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Shiv Kumar Sarin,Ajit Sood,Manoj Kumar,Anil Arora,Deepak Amrapurkar,Barjesh Chander Sharma,Ashokananda Konar,Yogesh Kumar Chawla,Rajendra Kumar Jain,Vijay Nanda,Arun Kumar,Syed Hissar,Piramal Lavate,Deepak Lahoti,National Collaborative Group on Hepatitis B, India  BACKGROUND: Lower hepatitis B virus DNA (HBV DNA) levels are associated with better responses in chronic hepatitis B (CHB). It is unclear whether an initial phase of antiviral treatment to lower HBV DNA levels before adding immunomodulator therapy is more effective than the strategy of using immuno... ( view more )modulators from the beginning. AIM: The aim of the study was to compare the efficacy of lamivudine followed by pegylated-interferon (peg-IFN) therapy with placebo followed by peg-IFN therapy in HBeAg-positive CHB patients. PATIENTS AND METHODS: Sixty-three treatment-naive HBeAg-positive patients with histologically proven CHB and alanine aminotransferase (ALT) > 1.2 x upper limit of normal (ULN) received placebo for 4 wk followed by peg-IFN 1.0 mug/kg/wk for next 24 wk (group A, N = 27; age 32 +/- 11 yr; M:F = 25:2) or lamivudine 100 mg per day for 4 wk followed by peg-IFN 1.0 mug/kg/wk for next 24 wk (group B, N = 36; age 32.5 +/- 10.5 yr; M:F = 31:5). Patients were followed for next 24 wk after completion of treatment. Biochemical and virologic responses were assessed at weeks 4, 28, and 52 and analysis was done on intention-to-treat basis. RESULTS: At wk 4, mean +/- SD of log change in DNA from baseline was 0.2594 +/- 1.7873 in group A and 1.2186 +/- 1.6347 in group B, respectively (P = 0.032). At week 28, undetectable HBV DNA was seen in eight (29.6%) and 16 (44.4%) patients in groups A and B, respectively (P= 0.298). At week 28, HBeAg loss occurred in eight (29.6%) in group A and 15 (41.7%) in group B (P = 0.43). Six months posttherapy, at week 52, undetectable HBV DNA was seen in four (14.8%) and 18 (50%) in groups A and B, respectively (P = 0.028) and HBeAg loss was maintained in four (14.8%) and 14 (38.9%) (P = 0.05) patients. Normal ALT was seen in five (18.5%) and 10 (27.8%) at week 28 (P = 0.552) and five (18.5%) and 13 (36.1%) at week 52 (P = 0.159) in groups A and B, respectively. There was a significant correlation among achievement of HBeAg loss, anti-HBe appearance, and undetectable HBV DNA levels at week 28 (P = 0.008) and 52 (P < 0.001) and HBV DNA levels at week 4. CONCLUSIONS: The strategy of using an antiviral initially to decrease HBV DNA levels before adding an immunomodulatory agent leads to improved sustained virological response as compared with using immunomodulator from the start. ( view less ) Asha Sharma,U Lourderaj,Deepak Deepak,N Sathyamurthy Polysilanes are potential candidates for active materials in light emitting diodes because of possible emission in the near-ultraviolet to blue region. Unfortunately, they degrade rapidly upon exposure to light because of scission of sigma bonds. Relative stability of four polysilanes, for example,... ( view more ) poly(di-n-butylsilane) (PDBS), poly(di-n-hexylsilane) (PDHS), poly(methylphenylsilane) (PMPS), and poly[bis(p-butylphenyl)silane] (PBPS), which have been reported as active materials in light emitting diodes, have been investigated theoretically through semiempirical (AM1) and ab initio (HF/6-31g) methods and density functional theory using B3LYP parametrization. The AM1 level of calculation predicts the absorption maxima reasonably, but it fails to explain the relative stabilities of the four polysilanes in the excited state. However, calculations based on configuration interaction with single excitation and time-dependent density functional theory suggest additional stabilization in the excited states through intersystem crossing to triplets for PMPS and PBPS, consistent with the experimental observation. In contrast, no such stabilization is predicted for PDBS and PDHS. Furthermore, the existence of a stable triplet state in PMPS may also explain the visible emission observed experimentally in PMPS. ( view less ) Hitinder S Gurm,Vivek Rajagopal,Robert Fathi,Deepak Vivekanathan,Jay S Yadav,Deepak L Bhatt,Stephen G Ellis,A Michael Lincoff,Eric J Topol A recent large-scale, randomized trial demonstrated the noninferiority of a strategy of bivalirudin with provisional glycoprotein (GP) IIb/IIIa inhibition compared with routine GP IIb/IIIa inhibition. There is a paucity of outcome data with bivalirudin use in the setting of real-world experience. W... ( view more )e evaluated 6,996 patients who underwent percutaneous coronary intervention between January 2001 and December 2004 to compare early and late outcomes with a bivalirudin-based antithrombotic regimen with those with a heparin-based regimen. Propensity adjustment was performed to correct for baseline differences in