Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression

Accumulating evidence suggests that angiotensin II type II (AT(2)) receptor subtype negatively regulates cell proliferation in pathophysiological conditions associated with tissue remodeling. However, the mechanisms through which AT(2) receptor achieves this effect remain poorly understood. In this study, we demonstrate that expression of AT(2) receptor inhibits the proliferation of rat fibroblasts in a ligand-independent manner. The antiproliferative action of AT(2) is dependent on the density of surface receptors. We show that AT(2) receptor expression negatively regulates G1 phase progression in both cycling cells and G0-arrested cells stimulated to re-enter the cell cycle, but has no detectable effect on apoptosis. The delay in cell-cycle progression of AT(2)-expressing cells is associated with downregulation of cyclin E expression, decreased assembly of cyclin E-Cdk2 complexes, and the resulting attenuation of Cdk2 activation. The induction of Cdk4 expression and activity is also markedly attenuated, which likely contributes to the inhibition of cyclin E expression. Ectopic expression of Cdk4 alleviates the proliferation defect of AT(2)-expressing cells. These findings suggest that the growth-inhibitory effects of the AT(2) receptor are attributable in part to its spontaneous inhibitory action on the cell cycle machinery.     

Efficient three-drug cocktail for disease induced by mutant superoxide dismutase

There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). Because evidence suggests that multiple pathways may contribute to ALS pathogenesis, we tested in a mouse model of ALS (SOD1(G37R) mice) a combination approach consisting of three drugs for distinct targets in the complex pathway to neuronal death: minocycline, an antimicrobial agent that inhibits microglial activation, riluzole, a glutamate antagonist, and nimodipine, a voltage-gated calcium channel blocker. The efficacy of this three-drug cocktail was remarkable when administered in the diet from late presymptomatic stage (8-9 months). It delayed the onset of disease, slowed the loss of muscle strength, and increased the average longevity of SOD1(G37R) mice by 6 weeks. The protective effect of the treatment was corroborated by the reduced immunodetection signals for markers of gliosis and neurodegeneration in the spinal cord of SOD1(G37R) mice. These results indicate that such three-drug combination may represent an effective strategy for ALS treatment.     

Sleep architecture and its clinical correlates in first episode and neuroleptic-naive patients with schizophrenia

The goal of the present study was to characterize sleep organization in first episode and neuroleptic-naive patients with schizophrenia and to evaluate relationships between those sleep parameters and clinical symptoms. Eleven patients with acute schizophrenia never treated with neuroleptics were compared to 11 healthy controls. Sleep stages and phasic events (sleep spindles and rapid-eye-movements during REM sleep (REMs) were visually identified. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). Compared to controls, patients with schizophrenia had difficulty initiating sleep, decreased stage 4 duration, reduced rapid eye movement (REM) sleep latency, and normal sleep spindles and REMs densities. Positive symptoms correlated negatively with REM sleep latency. The BPRS total score correlated negatively with REM sleep duration and REMs density. The present results indicate that first episode and neuroleptic-naive patients with schizophrenia have difficulties initiating, but not maintaining, sleep. These results also confirm that the duration of stage 4 and REM sleep latency are reduced in first episode and neuroleptic-naive patients with schizophrenia. The fact that measures of REM sleep correlate with clinical scales of schizophrenia suggests that REM sleep physiology shares common substrates with symptoms of this disease.     

Familial history of cancer and childhood acute leukemia: a French population-based case-control study.

A case-control study was conducted to investigate the role of a familial history of cancer in the etiology of childhood acute leukemia. The history of cancer in the relatives of 472 cases was compared with that of 567 population-based controls. Recruitment was frequency matched on age, sex and region. The familial history of cancer in each child's relatives was reported by the mother in response to a standardized self-administered questionnaire. A familial history of solid tumor in first or second-degree relatives was associated with an increased risk of acute lymphoblastic leukemia (odds ratio (OR)=1.6 [95% confidence interval, 1.2-2.1]), while a familial history of hematopoietic malignancies in first or second-degree relatives was associated with an increased risk of acute myeloid leukemia (OR=4.3 [1.4-13]). The ORs for the histories of cancer increased with the number of relatives with cancer (OR=1.5 [1.1-2.0] for one relative and OR=2.3 [1.3-3.8] for two relatives or more; Ptrend<0.0001). Significant associations between childhood acute leukemia and familial history of genital cancers and brain tumor were also observed (OR=2.7 [1.2-5.8] and OR=10.7 [1.3-86], respectively). This study supports the hypothesis that a familial history of cancer may play a role in the etiology of childhood acute leukemia. It also evidences some specific associations that require further investigation.     

Hydroxyapatite versus titanium ossiculoplasty.

