Association of Altered Collagen Content and Lysyl Oxidase Expression in Degenerative Mitral Valve Disease

Background—Collagen cross-linking is mediated by lysyl oxidase (LOX) enzyme in the extracellular matrix (ECM) of mitral valve leaflets. Alterations in collagen content and LOX protein expression in the ECM of degenerative mitral valve may enhance leaflet expansion and disease severity. Methods—Twenty posterior degenerative mitral valve leaflets from patients with severe mitral regurgitation were obtained at surgery. Five normal posterior mitral valve leaflets procured during autopsy served as controls. Valvular interstitial cells (VICs) density was quantified by immunohistochemistry, collagen types I and III by picro-sirius red staining and immunohistochemistry, and proteoglycans by alcian blue staining. Protein expression of LOX and its mediator TGFβ1 were quantified by immunofluorescence and gene expression by PCR. Results—VICs density was increased, structural type I collagen density was reduced, while reparative type III collagen and proteoglycan densities were increased (p \u3c 0.0001) with an increase in spongiosa layer thickness in myxomatous valves. These changes were associated with a reduction in LOX (p \u3c 0.0001) and increase in TGFβ1 protein expression (p \u3c 0.0001). However, no significant change was seen in gene expression. Linear regression analysis identified a correlation between type I collagen density and LOX grade (R2 = 0.855; p \u3c 0.0001). Conclusions—Reduced type I collagen density with a simultaneous increase in type III collagen and proteoglycan densities possibly contributes to spongiosa layer expansion resulting in incompetent mitral valve leaflets. Observed changes in type I and III collagen densities in DMVD may be secondary to alterations in LOX protein expression, contributing to disorganization of ECM and disease severity

AR2, a novel automatic muscle artifact reduction software method for ictal EEG interpretation: Validation and comparison of performance with commercially available software.

Objective: To develop a novel software method (AR2) for reducing muscle contamination of ictal scalp electroencephalogram (EEG), and validate this method on the basis of its performance in comparison to a commercially available software method (AR1) to accurately depict seizure-onset location. Methods: A blinded investigation used 23 EEG recordings of seizures from 8 patients. Each recording was uninterpretable with digital filtering because of muscle artifact and processed using AR1 and AR2 and reviewed by 26 EEG specialists. EEG readers assessed seizure-onset time, lateralization, and region, and specified confidence for each determination. The two methods were validated on the basis of the number of readers able to render assignments, confidence, the intra-class correlation (ICC), and agreement with other clinical findings. Results: Among the 23 seizures, two-thirds of the readers were able to delineate seizure-onset time in 10 of 23 using AR1, and 15 of 23 using AR2 (

A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia

Azacitidine/venetoclax is an active regimen in patients with newly diagnosed AML. However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL-1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL-1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/venetoclax in relapsed/refractory AML, we conducted a phase I multicenter openlabel study in 16 adults with relapsed/refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission (CR) in 5 of 7 (71.4%) patients who were naïve to the hypomethylating agent/venetoclax. No measurable residual disease (MRD) was detected in 80.0% of the patients who achieved CR. The median time to best response was 50 (range: 23 – 77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844)

Exploratory Cohort Study of Associations between Serum C - Reactive Protein and Fatigue after Stroke

Post-stroke fatigue is a common and distressing problem but little is known about its biological mechanisms. This cohort study was to investigate associations between C-reactive protein (CRP) and fatigue after stroke.Patients were assessed at one, six and 12 months after their stroke onset, with the Fatigue Assessment Scale, a case definition of post-stroke fatigue, Hospital Anxiety and Depression Scale, and daily step counts. Blood samples were collected at each assessment and the CRP level was determined by a standard CRP immunoassay. Cross-sectional associations between CRP and fatigue at each time point were determined by Pearson correlation coefficient and independent-samples t-test. Whether CRP levels at one month predict fatigue scores at six and 12 months was explored by multiple linear regression, with anxiety, depression, and daily step counts as covariates.Sixty-five patients (mean age 67 years, 65% men) were included: 61 at one month, 49 at six months, and 41 at 12 months. CRP levels and fatigue scores were not associated at one month (p = 0.88) or 12 months (p = 0.56), but weakly associated at six months (r = 0.27, p = 0.04); however, this association was no longer significant (p = 0.14) after controlling for the effects of covariates. The CRP level was not associated with the fulfilment of case definition of post-stroke fatigue at any time points (all p > 0.05). The CRP level at one month was not a significant predictor for fatigue levels at either six months (p = 0.93) or 12 months (p = 0.78).There is insufficient evidence for the association between CRP and PSF in stroke patients. Future studies with larger sample sizes and controlling for potential confounders are needed to investigate whether this association exists

Assessment of groundwater quality for drinking purpose in rural areas surrounding a defunct copper mine