patient characteristics. Bivalirudin-based therapy was used in 1,070 patients, heparin only in 801 patients, and heparin plus GP IIb/IIIa inhibitors in 5,125 patients. Compared with patients who received heparin or those who received heparin plus GP IIb/IIIa inhibitors, patients who received bivalirudin had lower incidences of bleeding (blood transfusion rate 1.7% vs 4.0%, p <0.001) and periprocedural myonecrosis (creatine kinase-MB >5 times the upper limit of normal 2.7% vs 4.3%, p = 0.016). Differences in bleeding end points remained significant after adjusting for the propensity to receive bivalirudin, but there was no difference in ischemic events. There was no difference in unadjusted long-term survival rate (log-rank test p = 0.46, total number of deaths 412, mean follow-up 17 months) or in propensity-adjusted long-term survival rate (hazard ratio 1.37, 95% confidence interval 0.90 to 2.08, p = 0.14). Compared with heparin with or without GP IIb/IIIa inhibition, the use of bivalirudin in a large consecutive patient registry at a tertiary care center was associated with fewer bleeding events and no evident increase in the incidence of ischemic complications. ( view less ) Deepak P Vivekananthan,Deepak L Bhatt,Derek P Chew,Frank J Zidar,Albert W Chan,David J Moliterno,Stephen G Ellis,Eric J TopolThis study sought to determine the effect of clopidogrel pretreatment on the increase in C-reactive protein (CRP) after percutaneous coronary intervention. Clopidogrel pretreatment attenuated the periprocedural increase in CRP by 65% and was independently associated with an attenuation in the CRP i... ( view more )ncrease in a multivariate model. ( view less ) Martin J Quinn,Deepak L Bhatt,Frank Zidar,Deepak Vivekananthan,Derek P Chew,Stephen G Ellis,Edward Plow,Eric J Topol Platelets play an important role in the inflammatory response. In a nonrandomized comparison, we examined the effect of clopidogrel pretreatment on platelet inflammatory marker expression in patients undergoing percutaneous coronary intervention (PCI). Platelet expression of the inflammatory marker... ( view more )s CD40 ligand (L) and CD62 P-selectin (P) and serum levels of interleukin-6 and CD40L were compared in patients pretreated (>24 hours before PCI) or not pretreated with clopidogrel. Blood samples were obtained before and after the procedure, and from 18 to 24 hours later. Marker expression in resting and adenosine diphosphate (ADP) (50 micromol/L) and thrombin receptor activating peptide (TRAP) (10 micromol/L) activated samples was quantified by flow cytometry. Serum CD40L and interleukin (IL)-6 levels were determined by enzyme-linked immunosorbent assay. Seventy-nine patients were recruited into the study. Forty-two percent were pretreated with clopidogrel for a median of 5 days (range 1 to 1,325). Clopidogrel pretreatment was associated with lower ADP-activated platelet CD40L expression in baseline and postprocedural samples. Similarly, platelet CD62P expression at all time points in ADP-activated and in baseline and postprocedural TRAP-activated samples was lower in patients pretreated with clopidogrel. These differences remained after multivariate adjustment between the groups. Serum CD40L levels increased from 2.13 +/- 2.37 ng/ml at baseline to 4.77 +/- 3.86 ng/ml at 18 to 24 hours after the procedure (p <0.0001). Similarly, serum IL-6 levels increased at 18 to 24 hours after the procedure (14.8 +/- 42.0 pg/ml before vs 25.5 +/- 36.0 pg/ml at 18 to 24 hours after the procedure, p <0.0001). Clopidogrel pretreatment did not affect serum IL-6 or CD40L levels. Thus, clopidogrel pretreatment reduces platelet inflammatory marker expression in patients undergoing PCI. ( view less ) Vandana Malhotra,Deepak Sharma,V D Ramanathan,H Shakila,Deepak K Saini,Soumitesh Chakravorty,Taposh K Das,Qing Li,Richard F Silver,P R Narayanan,Jaya Sivaswami Tyagi The devR-devS two-component system of Mycobacterium tuberculosis was identified earlier and partially characterized in our laboratory. A devR::kan mutant of M. tuberculosis was constructed by allelic exchange. The devR mutant strain showed reduced cell-to-cell adherence in comparison to the parenta... ( view more )l strain in laboratory culture media. This phenotype was reversed on complementation with a wild-type copy of devR. The devR mutant and parental strains grew at equivalent rates within human monocytes either in the absence or in the presence of lymphocytic cells. The expression of DevR was not modulated upon entry of M. tuberculosis into human monocytes. However, guinea pigs infected with the mutant strain showed a significant decrease in gross lesions in lung, liver and spleen; only mild pathological changes in liver and lung; and a nearly 3 log lower bacterial burden in spleen compared to guinea pigs infected with the parental strain. Our results suggest