicted BPRS remission (p=0.02) at study endpoint. A CGI-I score of 1 or 2 at Week 1 also successfully predicted remission in schizophrenia., Conclusion: The findings show a correlation between clinical and research scales (remission working group criteria) for the assessment of remission in schizophrenia. This proxy measure for the assessment of remission should be easy to apply in a clinical setting and facilitates the prediction of remission in schizophrenia., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Dysphoric mania is a common and often difficult to treat subset of bipolar mania that is associated with significant depressive symptoms., Objective: This post hoc analysis was designed to evaluate the efficacy of ziprasidone in the treatment of depressive and other symptoms in a cohort of patients with dysphoric mania., Methods: Pooled data were examined from two similarly designed, 3-week placebo-controlled trials in acute bipolar mania. Patients scoring >/=2 on at least two items of the extracted Hamilton Rating Scale for Depression (HAM-D) met criteria for dysphoric mania and were included in the post hoc analysis. Changes from baseline in symptom scores were evaluated by a mixed-model analysis of covariance., Results: 179 patients with dysphoric mania were included in the post hoc analysis (ziprasidone, n=124; placebo, n=55). Beginning at day 4, HAM-D scores were significantly lower at all visits in patients treated with ziprasidone compared with those treated with placebo (p<0.05). Ziprasidone-treated patients also demonstrated significant improvements on the Mania Rating Scale and all secondary efficacy measures, and had significantly higher response and remission rates compared with placebo., Limitations: The main limitations are the use of a post hoc analysis and the pooling of two studies with slightly different designs., Conclusion: In this analysis, ziprasidone significantly improved both depressive and manic mood symptoms in patients with dysphoric mania, suggesting that it might be a useful treatment option in this patient population. Further prospective controlled trials are needed to confirm these findings., (Copyright 2009 Elsevier B.V. All rights reserved.)

The objective of this study was to assess the impact of high levels of insomnia on response to pregabalin (PGB) in patients with generalized anxiety disorder (GAD). Pooled data were analyzed from six double-blind, placebo-controlled, 4- to 6-week trials of outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (fourth edition) criteria for GAD with a minimum Hamilton Rating Scale for Anxiety (HAM-A) score = 18. Response was evaluated for three fixed-dose PGB groups (150, 300-450, 600 mg/day), and for a benzodiazepine group (alprazolam or lorazepam). A 'high-insomnia' subgroup was defined by a baseline HAM for Depression (HAM-D) insomnia factor score greater than 3 (maximum = 6). At baseline, 1002 (54%) patients met the criteria for the high-insomnia subgroup, and 852 (46%) for the low-insomnia subgroup. Mean baseline HAM-A scores were 1-2 points higher in high-insomnia versus low-insomnia patients. In high-insomnia patients, PGB produced significantly greater improvement in HAM-A total scores at last observation carried forward endpoint on 300-450 mg (-13.1+/-0.6) and 600 mg (-11.2+/-0.5) dose groups compared with placebo (-8.3+/-0.5; P<0.0001 for both comparisons); the improvement on PGB 150 mg was not significant (-9.9+/-0.7; P = 0.051). Improvement was significant in the benzodiazepine group (-11.0+/-0.6; P<0.0001). In the high-insomnia subgroup, treatment with PGB significantly (P<0.001) improved the HAM-D insomnia factor scores on both the 300-450 mg (-2.73) and 600 mg (-2.35) doses, and on benzodiazepines (-2.52) compared with placebo (-1.51); improvement on PGB 150 mg (-1.69) was not significant. Rates of treatment-emergent insomnia were lower on PGB compared with placebo in both the high- and low-insomnia subgroups. In conclusion, PGB was well tolerated, and improved overall anxiety symptoms, while specifically improving insomnia in patients with GAD presenting with high levels of concurrent insomnia.

The objective of the study was to evaluate the response of generalized anxiety disorder (GAD) patients with prominent gastrointestinal (GI) symptoms to pregabalin (PGB) treatment. Data were pooled from six double-blind, placebo (PBO)-controlled, 4-6 week trials in outpatients who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria for GAD with a minimum Hamilton Anxiety Rating Scale (HAM-A) total score of 20. Treatment response was evaluated for three PGB fixed-dosage groups: 150, 300-450, and 600 mg/day, and for fixed doses of a benzodiazepine (alprazolam, 1.5 mg/day; lorazepam, 6 mg/day). A GI-high subgroup (high GI symptomatology) was defined by a baseline HAM-A item-11 (GI) score of 3 or greater (severe/very severe). At baseline, 301 patients (16.2%) met criteria for the GI-high subgroup. Baseline characteristics were approximately similar for the four study treatments in the GI-high subgroup. For the GI-high subgroup, last observation carried forward (LOCF) endpoint reduction in HAM-A was significantly higher on PGB-300/450 -13.8+/-1.2 and PGB-600 -14.7+/-1.0 compared with PBO -10.1+/-0.9 (P<0.01 for both comparisons); but the difference on PGB-150 did not achieve significance (-13.5+/-1.6; P=0.083). Also in the GI-high subgroup, endpoint reduction in HAM-A item-11 was significantly higher on PGB-300/450 compared with PBO (-1.93+/-0.16 vs. -1.52+/-0.13; P=0.04), but did not achieve significance on PGB-600 mg (-1.89+/-0.14; P=0.06), or PGB-150 mg (-1.90+/-0.23; P=0.16). In the GI-high subgroup, treatment with a benzodiazepine was not associated with significant endpoint reduction in either the HAM-A total score or the HAM-A item-11 score. Patients in the GI-high subgroup had higher discontinuation rates when treated with benzodiazepines, whereas treatment with PGB 300-600 mg/day was not associated with treatment-emergent worsening in GI symptoms compared with placebo. Treatment with PGB improved overall levels of anxiety, as well as specifically improving GI symptoms.

