Benign Phenotype Research Articles

Individual and joint associations of obesity and metabolic health parameters on arterial stiffness: Evidence from the UK Biobank.

There is conflicting evidence regarding whether excess adiposity without metabolic abnormalities reflects a truly benign phenotype. This study evaluated the independent and joint associations of the presence of excess adiposity and metabolic abnormalities on arterial stiffness. Participants in UK Biobank with body mass index (BMI) and arterial stiffness index (ASI) recorded between 2006 and 2010, free from cardiovascular diseases and not underweight (BMI <18.5 kg/m2) were included. The primary outcome was severity of ASI analysed using multivariate-adjusted linear regression. Of 162 590 participants, 42.5% were overweight and 24.4% were obese. Within the normal BMI strata, 50.7% had ≥1 metabolic abnormality. Compared to individuals with normal BMI and no metabolic abnormality (reference group), increased BMI or metabolic abnormalities were similarly associated with higher ASI: normal BMI with metabolic abnormalities (adjusted β-coefficient and 95% CI, 0.35; 0.30-0.40); overweight without metabolic abnormalities (0.32; 0.26-0.37). Individuals with obesity and no metabolic abnormality had higher ASI (0.65; 0.57-0.74) but was lower than individuals with overweight and metabolic abnormalities (0.80; 0.75-0.84). Individuals with obesity and metabolic abnormalities had the highest ASI (1.07; 1.02-1.12) among all six metabolic combinations, p < 0.001 for each versus reference group. Sensitivity analysis suggested higher ASI with increasing number of metabolic abnormalities within BMI categories and higher ASI in the presence of abdominal obesity within metabolic categories. Excess adiposity and metabolic abnormalities are independently associated with increased arterial stiffness to a similar degree, suggesting that metabolically healthy individuals with overweight and obesity are not benign groups. This reinforces the need to prevent excess adiposity and consider primary prevention strategies even before metabolic abnormalities emerge.

Novelty Seeking in Parkinson’s Disease: A Candidate Biomarker for Cognitive Changes

Background: Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by motor impairments, cognitive decline, and affective changes. Beyond the well-described motor symptoms, neuropsychiatric symptoms play a crucial role in PD disability burden. Novelty seeking, a trait extensively studied within various models of personality, may influence the manifestation of these non-motor symptoms. Methods: A narrative review of articles determined relevant by the author(s) was undertaken. Results: The literature indicates that PD patients typically exhibit low novelty seeking initially. However, dopaminergic therapies can increase novelty-seeking behaviors, sometimes leading to impulse control disorders (ICD). Studies using the Temperament and Character Inventory (TCI) suggest a complex interplay between disease state, medication, and baseline personality, which is not fully elucidated. High novelty seeking scores predict a higher risk of ICDs, yet they also correlate with a more benign clinical phenotype and improved quality of life post-DBS surgery. Conclusions: Novelty seeking is a significant trait in PD, influencing non-motor symptoms and treatment responses. Understanding its neurobiological basis and clinical implications could lead to better diagnostic and therapeutic strategies through the use of objective, practical tools for disease monitoring, individualized therapy, and pharmacological development.

Ventricular arrhythmias in association with athletic cardiac remodelling.

Athletes are predisposed to atrial arrhythmias but the association between intense endurance exercise training, ventricular arrhythmias (VAs) and sudden cardiac death is less well established. Thus, it is unclear whether the 'athlete's heart' promotes specific arrhythmias or whether it represents a more general pro-arrhythmogenic phenotype. Whilst direct causality has not been established, it appears possible that repeated exposure to high-intensity endurance exercise in some athletes contributes to formation of pro-arrhythmic cardiac phenotypes that underlie VAs. Theories regarding potential mechanisms for exercise-induced VAs include repeated bouts of myocardial inflammation and stretch-induced cellular remodelling. Small animal models provide some insights, but larger animal and human data are sparse. The current clinical approach to VAs in athletes is to differentiate those with and without structural or electrical heart disease. However, if the athlete's heart involves a degree of pro-arrhythmogenic remodelling, then this may not be such a simple dichotomy. Questions are posed by athletes with VAs in combination with extreme remodelling. Some markers, such as scar on magnetic resonance imaging, may point toward a less benign phenotype but are also quite common in ostensibly healthy athletes. Other clinical and invasive electrophysiology features may be helpful in identifying the at-risk athlete. This review seeks to discuss the association between athletic training and VAs. We will discuss the potential mechanisms, clinical significance and approach to the management of athletes with VAs.