that DevR is required for virulence in guinea pigs but is not essential for entry, survival and multiplication of M. tuberculosis within human monocytes in vitro. The attenuation in virulence of the devR mutant in guinea pigs together with DevR-DevS being a bona fide signal transduction system indicates that DevR plays a critical and regulatory role in the adaptation and survival of M. tuberculosis within tissues. ( view less ) Kalishwaralal Kalimuthu,Ramkumarpandian Suresh Babu,Deepak Venkataraman,Mohd Bilal,Sangiliyandi GurunathanThe use of microorganisms for the synthesis of nanoparticles is in the limelight of modern nanotechnology. Using the bacterium Bacillus licheniformis, the biosynthesis of silver nanoparticles was investigated. These silver nanoparticles were characterized by means of UV-vis spectroscopy, scanning e... ( view more )lectron microscopy (SEM), electron diffraction spectroscopy (EDX) and X-ray diffraction (XRD). The nanoparticles exhibited maximum absorbance at 440nm in UV-vis spectroscopy. The XRD spectrum of silver nanoparticles exhibited 2theta values corresponding to the silver nanocrystal. SEM micrographs revealed the formation of well-dispersed silver nanoparticles of 50nm, and the presence of silver was confirmed by EDX analysis. ( view less ) Rohan Dixit,Vaibhav Tiwari,Deepak ShuklaHerpes simplex virus type-1 (HSV-1) is a neurotropic virus with significant potential as a viral vector for central nervous system (CNS) gene therapy. This study provides visual evidence that recombinant green fluorescent protein (GFP)-expressing HSV-1 travel down dendrites in differentiated P19 ne... ( view more )uronal-like cells to efficiently reach the soma. The virus also promotes cytoskeletal rearrangements which facilitate viral spread in vitro, including often dramatic increases in dendritic filopodia. Viral movements, cell infection and filopodia induction were each reduced with the actin polymerization inhibitor cytochalasin D, suggesting the involvement of the actin cortex in these processes. The observation of neural cytoskeletal reorganization in response to HSV-1 may shed light on the mechanisms by which acute viral infection associated with herpes encephalitis produces cognitive deficits in patients. ( view less ) Deepak Kaul,A Gautam,S Varma,A AhlawatKeeping in view the fact that a single acquired genetic abnormality "Bcr-Abl chimeric gene" accompanied by elevated telomerase activity has been widely recognized to be responsible for the leukemic myelopoiesis observed in chronic myeloid leukemia (CML), the present study was addressed to understan... ( view more )d as to how selective and specific knock-down of human telomerase reverse transcriptase (hTERT) gene within mononuclear cells derived from untreated CML subjects could influence the apoptotic, genotypic (such as Bcr-Abl; C-myc; Bcl-2; IL-6; GMCSF; IL-3; and acetylated H(3) and H(4)), and phenotypic (such as CD34 and CD89) characteristics of these cells. Based upon these results, we propose that hTERT gene-based drug design may be useful in the treatment of leukemic myelopoiesis. ( view less ) Bethany J Slater,Matthew D Kwan,Deepak M Gupta,Nicholas J Panetta,Michael T Longaker BACKGROUND: Skeletal defects represent a significant socioeconomic burden to the US healthcare system. Current options for reconstructing osseous deficits have shortcomings. OBJECTIVE: To review the use of mesenchymal stem cells for skeletal tissue engineering. METHODS: We focused on the applicatio... ( view more )n of mesenchymal cells in skeletal regeneration, optimization of this technique, tropic effects of multipotent mesenchymal cells, and future directions. RESULTS/CONCLUSION: A number of cell-based modalities have been investigated. We have been interested in the role of adipose-derived stromal cells in bone regeneration and understanding the mechanisms behind osteogenic differentiation of progenitor cells and acceleration of this process. Future clinical applications of multipotent mesenchymal cells will depend on better understanding of the molecular signaling involved in osteogenic differentiation and maintaining pluripotency. ( view less ) Ping Kang,Deepak Dalvie,Evan Smith,Sue Zhou,Alan Deese,James A Nieman Flutamide, a widely used nonsteroidal antiandrogen drug for the treatment of prostate cancer, has been associated with rare incidences of hepatotoxicity in patients. It is believed that bioactivation of flutamide and subsequent covalent binding to cellular proteins is responsible for its toxicity. ... ( view more )A novel N-S glutathione adduct has been identified in a previous bioactivation study of flutamide (Kang et al., 2007). Due to the extensive first pass metabolism, flutamide metabolites such as 2-hydroxyflutamide and 4-nitro-3-(trifluoromethyl)phenylamine (Flu-1) have achieved plasma concentrations