Multicenter Ozone Study in oldEr Subjects (MOSES): Part 1. Effects of Exposure to Low Concentrations of Ozone on Respiratory and Cardiovascular Outcomes.

INTRODUCTION: Exposure to air pollution is a well-established risk factor for cardiovascular morbidity and mortality. Most of the evidence supporting an association between air pollution and adverse cardiovascular effects involves exposure to particulate matter (PM). To date, little attention has been paid to acute cardiovascular responses to ozone, in part due to the notion that ozone causes primarily local effects on lung function, which are the basis for the current ozone National Ambient Air Quality Standards (NAAQS). There is evidence from a few epidemiological studies of adverse health effects of chronic exposure to ambient ozone, including increased risk of mortality from cardiovascular disease. However, in contrast to the well-established association between ambient ozone and various nonfatal adverse respiratory effects, the observational evidence for impacts of acute (previous few days) increases in ambient ozone levels on total cardiovascular mortality and morbidity is mixed.Ozone is a prototypic oxidant gas that reacts with constituents of the respiratory tract lining fluid to generate reactive oxygen species (ROS) that can overwhelm antioxidant defenses and cause local oxidative stress. Pathways by which ozone could cause cardiovascular dysfunction include alterations in autonomic balance, systemic inflammation, and oxidative stress. These initial responses could lead ultimately to arrhythmias, endothelial dysfunction, acute arterial vasoconstriction, and procoagulant activity. Individuals with impaired antioxidant defenses, such as those with the null variant of glutathione S-transferase mu 1 (GSTM1), may be at increased risk for acute health effects.The Multicenter Ozone Study in oldEr Subjects (MOSES) was a controlled human exposure study designed to evaluate whether short-term exposure of older, healthy individuals to ambient levels of ozone induces acute cardiovascular responses. The study was designed to test the a priori hypothesis that short-term exposure to ambient levels of ozone would induce acute cardiovascular responses through the following mechanisms: autonomic imbalance, systemic inflammation, and development of a prothrombotic vascular state. We also postulated a priori the confirmatory hypothesis that exposure to ozone would induce airway inflammation, lung injury, and lung function decrements. Finally, we postulated the secondary hypotheses that ozone-induced acute cardiovascular responses would be associated with: (a) increased systemic oxidative stress and lung effects, and (b) the GSTM1-null genotype. METHODS: The study was conducted at three clinical centers with a separate Data Coordinating and Analysis Center (DCAC) using a common protocol. All procedures were approved by the institutional review boards (IRBs) of the participating centers. Healthy volunteers 55 to 70 years of age were recruited. Consented participants who successfully completed the screening and training sessions were enrolled in the study. All three clinical centers adhered to common standard operating procedures (SOPs) and used common tracking and data forms. Each subject was scheduled to participate in a total of 11 visits: screening visit, training visit, and three sets of exposure visits, each consisting of the pre-exposure day, the exposure day, and the post-exposure day. The subjects spent the night in a nearby hotel the night of the pre-exposure day.On exposure days, the subjects were exposed for three hours in random order to 0 ppb ozone (clean air), 70 ppb ozone, and 120 ppm ozone, alternating 15 minutes of moderate exercise with 15 minutes of rest. A suite of cardiovascular and pulmonary endpoints was measured on the day before, the day of, and up to 22 hours after, each exposure. The endpoints included: (1) electrocardiographic changes (continuous Holter monitoring: heart rate variability [HRV], repolarization, and arrhythmia); (2) markers of inflammation and oxidative stress (C-reactive protein [CRP], interleukin-6 [IL-6], 8-isoprostane, nitrotyrosine, and P-selectin); (3) vascular function measures (blood pressure [BP], flow-mediated dilatation [FMD] of the brachial artery, and endothelin-1 [ET-1]; (4) venous blood markers of platelet activation, thrombosis, and microparticle-associated tissue factor activity (MP-TFA); (5) pulmonary function (spirometry); (6) markers of airway epithelial cell injury (increases in plasma club cell protein 16 [CC16] and sputum total protein); and (7) markers of lung inflammation in sputum (polymorphonuclear leukocytes [PMN], IL-6, interleukin-8 [IL-8], and tumor necrosis factor-alpha [TNF-α]). Sputum was collected only at 22 hours after exposure.The analyses of