Tissue inhibitor of metalloproteinase 1 is an independent predictor of prognosis in patients with nonsmall cell lung carcinoma who undergo resection with curative intent

BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a role in the processes of extracellular matrix degradation. Changes in their expression levels have been observed in various tumor types, including lung carcinoma. However, their clinical significance and their prognostic importance in the progression of nonsmall cell lung carcinoma (NSCLC) remain to be specified. In this study, mRNA expression levels of MMP-1, MMP-9, TIMP-1, and TIMP-2 were evaluated in patients with resected NSCLC, and their associations with disease progression and prognosis were determined. METHODS: Between June 1996 and December 1999, 116 patients underwent resection for NSCLC. Expression levels of MMPs and TIMPs were evaluated using Northern blot analysis in these NSCLC tissue samples and in 39 matched samples of normal lung tissue. RESULTS: MMP-1, MMP-9, and TIMP-1 expression levels were increased in tumor samples compared with matched, corresponding normal tissues. In contrast, TIMP-2 expression was decreased in tumor samples. MMP-1 tumor expression was correlated significantly with the evolution of lymph node status and tumor-lymph node-metastasis (TNM) stage. In contrast, MMP-9 tumor expression was correlated significantly with increased T stage. TIMP-1 overexpression was an independent predictor of worse survival in patients with NSCLC that was not associated with other prognosis factors, such as TNM stage. CONCLUSIONS: The overexpression of TIMP-1 was an independent prognostic marker in patients with NSCLC, and evaluating TIMP-1 may be important for identifying patients who are at greater risk of disease recurrence.     

Longitudinal membrane function in functionally anuric patients treated with APD: data from EAPOS on the effects of glucose and icodextrin prescription

BACKGROUND: Peritoneal dialysis is associated with changes in membrane function that can lead eventually to ultrafiltration (UF) failure. Factors driving these changes are thought to include hypertonic glucose exposure, but previously reported associations are confounded by the presence of residual renal function. METHODS: Longitudinal membrane function (solute transport and UF capacity) were measured annually in a prospective cohort of 177 functionally anuric patients as part of the European Automated Peritoneal Dialysis Outcomes Study (EAPOS). Subgroup analysis was performed according to glucose exposure and icodextrin use at baseline. RESULTS: The whole cohort experienced an increase in solute transport and reduction in UF capacity at 12 and 24 months that could not be explained by informative censoring. These changes were accelerated and more severe in patients using either 2.27% or 3.86% glucose, or those not using icodextrin at baseline. These differences could not be explained by age, comorbidity score, previous time spent on renal replacement, differential dropout from the study, peritonitis rates, or, by definition, residual renal function. Patients using icodextrin at baseline had worse membrane function and were more likely to be diabetic. There was an association between membrane function changes and achieved 24-hour ultrafiltration over the 2-year study period. CONCLUSION: Anuric automated peritoneal dialysis (APD) patients experience significant detrimental changes in membrane function over a relatively short time period. Glucose appears to enhance these changes independent of residual renal function. Icodextrin use in these circumstances is associated with less deterioration in membrane function.     

The effects of acetaldehyde in vitro on proteasome activities and its potential involvement after alcoholization of rats by inhalation of ethanol vapours

Background/ AIMS: Some models of chronic ethanol administration resulted in decreased proteasome activities. The mechanisms still remain speculative. In the present study, we tested another model of alcoholization with high blood alcohol levels (BALs) and high acetaldehyde fluxes as well as the in vitro effect of acetaldehyde on proteasome. Methods/ RESULTS: Ethanol vapour chronically inhaled by adult Wistar rats up to a specific protocol, can reach high BALs (200 mg/dl) with significant circulating acetaldehyde levels. After 4 weeks of ethanol intoxication, although cytochrome CYP2E1 was increased, liver lipid peroxidation remained unchanged when protein carbonyls augmented selectively for high molecular weight with a decrease of the proteasome activities in ethanol rats. Several aldehydes inhibit proteasome function; we specifically explored the effects of acetaldehyde, the first alcohol metabolite. Adduction of acetaldehyde in vitro to cytosolic proteins inhibits proteasome in a dose-dependent manner. Acetaldehyde adducted to purified proteasome also exhibits a decrease in its activities. Furthermore, an acetaldehyde-adducted protein, i.e. bovine serum albumin (BSA) is less degraded than a native BSA by purified proteasome. These findings suggest that acetaldehyde, if overproduced, can inhibit proteasome activities and reduce the proteolysis of acetaldehyde-adducted proteins. CONCLUSIONS: Our study, for the first time, provided the evidence that acetaldehyde by itself inhibits proteasome activities. As the chronic inhalation model used in this study is not associated with an overt lipid peroxidation, one can suggest that high BALs and their subsequent high acetaldehyde fluxes contribute to impairment of proteasome function and accumulation of carbonylated proteins. This early phenomenon may have relevance in experimental alcohol liver disease.     

