Polymerase mu is up-regulated during the T cell-dependent immune response and its deficiency alters developmental dynamics of spleen centroblasts

Mammalian DNA polymerase mu (Polmu), preferentially expressed in secondary lymphoid organs, is shown here to be up-regulated in germinal centers after immunization. Alternative splicing appears to be part of Polmu regulation during an immune response. We generated Polmu-deficient mice that are viable and show no anatomical malformation or serious alteration in lymphoid populations, with the exception of an underrepresentation of the B cell compartment. Young and aged homozygous Polmu(-/-) mice generated similar immune responses after immunization with the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken gammaglobulin (CGG), compared with their wild-type littermates. Nonetheless, the kinetics of development of the centroblast population showed significant differences. Hypermutation analysis of the rearranged heavy chain intron region in centroblasts isolated from NP-CGG-immunized Polmu(-/-) mice showed a similar quantitative and qualitative somatic mutation spectrum, but a lower representation of heavily mutated clones. These results suggest that although it is not a critical partner, Polmu modulates the in vivo somatic hypermutation process.     

Protein C congenital deficiency. A case report

Protein C is a plasmatic protein that is synthesized by the liver with the help of vitamin K. It regulates thrombin formation and consequently prevents thrombosis. We present a case of a newborn male with change in the color of the right foot index finger who after 4 h showed cyanosis that reached malleolus level. Upon admission we observed generalized pallor, tachycardia and a necrotic lesion in the rightfoot. We suspected a septic process and thus administered cefotaxime, vancomycin and heparin. Platelet levels were 70,000 mm3, thromboplastin 16/12 sec., partial thromboplastin 5829 sec. PCfunctionality 20% and protein S 100%. Even though the patient evolvedfavourably and showed partial recovery, an intratuberous amputation was needed. One year later a prosthesis was fitted. We need to carry out studies that support the use of PC monoclonal antibodies in order to offer better baseline treatment to patients with PC congenital deficiency and improve their quality of live.     

Interferon gamma bound to extracellular matrix changes the hyporesponsiveness to LPS in crypt but not villous intestinal epithelial cells

Intestinal epithelial cells (IEC) are hyporesponsive to LPS. Responsiveness to luminal bacteria has been implicated in the pathogenesis of inflammatory bowel diseases (IBD). In support of this, previous studies have demonstrated that some intestinal epithelial cell lines are induced by IFN-gamma to respond to LPS. However, both the responsiveness to LPS and the effect of IFN-gamma in intestinal cell lines are heterogeneous. In addition, IFN-gamma may be sequestered in the extracellular matrix (ECM) compartment. The ECM-bound form is more effective than soluble IFN-gamma in producing its biological effects in several experimental models. We investigated the effect of ECM-bound and soluble IFN-gamma treatment on interleukin-8 (IL-8) secretion in response to LPS in freshly isolated villous and crypt cells. We demonstrate that ECM-bound, but not soluble IFN-gamma, induced an increase in IL-8 secretion in response to LPS in undifferentiated crypt cells. This effect was associated with an increase in TLR4 expression. In contrast, mature villous cells did not modify their response to LPS when treated with IFN-gamma (ECM-bound or soluble). These results suggest that selective changes in immature crypt cells induced by IFN-gamma bound to extracellular matrix could contribute to inappropriate responsiveness to commensal bacteria in IBD.     

Management of post-menopausal vaginal atrophy and atrophic vaginitis

The involution of the female genital tract seems to reflect a built-in biological life expectancy, inter-related with the hypothalamic-hypophyseal-ovarian axis. Lower levels of oestradiol have a number of adverse effects, including on the lower urinary tract. The major universal change is vaginal atrophy. The vaginal mucosa becomes thinner and dry, which can produce vaginal discomfort, dryness, burning, itching, and dyspareunia. The vaginal epithelium may become inflamed, contributing to urinary symptoms such as frequency, urgency, dysuria, incontinence, and/or recurrent infections. Moreover, it has been suggested that reduced oestrogen levels may affect periurethral tissues and contribute to pelvic laxity and stress incontinence. In association with hypoestrogenemia, changes in vaginal pH and vaginal flora may predispose post-menopausal women to urinary tract infection. Treatment to date has been based on local hormonal therapy, in the form of vaginal creams, tablets or suppositories. Other routes of hormone administration have also proved to be successful. Both local and systemic administration are both effective in maturation of the vaginal epithelium. However, despite the fact that the benefits of oestrogen replacement in preventing vaginal atrophy and reducing the incidence of related symptoms are well established, such therapy is contraindicated in some women and is not an acceptable option for others. Furthermore, the optimal HT administration route, the dosage regimen, and non-hormonal alternatives for improving symptoms and quality of life of the post-menopausal female population, have not been well studied. This review focuses on the changes involved in vaginal aging and efforts to present a synopsis of the pathophysiology and therapy of atrophic vaginitis and vaginal atrophy.     

