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Background: The 30‐day hospital re‐admission rate is a quality measure of hospital care to monitor the efficiency of the healthcare system. The hospital re‐admission of acute stroke (AS) patients is often associated with higher mortality rates, greater levels of disability and increased healthcare costs. The aim of our study was to identify predictors of unplanned 30‐day hospital re‐admissions after discharge of AS patients and define an early re‐admission risk score (RRS). Methods: This observational, retrospective study was performed on AS patients who were discharged between 2014 and 2019. Early re‐admission predictors were identified by machine learning models. The performances of these models were assessed by receiver operating characteristic curve analysis. Results: Of 7599 patients with AS, 3699 patients met the inclusion criteria, and 304 patients (8.22%) were re‐admitted within 30 days from discharge. After identifying the predictors of early re‐admission by logistic regression analysis, RRS was obtained and consisted of seven variables: hemoglobin level, atrial fibrillation, brain hemorrhage, discharge home, chronic obstructive pulmonary disease, one and more than one hospitalization in the previous year. The cohort of patients was then stratified into three risk categories: low (RRS = 0–1), medium (RRS = 2–3) and high (RRS >3) with re‐admission rates of 5%, 8% and 14%, respectively. Conclusions: The identification of risk factors for early re‐admission after AS and the elaboration of a score to stratify at discharge time the risk of re‐admission can provide a tool for clinicians to plan a personalized follow‐up and contain healthcare costs. [ABSTRACT FROM AUTHOR]

Currently, the size of CNA rearrangements range from 50 bp to several Mb; B Tumour I BRCA i (t I BRCA i ) testing b , t I BRCA i testing is the molecular evaluation of I BRCA i genes from tumour tissue, mainly on formalin-fixed paraffin-embedded (FFPE) samples. Reliability of tumor testing compared to germline testing for detecting BRCA1 and BRCA2 mutations in patients with epithelial ovarian cancer. For each reference study, the number of subjects with paired tumour and germline I BRCA i tests is reported, together with the cancer and specimen types. This approach allows the identification of inherited and non-inherited I BRCA i PVs; B Germline I BRCA i (g I BRCA i ) testing b , g I BRCA i testing is the molecular evaluation of I BRCA i genes mainly from blood samples. [Extracted from the article]

Background and Purpose: Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles and is currently incurable. Although considered to be a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single targeted drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi‐target drug used to treatment of coronary artery disease, trimetazidine, in SOD1G93A mice. Experimental Approach As a metabolic modulator, trimetazidine improves glucose metabolism. Furthermore, trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti‐inflammatory and antioxidant effect. We orally treated SOD1G93A mice with trimetazidine, solubilized in drinking water at a dose of 20 mg kg−1, from disease onset. We assessed the impact of trimetazidine on disease progression by studying metabolic parameters, grip strength and histological alterations in skeletal muscle, peripheral nerves and the spinal cord. Key Results: Trimetazidine administration delays motor function decline, improves muscle performance and metabolism, and significantly extends overall survival of SOD1G93A mice (increased median survival of 16 days and 12.5 days for male and female respectively). Moreover, trimetazidine prevents the degeneration of neuromuscular junctions, attenuates motor neuron loss and reduces neuroinflammation in the spinal cord and in peripheral nerves. Conclusion and Implications: In SOD1G93A mice, therapeutic effect of trimetazidine is underpinned by its action on mitochondrial function in skeletal muscle and spinal cord. [ABSTRACT FROM AUTHOR]

Background: Fuchs endothelial corneal dystrophy (FECD) is a progressive and potentially a sight threatening disease, and a common indication for corneal grafting in the elderly. Aberrant thickening of Descemet's membrane, formation of microscopic excrescences (guttae) and gradual loss of corneal endothelial cells are the hallmarks of the disease. The aim of this study was to identify differentially abundant proteins between FECD‐affected and unaffected Descemet's membrane. Methods: Label‐free quantitative proteomics using nanoscale ultra‐performance liquid chromatography‐mass spectrometry (nUPLC‐MSE) was employed on affected and unaffected Descemet's membrane extracts, and interesting findings were further investigated using quantitative reverse transcription‐polymerase chain reaction and immunohistochemical techniques. Results: Quantitative proteomics revealed significantly lower abundance of apolipoprotein E (APOE) and immunoglobulin heavy constant gamma 1 protein (IGHG1) in affected Descemet's membrane. The difference in the distribution of APOE between affected and unaffected Descemet's membrane and of IGHG1 detected by immunohistochemistry support their down‐regulation in the disease. Comparative gene expression analysis showed significantly lower APOE mRNA levels in FECD‐affected than unaffected corneal endothelium. IGHG1 gene is expressed at extremely low levels in the corneal endothelium, precluding relative expression analysis. Conclusions: This is the first study to report comparative proteomics of Descemet's membrane tissue, and implicates dysregulation of APOE and IGHG1 proteins in the pathogenesis of Fuchs endothelial corneal dystrophy. [ABSTRACT FROM AUTHOR]

