Changes in retinoblastoma gene expression during cervical cancer progression

The role of tumour suppressor genes in the development of human cancers has been studied extensively. In viral carcinogenesis, the inactivation of suppressor proteins such as retinoblastoma (pRb) and p53, and cellular oncogenes overexpression, such as c-myc, has been the subject of a number of investigations. In uterine-cervix carcinomas, where high-risk human papillomavirus (HPV) plays an important role, pRb and p53 are inactivated by E7 and E6 viral oncoproteins, respectively. However, little is known about the in situ expression of some of these proteins in pre-malignant and malignant cervical tissues. On the other hand, it has also been demonstrated that c-myc is involved in cervical carcinogenesis, and that pRb participates in the control of c-myc gene expression. By using immunostaining techniques, we investigated pRb immunodetection pattern in normal tissues, squamous intraepithelial lesions (SILs) and invasive carcinomas from the uterine cervix. Our data show low pRb detection in both normal cervical tissue and invasive lesions, but a higher expression in SILs. C-Myc protein was observed in most of the cellular nuclei of the invasive lesions, while in SILs was low. These findings indicate a heterogeneous pRb immunostaining during the different stages of cervical carcinogenesis, and suggest that this staining pattern could be a common feature implicated in the pathogenesis of uterine-cervix carcinoma.     

Amphetamine disrupts P50 suppression in normal subjects.

BACKGROUND: P50 suppression is viewed as an operational measure of sensory "gating" that is reduced in patients with schizophrenia and their family members. Previous reports have demonstrated that neural gating is regulated by monoaminergic tone in rodent models of P50 suppression. METHODS: In this study, 11 healthy subjects participated in P50 event-related potential recordings at baseline and after either oral administration of dextroamphetamine (.3 mg/kg) or placebo, to determine if the administration of a monoaminergic agonist produces P50 suppression deficits similar to those observed in patients with schizophrenia. RESULTS: As hypothesized, amphetamine disrupted the suppression of the P50 event-related potential. There was a statistically significant decrement in P50 suppression during the amphetamine challenge condition (t10 = 3.15, p < .01, mean difference = -44.1%, d = -2.5) relative to the baseline P50 condition. A comparison of P50 suppression in the placebo and amphetamine conditions (both after a baseline recording session) revealed a significant amphetamine-induced disruption of P50 suppression (t6 = 3.71, p < .01, mean difference = -54.4%, d = -3.14). CONCLUSIONS: The biochemical alterations associated with an amphetamine-induced disruption of P50 suppression in this study may be related to the pathophysiology of P50 suppression deficits in schizophrenia. The findings are consistent with several careful examinations of suppression deficits in rodent models that have identified the monoaminergic regulation of P50 suppression. These data indicate that amphetamine induces a disruption of P50 suppression in normal subjects.     

Opposite links of positive and negative symptomatology with memory errors in schizophrenia

We wished to confirm and extend a previous correlational study of our group, suggesting that positive symptoms in schizophrenia were linked to an increase in certain types of memory errors, and negative symptoms to a decrease in other types of errors. A post-hoc analysis was conducted in 33 schizophrenic patients and 40 normal control subjects on memory errors collected in a free recall task and two types of recognition tasks. The memory errors were intrusions and list errors in free recall, and decision bias towards false alarms in recognition, all assumed to reflect a source-monitoring failure. In a first analysis, the patient sample was split along the median for positive symptoms as rated by the Scale for the Assessment of Positive Symptoms (SAPS). In a second analysis, it was split along the median for negative symptoms as rated by the Scale for the Assessment of Negative Symptoms (SANS). Patients with high ratings of positive symptoms made more memory errors (intrusions, list errors, false alarms) than those with low ratings, supporting the hypothesis of a link between positive symptomatology and source-monitoring failure. On the other hand, patients with high ratings of negative symptoms made fewer of these errors than the other patients. Fewer errors were specifically associated with more affective flattening, alogia and anhedonia, whereas avolition was entirely unrelated to them.     