higher than the parent in prostate cancer patients. In vitro studies in human liver microsomes were conducted to probe the cytochrome P450 (P450)-mediated bioactivation of flutamide metabolites and identify the possible reactive species using reduced glutathione (GSH) as a trapping agent. Several GSH adducts (G1, Flu-1-G1, Flu-1-G2, Flu-6-Gs) derived from the metabolites of flutamide were identified and characterized. A comprehensive bioactivation mechanism was proposed to account for the formation of the observed GSH adducts. Of interest were the formation of a reactive intermediate by the desaturation of the isopropyl group of M5 and the unusual bioactivation of Flu-1. Studies using recombinant P450s suggested that the major P450 isozymes involved in the bioactivation of flutamide and its metabolites were CYP1A2, CYP3A4, and CYP2C19. These findings suggested that, in addition to the direct bioactivation of flutamide, the metabolites of flutamide could also be bioactivated and contribute to flutamide-induced hepatotoxicity. ( view less ) Theodore Chow,Deepak Joshi Extensive research and clinical interest has focused recently on use of microvolt T-wave alternans (MTWA) as a means for sudden death risk stratification in patients with cardiomyopathy. Emphasis has been placed on determining whether MTWA testing can more accurately identify high-risk patients fro... ( view more )m the broad population who are potentially eligible for prophylactic implantable cardioverter defibrillators. More recent studies seek to determine if additional patients not currently covered by primary prevention implantable cardioverter defibrillator guidelines could be defined using MTWA. Unfortunately, accumulation of clinical data has not necessarily led to clarity in the minds of the end-users as to the role of MTWA in clinical practice. This article serves to provide background information, selective review of relevant studies, and a perspective on where the field stands today. A general framework for incorporating MTWA into clinical practice is presented. ( view less ) Mamidipudi R Praveen,Archana Koul,Abhay R Vasavada,Deepak Pandita,Nirmit V Dixit,Farida F Dahodwala PURPOSE: To compare the effects and outcomes of DisCoVisc (hyaluronic acid 1.6%-chondroitin sulfate 4.0%) with those of the soft-shell technique using Viscoat (sodium hyaluronate 3.0%-chondroitin sulfate 4.0%) and Provisc (sodium hyaluronate 1.0%) in phacoemulsification. SETTING: Iladevi Cataract &... ( view more ) IOL Research Centre, Ahmedabad, India. METHODS: This prospective randomized clinical trial comprised 100 eyes having phacoemulsification by the same surgeon using a standardized technique. Eyes were randomly assigned to DisCoVisc (Group 1) or Viscoat and Provisc (Group 2). Preoperative and postoperative examinations included absolute change in pachymetry, percentage difference in endothelial cell density (ECD) and coefficient of variation (CV), and anterior segment inflammation. RESULTS: The mean postoperative central corneal thickness (CCT) in Group 1 and Group 2 was 590.96 +/- 46.05 mum and 586.94 +/- 50.57 mum, respectively, at 1 day; 554.14 +/- 35.45 mum and 551.65 +/- 37.69 mum, respectively, at 7 days; and 533.74 +/- 29.12 mum and 536.44 +/- 35.59 mum, respectively, at 1 month. The between-group differences in CCT were not statistically significant. At 3 months, the mean ECD was 2427.06 +/- 243.26 cells/mm(2) and 2475.30 +/- 222.83 cells/mm(2), respectively, and the mean CV, 42.38 +/- 7.94 cells/mm(2) and 41.66 +/- 7.71 cells/mm(2), respectively. There was no significant difference in the mean ECD between preoperatively and 3 months postoperatively or in corneal thickness between preoperatively and 1, 7, and 30 days postoperatively. CONCLUSION: A single injection of DisCoVisc was effective, and its postoperative outcomes were comparable to those of combined Viscoat and Provisc. ( view less ) Sandrine Arnaud-Dabernat,Deepak Yadav,Nora Sarvetnick Fibroblast growth factors (FGFs) are important regulators of the dynamic development and turnover of tissues. Among FGF receptors, FGFR3 expression is confined in the intestinal crypts. We examined FGFR3-deficient mice and saw increased intestinal crypt depth but no change in villae length or in th... ( view more )e distribution of differentiated intestinal cells, suggesting that the impact of lack of FGFR3 was limited to the progenitor cell compartment. Accordingly, enhancement of intestinal crypt proliferation was observed in FGFR3 mutant mice and interestingly, upon anti-FGFR3 antibody administration in wild type mice. Moreover, injection of FGF18, a ligand of FGFR3, in wild type mice resulted in decreased cell proliferation within the intestinal crypts. In addition, we found that ERK level of activation was increased in FGFR3-deficient intestinal epithelium. In vitro studies