The uremic toxin p-cresol (4-methylphenol) is either of environmental origin or can be synthetized from tyrosine by cresol-producing bacteria present in the gut lumen. Elevated p-cresol amounts have been previously found in the urines of Italian and French autism spectrum disorder (ASD) children up until 8 years of age, and may be associated with autism severity or with the intensity of abnormal behaviors. This study aims to investigate the mechanism producing elevated urinary p-cresol in ASD. Urinary p-cresol levels were thus measured by High Performance Liquid Chromatography in a sample of 53 Italian ASD children assessed for (a) presence of Clostridium spp. strains in the gut by means of an in vitro fecal stool test and of Clostridium difficile-derived toxin A/B in the feces, (b) intestinal permeability using the lactulose/mannitol (LA/MA) test, (c) frequent use of antibiotics due to recurrent infections during the first 2 years of postnatal life, and (d) stool habits with the Bristol Stool Form Scale. Chronic constipation was the only variable significantly associated with total urinary p-cresol concentration ( P < 0.05). No association was found with presence of Clostridium spp. in the gut flora ( P = 0.92), augmented intestinal permeability ( P = 0.18), or frequent use of antibiotics in early infancy ( P = 0.47). No ASD child was found to carry C. difficile in the gut or to release toxin A/B in the feces. In conclusion, urinary p-cresol levels are elevated in young ASD children with increased intestinal transit time and chronic constipation. Autism Res 2016, 9: 752-759. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objective Amyotrophic lateral sclerosis (ALS) is a motor neuron disease whose pathophysiological deficits, causing impairment in motor function, are largely unknown. Here we propose that hydrogen sulfide (H2S), as a glial-released inflammatory factor, contributes to ALS-mediated motor neuron death. Methods H2S concentrations were analyzed in the cerebrospinal fluid of 37 sporadic ALS patients and 14 age- and gender-matched controls, in tissues of a familial ALS (fALS) mouse model, and in spinal cord culture media by means of a specific and innovative high-performance liquid chromatography method. The effects of H2S on motor neurons cultures was analyzed immunohistochemically and by patch clamp recordings and microfluorometry. Results We found a significantly high level of H2S in the spinal fluid of the ALS patients. Consistently, we found increased levels of H2S in the tissues and in the media from mice spinal cord cultures bearing the fALS mutation SOD1G93A. In addition, NaHS, an H2S donor, added to spinal culture, obtained from control C57BL/6J mice, is toxic for motor neurons, and induces an intracellular Ca2+ increase, attenuated by the intracytoplasmatic application of adenosine triphosphate. We further show that H2S is mainly released by astrocytes and microglia. Interpretation This study unravels H2S as an astroglial mediator of motor neuron damage possibly involved in the cellular death characterizing ALS. Ann Neurol 2015;77:697-709 [ABSTRACT FROM AUTHOR]

This review is addressed to scientists working outside the field of proteomics and wishes to shed a light on the possibility offered by the latest proteomics strategies. Bottom-up and top-down platforms are critically examined outlining advantages and limitations of their application to qualitative and quantitative investigations. Discovery, directed and targeted proteomics as different options for the management of the MS instrument are defined emphasizing their integration in the experimental plan to accomplish meaningful results. The issue of data validation is analyzed and discussed. The most common qualitative proteomic platforms are described, with a particular emphasis on enrichment methods to elucidate PTMs codes (i.e. ubiquitin and histone codes). Label-free and labeled methods for relative and absolute quantification are critically compared. The possible contribution of proteomics platforms to the transition from structural proteomics to functional proteomics (study of the functional connections between different proteins) and to the challenging system biology (integrated study of all the functional cellular functions) is also briefly discussed. [ABSTRACT FROM AUTHOR]

