Choatepruitt6700

Of the seven currently known botulinum neurotoxin-producing species of Clostridium, C. parabotulinum, or C. botulinum Group I, is the species associated with the majority of human botulism cases worldwide. Phylogenetic analysis of these bacteria reveals a diverse species with multiple genomic clades. The neurotoxins they produce are also diverse, with over 20 subtypes currently represented. The existence of different bont genes within very similar genomes and of the same bont genes/gene clusters within different bacterial variants/species indicates that they have evolved independently. The neurotoxin genes are associated with one of two toxin gene cluster types containing either hemagglutinin (ha) genes or orfX genes. These genes may be located within the chromosome or extrachromosomal elements such as large plasmids. Although BoNT-producing C parabotulinum bacteria are distributed globally, they are more ubiquitous in certain specific geographic regions. Notably, northern hemisphere strains primarily containlocations of the bont gene clusters offers insights into common mechanisms of genetic transfer, chromosomal integration, and development of diversity among these genes.

The objective of our study was to assess the prevalence and incidence of HEV in people living with HIV (PLWH) in a Spanish national cohort.

Retrospective longitudinal study including PLWH recruited in the cohort of adult HIV-infected patients of the AIDS Research Network in follow-up at 28 Spanish hospitals with available serum samples in 2014 and 2015. All samples were tested for HEV IgG, IgM, and RNA. Samples with detectable HEV viral loads were genotyped. Prevalence and incidence of HEV infection were calculated.

The study sample comprised 845 PLWH. At baseline, 101 patients were positive for HEV IgG antibodies (11.9%), none had HEV IgM antibodies, and 2 presented detectable HEV RNA (0.23%). Forty-two seroconverted for IgG, supposing a cumulative incidence of 5.7%. One subject was positive for IgM (0.13%), and 2 showed detectable HEV RNA (0.27%). One case was infected by the emergent HEV genotype 3ra.

Our study identifies one case of HEV 3ra genotype infection, the main host of which is rabbit, showing a potential zoonotic role of this emerging genotype in Spain.

Our study identifies one case of HEV 3ra genotype infection, the main host of which is rabbit, showing a potential zoonotic role of this emerging genotype in Spain.Dietary fiber has been linked to improved gut health, yet the mechanisms behind this association remain poorly understood. One proposed mechanism is through its influence on the secretion of gut hormones, including glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2). We aimed to 1) investigate the impact of a fiber deficient diet on the intestinal morphological homeostasis; 2) evaluate L-cell secretion; and 3) to ascertain the role of GLP-1, GLP-2 and Takeda G protein-receptor-5 (TGR5) signaling in the response using GLP-1 receptor, GLP-2 receptor and TGR5 knockout mice. Female C57BL/6JRj mice (n = 8) either received a standard chow diet or were switched to a crude fiber-deficient diet for a short (21 days) and long (112 days) study period. Subsequent identical experiments were performed in GLP-1 receptor, GLP-2 receptor and TGR5 knockout mice. The removal of fiber from the diet for 21 days resulted in a decrease in small intestinal weight (p less then 0.01) and a corresponding decrease in intestinal crypt depth in the duodenum, jejunum and ileum (p less then 0.001, p less then 0.05, and p less then 0.01, respectively). Additionally, colon weight was decreased (p less then 0.01). These changes were associated with a decrease in extractable GLP-1, GLP-2 and PYY in the colon (p less then 0.05, p less then 0.01, and p less then 0.01). However, we could not show that the fiber-dependent size decrease was dependent on GLP-1 receptor, GLP-2 receptor or TGR5 signaling. Intestinal permeability was increased following the removal of fiber for 112 days. In conclusion, our study highlights the importance of dietary fiber to maintain intestinal weight, colonic L-cell secretion and intestinal integrity.

Women with polycystic ovary syndrome (PCOS) often have vitamin D deficiency, a known risk factor for severe COVID-19 disease. Alveolar macrophage-derived cytokines contribute to the inflammation underlying pulmonary disease in COVID-19. We sought to determine if basal macrophage activation, as a risk factor for COVID-19 infection, was present in PCOS and, if so, was further enhanced by vitamin D deficiency.

A cross-sectional study in 99 PCOS and 68 control women who presented sequentially. Plasma levels of a macrophage-derived cytokine panel were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. Vitamin D was measured by tandem mass spectroscopy.

Vitamin D was lower in PCOS women (p<0.0001) and correlated negatively with body mass index (BMI) in PCOS (r=0.28, p=0.0046). Basal macrophage activation markers CXCL5, CD163 and MMP9 were elevated, whilst protective CD200 was decreased (p<0.05); changes in these variables were related to, and fully accounted for, by BMI. PCOS and control women were then stratified according to vitamin D concentration. Vitamin D deficiency was associated with decreased CD80 and IFN-γ in PCOS and IL-12 in both groups (p<0.05). These factors, important in initiating and maintaining the immune response, were again accounted for by BMI.

Basal macrophage activation was higher in PCOS with macrophage changes related with increased infection risk associating with vitamin D; all changes were BMI dependent, suggesting that obese PCOS with vitamin D deficiency may be at greater risk of more severe COVID-19 infection, but that it is obesity-related rather than an independent PCOS factor.