showed that ERK, AKT and activation was regulated by FGFs and that ERK level of activation was inversely correlated to FGFR3 level of expression in the intestinal crypt cells. Furthermore, effects of FGF18 on ERK and AKT activation paralleled FGFR3 effects on these intracellular targets. Our data indicate that FGF18 and FGFR3 are involved, possibly as partners, in the control of intestinal precursor cell proliferation. ( view less ) Vikas Agarwal,Ram Singh, Wiclaf,Sandeep Chauhan,Anita Tahlan,Chirag Kamal Ahuja,Deepak Goel,Lily Pal Neuropathy in rheumatoid arthritis (RA) may result secondary to entrapment, vasculitis, and drug toxicity. We aimed to study clinical and electrophysiological neuropathy and pathological changes in sural nerve in patients with RA. One hundred eight patients of RA, fulfilling American College of Rhe... ( view more )umatology 1987 criteria (mean age, 45.83 years; M/F 1:3, 80.3% seropositive) were examined clinically and electrophysiologically for evidence of peripheral neuropathy. Sural nerve biopsies were performed in the involved cases. In all RA patient medications, disease activity, results of blood tests, and X-rays of affected joints were recorded. Twenty-three patients complained of paresthesias in the extremities. Vibration sensations were decreased in 9, and tendon reflexes were decreased or absent in 28 patients. Sixty-two (57.4%) patients had electrophysiologic evidence of neuropathy. Of these 53 (85.5%) patients had pure sensory or sensory motor axonal neuropathy (mononeuritis multiplex, n = 7), while 9 (14.5%) had demyelinating neuropathy (chronic inflammatory demyelinating polyneuropathy, n = 1). Carpal tunnel syndrome was seen in 11 (10.1%) patients (associated with neuropathy in 6). Of 23 sural nerve biopsies available, perineurial thickening (n = 5, amyloid deposits n = 4), perivascular lymphomononuclear cell infiltrate (n = 4), loss of myelin fibers (n = 2), and necrotizing vasculitis (n = 1) were found. Clinically, however, seven patients had evidence of cutaneous vasculitis. Comparing the clinical characteristics of the patients with or without electrophysiological neuropathy, absence of deep tendon jerks (p < 0.005) and presence of extra articular manifestations (p < 0.01) were conspicuous in the neuropathic group. There was no relation of neuropathy with the duration of RA, seropositivity, joint erosions, joint deformities, prior disease-modifying anti-rheumatic drugs or glucocorticoid intake, and 28-joint disease activity score. Neuropathy in RA was mostly subclinical and predominantly axonal. Pathologically, neuropathy secondary to amyloid infiltration was second only to vasculitic neuropathy. Absence of deep tendon jerks and presence of vasculitis were more commonly observed in patients with neuropathy. ( view less ) Manuel J Jayo,Deepak Jain,Belinda J Wagner,Timothy A Bertram PURPOSE: Internal organ regeneration holds promise for changing medical technology and decreasing organ shortages. Current medical treatment for internal organ failure is largely limited to organ transplantation. A construct composed of synthetic biopolymer with autologous cells has shown long-term... ( view more ) clinical benefit in patients undergoing augmentation cystoplasty. However, to our knowledge early cellular and stromal events during bladder regeneration have not been elucidated. MATERIALS AND METHODS: In situ cellular responses to 2 biopolymer implants, including a poly(lactic-co-glycolic acid) (Sigma-Aldrich) based biodegradable mesh scaffold with autologous urothelial and smooth muscle cells (construct) and a poly(lactic-co-glycolic acid) based biodegradable mesh scaffold alone without cells (scaffold), were compared in a canine model of augmentation cystoplasty. Healing events were correlated with urodynamic assessments. RESULTS: Construct implants regenerated baseline urodynamics as early as 4 months after implantation. Urodynamics following scaffold implantation failed to return to baseline by study termination at 9 months. Functional differences elicited by construct and scaffold implants correlated with structural differences in the neotissues. Construct stroma had greater vascularization with gently folded, interwoven connective tissue elements. Scaffold stroma was dense, haphazardly organized connective tissue. Urothelium regenerated in response to construct and scaffold implantation. However, only construct had normal stroma, well developed detrusor and abundant alpha-smooth muscle actin (Vector Laboratories, Burlingame, California) cell staining at early time points, leading to a structurally and functionally complete regenerated bladder wall at 9 months. CONCLUSIONS: Early cellular and stromal events distinguish healing processes that lead to bladder wall regeneration or repair. Construct implants containing cells elicit early