Pathological assessment of mismatch repair gene variants in Lynch syndrome: Past,present, and future

Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and is the most prevalent hereditary colorectal cancer syndrome. A significant proportion of variants identified in MMR and other common cancer susceptibility genes are missense or noncoding changes whose consequences for pathogenicity cannot be easily interpreted. Such variants are designated as “variants of uncertain significance” (VUS). Management of LS can be significantly improved by identifying individuals who carry a pathogenic variant and thus benefit from screening, preventive, and therapeutic measures. Also, identifying family members that do not carry the variant is important so they can be released from the intensive surveillance. Determining which genetic variants are pathogenic and which are neutral is a major challenge in clinical genetics. The profound mechanistic knowledge on the genetics and biochemistry of MMR enables the development and use of targeted assays to evaluate the pathogenicity of variants found in suspected patients with LS. We describe different approaches for the functional analysis of MMR gene VUS and propose development of a validated diagnostic framework. Furthermore, we call attention to common misconceptions about functional assays and endorse development of an integrated approach comprising validated assays for diagnosis of VUS in patients suspected of LS. Hum Mutat 33:1617–1625, 2012. © 2012 Wiley Periodicals, Inc.     

Prevalence of early stages of chronic kidney disease in healthy army personnel

Introduction: Chronic kidney disease (CKD) is associated with significant morbidity and mortality. Screening and detection of early stages of CKD can help institute interventions that may delay the progression of the disease. One aim was to study the prevalence of early stages of CKD in the Army.Methods: A cross-sectional study ofArmy Personnel in an Army cantt in Central India was carried out. All participants filled a structured questionnaire and anthropometric data was collected. Investigative profile included routine urine exam, semi-quantitative microalbuminuria (MAU), serum creatinine, lipid profile and fasting blood glucose. Glomerular Filteration rate (eGFR) was calculated using the Modification of Diet in Renal Diseases (MDRD) study equation.Result: A total of 1920 subjects were examined with 731 (38.07%) from Arms and 1189 (6I.93%) from Services. 348 were excluded and of the remaining 1572 subjects, 141 (8.97%) had MAU and 157 (9.99%) had deranged Albumin Creatinine Ratio (ACR). Mean eGFR by MDRD equation was 102 ± 25.84 ml/min/1.73m². Early CKD was seen in 150 (9.54%) with 84 (5.34%) in stage I CKD, 55 (3.5%) in stage II and 11 (0.7%) in stage III. Multiple logistic regression showed BMI > 23, the presence of DM and HTN were independent risk factors for CKD.Conclusion: 9.54 % of healthy army personnel were found to have early stages of CKD. Institution of screening programs can result in early detection of CKD.     

Neuropsychological aspects of childhood multiple sclerosis: an overview

While cognitive impairment, major depression, and fatigue have been well documented in adult patients with multiple sclerosis (MS), there is still little information regarding MS-associated cognitive disabilities in infants and adolescents who represent 3 to 5% of all MS cases. Recent studies show that cognitive decline related to MS profoundly interferes with academic success and psychosocial adjustment. Neuropsychological dysfunction affects quality of life more significantly than mere Expanded Disability Status Scale is able to reflect. We herein give an overview of the knowledge available to date. Affective and emotional disturbances together with other comorbidities interfering with cognition are also reviewed. Finally, possible suggestions and future directions for the assessment of cognitive capabilities in children with MS are envisioned.     

Carrier detection in hemophilia A: a cooperative international study. I. The carrier phenotype

Eight laboratories in six countries cooperated to clarify several issues concerning the phenotypes of heterozygous carriers of hemophilia "A." Plasma levels of factor VIII (F.VIII:C, formerly VIII:C) and von Willebrand factor (VWF:Ag, formerly VIIIR:Ag) of carriers and normal women were determined by various "in-house" methods; a single lyophilized plasma standard was used for all assays. Analysis of the collated data from 336 carriers (296 obligatory carriers and 40 sporadic carriers) and 137 normal women showed that there was no difference in the F.VIII:C levels of "paternal" carriers (women who had obtained the abnormal gene from their fathers) and "maternal" carriers. Neither was there a difference in the VWF:Ag levels of normal women and either type of carrier. Age was found to have a significant effect on both F.VIII:C and VWF:Ag, values being higher at very young and very old ages, the minima occurring in the 25- to 30-year range. ABO blood type had a striking effect. Women of types A, B, and AB (designated non- O in the study), both normals and carriers, had significantly higher levels of both factors than did women of type O. Analysis by laboratories showed that differences in mean levels of both factors between laboratories were highly significant. It was concluded that age, ABO blood type, and laboratory variation should be taken into account in carrier detection.     

EXPERIENCE WITH VIPERINE ENVENOMATION

Two hundred and twenty one cases of viperine envenomation, who presented to hospital without specific treatment, seen over an twenty five years period, have been presented. Mild, moderate and severe envenomation was encountered in 33 per cent, 47 per cent and 20 per cent respectively. Bites on feet and ankles were seen in 85.5 per cent of cases. The average time interval between bite and hospitalisation was 4.8 hours, range being 15 minutes to 7 days. Local swelling was observed in 97.7 per cent, hematuria in 62 per cent, mucosal haemorrhages in 24.8 per cent and haematemesis in 19 per cent of patients. Average Antisnake Venom (ASV) required in mild, moderate and severe envenomation was 50 ml, 147.5 ml and 324 ml respectively. Major complications observed were renal failure in 10, intracompartmental syndrome in 3, intracerebral bleed and septicaemia in 2 each. One patient each developed finger gangrene, osteomyelitis, perirenal haematoma, sinus bradycardia and uncontrolled bleeding. Blood transfusion was required in 32 patients. Reactions to ASV were seen in 12 patients and overall there were 5 deaths.KEY WORDS: Antisnake venom, Viperine envenomation     

A Stat5b transgene is capable of inducing CD8+ lymphoblastic lymphoma in the absence of normal TCR/MHC signaling

Stat5 proteins are critical signaling molecules activated by many cytokines. Within the immune system, Stat5 plays important roles related to the development of thymocytes and proliferation of T cells. Stat5 has been implicated in malignant transformation, and moreover, the activated tyrosine phosphorylated form of Stat5 is frequently observed in human lymphomas. We previously demonstrated the oncogenic potential of Stat5, with thymic lymphoblastic lymphomas developing in a significant proportion of transgenic (TG) mice overexpressing Stat5a or Stat5b in lymphocytes. In addition, immunization or expression of a T-cell receptor (TCR) transgene augmented the rate of tumor formation. Here, we investigate the mechanism of Stat5-mediated lymphomagenesis by exploring the contributions of major histocompatibility complex (MHC)/TCR and pre-TCR signals. We present data demonstrating that Stat5b TG mice unexpectedly develop CD8(+) lymphoma even in the absence of either pre-TCR signaling or normal thymic selection. Indeed, acceleration of Stat5b transgene-mediated lymphoma occurred on TCRalpha(-/-) and pre-TCRalpha(-/-) backgrounds. In light of these data, we propose a model in which alterations in T-cell development at the double-negative/double-positive (DN/DP) stages cooperate with cytokine-mediated pathways in immature thymocytes to give rise to lymphoblastic T-cell lymphomas in Stat5b TG mice.