the continuous electrocardiographic monitoring, the brachial artery ultrasound (BAU) images, and the blood and sputum samples were carried out by core laboratories. The results of all analyses were submitted directly to the DCAC.The variables analyzed in the statistical models were represented as changes from pre-exposure to post-exposure (post-exposure minus pre-exposure). Mixed-effect linear models were used to evaluate the impact of exposure to ozone on the prespecified primary and secondary continuous outcomes. Site and time (when multiple measurements were taken) were controlled for in the models. Three separate interaction models were constructed for each outcome: ozone concentration by subject sex; ozone concentration by subject age; and ozone concentration by subject GSTM1 status (null or sufficient). Because of the issue of multiple comparisons, the statistical significance threshold was set a priori at P < 0.01. RESULTS: Subject recruitment started in June 2012, and the first subject was randomized on July 25, 2012. Subject recruitment ended on December 31, 2014, and testing of all subjects was completed by April 30, 2015. A total of 87 subjects completed all three exposures. The mean age was 59.9 ± 4.5 years, 60% of the subjects were female, 88% were white, and 57% were GSTM1 null. Mean baseline body mass index (BMI), BP, cholesterol (total and low-density lipoprotein), and lung function were all within the normal range.We found no significant effects of ozone exposure on any of the primary or secondary endpoints for autonomic function, repolarization, ST segment change, or arrhythmia. Ozone exposure also did not cause significant changes in the primary endpoints for systemic inflammation (CRP) and vascular function (systolic blood pressure [SBP] and FMD) or secondary endpoints for systemic inflammation and oxidative stress (IL-6, P-selectin, and 8-isoprostane). Ozone did cause changes in two secondary endpoints: a significant increase in plasma ET-1 (P = 0.008) and a marginally significant decrease in nitrotyrosine (P = 0.017). Lastly, ozone exposure did not affect the primary prothrombotic endpoints (MP-TFA and monocyte-platelet conjugate count) or any secondary markers of prothrombotic vascular status (platelet activation, circulating microparticles [MPs], von Willebrand factor [vWF], or fibrinogen.).Although our hypothesis focused on possible acute cardiovascular effects of exposure to low levels of ozone, we recognized that the initial effects of inhaled ozone involve the lower airways. Therefore, we looked for: (a) changes in lung function, which are known to occur during exposure to ozone and are maximal at the end of exposure; and (b) markers of airway injury and inflammation. We found an increase in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) after exposure to 0 ppb ozone, likely due to the effects of exercise. The FEV1 increased significantly 15 minutes after 0 ppb exposure (85 mL; 95% confidence interval [CI], 64 to 106; P < 0.001), and remained significantly increased from pre-exposure at 22 hours (45 mL; 95% CI, 26 to 64; P < 0.001). The increase in FVC followed a similar pattern. The increase in FEV1 and FVC were attenuated in a dose-response manner by exposure to 70 and 120 ppb ozone. We also observed a significant ozone-induced increase in the percentage of sputum PMN 22 hours after exposure at 120 ppb compared to 0 ppb exposure (P = 0.003). Plasma CC16 also increased significantly after exposure to 120 ppb (P < 0.001). Sputum IL-6, IL-8, and TNF-α concentrations were not significantly different after ozone exposure. We found no significant interactions with sex, age, or GSTM1 status regarding the effect of ozone on lung function, percentage of sputum PMN, or plasma CC16. CONCLUSIONS: In this multicenter clinical study of older healthy subjects, ozone exposure caused concentration-related reductions in lung function and presented evidence for airway inflammation and injury. However, there was no convincing evidence for effects on cardiovascular function. Blood levels of the potent vasoconstrictor, ET-1, increased with ozone exposure (with marginal statistical significance), but there were no effects on BP, FMD, or other markers of vascular function. Blood levels of nitrotyrosine decreased with ozone exposure, the opposite of our hypothesis. Our study does not support acute cardiovascular effects of low-level ozone exposure in healthy older subjects. Inclusion of only healthy older individuals is a major limitation, which may affect the generalizability of our findings. We cannot exclude the possibility of effects with higher ozone exposure concentrations or more prolonged exposure, or the possibility that subjects with underlying vascular disease, such as hypertension or diabetes, would show effects under these conditions.