The objective of this study was to evaluate the anxiolytic efficacy, and speed of onset of efficacy, of pregabalin (PGB) and venlafaxine-XR (VXR) in patients with generalized anxiety disorder (GAD). In this double-blind trial, outpatients, ages 18-65 years, who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for GAD were randomized to 8 weeks of flexible-dose treatment with PGB (300-600 mg/day), VXR (75-225 mg/day), or placebo (PBO). The intent-to-treat sample consisted of 121 patients on PGB [least square (LS) mean ± SE baseline Hamilton Anxiety Rating Scale (HAM-A), 27.6 ± 0.4], 125 patients on VXR (baseline HAM-A, 27.4 ± 0.4), and 128 patients on PBO (baseline HAM-A, 26.8 ± 0.4). Treatment with PGB was associated with a significantly greater LS mean change in the HAM-A total score at last observation carried forward endpoint versus PBO (-14.5 ± 0.9 vs. -11.7 ± 0.9; P = 0.028). Treatment with VXR was not significant versus PBO at endpoint (-12.0 ± 0.9; -11.7 ± 0.9; P =0.968). Treatment with PGB showed an early onset of improvement, with significantly greater LS mean change in the HAM-A by day 4 versus both PBO (-5.3 ± 0.5 vs. -3.4± 0.5; P = 0.008) and VXR (-2.9 ± 0.5; P = 0.0012). The proportion of patients reporting a severe adverse event was similar for PGB (9.1%) and PBO (7.8%), but higher for VXR (20.0%; P < 0.05). In conclusion, PGB was a safe and effective treatment of GAD, with a significantly earlier onset of anxiolytic activity than VXR.

Objective: This randomized, double-blind, multicentre extension study compared the efficacy, tolerability, and safety of ziprasidone and risperidone for schizophrenia or schizoaffective disorder., Methods: Patients who had responded to treatment for an acute exacerbation of illness in an 8-week study received ziprasidone, 80 to 160 mg/day (n = 62), or risperidone, 6 to 10 mg/day (n = 77), for up to 44 additional weeks. Primary efficacy variables included changes in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impression Severity (CGI-S) score. Tolerability and safety assessments included movement disorders, adverse events, study discontinuation rates, and weight and metabolic parameters., Results: Both the ziprasidone and risperidone groups showed statistical improvement from baseline in PANSS and CGI-S scores at study end point with no significant differences between treatment groups. More risperidone-treated patients completed the study (41.6%) than ziprasidone-treated patients (33.9%), but the difference was not statistically significant. Ziprasidone-treated patients who completed the study showed greater improvement in depressive symptoms assessed by Montgomery and Asberg Depression Rating Scale than risperidone-treated patients (P < 0.05). Ziprasidone was associated with a more favourable effect on extrapyramidal symptom (EPS) measures and prolactin as well as less weight gain than risperidone. Median dosages were ziprasidone 120 mg/day and risperidone 8 mg/day., Conclusions: Ziprasidone and risperidone demonstrated similar efficacy during long-term treatment of patients with schizophrenia or schizoaffective disorder. While more subjects on risperidone completed the extension study, ziprasidone was associated with fewer adverse effects on weight, EPS measures, and prolactin than risperidone.

Objective: The objective was to determine the effects of sequential intramuscular/oral ziprasi-done on hostility., Method: A total of 572 inpatients diagnosed with DSM-IV schizophrenia or schizoaffective disorder were the subjects in a randomized, rater-blinded, 6-week, open-label study comparing sequential intramuscular and oral ziprasidone with haloperidol. The Brief Psychiatric Rating Scale (BPRS) was the principal outcome measure. To determine the effect of ziprasidone on hostility, post hoc analyses of scores on the hostility item from the BPRS were conducted. Introducing positive symptoms and akathisia as covariates tested specific antihostility effect. The study was conducted from October 23, 1998, to August 15, 2000., Results: Ziprasidone demonstrated specific antihostility effects over time throughout the 42-day study period and statistically significant superiority to haloperidol on this measure in the first week of treatment (p = .0149 at first evaluation [day 1, 2, or 3]; p = .0358 at day 7)., Conclusion: Ziprasidone is an effective treatment for hostility in patients with schizophrenia or schizoaffective disorder.

Objective: To evaluate the efficacy and safety of high-dose sertraline for patients with obsessive-compulsive disorder (OCD) who failed to respond to standard sertraline acute treatment., Method: Sixty-six nonresponders to 16 weeks of sertraline treatment who met DSM-III-R criteria for current OCD were randomly assigned, in a double-blind continuation phase of a multicenter trial, either to continue on 200 mg/day of sertraline or to increase their dose to between 250 and 400 mg/day for 12 additional weeks. Efficacy measures included the Yale-Brown Obsessive Compulsive Scale (YBOCS), the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH Global OC Scale), and the Clinical Global Impressions-Severity of Illness and -Improvement (CGI-I) scales. Data were collected from July 26, 1994, to October 26, 1995., Results: The high-dose (250-400 mg/day, mean final dose = 357, SD = 60, N = 30) group showed significantly greater symptom improvement than the 200-mg/day group (N = 36) as measured by the YBOCS (p = .033), NIMH Global OC Scale (p = .003), and CGI-I (p = .011). Responder rates (decrease in YBOCS score of > or = 25% and a CGI-I rating < or = 3) were not significantly different for the 200-mg/day versus the high-dose sertraline group, either on completer analysis, 34% versus 52%, or on endpoint analysis, 33% versus 40%. Both treatments showed similar adverse event rates., Conclusion: Greater symptom improvement was seen in the high-dose sertraline group compared to the 200-mg/day dose group during continuation treatment. Both dosages yielded similar safety profiles. Administration of higher than labeled doses of selective serotonin reuptake inhibitors may be a treatment option for certain OCD patients who fail to respond to standard acute treatment.

Objectives: To report on the efficacy, safety, and tolerability of sertraline in the treatment of elderly depres-sed patients with and without comorbid medical illness., Setting: Multicenter., Design: Randomized, double-blind, placebo-controlled study., Participants: A total of 752 patients aged 60 and older with diagnosis of major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis., Measurements: Outcome measures included the 17-item Hamilton Depression Scale (HAMD); the Clinical Global Depression-Severity/Improvement (CGI-S/CGI-I); efficacy and safety/adverse event assessments; Quality of Life, Enjoyment, and Satisfaction Questionnaire; and the Medical Outcomes Study 36-Item Short-Form Health Status Survey., Results: In the overall sample, sertraline was superior to placebo on all three primary outcome measures, HAMD, and overall clinical severity and change (CGI-S/CGI-I). Furthermore, therapeutic response to sertraline was comparable in those with or without medical comorbidity, and there were no treatment-by-comorbidity group interactions. Sertraline was also associated with a faster time to response than placebo in the comorbid group (P<.006). Sertraline-treated patients in the comorbid group had similar adverse events and discontinuations when compared to those in the noncomorbid group., Conclusion: Sertraline was efficacious in reducing depressive symptomatology, regardless of the presence of comorbid medical illness. Sertraline was safe and well tolerated by patients with or without medical illness.