healing processes that culminate with the regeneration of complete mucosal and muscular components, whereas the response to scaffold implantation is consistent with reparative healing, that is with mucosal growth but incomplete tissue layer development. ( view less ) Anthony A Bavry,Deepak L Bhatt Restenosis is a serious occurrence that can lead not only to recurrent angina and repeat revascularisation but also to acute coronary syndromes. Drug-eluting stents revolutionised interventional cardiology owing to their pronounced ability to reduce restenosis compared with bare-metal stents. Atten... ( view more )tion has now shifted to safety of these devices because of evidence suggesting an association with late stent thrombosis. Findings of randomised clinical trials have not shown that drug-eluting stents result in excess mortality after 4-5 years of follow-up. Current recommendations are that individuals with a drug-eluting stent should receive at least 12 months of uninterrupted dual antiplatelet treatment; patients must understand the importance of this long-term regimen. Patients' assessment should focus on bleeding abnormalities, pre-existing disorders that need anticoagulation treatment, and possible future surgical procedures, since these factors could all contraindicate use of drug-eluting stents. Many people will do well with a bare-metal stent, whereas for individuals with a high likelihood of restenosis and late thrombosis, medical management or surgical revascularisation might be preferred options. ( view less ) William J Groh,Miriam R Groh,Chandan Saha,John C Kincaid,Zachary Simmons,Emma Ciafaloni,Rahman Pourmand,Richard F Otten,Deepak Bhakta,Girish V Nair,Mohammad M Marashdeh,Douglas P Zipes,Robert M Pascuzzi BACKGROUND: Sudden death can occur as a consequence of cardiac-conduction abnormalities in the neuromuscular disease myotonic dystrophy type 1. The determinants of the risk of sudden death remain imprecise. METHODS: We assessed whether the electrocardiogram (ECG) was useful in predicting sudden dea... ( view more )th in 406 adult patients with genetically confirmed myotonic dystrophy type 1. A patient was characterized as having a severe abnormality if the ECG had at least one of the following features: rhythm other than sinus, PR interval of 240 msec or more, QRS duration of 120 msec or more, or second-degree or third-degree atrioventricular block. RESULTS: Patients with severe abnormalities according to the entry ECG were older than patients without severe abnormalities, had more severe skeletal-muscle impairment, and were more likely to have heart failure, left ventricular systolic dysfunction, or atrial tachyarrhythmia. Such patients were more likely to receive a pacemaker or an implantable cardioverter-defibrillator during the follow-up period. During a mean follow-up period of 5.7 years, 81 patients died; there were 27 sudden deaths, 32 deaths from progressive neuromuscular respiratory failure, 5 nonsudden deaths from cardiac causes, and 17 deaths from other causes. Among the 17 patients who died suddenly in whom postcollapse rhythm was evaluated, a ventricular tachyarrhythmia was observed in 9. A severe ECG abnormality (relative risk, 3.30; 95% confidence interval [CI], 1.24 to 8.78) and a clinical diagnosis of atrial tachyarrhythmia (relative risk, 5.18; 95% CI, 2.28 to 11.77) were independent risk factors for sudden death. CONCLUSIONS: Patients with adult myotonic dystrophy type 1 are at high risk for arrhythmias and sudden death. A severe abnormality on the ECG and a diagnosis of an atrial tachyarrhythmia predict sudden death. (ClinicalTrials.gov number, NCT00622453.) ( view less ) Ranjana Verma,Peter Holmans,James A Knowles,Deepak Grover,Oleg V Evgrafov,Raymond R Crowe,William A Scheftner,Myrna M Weissman,J Raymond DePaulo,James B Potash,Douglas F Levinson BACKGROUND: We reported genome-wide significant linkage on chromosome 15q25.3-26.2 to recurrent early-onset major depressive disorder (MDD-RE). Here we present initial linkage-disequilibrium (LD) fine mapping of this signal and sequence analysis of NTRK3 (neurotrophic receptor kinase-3), a biologic... ( view more )ally plausible candidate gene. METHODS: In 300 pedigrees informative for family-based association, 1195 individuals were genotyped for 795 single nucleotide polymorphism (SNPs). We resequenced 21 exons and 7 highly conserved NTRK3 regions in 176 MDD-RE cases to test for an excess of rare functional variants and, 176 controls for case-control analysis of common variants. RESULTS: LD mapping showed nominally significant association in NTRK3, FLJ12484, RHCG, DKFZp547K1113, VPS33B, SV2B, SLCO3A1, RGMA, and MCTP2 with MDD-RE. In NTRK3, five SNPs had nominally significant p values (.035-.001). Sequence analysis revealed 35 variants (24 novel, including 9 rare exonic); the number of rare variants