Telemedicine-Guided Two-Incision Lower Leg Fasciotomy Performed by Combat Medics During Tactical Combat Casualty Care: A Feasibility Study.

INTRODUCTION: During tactical combat casualty care, life- and limb-saving procedures might also be performed by combat medics. This study assesses whether it is feasible to use a head-mounted display (HMD) to provide telemedicine (TM) support from a consulted senior surgeon for combat medics when performing a two-incision lower leg fasciotomy. MATERIALS AND METHODS: Nine combat medics were randomized into groups to perform a two-incision lower leg fasciotomy. One group used the Vuzix M400 and the second group used the RealWear HMT-1Z1. A third, control, group received no guidance. In the Vuzix M400 group and RealWear HMT-1Z1 group, a senior surgeon examined the results after the two-incision lower leg fasciotomy was finished to assess the release of compartments, possible collateral damage, and performance of the combat medics. In the control group, these results were examined by a surgical resident with expertise in two-incision lower leg fasciotomies. The resident's operative performance questionnaire was used to score the performance of the combat medics. The telehealth usability questionnaire was used to evaluate the usability of the HMDs as perceived by the combat medics. RESULTS: Combat medics using an HMD were considered competent in performing a two-incision lower leg fasciotomy (Vuzix: median 3 [range 0], RealWear: median 3 [range 1]). These combat medics had a significantly better score in their ability to adapt to anatomical variances compared to the control group (Vuzix: median 3 [range 0], RealWear: median 3 [range 0], control: median 1 [range 0]; P = .018). Combat medics using an HMD were faster than combat medics in the control group (Vuzix: mean 14:14 [SD 3:41], RealWear: mean 15:42 [SD 1:58], control: mean 17:45 [SD 2:02]; P = .340). The overall satisfaction with both HMDs was 5 out of 7 (Vuzix: median 5 [range 0], RealWear: median 5 [range 1]; P = .317). CONCLUSIONS: This study shows that it is feasible to use an HMD to provide TM support performance from a consulted senior surgeon for combat medics when performing a two-incision lower leg fasciotomy. The results of this study suggest that TM support might be useful for combat medics during tactical combat casualty care when performing life- and limb-saving procedures.

Treatment planning in dentistry using an electronic health record: implications for undergraduate education.

OBJECTIVE: Treatment planning, an essential component of clinical practice, has received little attention in the dental literature and there appears to be no consistent format being followed in the teaching and development of treatment plans within dental school curricula. No investigation, to our knowledge, has been carried out to explore the subject of treatment planning since the advent of electronic health record (EHR) use in dentistry. It is therefore important to examine the topic of treatment planning in the context of EHRs. METHODS: This paper reports on how 25 predoctoral dental students from two U.S. schools performed when asked to complete diagnosis and treatment planning exercises for two clinical scenarios in an EHR. Three calibrated clinical teaching faculty scored diagnosis entry, diagnosis-treatment (procedure) pairing, and sequencing of treatment according to criteria taught in their curriculum. Scores were then converted to percent correct and reported as means (with standard deviations). RESULTS: Overall, the participants earned 48.2% of the possible points. Participants at School 2 earned a mean of 54.3% compared with participants at School 1, who earned 41.9%. Students fared better selecting the appropriate treatment (59.8%) compared with choosing the correct diagnoses (41.9%) but performed least favorably when organizing the sequence of their treatment plans (41.7%). CONCLUSION: Our results highlight the need to improve the current process by which treatment planning is taught and also to consider the impact of technology on the fundamental skills of diagnosis and treatment planning within the modern educational setting.

ELISA test for p63 antibodies in chronic ulcerative stomatitis.

