The Role of PIEZO2 in Human Mechanosensation Chesler, Alexander T; Szczot, Marcin; Bharucha-Goebel, Diana ...
The New England journal of medicine,
10/2016, Letnik:
375, Številka:
14
Journal Article
Recenzirano
Odprti dostop
The senses of touch and proprioception evoke a range of perceptions and rely on the ability to detect and transduce mechanical force. The molecular and neural mechanisms underlying these sensory ...functions remain poorly defined. The stretch-gated ion channel PIEZO2 has been shown to be essential for aspects of mechanosensation in model organisms.
We performed whole-exome sequencing analysis in two patients who had unique neuromuscular and skeletal symptoms, including progressive scoliosis, that did not conform to standard diagnostic classification. In vitro and messenger RNA assays, functional brain imaging, and psychophysical and kinematic tests were used to establish the effect of the genetic variants on protein function and somatosensation.
Each patient carried compound-inactivating variants in PIEZO2, and each had a selective loss of discriminative touch perception but nevertheless responded to specific types of gentle mechanical stimulation on hairy skin. The patients had profoundly decreased proprioception leading to ataxia and dysmetria that were markedly worse in the absence of visual cues. However, they had the ability to perform a range of tasks, such as walking, talking, and writing, that are considered to rely heavily on proprioception.
Our results show that PIEZO2 is a determinant of mechanosensation in humans. (Funded by the National Institutes of Health Intramural Research Program.).
Acute neuromuscular disorders occasionally occur in the Pediatric Neurologic Intensive Care Unit. Many of these are primary disorders of the motor unit that may present acutely or exacerbate during ...an intercurrent illness. Additionally, acute neuromuscular disorders may develop during an acute systemic illness requiring intensive care management that predispose the child to another set of acute motor unit disorders. This chapter discusses acute neuromuscular crises in the infant, toddler, and adolescent, as well as neuromuscular disorders resulting from critical illness.
To explore the challenges in diagnosing acute flaccid myelitis (AFM) and evaluate clinical features and treatment paradigms associated with under recognition.
This was a retrospective multicenter ...study of pediatric patients (≤18 years) who were diagnosed with AFM from 2014 to 2018 using the Centers for Disease Control and Prevention’s case definition.
In 72% of the cases (126 of 175), AFM was not considered in the initial differential diagnosis (n = 108; 61.7%) and/or the patient was not referred for acute care (n = 90; 51.4%) at the initial clinical encounter, and this did not improve over time. Although many features of the presentation were similar in those initially diagnosed with AFM and those who were not; preceding illness, constipation, and reflexes differed significantly between the 2 groups. Patients with a non-AFM initial diagnosis more often required ventilatory support (26.2% vs 12.2%; OR, 0.4; 95% CI, 0.2-1.0; P = .05). These patients received immunomodulatory treatment later (3 days vs 2 days after neurologic symptom onset; 95% CI, −2 to 0; P = .05), particularly intravenous immunoglobulin (5 days vs 2 days; 95% CI, −4 to −2; P < .001).
Delayed recognition of AFM is concerning because of the risk for respiratory decompensation and need for intensive care monitoring. A non-AFM initial diagnosis was associated with delayed treatment that could have a clinical impact, particularly as new treatment options emerge.
Only a few small studies have previously reported episodes of hypoglycemia in children with neuromuscular diseases; however, there has been no broader investigation into the occurrence of ...hypoglycemia in children with congenital muscle disease (CMD).
Pediatric patients enrolled in the CMD International Registry (CMDIR) with a history of hypoglycemia were included in this retrospective review. Hypoglycemic episodes and associated clinical and biochemical characteristics were characterized.
Ten patients with CMD (5 with LAMA2-related muscular dystrophy) reported at least one episode of hypoglycemia beginning at an average age of 3.5 years. Predominant symptoms included altered mental status and nausea/vomiting, and laboratory studies demonstrated metabolic acidosis and ketonuria, consistent with ketotic hypoglycemia.
Patients with CMD may have an increased risk of hypoglycemia during fasting, illness, or stress due to their relatively low muscle mass and hence, paucity of gluconeogenic substrate. Clinicians should therefore maintain a high index of suspicion for hypoglycemia in this high-risk patient population and caregivers should routinely be trained to recognize and treat hypoglycemia.
Highlights • ACTA1 -myopathy can present with cytoplasmic bodies in the absence of nemaline rods. • p.Asn94Lys ACTA1 mutation may be linked to this pathology and severe phenotype. • ACTA1 mosaicism ...may masquerade as recessive inheritance, complicating the workup.
Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy ...(LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dyw/dyw) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy2J/dy2J) LAMA2-RD mouse model and the (Col6a1-/-) COL6-RD mouse model demonstrated decreased apoptosis.Background and ObjectivesOmigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dyw/dyw) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy2J/dy2J) LAMA2-RD mouse model and the (Col6a1-/-) COL6-RD mouse model demonstrated decreased apoptosis.A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data.MethodsA phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data.Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC0-24h) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study.ResultsTwenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC0-24h) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study.This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations.DiscussionThis study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations.This study provides Class IV evidence of omigapil in a dose-finding phase 1 study.Classification of EvidenceThis study provides Class IV evidence of omigapil in a dose-finding phase 1 study.Clinical Trials NCT01805024.Trial Registration InformationClinical Trials NCT01805024.