Basal macrophage activation was higher in PCOS with macrophage changes related with increased infection risk associating with vitamin D; all changes were BMI dependent, suggesting that obese PCOS with vitamin D deficiency may be at greater risk of more severe COVID-19 infection, but that it is obesity-related rather than an independent PCOS factor.Daily recombinant human GH (rhGH) is currently approved for use in children and adults with GH deficiency (GHD) in many countries with relatively few side-effects. Nevertheless, daily injections can be painful and distressing for some patients, often resulting in non-adherence and reduction of treatment outcomes. This has prompted the development of numerous long-acting GH (LAGH) analogs that allow for decreased injection frequency, ranging from weekly, bi-weekly to monthly. These LAGH analogs are attractive as they may theoretically offer increased patient acceptance, tolerability, and therapeutic flexibility. Conversely, there may also be pitfalls to these LAGH analogs, including an unphysiological GH profile and differing molecular structures that pose potential clinical issues in terms of dose initiation, therapeutic monitoring, incidence and duration of side-effects, and long-term safety. Furthermore, fluctuations of peak and trough serum GH and IGF-I levels and variations in therapeutic efficacy may depend on the technology used to prolong GH action. Previous studies of some LAGH analogs have demonstrated non-inferiority compared to daily rhGH in terms of increased growth velocity and improved body composition in children and adults with GHD, respectively, with no significant unanticipated adverse events. Currently, two LAGH analogs are marketed in Asia, one recently approved in the United States, another previously approved but not marketed in Europe, and several others proceeding through various stages of clinical development. Nevertheless, several practical questions still remain, including possible differences in dose initiation between naïve and switch-over patients, methodology of dose adjustment/s, timing of measuring serum IGF-I levels, safety, durability of efficacy and cost-effectiveness. Long-term surveillance of safety and efficacy of LAGH analogs are needed to answer these important questions.The functioning of the ovary is influenced by the autonomic system (sympathetic and cholinergic intraovarian system) which contributes to the regulation of steroid secretion, follicular development, and ovulation. There is no information on the primary signal that activates both systems. The nerve growth factor (NGF) was the first neurotrophic factor found to regulate ovarian noradrenergic neurons and the cholinergic neurons in the central nervous system. The aim of this study was to determine whether NGF is one of the participating neurotrophic factors in the activation of the sympathetic and cholinergic system of the ovary in vivo and its role in follicular development during normal or pathological states. The administration of estradiol valerate (a polycystic ovary [PCO] phenotype model) increased norepinephrine (NE) (through an NGF-dependent mechanism) and acetylcholine (ACh) levels. Intraovarian exposure of rats for 28 days to NGF (by means of an osmotic minipump) increased the expression of tyrosine hyd, NGF also regulates the ovarian cholinergic system, implying that NGF is the main regulator of the dual autonomic control. These findings highlight the need for research in the treatment of PCO syndrome by modification of locally produced ACh as an in vivo regulator of follicular development.Restoring the number of glucose-responsive β-cells in patients living with diabetes is critical for achieving normoglycemia since functional β-cells are lost during the progression of both type 1 and 2 diabetes. Stem cell-derived β-cell replacement therapies offer an unprecedented opportunity to replace the lost β-cell mass, yet differentiation efficiencies and the final yield of insulin-expressing β-like cells are low when using established protocols. Driving cellular proliferation at targeted points during stem cell-derived pancreatic progenitor to β-like cell differentiation can serve as unique means to expand the final cell therapeutic product needed to restore insulin levels. Numerous studies have examined the effects of β-cell replication upon functionality, using primary islets in vitro and mouse models in vivo, yet studies that focus on proliferation in stem cell-derived pancreatic models are only just emerging in the field. This mini review will discuss the current literature on cell proliferation in pancreatic cells, with a focus on the proliferative state of stem cell-derived pancreatic progenitors and β-like cells during their differentiation and maturation. The benefits of inducing proliferation to increase the final number of β-like cells will be compared against limitations associated with driving replication, such as the blunted capacity of proliferating β-like cells to maintain optimal β-cell function. Potential strategies that may bypass the challenges induced by the up-regulation of cell cycle-associated factors during β-cell differentiation will be proposed.Growth hormone deficiency (GHD) in adults is due to a reduced growth hormone (GH) secretion by the anterior pituitary gland which leads to a well-known syndrome characterized by decreased cognitive function and quality of life (QoL), decreased bone mineral density (BMD), increased central adiposity with a reduction in lean body mass, decreased exercise tolerance, hyperlipidemia and increased predisposition to atherogenesis. Considering some similar features between aging and GHD, it was thought that the relative GH insufficiency of the elderly person could make an important contribution to the fragility of elderly. GH stimulation tests are able to differentiate GHD in elderly patients (EGHD) from the physiological reduction of GH secretion that occurs with aging. Although there is no evidence that rhGH replacement therapy increases the risk of developing Diabetes Mellitus (DM), reducing insulin sensitivity and inducing cardiac hypertrophy, long-term monitoring is, however, also