Background
Nephropathic cystinosis is a lysosomal storage disorder with late‐onset systemic complications, such as myopathy and dysphagia. Currently employed outcome measures lack sensitivity and ...responsiveness for dysphagia and myopathy, a limitation to clinical trial readiness.
Methods
We evaluated 20 patients with nephropathic cystinosis in two visits over the course of a year to identify outcomes sensitive to detect changes over time. Patients also underwent an expiratory muscle strength training program to assess any effects on aspiration and dysphagia.
Results
There were significant differences in the Timed Up and Go Test (TUG) and Timed 25‐Foot Walk (25‐FW) between baseline and 1‐y follow‐up (P < .05). Maximum expiratory pressure (MEP) and peak cough flow (PCF) significantly improved following respiratory training (P < .05).
Conclusions
Improved respiratory outcomes may enhance patients ability to expel aspirated material from the airway, stave off pulmonary sequelae associated with chronic aspiration, and yield an overall improvement in physical health and well‐being.
See Editorial on pages 652–652 in this issue.
A diagnostic confidence scheme for CLN3 disease Masten, Margaux C.; Corre, Camille; Paciorkowski, Alex R. ...
Journal of inherited metabolic disease,
November 2021, Letnik:
44, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Over the past 20 years, diagnostic testing for genetic diseases has evolved, leading to variable diagnostic certainty for individuals included in long‐term natural history studies. Using genotype and ...phenotype data from an ongoing natural history study of CLN3 disease, we developed a hierarchical diagnostic confidence scheme with three major classes: Definite, Probable, or Possible CLN3 disease. An additional level, CLN3 Disease PLUS, includes individuals with CLN3 disease plus an additional disorder with a separate etiology that substantially affects the phenotype. Within the Definite and Probable CLN3 disease classes, we further divided individuals into subclasses based on phenotype. After assigning participants to classes, we performed a blinded reclassification to assess the reliability of this scheme. A total of 134 individuals with suspected CLN3 disease were classified: 100 as Definite, 21 as Probable, and 7 as Possible. Six individuals were classified as CLN3‐PLUS. Phenotypes included the classical juvenile‐onset syndromic phenotype, a “vision loss only” phenotype, and an atypical syndromic phenotype. Some individuals were too young to fully classify phenotype. Test‐retest reliability showed 96% agreement. We created a reliable diagnostic confidence scheme for CLN3 disease that has excellent face validity. This scheme has implications for clinical research in CLN3 and other rare genetic neurodegenerative disorders.
Under caloric restriction, bone marrow adipocytes (BM-Ads) do not decrease in size compared to white adipocytes, suggesting they harbor unique metabolic properties. We compare human primary BM-Ads ...with paired subcutaneous adipocytes (SC-Ads) using proteomic and lipidomic approaches. We find that, although SC-Ads and BM-Ads share similar morphological features, they possess distinct lipid metabolism. Although BM-Ad shows enrichment in proteins involved in cholesterol metabolism, correlating with increased free cholesterol content, proteins involved in lipolysis were downregulated. In particular, monoacylglycerol lipase expression is strongly reduced in BM-Ads, leading to monoacylglycerol accumulation. Consequently, basal and induced lipolytic responses are absent in BM-Ads, affirming their differences in metabolic fitness upon caloric restriction. These specific metabolic features are not recapitulated in vitro using common protocols to differentiate bone marrow mesenchymal stem cells. Thus, contrary to classical SC-Ads, BM-Ads display a specific lipid metabolism, as they are devoid of lipolytic activity and exhibit a cholesterol-orientated metabolism.
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•Like white adipocytes, BM-Ads contain a large lipid droplet filled with neutral lipids•Lipolysis is altered in BM-Ads by a profound downregulation in expression of MGLL•A defect in lipolysis explains why BM-Ads do not respond to caloric restriction•BM-Ads exhibit a cholesterol-oriented metabolism
Attané et al. show that, although human bone marrow adipocytes (BM-Ads) resemble classic white adipocytes on a morphological level, their lipid metabolism is highly specific. They are devoid of lipolytic activity, one of the main metabolic functions of white adipocytes, which explains why they behave like a preserved lipid source under energy-demanding conditions.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced acute respiratory distress syndrome (ARDS) causes high mortality. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have ...potentially relevant immune-modulatory properties, whose place in ARDS treatment is not established. This phase 2b trial was undertaken to assess the efficacy of UC-MSCs in patients with SARS-CoV-2-induced ARDS.
This multicentre, double-blind, randomized, placebo-controlled trial (STROMA-CoV-2) recruited adults (≥ 18 years) with SARS-CoV-2-induced early (< 96 h) mild-to-severe ARDS in 10 French centres. Patients were randomly assigned to receive three intravenous infusions of 10
UC-MSCs/kg or placebo (0.9% NaCl) over 5 days after recruitment. For the modified intention-to-treat population, the primary endpoint was the partial pressure of oxygen to fractional inspired oxygen (PaO
/FiO
)-ratio change between baseline (day (D) 0) and D7.
Among the 107 patients screened for eligibility from April 6, 2020, to October 29, 2020, 45 were enrolled, randomized and analyzed. PaO
/FiO
changes between D0 and D7 did not differ significantly between the UC-MSCs and placebo groups (medians IQR 54.3 - 15.5 to 93.3 vs 25.3 - 33.3 to 104.6, respectively; ANCOVA estimated treatment effect 7.4, 95% CI - 44.7 to 59.7; P = 0.77). Six (28.6%) of the 21 UC-MSCs recipients and six of 24 (25%) placebo-group patients experienced serious adverse events, none of which were related to UC-MSCs treatment.
D0-to-D7 PaO
/FiO
changes for intravenous UC-MSCs-versus placebo-treated adults with SARS-CoV-2-induced ARDS did not differ significantly. Repeated UC-MSCs infusions were not associated with any serious adverse events during treatment or thereafter (until D28). Larger trials enrolling patients earlier during the course of their ARDS are needed to further assess UC-MSCs efficacy in this context.
NCT04333368. Registered 01 April 2020, https://clinicaltrials.gov/ct2/history/NCT04333368 .
The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrP
, which represents a candidate ...therapeutic target. How PrP
is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrP
expression and to shed light on the gene regulatory networks linked to PrP
.
We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients.
In silico analyses combined with cell-based assays identified the Wnt-β-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrP
and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrP
, β-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence.
An unleashed PrP
-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.
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