Impaired HBsAg release and antiproliferative/antioxidant cell regulation by HBeAg-negative patient isolates reflects an evolutionary process.

The hepatitis B e antigen (HBeAg)-negative infection Phase 3 is characterized by no or minimal signs of hepatic inflammation and the absence of hepatic fibrosis. However, underlying molecular mechanisms leading to this benign phenotype are poorly understood. Genotype A, B and D HBeAg-negative patient isolates with precore mutation G1896A from Phase 3 were analysed in comparison with respective HBeAg-positive rescue mutant and HBeAg-positive wild-type reference genomes regarding differences in viral replication, morphogenesis, infectivity and impact on NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE)-dependent gene expression and cellular kinome. In comparison with reference genomes, the patient isolates are characterized by a lower intra- and extracellular hepatitis B surface antigen (HBsAg)-amount, and HBsAg-retention in the endoplasmic reticulum. Rescue of HBeAg expression increased HBsAg-amount but not its release. Expression of the isolated genomes is associated with a higher Nrf2/ARE-dependent gene expression as compared to reference genomes independent of HBeAg expression. Kinome analyses revealed a decreased activity of receptors involved in regulation of proliferative pathways for all patient isolates compared to the reference genomes. No specific conserved mutations could be found between all genomes from Phase 3. HBeAg-negative genomes from Phase 3 exhibit distinct molecular characteristics leading to lower HBsAg synthesis and release, enhanced oxidative stress protection and decreased activity of key kinases, triggering an antiproliferative stage, which might contribute to the lower probability of hepatocellular carcinoma. The observed differences cannot be associated with loss of HBeAg or specific mutations common to all analysed isolates, indicating the phenotype of Phase 3 derived genomes to be the result of a multifactorial process likely reflecting a conserved natural selection process.

Premarital Counseling on the Alpha Thalassemia Allele HBA2:c.*94A&gt;G

The mutation HBA2:c.*94A&gt;G (AATAAA&gt;AATAAG; rs63751269) is a 3′-UTR (3 prime untranslated region) single-nucleotide substitution in the polyadenylation (PA) signal of HBA2 (αPA:A→G). This pathogenic (CADD score, 14.92) variant is sporadic in the Arabian Peninsula. It results in inefficient mRNA processing, transcription termination, and possibly using an alternate cryptic downstream polyadenylation signal. As a result, the allele αT (or αT-Saudi) poses challenges in premarital counseling with respect to fetal risk of hemoglobin H disease. Homozygous HBA2:c.*94A&gt;G (αTα/αTα) results in moderate-to-severe microcytosis (mean red cell volume, MCV, 55 to 65 fL), reflecting markedly impaired hemoglobin synthesis (hemoglobin H disease). Homozygous rightward -α3.7 (a 3804-neocleotide deletion allele, NM_000517.4:c.[-2_-3delAC; −α3.7]), on the other hand, results in mild microcytosis (MCV, 70 to 75 fL, alpha-thalassemia trait). Thus, HBA2:c.*94A&gt;G is more damaging than -α3.7. Consistently, the value of MCV in compound heterozygosity, HBA2:c.*94A&gt;G and −α3.7, is 65 to 70 fL. We report here a healthy couple who presented for premarital counseling on their hemoglobinopathy. The man has homozygous HBA2:c.*94A&gt;G (αTα/αTα), and the woman has compound heterozygous (−α3.7/αTα, also annotated as: −3.7α/αTα). As a result, the genotype of their offspring would be that of the father (αTα/αTα) or the mother (−α3.7/αTα). The counseling was mainly based on the benign phenotypes of the parents. As both were asymptomatic and their anemia was clinically insignificant, they proceeded with the marriage.