OBJECTIVE: To develop a novel test for chronic ulcerative stomatitis (CUS), a chronic immunologically mediated condition that produces oral ulcerations. Current diagnostic methods require expensive and technically demanding in situ immunofluorescence (IF) studies. DESIGN: An Enzyme-Linked ImmunoSorbent Assay (ELISA) was prepared and tested with serum samples from patients with CUS and negative controls. MATERIALS AND METHODS: The N-terminal portion of the CUS autoantigen, DeltaNp63alpha, was produced as a purified recombinant protein and used to coat ELISA plates. Sera from 25 patients with CUS and 16 negative controls were analyzed for reactive antibodies. The optimal cut-offs for positive and negative samples were determined. MAIN OUTCOME MEASURES: The optimal cut-off of 0.236 resulted in a sensitivity and specificity of the ELISA of 0.80 and 0.75, respectively (exact 95% confidence intervals, P-value of <0.001). RESULTS: The ELISA developed in this study provides a novel and reliable diagnostic assessment to distinguish CUS from other oral ulcerative diseases. CONCLUSIONS: Immunoassay will allow the true incidence and prevalence of CUS to be determined in future studies. When combined with clinical correlations, the ELISA results will facilitate the evaluation of the prognostic utility of antibody titers and allow correlation with treatment responses in individual CUS cases.

Gender differences in final year medical students' experience of teaching of intimate examinations: a questionnaire study.

OBJECTIVES: To examine final year medical students' experience of being taught to conduct intimate examinations. DESIGN: Prospective questionnaire study. SETTING: Medical school in the UK. POPULATION: Medical students in the final year cohort 2005/06. METHODS: Questionnaires were distributed to students in the final week of a final year obstetrics and gynaecology course. Responses to questions about course experience were analysed using frequencies and single-variable analyses. MAIN OUTCOME MEASURES: Students' experience of and satisfaction with the teaching of intimate examinations and differences between male and female students. RESULTS: Male and female students performed similar numbers of intimate examinations, but clinical tutors were significantly more likely to introduce female students to patients (76 versus 52%; P = 0.001) and obtain consent on their behalf (75 versus 53%; P = 0.009) when compared with male students. Male students reported a greater degree of embarrassment (mean score 2.41 +/- 1.25 versus 1.69 +/- 0.90; P = 0.002), and a higher number of patients refusing consent to examination (median 2; range 0-12 versus 0; range 0-6; P = 0.0001). CONCLUSIONS: Gender discrimination in the behaviour of tutors may impact on students' experience of intimate examinations. It is highly improbable that differences in behaviour are deliberately intended to disadvantage male students, and further research is needed to understand why tutors behave differently with them. In the meantime, tutors need to be aware of potential bias and ensure appropriate support is provided for both male and female students.

Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas.

BACKGROUND/METHODS: Gliomas are common malignant neoplasms of the central nervous system. Among the major subtypes of gliomas, oligodendrogliomas are distinguished by their remarkable sensitivity to chemotherapy, with approximately two thirds of anaplastic (malignant) oligodendrogliomas responding dramatically to combination treatment with procarbazine, lomustine, and vincristine (termed PCV). Unfortunately, no clinical or pathologic feature of these tumors allows accurate prediction of their response to chemotherapy. Anaplastic oligodendrogliomas also are distinguished by a unique constellation of molecular genetic alterations, including coincident loss of chromosomal arms 1p and 19q in 50%-70% of tumors. We have hypothesized that these or other specific genetic changes might predict the response to chemotherapy and prognosis in patients with anaplastic oligodendrogliomas. Therefore, we have analyzed molecular genetic alterations involving chromosomes 1p, 10q, and 19q and the TP53 (on chromosome 17p) and CDKN2A (on chromosome 9p) genes, in addition to clinicopathologic features in 39 patients with anaplastic oligodendrogliomas for whom chemotherapeutic response and survival could be assessed. RESULTS/CONCLUSIONS: Allelic loss (or loss of heterozygosity) of chromosome 1p is a statistically significant predictor of chemosensitivity, and combined loss involving chromosomes 1p and 19q is statistically significantly associated with both chemosensitivity and longer recurrence-free survival after chemotherapy. Moreover, in both univariate and multivariate analyses, losses involving both chromosomes 1p and 19q were strongly associated with longer overall survival, whereas CDKN2A gene deletions and ring enhancement (i.e., contrast enhancement forming a rim around the tumor) on neuroimaging were associated with a significantly worse prognosis. The inverse relationship between CDKN2A gene deletions and losses of chromosomes 1p and 19q further implies that these differential clinical behaviors reflect two independent genetic subtypes of anaplastic oligodendroglioma. These results suggest that molecular genetic analysis may aid therapeutic decisions and predict outcome in patients with anaplastic oligodendrogliomas.

Linkage analysis for ATM in familial B cell chronic lymphocytic leukaemia.