OBJECTIVE: To compare the results of ossicular chain reconstruction using hydroxyapatite (HA) and titanium (TI) prostheses. STUDY DESIGN: Retrospective study and case series. SETTING: Tertiary referral center. PATIENTS: One hundred sixty-eight patients presenting chronic otitis media with or without cholesteatoma. INTERVENTION: Ossiculoplasty using partial or total HA and TI ossicular replacement prostheses (TORP and PORP, respectively). MAIN OUTCOME MEASURES: Patients were assessed at 2 months postoperatively to establish short-term results. Results of treatment for conductive hearing loss were reported according to guidelines. Available audiometric data at 1, 2, 3, and 5 years were used to assess prosthesis stability. Average postoperative air-conduction gain, air-bone gap, and sensorineural hearing level were measured at four frequencies: 0.5, 1, 2, and 4 kHz. Statistical analyses compared outcomes for HA TORP versus TI TORP and HA PORP versus TI PORP. RESULTS: Postoperative air-bone gap of less than 20 dB was obtained in 50% of HA TORP versus 45.8% of TI TORP cases and in 63.2% of HA PORP versus 72% of TI PORP cases. Preoperative middle ear status and presence/absence of malleus significantly influenced postoperative audiometric results. All types of prosthesis demonstrated significant postoperative air-conduction gain decrease on follow-up. Prosthesis exclusion was observed in three cases (1.78%). CONCLUSION: Prostheses using both types of biomaterial gave good functional results and stability with low exclusion rates, with no statistically significant differences between the two. Trends could be observed for slightly better results for HA in total reconstruction and for TI in partial reconstruction. The degradation in postoperative functional gain seemed to be independent of prosthesis type.     

Cyclical mastalgia and breast cancer risk: results of a French cohort study.

Cyclical mastalgia is a common complaint, with a potentially important relationship to breast cancer risk. In the last decade, case-control studies have reported that cyclical mastalgia could be considered as an independent risk factor for breast cancer. The subjectivity of a retrospectively collected symptom questioned the validity of this finding. We have examined the association between cyclical mastalgia and breast cancer risk in the French cohort study of women with benign breast disease diagnosed in two breast clinics between 1976 and 1979 and followed-up until 1997. The present study was restricted to the women free of any hormonal treatment (n = 247). The mean follow-up was 16 +/- 5 years, and a total of 22 breast cancers occurred during the follow-up. Using a Cox model with duration of cyclical mastalgia as a time-varying variable, the adjusted relative risk of breast cancer increased with the duration of cyclical mastalgia (P = 0.006). The corresponding relative risk for 37 months of cyclical mastalgia was 5.31 (95% confidence interval, 1.92-14.72). We show here that the conclusion still holds when the symptom cyclical mastalgia was collected prospectively in a cohort study, bringing additional evidence that cyclical mastalgia may represent an independent and useful clinical marker of increased breast cancer risk. It might be a confounding factor when assessing the effects of hormonal treatments on breast cancer risk such as hormonal replacement therapy or oral contraceptives.     

Impact of vital status investigation procedures on estimates of survival in cohorts of HIV-infected patients from Sub-Saharan Africa

In HIV cohorts in sub-Saharan Africa, documenting vital status of patients lost to follow-up is a major challenge. The effect of specific vital status investigation procedures (VSIPs) on the number of known deaths has never been shown. We assessed the effects of VSIP on survival estimates in a 4-year prospective cohort study in Abidjan, C?te d'Ivoire. As of June 2000, 545 HIV-infected adults had been followed for 1186 person-years, of whom 233 were documented as deceased. Forty-eight percent of deaths were known through scheduled VSIPs, including reading of the newspaper obituaries (2%), telephone calls to relatives (10%), and home visits (36%). Survival probability at 1, 2, and 3 years was estimated to be 0.79, 0.65, and 0.56, respectively. Without VSIP, survival at 1, 2, and 3 years would have been estimated to be 11, 23, and 30% higher, respectively. In this large African capital city, survival estimates closely depended on VSIPs, mainly home visits. We suggest that the percentage of deaths known through VSIPs would be a useful indicator to be added when reporting survival data from urban HIV cohort studies in sub-Saharan Africa.     

Seasonal depressive disorder: a controlled study in Tunisian psychiatric sample

Seasonal affective disorder is considered as a clinical subtype of major depression. The criteria for seasonal pattern has been recently described in the international classification of mental disorders. The aim of this study was to compare the clinical characteristics of patients with major depression and with a seasonal and a non seasonal pattern. The study was conducted at the psychiatric ward at Monastir university hospital. 16 inpatients with major depression and seasonal pattern, diagnosed with DSM-IV criteria, were matched in age, sex and diagnostic sub-type to 32 inpatients with non seasonal mood disorders. Clinical symptoms and short term course during the most recent depressive episode were obtained. The onset of the depression with seasonal pattern was frequently in winter. It was marked by significantly higher rates of anxiety. The patients with seasonal depression had significantly higher rates of dysphoria, atypical vegetative symptomatology and lower rates of psychotic characteristics and suicidal thoughts. No differences were found as to the psychiatric family histories or the age at the first depressive episode. This study could focus of the novel psychiatric entity and may lead to the development of the genetic and neurobiologic research related to seasonal affective disorder.