Citrus reticulata fruit peel extract ameliorates testesterone-induced benign prostatic hyperplasia-like phenotypes in rats

Benign prostatic hyperplasia is a major pathophysiologic event that presents a high risk for prostate cancer (the second most frequently diagnosed cancer in men). The prognosis of conventional therapy for BPH remains poor due to treatment failures. Thus, natural remedies such as botanical drugs remain a promising alternative therapy to be explored for the treatment of BPH and prostate cancer. Citrus fruits, specifically fruit peels of Citrus reticulata (CRE) contain bioactive compounds that exhibit anti-inflammatory properties and have been used in crude form in traditional settings to manage benign prostatic hyperplasia and prostate cancer, however, scientific scrutiny of this ethnobotanical claim remains incomplete. This study assessed the protective effect of CRE in testosterone-induced benign prostatic hyperplasia-like phenotypes in rats. Male Wistar rats (n = 30, 150-200 g) were randomly assigned into six groups (n = 5), and treated for 28 days as follows: control group (normal saline, 5 mg/kg s.c.), model group (testosterone,5 mg/kg, i.p.), the finasteride (1 mg/kg, p.o.), and CRE (50, 100, and 200 mg/kg, p.o.) groups received testosterone (5 mg/kg, i.p.) in the morning and their respective treatments (either finasteride or CRE). All rats were given chow and water ad libitum. On the 28th day, the rats were sacrificed following deep anesthesia. Blood and the prostate gland were collected. Full blood count, serum levels of prostate-specific antigen (PSA), testosterone, C-reactive protein (CRP), and histology of the prostate gland were assessed. Compared to the model, treatment with C. reticulata peel extracts markedly reduced prostate weight, attenuated atresia of the prostatic glands, stromal fibrosis, and mast cell infiltration, and increased glandular secretion. Additionally, serum levels of testosterone, CRP, PSA, and white blood count were reduced in the high-dose C. reticulata peel extract-treated group. Fruit peels of C. reticulata exhibited a protective effect against BPH partly by attenuating inflammatory activity. Thus, this finding provides a rationale for further exploration of CRE for novel anti-BPH molecules that could be used to develop therapeutics against prostate cancer.

Novel small molecule DMAMCL induces differentiation in rhabdomyosarcoma by downregulating of DLL1

Rhabdomyosarcoma (RMS), a mesenchymal tumor occurring in the soft tissue of children, is associated with a defect in differentiation. This study unveils a novel anti-tumor mechanism of dimethylaminomicheliolide (DMAMCL), which is a water-soluble derivative of Micheliolide. First, we demonstrate that DMAMCL inhibits RMS cell growth without obvious cell death, leading to morphological alterations, enhanced expression of muscle differentiation markers, and a shift from a malignant to a more benign metabolic phenotype. Second, we detected decreased expression of DLL1 in RMS cells after DMAMCL treatment, known as a pivotal ligand in the Notch signaling pathway. Downregulation of DLL1 inhibits RMS cell growth and induces morphological changes similar to the effects of DMAMCL. Furthermore, DMAMCL treatment or loss of DLL1 expression also inhibits RMS xenograft tumor growth and augmented the expression of differentiation markers. Surprisingly, in C2C12 cells DMAMCL treatment or DLL1 downregulation also induces cell growth inhibition and an elevation in muscle differentiation marker expression. These data indicated that DMAMCL induced RMS differentiation and DLL1 is an important factor for RMS differentiation, opening a new window for the clinical use of DMAMCL as an agent for differentiation-inducing therapy for RMS treatment.

Inhibitory Effects of Alpha-Connexin Carboxyl-Terminal Peptide on Canine Mammary Epithelial Cells: A Study on Benign and Malignant Phenotypes.