The suitability of groundwater quality of 22 wells located in the rural areas surrounding Ingaldhal defunct copper mine in Chithradurga district of Karnataka state was assessed for drinking purpose based on the various water quality parameters. Standard methods for physicochemical analysis of groundwater samples were employed. The results of analysis carried out showed the following concentration ranges: pH (7.61-8.34), EC (950-3120 µS/cm), TH (410-1400 mg/l), TDS (594-1913 mg/l), F- (0.15-1.43mg/l), NO3- (14-162mg/l), HCO3- (417-574mg/l), SO42- (68-286mg/l) and Ca2+ (59-150mg/l), Mg2+ (49-250mg/l), Na+ (38-290mg/l), K+ (6-58mg/l). The ionic dominance for the major cations and the anions respectively were in the order of Mg2+ > Na+ > Ca2+ > K+ and HCO3- > Cl- > SO42- > NO3- > Fe- > F- > CO3-. Most of the samples analyzed were above the Guidelines set by both national (BIS) and international (WHO, 2011) bodies for drinking water. Geographical Information System (GIS) capabilities are used to classify zones with acceptable groundwater quality for drinking purpose. The Gibbs diagrams show that the groundwater samples fall both in the rock and evaporation dominance fields as well as about 18 samples fall outside the defined fields indicating integrated mechanisms for hydrochemistry such as high weathering and low rates of evaporation in addition to input from the anthropogenic activities. According to plots on the piper diagram the groundwater of the Ingaldhal and surrounding regions consists of 4 hydrochemical types, viz., Ca-Mg-HCO3 type (n=9), Ca-Mg-SO4 (n=6), mixed Ca-Na-HCO3 (n=6) and Na-Cl type (n=1). Assessment of groundwater samples from various parameters indicates that groundwater in most part of the study area is chemically unsuitable for drinking purpose

Nuts: Natural Pleiotropic Nutraceuticals

Common nuts (tree nuts and peanuts) are energy-dense foods that nature has gifted with a complex matrix of beneficial nutrients and bioactives, including monounsaturated and polyunsaturated fatty acids, high-quality protein, fiber, non-sodium minerals, tocopherols, phytosterols, and antioxidant phenolics. These nut components synergize to favorably influence metabolic and vascular physiology pathways, ameliorate cardiovascular risk factors and improve cardiovascular prognosis. There is increasing evidence that nuts positively impact myriad other health outcomes as well. Nut consumption is correlated with lower cancer incidence and cancer mortality, and decreased all-cause mortality. Favorable effects on cognitive function and depression have also been reported. Randomized controlled trials consistently show nuts have a cholesterol-lowering effect. Nut consumption also confers modest improvements on glycemic control, blood pressure (BP), endothelial function, and inflammation. Although nuts are energy-dense foods, they do not predispose to obesity, and in fact may even help in weight loss. Tree nuts and peanuts, but not peanut butter, generally produce similar positive effects on outcomes. First level evidence from the PREDIMED trial shows that, in the context of a Mediterranean diet, consumption of 30 g/d of nuts (walnuts, almonds, and hazelnuts) significantly lowered the risk of a composite endpoint of major adverse cardiovascular events (myocardial infarction, stroke, and death from cardiovascular disease) by ≈30% after intervention for 5 y. Impressively, the nut-supplemented diet reduced stroke risk by 45%. As they are rich in salutary bioactive compounds and beneficially impact various health outcomes, nuts can be considered natural pleiotropic nutraceuticals

Cortical plasticity and functional change in human spinal cord injury investigated using repetitive transcranial magnetic simulation

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Role of dental findings in the diagnosis of idiopathic hypoparathyroidism

Idiopathic hypoparathyroidism (IHP) is a rare endocrinopathy, characterized by the disturbances in the calcium and phosphorous metabolism, owing to deficiency in parathyroid hormone, which leads to tetanic manifestations. Onset of the clinical features occurs early in the life and the seventy depends on the extent of chemical imbalance. This article describes a case of 22-year-old male patient undiagnosed for 12 years with this endocrinopathy (IHP). Overretained deciduous teeth, delayed eruption, impacted tooth and short roots probably resulting from untreated hypocalcemia during the developmental phase of dentition enabled us to unearth this endocrinopathy through a series of investigations. Thus, the article emphasizes the importance of dental findings of this endocrinopathy

The Effect of TAVR on Left Ventricular and Left Atrial Mechanics in Patients with Aortic Stenosis

Background. Measures of adverse cardiac remodeling, left ventricular global longitudinal strain (LVGLS) and left atrial (LA) phasic function, are predictive of cardiac events in patients with severe aortic stenosis (AS). How these parameters of cardiac function change following TAVR requires further investigation. Methods. A number of 109 consecutive patients with symptomatic severe AS who were seen in the heart valve clinic between 2014 and 2019 for TAVR were included. All patients underwent echocardiographic assessment prior to and 30 days following TAVR, with LVGLS and LA phasic function evaluation using 2D speckle-tracking echocardiography. Heart failure hospitalization, and death were assessed at 12 months. Results. The mean age of the study cohort was 81 ± 7.3 years. Following TAVR, there was a significant reduction in NYHA class III/IV symptoms [89 (82%) vs. 12 (11%), p < 0.01], and median mean aortic valve gradient [44 mmHg (16) vs. 9 mmHg (7), p < 0.01]. There was no significant change in the median LVEF [62% (13) vs. 62% (6.0), p = 0.2]; however, the LVGLS significantly increased following TAVR [15 ± 3.5% vs. 18 ± 3.3%, p < 0.01]. The median LA reservoir, conduit and contractile function significantly improved following TAVR [22.0% (14.0) vs. 18.0% (14.0) p < 0.01, 8.9% (5.4) vs. 7.8% (4.8) p < 0.01, 12% (11.0) vs. 9.6% (11.0) p < 0.01, respectively]. The incidence of death or heart failure hospitalization at 12 months was low, and occurred in eight patients (7.3%). Conclusions. TAVR results in significant short-term reverse LV and LA remodeling, as shown by improvement in LV GLS and all three components of LA phasic function, despite no change in the LVEF. The findings indicate the possible utility of strain imaging for the assessment of global LV and LA function following TAVR