Objective: The purpose of this study was to explore the interactional effects of parental marital disruption and physical abuse on risk for adolescent psychopathology in a nonclinical sample with a randomly selected control group., Method: The sample was drawn from 99 community-based adolescents indicated as physically abused by Child Protective Services and 99 randomly selected controls. Nonabused adolescents whose parents were married, abused adolescents whose parents were married, nonabused adolescents with a parental marital disruption, and abused adolescents with a parental marital disruption were compared. Outcome was psychopathology as measured by psychiatric diagnosis based on a best-estimate procedure subsequent to semistructured diagnostic interviewing., Results: Interactional effects of marital disruption and abuse were found for risk for lifetime Attention Deficit Hyperactivity Disorder (ADHD), with parental marital disruption and having been physically abused combining to increase the risk 15 times for diagnosis of lifetime ADHD. Parental marital status alone was not a significant risk factor for adolescent psychopathology, but physical abuse was a significant risk factor for several diagnostic categories., Conclusions: Future divorce research should include abuse history as a possible confounding variable. Possible reasons for the findings are reviewed and clinical implications are discussed.

Objective: To describe differences between adolescents and adults in clinical presentation of eating disorders., Methods: Data from the charts of 622 female patients treated for an eating disorder in a division of adolescent medicine between 1980 and 1994 were coded and computerized. General categories included demographic and family factors, weight loss and weight changes, eating-related behaviors, diagnosis and severity, and treatment issues. Differences between the 438 patients who were aged 9-19 years (adolescents) and 184 patients who were aged 20-46 years (adults) were analyzed., Results: Adolescents were more likely than adults (p <.05) to have a diagnosis of "eating disorder not otherwise specified," lower global severity score, greater denial and less desire for help, weight loss > or = 3 lb/month, lower original and maximum weights, and history of fasting and elimination of junk food from their diets. Adults were more likely than adolescents (p <.05) to have >1 year of weight loss, greater total weight loss, history of binge eating and laxative use, history of diuretic and ipecac use, diagnosis of bulimia nervosa, and prior use of psychiatric medications. Adolescents and adults did not differ (p >.05) in parents' occupational level; height, weight, and percent ideal body weight at presentation; original percent ideal body weight; use of diet pills, elimination of meat and use of a low-fat diet; daily calorie intake; prior eating disorder hospitalizations; and hospitalization during the course of treatment., Conclusions: The findings in this study document and confirm that there are important differences between adolescents and adults that must be taken into account in the evaluation and treatment of patients with eating disorders.

Preliminary psychometric properties of a new instrument, Angie/Andy Cartoon Trauma Scales (ACTS), are presented. Angie/Andy features a cartoon-based methodology, measuring trauma-related sequelae of prolonged, repeated abuse. A sample of 208 children comprised intrafamilial trauma, extrafamilial trauma, combined trauma, and nontrauma groups. Angie/Andy demonstrated high internal consistency, with coefficient alphas from 0.70 to 0.95. The three trauma groups scored significantly higher than the nontrauma group on all scales (p's < 0.0001). Generally, the most severely traumatized group scored significantly higher than the less severely traumatized groups. The number of types of violence exposures correlated with Angie/Andy scores from 0.55 to 0.74. The frequency and severity of trauma exposure correlated with Angie/Andy scores from 0.44 to 0.56. The Angie/Andy parent version correlated with a standardized parent scale from 0.71 to 0.81. Parent/child agreement was significant. Angie/Andy is a promising tool for clinical assessment of chronic childhood abuse.

The relationship between abuse and psychiatric diagnoses was investigated in two groups of physically abused adolescents, 57 living in homes with interparental violence and 32 in homes without such violence, and in 96 nonabused adolescents living in nonviolent homes. Adolescents in the first group were found to be at greater risk for depression, separation anxiety disorder, post-traumatic stress disorder, and oppositional defiant disorder than were those in the second group. Adolescents in the first group also appeared more vulnerable to anxiety and depression.

Remarkably few reported studies tested the assumption that a research sample can be constructed which is representative of the population of interest. In order to investigate potential volunteer bias in abuse research, we utilized a database assembled for an NIMH funded study investigating the relationship among adolescent physical abuse, suicidal behavior, and psychopathology. Extensive information was available concerning the nonparticipant pool from which this sample was assembled, allowing for a comprehensive assessment of possible sample bias. The volunteer sample of 99 abused families who agreed to participate in our study was compared on a large number of variables with a random sample of 99 abused families who declined to participate. Comparisons of the two groups did not support the hypothesis that the non-participating families represented a more dysfunctional population. The two groups were far more similar to, than disparate from, each other.

This study investigated the relationship between the perception of family functioning and depressive symptomatology in individuals with eating disorders (EDs). Subjects were evaluated by diagnostic clinical interview using DSM-III-R criteria for EDs, the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L), and two self-report measures, the Beck Depression Inventory (BDI) and the Family Assessment Device (FAD). A significant association was found between self-reported depressive symptomatology and perceived poor family functioning. Subjects with bulimia nervosa (BN) reported a significantly more dysfunctional family background than subjects with anorexia nervosa (AN). In our sample, the presence of self-reported depressive symptomatology was a more powerful predictive variable for perceived family dysfunction than the diagnosis of affective disorder. Also, the diagnosis of BN was a more consistent predictor of dysfunctional family interaction than the diagnosis of affective disorder. Depressive symptoms and EDs seem to play different roles in the way in which they contribute to dysfunctional family patterns.