Brussels sprouts, inulin and fermented milk alter the faecal microbiota of human microbiota-associated rats as shown by PCR-temporal temperature gradient gel electrophoresis using universal, Lactobacillus and Bifidobacterium 16S rRNA gene primers

We investigated the effect of Brussels sprouts, inulin and a fermented milk on the faecal microbiota diversity of human microbiota-associated (HMA) rats by PCR-temporal temperature gradient gel electrophoresis (PCR-TTGE) using universal and group-specific 16S rRNA gene primers. The HMA rats were submitted to a control diet for 10 d (initial time), then switched to the experimental diets for 4 weeks (final time). Using universal primers, the mean degree of similarity between all faecal samples at initial time was 80.8 %. In the group consuming the control diet throughout the experiment, the mean degree of similarity between the PCR-TTGE profiles at initial v. final time was 76.8 %, reflecting a spontaneous temporal variation. The mean degree of similarity between control and experimental groups at final time was lower, 72.4 %, 74.4 % and 75.6 % for inulin, Brussels sprouts and fermented milk, respectively, indicating a dietary effect on the predominant populations. Using specific primers, bifidobacteria could be detected only in those rats that had consumed inulin, showing a specific increasing effect of this dietary compound. The Lactobacillus population was very heterogeneous at initial time but tended to homogenize within each dietary group. At final time, caecal contents were collected for analysis of SCFA and beta-glucuronidase activity. Inulin and Brussels sprouts increased the butyrate and acetate proportion, respectively, while the fermented milk did not modify the caecal biochemistry. This experiment shows for the first time that cruciferous vegetables are able to alter the diversity and the metabolic activities of the digestive microbiota in HMA rats.     

New thiophene analogues of kenpaullone: synthesis and biological evaluation in breast cancer cells

Thieno analogues of kenpaullone have been synthesized using an established method. We investigated the effect of five structural analogues of kenpaullone on vincristine sensitive and resistant MCF7 (human mammary adenocarcinoma) cells. One analogue, 8-Bromo-6,11-dihydro-thieno-[3',2':2,3]azepino[4,5-b]indol-5(4H)-one (3a), showed an antiproliferative activity in the drug sensitive cell line that led to cell accumulation in G2/M phase. In addition, repression of cdk1, a G2/M transition key regulator, as well as induction of p21 were observed at the mRNA level. Programmed cell death (apoptosis) was induced in early time treatments and was accompanied by p53 mRNA induction. The antiproliferative and proapoptotic properties of 3a make this CDK inhibitor an interesting candidate for further investigations.     

Virological and pharmacological parameters predicting the response to lopinavir-ritonavir in heavily protease inhibitor-experienced patients

The genotypic inhibitory quotient (GIQ) has been proposed as a way to integrate drug exposure and genotypic resistance to protease inhibitors and can be useful to enhance the predictivity of virologic response for boosted protease inhibitors. The aim of this study was to evaluate the predictivity of the GIQ in 116 protease inhibitor-experienced patients treated with lopinavir-ritonavir. The overall decrease in human immunodeficiency virus type 1 (HIV-1) RNA from baseline to month 6 was a median of -1.50 log(10) copies/ml and 40% of patients had plasma HIV-1 RNA below 400 copies/ml at month 6. The overall median lopinavir study-state C(min) concentration was 5,856 ng/ml. Using univariate linear regression analyses, both lopinavir GIQ and the number of baseline lopinavir mutations were highly associated with virologic response through 6 months. In the multivariate analysis, only lopinavir GIQ, baseline HIV RNA, and the number of prior protease inhibitors were significantly associated with response. When the analysis was limited to patients with more highly mutant viruses (three or more lopinavir mutations), only lopinavir GIQ remained significantly associated with virologic response. This study suggests that GIQ could be a better predictor of the virologic response than virological (genotype) or pharmacological (minimal plasma concentration) approaches used separately, especially among patients with at least three protease inhibitor resistance mutations. Therapeutic drug monitoring for patients treated by lopinavir-ritonavir would likely be most useful in patients with substantially resistant viruses.     