mandatory in terms of glucose mid profile are prominent.The role of growth hormone (GH) during childhood and adulthood is well established. Once final stature is reached, GH continues to act during the transition, the period between adolescence and adulthood in which most somatic and psychological development is obtained. The achievement of peak bone mass represents the most relevant aspect of GH action during the transition period; however, equally clear is its influence on body composition and metabolic profile and, probably, in the achievement of a complete gonadal and sexual maturation. Despite this, there are still some aspects that often make clinical practice difficult and uncertain, in particular in evaluating a possible persistence of GH deficiency once final stature has been reached. It is also essential to identify which subjects should undergo re-testing and, possibly, replacement therapy, and the definition of unambiguous criteria for therapeutic success. Moreover, even during the transition phase, the relationship between GH substitution therapy and cancer survival is of considerable interest. In view of the above, the aim of this paper is to clarify these relevant issues through a detailed analysis of the literature, with particular attention to the clinical, diagnostic and therapeutic aspects.Enzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic GluCreERT2 ;ROSA26-eYFP and Ins1 Cre/+;Rosa26-eYFP mouse models have been used to study effects of sustained NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitioning. STZ induced a particularly severe form of diabetes in Ins1 Cre/+;Rosa26-eYFP mice, but twice-daily administration (25 nmol/kg) of SL-PYY(1-36) for 11 days consistently improved metabolic status. Blood glucose was decreased (p less then 0.05 - p less then 0.001) and both fasted plasma and pancreatic insulin significantly increased by SL-PYY(1-36). In both GluCreERT2 ;ROSA26-eYFP and Ins1 Cre/+; Rosa26-eYFP mice, STZ provoked characteristic losses (p less then 0.05 - p less then 0.001) of islet numbers, beta-cell and pancreatic islet areas together with increases in area and central islet location of alpha-cells. With exception of alpha-cell area, these morphological changes were fully, or partially, returned to non-diabetic control levels by SL-PYY(1-36). Interestingly, STZ apparently triggered decreased (p less then 0.001) alpha- to beta-cell transition in GluCreERT2 ;ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1 Cre/+;Rosa26-eYFP mice, but both effects were significantly (p less then 0.001) reversed by SL-PYY(1-36). SL-PYY(1-36) also apparently reduced (p less then 0.05) beta- to alpha-cell conversion in Ins1 Cre/+;Rosa26-eYFP mice and glucagon expressing alpha-cells in GluCreERT2 ;ROSA26-eYFP mice. These data indicate that islet benefits of prolonged NPY1R activation, and especially restoration of beta-cell mass, are observed irrespective of diabetes status, being linked to cell lineage alterations including transdifferentiation of alpha- to beta-cells.Since its introduction more than twenty years ago, intraportal allogeneic cadaveric islet transplantation has been shown to be a promising therapy for patients with Type I Diabetes (T1D). Despite its positive outcome, the impact of islet transplantation has been limited due to a number of confounding issues, including the limited availability of cadaveric islets, the typically lifelong dependence of immunosuppressive drugs, and the lack of coverage of transplant costs by health insurance companies in some countries. Despite improvements in the immunosuppressive regimen, the number of required islets remains high, with two or more donors per patient often needed. Insulin independence is typically achieved upon islet transplantation, but on average just 25% of patients do not require exogenous insulin injections five years after. For these reasons, implementation of islet transplantation has been restricted almost exclusively to patients with brittle T1D who cannot avoid hypoglycemic events despite optimized ination devices and microencapsulation technologies, are being tested to balance the necessity of immune protection with the need for vascularization. Here, we compare the diverse human stem cell approaches and outcomes of recently completed and ongoing clinical trials, and discuss innovative strategies developed to overcome the most significant challenges remaining for transplanting stem cell-derived β cells.The innate immune system is the first line of defense specialized in the clearing of invaders whether foreign elements like microbes or self-elements that accumulate abnormally including cellular debris. Inflammasomes are master regulators of the innate immune system, especially in macrophages, and are key sensors involved in maintaining cellular health in response to cytolytic pathogens or stress signals. Inflammasomes are cytoplasmic complexes typically composed of a sensor molecule such as NOD-Like Receptors (NLRs), an adaptor protein including ASC and an effector protein such as caspase 1. Upon stimulation, inflammasome complex components associate to promote the cleavage of the pro-caspase 1 into active caspase-1 and the subsequent activation of pro-inflammatory cytokines including IL-18 and IL-1β. Deficiency or overactivation of such important sensors leads to critical diseases including Alzheimer diseases, chronic inflammatory diseases, cancers, acute liver diseases, and cardiometabolic diseases. Inflammasomes are tightly controlled by a two-step activation regulatory process consisting in a priming step, which activates the transcription of inflammasome components, and an activation step which leads to the inflammasome complex formation and the subsequent cleavage of pro-IL1 cytokines. Apart from the NF-κB pathway, nuclear receptors have recently been proposed as additional regulators of this pathway. This review will discuss the role of nuclear receptors in the control of the NLRP3 inflammasome and the putative beneficial effect of new modulators of inflammasomes in the treatment of inflammatory diseases including colitis, fulminant hepatitis, cardiac ischemia-reperfusion and brain diseases.

