Characterization of the serotonin transporter in lymphocytes and platelets of schizophrenia patients treated with atypical or typical antipsychotics compared to healthy individuals.

A rapidly growing body of data suggests that abnormalities in serotonergic function might be involved in the pathophysiology of schizophrenia and that serotonergic mechanisms play a role in the therapeutic effects of antipsychotics. The activity of the serotonin transporter (5-HTT), as determined by [(3)H]5-HT uptake to blood lymphocytes, was measured in 38 medicated schizophrenia patients (15 of them treated with typical antipsychotics and 23 treated with atypical antipsychotics) and 15 healthy control subjects. In addition, the pharmacodynamic characteristics of platelet 5-HTT were assessed by [(3)H]citalopram binding. There were no significant differences in the density (B(max)) of platelet [(3)H]citalopram binding sites between the three groups. Similarly, the dissociation constant (K(d)) values were indistinguishable. There were no significant differences in the maximal uptake velocity (V(max)) of [(3)H]5-HT to fresh lymphocytes between the three groups. The affinity (K(m)) values of 5-HT to the 5-HTT were significantly higher in schizophrenia patients treated with typical antipsychotics compared with control subjects. The K(m) values in schizophrenia patients treated with atypical antipsychotics were significantly lower compared with those observed in the group of schizophrenia patients treated with typical antipsychotics; however, they were comparable to values in the control group. The high values of K(m) associated with typical antipsychotic treatment may be relevant to the high risk of developing extrapyramidal side effects (EPS). The role of the various components of the serotonergic system in the etiopathology of schizophrenia and the mechanisms by which antipsychotics achieve their therapeutic effects need to be further evaluated.     

Serotonin transporter characteristics in lymphocytes and platelets of male aggressive schizophrenia patients compared to non-aggressive schizophrenia patients

A large body of literature indicates that disturbances of central serotonin (5-HT) function play an important role in aggressive behavior. Results from open-label and placebo-controlled trials as well as the reported inverse relationship between 5-HT function and aggression in human subjects, suggest that reduced 5-HT activity is associated with aggressive behavior. The activity of the 5-HT transporter (5-HTT), as determined by [³H]5-HT uptake to blood lymphocytes, was measured in 20 currently aggressive and 20 non-aggressive male schizophrenia patients. In addition, the pharmacodynamic characteristics of platelet 5-HTT were assessed by [³H]citalopram binding.

There were no significant differences in the density (B_max) of platelet [³H]citalopram binding sites between the two groups. Similarly, the dissociation constant (K_d) values were indistinguishable. The maximum uptake velocity (V_max) of [³H]5-HT to fresh lymphocytes and the K_m values of the 5-HT to the transporter were significantly higher in currently aggressive compared to the non-aggressive schizophrenia patients. The association of high V_max values with current aggressive behavior provides further support to the involvement of the 5-HTT in aggressive behavior as well as to the efficacy of 5-HTT blockers in the control of aggression. The role of the various components of the serotonergic system in the pathophysiology and treatment of aggressive behavior in schizophrenia needs to be further evaluated.     

Inner ear decompression sickness and mal de debarquement.

OBJECTIVE: To present a case series of vestibular symptoms appearing after combined sailing and diving activity, and to discuss the differential diagnosis and the workup algorithm. STUDY DESIGN: Case series. SETTING: Tertiary referral center. PATIENTS: Three patients aged 25 to 31 years suffering from unsteadiness and movement sensations after sailing and scuba diving. INTERVENTIONS: Neurotologic evaluation and recompression therapy in a hyperbaric chamber. MAIN OUTCOME MEASURES: The increasing popularity of marine sports and leisure activities has resulted in the exposure of a growing number of people to unique abnormalities not encountered under terrestrial conditions. The otolaryngologist who is involved in the care of these patients is required to diagnose and treat diving-related sinus and ear injuries such as barotrauma and decompression sickness, and also to be familiar with sailing-related disorientation syndromes such as seasickness and mal de debarquement. Treatment modalities for the various abnormalities differ significantly, and early commencement of treatment is often crucial for a successful outcome. CONCLUSION: Whenever doubt exists, recompression treatment must be instituted as soon as possible because of the potential for severe sequelae if the patient is left untreated, and because the risks involved in this therapy are minimal.     

RNASEL mutation screening and association study in Ashkenazi and non-Ashkenazi prostate cancer patients.

Epidemiologic and genetic studies support the considerable effect of heritable factors on prostate tumorigenesis, although to date, no unequivocal susceptibility gene has been identified. The extensive study of RNASEL in prostate cancer patients worldwide has yielded conflicting results. We reevaluated the role of the RNASEL 471delAAAG Ashkenazi founder mutation in 1,642 Ashkenazi patients with prostate, bladder, breast/ovarian, and colon cancers; Ashkenazi controls; and in non-Ashkenazi prostate cancer patients and controls. The entire RNASEL coding sequence was also screened using denaturing high-performance liquid chromatography and multiplex ligation-dependent probe amplification for possible sequence variations or copy number changes in a population of prostate cancer patients. The 471delAAAG mutation was detected in 2.4% of the Ashkenazi prostate cancer patients; in 1.9% of patients with bladder, breast/ovarian, and colon cancers; and in 2.0% of the Ashkenazi controls. Seven additional variants were detected in RNASEL, including a novel potentially pathogenic splice site mutation, IVS5+1delG, although none were associated with increased prostate cancer risk. Multiplex ligation-dependent probe amplification analysis showed two RNASEL gene copies in all 300 prostate cancer patients tested. We estimated that the RNASEL 471delAAAG founder mutation, which was detected in 2% of the Ashkenazi Jews, originated between the 2nd and 5th centuries A.D., compared with the less frequent (1%) BRCA1 185delAG founder mutation, which originated hundreds of years earlier. Taken together, our analysis does not support a role for the RNASEL 471delAAAG Ashkenazi mutation nor for the other alterations detected in RNASEL in prostate cancer risk in Jewish men.     