Coinfections by HIV, hepatitis B and hepatitis C in imprisoned injecting drug users

In order to know the prevalence and risk factors for coinfections by human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) among injecting drug users (IDUs), a cross-sectional study was carried out in two prisons of the province of Cantabria, northern Spain. Three hundred and sixty-two IDU inmates were recruited. All inmates were interviewed and their blood tested for HIV, HBV and HCV. Crude and multiple risk factor adjusted for (by polychotomous logistic regression) odds ratios were calculated. Prevalence of HBV-HCV coinfection (42.5%) was higher than HIV-HBV-HCV coinfection (37.3%), whereas monoinfections were very uncommon (overall: 13%). Long-term injectors and reincarceration were the foremost risk factors for both coinfections, showing a trend between the degree of association and the number of viruses infecting a patient. No significant relationship between coinfection status and sexual practices was observed. The results related to coinfections are consistent with previous studies of prevalence and risk factors for HIV, HBV and HCV, in indicating that the high rates of coinfections among IDU inmates emphasise the need to harm-reduction policy across prisons in Spain.     

Premorbid speech and language impairments in childhood-onset schizophrenia: association with risk factors

OBJECTIVE: As both premorbid neurodevelopmental impairments and familial risk factors for schizophrenia are prominent in childhood-onset cases (with onset of psychosis by age 12), their relationship was examined. METHOD: Premorbid language, motor, and social impairments were assessed in a cohort of 49 patients with childhood-onset schizophrenia. Familial loading for schizophrenia spectrum disorders, familial eye-tracking dysfunction, and obstetrical complications were assessed without knowledge of premorbid abnormalities and were compared in the patients with and without developmental impairments. RESULTS: Over one-half of the patients in this group had developmental dysfunction in each domain assessed. The patients with premorbid speech and language impairments had higher familial loading scores for schizophrenia spectrum disorders and more obstetrical complications, and their relatives had worse smooth-pursuit eye movements. The boys had more premorbid motor abnormalities, but early language and social impairments did not differ significantly between genders. There were no other significant relationships between premorbid social or motor abnormalities and the risk factors assessed here. CONCLUSIONS: Premorbid developmental impairments are common in childhood-onset schizophrenia. The rates of three risk factors for schizophrenia (familial loading for schizophrenia spectrum disorders, familial eye-tracking dysfunction, and obstetrical complications) were increased for the probands with premorbid speech and language impairments, suggesting that the pathophysiology of schizophrenia involves the abnormal development of language-related brain regions.     

Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets.

Isolated rat hepatocyte couplets were used to perform the comparative study of two widely used immunosuppressors, cyclosporin A (CsA) and tacrolimus (FK506) on hepatocanalicular function. We assessed canalicular function by counting the percentage of couplets that were able to accumulate the fluorescent cholephile, cholyl-lysyl-fluorescein (CLF), into the canalicular vacuole between the two cells, i.e., canalicular vacuole accumulation (CVA) of CLF. Compared to controls (DMSO-treated cells), CsA, in the approximate range of concentrations used therapeutically, caused inhibition of CVA of CLF, disorganization of the bile salt export pump (Bsep) localization at canalicular level resulting in its relocation into the cell, and disruption of the pericanalicular F-actin cytoskeleton. In contrast, FK506, at both approximately therapeutic and supratherapeutic concentrations, had no deleterious effect upon CVA of CLF, upon the localization of the bile salt transporter at the canalicular membrane, or on the organization of the pericanalicular F-actin cytoskeleton. These results point to transporter and cytoskeletal disorganization as contributors or determinants of CsA-induced cholestasis at canalicular level, whereas FK506 does not appear to produce these cholestasis-determining responses even at supratherapeutic concentrations.     

Radioquimioterapia de la enfermedad limitada del carcinoma pulmonar de célula pequeña. ¿Tratamiento concomitante en protocolos asistenciales?