Iron deficiency (ID) is concerned as the most common nutritional deficiency worldwide. The effects of ID on thyroid function and autoimmunity in pregnant women and reproductive-age women are controversial. The aim of the current study was to summarize the evidences and evaluate the relationship between ID and thyroid disorders.

In this systematic review and meta-analysis, studies published on the Cochrane, Embase, Medline, and PubMed databases by October 2020 were searched. A total of 636 studies which discussed the correlation between ID and thyroid disorders were eligible in the initial search. Pooled mean differences (MD) and 95% confidence intervals (CI) were calculated for the assessment of thyrotropin (TSH) and free thyroxine (FT4) levels. Combined odd ratios (OR) and 95% CI were calculated for the assessment of the prevalence of overt and subclinical hypothyroidism, positive thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb).

For women of reproductive age, ID could significantly increase the risk of positive TPOAb (OR 1.89; 95% CI 1.17, 3.06

= 0.01) and both positive TPOAb and TgAb (OR 1.48; 95% CI 1.03, 2.11

= 0.03). The meta-analysis of pregnant women showed that pregnant women with ID had increased serum TSH levels (MD 0.12; 95% CI 0.07, 0.17; P < 0.00001) and decreased FT4 levels (MD -0.73; 95% CI -1.04, -0.41; P < 0.00001). Meanwhile, the prevalence of overt (OR 1.60; 95% CI 1.17, 2.19; P = 0.004) and subclinical (OR 1.37; 95% CI 1.13, 1.66; P = 0.001) hypothyroidism in pregnant women with ID was significantly increased.

ID may adversely affect thyroid function and autoimmunity of pregnant and reproductive-age women and it is very necessary for monitoring iron nutritional status and early treatment of ID for them.

ID may adversely affect thyroid function and autoimmunity of pregnant and reproductive-age women and it is very necessary for monitoring iron nutritional status and early treatment of ID for them.Premature ovarian insufficiency (POI) occurs in at least 1% of all women and causes life-long health problems and psychological stress. Infertility caused by POI used to be considered absolute, with infertility treatment having little or no value. Generally, it has been thought that medicine can provide little service to these patients. The etiology of POI has been found to be genetic, chromosomal, and autoimmune. In addition, the increasing numbers of cancer survivors are candidates for iatrogenic POI, along with patients who have undergone ovarian surgery, especially laparoscopic surgery. Over 50 genes are known to be causally related to POI, and the disease course of some cases has been clarified, but in most cases, the genetic background remains unexplained, suggesting that more genes associated with the etiology of POI need to be discovered. Thus, in most cases, the genetic background of POI has not been clarified. Monosomy X is well known to manifest as Turner's syndrome and is associated with primary amenorrhea, but recent studies have shown that some women with numerical abnormalities of the X chromosome can have spontaneous menstruation up to their twenties and thirties, and some even conceive. Hormone replacement therapy (HRT) is recommended for women with POI from many perspectives. It alleviates vasomotor and genitourinary symptoms and prevents bone loss and cardiovascular disease. POI has been reported to reduce quality of life and life expectancy, and HRT may help improve both. Most of the problems that may occur with HRT in postmenopausal women do not apply to women with POI; thus, in POI, HRT should be considered physiological replacement of estrogen (+progesterone). This review describes some new approaches to infertility treatment in POI patients that may lead to new treatments for POI, along with the development of more sensitive markers of secondary/preantral follicles and genetic diagnosis.

Metabolically healthy obese (MHO) individuals and their association with cardiometabolic diseases have remained controversial. We aimed to explore the risk of incident heart failure (HF) based on the baseline metabolic health and obesity status as well as their transition over 2 years.

The Korean National Health Insurance Service-National Health Screening Cohort data of 514,886 participants were analyzed. Obesity was defined as BMI ≥25 kg/m

according to the Korean Centers for Disease Control and Prevention. The metabolic health and obesity status were evaluated at baseline and after two years. Study participants were followed to either the date of newly diagnosed HF or the last follow-up visit, whichever occurred first.