did not exceed chance expectation. Case-control analysis of 13 common variants showed modest nominal association of MDD-RE with rs4887379, rs6496463, and rs3825882 (p = .008, .048, and .034), which were in partial LD with four of five associated SNPs from the family-based experiment. CONCLUSIONS: Common variants in NTRK3 or other genes identified might play a role in MDD-RE. However, much larger studies are required for full evaluation of this region. ( view less ) Hongbin Li,Hui-Chuan Wang,Yi Cao,Deepak Sharma,Meijia Wang Configurational entropy plays important roles in defining the thermodynamic stability as well as the folding/unfolding kinetics of proteins. Here we combine single-molecule atomic force microscopy and protein engineering techniques to directly examine the role of configurational entropy in the mech... ( view more )anical unfolding kinetics and mechanical stability of proteins. We used a small protein, GB1, as a model system and constructed four mutants that elongate loop 2 of GB1 by 2, 5, 24 and 46 flexible residues, respectively. These loop elongation mutants fold properly as determined by far-UV circular dichroism spectroscopy, suggesting that loop 2 is well tolerant of loop insertions without affecting GB1's native structure. Our single-molecule atomic force microscopy results reveal that loop elongation decreases the mechanical stability of GB1 and accelerates the mechanical unfolding kinetics. These results can be explained by the loss of configurational entropy upon closing an unstructured flexible loop using classical polymer theory, highlighting the important role of loop regions in the mechanical unfolding of proteins. This study not only demonstrates a general approach to investigating the structural deformation of the loop regions in mechanical unfolding transition state, but also provides the foundation to use configurational entropy as an effective means to modulate the mechanical stability of proteins, which is of critical importance towards engineering artificial elastomeric proteins with tailored nanomechanical properties. ( view less ) Zhong Xie,Huzefa Photowala,Michael E Cahill,Deepak P Srivastava,Kevin M Woolfrey,Cassandra Y Shum,Richard L Huganir,Peter Penzes Remodeling of central excitatory synapses is crucial for synapse maturation and plasticity, and contributes to neurodevelopmental and psychiatric disorders. Remodeling of dendritic spines and the associated synapses has been postulated to require the coordination of adhesion with spine morphology a... ( view more )nd stability; however, the molecular mechanisms that functionally link adhesion molecules with regulators of dendritic spine morphology are mostly unknown. Here, we report that spine size and N-cadherin content are tightly coordinated. In rat mature cortical pyramidal neurons, N-cadherin-dependent adhesion modulates the morphology of existing spines by recruiting the Rac1 guanine-nucleotide exchange factor kalirin-7 to synapses through the scaffolding protein AF-6/afadin. In pyramidal neurons, N-cadherin, AF-6, and kalirin-7 colocalize at synapses and participate in the same multiprotein complexes. N-cadherin clustering promotes the reciprocal interaction and recruitment of N-cadherin, AF-6, and kalirin-7, increasing the content of Rac1 and in spines and PAK (p21-activated kinase) phosphorylation. N-cadherin-dependent spine enlargement requires AF-6 and kalirin-7 function. Conversely, disruption of N-cadherin leads to thin, long spines, with reduced Rac1 contact, caused by uncoupling of N-cadherin, AF-6, and kalirin-7 from each other. By dynamically linking N-cadherin with a regulator of spine plasticity, this pathway allows synaptic adhesion molecules to rapidly coordinate spine remodeling associated with synapse maturation and plasticity. This study hence identifies a novel mechanism whereby cadherins, a major class of synaptic adhesion molecules, signal to the actin cytoskeleton to control the morphology of dendritic spines, and outlines a mechanism that underlies the coordination of synaptic adhesion with spine morphology. ( view less ) Deepak Lamba,Mike Karl,Thomas RehNeuronal degenerations in the retina are leading causes of blindness. Like most other areas of the CNS, the neurons of the mammalian retina are not replaced following degeneration. However, in nonmammalian vertebrates, endogenous repair processes restore neurons very efficiently, even after complet... ( view more )e loss of the retina. We describe the phenomenon of retinal regeneration in nonmammalian vertebrates and attempts made in recent years to stimulate similar regenerative processes in the mammalian retina. In addition, we review the various strategies employed to replace lost neurons in the retina and the recent use of stem cell technologies to address problems of retinal repair. ( view less ) P