Overestimation of chronic disability among elderly persons

BACKGROUND: Although there is no generally accepted definition for the term short-term disability, chronic disability has been defined as disability lasting or expected to last at least 90 days according to a protocol that was established by the National Long-Term Care Survey. We evaluated the validity of the established protocol and determined the accuracy of prevalence estimates of chronic disability among elderly persons in the United States. METHODS: Chronic disability was ascertained during a comprehensive assessment using the established protocol. Participants were subsequently classified as having chronic disability (the gold standard) based on the presence of disability during consecutive monthly interviews immediately before or after the comprehensive assessment. RESULTS: Of the 552 participants, 120 (21.7%) met criteria for chronic disability according to the established protocol. Of these, 30 (25.0%) and 39 (32.5%) did not meet criteria according to the gold standard under assumptions that were favorable and unfavorable (ie, stringent) to the established protocol, respectively. Conversely, of the 95 participants (17.2%) who met the gold standard criteria for chronic disability according to the favorable strategy and the 89 (16.1%) who met the criteria according to the stringent strategy, 5 (5.3%) and 8 (9.0%), respectively, did not meet criteria for chronic disability according to the established protocol. Relative to the established estimate of 7.0 million, our projections yielded about 2.0 million fewer chronically disabled elderly Americans in 1999. CONCLUSION: Our results threaten the validity of the currently established protocol for ascertaining chronic disability and suggest that the burden of chronic disability among elderly Americans has been substantially overestimated.     

Factors associated with fragmented sleep at night across early childhood

OBJECTIVE: To identify the factors most strongly associated with sleeping less than 6 consecutive hours at night for children aged 5, 17, and 29 months. DESIGN, SETTING, AND PARTICIPANTS: A randomized survey design used a representative sample of infants born in 1997-1998 in the Canadian province of Quebec. Data were collected by questionnaires and interviews. Interviews were scheduled at home with the mothers. The number of consecutive hours slept at night by 1741 children aged 5, 17, and 29 months was assessed from parental reports. Factors associated with fragmented sleep were investigated for each age in a cross-sectional design. RESULTS: At 5 months of age, 23.5% of children did not sleep 6 consecutive hours. Of the children who did not sleep 6 consecutive hours at night at 5 months or 17 months of age, 32.9% were still not sleeping 6 consecutive hours at night at 29 months of age. The factor most strongly associated with not sleeping at least 6 consecutive hours per night at 5 months of age was feeding the child after an awakening. Parental presence until sleep onset was the factor most strongly associated with not sleeping at least 6 consecutive hours per night at 17 months and 29 months of age. CONCLUSIONS: Sleep consolidation evolves rapidly in early childhood. Parental behaviors at bedtime and in response to a nocturnal awakening are highly associated with the child's sleep consolidation. The effects are probably bidirectional and probably create a long-term problem. Early interventions could possibly break the cycle.     

Retiring: a test of resilient capacities

This article deals with the question of retiring as a test of the conjunctural resilience capacities. The continuity theory and the rupture theory are developed because their content is related to protective factors and risk factors met by retirees: the first theory advocates the use of familiar strategies in familiar areas to maintain internal and external structures. This continuity would protect mental health. The second one emphasises the gap with the working world and its affiliated status. The loss of the professional status would endanger, in a way more or less important, the subjects' mental health. Retiring, as a life event, can be experienced as a trauma or can even be compared by the subjects themselves to other significant periods of their life which have been more or less well overcome. In order to attempt to figure out the conjunctural resilience capacities requested on the first year of retirement, and at the same time, highlighting the available protective factors, two clinical vignettes of two potentially young resilient retirees are presented.