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101.
Sajad Hussain Syed Damien Goutte-Gattat Nils Becker Sam Meyer Manu Shubhdarshan Shukla Jeffrey J. Hayes Ralf Everaers Dimitar Angelov Jan Bednar Stefan Dimitrov 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(21):9620-9625
Despite the key role of the linker histone H1 in chromatin structure and dynamics, its location and interactions with nucleosomal DNA have not been elucidated. In this work we have used a combination of electron cryomicroscopy, hydroxyl radical footprinting, and nanoscale modeling to analyze the structure of precisely positioned mono-, di-, and trinucleosomes containing physiologically assembled full-length histone H1 or truncated mutants of this protein. Single-base resolution •OH footprinting shows that the globular domain of histone H1 (GH1) interacts with the DNA minor groove located at the center of the nucleosome and contacts a 10-bp region of DNA localized symmetrically with respect to the nucleosomal dyad. In addition, GH1 interacts with and organizes about one helical turn of DNA in each linker region of the nucleosome. We also find that a seven amino acid residue region (121–127) in the COOH terminus of histone H1 was required for the formation of the stem structure of the linker DNA. A molecular model on the basis of these data and coarse-grain DNA mechanics provides novel insights on how the different domains of H1 interact with the nucleosome and predicts a specific H1-mediated stem structure within linker DNA. 相似文献
102.
Efficacy and safety of cryobiopsy versus forceps biopsy for interstitial lung diseases and lung tumours: A systematic review and meta‐analysis 下载免费PDF全文
Oormila Ganganah Shu Liang Guo Manu Chiniah Yi Shi Li 《Respirology (Carlton, Vic.)》2016,21(5):834-841
Forceps biopsy (FB) is the most commonly used diagnostic tool for lung pathologies. FB is associated with a high diagnostic failure rate. Cryobiopsy (CB) is a novel technique providing a larger specimen size, few artefacts, more alveolar parts and superior diagnostic yield. CB, however, has drawbacks such as higher bleeding and pneumothorax rate. We conducted a meta‐analysis to investigate the specimen area, diagnostic rate and bleeding severity in CB versus FB in interstitial lung diseases (ILDs) and lung tumours. A systematic literature search of PUBMED, BIOSIS PREVIEW and OVID databases was conducted using specific search terms. Eligible studies including RCTs and non‐RCTs comparing cryobiopsy/cryotransbronchial biopsy (CB/CTBB) and forceps biopsy/forceps transbronchial biopsy (FB/FTBB) for specimen area, diagnostic rate and bleeding rate in ILDs and lung tumours were analysed. Two reviewers independently extracted data and evaluated the quality of the studies. Eight studies involving 916 patients were analysed. Specimen area (mm2) was significantly larger in CB/CTBB than FB/FTBB (standard mean difference = 1.21, 95% confidence interval (0.94, 1.48), P < 0.00001). The diagnostic rate was significantly higher in CB/CTBB than FB/FTBB (Risk ratio 1.36, 95% confidence interval (1.16, 1.59), P = 0.0002). Three studies compared the bleeding severity with only one showing significantly more bleeding in CB. Cryobiopsy/cryotransbronchial shows superiority to FB/FTBB for specimen area and diagnostic rate. CB/CTBB has better efficacy over FB/FTBB. 相似文献
103.
