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Brain : a Journal of Neurology Jun 2024Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair...
Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.
Topics: Animals; Female; Humans; Male; Mice; Acyltransferases; Carboxylic Ester Hydrolases; Mutation, Missense; Phenotype; Phospholipases; Retinal Diseases
PubMed: 38735647
DOI: 10.1093/brain/awae055 -
Journal of Psychosomatic Research Jun 2024This systematic review aims to analyze the existing literature investigating respiratory functioning in people with Persistent Somatic Symptoms (PSS) compared to healthy...
OBJECTIVE
This systematic review aims to analyze the existing literature investigating respiratory functioning in people with Persistent Somatic Symptoms (PSS) compared to healthy controls, to identify patterns of respiratory disturbances by symptom or syndrome, and describe any respiratory outcomes consistent across diagnoses.
METHODS
A systematic review following PRISMA guidelines was conducted. A comprehensive search was carried out across five databases (PubMed (NCBI), PsycArticles (Ovid), Web of Science (Core Collection), Embase, and Scopus) using two customised search strings for persistent somatic symptoms and objective respiratory parameters. Title/abstract screening and data extraction were carried out independently by two reviewers. The modified Newcastle-Ottawa Scale was used for quality assessment of the studies. Studies investigating baseline respiratory functioning in adult patients with PSS compared to healthy controls, using at least one objective respiratory were included.
RESULTS
18 studies met the inclusion criteria for the review, with a pooled sample size of n = 3245. Chronic pain conditions were found to be the most prevalent subset of diagnoses of interest, comprising six of the studies. 10 studies included measures of lung capacity, flow and/or volume, nine studies reported measures of ventilation, and four studies investigated respiratory muscle functioning. 13 of the included studies reported significant differences in at least one objective respiratory measure between groups (at rest). Scores on self-reported measures of dysnpea and breathlessness were higher in patients compared to healthy controls, while objective respiratory outcomes were varied.
CONCLUSION
The current systematic review is consistent with previous literature suggesting more pronounced experiences of breathlessness in patients with PSS, and significant disparities between reported dyspnea and objective respiratory outcomes. Research investigating the uncoupling between subjective and objective respiratory outcomes is needed to understand the mechanisms behind breathing disturbances in PSS.
Topics: Humans; Medically Unexplained Symptoms; Observational Studies as Topic; Respiration Disorders
PubMed: 38388305
DOI: 10.1016/j.jpsychores.2024.111607 -
Kardiologia Polska 2024Cardiovascular disease is a leading cause of mortality worldwide and is likely to rise. Acute coronary syndrome (ACS) is consequent on inflammation. As a common and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cardiovascular disease is a leading cause of mortality worldwide and is likely to rise. Acute coronary syndrome (ACS) is consequent on inflammation. As a common and cost-effective inflammatory biomarker, the neutrophil-to-lymphocyte ratio (NLR) may be beneficial in cardiovascular medicine.
AIMS
This meta-analysis examines the diagnostic and prognostic performance of the NLR in ACS.
METHODS
We systematically searched PubMed Central, Medline, Scopus, EMBASE, Cochrane Central Register of Controlled Trials, and Clinicaltrial.gov databases. The search spanned from databases inception to January 10, 2024. The findings were aggregated into normalized mean differences with 95% confidence intervals.
RESULTS
Ninety articles, with 45 990 participants, were included. Pooled analysis of the NLR varied and was higher in ST-segment elevation myocardial infarction (STEMI) vs. non-ST-segment elevation myocardial infarction patients (4.94 ± 3.24 vs. 3.24 ± 2.74), acute myocardial infarction vs. unstable angina (4.47 ± 3.43 vs. 2.97 ± 1.58), ACS vs. stable angina (SA) (5.45 ± 4.28 vs. 2.46 ± 2.15), and ACS vs. controls (5.31 ± 4.01 vs. 2.46 ± 2.45). The NLR also was associated with ACS mortality, with survivors having lower results (3.67 ± 2.72 vs. 5.56 ± 3.93). Subanalysis showed that differences in the NLR were observed in STEMI survivors (4.28 ± 3.24 vs. 6.79 ± 3.98). Of ACS patients with major cardiovascular events (MACE) vs. without MACE, the NLR was 6.29 ± 4.89 vs. 3.82 ± 4.12. In STEMI patients, the NLR differed between those with and without MACE (6.99 ± 5.27 vs. 4.99 ± 4.12).
CONCLUSIONS
The NLR is an effective tool for differentiating between different types of ACS. A high NLR is associated with ACS and increased MACE at 30 days. The NLR also appears to be a good predictor of MACE risk, at least in STEMI patients.
Topics: Humans; Prognosis; Acute Coronary Syndrome; ST Elevation Myocardial Infarction; Neutrophils; Lymphocytes; Myocardial Infarction; Non-ST Elevated Myocardial Infarction; Percutaneous Coronary Intervention
PubMed: 38493452
DOI: 10.33963/v.phj.99554