Introduction: Spinobulbar muscular atrophy (SBMA) is an inherited adult-onset motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor. Autonomic nervous system involvement (ANS) is not considered part of SBMA. The aim of this study was to assess autonomic cardiovascular function in 5 SBMA patients. Methods: Five quantitative autonomic function tests (AFTs) were performed in 5 SBMA patients. Plasma noradrenaline (NA) concentration in patients and in 5 healthy subjects was also measured. Results: AFTs were abnormal in 4 of the 5 patients, and plasma NA concentration was significantly reduced in patients with respect to controls. Conclusion: The impairment of cardiovascular responses to AFTs in addition to reduced plasma NA concentration observed in our patients suggests subclinical involvement of the ANS in Kennedy disease. Muscle Nerve, 2011 [ABSTRACT FROM AUTHOR]

Recently, Irani and colleagues proposed a C-terminal cleaved isoform cystatin C (12.5kDa) in cerebrospinal fluid as a marker of multiple sclerosis. In this study, we demonstrate that the 12.5kDa product of cystatin C is formed by degradation of the first eight N-terminal residues. Moreover, such a degradation is not specific in the cerebrospinal fluid of multiple sclerosis, but rather is given by an inappropriate sample storage at −20°C. We conclude that the use of the 12.5kDa product of cystatin C in cerebrospinal fluid might lead to a fallacious diagnosis of multiple sclerosis. Preanalytical validation procedure is mandatory for proteomics investigations. Ann Neurol 2007 [ABSTRACT FROM AUTHOR]

The yeast myosin light chain 1 (Mlc1p) belongs to a branch of the calmodulin superfamily and is essential for vesicle delivery at the mother-bud neck during cytokinesis due to is ability to bind to the IQ motifs of the class V myosin Myo2p. While calcium binding to calmodulin promotes binding/release from the MyoV IQ motifs, Mlc1p is unable to bind calcium and the mechanism of its interaction with target motifs has not been clarified. The presence of Mlc1p in a complex with the Rab/Ypt Sec4p and with Myo2p suggests a role for Mlc1p in regulating Myo2p cargo binding/release by responding to the activation of Rab/Ypt proteins. Here we show that GTP or GTPγS potently stimulate Mlc1p interaction with Myo2p IQ motifs. The C-terminus of the Rab/Ypt GEF Sec2p, but not Sec4p activation, is essential for this interaction. Interestingly, overexpression of constitutively activated Ypt32p, a Rab/Ypt protein that acts upstream of Sec4p, stimulates Mlc1p/Myo2p interaction similarly to GTP although a block of Ypt32 GTP binding does not completely abolish the GTP-mediated Mlc1p/Myo2p interaction. We propose that Mlc1p/Myo2p interaction is stimulated by a signal that requires Sec2p and activation of Ypt32p. [ABSTRACT FROM AUTHOR]

In this work, evidence for the presence of ferritins in plant mitochondria is supplied. Mitochondria were isolated from etiolated pea stems and Arabidopsis thaliana cell cultures. The proteinswere separated by SDS/PAGE.Aprotein, with an apparent molecular mass of approximately 25-26 kDa (corresponding to that of ferritin), was cross-reacted with an antibody raised against pea seed ferritin. The mitochondrial ferritin from pea stems was also purified by immunoprecipitation. The purified protein was analyzed by MALDITOF mass spectrometry and the results of both mass finger print and peptide fragmentation by post source decay assign the polypeptide sequence to the pea ferritin (P &<0.05). The mitochondrial localization of ferritin was also confirmed by immunocytochemistry experiments on isolated mitochondria and cross-sections of pea stem cells. The possible role of ferritin in oxidative stress of plant mitochondria is discussed. [ABSTRACT FROM AUTHOR]