The MHO group comprised 9.1% of the entire population and presented a better baseline metabolic profile than the metabolically unhealthy non-obese (MUNO) and metabolicavlly unhealthy obese (MUO) groups. During the median 71.3 months of follow-up, HF developed in 5,406 (1.5%) participannd obese individuals and remaining obese in baseline obese individuals showed a significantly increased risk of incident HF. Maintaining good metabolic health and a lean body may prevent the development of HF.The proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is one of the most extensively studied ligand-inducible transcription factors. Since its identification in the early 1990s, PPARγ is best known for its critical role in adipocyte differentiation, maintenance, and function. Emerging evidence indicates that PPARγ is also important for the maturation and function of various immune system-related cell types, such as monocytes/macrophages, dendritic cells, and lymphocytes. Furthermore, PPARγ controls cell proliferation in various other tissues and organs, including colon, breast, prostate, and bladder, and dysregulation of PPARγ signaling is linked to tumor development in these organs. Recent studies have shed new light on PPARγ (dys)function in these three biological settings, showing unified and diverse mechanisms of action. Classical transactivation-where PPARγ activates genes upon binding to PPAR response elements as a heterodimer with RXRα-is important in all three settings, as underscored by natural loss-of-function mutations in FPLD3 and loss- and gain-of-function mutations in tumors. Transrepression-where PPARγ alters gene expression independent of DNA binding-is particularly relevant in immune cells. Interestingly, gene translocations resulting in fusion of PPARγ with other gene products, which are unique to specific carcinomas, present a third mode of action, as they potentially alter PPARγ's target gene profile. Improved understanding of the molecular mechanism underlying PPARγ activity in the complex regulatory networks in metabolism, cancer, and inflammation may help to define novel potential therapeutic strategies for prevention and treatment of obesity, diabetes, or cancer.Gemcitabine plus Capecitabine (Gem/Cape) is a frequently adopted second line chemotherapy for metastatic adrenocortical carcinoma (ACC), but only a minority of patients is destined to obtain a clinical benefit. The identification of baseline predictive factors of efficacy is relevant. We retrospectively analyzed clinical data from 50 consecutive patients with metastatic progressing ACC treated between 2011 and 2019. Patients received intravenous Gemcitabine and oral Capecitabine on a metronomic schedule. Previous mitotane therapy was maintained. Clinical benefit (partial response + stable disease) at 4 months was 30%, median progression-free survival (PFS) and disease-specific survival (DSS) from Gem/Cape start were 3 and 8 months, respectively. Among clinical variables evaluated before the start of Gem/Cape, presence of ECOG performance status ≥1 [HR 6.93 95% confidence interval (CI) 0.03-0.54, p.004] and neutrophil-to-lymphocyte ratio (NLR) ≥5 [HR 3.88, 95% (CI) 0.81-0.90, p.003] were independent indicators of poor PFS at multivariate analysis. Conversely, surgery of primary tumor, the presence of lung or lymph-node metastases, blood mitotane level, anemia, and the Advanced Lung cancer Inflammation index (ALI) failed to be independently associated. This study confirms that the Gem/Cape schedule is modestly active in heavily pretreated ACC patients (28% received at least two previous chemotherapy lines). NLR and performance status (PS) are easily available clinical parameters that are helpful to identify patients not likely to derive significant advantage from Gem/Cape chemotherapy.Regulation of the serum calcium level in humans is achieved by the endocrine action of parathyroid glands working in concert with vitamin D and a set of critical target cells and tissues including osteoblasts, osteoclasts, the renal tubules, and the small intestine. The parathyroid glands, small highly vascularized endocrine organs located behind the thyroid gland, secrete parathyroid hormone (PTH) into the systemic circulation as is needed to keep the serum free calcium concentration within a tight physiologic range. Primary hyperparathyroidism (HPT), a disorder of mineral metabolism usually associated with abnormally elevated serum calcium, results from the uncontrolled release of PTH from one or several abnormal parathyroid glands. Although in the vast majority of cases HPT is a sporadic disease, it can also present as a manifestation of a familial syndrome. Many benign and malignant sporadic parathyroid neoplasms are caused by loss-of-function mutations in tumor suppressor genes that were initially identified by the study of genomic DNA from patients who developed HPT as a manifestation of an inherited syndrome. Somatic and inherited mutations in certain proto-oncogenes can also result in the development of parathyroid tumors. The clinical and genetic investigation of familial HPT in kindreds found to lack germline variants in the already known HPT-predisposition genes represents a promising future direction for the discovery of novel genes relevant to parathyroid tumor development.Management of metastatic radioiodine refractory differentiated thyroid cancer (DTC) can be a therapeutic challenge. Generally, little is known about the paired molecular profile of the primary tumor and the metastases and whether they harbor the same genetic abnormalities. The present study compared the molecular profile of paired tumor specimens (primary tumor/metastatic sites) from patients with radioiodine refractory DTC in order to gain insight into a possible basis for resistance to radioiodine. Twelve patients with radioiodine refractory metastases were studied; median age at diagnosis of 61 years (range, 25-82). Nine patients had papillary TC (PTC), one had follicular TC (FTC), and two had Hürthle cell TC (HTC). Distant metastases were present in the lungs (n = 10), bones (n = 4), and liver (n = 1). The molecular profiling of paired tumors was performed with a panel of 592 genes for Next Generation Sequencing, RNA-sequencing, and immunohistochemistry. Digital microfluidic PCR was used to investigate TERT promoter mutations. The genetic landscape of all paired sites comprised BRAF, NRAS, HRAS, TP53, ATM, MUTYH, POLE, and NTRK genes, including BRAF and NTRK fusions. BRAF V600E was the most common point mutation in the paired specimens (5/12). TERT promoter mutation C228T was detected in one case. PD-L1 expression at metastatic sites was highly positive (95%) for one patient with HTC. All specimens were stable for microsatellite instability testing, and the tumor mutation burden was low to intermediate. Therefore, the molecular profile of DTC primary and metastatic lesions can show heterogeneity, which may help explain some altered responses to therapeutic intervention.

The scoring system for human blastocysts is traditionally based on morphology; however, there are controversies on the effect of morphology parameters on pregnancy outcomes. The aim of this study is to evaluate the predicting value of each morphology parameter on pregnancy outcomes in a setting of single embryo transfer.

This is a retrospective cohort study on patients undergoing frozen-thawed single blastocyst transfer at our center, between Jan. 2009 and Dec. 2018.A total of 10,482 cycles were analyzed. The blastocysts were scored according to the expansion and hatching status, morphology of inner cell mass (ICM), and cells of trophectoderm (TE). The primary outcome measure was live birth rate. One-way analysis of variance, chi-square test, and multiple logistic regression were used for statistical analysis.

The clinical pregnancy rate was lower in the blastocysts of stage 3 (48.15%), compared with those of stage 4 (56.15%), stage 5 (54.91%), and stage 6 (53.37%). The live birth rate was lower in the TE grade A/B should be given priority for single embryo transfer.

The blastocyst expansion stage, ICM grade, and TE grade are all associated with pregnancy outcomes. ICM grade is the strongest predictor of live birth. A blastocyst with stage 4-5, ICM grade A, and TE grade A/B should be given priority for single embryo transfer.

Individuals exhibit fluctuations in the concentration of serum thyroid-stimulating hormone (TSH) over time. The scale of these variations ranges from minutes to hours, and from months to years. The main factors contributing to the observed within-person fluctuations in serum TSH comprise pulsatile secretion, circadian rhythm, seasonality, and ageing. In clinical practice and clinical research however, such within-person biological variation in serum TSH concentrations is often not considered. The aim of this review is to present an overview of the main sources of within-person variation in TSH levels, as well as the potential underlying biological mechanisms, and the clinical implications.