Effects of Middle Ear Oxygen and Carbon Dioxide Tensions on Eustachian Tube Ventilatory Function

The objective of this study was to determine the effect of middle ear (ME) gas composition on eustachian tube ventilatory function (ETVF). ETVF was evaluated by using forced-response and inflation-deflation tests in four alert cynomolgus monkeys during test sessions with different gas compositions. The ME was flushed with one of the four gas mixtures: 1. air; 2. 12% oxygen, 88% nitrogen; 3. 100% oxygen; and 4. 5% carbon dioxide, 21% oxygen, and 74% nitrogen before and during testing. The results documented lower opening, steady-state, and closing pressures, lower passive and active resistance, and greater dilatory efficiency following ME flushes with the hypercarbic and hypoxic gas mixtures when compared to the others. Also, for applied ME overpressure, the maximum pressure change during a swallow, the average pressure drop for all swallows, and the percentage of the applied pressure equalized were greater under hypoxic and hypercarbic conditions. These results show that ME gas composition affects ETVF and support feedback modulation of ME pressure regulation.     

Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat

To examine the effects of exposure to post-weaning pre-puberty (juvenile) stress on the emotional and cognitive abilities in response to exposure to stress in adulthood, we first exposed rats to a platform stress at the age of 28 d. Two months later the rats were exposed to acute swim stress. Rats exposed to both stressors showed a higher level of anxiety (as measured both in open-field and startle response tests) than controls or rats exposed to either the juvenile or the adulthood stressor. In the Morris water-maze, rats that were exposed to both juvenile and adulthood stress performed better than the other groups. In a second experiment we verified that the effect of the juvenile stress was indeed age-dependent. One group was exposed at the age of 26-28 d and again at the age of 60 d (juvenile + adulthood stress); the other group was exposed to the first stressor at the age of 60-62 d and to the second at the age of 90 d [adulthood (60) + adulthood (90) stress]. Juvenile + adulthood stress had a significantly greater effect than exposure to stress twice in adulthood, on anxiety level and on the performance in the water-maze. Finally, in a third experiment we found that the juvenile+adulthood stress group swam faster and tended to explore the central area more than the other groups--a finding that could explain their better performance on the first trial of the spatial task. These results indicate that an exposure to a relatively brief juvenile stressful experience has profound and long-lasting effects on the ability to cope with stress in adulthood.     

N-acetyl-L-cysteine mitigates aortic tone injury following liver ischemia-reperfusion

Liver ischemia and subsequent reperfusion (IR) are associated with secondary, remote organ reperfusion injury attributable to oxidative stress mediators. Because N-acetyl-L-cysteine (NAC) was effective in attenuating lung reperfusion injury, its properties on aortic dysfunction were tested. Rat isolated perfused aortic rings (n = 8/group) were evaluated during and after exposure to liver postischemia perfusate. Aortic response to phenylephrine under these conditions was also assessed in the presence or absence of increasing concentrations of NAC. Aortic rings incubated with postischemia perfusates exhibited abnormally protracted contraction. Their response to phenylephrine was reduced to 18 +/- 7% and 65 +/- 11% of controls during and after the exposure, respectively, and their subsequent relaxation was irregular. NAC 0.25 mM best attenuated the IR-induced aortic tone impairments, 0.12 mM affected it slightly, and IR-NAC 0.5 mM and IR-NAC 0.74 mM solutions dilated the rings proportionately, abolishing reactions to both IR solutions and phenylephrine. Xanthine oxidase activity and reduced glutathione (GSH) level in all IR ring tissues were inversely proportionate, but not directly so. Thus, liver IR impaired aortic tone and its response to phenylephrine, even after removal of toxic elements. NAC concentrations directly and inversely correlated with xanthine oxidase activity but not with GSH level. It preserved aortic functions dose-specifically, mainly by oxidant quenching.     

A wolf dressed in sheep’s clothing

Introduction

While there has been much discussion in recent years concerning the construction of hospital quality indexes, researchers have often failed to adequately test these quality measures against testable hypotheses. Our objective is to create a quality index using a fixed-effects methodology (FE-score) and use the resulting index to explain price variation across hospitals and theoretically grounded hypotheses.

Methods

Medicare data (MEDPAR) are used for the risk adjustment of patient characteristics and the calculation of a quality score using a fixed-effects methodology for all US hospitals that provide coronary artery bypass graft (CABG). The resulting FE-score then serves as an independent variable, among others, to explain market prices for patients treated at a subset of the hospitals who have health insurance supplied from a self-insured employer.

Results

We find that the FE-score is positively correlated with prices, which is the opposite to the theory that hospitals with higher-than-expected adverse events would receive a lower price than higher quality hospitals. Other covariates such as insurance status and number of procedures do have the expected sign.

Conclusions

We conclude that the positive correlation between the FE-score and prices demonstrates that it is behaving more like a severity scale. This indicates either an inability to isolate true quality using administrative data (i.e. incomplete risk adjustment) or a possible market failure.