Objective: To assess whether mannose receptor assays can predict fertilization outcome in vitro., Design: A prospective, double-blind study of the mannose receptor properties of spermatozoa., Setting: Assisted human reproduction program at a university hospital., Patient(s): Partners of 140 consecutive women undergoing their first in vitro fertilization cycle., Intervention(s): Motile sperm populations were tested for surface receptors for mannose by measuring their ability to bind fluorescein-labeled mannosylated albumin and to undergo a free mannose-induced acrosome reaction as judged by Pisum, sativum agglutinin binding., Main Outcome Measure(s): Mannose receptor assay results were correlated with fertilization outcomes using several statistical tests, including the chi2 test, chi2 for proportions, t-tests, analysis of variance with Student-Newman-Keuls tests and correlational and receiver operating characteristic (ROC) curve analysis., Result(s): The fractional increment increase on incubation in the percent of sperm binding mannose ligand over an intact acrosome correlated with fertilization rates in vitro. Threshold values of mannose ligand binding and of mannose-induced acrosome reactions predictive of fertilization rates were identified by ROC curve analysis. Men were thus classified into one of four groups with differing fertilization rates in vitro., Conclusion(s): The increment increase in sperm surface mannose ligand binding by acrosome-intact sperm correctly predicts high and low fertilization rates in vitro and identifies cases where conventional insemination can result in failed fertilization.

Objective: The present study examined whether physical abuse functions as an additional risk factor for adolescent psychopathology after other important known risk factors are controlled for., Method: The authors recruited 99 adolescents aged 12 to 18 years directly from the New York State Department of Social Services after official documentation of physical abuse. The abused adolescents were compared to 99 nonabused adolescents matched for age, gender, race, and community income. Diagnostic interviews and measures of selected risk factors for psychopathology were administered to the adolescents and their parents and then entered into a multiple logistic regression model testing the added risk contributed by physical abuse to adolescent psychopathology., Results: Physical abuse added significantly to other risk factors in accounting for lifetime diagnoses of major depression, dysthymia, conduct disorder, drug abuse, and cigarette smoking. Physical abuse also contributed significantly to prediction of current adolescent unipolar depressive disorders, disruptive disorders, and cigarette smoking., Conclusions: Since physically abused adolescents are at greater risk for the development of psychiatric disorders, recognition of adolescent abuse and the provision of psychiatric and substance abuse services may reduce morbidity.

Until recently, Thalassemia Major was considered a fatal disease and patients did not usually live into adulthood. Advances in the medical management of the disease have greatly increased the life expectancy of these patients. The present study aims to evaluate the future orientation and other aspects of psychosocial functioning of thalassemics compared to healthy controls. Thirty patients and 33 healthy subjects of similar age, ethnicity, education, and geographic area were compared on measures of future expectations, perceived social support, life orientation, health locus of control and hopelessness. Results show no significant differences between thalassemics and controls on all measures except for higher levels of internal health locus of control among the patient group. Results and implications of perceptions of thalassemics' future orientation relevant to patient care are discussed.

Background: The goal of the study was to measure the blood flow parameters of the fetal internal jugular vein during the second half of normal pregnancy using Doppler ultrasound., Methods: Jugular blood flow was analyzed in 95 normal singleton fetuses between 20 and 42 weeks gestation. Color and pulsed Doppler ultrasound was used to obtain jugular venous waveforms at the level of the mid-neck. Peak velocities, ratios of velocities, and time-averaged maximum velocities were measured., Results: Jugular venous waveforms in healthy fetuses consist of three phases--the first forward peak occurs during ventricle systole; the second forward peak occurs during early diastole and the third peak occurs during atrial contraction. Forty-eight percent of the fetuses demonstrated absent flow during atrial contraction; 32% of fetuses demonstrated forward flow during atrial contraction and finally 20% of fetuses demonstrated flow reversal during atrial contraction., Conclusions: The reported jugular venous profile may serve as a foundation for future studies of jugular blood flow in high risk fetuses.

Objectives: To assess the percentage of adult patients presenting to an urban ED who have a written advance directive (AD) and to determine whether age, sex, a patient's perception of his or her health status, and having a regular physician are associated with the patient's having an AD., Methods: This was a cross-sectional patient survey performed at a community teaching hospital ED. Surveys were completed by 511 adult ED patients during representative shifts over a 3-month period. The questions included age, sex, "self-reported" health status, whether the patient had a "regular" physician, a patient-generated list of medical problems, and whether the patient had a written AD. For this study, ADs included health care proxies, living wills, and do-not-attempt-resuscitation (DNAR) orders., Results: Of the patients surveyed, 27% reported having an AD. Males and females were equally likely to have an AD. Factors associated with an increased likelihood of having an AD were older age, having a "regular" physician, and the patient's perception of his or her health status as ill. Most patients who had an AD (82%) discussed it with their families, but only 48% discussed it with their physicians., Conclusion: Only 27% of the adult patients presenting to the ED had an AD. Older age, the patient's perception of his or her health status as ill, and having a "regular" physician increased the likelihood of having an AD.

In the interest of classifying cases of male factor infertility, we have paid particular attention to the sugar ligand binding properties of the human sperm surface and the functional capacity of the acrosome for exocytosis--key parameters for assessing sperm fertilizing ability. Zona recognition and binding involve the interactions of sperm surface mannose receptors (lectins) with mannose ligands on the zona pellucida. Sperm surface mannose lectins can be visualized by their ability to bind a synthetic model zona ligand, fluorescein isothiocyanate (FITC)-conjugated mannosylated bovine serum albumin (BSA) (Man-FITC-BSA). We now report that Man-FITC-BSA biologically also mimics the effects of solubilized authentic human zonae, in that binding of Man-FITC-BSA results in a time-dependent receptor aggregation and the induction of acrosome exocytosis in capacitated sperm populations from fertile donors. In our assay, the addition of mM amounts of mannose monosaccharide to Man-FITC-BSA increases the number of polyvalent mannose ligands bound by individual spermatozoa and increases the rate of the acrosome reactions induced by Man-FITC-BSA, thereby increasing specimen processing efficiency. We conclude that exposure of human spermatozoa to polyvalent mannose ligands + D-mannose monosaccharide offers a new, convenient and readily available system to study sperm capacity for induced acrosome loss.

