Reserpine modulates neurotransmitter release to extend lifespan and alleviate age-dependent Aβ proteotoxicity in Caenorhabditis elegans

Aging is a debilitating process often associated with chronic diseases such as diabetes, cardiovascular and neurodegenerative diseases like Alzheimer's disease (AD). AD occurs at a very high incidence posing a huge burden to the society. Model organisms such as C. elegans become essential to understand aging or lifespan extension - the etiology, molecular mechanism and identification of new drugs against age associated diseases. The AD model, manifesting Aβ proteotoxicity, in C. elegans is well established and has provided valuable insights. Earlier, we have reported that Reserpine, an FDA-approved antihypertensive drug, increases C. elegans lifespan with a high quality of life and ameliorates Aβ toxicity in C. elegans. But reserpine does not seem to act through the known lifespan extension pathways or inhibition of its known target, vesicular monoamine transporter, VMAT. Reserpine's mode of action and the pathways it activates are not known. Here, we have evaluated the presynaptic neurotransmitter(s) release pathway and identified acetylcholine (ACh) as the crucial player for reserpine's action. The corroborating evidences are: i) lack of lifespan extension in the ACh loss of function (hypomorphic) - synthesis (cha-1) and transport (unc-17) mutants; ii) mitigation of chronic aldicarb effect; iii) lifespan extension in dopamine (cat-2) and dopamine and serotonin (bas-1) biosynthetic mutants; iv) no rescue from exogenous serotonin induced paralysis in the AD model worms; upon reserpine treatment. Thus, modulation of acetylcholine is essential for reserpine's action.     

Novel Mutations in Cyclin-Dependent Kinase-Like 5 (CDKL5) Gene in Indian Cases of Rett Syndrome

Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Both the classic and atypical forms of Rett syndrome are primarily due to mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with atypical Rett syndrome, X-linked infantile spasms sharing common features of generally early-onset seizures and mental retardation. CDKL5 is known as serine/threonine protein kinase 9 (STK9) and is mapped to the Xp22 region. It has a conserved serine/threonine kinase domain within its amino terminus and a large C-terminal region. Disease-causing mutations are distributed in both the amino terminal domain and in the large C-terminal domain. We have screened the CDKL5 gene in 44 patients with atypical Rett syndrome who had tested negative for MECP2 gene mutations and have identified 6 sequence variants, out of which three were novel and three known mutations. Two of these novel mutations p.V966I and p.A1011V were missense and p.H589H a silent mutation. Other known mutations identified were p.V999M, p.Q791P and p.T734A. Sequence homology for all the mutations revealed that the two mutations (p.Q791P and p.T734A) were conserved across species. This indicated the importance of these residues in structure and function of the protein. The damaging effects of these mutations were analysed in silico using PolyPhen-2 online software. The PolyPhen-2 scores of p.Q791P and p.T734A were 0.998 and 0.48, revealing that these mutations could be deleterious and might have potential functional effect. All other mutations had a low score suggesting that they might not alter the activity of CDKL5. We have also analysed the position of the mutations in the CDKL5 protein and found that all the mutations were present in the C-terminal domain of the protein. The C-terminal domain is required for cellular localization through protein–protein interaction; any mutations in this domain might alter this function of the protein. This is the first report from India showing the mutation in CDKL5 gene in Indian cases of Rett syndrome. Our study emphasizes the role of CDKL5 mutation screening in cases of atypical Rett syndrome with congenital seizure variant.     

QTc-Prolongation in Posterior Circulation Stroke

Background and Purpose

To evaluate the relationship between infarct location and QTc-prolongation in patients with posterior circulation strokes.

Methods

Admission electrocardiograms (ECG) of 131 patients among a prospective sample of 407 consecutive adult patients in the New England Medical Center Posterior Circulation Registry were retrospectively analyzed. The QT interval (ms) was measured and corrected using Bazett’s formula (QTc_Bazett) as well as linear regression functions (QTc_Linear). QTc_Bazett > 440 ms and QTc_Linear ≥ 450 ms for men (≥460 ms for women) were considered prolonged. Multivariable linear and logistic regression analyses were used to identify independent predictors of the QTc.

Results

Overall, 34 % of patients had a prolonged QTc_Bazett and 7 % had a prolonged QTc_Linear noted on the admission ECG. There was a significant association between temporal lobe infarction and QTc_Bazett and QTc_Linear (p < 0.001 for both) in multivariable linear regression analyses adjusting for demographics, ECG parameters, and preadmission medication use. In multivariable logistic regression analysis, temporal lobe infarction emerged as an independent predictor of prolonged QTc_Bazett (p = 0.009) and QTc_Linear (p = 0.008), respectively. Sensitivity analyses excluding patients with transient ischemic attack yielded similar results. Exploratory analyses indicated that patients with temporal lobe infarction had worse functional 30-day outcomes in multivariable logistic regression (p = 0.022). However, there was no significant association between QTc and 30-day functional outcome.

Conclusions

QTc-prolongation is common after posterior circulation stroke and associated with temporal lobe infarction. Prospective studies are needed to confirm these preliminary findings and to examine potential long-term consequences.     

