Autosomal dominant ANO5-related disorder associated with myopathy and gnathodiaphyseal dysplasia

OBJECTIVE: To investigate the molecular basis of muscle disease and gnathodiaphyseal dysplasia (GDD) in a large kindred with 11 (6 women and 5 men) affected family members. METHODS: We performed clinical assessment of 3 patients and collected detailed clinical and family history data on 8 additional patients. We conducted molecular genetic analyses on 5 patients using comprehensive neuromuscular disorder panels, exome sequencing (ES), and targeted testing for specific genetic variants. We analyzed the segregation of the muscle and bone phenotypes with the underlying molecular cause. RESULTS: The unique clinical presentation of recurrent episodes of rhabdomyolysis associated with muscle cramps, hyperCKemia, muscle hypertrophy, with absent or mild muscle weakness, as well as cemento-osseous lesions of the mandible, with or without bone fractures and other skeletal abnormalities, prompted us to look for the underlying molecular cause of the disorder in this kindred. Molecular testing revealed a missense variant in anoctamin 5 (ANO5) designated as c.1538C>T; p.Thr513Ile, which was previously described in a large kindred with GDD. In silico analysis, searching publicly available databases, segregation analysis, as well as functional studies performed by another group provide strong evidence for pathogenicity of the variant. ES data in the proband excluded the contribution of additional genetic factors. CONCLUSIONS: This report described the coexistence of muscle and bone phenotypes in the same patients with ANO5-related disorder. Our data challenge recent results that suggested complete dichotomy of these phenotypes and the proposed loss-of-function and gain-of-function mechanisms for the skeletal and muscle phenotypes, respectively

Sustainable green nanoadsorbents for remediation of pharmaceuticals from water and wastewater: A critical review

In the last three decades, pharmaceutical research has increased tremendously to offer safe and healthy life. However, the high consumption of these harmful drugs has risen devastating impact on ecosystems. Therefore, it is worldwide paramount concern to effectively clean pharmaceuticals contaminated water streams to ensure safer environment and healthier life. Nanotechnology enables to produce new, high-technical material, such as membranes, adsorbent, nano-catalysts, functional surfaces, coverages and reagents for more effective water and wastewater cleanup processes. Nevertheless, nano-sorbent materials are regarded the most appropriate treatment technology for water and wastewater because of their facile application and a large number of adsorbents. Several conventional techniques have been operational for domestic wastewater treatment but are inefficient for pharmaceuticals removal. Alternatively, adsorption techniques have played a pivotal role in water and wastewater treatment for a long, but their rise in attraction is proportional with the continuous emergence of new micropollutants in the aquatic environment and new discoveries of sustainable and low-cost adsorbents. Recently, advancements in adsorption technique for wastewater treatment through nanoadsorbents has greatly increased due to its low production cost, sustainability, better physicochemical properties and high removal performance for pharmaceuticals. Herein, this review critically evaluates the performance of sustainable green nanoadsorbent for the remediation of pharmaceutical pollutants from water. The influential sorption parameters and interaction mechanism are also discussed. Moreover, the future prospects of nanoadsorbents for the remediation of pharmaceuticals are also presented

A Comparison of quality of life outcomes following different techniques of mastoid surgery

- Background: Mastoid surgery carried out to treat chronic otitis media (COM) can lead to an improvement in objective and subjective measures post-operatively. This study aims to look at the subjective change in quality of life using the Glasgow Benefit Inventory relative to the type of mastoid surgery undertaken. - Method: A retrospective multi-centre postal questionnaire survey of 157 patients who underwent mastoid surgery from 2008-2012. - Results: 83 questionnaire responses were received from patients having the surgery at 3 different hospitals (a response rate of 53%). 57% of patients had a Glasgow benefit Score of 0 indicating no change in quality of life post-operatively. 35% scored +50 indicating a significant improvement. The only significant difference found was that women fare worse after surgery than men. - Conclusions: The choice of mastoid surgery technique should be determined by clinical need and surgeon preference. There is no improvement in quality of life for most patients

Self-Configurable Current-Mirror Technique for Parallel RGB Light-Emitting Diodes (LEDs) Strings

Traditional current-mirror circuits require buck converter to deal with one fixed current load. This paper deals with improved self-adjustable current-mirror methods that can address different LED loads under different conditions with the help of one buck converter. The operating principle revolves around a dynamic and self-configurable combinational circuit of transistor and op-amp based current balancing circuit, along with their op-amp based dimming circuits. The proposed circuit guarantees uniformity in the outputs of the circuit. This scheme of current-balancing circuits omitted the need for separate power supply to control the load currents through different kinds of LEDs, i.e. RGB LEDs. The proposed methods are identical and modular, which can be scaled to any number of parallel current sources. The principle methodology has been successfully tested in Simulink environment to verify the current balancing of parallel LED strings