Wojciech Dabrowski Todd T. Schlegel Jaroslaw Wosko Radoslaw Rola Ziemowit Rzecki Manu L.N.G. Malbrain Andrzej Jaroszynski 《Journal of electrocardiology》2018,51(3):499-507
Introduction
Traumatic brain injury (TBI) affects cardiac electrical function, and several extra-cerebral factors, including intra-abdominal pressure (IAP), might further modulate this brain-heart interaction. The purpose of this study was to investigate the impact of TBI, and of increased IAP during TBI, on cardiac electrical function as measured by vectorcardiographic (VCG) variables.Methods
Survival, IAP and changes in VCG variables including spatial QRS-T angle and QTc interval were measured in consecutive adult patients with either isolated TBI (iTBI), or with TBI accompanied by polytrauma to the abdomen and/or limbs (pTBI). For all patients, observations were performed just after the admission to the ICU (baseline) and at 24, 48, 72 and 96 h after admission.Results
74 patients aged 45 ± 18 were studied. 44 were treated for iTBI and 30 for pTBI. In all patients, spatial QRS-T angle and QTc interval increased after TBI (p < 0.001), relatively more so in patients with pTBI. Compared to survivors, non-survivors also ultimately had greater widening of the spatial QRS-T angle (p < 0.001), most notably just before foraminal herniation. Wider spatial QRS-T angle and longer QTc interval were also noted in patients with IAP > 12 mmHg (p < 0.001), and with right compared to left hemispheric injury (p < 0.001). ST segment level at the J point decreased 24 and 48 h after TBI in leads I, II, III, aVR, aVF, V1, V2, V3 and V6, and increased in lead V1, especially in non-survivors.Conclusions
Spatial QRS-T angle and QTc interval increase after TBI. If foraminal herniation complicates TBI, further widening of the spatial QRS-T angle typically precedes it, followed by notable narrowing thereafter. Increased IAP also intensifies TBI-associated increases in spatial QRS-T angle and QTc interval. 相似文献104.
Ritika Sharma Manu Jamwal Hari Kishan Senee Varun Uppal Jasbir Kaur Hira Parveen Bose Narender Kumar Deepak Bansal Amita Trehan Pankaj Malhotra Jasmina Ahluwalia Reena Das 《Indian journal of hematology & blood transfusion》2021,37(3):414
Glanzmann thrombasthenia (GT) is an autosomal recessive platelet function disorder characterized by mucocutaneous bleeding as the most common clinical phenotype. Patients with GT have normal platelet counts, platelet morphology but reduced platelet aggregation in response to various agonists. Homozygosity or compound heterozygosity for variants in the ITGA2B/ITGB3 genes is the genetic basis for GT. Establishing a molecular diagnosis is definitive and is important for predictive testing. Using multi-gene panels is an accurate, faster, and cost-effective mode as compared to Sanger sequencing in large genes. We used a targeted resequencing based approach to identify pathogenic variants in eight cases in seven families. These variants were validated using Sanger sequencing in patients as well as family members and were predicted probably pathogenic using in-silico prediction tools. The variants include three missense (3/7 = 43%) (ITGA2B:c.1028 T > C, ITGA2B:c.1186G > A, ITGB3:c.1388G > C), two deletions (ITGA2B:c.559delG, ITGA2B:c.3092delT), one duplication (ITGA2B:c.1424_1427dupAGGT) and nonsense variant (ITGA2B:c.2578C > T, p.Gln860Ter). Except for one case which was compound heterozygous, the rest of the cases were homozygous. We found two novel variants that are reported for the first time in GT. The targeted resequencing based approach revealed varied genetic variants in North Indian patients, including two novels ones. The high yield of our panel indicates its suitability for usage in larger cohorts for the genetic diagnosis of GT patients. This approach is cost-effective and less cumbersome as compared to Sanger sequencing for these large size genes with multiple exons. The information so obtained is helpful in prenatal testing, carrier analysis, and genetic counseling. 相似文献
105.