Double-blind randomized controlled study showing symptomatic and cognitive superiority of bifrontal over bitemporal electrode placement during electroconvulsive therapy for schizophrenia

BackgroundSeveral studies show that bifrontal electrode placement produces relatively fewer cognitive adverse effects than bitemporal placement during electroconvulsive therapy (ECT) in depression. There are no reports comparing these electrode placements in schizophrenia.ObjectivesThis study compared the clinical and cognitive effects of bifrontal and bitemporal electrode placements in schizophrenia patients referred for electroconvulsive therapy (ECT).Methods122 schizophrenia patients who were prescribed ECT were randomized to receive ECT with either bifrontal (BFECT; n = 62) or bitemporal (BTECT; n = 60) placement. Their concomitant anti-psychotic medications and the number of ECT sessions were not controlled. Psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS), Bush-Francis Catatonia Rating Scale (BFCRS), and the Nurse Observation Scale for Inpatient Evaluation (NOSIE). Cognitive functions were assessed 24-h after the final ECT using a battery of tests. Clinical improvement was compared using chi-square test, repeated measures ANOVA and analysis of covariance (ANCOVA). Cognitive adverse effects were compared using t-test.ResultsAt the end of 2 weeks (after 6 ECT sessions) 63% and 13.2% of BFECT and BTECT patients respectively had met the response criterion for BPRS (40% reduction in total score; OR = 20.8; 95% CI = 3.61–34.33). BFECT patients showed significantly faster clinical response on BPRS (Time × Group interaction effect: P = 0.001), BFCRS (P < 0.001) and the NOSIE total assets score (P = 0.003). ANCOVA using baseline scores as covariates and treatment-resistance status as between-subject factor showed that BFECT patients had significantly greater improvement in all measures. BFECT patients had significantly higher PGI-memory-scale total score than BTECT patients (t = 5.16; P < 0.001). They also showed superior performance in other cognitive measures.ConclusionsBFECT results in superior clinical and cognitive outcomes than BTECT in schizophrenia patients referred for ECT.     

Diabetes and Tooth Loss: An analysis of data from the National Health and Nutrition Examination Survey, 2003–2004

BackgroundThe authors conducted an analysis of data from the National Health and Nutrition Examination Survey (NHANES) to understand the association between diabetes and tooth loss in the United States.MethodsThe authors analyzed the oral examination and self-reported diabetes data obtained from the NHANES 2003–2004 cycle and included 2,508 participants representing a civilian, noninstitutionalized U.S. population 50 years and older. The authors calculated the prevalence of edentulism and the number of missing teeth among dentate people, and they used multiple regression analyses to assess the association between diabetes and tooth loss.ResultsThe prevalence of edentulism was 28 percent and 14 percent among people with and without diabetes, respectively. The multiple logistic regression analysis revealed that people with diabetes were more likely to be edentulous than were those without diabetes (adjusted odds ratio = 2.25; 95 percent confidence interval, 1.19–4.21). Among dentate adults, those with diabetes had a higher number of missing teeth than did adults without diabetes (mean [standard error {SE}] = 9.8 [0.67]), mean [SE] = 6.7 [0.29]); P < .01).ConclusionsThese study results revealed that adults with diabetes are at higher risk of experiencing tooth loss and edentulism than are adults without diabetes. One of every five cases of edentulism in the United States is linked to diabetes.Practical ImplicationsAlthough the association between diabetes and periodontal disease is well established, health care professionals also need to recognize the risk of tooth loss and its effect on quality of life among people with diabetes.     

Non‐Hodgkin's lymphoma presenting as breast masses: A series of 10 cases diagnosed on FNAC

Primary breast lymphoma (PBL) is a rare disease, which comprises 0.04–0.53% of all primary malignant tumors of the breast. The most frequent histological subtype is diffuse large B‐cell type (DLBCL) (40–70%). Differentiation of PBLs from other breast tumors such as poorly differentiated carcinomas and lobular carcinoma may at times be difficult on cytomorphology alone. An audit of breast lymphomas diagnosed on fine needle aspiration cytology (FNAC) over a period of 9 years (2001–2009) was performed. Ten cases were retrieved and the cytomorphology was reviewed along with immunochemistry (IHC), flow cytometry as well as histopathology, wherever available. The age of patients ranged from 17 to 83 years. Eight cases were diagnosed as non‐Hodgkin's lymphoma, high‐grade on FNAC. Histopathology was available in four of these cases and cell block was available in one case. Lymphoid cells were positive for leukocyte‐common antigen (LCA) and CD20 and negative for CD3 in these cases. The same was confirmed by flow cytometry on aspirated material in one case. A diagnosis of DLBCL was offered in these five cases. One case was a low‐grade NHL and another case was a young male, a known case of acute leukemia and had leukemic infiltration in the breast lump. We wish to emphasize the potential importance of FNAC in breast lymphoma and the same can be helpful to avoid unnecessary surgery in these cases. The differential diagnostic entities have been discussed. IHC and flow cytometry can be performed on the aspirated material and provide valuable information. Diagn. Cytopathol. 2013. © 2011 Wiley Periodicals, Inc.     

Odds ratio of risk factors for oral submucous fibrosis in a case control model

Our aim was to calculate the odds ratio (OR) of various epidemiological, social, behavioural, and dietary risk factors for oral submucous fibrosis in a population-based case control study. We did this in rural and urban Lucknow by organising oral health camps in the community, where a total of 3136 subjects were enrolled. Panmasala, a dry commercial preparation containing areca nut, slaked lime, catechu, and condiments, with or without tobacco, was the most important aetiological factor for the disease. The 95% confidence interval (CI) of the OR for tobaccoless panmasala ranged from 4.77 to 6.88 and for tobacco panmasala from 4.55 to 9.71. OR using multivariate analysis was 14.09 for tobaccoless panmasala and 5.39 for tobacco panmasala. Patients who use panmasala are at high risk of developing oral submucous fibrosis.