Integrating signals from T-cell receptor and serum by T cells enhance translation of tumour necrosis factor-alpha

Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine produced by several cell types, including T cells upon antigen stimulation. Its production is crucial for the development of an early defence against many pathogens, but its beneficial effects are dependent on the strength and duration of its expression. In this paper we present evidence indicating that serum increases translational efficiency of TNF-alpha in human peripheral blood mononuclear cells stimulated with superantigen. The increase in translation of TNF-alpha due to serum could be inhibited by the phosphatidylinositol (PI) 3-K inhibitors, wortmannin and LY294002, suggesting that PI 3-K is involved in the translational control of TNF-alpha by serum. Similarly to primary T cells, stimulation of Jurkat T cells with superantigen led to TNF-alpha secretion and this was up-regulated by serum. Transfection of Jurkat cells with a constitutively active form of PI 3-Kalpha increased the production of TNF-alpha in cells stimulated with superantigen. Additionally, we used the specific inhibitors targeting ERK kinase and p38 mitogen-activated protein kinase (MAPK), potentially downstream of PI 3-kinase, PD98059 and SB203580. Differently from with PI 3-K inhibitors, the accumulation of TNF-alpha mRNA was inhibited by PD98059 or SB203580. These results suggest that, in T cells, activation of PI 3-K is an important step in controlling TNF-alpha protein synthesis in response to growth factors.     

Molecular evolution of human immunodeficiency virus type 1 subtype A in Senegal: 1988-1997

OBJECTIVE: Few studies have been able to track the genetic diversity of HIV-1 viruses in human populations over time. We analyzed the molecular evolution of subtype A over a 10-year period, in a cohort of female sex workers with a known time of infection. STUDY DESIGN/METHODS: We amplified and sequenced the C2-V3 region of the surface envelope glycoprotein from 73 HIV-1-infected women, infected between 1987-1997. RESULTS: Fifty-one patients were infected by subtype A viruses. The viruses demonstrated significant diversification (p < 0.001) with mean genetic distance increasing from 8.6% in 1989 to 15.9% in 1997. The slope of the fitted curve suggested a rate of diversification of 0.7% per year. The majority of subtype A viruses clustered with HIV-1 subtype A/G recombinant form (IbNG). CONCLUSION: The genetic diversity of HIV-1 subtype A infections doubled over the first 10 years of this high risk population's epidemic, suggesting that implementation of vaccines early in the epidemic may have a higher likelihood of success based on levels of genetic diversity. The A/G recombinant form (IbNG) has taken epidemic proportions in West Africa. This is of particular importance in understanding the epidemiology of HIV-1 subtypes in Africa and to further dissect the potential phenotypic and biological characteristics of these viruses.     

Interstitial telomeric DNA sequences of Chinese hamster cells are hypersensitive to nitric oxide damage, and DNA-PKcs has a specific local role in its repair

The DNA breakage detection-fluorescence in situ hybridization (DBD-FISH) procedure was used to analyze DNA single-strand breaks (SSBs) and alkali-labile sites induced by exposure to the nitric oxide (NO) donors sodium nitroprusside (SNP) and 3-morpholinosydnomine hydrochloride (SIN-1) in the whole genome and in long interstitial telomeric repeat sequence (ITRS) blocks from Chinese hamster cells. The relative density of DNA damage generated in the ITRS by X-rays was similar to that induced in the genome overall, whereas it was 1.7 times higher when the alkylating agent MNNG was assayed. Nevertheless, after SNP or SIN-1 treatment, ITRSs proved to be 2.8 and 2.7 times relatively more damaged, respectively, than the whole genome. When the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) was not active, as in XR-C1 mutant cells, the repair kinetics in the whole genome did not differ from that in the parental cell line with X-ray or SNP exposure. However, whereas the SSBs and alkali-labile sites induced in the ITRS by X-rays exhibited rejoining kinetics similar to that of the parental cell line, the damage induced by SNP was more slowly rejoined. This implies a role for DNA-PKcs in the repair of DNA damage induced by NO, especially in ITRSs. The results demonstrated intragenomic heterogeneity of NO-induced DNA damage and repair; there was a higher density of DNA damage in the ITRS blocks, possibly because of their guanine richness. This suggests that a parallel process may occur in the terminal telomeres, which has implications for premature aging and neoplastic development by chronic NO exposure in vivo.     

