Allelic 'choice' governs somatic hypermutation in vivo at the immunoglobulin kappa-chain locus

Monoallelic demethylation and rearrangement control allelic exclusion of the immunoglobulin kappa-chain locus (Igk locus) in B cells. Here, through the introduction of pre-rearranged Igk genes into their physiological position, the critical rearrangement step was bypassed, thereby generating mice producing B cells simultaneously expressing two different immunoglobulin-kappa light chains. Such 'double-expressing' B cells still underwent monoallelic demethylation at the Igk locus, and the demethylated allele was the 'preferred' substrate for somatic hypermutation in each cell. However, methylation itself did not directly inhibit the activation-induced cytidine-deaminase reaction in vitro. Thus, it seems that the epigenetic mechanisms that initially bring about monoallelic variable-(diversity)-joining rearrangement continue to be involved in the control of antibody diversity at later stages of B cell development.     

Successful treatment with intravenous immunoglobulins in a patient affected by dermatomyositis/systemic lupus erythematosus overlap syndrome and tuberculosis

The case of a 56-year-old woman, with a previous history of systemic lupus erythematosus (SLE), later diagnosed as also affected by active dermatomyositis (DM) associated with tuberculosis (TB) is reported. Since TB is a contra-indication to receive immunosuppressive therapy for DM/SLE, intravenous immunoglobulins (IVIG) with low-dose steroids and anti-TB therapy were administered with excellent clinical results. This report underlines the crucial role of IVIG in the treatment of critical patients suffering from connective tissue disorders associated with severe infections.     

Retroviral microarray-based platform on nanostructured TiO2 for functional genomics and drug discovery

Living-cell microarrays are powerful tools for functional genomics and drug discovery. However, despite several attempts to improve this technology, it is still a challenge to obtain microarrays of cells efficiently overexpressing or downregulating specific genes to address complex phenotypes. Here, we present a cell-based microarray for phenotype screening on primary and cancer cells based on the localized reverse infection by retroviruses. Viral vectors are immobilized on a nanostructured titanium dioxide (ns-TiO2) film obtained by depositing a supersonic beam of titania clusters on a glass substrate. We validated the retroviral cell array by overexpression of GFP reporter genes in primary and cancer cells, and by RNA interference of p53 in primary cells by analyzing effects in cell growth. We demonstrate that ns-TiO2 retroviral arrays are an enabling tool for the study of gene function of families of genes for complex phenotypes and for the identification of novel drug targets.     

Association between infant birth weight and maternal cardiovascular risk factors in the health, aging, and body composition study

PURPOSE: Mothers who deliver a low-birth-weight (LBW) infant may themselves be at excess risk for cardiovascular disease. We investigated whether older women who bore LBW infants had higher blood pressure, lipid, glucose, insulin, interleukin 6 (IL-6), and C-reactive protein concentrations, and pulse wave velocity compared to women with normal-weight births. METHODS: Participants were 446 women with a mean age of 80 years and 47% black. Women reported birth weight and complications for each pregnancy. Analysis was limited to first births not complicated by hypertension or preeclampsia. RESULTS: Women who had delivered a first-birth infant weighing less than 2500 g had a lower body mass index (BMI) compared with women with a normal-weight (>or=2500 g) infant (26.7 versus 28.4 kg/m2; p=0.02), but they had a larger abdominal circumference for BMI (97.9 versus 95.5 cm; p=0.05). They also were marginally more likely to be administered antihypertensive medication (p=0.06). After adjustment for BMI, race, and age, women with a history of a small infant had elevations in systolic blood pressure (p=0.05) and greater IL-6 levels (p=0.02) and were more insulin resistant (p=0.05) compared with women with a normal-weight infant. CONCLUSIONS: These findings suggest that a history of LBW delivery identifies women with elevated cardiovascular risk factors.     

Potential role of serum mesothelin in predicting survival of patients with malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor survival rates. Therefore, it is essential to have effective biological markers predicting the course of the disease and prognosis. The aim of the present study was to highlight the prognostic significance of serum soluble mesothelin-related protein (Se-SMRP) in patients with MPM at diagnosis. Se-SMRP was determined in 60 patients using an ELISA commercial kit. Se-SMRP levels were subdivided into three tertile-based categories and in each category overall survival (OS) indexes were determined using the Kaplan-Meier and Cox regression analyses. The association between Se-SMRP levels and OS was also assessed by restricted cubic spline (RCS) analysis. No notable differences in the Kaplan-Meier probabilities were identified across the Se-SMRP categories (<0.66 nM, 0.66–1.46 nM, >1.46 nM) although an upward trend in death rate ratios (RR) was pointed out by comparing the higher (RR=1.95) and intermediate (RR=1.86) categories with the lower category (RR=1.00). In addition, such an increasing tendency, particularly when the biomarker exceeded 1.0 nM, was confirmed by an RCS function of Se-SMPR levels fitted to survival data using the Cox regression equation. The present study provided evidence in favor of a prognostic value of Se-SMRP in patients with MPM.     