The mosquito, Anopheles gambiae, is an important vector of Plasmodium falciparum malaria. Full genome analysis revealed that, as in Drosophila melanogaster, the enzyme glutathione reductase is absent in A. gambiae and functionally substituted by the thioredoxin system. The key enzyme of this system is thioredoxin reductase-1, a homodimeric FAD-containing protein of 55.3 kDa per subunit, which catalyses the reaction NADPH + H+ + thioredoxin disulfide→NADP+ + thioredoxin dithiol. The A. gambiae trxr gene is located on chromosome X as a single copy; it represents three splice variants coding for two cytosolic and one mitochondrial variant. The predominant isoform, A. gambiae thioredoxin reductase-1, was recombinantly expressed in Escherichia coli and functionally compared with the wild-type enzyme isolated in a final yield of 1.4 U·ml−1 of packed insect cells. In redox titrations, the substrate A. gambiae thioredoxin-1 ( Km = 8.5 µ m, kcat = 15.4 s−1 at pH 7.4 and 25 °C) was unable to oxidize NADPH-reduced A. gambiae thioredoxin reductase-1 to the fully oxidized state. This indicates that, in contrast to other disulfide reductases, A. gambiae thioredoxin reductase-1 oscillates during catalysis between the four-electron reduced state and a two-electron reduced state. The thioredoxin reductases of the malaria system were compared. A. gambiae thioredoxin reductase-1 shares 52% and 45% sequence identity with its orthologues from humans and P. falciparum, respectively. A major difference among the three enzymes is the structure of the C-terminal redox centre, reflected in the varying resistance of catalytic intermediates to autoxidation. The relevant sequences of this centre are Thr–Cys–Cys–SerOH in A. gambiae thioredoxin reductase, Gly–Cys–selenocysteine–GlyOH in human thioredoxin reductase, and Cys–X–X–X–X–Cys–GlyOH in the P. falciparum enzyme. These differences offer an interesting approach to the design of species-specific inhibitors. Notably, A. gambiae thioredoxin reductase-1 is not a selenoenzyme but instead contains a highly unusual redox-active Cys–Cys sequence. [ABSTRACT FROM AUTHOR]

Examines the structure of the cytochrome cbb&sub3; purified from Pseudomonas stutzeri. Presence of nitric oxide reductase (NOR) activity in the enzyme; Re-oxidation of cytochrome cbb&sub3; by NO; Similarities between NOR and cytochrome oxidase.

The effects of 0.1-100 µM riluzole, a neuroprotective agent with anticonvulsant properties, were studied on neurons from rat brain cortex. Patch-clamp whole-cell recordings in voltage-clamp mode were performed on thin slices to examine the effects of the drug on a noninactivating (persistent) Na[sup +] current (/[sub Na,p]). /[sub Na,p] was selected because it enhances neuronal excitability near firing threshold, which makes it a potential target for anticonvulsant drugs. When added to the external solution, riluzole dose-dependently inhibited /[sub Na,p] up to a complete blocking of the current (EC[sub 50] 2 µM), showing a significant effect at therapeutic drug concentrations. A comparative dose-effect study was carried out in the same cells for the other main known action of riluzole, the inhibitory effect on the fast transient sodium current. This effect was confirmed in our experiments, but we found that it was achieved at levels much higher than putative therapeutic concentrations. Only the effect on/[sub Na,p], and not that on fast sodium current, can account for the reduction in neuronal excitability observed in cortical neurons following riluzole treatment at therapeutic concentrations, and this might represent a novel mechanism accounting for the anticonvulsant and neuroprotective properties of riluzole. [ABSTRACT FROM AUTHOR]

Background and Aims: Adaptive immunity is gaining a significant role in progression of metabolic dysfunction-associated steatotic liver disease (MASLD). B-cell activity can be assessed by serum-free light chains (sFLCs) k and λ levels. The objective of the present investigation is to examine the utility of sFLCs as non-invasive biomarkers for the stratification of MASLD., Methods: We enrolled a consecutive cohort from an outpatient liver unit. Diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) was made with liver biopsy according to current guidelines. Compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension (CSPH) were defined according to Baveno VII criteria. sFLCs were measured by turbidimetry using an immunoassay., Results: We evaluated 254 patients, 162/254 (63.8%) were male. Median age was 54 years old, and the median body mass index was 28.4 kg/m 2 . A total of 157/254 (61.8%) subjects underwent liver biopsy: 88 had histological diagnosis of MASH, 89 were considered as simple metabolic dysfunction-associated steatotic liver (MASL) and 77/254 (30.3%) patients with compensated metabolic dysfunction-associated cirrhosis. By using Baveno VII criteria, 101/254 (39.7%) patients had cACLD; among them, 45/101 (44.5%) had CSPH. Patients with cACLD showed higher sFLC levels compared with patients without cACLD (p < .01), and patients with CSPH showed higher sFLC levels than patients without CSPH (p < .01). At multivariable analysis, sFLCs were associated with cACLD (p < .05) independently from γ-globulins and other known dysmetabolic risk factors. κFLC was associated with CSPH (p < .05) independently from γ-globulins and other known dysmetabolic risk factors., Conclusion: sFLCs could be a simple biomarker for stratification of cACLD in MASLD patients., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)