A predictive test for determining whether motile populations of human spermatozoa will fertilize eggs in vitro has been an elusive goal of clinical research. We have developed an assay for the ability of motile human spermatozoa to bind fluorescein isothiocyanate-labelled mannosylated bovine serum albumin (Man-FITC-BSA) as a test for the presence of sperm surface receptors (lectins) for mannose ligands. Mannosylated ligands are present on the human zona pellucida and are involved in the species-specific binding of human spermatozoa to the zona pellucida. We now demonstrate in prospective blinded analysis that the fractional increase in acrosome loss following a mannose ligand challenge is highly correlated with the rate of fertilization in vitro. Using an incremental increase of acrosome exocytosis of >0.1 as a threshold to predict which specimens will yield normal fertilization, the assay has a sensitivity of 97.8%, a specificity of 83.3%, a positive predictive value of 95.7% and a negative predictive value of 90.7%. These data indicate that testing for a mannose-induced acrosome reaction may be useful in assessment of sperm function prior to in-vitro fertilization in order to assign males to conventional insemination or intracytoplasmic sperm injection protocols.

Two hundred thirty four participants in the DSM-IV Posttraumatic Stress Disorder (PTSD) Field Trial who reported sexual and/or physical abuse were evaluated. Participants were categorized according to type of abuse (physical, sexual, both), duration of abuse (acute versus chronic), and onset of abuse (early versus late). Separate logistic regression analyses examined the relationship between age of onset, duration, abuse type, and the complex PTSD (CP) lifetime diagnosis for women and men. Sexually abused women, especially those who also experienced physical abuse, had a higher risk of developing CP, although CP symptoms occurred at a high base rate among physically abused women. The theoretical implications and incremental clinical usefulness of targeting CP symptoms with abused populations are discussed.

Problem: To determine whether the results of the Acrobeads test, which measures the expression of the complement regulator molecule CD46 on the inner acrosomal membrane following the acrosome reaction, accurately identifies semen specimens that will exhibit reduced or failed fertilization following conventional IVF insemination., Method: The Acrobeads test was performed on semen specimens from 97 consecutive patients preparing to undergo an IVF cycle utilizing a standardized insemination protocol. Motile sperm populations were examined at 6 h and 24 h post-isolation for sperm-bead agglutination. Results of the Acrobeads test were compared to that of TRITC-PSA staining in matched specimens to directly measure the spontaneous loss of acrosome content. The percentages of TRITC-PSA-negative sperm were determined in freshly isolated motile populations and in duplicate aliquots incubated 18 to 20 h under sperm capacitating conditions. The relationship between the results of both analyses estimating spontaneous acrosome reactions and the rate of fertilization of metaphase II oocytes was examined., Results: The Acrobeads score did not correlate significantly with the rate of fertilization by insemination at 6 h or at 24 h. The negative predictive value of this test was 21.4%. There was no correlation between the Acrobeads score and the percentage of sperm undergoing a spontaneous acrosome reaction as detected by TRITC-PSA labeling. In contrast, the increment increase in the percentage of spontaneous acrosome reactions as quantified by TRITC-PSA staining was correlated with the fertilization rate., Conclusions: Contrary to previous reports, our prospective, double-blinded study failed to demonstrate that the Acrobeads test can accurately predict fertilization outcome in IVF. Therefore, the routine use of this test to screen patients prior to an IVF cycle in order to select appropriate treatment (i.e., ICSI) cannot be recommended.

Therapeutic administration of calcium channel-blocking medications has been correlated with reduced mannose receptor expression and iatrogenic human male infertility. In this report, we investigate whether the pharmacological activity of dihydropyridines, which block calcium influx through voltage-dependent calcium channels, contributes to the production of an infertile state. An influx of extracellular calcium is an absolute requirement for the initiation of a progesterone-stimulated acrosome reaction by human spermatozoa. To determine whether dihydropyridines could inhibit progesterone-induced acrosome loss, we have studied a protein expressed in rat and human spermatozoa which is related both antigenically and by cDNA sequence to the alpha 1 subunit of the rat cardiac muscle voltage-dependent calcium channel, which forms the pore of the channel. Using reverse transcription-polymerase chain reaction, we have isolated a 2169 base clone from rat testis mRNA whose sequence was largely identical to that of the alpha 1 subunit of the rat cardiac muscle calcium channel, but had an 84 base change, attributable to splicing and alternate exon usage. This change inserts a peptide cassette encoding an amphipathic membrane-spanning helix that constitutes part of the ionic pore of the skeletal muscle calcium channel regulating the kinetics of activation of the calcium channel and may serve as an intramembrane dihydropyridine binding site. In parallel, human spermatozoa from fertile donors were exposed to nifedipine in vitro. Nifedipine inhibited progesterone-stimulated calcium influx and subsequent acrosome reactions in human spermatozoa at concentrations effective in excitable cells, but required a prolonged time to do so. In contrast, progesterone ligand binding was unaffected by nifedipine treatment. These data demonstrate that human spermatozoa express an L-type calcium channel which is responsive to nifedipine. Assuming sperm calcium transport pathways are highly conserved, the slow kinetics by which the blockade of the human sperm channel was obtained can be correlated with alterations in channel activation and conductance associated with isoform diversity generated by alternate splicing as observed in the rat. These data provide unequivocal evidence for the presence of functional L-type voltage-dependent calcium channels in rat and human spermatozoa. The data also define an altered binding site for calcium entry antagonists in this channel and offer a unique target for the design of new male contraceptive agents.