Mammary cancer is highly prevalent in non-castrated female dogs. Cell-to-cell communication is an important mechanism to maintain homeostasis, and connexins are proteins that assemble to form the communicating gap junctions. In many cancers, communication capacity is reduced; several approaches are being tested in order to increase the communication capacity in cancer cells and, therefore, alter their viability. This study analyzed the effects of the alpha-connexin carboxyl-terminal peptide (αCT1) on canine mammary non-neoplastic and neoplastic epithelial cells. Seven canine epithelial mammary cell lines were used. Among these, one was a normal canine epithelial mammary cell line (LOEC-NMG), two canine mammary adenomas (LOEC-MAd1 and LOEC-MAd2), and four canine mammary adenocarcinomas (LOEC-MCA1, LOEC-MCA2, LOEC-MCA3 and CF41). The αCT1 corresponds to a short Cx43 C-terminal sequence linked to an internalization sequence called the antennapedia. After 24 h of incubation, the medium containing different αCT1 peptide concentrations was added to the cells, and only the culture medium was used for control. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was used to quantify cell viability before treatment and 48, 72, and 96 h after the treatment. Results showed that the normal mammary epithelial cell line (LOEC-NMG) was resistant to treatment with αCT1, which is consistent with a previous study on human mammary cell lines. One of the adenoma cell lines (LOEC-MAd2) was also resistant to treatment with αCT1, although the other (LOEC-MAd1) was susceptible to treatment, mostly at 72 h after treatment. Regarding the four canine adenocarcinoma cell lines, they differ regarding the susceptibility to the treatment with αCT1. Three cell lines, canine mixed adenocarcinoma (LOEC-MCA1), canine complex adenocarcinoma (LOEC-MCA2), and commercial canine mammary adenocarcinoma cell line CF41, were susceptible to treatment with αCT1, while one canine mammary adenocarcinoma cell line (LOEC-MCA3) was resistant to treatment. In most αCT1 treated cell lines, Cx43 was strongly detected in cell membranes by immunofluorescence. We propose that αCT1 restored the cell-to-cell communication capacity of neoplastic cells and induced inhibitory effects on cell viability.

Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage

Medulloblastomas with extensive nodularity are cerebellar tumors characterized by two distinct compartments and variable disease progression. The mechanisms governing the balance between proliferation and differentiation in MBEN remain poorly understood. Here, we employ a multi-modal single cell transcriptome analysis to dissect this process. In the internodular compartment, we identify proliferating cerebellar granular neuronal precursor-like malignant cells, along with stromal, vascular, and immune cells. In contrast, the nodular compartment comprises postmitotic, neuronally differentiated malignant cells. Both compartments are connected through an intermediate cell stage resembling actively migrating CGNPs. Notably, we also discover astrocytic-like malignant cells, found in proximity to migrating and differentiated cells at the transition zone between the two compartments. Our study sheds light on the spatial tissue organization and its link to the developmental trajectory, resulting in a more benign tumor phenotype. This integrative approach holds promise to explore intercompartmental interactions in other cancers with varying histology.

Reprogramming and multi-lineage transdifferentiation attenuate the tumorigenicity of colorectal cancer cells

Significant advances have been made in reprogramming various somatic cells into induced pluripotent stem cells (iPSCs) and in multi-lineage differentiation (transdifferentiation) into different tissues. These manipulable transdifferentiating techniques may be applied in cancer therapy. Limited works have been reported that cancer cell malignancy can be switched to the benign phenotypes through reprogramming techniques. Here, we reported that two colorectal cancer (CRC) cell lines (DLD1, HT29) could be reprogrammed into iPSCs (D-iPSCs, H-iPSCs). D- and H-iPSCs showed reduced tumorigenesis. Furthermore, we successfully induced D- and H-iPSCs differentiation into terminally differentiated cell types such as cardiomyocyte, neuron, and adipocyte-like cells. Impressively, the differentiated cells exhibited further attenuated tumorigenesis in vitro and in vivo. RNA-Seq further indicated that epigenetic changes occurred after reprogramming and transdifferentiation that caused reduce tumorigenicity. Overall, our study indicated that CRC cells can be reprogrammed and further differentiate to terminally differentiated lineages with attenuation of their malignancy in vitro and in vivo. The current work sheds light on a potential multi-lineage differentiation therapeutic strategy for colorectal cancer.