An efficient color LED driver based on self-configuration current mirror circuit

The string channel of Color LED driver with precise current balancing is proposed. It is noted that to drive a multiple LEDs string is by using a proper current source, due to the level of the brightness LED depends on the quantity of the current flows. In the production of LEDs, the variation in the forward voltage for each LED has been found significantly high. This variation causes different levels of brightness in LEDs. Then, controlling load current of LED by using a resistor to limit the LED current flowing is considered by associated with the forward voltage, instantly. Current sources have been designed to become immune to the above problem since it regulates the current, and not the voltage which flows through the LEDs. Hence, constant current source is the essential requirement to drive the LEDs. Besides, it is complex for color LEDs, dependent on the number of control nodes and dimming configuration. To arrange an accurate load current for the different sets of string color LEDs, the efficient LED driver is required, in which the current sharing is complement to each LED strings. Therefore, this paper suggests a color LED driver with self-configuration of enhanced current mirrors in multiple LED strings. The load currents have been efficiently balanced among the identical loads and unequal loads. The comparable efficiency of the string color LEDs losses has been shown thoroughly

Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy

Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder that may result in multisystem involvement of varying phenotypes including inclusion body myopathy, Paget’s disease of bone (PDB), frontotemporal dementia (FTD), parkinsonism, and amyotrophic lateral sclerosis (ALS), among others. An international multidisciplinary consortium of 40+ experts in neuromuscular disease, dementia, movement disorders, psychology, cardiology, pulmonology, physical therapy, occupational therapy, speech and language pathology, nutrition, genetics, integrative medicine, and endocrinology were convened by the patient advocacy organization, Cure VCP Disease, in December 2020 to develop a standard of care for this heterogeneous and under-diagnosed disease. To achieve this goal, working groups collaborated to generate expert consensus recommendations in 10 key areas: genetic diagnosis, myopathy, FTD, PDB, ALS, Charcot Marie Tooth disease (CMT), parkinsonism, cardiomyopathy, pulmonology, supportive therapies, nutrition and supplements, and mental health. In April 2021, facilitated discussion of each working group’s conclusions with consensus building techniques enabled final agreement on the proposed standard of care for VCP patients. Timely referral to a specialty neuromuscular center is recommended to aid in efficient diagnosis of VCP MSP via single-gene testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases. Additionally, regular and ongoing multidisciplinary team follow up is essential for proactive screening and management of secondary complications. The goal of our consortium is to raise awareness of VCP MSP, expedite the time to accurate diagnosis, define gaps and inequities in patient care, initiate appropriate pharmacotherapies and supportive therapies for optimal management, and elevate the recommended best practices guidelines for multidisciplinary care internationally. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-022-02172-5

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Predictors of Death in Adults With Duchenne Muscular Dystrophy–Associated Cardiomyopathy

BACKGROUND: Duchenne muscular dystrophy (DMD) is frequently complicated by development of a cardiomyopathy. Despite significant medical advances provided to DMD patients over the past 2 decades, there remains a group of DMD patients who die prematurely. The current study sought to identify a set of prognostic factors that portend a worse outcome among adult DMD patients. METHODS AND RESULTS: A retrospective cohort of 43 consecutive patients was followed in the adult UT Southwestern Neuromuscular Cardiomyopathy Clinic. Clinical data were abstracted from the electronic medical record to generate baseline characteristics. The population was stratified by survival to time of analysis and compared with characteristics associated with death. The DMD population was in the early 20s, with median follow-up times over 2 years. All the patients had developed a cardiomyopathy, with the majority of the patients on angiotensin-converting enzyme inhibitors (86%) and steroids (56%), but few other guideline-directed heart failure medications. Comparison between the nonsurviving and surviving cohorts found several poor prognostic factors, including lower body mass index (17.3 [14.8-19.3] versus 25.8 [20.8-29.1] kg/m2, P<0.01), alanine aminotransferase levels (26 [18-42] versus 53 [37-81] units/L, P=0.001), maximum inspiratory pressures (13 [0-30] versus 33 [25-40] cmH2O, P=0.03), and elevated cardiac biomarkers (N-terminal pro-brain natriuretic peptide: 288 [72-1632] versus 35 [21-135] pg/mL, P=0.03]. CONCLUSIONS: The findings demonstrate a DMD population with a high burden of cardiomyopathy. The nonsurviving cohort was comparatively underweight, and had worse respiratory profiles and elevated cardiac biomarkers. Collectively, these factors highlight a high-risk cardiovascular population with a worse prognosis