Oral protein-energy supplements in peritoneal dialysis: a multicenter study.

BACKGROUND: Protein-energy malnutrition is prevalent in peritoneal dialysis (PD) patients and is associated with increased morbidity and mortality. OBJECTIVE: To evaluate the impact of prophylactic treatment with an oral protein-energy supplement (Protenplus; Fresenius AG, Bad Homburg, Germany) on nutritional parameters in patients starting PD. DESIGN: Prospective, multicenter, randomized study of group A patients (Protenplus, n = 35) and group B (controls, n = 30), with evaluations at baseline and at 6 and 12 months. Statistical Methods: Efficacy of factors by linear mixed model analysis for repeated measurements, chi-square, t-test, and Mann-Whitney test. OUTCOME PARAMETERS: Patient compliance, serum albumin, and other nutritional parameters. RESULTS: No significant differences were found at baseline evaluation. During follow-up, a significant number of group A patients abandoned intake of the supplement due to non-compliance (n = 7) or side effects (n = 8) (chi2 p < 0.01). Patients with lower residual renal function were less likely to comply. The mixed model in the "intention to treat" analysis showed a significant increase related to supplement intake only in total lymphocyte count in group A. The "as treated" analysis of the 29 patients who fulfilled the study (9 in group A, 20 in group B) disclosed that belonging to group A constituted an independent factor for increased lymphocyte count (p < 0.001), body weight (p < 0.03), tricipital skinfold thickness (p < 0.01), middle-arm muscle circumference (p < 0.025), lean body mass (LBM) (p < 0.002), creatinine LBM related to body surface area (p < 0.001), and creatinine generation rate (p < 0.002). However, these data may have been biased by the high rate of noncompliance in group A. CONCLUSIONS: Protenplus proved to be unsuitable as a long term, oral protein-energy supplement in PD patients due to a high rate of noncompliance and intolerance, primarily among patients with lower residual renal function. The question of whether other products, better-tolerated as nutritional supplements, could compensate for daily protein peritoneal losses in long-term PD remains open.     

Primary breast lymphoma: results of a controlled clinical trial

OBJECTIVES: To assess the efficacy and toxicity of the most employed therapeutic approaches in the treatment of primary breast lymphoma (PBL). METHODS: Ninety-six patients with PBL in the early stage (I or II) were enrolled to receive radiotherapy (45 Gy); chemotherapy (six cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), every 21 days), or combined therapy. RESULTS: Complete response was achieved in 20 of 30 patients treated with radiotherapy, 19 of 32 who were treated with chemotherapy and 30 of 34 in the combined arm (p<0.01). Actuarial curves at 10 years showed that event-free survival was 50, 57 and 83%, respectively (p<0.01). Actuarial curves for overall survival were 50, 50 and 76% (p<0.01), respectively. The most common site of relapse was the central nervous system. Acute toxicity was mild. Until now, no second neoplasm or acute leukemia has been observed. CONCLUSIONS: In our study combined therapy is the best treatment in this special setting of patients; with improvement in event-free survival and overall survival without acute or severe late side effects. Prophylaxis to the central nervous system will be considered in the initial treatment to improve outcome.     

Tissue classification for the epidemiological assessment of surgical transmission of sporadic Creutzfeldt-Jakob disease. A proposal on hypothetical risk levels

Background  

Epidemiological studies on the potential role of surgery in Creutzfeldt-Jakob Disease transmission have disclosed associations with history of specific surgical interventions or reported negative results.     

Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients

The cardiac glycosides digitoxin (1) and digoxin (3) have been used in cardiac diseases for many years. During this time several reports have suggested the possible use of digitalis in medical oncology. Several analogues of digitoxin (1) were evaluated for growth inhibition activity in three human cancer cell lines; this study showed that digitoxin (1) was the most active compound and revealed some structural features that may play a role in the growth inhibition activity of these drugs. The IC50 values for 1 (3-33 nM) were within or below the concentration range seen in the plasma of patients with cardiac disease receiving this glycoside (20-33 nM). A renal adenocarcinoma cancer cell line (TK-10) was hypersensitive to this drug, and digitoxin toxicity on these cells was mediated by apoptosis. In vitro experiments showed that 1 at 30 nM induced levels of DNA-topoisomerase II cleavable complexes similar to etoposide, a topoisomerase II poison widely used in cancer chemotherapy. Using the individual cell assay TARDIS, cells exposed to 1 for 30 min showed low but statistically significant levels of DNA-topoisomerase II cleavable complexes; however these complexes disappeared after 24 h exposure.