Po Wei Kang Nourdine Chakouri Johanna Diaz Gordon F. Tomaselli David T. Yue Manu Ben-Johny 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(21)
In cardiomyocytes, NaV1.5 channels mediate initiation and fast propagation of action potentials. The Ca2+-binding protein calmodulin (CaM) serves as a de facto subunit of NaV1.5. Genetic studies and atomic structures suggest that this interaction is pathophysiologically critical, as human mutations within the NaV1.5 carboxy-terminus that disrupt CaM binding are linked to distinct forms of life-threatening arrhythmias, including long QT syndrome 3, a “gain-of-function” defect, and Brugada syndrome, a “loss-of-function” phenotype. Yet, how a common disruption in CaM binding engenders divergent effects on NaV1.5 gating is not fully understood, though vital for elucidating arrhythmogenic mechanisms and for developing new therapies. Here, using extensive single-channel analysis, we find that the disruption of Ca2+-free CaM preassociation with NaV1.5 exerts two disparate effects: 1) a decrease in the peak open probability and 2) an increase in persistent NaV openings. Mechanistically, these effects arise from a CaM-dependent switch in the NaV inactivation mechanism. Specifically, CaM-bound channels preferentially inactivate from the open state, while those devoid of CaM exhibit enhanced closed-state inactivation. Further enriching this scheme, for certain mutant NaV1.5, local Ca2+ fluctuations elicit a rapid recruitment of CaM that reverses the increase in persistent Na current, a factor that may promote beat-to-beat variability in late Na current. In all, these findings identify the elementary mechanism of CaM regulation of NaV1.5 and, in so doing, unravel a noncanonical role for CaM in tuning ion channel gating. Furthermore, our results furnish an in-depth molecular framework for understanding complex arrhythmogenic phenotypes of NaV1.5 channelopathies.Voltage-gated sodium channels (NaV) are responsible for the initiation and spatial propagation of action potentials (AP) in excitable cells (1, 2). NaV channels undergo rapid activation that underlie the AP upstroke while ensuing inactivation permits AP repolarization. The NaV1.5 channel constitutes the predominant isoform in cardiomyocytes, whose pore-forming α-subunit is encoded by the SCN5A gene. NaV1.5 dysfunction underlies diverse forms of cardiac disease including cardiomyopathies, arrhythmias, and sudden death (3–6). Human mutations in NaV1.5 are associated with two forms of inherited arrhythmias–congenital long QT syndrome 3 (LQTS3) and Brugada syndrome (BrS) (7). LQTS3 stems from delayed or incomplete inactivation of NaV1.5 that causes persistent Na influx that prolongs AP repolarization—a “gain-of-function” phenotype (7–9). BrS predisposes patients to sudden death and is associated with a reduction in the peak Na current that may slow cardiac conduction or cause region-specific repolarization differences—a “loss-of-function” phenotype (10, 11). Genetic studies have identified an expanding array of mutations in multiple NaV1.5 domains, including the channel carboxy-terminus (CT) that is a hotspot for mutations linked to both LQTS3 and BrS (12, 13). This domain interacts with the Ca2+-binding protein calmodulin (CaM), suggesting that altered CaM regulation of NaV1.5 may be a common pathophysiological mechanism (12, 14–16). More broadly, human mutations in the homologous regions of neuronal NaV1.1 (17, 18), NaV1.2 (19, 20), and NaV1.6 (21) as well as skeletal muscle NaV1.4 (22) are linked to varied clinical phenotypes including epilepsy, autism spectrum disorder, neurodevelopmental delay, and myotonia (23). Taken together, a common NaV mechanistic deficit—defective CaM regulation—may underlie these diverse diseases.CaM regulation of NaV channels is complex, isoform specific, and mediated by multiple interfaces within the channel (14–16). The NaV CT consists of a dual vestigial EF hand segment and a canonical CaM-binding “IQ” (isoleucine–glutamine) domain (24, 25) (Fig. 1A). The IQ domain of nearly all NaV channels binds to both Ca2+-free CaM (apoCaM) and Ca2+/CaM, similar to CaV channels (26–31). As CaM is typically a Ca2+-dependent regulator, much attention has been focused on elucidating