Comparison of Two Pediatric-Inspired Regimens to Hyper-CVAD in Hispanic Adolescents and Young Adults With Acute Lymphoblastic Leukemia

BackgroundPediatric-inspired regimens (PIR) in adolescents and young adults with acute lymphoblastic leukemia have led to better long-term outcomes. In Latin America, the adolescent and young adult population has an increasing incidence of acute lymphoblastic leukemia with poor outcomes (5-year OS of approximately 20%) with traditional regimens.Patients and MethodsA retrospective cohort study was performed of adolescent and young adult acute lymphoblastic leukemia patients treated with PIR in two reference centers in Mexico City between March 2016 and June 2019, in which the primary endpoint was OS, compared to a historic cohort of patients treated with hyper-CVAD treated between February 2009 and June 2015.ResultsWe compared 73 patients treated with PIR (46 and 27 received modified versions of the ALL-BFM 90 and CALGB C10403 regimens, respectively) and 173 patients treated with hyper-CVAD. Patients treated with PIR experienced higher 4-week complete response rates (79.5% vs. 64.2%; P = .02) and lower relapse rates (44.1% vs. 60.0%; P = .04). OS was significantly higher with PIR than with hyper-CVAD (24 months: 41.5% vs. 28.1%; P = .012). The benefit on OS for PIR was only significant for CALGB (24-month OS: 61.1% vs. 28.0%; P = .01) but not for BFM. In the multivariate analysis, hyperleukocytosis (hazard ratio [HR] = 1.90; 95% confidence interval [CI], 1.11-3.22; P = .02), autologous stem-cell transplantation (HR = 0.38; 95% CI, 0.17-0.86; P = .02), and 4-week complete response (HR = 0.43; 95% CI, 0.26-0.70; P < .01) were independent prognostic factors. For the group of patients older than 20 years, only CALGB had an independent prognostic factor for OS (HR = 0.44; 95% CI, 0.20-0.97; P = .04).ConclusionIn terms of 4-week complete response, relapse rates, and OS, PIR provides benefits to Hispanic patients.     

Comparison of monounsaturated fat with carbohydrates as a replacement for saturated fat in subjects with a high metabolic risk profile: studies in the fasting and postprandial states

BACKGROUND: In subjects with a high prevalence of metabolic risk abnormalities, the preferred replacement for saturated fat is unresolved. OBJECTIVE: The objective was to study whether carbohydrate or monounsaturated fat is a preferred replacement for saturated fat. DESIGN: Fifty-two men and 33 women, selected to have any combination of HDL cholesterol < or = 30th percentile, triacylglycerol > or = 70th percentile, or insulin > or = 70th percentile, were enrolled in a 3-period, 7-wk randomized crossover study. The subjects consumed an average American diet (AAD; 36% of energy from fat) and 2 additional diets in which 7% of energy from saturated fat was replaced with either carbohydrate (CHO diet) or monounsaturated fatty acids (MUFA diet). RESULTS: Relative to the AAD, LDL cholesterol was lower with both the CHO (-7.0%) and MUFA (-6.3%) diets, whereas the difference in HDL cholesterol was smaller during the MUFA diet (-4.3%) than during the CHO diet (-7.2%). Plasma triacylglycerols tended to be lower with the MUFA diet, but were significantly higher with the CHO diet. Although dietary lipid responses varied on the basis of baseline lipid profiles, the response to diet did not differ between subjects with or without the metabolic syndrome or with or without insulin resistance. Postprandial triacylglycerol concentrations did not differ significantly between the diets. Lipoprotein(a) concentrations increased with both the CHO (20%) and MUFA (11%) diets relative to the AAD. CONCLUSIONS: In the study population, who were at increased risk of coronary artery disease, MUFA provided a greater reduction in risk as a replacement for saturated fat than did carbohydrate.     

Knowledge and practices by adolescents in preventing occupational injuries: a qualitative study

OBJECTIVE: To describe knowledge and practices adopted by high school students to prevent occupational injuries. STUDY DESIGN: The study was carried out in a public school located in S?o Paulo, in 2003. Fifty-three evening students aged 14 to 21 years old participated the study, they were divided into two groups with and without job experience (32 and 21 students, respectively). The students answered two questions: "Why do occupational injuries occur?" and "How do you avoid occupational injuries?" Analyses were performed using the software "Quali-quanti" to structure collective discourses. ANALYSIS OF DISCOURSES: Adolescents with work experience reported that occupational injuries occur due to carelessness of the employee, bad luck of the employee, employer's negligence, lack of training, and unsafe workplace. Adolescents without work experience reported that the main causes of work injuries were carelessness of the employee and employer's negligence. Regarding the ways to protect themselves against occupational injuries, both groups reported that: they pay attention (would pay attention) and wear safety equipment (would wear) safety equipment. CONCLUSIONS: Adolescents from both groups showed limited knowledge about occupational injuries and prevention methods. Students "blamed the victim" to explain the injuries and considered "paying attention to work" as the best way to protect themselves. These facts showed that the culture of blaming the victim is present since adolescence and probably it is an outcome of a learning process of the society.