In euthyroid individuals, the circadian rhythm, with a nocturnal surge around 0200-0400 h and a nadir during daytime has the greatest impact on variations in serum TSH concentrations. Another source of within-person variation in TSH levels is seasonality, with generally higher levels during the cold winter months. Sincerations vary over time within an individual, which is caused by multiple different internal and external factors. It is important to take the within-person variations in serum TSH concentrations into account when testing a patient in clinical practice, but also in performing clinical research.

Serum TSH concentrations vary over time within an individual, which is caused by multiple different internal and external factors. It is important to take the within-person variations in serum TSH concentrations into account when testing a patient in clinical practice, but also in performing clinical research.Significant progress has been made in understanding the phenotypes of circulating immune cell sub-populations in human type 1 diabetes but much less is known about the equivalent populations that infiltrate the islets to cause beta-cell loss. In particular, considerable uncertainties remain about the phenotype and role of B-lymphocytes in the pancreas. This gap in understanding reflects both the difficulty in accessing the gland to study islet inflammation during disease progression and the fact that the number and proportion of islet-associated B-lymphocytes varies significantly according to the disease endotype. In very young children (especially those less then 7 years at onset) pancreatic islets are infiltrated by both CD8+ T- and CD20+ B-lymphocytes in roughly equal proportions but it is widely held that the CD8+ T-lymphocytes are responsible for driving beta-cell toxicity. By contrast, the role played by B-lymphocytes remains enigmatic. This is compounded by the fact that, in older children and teenagers (those ≥13 years at diagnosis) the proportion of B-lymphocytes found in association with inflamed islets is much reduced by comparison with those who are younger at diagnosis (reflecting two endotypes of disease) whereas CD8+ T-lymphocytes form the predominant population in both groups. In the present paper, we review the current state of understanding and develop a proposal to stimulate further discussion of the roles played by islet-associated B-lymphocytes in human type 1 diabetes. We cite evidence indicating that sites of direct contact can be found between CD8+ and CD20+-lymphocytes in and around inflamed islets and propose that such interactions may be important in determining the efficiency of beta cell killing.

Prediction of therapy response to intravenous methylprednisolone pulses (ivMP) is crucial for thyroid-associated ophthalmopathy (TAO). Image histograms may offer sensitive imaging biomarkers for therapy effect prediction. This study aimed to investigate whether pretherapeutic, multiparametric T2 relaxation time(T2RT) histogram features of extraocular muscles (EOMs) can be used to predict therapy response.

Forty-five active and moderate-severe TAO patients, who were treated with standard ivMP and underwent orbital MRI before therapy, were retrospectively included in this study. The patients were divided into responsive (n = 24, 48 eyes) and unresponsive group(n = 21, 42 eyes) according to clinical evaluation. Baseline clinical features of patients and histogram-derived T2RT parameters of the EOMs were analyzed and compared. Logistic regression model was conducted to determine independent predictors, and a histogram features nomogram was formulated for personalized prediction.

Responsive group displayed lto predict the response to ivMP in patients with TAO. The nomogram based on histogram features facilitates the selection of patients who will derive maximal benefit from ivMP.

The management of patients with indeterminate thyroid nodules, which account for 10-25% of thyroid fine needle aspiration biopsies (FNABs), is still very challenging.

To verify the utility of the seven-gene panel in combination with ultrasound features in the clinical management of indeterminate thyroid nodules.

The study group included 188 indeterminate thyroid nodules, divided into TIR3A (56.4%) and TIR3B (43.6%). A significant correlation between US categories and both cytological and molecular results was observed. In detail, TIR3B cytology was more frequent in EU-TIRADS 4 and 5 nodules (54.7 and 50%, respectively) than in EU-TIRADS 2 and 3 nodules (31%,

= 0.04). Similarly, the rate of a nodule with a mutation increased with the increase of US risk class (6.0% in EU-TIRADS 2 and 3, 9.3% in EUTIRADS-4 and 27.8% in EUTIRAD-5,

= 0.01). Among thyroid nodules submitted to surgery, final histology was benign in 61.4% nodules, while malignancy was diagnosed in 38.6% nodules. Using US score as tool foardless of US score and mutational status.