Deepak,S Kumar,A Acharya Interleukin (IL)-13 is a T(H)2 type of cytokine that plays a crucial role in the pathophysiology of different type of infections, autoimmune diseases and malignancies. It has been shown to dampen the T(H)1 type of immune responses and favours tumour growth. In the present investigation, we have det... ( view more )ermined IL-13 level in serum and ascitic fluid in both the sexes of BALB/c strain of mice bearing a T-cell lymphoma of spontaneous origin, designated as Dalton's Lymphoma (DL). Further, we have studied the involvement of gender hormones on the IL-13 level and NKT-cell production of IL-13. It has been observed that there exists a gender variation or gender dimorphism in the IL-13 production. IL-13 level in serum is directly correlated with in vivo progressive growth of DL cells. We observed a tendency in female DL-bearing mice to have higher serum IL-13 level and faster growth of DL cells. This study, therefore, indicates that sex hormones are directly involved in the differential production of IL-13 that may be a factor responsible, at least in part, for the differential in vivo progressive growth of a T-cell lymphoma. ( view less ) Mamidipudi R Praveen,Abhay R Vasavada,Devarshi Gajjar,Deepak Pandita,Vaishali A Vasavada,Viraj A Vasavada,Shetal M Raj PURPOSE: To compare ocular surface fluid ingress into the anterior chamber at the end of microcoaxial, standard coaxial, and bimanual phacoemulsification using trypan blue as the quantifying tracer. SETTING: Iladevi Cataract and IOL Research Centre, Ahmedabad, India. METHODS: This prospective rando... ( view more )mized observational study comprised 180 consecutive patients who had microcoaxial, standard coaxial, or bimanual phacoemulsification. Trypan blue was applied over the conjunctival surface, and the amount of ingress was assessed after cortex removal (time point 1) and at the end of the surgery after intraocular lens insertion and stromal hydration (time point 2). Logs of dilution were used for statistical analysis. RESULTS: At time point 1, a statistically significant difference was observed in the ingress of trypan blue in the aqueous aspirate. The bimanual group had the highest ingress and the microcoaxial group, the lowest. The amount of ingress in the standard coaxial group fell between the other 2 groups (P< .001). At time point 2, there was no statistically significant difference between the microcoaxial group and the standard coaxial group (P = 1.00); however, in the bimanual group, trypan blue ingress was statistically significantly higher than in the other 2 groups (P< .001). CONCLUSION: At both time points, trypan blue ingress was statistically significantly higher in the bimanual group than in the standard coaxial and microcoaxial groups. At time point 2, there was no statistically significant difference between the standard coaxial and microcoaxial groups. ( view less ) Sanjay K Bhadada,Harsh P Udawat,Anil Bhansali,Surinder S Rana,Saroj K Sinha,Deepak K Bhasin BACKGROUND: Primary hyperparathyroidism is a rare cause of chronic pancreatitis and there is a paucity of data on this interesting association. There is also no data comparing the clinical profile of chronic pancreatitis secondary to primary hyperparathyroidism with that of alcohol related and idio... ( view more )pathic chronic pancreatitis. METHODS: The clinical and biochemical spectrum of chronic pancreatitis secondary to primary hyperparathyroidism was evaluated retrospectively and compared with nine age-matched patients with alcohol related and idiopathic chronic pancreatitis. RESULTS: Renal colic, nephrolithiasis, nephrocalcinosis, bone disease, palpable neck nodule, and psychiatric abnormality were significantly more common in chronic pancreatitis due to hyperparathyroidism in comparison to alcoholic and idiopathic groups. The corrected calcium (10.8 +/- 0.9 vs 9.3 +/- 0.6 vs 9.2 +/- 0.8 mg/dL; P = 0.001) and intact parathormone (425 +/- 130 [SE]vs 22.2 +/- 14.3 [SE]vs 30 +/- 27.3 [SE] pg/mL; P = 0.009) levels were significantly elevated, while levels of serum phosphate were significantly less (3.1 +/- 0.4 vs 3.9 +/- 0.5 vs 3.4 +/- 0.7 mg/dL, respectively; P = 0.04) in chronic pancreatitis due to hyperparathyroidism in comparison to the alcoholic and idiopathic groups. No significant difference was observed in the frequency of steatorrea, diabetes mellitus, pancreatic calcification, and pseudocyst between the three groups. Six out of nine patients underwent parathyroidectomy and none had recurrence of pancreatic pain over 14.3 +/- 13.8 months. CONCLUSIONS: Chronic pancreatitis due to hyperparathyroidism has important characteristics in its biochemical and clinical manifestations. Parathyroidectomy relieves pancreatic pain in majority of patients. ( view less )
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