Aortic pulse wave velocity in subjects with aortic valve sclerosis

Background: Aortic stiffness is an independent risk factor for cardiovascular events and mortality. The measurement of pulse‐wave velocity (PWV) is the most simple, noninvasive, and robust method to determine aortic stiffness. Whether aortic stiffness contributes to aortic valve sclerosis (AVS) remains unknown. The aim of the present study was to examine the relationship between PWV and AVS in subjects free of clinically evident atherosclerotic disease. Methods: We enrolled 62 patients (48 men; age 65 ± 8 years) diagnosed with AVS and an additional 62 age‐, hypertension‐, diabetes mellitus‐, and history of smoking‐matched subjects without AVS. Applanation tonometry was applied to assess the augmentation index and aortic PWV. The subjects with symptomatic vascular disease were excluded from the study. AVS was defined by echocardiography as thickening and calcification of the normal trileaflet aortic valve without obstruction to the left ventricular outflow. Results: There was no significant difference between the two groups regarding the aortic PWV and augmentation index (11.7±3.3 vs 11.8±3.7, P=0.85; 28.0±9.4 vs 25.0±8.6, P=0. 17, respectively). The presence of AVS was significantly correlated with ejection fraction (r=0.211, P=0.011), male gender (r=0.362, P=0.0001), and age (r=0.200, P=0.026). Conclusions: The lack of an association between the aortic PWV and AVS suggests that AVS is a complex phenomenon consisting of several distinct processes, related to both atherosclerotic and nonatherosclerotic processes.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity

The structure-guided design of chloride-conducting channelrhodopsins has illuminated mechanisms underlying ion selectivity of this remarkable family of light-activated ion channels. The first generation of chloride-conducting channelrhodopsins, guided in part by development of a structure-informed electrostatic model for pore selectivity, included both the introduction of amino acids with positively charged side chains into the ion conduction pathway and the removal of residues hypothesized to support negatively charged binding sites for cations. Engineered channels indeed became chloride selective, reversing near −65 mV and enabling a new kind of optogenetic inhibition; however, these first-generation chloride-conducting channels displayed small photocurrents and were not tested for optogenetic inhibition of behavior. Here we report the validation and further development of the channelrhodopsin pore model via crystal structure-guided engineering of next-generation light-activated chloride channels (iC++) and a bistable variant (SwiChR++) with net photocurrents increased more than 15-fold under physiological conditions, reversal potential further decreased by another ∼15 mV, inhibition of spiking faithfully tracking chloride gradients and intrinsic cell properties, strong expression in vivo, and the initial microbial opsin channel-inhibitor–based control of freely moving behavior. We further show that inhibition by light-gated chloride channels is mediated mainly by shunting effects, which exert optogenetic control much more efficiently than the hyperpolarization induced by light-activated chloride pumps. The design and functional features of these next-generation chloride-conducting channelrhodopsins provide both chronic and acute timescale tools for reversible optogenetic inhibition, confirm fundamental predictions of the ion selectivity model, and further elucidate electrostatic and steric structure–function relationships of the light-gated pore.Discovery and engineering of the microbial opsin genes not only has stimulated basic science investigation into the structure–function relationships of proteins involved in light-triggered ion flow but also has opened up opportunities for biological investigation (reviewed in ref. 1) via the technique of optogenetics, which involves targeting these genes and corresponding optical stimuli to control activity within specified types of cells within intact and functioning biological systems. For example, optogenetics has been used to identify causally the brain cells and projections involved in behaviors relevant to memory formation, affective states, and motor function, among many other discoveries (2–4). For the channelrhodopsins, an important member of this protein family widely used in optogenetics (5, 6), the light-activated cation-conducting channel pore has been the subject of structural investigation, both because of curiosity regarding the physical properties of its ion conduction and because the creation of inhibitory channels had been sought for optogenetic applications. Converging lines of work recently achieved the latter goal; resolving the high-resolution structure of channelrhodopsin (7) allowed a principled structure-guided approach to engineering for chloride selectivity by testing an electrostatic model for pore function (8, 9). Subsequently, by screening the genome of the Guillardia theta microbe, two naturally occurring light-gated chloride-conducting channelrhodopsins (10) were identified.Because optogenetic control of behavior has not yet been demonstrated with chloride channelrhodopsins, and to test further integrative ideas regarding pore function from structural considerations as shown here, we sought to design and test the next generation of enhanced chloride channels (iC++ and SwiChR++). Along the way, we provide the initial test of the hypothesis that light-activated channels will be more efficient tools than pumps for optogenetic neuronal inhibition at the cellular level, demonstrate the initial utility of light-gated chloride channels in controlling behavior in freely moving animals, and reveal key principles regarding the functional selectivity of light-gated ion channel pores.     

Hepatitis-G Virus Infection in Multi-transfused Patients and Intravenous Drug Abusers: New Delhi Experience

Hepatitis G virus (HGV) is a newly described virus that has been implicated in transfusion-associated hepatitis. HGV-RNA indicating current infection has frequently been isolated from the sera of multi-transfused patients (MTPs) and that of intravenous drug abusers (IVDAs). There is insufficient data on its prevalence among these high-risk groups in India. Hence this study was designed to evaluate the prevalence of HGV infection in MTPs and IVDAs. A total of 90 (57 males and 33 females) MTPs and 65 (44 males and 21 females) IVDAs were recruited in the study. Patients’ sera were tested for liver function profile, HGV-RNA, anti-HCV, HCV-RNA, HBsAg, and HBV-DNA. HGV-RNA was detected in 17.7% (16/90) MTPs and 23% (15/65) IVDAs, and 93.5% of our HGV-positive patients were found to be co-infected with either HBV (38.7%) or HCV (74.1%). The sero-prevalence of HBV was found out to be 40% and 21.5%, respectively, in the two groups, that of HCV was 32.2% and 32.3%, respectively, and dual infection was observed in 15.5% and 10.7% of the subjects, respectively. There were no statistically significant differences between the clinical, biochemical, and serological profiles of HGV-positive and negative patients. The prevalence of HGV infection in these high-risk groups is significantly higher than in controls. HGV is found to be co-infected more frequently with HCV than with HBV.     