US score seems able to correctly discriminate between TIR3A nodules in which a conservative approach may be used, and those in which additional test, such as molecular test, may be indicated. On the contrary, in TIR3B nodules both US risk stratification and seven-gene panel seem to be of little use, because the risk of thyroid cancer remains high regardless of US score and mutational status.Alternative RNA splicing is a process by which introns are removed and exons are assembled to construct different RNA transcript isoforms from a single pre-mRNA. Previous studies have demonstrated an association between dysregulation of RNA splicing and a number of clinical syndromes, but the generality to common disease has not been established. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease affecting one-third of adults worldwide, increasing the risk of cirrhosis and hepatocellular carcinoma (HCC). In this review we focus on the change in alternative RNA splicing in fatty liver disease and the role for splicing regulation in disease progression.Thyroid hormones mediate a remarkable range of functions in many tissues and organ systems through the thyroid hormone receptors-THRA and THRB. Tissues and organs are composed of heterogeneous cells of different cell types. These different cell types have varying receptor expression abilities, which lead to variable responses in thyroid hormone regulation. The tissue-specific Thra and Thrb gene expression patterns help us understand the action of thyroid hormones at the tissue level. However, the situation becomes complicated if we wish to focus on tissues more closely to trace the responsive cells, which is a vital step in the process of understanding the molecular mechanism of diseases related to thyroid hormone regulation. Single-cell RNA sequencing technology is a powerful tool used to profile gene expression programs in individual cells. The Tabula Muris Consortium generates a single-cell transcriptomic atlas across the life span of Mus musculus that includes data from 23 tissues and organs. It provides r wet lab researchers.The second generation antipsychotic drug clozapine represents the most effective pharmacotherapy for treatment-resistant psychosis. It is also associated with low rates of extrapyramidal symptoms and hyperprolactinemia compared to other antipsychotic drugs. However, clozapine tends to be underutilized in clinical practice due to a number of disabling and serious side-effects. These are characterized by a constellation of metabolic side-effects which include dysregulation of glucose, insulin, plasma lipids and body fat. Many patients treated with clozapine go on to develop metabolic syndrome at a higher rate than the general population, which predisposes them for Type 2 diabetes mellitus and cardiovascular disease. Treatments for the metabolic side-effects of clozapine vary in their efficacy. There is also a lack of knowledge about the underlying physiology of how clozapine exerts its metabolic effects in humans. In the current review, we focus on key studies which describe how clozapine affects each of the main symptoms of the metabolic syndrome, and cover some of the treatment options. The clinical data are then discussed in the context of preclinical studies that have been conducted to identify the key biological substrates involved, in order to provide a better integrated overview. Suggestions are provided about key areas for future research to better understand how clozapine causes metabolic dysregulation.Previous studies have demonstrated that, in addition to inducing structural changes in thyroid follicles, cadmium (Cd) increased the number of C cells. We examined the effects of myo-inositol (MI), seleno-L-methionine (Se), MI + Se, and resveratrol on C cells of mice exposed to cadmium chloride (Cd Cl2), as no data are currently available on the possible protective effects of these molecules. In contrast, we have previously shown this protective effect against CdCl2 on the thyroid follicles of mice. Ninety-eight C57 BL/6J adult male mice were divided into 14 groups of seven mice each (i) 0.9% NaCl (vehicle; 1 ml/kg/day i.p.); (ii) Se (0.2 mg/kg/day per os); (iii) Se (0.4 mg/kg/day per os); (iv) MI (360 mg/kg/day per os); (v) Se (0.2 mg/kg/day) + MI; (vi) Se (0.4 mg/kg/day) + MI; (vii) resveratrol (20 mg/kg); (viii) CdCl2 (2 mg/kg/day i.p.) + vehicle; (ix) CdCl2 + Se (0.2 mg/kg/day); (x) CdCl2 + Se (0.4 mg/kg/day); (xi) CdCl2 + MI; (xii) CdCl2 + Se (0.2 mg/kg/day) + MI; (xiii) CdCl2 + Se (0.4 mg/kg/day) + MI; and cytoplasmic density decreased significantly. Thus, all five indices overlapped those observed in vehicle-treated mice. Resveratrol improved significantly all the considered parameters, with a magnitude comparable to that of MI alone. In conclusion, the association Myo + Se is effective in protecting the mouse thyroid from the Cd-induced hyperplasia and hypertrophy of C cells. This benefit adds to that exerted by Myo + Se on thyrocytes and testis.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder of calcium metabolism. However, data concerning a large cohort of PHPT patients in the Chinese population are scarce. Thus, the objective of this study was to determine the general clinical signatures of 457 Chinese PHPT patients and explore the clinical characteristic differences between benign and malignant PHPT.

A single-center retrospective study was designed. Medical records between preoperation and postoperative follow-up, were assessed and statistical analysis of the clinical data was performed.

Patients with PHPT aged 12-87 years, with a mean onset age of 56.16 ± 14.60 years, were included. Most patients (68.7%) in our center had symptomatic patterns described as bone pain (74.8%), urolithiasis (25.5%), fatigue (17.5%), and pathological fracture (13.1%), but an increasing tendency has been established in the proportion of patients with asymptomatic forms. Correlation analysis revealed that patients with higher serum levels of para differentiate parathyroid carcinoma from parathyroid adenoma and hyperplasia to some extent. In addition, anti-osteoporosis drugs could be used when necessary to avoid hip fractures in patients with parathyroid carcinoma.

In general, patients with type 2 diabetes have lower cardiorespiratory fitness levels and perform exercise at lower intensities compared to healthy controls. Since metformin (MET) has been shown to increase the rate of perceived exertion (RPE) during exercise with a fixed intensity, MET

may reduce self-selected exercise intensity. The aim of this study was to assess the effect of MET on self-selected exercise intensity.

Healthy males were eligible for this crossover, counterbalanced study with two treatment periods MET and placebo (PLA), each lasting 17 days. Treatment dose was gradually increased and reached 2 g/day on treatment day 9, and continued at that level for the rest of the treatment period. The two periods were performed in randomized order. Two experimental days (A+B) were conducted on Day 15 (A) and Day 17 (B) of each period, respectively. Day A consisted of an exercise bout with self-selected exercise intensity (equal to RPE = 14-15 on the Borg Scale). Day B consisted of an exercise bout with fixed intensity (70% of VO

peak). Oxygen consumption rate was assessed continuously during both exercise bouts.

Fifteen males (age 23.7 ± 0.6 years, BMI 22.3 ± 2.0, VO

3.5 ± 0.6 L/min) were included in the study. On Day B, RPE was higher in MET compared to PLA (14.8 ± 0.4 vs. 14.0 ± 0.3,

= 0.045). On Day A, no difference in self-selected exercise intensity measured by oxygen consumption rate (PLA 2.33 ± 0.09 L O

/min, MET 2.42 ± 0.10 L O

/min,

= 0.09) was seen between treatment periods.

Self-selected exercise intensity was not reduced by MET in healthy males, despite the fact that MET increased RPE during an exercise bout with fixed intensity.