B cell chronic lymphocytic leukaemia (CLL) shows evidence of familial aggregation, but the inherited basis is poorly understood. Mutations in the ATM gene have been demonstrated in CLL. This, coupled with a possibly increased risk of leukaemia in relatives of patients with Ataxia Telangiectasia, led us to question whether the ATM gene is involved in familial cases of CLL. To examine this proposition we typed five markers on chromosome 11q in 24 CLL families. No evidence for linkage between CLL and ATM in the 24 families studied and the best estimates of the proportion of sibling pairs that share no, one or both haplotypes at ATM were not different from their null expectations. This would imply that ATM is unlikely to make a significant contribution to the three-fold increase in risk of CLL seen in relatives of patients.

Cannabinoids. 1. 1-Amino- and 1-mercapto-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyrans.

A series of 1-amino- and 1-mercapto-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyrans was synthesized and subsequently evaluated in three rodent test systems for CNS activity. The structure-activity data generated indicate that, in general, a change of the 1-hydroxy group to an amine results in a retention of pharmacological activity but that a change to sulfur results in loss of pharmacological activity. Derivatization of the 1-amino group with various functions decreased the activity of the parent compound. For optimum potency, in all series, the 3-position alkyl side chain should be either 1,1- or 1,2-dimethylheptyl. With either the 1-hydroxy- or 1-amino-7,8,9,10-tetrahydro-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6H-dibenzo[b,d]pyran (4c or 10c), preparation of the optically active antipodes did not lead to any great degree of spearation of activity. Both of the antipodes possess pharmacological activity as measured in these rodent test systems.

Cannabinoids. 2. Synthesis and central nervous system activities of some B-ring homocannabinoid derivatives and related lactones.

The syntheses of some novel B-ring homocannabinoid derivatives 1,2, and 4 and related lactones 3 and 5 are described. Compounds 1-5 are 6,7,8,9,10,11-hexahydrodibenz[b,d]oxepins. CNS structure-activity correlations were determined using three rodent models. The potency and activity profile of these seven-membered ring compounds were compared with the corresponding six-membered ring homologues 6 and 7. A possible seperation of CNS activities was noted with compound 1. Unexpected pharmacological activity was discovered with lactone 3, which was about equipotent to 1-delta9-tetrahydrocannabinol. It was found that dimethylation at the 7 postition decreased CNS activity when the 6 position was either a carbonyl or methylene group.

Synthesis and blood pressure lowering activity of 3-(substituted-amino)-1,2,4-benzothiadiazine 1-oxide derivatives.

A series of (substituted amino)-1,2,4-benzothiadiazine 1-oxides has been synthesized and most members of the series have been shown to have blood pressure lowering effects in normotensive rabbits and in spontaneously hypertensive rats. The most active member of the series was 3-[4-(2-furoyl)-1-piperazinyl]-6,7-dimethoxy-1-methyl-1H-1,2,4-benzothiadiazine 1-oxide hydrochloride. This compound in animal tests was equipotent to the known antihypertensive Prazosin.

Synthesis and evaluation of novel spermidine derivatives as targeted cancer chemotherapeutic agents.

The utility of the spermidine moiety as the homing device for the selective delivery of chemotherapeutic and diagnostic agents into cancer cells was explored. Two spermidine analogs containing a cytotoxic agent were synthesized, N-[3,4-bis(benzyloxy)phenethyl]-N alpha-(3-amino-propyl)-L-ornithinamide trihydrochloride, 1a and N-[4-]bis(2-chloroethyl)amino]phenethyl]-N alpha-(3-aminopropyl)-L- ornithinamide tetrahydrochloride, 1b. These compounds were prepared from the fully protected spermidine molecule with a carboxyl group side chain, 8. The ability of the polyamine cytotoxic agents to inhibit B16-BL6 melanoma cell growth in culture was examined. The effects of pretreatment with DFMO on the activity of the synthesized compounds was also studied. The IC50 values of compounds 1a and 1b were on the same order of magnitude as the control compounds, N-acetyldopamine and chlorambucil, respectively. The inhibitory activities of compounds 1a and 1b were not enhanced by pretreatment with DFMO, suggesting that depletion of intracellular polyamines did not enhance the activity of these compounds.