Background: Hospitalization for respiratory syncytial virus (RSV) bronchiolitis is considered a risk factor for reactive airway disease and/or abnormal pulmonary function tests (PFTs) later in childhood. This study attempted to assess this observation with newer PFTs and to determine whether ribavirin therapy of initial RSV infection may affect the long term outcome., Methods: Medical records of all infants hospitalized with RSV infection in 1986 and 1987 at six institutions (North Shore University Hospital, Children's Hospital of Buffalo, University Florida-Gainesville, University of Connecticut, Children's Hospital National Medical Center, Denver Children's Hospital) were requested. Patients who could be contacted were recalled in 1993 and 1994 for PFTs and given a pulmonary status questionnaire., Results: One hundred patients were evaluated. Overall PFTs were within normal ranges. There was less "bronchitis" over the interval years in the ribavirin-treated patients (13 of 33) vs. those who did not receive ribavirin (44 of 67, P < 0.01). There was no difference for the diagnosis of reactive airway disease (15 of 33 ribavirin vs. 36 of 67 no ribavirin). Patients who received ribavirin were then matched by age (within 2 weeks) at initial RSV infection and underlying risk factor (bronchopulmonary dysplasia, heart disease). Of the 27 patients matched, the ribavirin patients had longer intensive care unit stays (median (25 to 75% interquartile range): 2 (0 to 7) vs. 0 (0 to 0), P < 0.05). On follow-up evaluation there were no significant differences in PFTs or reactive airway disease between the 2 groups. There was a trend toward lower forced expiratory volume at 1 s and midexpiratory flow rate (25 to 75%) in the ribavirin-treated group, and there were more reported pneumonias on follow-up in the ribavirin patients., Conclusion: During our 5- to 6- year follow-up of children, status post bronchiolitis, we noted a good long term prognosis. No long term adverse effects on pulmonary function were detected. Despite being potentially sicker at presentation as assessed by intensive care unit stay, ribavirin recipients were doing equally well at the time of follow-up.

Objective: To determine whether mannose ligand receptor and acrosome reaction deficits in sperm from men with varicocele are related to the transition metal content of their semen., Design: Cadmium and zinc in semen and blood plasma were assayed for fertile males, men without varicocele who required intracytoplasmic sperm injection to achieve fertilization, and men evaluated for potential varicocele-associated infertility. The relationship between actin cytoskeletal distributions and acrosome status was determined for fertile donor sperm in the presence and absence of exogenous cadmium., Setting: University hospital-based molecular biology research laboratory., Patient(s): Patients from two university hospital-based IVF-assisted reproductive technology programs and two male urology private practices., Intervention(s): Fertile donor sperm were exposed to exogenous cadmium during capacitating incubations followed by culture at temperatures up to 41 degrees C., Main Outcome Measure(s): Metal ion levels in semen and blood plasma were determined by graphite furnace atomic absorption spectroscopy. Motile sperm were examined for mannose ligand binding and the ability to undergo spontaneous and induced acrosome reactions. Unfixed, Triton-permeabilized sperm were probed with antiactin and antimyosin antibodies., Result(s): Cadmium was elevated and zinc was decreased in the seminal plasma of men with varicocele. The content of these metals in semen and blood was not correlated. Cadmium exposure in vitro reduced mannose receptor expression, acrosome exocytosis, and cytoskeletal formation by fertile donor sperm., Conclusion(s): Defects in transition metal regulation or excessive cadmium exposure are involved in varicocele-associated infertility.

Some cases of familial amyotrophic lateral sclerosis (FALS) are associated with copper/zinc superoxide dismutase (Cu/Zn-SOD) mutations, which are implicated in the death of motor neurons. Because Cu/Zn-SOD is present in high amounts in nigrostriatal dopaminergic neurons, we considered the possibility that FALS may be associated with subclinical nigrostriatal dopaminergic dysfunction. We used [18F]fluorodopa (FDOPA) and PET to study 14 FALS patients (50 +/- 11 years [mean +/- SD]): seven with (FALS-1) and seven without (FALS-0) Cu/Zn-SOD mutations. Fourteen age-matched normal volunteers (48 +/- 18 years) served as controls. Striato-occipital ratios (SORs) for the caudate and the putamen were calculated. Five of the 14 FALS patients had reduced striatal FDOPA uptake in the caudate nucleus, putamen, or both. Mean caudate SOR did not differ among FALS-1, FALS-0, and control subjects. Mean putamen SOR was significantly abnormal in FALS-0 but not in FALS-1 patients. These findings indicate that subclinical nigrostriatal dopaminergic dysfunction is present in some FALS patients and that FDOPA/PET abnormalities are more likely to be associated with FALS-0 status. This suggests that SOD mutations are less cytotoxic to dopaminergic than to motor neurons.

Objectives: To assess the reliability of faculty evaluations of non-emergency medicine (non-EM) residents during clinical ED rotations and to determine the effect that the "leniency" of grading by these evaluators had on the residents' final evaluations., Methods: A prospective, observational study of the evaluation patterns of EM faculty was performed in an academic ED (50,000 visits yearly census). Each resident was evaluated on a daily basis by a board-certified or board-prepared emergency physician. The evaluation form rated 7 characteristics, but only the rating for overall clinical competence was used for data analysis. If an attending evaluated the same resident more than once, only the first evaluation was used to avoid bias from prior exposure. The scoring patterns of the evaluators, both individually and in groups, were analyzed using 1-way analysis of variance. Evaluator leniency was estimated using the mean evaluator score across all residents. Since each resident was evaluated by a different combination of evaluators, evaluator leniency for each resident was estimated from the mean leniency of the evaluators who specifically assessed that resident., Results: During the period of the study, 66 residents rotated through the ED, yielding a total of 401 evaluations. When the scoring patterns of individual evaluators were analyzed, a high degree of variability was found in the mean scores (range 5.23-8.09) and SDs (range 0.45-1.55) across evaluators; p = 0.0001. There was a moderate correlation between the mean overall competence score received by each resident and that resident's evaluators' leniency, r = 0.52; p = 0.0001., Conclusions: There is significant variability in the scoring patterns of individual evaluators. The evaluators in this study showed large variations in both leniency (as measured by their mean score) and range restriction (as measured by their SD). The differences in evaluator scoring leniency have a moderate correlation with the overall score received by the resident.