Self-selected exercise intensity was not reduced by MET in healthy males, despite the fact that MET increased RPE during an exercise bout with fixed intensity.

Obesity has been reported as a risk factor for adverse outcomes in COVID-19. However, available studies presenting data on obesity prevalence in patients with COVID-19 have conflicting results. The objective of this systematic review and meta-analysis is to evaluate the prevalence of obesity in these patients and to stratify the estimates by illness severity.

We performed a literature search with the use of Medline/PubMed and Google Scholar database from December 1, 2019 to June 27, 2020 and systematically reviewed studies reporting the number of obese patients with real-time reverse transcriptase polymerase chain reaction (rRT-PCR)-confirmed SARS-CoV-2 infection.

Nineteen studies were identified. The pooled obesity prevalence rates were 0.32 (95% CI 0.24-0.41) in hospitalized patients, 0.41 (95% CI 0.36-0.45) in patients admitted to intensive care unit, 0.43 (95% CI 0.36-0.51) in patients needing invasive mechanic ventilation (IMV), and 0.33 (95% CI 0.26-0.41) in those who died. Obesity was associated with a higher risk for hospitalization [Odds ratio (OR) 1.3, 95% CI 1.00-1.69; I

52%,

= 0.05], ICU admission (OR 1.51, 95% CI 1.16-1.97; I

72%,

= 0.002), and IMV requirement (OR 1.77, 95% CI 1.34-2.35; I

0%,

< 0.001). The increase in risk of death did not reach statistical significance (OR 1.28, 95% CI 0.76-2.16, p = 0.35) which might be due to obesity survival paradox and/or unidentified factors.

Our data indicate that obese subjects may be at higher risk for serious illness if infected and obesity may play a role in the progression of COVID-19.

Our data indicate that obese subjects may be at higher risk for serious illness if infected and obesity may play a role in the progression of COVID-19.Fibroblast growth factor 23 (FGF23) has been described as an important regulator of mineral homeostasis, but has lately also been linked to iron deficiency, inflammation, and erythropoiesis. FGF23 is essential for the maintenance of phosphate homeostasis in the body and activating mutations in the gene itself or inactivating mutations in its upstream regulators can result in severe chronic hypophosphatemia, where an unbalanced mineral homeostasis often leads to rickets in children and osteomalacia in adults. FGF23 can be regulated by changes in transcriptional activity or by changes at the post-translational level. The balance between O-glycosylation and phosphorylation is an important determinant of how much active intact or inactive cleaved FGF23 will be released in the circulation. In the past years, it has become evident that iron deficiency and inflammation regulate FGF23 in a way that is not associated with its classical role in mineral metabolism. These conditions will not only result in an upregulation of FGF23 transcription, but also in increased cleavage, leaving the levels of active intact FGF23 unchanged. The exact mechanisms behind and function of this process are still unclear. However, a deeper understanding of FGF23 regulation in both the classical and non-classical way is important to develop better treatment options for diseases associated with disturbed FGF23 biology. In this review, we describe how the currently known upstream regulators of FGF23 change FGF23 transcription and affect its post-translational modifications at the molecular level.FDA approved anti-obesity medications may not be cost effective for patients struggling with pre-operative weight loss prior to bariatric surgery. Metformin, a biguanide, and Topiramate, a carbonic anhydrase inhibitor, both cost effective medications, have demonstrated weight loss when used for the treatment of type 2 diabetes or seizures, respectively. The aim of the three cases is to demonstrate the clinical utility of topiramate and metformin for preoperative weight loss in patients with a body mass index (BMI) ≥ 50 kg/m2 prior to bariatric surgery who are unable to follow the bariatric nutritional prescription due to a dysregulated appetite system Each patient was prescribed metformin and/or topiramate in an off-label manner in conjunction with lifestyle modifications and achieved >8% total body weight loss during the preoperative period.

Subclinical hypothyroidism (SCH) brain structure and resting state of functional activity have remained unexplored.

To investigate gray matter volume (GMV) and regional brain activity with the fractional amplitude of low-frequency fluctuations (fALFF) in subclinical hypothyroidism (SCH) patients before and after treatment.

We enrolled 54 SCH and 41 age-, sex-, and education-matched controls. GMV and fALFF of SCH were compared with controls and between pre- and post-treatment within SCH group. Correlations of GMV and fALFF in SCH with thyroid function status and mood scales were assessed by multiple linear regression analysis.

Compared to controls, GMV in SCH was significantly decreased in Orbital part of inferior frontal, superior frontal, pre-/postcentral, inferior occipital, and temporal pole gyrus. FALFF values in SCH were significantly increased in right angular, left middle frontal, and left superior frontal gyrus. After treatment, there were no significant changes in GMV and the local brain function compared to pre-treatment, however the GMV and fALFF of the defective brain areas were improved. Additionally, decreased values of fALFF in left middle frontal gyrus were correlated with increased mood scales.

In this study we found that patients with SCH, the gray matter volume in some brain areas were significantly reduced, and regional brain activity was significantly increased. After treatment, the corresponding structural and functional deficiencies had a tendency for improvement. These changes may reveal the neurological mechanisms of mood disorder in SCH patients.

In this study we found that patients with SCH, the gray matter volume in some brain areas were significantly reduced, and regional brain activity was significantly increased. After treatment, the corresponding structural and functional deficiencies had a tendency for improvement. These changes may reveal the neurological mechanisms of mood disorder in SCH patients.