Clinical outcomes and risk factors for severe COVID-19 in patients with haematological disorders receiving chemo- or immunotherapy

Haematology patients receiving chemo- or immunotherapy are considered to be at greater risk of COVID-19-related morbidity and mortality. We aimed to identify risk factors for COVID-19 severity and assess outcomes in patients where COVID-19 complicated the treatment of their haematological disorder. A retrospective cohort study was conducted in 55 patients with haematological disorders and COVID-19, including 52 with malignancy, two with bone marrow failure and one immune-mediated thrombotic thrombocytopenic purpura (TTP). COVID-19 diagnosis coincided with a new diagnosis of a haematological malignancy in four patients. Among patients, 82% were on systemic anti-cancer therapy (SACT) at the time of COVID-19 diagnosis. Of hospitalised patients, 37% (19/51) died while all four outpatients recovered. Risk factors for severe disease or mortality were similar to those in other published cohorts. Raised C-reactive protein at diagnosis predicted an aggressive clinical course. The majority of patients recovered from COVID-19, despite receiving recent SACT. This suggests that SACT, where urgent, should be administered despite intercurrent COVID-19 infection, which should be managed according to standard pathways. Delay or modification of therapy should be considered on an individual basis. Long-term follow-up studies in larger patient cohorts are required to assess the efficacy of treatment strategies employed during the pandemic.     

Disruption of actin‐binding domain‐containing Dystonin protein causes dystonia musculorum in mice

The Dystonin gene (Dst) is responsible for dystonia musculorum (dt), an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. Dst‐a isoforms, which contain actin‐binding domains, are predominantly expressed in the nervous system. Although sensory neuron degeneration in the peripheral nervous system during the early postnatal stage is a well‐recognised phenotype in dt, the histological characteristics and neuronal circuits in the central nervous system responsible for motor symptoms remain unclear. To analyse the causative neuronal networks and roles of Dst isoforms, we generated novel multipurpose Dst gene trap mice, in which actin‐binding domain‐containing isoforms are disrupted. Homozygous mice showed typical dt phenotypes with sensory degeneration and progressive motor symptoms. The gene trap allele (Dst^Gt) encodes a mutant Dystonin‐LacZ fusion protein, which is detectable by X‐gal (5‐bromo‐4‐chloro‐3‐indolyl‐β‐D‐galactoside) staining. We observed wide expression of the actin‐binding domain‐containing Dystonin isoforms in the central nervous system (CNS) and peripheral nervous system. This raised the possibility that not only secondary neuronal defects in the CNS subsequent to peripheral sensory degeneration but also cell‐autonomous defects in the CNS contribute to the motor symptoms. Expression analysis of immediate early genes revealed decreased neuronal activity in the cerebellar‐thalamo‐striatal pathway in the homozygous brain, implying the involvement of this pathway in the dt phenotype. These novel Dst^Gt mice showed that a loss‐of‐function mutation in the actin‐binding domain‐containing Dystonin isoforms led to typical dt phenotypes. Furthermore, this novel multipurpose Dst^Gt allele offers a unique tool for analysing the causative neuronal networks involved in the dt phenotype.     

Efficacy of zoledronic acid treatment in Paget disease of bone

Summary

Clinical trials have shown that zoledronic acid was more effective than other bisphosphonates in the treatment of Paget disease. We retrospectively reviewed remission and relapse statuses of 12 patients with Paget disease. Remission was achieved in all patients after treatment. We recommend zoledronic acid in the first-line treatment of Paget disease.

Introduction

Paget disease is a disease of bone of unknown etiology with increased bone turnover that results in defective bone microarchitecture and bone deformity. Bisphosphonates are used in symptomatic Paget disease of bone. Clinical trials have shown that zoledronic acid was more effective than other bisphosphonates in the treatment of Paget disease.

Methods

In this study, we retrospectively reviewed the remission and relapse statuses of 12 patients with Paget disease of bone who were seen as outpatients between October 2011 and October 2013.We evaluated alkaline phosphates, osteocalcin, and deoxypyridinoline levels measured before and at 6th, 12th, and 18th months of treatment.

Results

Pretreatment and posttreatment values for alkaline phosphates, deoxypyridinoline, and osteocalcin were as follows: 473?±?256 U/L, 14.99?±?7.63 mmol/L, 21.09?±?3.18 ng/ml, and 82?±?13 U/L, 5.14?±?1.11 mmol/L, and 8.57?±?4.31 ng/ml. Remission was achieved in all patients after treatment. The levels indicated that remission continued at 12th and 18th months of treatment. There was statistically significant difference between pretreatment and posttreatment values. No statistically significant difference between the levels measured at 6th, 12th, and 18th months of treatment was detected.

Conclusion

We recommend zoledronic acid in the first-line treatment of Paget disease of bone in achieving and maintaining remission.