Potentially Pathogenic SORL1 Mutations Observed in Autosomal-Dominant Cases of Alzheimer's Disease Do Not Modulate APP Physiopathological Processing.

The SORL1 gene encodes LR11/SorLA, a protein that binds β-amyloid precursor protein (APP) and drives its intracellular trafficking. SORL1 mutations, occurring frequently in a subset of familial cases of Alzheimer's disease (AD), have been documented, but their pathogenic potential is not yet clear and questions remain concerning their putative influence on the physiopathological processing of APP. We have assessed the influence of two SORL1 mutations that were described as likely disease-causing and that were associated with either benign (SorLA924) or severe (SorLA511) AD phenotypes. We examined the influence of wild-type and mutants SorLA in transiently transfected HEK293 cells expressing either wild-type or Swedish mutated APP on APP expression, secreted Aβ and sAPPα levels, intracellular Aβ 40 and Aβ42 peptides, APP-CTFs (C99 and C83) expressions, α-, β- and γ-secretases expressions and activities as well as Aβ and CTFs-degrading enzymes. These paradigms were studied in control conditions or after pharmacological proteasomal modulation. We also established stably transfected CHO cells expressing wild-type SorLA and established the colocalization of APP and either wild-type or mutant SorLA. SorLA mutations partially disrupt co-localization of wild-type sorLA with APP. Overall, although we mostly confirmed previous data concerning the influence of wild-type SorLA on APP processing, we were unable to evidence significant alterations triggered by our set of SorLA mutants, whatever the cells or pharmacological conditions examined. Our study , however, does not rule out the possibility that other AD-linked SORL1 mutations could indeed affect APP processing, and that pathogenic mutations examined in the present study could interfere with other cellular pathways/triggers in AD.

Prevalence of Fabry disease in patients with chronic kidney disease: A systematic review and meta-analysis

Fabry disease (FD) is an X-linked lysosomal storage disease caused by pathogenic variants in the GLA gene. It has a wide range of clinical manifestations, typically related to the specific underlying GLA variant. One of the main features of FD is kidney involvement; therefore, several studies have addressed the prevalence of FD in all types of patients with chronic kidney disease. We performed a systematic review and meta-analysis of screening studies in chronic kidney disease patients, including those on dialysis, had undergone a kidney transplantation, and those who did not receive kidney replacement therapy, and assessed the prevalence of pathogenic variants in these cohorts. Fifty-five studies were included, involving a total of 84,062 individuals. Of these, 251 cases were positive for FD; a third of the reported GLA variants were of a benign phenotype (37.8%), followed by classical phenotype (31.7%), late onset (15.5%), and of uncertain significance (14.7%). The overall prevalence among dialysis patients was 0.10% (CI95%, 0.06–0.15), 0.28% (CI95%, 0.06–0.15) among patients with kidney transplantation, and 0.17% (CI95%, 0.11–0.39) among those without kidney replacement therapy. Although the overall prevalence of FD is low in patients with kidney involvement, screening, especially in patients who have not yet undergone kidney replacement therapy, is important, in order to provide timely and effective treatment interventions, including disease modifying therapies. The prevalence of kidney involvement in females with Fabry Disease is lower but this should not lead to inadequate follow up. Further research is also needed on the impact of genetic variants of uncertain significance to elucidate their role in Fabry disease.

Cell Reprogramming Techniques: Contributions to Cancer Therapy.

The reprogramming of terminally differentiated cells over the past few years has become important for induced pluripotent stem cells (iPSCs) in the field of regenerative medicine and disease drug modeling. At the same time, iPSCs have also played an important role in human cancer research. iPSCs derived from cancer patients can be used to simulate the early progression of cancer, for drug testing, and to study the molecular mechanism of cancer occurrence. In recent years, with the application of cellular immunotherapy in cancer therapy, patient-derived iPSC-induced immune cells (T, natural killer, and macrophage cells) solve the problem of immune rejection and have higher immunogenicity, which greatly improves the therapeutic efficiency of immune cell therapy. With the continuous progress of cancer differentiation therapy, iPSC technology can reprogram cancer cells to a more primitive pluripotent undifferentiated state, and successfully reverse cancer cells to a benign phenotype by changing the epigenetic inheritance of cancer cells. This article reviews the recent progress of cell reprogramming technology in human cancer research, focuses on the application of reprogramming technology in cancer immunotherapy and the problems solved, and summarizes the malignant phenotype changes of cancer cells in the process of reprogramming and subsequent differentiation.