Objectives: (a) To examine the frequency, type, and severity of complications occurring in a pediatric intensive care unit; (b) to identify populations at risk; and (c) to study the impact of complications on morbidity and mortality., Design: Prospective survey., Setting: Pediatric intensive care unit (PICU) of a university-affiliated hospital., Patients: 1035 consecutive admissions over an 18-month period., Results: 115 complications occurred during 83 (8.0%) admissions, for 2.7 complications per 100 PICU-days; 48 (42%) complications were major, 45 (39%) moderate, and 22 (19%) minor. Sixty complications (52%) were ventilator-related, 14 were drug-related, 13 procedure-related, 24 infectious, and 22 involved invasive devices (18 vascular catheters). Human error was involved in 41 (36%) cases, 21 of which were major (18%). Treatments included reintubation < 24 h (28), intravenous antimicrobials (24), and invasive bedside procedures (14). Cardiopulmonary resuscitation was required in 6 patients. Thirteen patients with complications died (15.7%); 2 deaths were directly due to complications. Patients with complications were younger, had longer lengths of stay, and had a higher mortality. Length of stay was a positive risk factor for complication risk (odds ratio = 1.09, 95% confidence interval: 1.05 to 1.13; p = 0.0001); other patient characteristics had no predictive effect. Kaplan-Meier estimates showed that the most severe complications occurred early in the PICU stay. The best indicators of patient mortality were number of complications (odds ratio = 2.96, 95% confidence interval 1.72 to 5.08; p = 0.0001), and mortality risk derived from the Pediatric Risk of Mortality Score (odds ratio = 1.08, 95% confidence interval 1.06 to 1.10; p = 0.0001). Mortality was correlated with increasing severity of complications., Conclusion: Complications have a significant impact on patient care. Patients may be at increased risk earlier in their PICU course, when the number of interventions may be greatest. Complications may increase patient mortality and predict patient death better than other patient variables.

Polyvalent mannose ligands in the presence of free mannose act as zona pellucida agonists which rapidly induce acrosome exocytosis in competent motile human sperm from fertile donors following in-vitro capacitation. Quantification of the binding patterns of fluorescein isothiocyanate-labelled mannosylated albumins and of specific antisera which recognize mannose receptors and other related integral sperm membrane proteins as well as the incidence of induced acrosome exocytosis after capacitation has allowed us to identify three categories of male infertility. Category 1 males have normozoospermic semen parameters, their spermatozoa have elevated sperm cholesterol values and fail to fertilize oocytes in vitro after standard short-term incubations. These spermatozoa do not bind mannose ligands and do not show spontaneous or induced acrosome reactions, but treatments to remove cholesterol from the spermatozoa (e.g. prolonged incubation in the presence of sterol acceptors) confer the ability to fertilize. Cholesterol loading and unloading experiments have demonstrated the reversible character of sperm membrane properties in category 1 male infertility. Category 2 males have normal-appearing spermatozoa in semen which express mannose ligand receptors on incubation, but fail to undergo acrosome reactions in response to mannose treatment. Interestingly, all category 2 males identified in this study have clinical varicocele. Category 3 males have semen which may be normozoospermic or teratozoospermic with, in some cases, high percentages of tapering spermatozoa in the absence of clinical varicocele. Spermatozoa from category 3 men are deficient in a superfamily of integral membrane proteins whose cytoplasmic tails have myosin motors as identified by amino acid sequence analysis and anti-myosin antibody reactivity. Their spermatozoa do not express mannose ligand receptors or undergo induced acrosome reactions. Fertilization with category 2 and 3 semen is only achieved by micromanipulation procedures. These findings illustrate the practical application of basic research for infertility classification.

Objective: A century of clinical research has noted a range of trauma-related psychological problems that are not captured in the DSM-IV framework of posttraumatic stress disorder (PTSD). This study investigated the relationships between exposure to extreme stress, the emergence of PTSD, and symptoms traditionally associated with "hysteria," which can be understood as problems with stimulus discrimination, self-regulation, and cognitive integration of experience., Method: The DSM-IV field trial for PTSD studied 395 traumatized treatment-seeking subjects and 125 non-treatment-seeking subjects who had also been exposed to traumatic experiences. Data on age at onset, the nature of the trauma, PTSD, dissociation, somatization, and affect dysregulation were collected., Results: PTSD, dissociation, somatization, and affect dysregulation were highly interrelated. The subjects meeting the criteria for lifetime (but not current) PTSD scored significantly lower on these disorders than those with current PTSD, but significantly higher than those who never had PTSD. Subjects who developed PTSD after interpersonal trauma as adults had significantly fewer symptoms than those with childhood trauma, but significantly more than victims of disasters., Conclusions: PTSD, dissociation, somatization, and affect dysregulation represent a spectrum of adaptations to trauma. They often occur together, but traumatized individuals may suffer from various combinations of symptoms over time. In treating these patients, it is critical to attend to the relative contributions of loss of stimulus discrimination, self-regulation, and cognitive integration of experience to overall impairment and provide systematic treatment that addresses both unbidden intrusive recollections and these other symptoms associated with having been overwhelmed by exposure to traumatic experiences.

Background: The purpose of this study was to design and implement a comprehensive infection control program and measure its effects on the number and types of infectious illnesses experienced by children attending a specialized preschool program., Methods: Participants in the study were children with Down syndrome enrolled in a school-based early intervention program. The ages of the children ranged from 6 weeks to 5 years. Through a series of parental questionnaires, the number and types of infections in the children were chronicled for a year before and a year after the implementation of an infection control intervention program. Interventions included infection control lectures, handouts, posters, and attention to environmental cleaning and disinfection, with an emphasis on toys. Compliance with these measures was monitored and recorded., Results: During the interventional year the median number of total illnesses/child/month decreased significantly from the baseline year (0.70 vs 0.53, p < 0.05), with a trend toward a decrease in the number of respiratory illnesses (0.67 vs 0.42, p < 0.07). Significant decreases were also seen for the median number of physician visits (0.50 vs 0.33, p < 0.05), courses of antibiotics administered (0.33 vs 0.28, p < 0.05), and days of school missed as a result of respiratory illness (0.75 vs 0.40, p < 0.05)., Conclusions: This study demonstrates a decrease in infection rates with the implementation of a comprehensive educational and environmental infection control program in a day care setting.