Opioid agonist and antagonist activities of peripherally selective derivatives of naltrexamine and oxymorphamine.

A series of beta-naltrexamine and beta-oxymorphamine derivatives that contain ionizable moieties coupled to the 6 beta-amino group were synthesized in an effort to develop antagonists and agonists that have negligible access into the central nervous system (CNS). Among the beta-naltrexamine derivatives 1-7, all displayed partial agonism on the guinea pig ileal longitudinal muscle preparation except for aspartyl derivative 6, which was a full agonist with activity in the range of morphine. The beta-oxymorphamine derivatives 8-12 were all full agonists with potencies ranging from 1.5 to 6.1 times that of morphine. Among the compounds evaluated in mice for antinociceptive or opioid antagonist activities, aspartyl derivative 6 possessed the greatest difference between peripheral (po or iv) and icv equiactive antagonist doses. Compared to naltrexone, 6 was greater than 100 times more potent by the icv route, but 6000-10,000 times less potent when administered po or icv. The present study suggests that zwitterionic groups are highly effective in preventing penetration of ligands into the CNS. Such ligands may be useful pharmacologic tools for investigation of peripheral opioid mechanisms. Moreover, they could find clinical applications when the central actions are unwanted.

Enantiomers of diastereomeric cis-N-[1-(2-hydroxy-2-phenylethyl)- 3-methyl-4-piperidyl]-N-phenylpropanamides: synthesis, X-ray analysis, and biological activities.

(+/-)-cis-N-[1-(2-Hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N- phenylpropanamide (1) is a mixture of four stereoisomers [(2S,3R,4S)-1a, (2R,3R,4S)-1b, (2R,3S,4R)-1c, and (2S,3S,4R)-1d], which together constitute two diastereoisomeric pairs of optical isomers. These four stereoisomers were prepared from optically active intermediates of known absolute configuration by procedures which had no effect on the configurations of the piperidine 3- and 4-carbons. The configuration of the phenylethyl 2-carbon in the final products was determined by X-ray analysis of (2S,3S,4R)-1d. A 1H NMR comparison of the final products to ohmefentanyl established that the racemic pair previously known as ohmefentanyl was a mixture of (2S,3R,4S)-1a and (2R,3S,4R)-1c. The individual activities of 1a, 1b, 1c, and 1d were evaluated in a variety of binding and pharmacological assays. The binding data revealed that isomers 1b and 1c had the highest affinity and selectivity for the mu site labeled with [3H]DAMGO. In contrast, the four isomers displaced [3H]etorphine in the order 1a approximately 1b > 1c approximately 1d. Evaluation of the four isomers on the mouse vas deferens (MVD) preparation revealed a potency order of 1a > 1b > 1c > 1d with concentrations of 1a and 1b in the femtomolar range causing inhibition. Experiments using the antagonists naltrexone (mu), ICI 174864 (delta), and norbinaltorphimine (kappa) demonstrated that the effects of 1a were mediated largely by the mu receptor while both delta and kappa agonist effects contributed to the actions of 1b and 1c. Isomer 1d acted as a weak mu antagonist in the MVD preparation. The same potency order was observed in a mouse analgesic assay and a rhesus monkey single dose suppression study. From the latter study the potency of 1a was estimated to be 20,000-50,000 times that of morphine, making this isomer one of the most potent opiates known. In the rhesus monkey study, isomer 1d failed to substitute for morphine and seemed to exacerbate withdrawal at doses of 0.6, 3.0, and 6.0 mg/kg. On the basis of the mouse data, isomer 1a was 21,000 times more potent than 1d, whereas isomers 1b and 1c were similar in their opiate activity in vivo. Using the optical isomers of cis-3-methylfentanyl as reference compounds, we analyzed the effects on the pharmacological activities of introducing a phenylethyl 2-hydroxyl group into the molecule.(ABSTRACT TRUNCATED AT 400 WORDS)

A review of multicenter controlled studies of fluoxetine vs. imipramine and placebo in outpatients with major depressive disorder.