Newborn screening for primary carnitine deficiency: who will benefit? – a retrospective cohort study

BackgroundNewborn screening (NBS) programmes identify a wide range of disease phenotypes, which raises the question whether early identification and treatment is beneficial for all. This study aims to answer this...

Characterization of an MLC patient carrying two MLC1 variants showing radiological improvement

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of vacuolating leukodystrophy. Approximately 75% of MLC patients have variants in MLC1, while the rest in GLIALCAM, GPRC5B and AQP4. From the GLIALCAM patients, a classical and a benign phenotype can be distinguished, in which a recessive and dominant inheritance is observed, respectively. Here, we report a new MLC patient harboring two variants in MLC1 with radiological improvement. The patient is heterozygous for the variants c.597+37C>G and c.895–1G>T affecting both mRNA splicing, and the latest causes the deletion p.Pro299_Glu353del. By analyzing mRNA and protein obtained from patient's peripheral blood leukocytes, we could demonstrate the expression of a small amount of wild-type MLC1 mRNA and protein in the patient. Thus, we suggest that the improvement of clinical and radiological abnormalities observed in all remitting MLC patients might be due to the presence of residual amounts of MLC1 protein.

Increased basal forebrain volumes could prevent cognitive decline in LRRK2 Parkinson's disease

Background and objectivesIt has been recently suggested that LRRK2 mutations are associated with a more benign clinical phenotype and a potentially more preserved cholinergic function in Parkinson's disease (PD). However, to our knowledge, no studies have tested whether the better clinical progression observed in LRRK2-PD patients is associated with more preserved volumes of a cholinergic brain area, the basal forebrain (BF). To address this hypothesis, here we compared BF volumes in LRRK2 carriers with and without PD with respect to idiopathic PD (iPD) patients and controls, and assessed whether they are associated with better clinical progression observed in LRRK2-PD compared to iPD. MethodsThirty-one symptomatic LRRK2-PD patients and 13 asymptomatic LRRK2 individuals were included from the Parkinson's Progression Markers Initiative. In addition, 31 patients with iPD and 13 healthy controls matched to the previous groups were also included. BF volumes were automatically extracted from baseline T1-weighted MRI scans using a stereotactic atlas of cholinergic nuclei. These volumes were then compared between groups and their relationship with longitudinal cognitive changes was evaluated using linear mixed effects models. Mediation analyses assessed whether BF volumes mediated differences in cognitive trajectories between groups. ResultsLRRK2-PD patients showed significantly higher BF volumes compared to iPD (P = 0.019) as did asymptomatic LRRK2 subjects compared to controls (P = 0.008). There were no other significant differences in cortical regions or subcortical volumes between these groups. BF volumes predicted longitudinal decline in several cognitive functions in iPD patients but not in LRRK2-PD, who did not show cognitive changes over a 4-year follow-up period. BF volumes were a significant mediator of the different cognitive trajectories between iPD and LRRK2-PD patients (95% CI 0.056–2.955). DiscussionOur findings suggest that mutations in LRRK2 are associated with increased BF volumes, potentially reflecting a compensatory hypercholinergic state that could prevent cognitive decline in LRRK2-PD patients.