Problem: To determine whether surface expression of receptors for progesterone and mannose can be used to identify spermatozoa likely to undergo an acrosome reaction after zona binding and to compare the reactivity of these receptors with naturally occurring sperm head-directed anti-sperm antibodies (ASAs)., Method: Progesterone binding sites on the surface of fresh and capacitated motile human sperm in relation to acrosome status were visualized using a cell-impermeant progesterone. Free progesterone and/or mannose ligands were compared for percent sperm binding and ability to induce an acrosome reaction. Western blots of sperm proteins localized to the plasma membrane and surface proteins precipitated following passive transfer of serum ASAs were probed with progesterone-horseradish peroxidase. The effects of the same ASAs on ligand binding and on the induced acrosome reaction were examined., Results: The two receptors are located in close proximity on a subset of capacitated motile sperm and are coordinately cleared from the plasma membrane overlying the acrosomal cap prior to exocytosis. The surface appearance of functional binding sites for each ligand, however, is regulated by different mechanisms and the progesterone receptor alone is specifically precipitated by ASAs. Passive transfer of ASAs to capacitated sperm selectively inhibits the progesterone-stimulated acrosome reaction but not the ionomycin-induced acrosome reaction or the ability of sperm to bind mannose ligands., Conclusions: Sperm from fertile donors incubated under capacitating conditions in vitro can be subdivided into acrosome reaction inducible and noninducible subpopulations on the basis of the co-expression or total absence of these receptors. The combined data indicate that reaction of sperm surface progesterone receptors with ASAs contributes to the acrosome reaction insufficiency observed in anti-sperm immune infertility.

Patients with bulimia nervosa (BN) often have seasonal patterns of mood and appetite that compare with patterns seen in seasonal affective disorder (SAD). Seasonal patterns in other eating disorder (ED) subgroups have not been adequately described. We report on seasonal patterns in mood, weight, appetite, sleep, social activity, and energy in 154 consecutive admissions to an outpatient ED program: 60 patients with anorexia nervosa (AN), 31 with BN, 34 with a history of both AN and BN (AN/BN), and 29 with an ED not otherwise specified (ED-NOS). AN patients had significantly less seasonal variation overall than either bulimic subgroup, as measured by the global seasonality score (GSS) on the Seasonal Patterns Assessment Questionnaire (SPAQ). AN patients also showed less seasonal change in mood, weight, and energy than BN patients, and less variation in mood and appetite than AN/BN patients.

Objective: To determine the effect of graded levels of intervention by a dysphagia therapist on the occurrence of pneumonia, dehydration, calorie-nitrogen deficit, recurrent upper airway obstruction, and death following stroke., Design: A randomized control trial., Setting: Inpatient stroke rehabilitation unit., Patients: All patients met the following eligibility criteria: (1) stroke defined by clinical history and neurologic examination with compatible CT or MRI, (2) ages 20 to 90 years inclusive, (3) no known history of significant oral or pharyngeal anomaly, (4) laboratory values below end point criteria, (5) failure on the Burke Dysphagia Screening Test, and (6) modified barium swallow evaluation evidence of dysphagia (patients who aspirated > or = 50% of all consistencies presented, even using compensatory swallowing techniques, were excluded). Of 123 eligible patients, eight refused study participation. One hundred fifteen patients were randomized., Interventions: Three graded levels of dysphagia therapist control of diet consistency and reinforcement of compensatory swallowing techniques were provided during the inpatient rehabilitation stay., Main Outcome Measures: Pneumonia, dehydration, calorie-nitrogen deficit, recurrent upper airway obstruction, and death., Results: The log rank statistic showed no significant difference between the three treatment groups for the distribution of time until end point during the inpatient stay or to 1 year post-stroke., Conclusion: Limited patient and family instruction regarding use of diet modification and compensatory swallowing techniques during inpatient rehabilitation is as effective as therapist control of diet consistency and daily rehearsal of compensatory swallowing techniques for the prevention of medical complications associated with dysphagia following stroke.

Objective: To evaluate the effects of calcium ion (Ca2+) channel blockers on male fertility potential., Design: A case comparison of the surface expression of mannose-ligand receptors on motile spermatozoa from 10 known fertile males and from 10 normospermic men taking Ca2+ channel blockers who were seeking infertility treatment. Examination of the effects of in vitro exposure of sperm from fertile donors (n = 14) to antihypertensive medications., Setting: Patients from a successful university hospital-based IVF-assisted reproductive technology program and from a male urology private practice., Interventions: Prescription of alternate hypotensive medications for four male patients; cholesterol loading and unloading in vitro of fertile donor sperm., Main Outcome Measures: Motile sperm were tested for their ability to bind fluorescein isothiocyanate-labeled, mannosylated bovine serum albumin as an index of the surface expression of mannose-ligand receptors associated with fertility potential. Acrosome status was simultaneously evaluated by fluorescence microscopy with rhodamine-labeled Pisum sativum lectin. Sperm were assayed before and after an 18-hour or 3-day incubation under capacitating conditions in vitro., Results: Motile spermatozoa of normospermic men taking calcium antagonists for hypertension control do not express head-directed mannose-ligand receptors at high frequency, nor do they undergo spontaneous acrosome loss. Unexpectedly, mannose-ligand receptor translocation from the subplasmalemmal space over the acrosome to the sperm surface and aggregation over the equatorial-postacrosomal regions occurred in acrosome-intact sperm. This differs from fertile controls in whom receptor translocation to the equatorial-postacrosomal segment is coupled with the acrosome reaction (AR). Discontinuation of calcium antagonists results in complete recovery of parameters associated with sperm fertilizing potential: time-dependent increases in the percentages of spermatozoa exhibiting surface mannose-ligand binding and spontaneous ARs in vitro. The effects of in vivo administration of calcium antagonists is mimicked in control fertile donor sperm by inclusion of a Ca2+ channel blocker in the media employed during capacitating incubations., Conclusions: Therapeutic administrations of calcium antagonists for hypertension control cause reversible male infertility associated with an IVF failure. A mechanism of inhibition of sperm fertilizing potential through insertion of lipophilic calcium ion antagonists into the lipid bilayer of the sperm plasma membrane is consistent with our in vitro studies.

The attention deficit hyperactive disorder (ADHD) is a neurophysiologic problem that is detrimental to children and their parents. Despite previous studies on the role of foods, preservatives and artificial colorings in ADHD this issue remains controversial. This investigation evaluated 26 children who meet the criteria for ADHD. Treatment with a multiple item elimination diet showed 19 children (73%) responded favorably, P < .001. On open challenge, all 19 children reacted to many foods, dyes, and/or preservatives. A double-blind placebo controlled food challenge (DBPCFC) was completed in 16 children. There was a significant improvement on placebo days compared with challenge days (P = .003). Atopic children with ADHD had a significantly higher response rate than the nonatopic group. This study demonstrates a beneficial effect of eliminating reactive foods and artificial colors in children with ADHD. Dietary factors may play a significant role in the etiology of the majority of children with ADHD.