The efficacy of fluoxetine was evaluated in depressed patients in double-blind imipramine- and placebo-controlled clinical trials. Fluoxetine produced greater improvement than placebo on all major efficacy parameters and was comparable to imipramine with respect to the primary indicators of depression. Fluoxetine had significantly less associated anticholinergic effects, dizziness, drowsiness, somatosensory disturbance, and excessive sweating than imipramine. Although nausea occurred more frequently in fluoxetine patients, it was generally mild and well tolerated. A significantly smaller percentage of fluoxetine than imipramine patients terminated therapy because of adverse experiences.

The pharmacologic profile of fluoxetine.

Fluoxetine is a selective inhibitor of serotonin uptake in vitro. Unlike many antidepressant drugs, fluoxetine has little affinity for muscarinic, histaminic H1, serotonergic 5-HT1 or 5-HT2, or noradrenergic alpha 1 or alpha 2 receptors on rat brain membranes in vitro. Fluoxetine inhibits serotonin uptake in vivo without affecting norepinephrine uptake. Neuroendocrine and behavioral consequences of enhanced serotonergic function resulting from fluoxetine's inhibition of serotonin uptake in vivo are described. Fluoxetine is relatively nontoxic in several animal species. The specificity of action of fluoxetine makes it a good candidate as an antidepressant drug.

A 102-center prospective study of seizure in association with bupropion.

BACKGROUND: This trial was conducted to determine the incidence of seizures associated with the use of bupropion. METHOD: A total of 3341 depressed patients from 102 sites were enrolled in this 8-week, prospective, open trial. Following the 8-week treatment phase, patients could elect to enroll in a humanitarian continuation phase of unlimited duration. Dosing was initiated at 225 mg/day and increased to 450 mg/day as tolerated. Investigators carefully monitored seizure occurrences and rated their patients' response to and tolerance of bupropion. RESULTS: A total of 1986 patients (61%) completed the 8-week treatment phase, and 1616 (81%) of these elected to be maintained on bupropion treatment in the humanitarian continuation phase. The observed seizure rate was 0.24% for the treatment phase and 0.40% for the entire study. An 8-week survival analysis performed on patients with a dosing regimen of 300 to 450 mg/day yielded a cumulative rate of 0.36%. Patients, including those previously resistant to antidepressant treatment, responded to and tolerated bupropion well. CONCLUSION: These rates confirm earlier seizure estimates and fall within accepted parameters for antidepressant drugs. This trial enhances bupropion's position as a valuable alternative for the management of depression.

A peptidergic basis for sexual behavior in mammals.

Vasopressin (VP) is a peptide neurotransmitter in the limbic system of rats. It is synthesized in the medial amygdaloid nucleus in the presence of sex steroids, transported to other limbic structures such as the hippocampus and septum and secreted there by a calcium-dependent process. In the hippocampus, VP acts on cerebral microvessels and local circuit interneurons. Its excitatory action on the inhibitory interneurons produces near-total shutdown of electrical activity of the efferent fibers of pyramidal cells, the projection neurons of the hippocampus. Stimulation of the medial amygdala and release of the endogenous VP duplicates these effects and, since they are blocked by ventricular application of a VP antagonist, the effects are almost certainly mediated by endogenous VP. Recording from the VP-containing cell bodies or of the hippocampal action of the peptide indicates that the system is selectively involved with the early stages of sexual behavior, specifically those appetitive behaviors that anticipate coitus. Stimulation of the VP cells produces alterations in sexual behavior in a manner consistent with the hypothesis that the medial amygdala organizes the appetitive phase of recognition of an appropriate partner and sexual arousal. This role for the medial amygdala complements the proposed role of nearby structures in the consummatory, reward and learned aspects of sexual behavior. Association between VP, oxytocin (OT) and homologs with sexual behavior is very widespread among vertebrates, including amphibians, reptiles, primates and humans. Humans and other primates display a phenomenon called 'concealed ovulation' that may have played a role in the evolution of social structures. The review concludes with a discussion of possible experimental strategies for evaluating the possible role of VP in concealed ovulation and other conditions in which sexual behavior occurs outside of estrus.

Pseudolesion of the chest. A conglomerate shadow on the lateral radiograph.

A pseudolesion encountered in the lateral chest roentgenogram of normal patients is described. This concatenation of shadows can produce an opacity which projects over the distal aortic arch and can simulate a mass or pneumonia. This pseudolesion can be found in 4 to 5 percent of normal lateral chest films and is formed by superimposition of normal upper lobe vascular structures.