Abstract An educational program was developed to educate beef producers interested in marketing beef directly to the consumer. The program consisted of online webinars and two in-person sessions that ...were held in 6 locations throughout the state. Online webinar topics included marketing, working with the processor, food safety, forage management, confinement facilities, and environmental stewardship. In-person topics included growth and development and nutrition. The program participants were asked to complete a post-program survey at the end of the in-person session. Twenty-five survey responses were collected from the 95 in-person participants. Of the respondents, 44% indicated they were currently finishing cattle on-farm for direct markets, and the remaining participants included commercial cow-calf producers (44%), backgrounder-stocker producers (8%), and seedstock producers (4%). Participants were asked to indicate the overall level of information gained from the in-person sessions using a 5-point Likert scale (1 = not very informative; 5 = very informative), with an average response of 4.0. When asked to rate whether participating in the in-person sessions was an effective use of time using a 5-point Likert scale (1 = not very effective; 5 = very effective), the average response was 4.45. Participants were asked to rate their knowledge of various topics before and after each session using a 5-point Likert scale. Differences in pre- and post-knowledge levels were compared using the Wilcoxon signed rank test (SAS; Version 9.4; Cary, NC, USA). Participants reported increased knowledge of the length of time required to finish cattle in various production systems (P < 0.001). Participants reported an increased understanding of bunk scoring systems (P = 0.004). Participants also reported an increased knowledge related to mineral nutrition of finishing cattle (P = 0.01). When asked if participants planned to implement management changes due to this educational program 83% of respondents stated that they would implement management changes on their operations. The results from this survey suggest that participants increased their knowledge related to finishing cattle nutrition and management and that this increase in knowledge should result in on-farm changes improving the efficiency of finishing cattle for direct marketing.
Abstract Introduction There are overlapping features between inflammatory myopathies and muscular dystrophies, particularly laminopathies. Key features that characterize laminopathies include axial ...and proximal weakness, contractures, and cardiac abnormalities. Methods/Results A 12‐year‐old girl diagnosed with juvenile dermatomyositis as a child presented with cardiac failure and was found to have an LMNA likely pathogenic variant, with a phenotype most consistent with Emery–Dreifuss muscular dystrophy type 2. Discussion The spectrum of clinical features of LMNA ‐related muscular dystrophies can mimic or present with inflammatory myopathy‐like features. Early identification of LMNA ‐related muscular dystrophies is crucial to ensure appropriate cardiac screening and prevent devastating cardiac complications.
Lung cancer is the leading cause of cancer-related deaths worldwide, and lung squamous carcinomas (LUSC) represent about 30% of cases. Molecular aberrations in lung adenocarcinomas have allowed for ...effective targeted treatments, but corresponding therapeutic advances in LUSC have not materialized. However, immune checkpoint inhibitors in sub-populations of LUSC patients have led to exciting responses. Using computational analyses of The Cancer Genome Atlas, we identified a subset of LUSC tumors characterized by dense infiltration of inflammatory monocytes (IMs) and poor survival. With novel, immunocompetent metastasis models, we demonstrated that tumor cell derived CCL2-mediated recruitment of IMs is necessary and sufficient for LUSC metastasis. Pharmacologic inhibition of IM recruitment had substantial anti-metastatic effects. Notably, we show that IMs highly express Factor XIIIA, which promotes fibrin cross-linking to create a scaffold for LUSC cell invasion and metastases. Consistently, human LUSC samples containing extensive cross-linked fibrin in the microenvironment correlated with poor survival.
Optimization of surgical instrument trays improves efficiency and reduces cost. The purpose of this study is to assess the economic impact of optimizing orthopedic instrument trays at a tertiary ...medical center.
Twenty-three independent orthopedic surgical instrument trays at a single academic hospital were reviewed from 2017 to 2018. Using Lean methodology, surgeons agreed upon the fewest number of instruments needed for each of the procedure trays. Instrument usage counts, cleaning times, room turnover times, tray weight, holes in tray wrapping, wet trays, and time invested to optimize each tray were tracked. Cost savings were calculated. Student’s t-test was used to determine statistical significance, with P < .05 considered significant.
The mean instrument usage before and after Lean optimization was 23.4% and 54.2% (P < .0001). By Lean methods, 433 of 792 instruments (55%) were removed from 11 unique instrument trays (102 total trays), resulting in a reduction of 3520 instruments. Total weight reduction was 574.3 pounds (22%), ranging from 2.1-16.2 pounds per tray. The number of trays with wrapping holes decreased from 13 to 1 (P < .0001). The process of examining and removing instruments took an average of 7 minutes 35 seconds per tray. The calculated total annual savings was $270,976 (20% overall cost reduction).
In addition to substantial cost savings, tray optimization decreases tray weights and cleaning times without negatively impacting turnover times. Lean methodology improves efficiency in instrument tray usage, and reduces hospital cost while encouraging surgeon and staff participation through continuous process improvement.
Economic Quality Improvement, Level III.
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