Kallikrein 4 expression is up-regulated in epithelial ovarian carcinoma cells in effusions

We immunohistochemically analyzed kallikrein 4 protein (hK4) expression in patients with epithelial ovarian carcinoma (181 malignant effusions and 103 solid carcinoma lesions). Expression of hK4 was also studied in 32 effusions using immunoblotting. Carcinoma cells expressed hK4 in 144 (79.6%) of 181 effusions and 85 (82.5%) of 103 solid tumors. Expression was seen in 51% or more of tumor cells in 70 effusions but often was limited to 5% or fewer cells in solid tumors (P = .009, primary tumors vs effusions; P = .002, metastases vs effusions). Immunoblotting showed hK4 expression in 31 of 32 specimens. Stromal cell hK4 expression, seen in 48 (46.6%) of 103 lesions, was significantly higher in primary tumors than metastases (26/43 vs 22/60, P = .019). hK4 expression in tumor cells was significantly lower in International Federation of Gynecology and Obstetrics stage IV than stage III tumors (P = .004, all lesions; P = .012, primary tumors). hK4 expression in carcinoma cells was associated with longer overall survival (not significant; P = .14, peritoneal effusions). hK4 is expressed widely in ovarian carcinoma; levels in carcinoma cells are highest in effusions, which might be related to loss of stromal contribution and/or altered microenvironment. hK4 expression in carcinoma cells of effusions or solid tumors does not predict survival.     

Hormonal responses to training and its tapering off in competitive swimmers: relationships with performance

During a winter training season, the effects of 12 weeks of intense training and 4 weeks of tapering off (taper) on plasma hormone concentrations and competition performance were investigated in a group of highly trained swimmers (n = 8). Blood samples were collected and the swimmers performed their speciality in competition at weeks 10 (mid-season), 22 (pre-taper) and 26 (post-taper). No statistically significant changes were observed in the concentrations of total testosterone (TT), non-sex hormone binding globulin-boundtestosterone (NSBT), cortisol (C), luteinising hormone, thyroid stimulating hormone, triiodothyronine, thyroxine plasma catecholamines, creatine kinase and ammonia during training and taper. Mid-season NSBT: C ratio and the amount of training were statistically related (r = 0.82,P < 0.05). Competition performance slightly declined during intense training [0.52 (SD 2.51) %, NS] and improved during taper [2.32 (SD 1.69)%,P < 0.01]. Changes in performance during training and taper correlated with changes in ratios TT: C (r = 0.86,P < 0.01andr = 0.81,P < 0.05, respectively) and NSBT: C (r = 0.77,P < 0.05 andr = 0.76,P < 0.05, respectively). In summary, these results showed that the monitored plasma hormones and metabolic indices were unaltered by 12 weeks of intense training and 4 weeks of taper. The TT: C and NSBT: C ratios, however, appeared to be effective markers of the swimmers' performance capacities throughout the training season.     

Effect of different types of high carbohydrate diets on glycogen metabolism in liver and skeletal muscle of endurance-trained rats

Male Wistar rats were fed ad libitum four different diets containing fructose, sucrose, maltodextrins or starch as the source of carbohydrate (CH). One group was subjected to moderate physical training on a motor-driven treadmill for 10 weeks (trained rats). A second group received no training and acted as a control (sedentary rats). Glycogen metabolism was studied in the liver and skeletal muscle of these animals. In the sedentary rats, liver glycogen concentrations increased by 60%–90% with the administration of simple CH diets compared with complex CH diets, whereas skeletal muscle glycogen stores were not significantly affected by the diet. Physical training induced a marked decrease in the glycogen content in liver (20%–30% of the sedentary rats) and skeletal muscle (50%–80% of the sedentary rats) in animals fed simple (but not complex) CH diets. In liver this was accompanied by a two-fold increase of triacylglycerol concentrations. Compared with simple CH diets, complex CH feeding increased by 50%–150% glycogen synthase (GS) activity in liver, whereas only a slight increase in GS activity was observed in skeletal muscle. In all the animal groups, a direct relationship existed between tissue glucose 6-phosphate concentration and glycogen content (r = 0.9911 in liver, r = 0.7177 in skeletal muscle). In contrast, no relationship was evident between glycogen concentrations and either glycogen phosphorylase activity or adenosine 5-monophosphate tissue concentration. The results from this study thus suggest that for trained rats diets containing complex CH (compared with diets containing simple CH) improve the glycogenic capacity of liver and skeletal muscle, thus enabling the adequate regeneration of glycogen stores in these two tissues.     

Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects

Background

Hemihyperplasia (hemihypertrophy) is defined as asymmetric body overgrowth of one or more body parts. Hemihyperplasia can be isolated or be part of well-defined syndromes such as in the case of Beckwith-Wiedemann syndrome (BWS). Isolated hemihyperplasia is usually sporadic, but a number of familial occurrences have been described.

Case presentation

We describe a Tunisian family in which three maternal cousins and their maternal grandfather present with isolated hemihyperplasia.

Conclusions

The etiology of isolated hemihyperplasia is unknown although in BWS, genomic imprinting has been shown to play a role in the asymmetric overgrowth. Given the similarity between these two conditions, it is possible that both may share a common pathogenesis. We also discuss the possible genetic mechanisms leading to the production of hemihyperplasia in this family.     

Fatigue and fitness modelled from the effects of training on performance

Summary The purpose of this study was to compare two ways of estimating both fatigue and fitness indicators from systems model of the effects of training on performance. The model was applied to data concerning the training of a hammer thrower. The variations in performance were mathematically related to the successive amounts of training. The model equation was composed of negative (NF) and positive (PF) functions. The NF and PF were associated with the fatigue and fitness estimated in previous studies. Using another method, fatigue and fitness indicators were estimated from a combination of NF and PF. The influence of training on performance was negatively associated with fatigue (NI), and positively to fitness (PI). The changes in performance were well described by the model in the present study (r = 0.96,N = 19,P<0.001). Significant correlations were observed between NF and NI (r = 0.93,P < 0.001) on the one hand and between PF and PI (r = 0.90,P < 0.001) on the other. The absolute values and the time variations of PI and NI were closer to the change in performance than NF and PF. The NF and PF were accounted for mainly by the accumulation of amounts of training. On the other hand, NI and PI were accounted for rather by the impact of these amounts of training on performance.     

Efficacy and tolerability of a new estradiol delivering matrix patch (Estraderm MX) in postmenopausal women

OBJECTIVE: To examine the efficacy and tolerability of a new matrix patch delivering estradiol (E2 Matrix) at doses of 0.05 and 0.10 mg per day (Estraderm MX 50, 100) in the treatment of moderate to severe postmenopausal symptoms. METHODS: A total of 254 postmenopausal women were randomized to receive treatment with E2 Matrix 0.10 mg (N = 86), E2 Matrix 0.05 mg (N = 82), or placebo (N = 86) in a double-blind, double-dummy fashion for a period of 12 weeks continuously. Patches were applied twice weekly to the buttocks with each patient wearing two patches at all times. The primary efficacy criterion was the difference from baseline of the mean number of moderate to severe hot flushes per 24 h during the last 2 weeks of treatment. Other efficacy variables included reduction in hot flushes at 4 and 8 weeks, reduction in daytime flushing and night sweats, and Kupperman Index at 4, 8, and 12 weeks. RESULTS: E2 Matrix 0.10 and 0.05 mg were both significantly superior to placebo in reducing hot flushes per 24 h after 4, 8, and 12 weeks of treatment (P < 0.001). Also, for all other efficacy parameters studied, both dosage strengths of E2 Matrix were statistically significantly superior to placebo at all time points (P < 0.001). Local tolerability was good in both groups. A slight increase in estrogen related adverse effects (breast tenderness, leukorrhoea) was seen with the 0.10 mg patch. Adhesion of patches and compliance were good. Overall systemic tolerability was good in both treated groups. However, a 4.8% overall incidence of endometrial hyperplasia was observed in patients with an intact uterus. CONCLUSIONS: This new matrix patch offers an effective and well tolerated dosage form for delivery of 0.05 and 0.1 mg estradiol per day. It may be particularly suitable for those women who experience local sensitivity to alcohol-containing systems. In light of the observed hyperplasia after treatment in five patients, estrogen therapy should as yet be supplemented monthly with a progestogen in women with an intact uterus.