Ca2+-dependent changes in NaV gating. For skeletal muscle NaV1.4, transient elevation in cytosolic Ca2+ causes a dynamic reduction in the peak current, a process reminiscent of Ca2+/CaM-dependent inactivation of CaV channels (32). Cardiac NaV1.5 by comparison exhibits no dynamic effect of Ca2+ on the peak current (32–34). Instead, sustained Ca2+ elevation has been shown to elicit a depolarizing shift in NaV1.5 steady-state inactivation (SSI or h∞), although the magnitude and the presence of a shift have been debated (32, 35). Additional CaM-binding sites have been identified in the channel amino terminus domain (36) and the III-IV linker near the isoleucine, phenylalanine, and methionine (IFM) motif that is well recognized for its role in fast inactivation (35, 37). However, recent cryogenic electron microscopy structures, biochemical, and functional analyses suggest that both the III-IV linker and the Domain IV voltage-sensing domain might instead interact with the channel CT in a state-dependent manner (38–43).Open in a separate windowFig. 1.Absence of dynamic Ca2+/CaM effects on WT NaV1.5 SSI. (A, Left) Structure of NaV1.5 transmembrane domain (6UZ3) (70) juxtaposed with that of NaV1.5 CT–apoCaM complex (4OVN) (28). (Right) Arrhythmia-linked CT mutations highlighted in NaV1.5 CT–apoCaM structure (LQTS3, blue; BrS, magenta; mixed syndrome, purple). (B) Dynamic Ca2+-dependent changes in NaV1.5 SSI probed using Ca2+ photouncaging. Na currents specifying h∞ at ∼100 nM (Left) and ∼4 μM Ca2+ step (Right). (C) Population data for NaV1.5 SSI under low (black, Left) versus high (red, Right) intracellular Ca2+ reveal no differences (P = 0.55, paired t test). Dots and bars are mean ± SEM (n = 8 cells). (D) FRET two-hybrid analysis of Cerulean-tagged apoCaM interaction with various Venus-tagged NaV1.5 CT (WT, black; IQ/AA, red; S[1904]L, blue). Each dot is FRET efficiency measured from a single cell. Solid line fits show 1:1 binding isotherm.Beyond Ca2+-dependent effects, the loss of apoCaM binding to the NaV1.5 IQ domain increases persistent current (34, 44), suggesting that apoCaM itself may be pathophysiologically relevant. Indeed, NaV1.5 mutations in the apoCaM-binding interface are associated with LQTS3 and atrial fibrillation (7), as well as a loss-of-function BrS phenotype and a mixed-syndrome phenotype whereby some patients present with BrS while others with LQTS3 (Fig. 1A) (13, 45). How alterations in CaM binding paradoxically elicits both gain-of-function and loss-of-function effects is not fully understood, though important to delineate pathophysiological mechanisms and for personalized therapies.Here, using single- and multichannel recordings, we show that apoCaM binding elicits two distinct effects on NaV1.5 gating: 1) an increase in the peak channel open probability (PO/peak) and 2) a reduction in the normalized persistent channel open probability (Rpersist), consistent with previous studies (34, 44). The two effects may explain how mixed-syndrome mutations in the NaV1.5 CT produce either BrS or LQTS3 phenotypes. On one hand, the loss of apoCaM association may diminish PO/peak and induce BrS by shunting cardiac AP. On the other hand, increased Rpersist may prevent normal AP repolarization, resulting in LQTS3. Analysis of elementary mechanisms suggests that these changes relate to a switch in the state dependence of channel inactivation. Furthermore, dynamic changes in Ca2+ can inhibit persistent current for certain mutant NaV1.5 owing to enhanced Ca2+/CaM binding that occurs over the timescale of a cardiac AP. This effect may result in beat-to-beat variability in persistent Na current for some mutations. In all, these findings explain how a common deficit in CaM binding can contribute to distinct arrhythmogenic mechanisms. 相似文献
106.
Satoshi Watanabe Nikolay S. Markov Ziyan Lu Raul Piseaux Aillon Saul Soberanes Constance E. Runyan Ziyou Ren Rogan A. Grant Mariana Maciel Hiam Abdala-Valencia Yuliya Politanska Kiwon Nam Lango Sichizya Hermon G. Kihshen Nikita Joshi Alexandra C. McQuattie-Pimentel Katherine A. Gruner Manu Jain Jacob I. Sznajder Richard I. Morimoto Paul A. Reyfman Cara J. Gottardi G. R. Scott Budinger Alexander V. Misharin 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(20)
107.
