Impact of age and gender on in-hospital and late mortality after acute myocardial infarction: increased early risk in younger women: results from the French nation-wide USIC registries.

AIMS: To determine whether sex differences of in-hospital and after-discharge mortality differ according to the age. METHODS AND RESULTS: Data of 4347 consecutive patients hospitalized within 48 h of the onset of acute myocardial infarction (AMI) were analysed. Patients were classified according to median age (68 years): Group 1 (G1) (308 women, 30-67 years), G2 (1878 men, 30-67 years), G3 (860 women, 68-89 years), and G4 (1301 men, 68-89 years). In both age groups, women were older, had more frequent co-morbidities, lower rate of reperfusion therapy, and received less anti-platelet agents, beta-blockers, and statins than men. The overall 1-year mortality was higher in women (25% vs. 16% in men, P<0.0001). After adjustment, in-hospital mortality was higher only for the women in the younger age group. (G1 vs. G2: OR=2.2, 95%CI=1.3-3.8; G3 vs. G4: OR=1.1, 95%CI=the risk of death, after hospital discharge, was no longer related to gender in any age group. CONCLUSION: The higher 1-year mortality following AMI in women is explained by the higher risk of death in young women during the first days of hospitalization. Further investigations are crucial to determine the cause in order to improve the chance of survival in younger women.     

Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis

The lysosomal aspartic protease cathepsin D (cath-D) is over-expressed and hyper-secreted by epithelial breast cancer cells. This protease is an independent marker of poor prognosis in breast cancer being correlated with the incidence of clinical metastasis. Cath-D over-expression stimulates tumorigenicity and metastasis. Indeed it plays an essential role in the multiple steps of tumor progression, in stimulating cancer cell proliferation, fibroblast outgrowth and angiogenesis, as well as in inhibiting tumor apoptosis. A mutated cath-D devoid of catalytic activity still proved mitogenic for cancer, endothelial and fibroblastic cells, suggesting an extra-cellular mode of action of cath-D involving a triggering, either directly or indirectly, of an as yet unidentified cell surface receptor. Cath-D is also a key mediator of induced-apoptosis and its proteolytic activity has been involved generally in this event. During apoptosis, mature lysosomal cath-D is translocated to the cytosol. Since cath-D is one of the lysosomal enzymes which requires a more acidic pH to be proteolytically-active relative to the cysteine lysosomal enzymes, such as cath-B and -L, it is open to question whether cytosolic cath-D might be able to cleave substrate(s) implicated in the apoptotic cascade. This review summarises our current knowledge on cath-D action in cancer progression and metastasis, as well as its dual function in apoptosis.     

GLP-1 and type 2 diabetes: physiology and new clinical advances

The first antidiabetic treatment (exenatide; Byetta) based on the incretin hormone glucagon-like peptide-1 (GLP-1) was approved in 2005 as an adjunctive therapy in diabetic patients in whom sulfonylurea, metformin or both had failed. Many GLP-1 mimetics or dipeptidyl peptidase IV inhibitors are currently in clinical development for the treatment of type 2 diabetes and show promising results in the improvement of glucose homeostasis. Furthermore, the ability of GLP-1 to enhance pancreatic beta-cell mass could delay progression of the disease. However, only several years of treatment in humans will confirm the long-term efficacy of GLP-1 mimetics and enhancers on glycemic control. To take advantage of the multifaceted actions of GLP-1, a better understanding of the physiological roles of GLP-1 is required.     

Recent advances on multiple tumorigenic cascades involved in prostatic cancer progression and targeting therapies

Recent advances on differently-expressed gene products and their functions during the progression from localized androgen-dependent states into androgen-independent and metastatic forms of prostate cancer are reported. The expression levels of numerous oncogenes and tumor suppressor genes in distinct prostatic cancer epithelial cell lines and tissues relative to normal prostate cells are described. This is carried out to identify the signaling elements that are altered during the initiation, progression and metastatic process of prostate cancer. Additional information on the interactions between certain deregulated signaling pathways such as androgen receptor (AR), estrogen receptors, epidermal growth factor receptor (EGFR), hedgehog and Wnt/beta-catenin cascades in controlling the proliferation, survival and invasion of tumor prostate epithelial cells during the disease progression is described. The emphasis is on the critical functions of the AR and EGF-EGFR systems at all stages during prostate carcinogenesis. Of therapeutic interest, new strategies for the diagnosis and treatment of localized and metastatic forms of prostate cancer by targeting multiple tumorigenic signaling elements are also reported.     