Purpose We retrospectively reviewed our institution’s database to investigate the outcome and impact of combined radiochemotherapy (RT/CT; concomitant or in sequence) in localised small-cell lung cancer (L-SCLC). Material and methods Between January 1995 to November 1999, 79 patients with L-SCLC received combined RT/CT at our Institution. RT was delivered concurrently or sequentially following the CT. Patients with treatment response received additional prophylactic cranial irradiation (PCI). Results Of the patients treated, 54% had received concurrent CT/RT compared to 46% receiving RT following the CT. PCI was administered to 80% of the patients. Complete response was observed in 66% of patients. With a median follow up of 30 months, median overall survival was 15.9 months; 14.3 months for patients who received RT following CT and 21.6 months for those receiving concurrent CT/RT. The type of schedule of combined radiochemotherapy was an independent prognostic factor for survival free of local recurrence, as was additional PCI for distant metastasis-free survival. Conclusions Our results are similar to those reported previously in the literature. The main point of interest is that our patients were non-selected. We strongly support the use of concurrent CT/RT so as to achieve results comparable to the best in the literature.

     

Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q- and 17p-).

PURPOSE: To evaluate the efficacy of reduced intensity conditioning (RIC) allogeneic transplant in 30 patients with poor-prognosis chronic lymphocytic leukemia (CLL) and/or high-risk molecular/cytogenetic characteristics. EXPERIMENTAL DESIGN: Eighty-three percent of patients had active disease at the moment of transplant. That is, 14 of the 23 patients analyzed (60%) had unmutated immunoglobulin variable heavy-chain gene (IgV(H)) status; 8 of 25 patients (32%) had 11q-, with four of them also displaying unmutated IgV(H); and six (24%) had 17p- (five were also unmutated). RESULTS: After a median follow-up of 47.3 months, all 22 patients alive are disease free; overall survival and event-free survival (EFS) at 6 years were 70% and 72%, respectively. According to molecular/cytogenetic characteristics, overall survival and EFS for unmutated CLL and/or with 11q- aberration (n = 13) were 90% and 92%, respectively, not significantly different to those with normal in situ hybridization, 13q- and +12, or mutated CLL (n = 7). All six patients with 17p deletion were transplanted with active disease, including three with refractory disease; all except one reached complete remission after the transplant and two are alive and disease free. Nonrelapse mortality (NRM) was 20%; more than two lines before transplant is an independent prognostic factor for NRM (P = 0,02), EFS (P = 0.02), and overall survival (P = 0.01). Patients older than 55 years have a higher risk of NRM (hazard ratio, 12.8; 95% confidence interval, 1.5-111). Minimal residual disease was monitored by multiparametric flow cytometry in 21 patients. Clearance of CD79/CD5/CD19/CD23 cells in bone marrow was achieved in 68% and 94% of the patients at days 100 and 360, respectively. CONCLUSION: According to these results, RIC allogeneic transplant could overcome the adverse prognosis of patients with unmutated CLL as well as those with 11q- or 17p-.     

Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats

Butyl benzyl phthalate (BBP) was administered in the diet at 0, 750, 3750, and 11,250 ppm ad libitum to 30 rats per sex per dose for two offspring generations, one litter/breeding pair/generation, through weaning of F2 litters. Adult F0 systemic toxicity and adult F1 systemic and reproductive toxicity were present at 11,250 ppm (750 mg/kg per day). At 11,250 ppm, there were reduced F1 and F2 male anogenital distance (AGD) and body weights/litter during lactation, delayed acquisition of puberty in F1 males and females, retention of nipples and areolae in F1 and F2 males, and male reproductive system malformations. At 3750 ppm (250 mg/kg per day), only reduced F1 and F2 offspring male AGD was present. There were no effects on parents or offspring at 750 ppm (50 mg/kg per day). The F1 parental systemic and reproductive toxicity no observable adverse effect level (NOAEL) was 3750 ppm. The offspring toxicity NOAEL was 3750 ppm. The offspring toxicity no observable effect level (NOEL) was 750 ppm, based on the presence of reduced AGD in F1 and F2 males at birth at 3750 ppm, but no effects on reproductive development, structures, or functions.