Nitin Jagtap Harshal Shah Anuradha Kancharla Manu Tandan Partha Pal Sundeep Lakhtakia Mohan Ramchandani D. N. Reddy 《Indian journal of gastroenterology》2017,36(2):141-144
Melioidosis, being increasing, is reported from India. Gastrointestinal manifestations are typically reported as unusual cause of liver and/or splenic abscess. We aimed to describe various gastrointestinal manifestation of melioidosis in the present study. We retrospectively collected data of culture positive melioidosis cases from hospital database during August 2014–October 2016 at Asian Institute of Gastroenterology, Hyderabad. A total of nine culture positive cases (8 male) of melioidosis with median age of 40 years (range 23–66) were analyzed. Median duration of symptoms was 45 days. Two patients were being treated as tuberculosis. Three patients presented with liver abscess with two of them having simultaneous splenic abscess, and one had prostatic abscess. Three patients (43%) with history of acute pancreatitis had infected pancreatic collection, and one patient had left empyema with splenic abscess. One patient had wound infection with left lower limb cellulitis, presented as acute in chronic liver failure and another as spontaneous bacterial peritonitis (SBP). Diabetes and/or alcoholism was present in all patients. Seven patients had disseminated organ involvement. Seven patients underwent percutaneous intervention for drainage of abscess. Induction therapy as ceftazidime (n=4) or meropenem (n=5) followed by continuation therapy as oral cotrimoxazole (n=6) and doxycycline (n=1) was given. Six patients completed therapy and asymptomatic at end of follow up. Two patients died in the study period. One patient died due to acute-on-chronic liver failure (ACLF) with acute kidney injury and the other due to cardiac failure. One patient with SBP had lost to follow up. Apart from being unusual cause of liver/splenic abscess, melioidosis can present with infection of pancreatic collection, SBP, and infection in a compensated cirrhosis which can precipitate ACLF. Early recognition and specific therapy can improve prognosis. 相似文献
108.
Manu Prasad Tejraj P. Kale Rajshekhar Halli S. M. Kotrashetti S. D. Baliga 《Journal of maxillofacial and oral surgery》2009,8(1):40-42
Background & objectives The purpose of this study was to evaluate effectiveness and convenience of cryosurgical procedure, to assess the events during
postoperative healing and to find out the incidence of recurrence
Materials and methods This study was conducted in the Department of Oral and Maxillofacial Surgery, KLESVK Institute of Dental Sciences, Belgaum.
The 40 patients selected for the study were divided into 2 groups of 20 patients each irrespective of age and sex.
Group I 20 patients with Pre-Malignant Lesions
Group II 20 patients with Oral Mucous Cyst
Results It was observed that all the 20 patients of mucocele were cured without any complication and recurrence, but in 20 patients
of leukoplakia 5 patients had recurrence which was directly attributed to their persisting habits.
Conclusion We state that this modality of treatment is promising with good results and has certain advantage over other modalities of
treatment. 相似文献
109.
Raj M Sundaram KR Paul M Deepa AS Kumar RK 《The National medical journal of India》2007,20(6):288-293
BACKGROUND: Limited data are available from India regarding the distribution and profile of childhood obesity and hypertension. We examined the time trends in childhood obesity in a representative sample of schoolchildren from Ernakulam District, Kerala and determined the relationship of obesity with blood pressure. METHODS: We used a stratified random cluster sampling method to select the children. Anthropometric data were collected from 24 842 students, 5-16 years of age, during 2003-04. Blood pressure and anthropometric data were collected from 20 263 students during 2005-06. Overweight and obesity were defined by body mass index for gender and age. Gender, age and height were considered for determining hypertension. RESULTS: The proportion of overweight children increased from 4.94% of the total students in 2003 to 6.57% in 2005 (OR: 1.36; 95% CI: 1.25-1.47; p < 0.0001). The increase was significant in both boys and girls. The proportion of overweight children was significantly higher in urban regions and in private schools, and the rising trend was limited to private schools. Systolic or diastolic incident hypertension was found in 17.34% of overweight children versus 10.1% of the remaining students (OR: 1.87; 95% CI: 1.60-2.17; p < 0.0001). CONCLUSION: Childhood obesity showed an increasing trend in a short period of 2 years. Hypertension was common in overweight children. The results suggest the need for greater public awareness and prevention programmes on childhood obesity and hypertension. 相似文献
110.
Distal airways are less than 2 mm in diameter, comprising a relatively large cross-sectional area that allows for slower, laminar airflow. The airways include both membranous bronchioles and gas exchange ducts, and have been referred to in the past as the 'quiet zone', in part because these structures were felt to contribute little to lung mechanics and in part because they were difficult to study directly. More recent data suggest that distal airway dysfunction plays a significant role in acute respiratory distress syndrome. In addition, injurious mechanical ventilation strategies may contribute to distal airway dysfunction. The presence of elevated airway resistance, intrinsic positive end-expiratory pressure or a lower inflection point on a pressure–volume curve of the respiratory system may indicate the presence of impaired distal airway function. There are no proven specific treatments for distal airway dysfunction, and protective ventilation strategies to minimize distal airway injury may be the best therapeutic approach at this time. 相似文献