Spirometry in 3-5-year-old children with asthma

Spirometry with incentive games was applied to 207 2-5-year-old preschool children (PSC) with asthma in order to refine the quality-control criteria proposed by Aurora et al. (Am J Respir Crit Care Med 2004;169:1152-159). The data set in our study was much larger compared to that in Aurora et al. (Am J Respir Crit Care Med 2004;169:1152-159), where 42 children with cystic fibrosis and 37 healthy control were studied. At least two acceptable maneuvers were obtained in 178 (86%) children. Data were focused on 3-5-year-old children (n = 171). The proportion of children achieving a larger number of thresholds for each quality-control criterion (backward-extrapolated volume (Vbe), Vbe in percent of forced vital capacity (FVC, Vbe/FVC), time-to-peak expiratory flow (time-to-PEF), and difference (Delta) between the two FVCs (DeltaFVC), forced expiratory volume in 1 sec (DeltaFEV(1)), and forced expiratory volume in 0.5 sec (DeltaFEV(0.5)) from the two "best" curves) was calculated, and cumulative plots were obtained. The optimal threshold was determined for all ages by derivative function of rate of success-threshold curves, close to the inflexion point. The following thresholds were defined for acceptability: Vbe 相似文献   

Role of heat-shock factor 2 in cerebral cortex formation and as a regulator of p35 expression

Heat-shock factors (HSFs) are associated with multiple developmental processes, but their mechanisms of action in these processes remain largely enigmatic. Hsf2-null mice display gametogenesis defects and brain abnormalities characterized by enlarged ventricles. Here, we show that Hsf2-/- cerebral cortex displays mispositioning of neurons of superficial layers. HSF2 deficiency resulted in a reduced number of radial glia fibers, the architectural guides for migrating neurons, and of Cajal-Retzius cells, which secrete the positioning signal Reelin. Therefore, we focused on the radial migration signaling pathways. The levels of Reelin and Dab1 tyrosine phosphorylation were reduced, suggesting that the Reelin cascade is affected in Hsf2-/- cortices. The expression of p35, an activator of cyclin-dependent kinase 5 (Cdk5), essential for radial migration, was dependent on the amount of HSF2 in gain- and loss-of-function systems. p39, another Cdk5 activator, displayed reduced mRNA levels in Hsf2-/- cortices, which, together with the lowered p35 levels, decreased Cdk5 activity. We demonstrate in vivo binding of HSF2 to the p35 promoter and thereby identify p35 as the first target gene for HSF2 in cortical development. In conclusion, HSF2 affects cellular populations that assist in radial migration and directly regulates the expression of p35, a crucial actor of radial neuronal migration.     

High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a

V617F JAK2 mutation is a reliable molecular marker of polycythemia vera (PV), potentially useful to monitor the effect of treatments in this disease. In a phase 2 study of pegylated (peg) IFN-alpha-2a in PV, we performed prospective sequential quantitative evaluation of the percentage of mutated JAK2 allele (%V617F) by real-time polymerase chain reaction (PCR). The %V617F decreased in 24 (89%) of 27 treated patients, from a mean of 49% to a mean of 27% (mean decrease of 44%; P < .001), and no evidence for a plateau was observed. In one patient, mutant JAK2 was no longer detectable after 12 months. In 3 patients homozygous for the mutation, reappearance of 50% of wild-type allele was observed during treatment. The results seem to confirm the hypothesis that IFN-alpha preferentially targets the malignant clone in PV and show that %V617F assessment using a quantitative method may provide the first tool to monitor minimal residual disease in PV. This trial was registered at www.clinicaltrials.gov as #NCT00241241.