OVERWEIGHT OR OBESITY DOES NOT CARRY AN INCREASED RISK OF ADVERSE OUTCOME IN YOUNG TO MIDDLE AGE PEOPLE WITHOUT METABOLIC ABNORMALITIES

Objective: Overweight or obesity (OvOb) is a risk factor for the development of cardiometabolic complications. However, according to some investigators, OvOb developed without hypertension and insulin resistance may be considered as a benign phenotype. The aim of the present study was to investigate the prognostic significance of OvOb (BMI&gt; = 25 kg/m2) without concomitant metabolic abnormalities in young-to-middle-age subjects screened for stage 1 hypertension. Design and method: We examined 1208, 18-to-45-year-old participants from the HARVEST study. Mean age was 33.1 ± 8.6 years and BP 145.5 ± 10.6/93.5 ± 5.7 mmHg. Participants were classified into four groups according to whether they had OvOb or not (0/1) and had normal (group 0) or at least one abnormal (group 1) metabolic syndrome parameter (glucose, triglyceride, HDL-cholesterol, and average 24-hour BP). The predictive role of OvOb/metabolic group for incident hypertension and cardiovascular or renal events (MACE) was evaluated in Cox survival analyses, adjusting for other risk factors and several confounders. Results: ObOv was present in 51.1% of the participants and at least one metabolic abnormality was present in 74.5%. Among the subjects with OvOb, 20.2% had no metabolic abnormalities, 40.5% had one metabolic abnormality, and 39.3% had two or more metabolic abnormalities. During a median follow-up of 17.4 years, 80.6% of the participants developed hypertension requiring pharmacological treatment and 8.9% had a MACE. In adjusted Cox models, OvOb participants with at least one metabolic abnormality had an increased risk of incident hypertension (HR, 1.43; 95%CI,1.12 - 1.81, p = 0.003) and MACE (2.34,1.03 - 5.36, p = 0.043) compared to those with normal metabolic parameters. Among the participants with normal BMI, a similar metabolic-related increase in risk was found for the hypertension outcome (HR, 1.52;95%CI,1.21 - 1.92, p = 0.0003), but not for MACE (1.64,0.70 - 3.81, p = 0.25). In a Cox model in the whole population, when controlled for each other the metabolic group (0/1) was a predictor of hypertension (p &lt; 0.0001) and MACE (p = 0.028) whereas the ObOv group was not (p&gt;0.05). Conclusions: These data show that in young-to-middle-age people, an abnormal metabolic profile is an important predictor of future hypertension needing treatment and MACE. OvOb without metabolic abnormalities does not carry an increased risk of adverse outcomes.

Association between sarcoidosis and HLA polymorphisms in a Czech population from Central Europe: focus on a relationship with clinical outcome and treatment.

Sarcoidosis is an immune-mediated systemic disease with unknown etiology affecting the lung predominantly. The clinical manifestation of sarcoidosis is rather diverse ranging from Löfgren's syndrome to fibrotic disease. Also, it differs among patients with distinct geographical and ethnic origins, consistent with environmental and genetic factors' role in its pathogenesis. Of those, the polymorphic genes of the HLA system have been previously implicated in sarcoidosis. Therefore, we have performed an association study in a well-defined cohort of Czech patients aiming to define how variation in HLA genes, may contribute to disease origin and development. Total of the 301 Czech unrelated sarcoidosis patients were diagnosed according to international guidelines. In those, HLA typing was performed using next-generation sequencing. The allele frequencies at six HLA loci (HLA-A,-B,-C,-DRB1,-DQA1, and -DQB1) observed in the patients were compared with HLA allele distribution determined in 309 unrelated healthy Czech subjects; sub-analyses of relationships between HLA and distinct sarcoidosis clinical phenotypes were performed. Associations were assessed by two-tailed Fischer's exact test with correction for multiple comparisons. We report two variants, HLA-DQB1*06:02, and HLA-DQB1*06:04, as risk factors for sarcoidosis, and three variants, HLA-DRB1*01:01, HLA-DQA1*03:01, and HLA-DQB1*03:02 as protective factors. HLA-B*08:01, HLA-C*07:01, HLA-DRB1*03:01, HLA-DQA1*05:01, and HLA-DQB1*02:01 variants associated with Löfgren's syndrome, a more benign phenotype. HLA- DRB1*03:01 and HLA-DQA1*05:01 alleles were connected with better prognosis-chest X-ray (CXR) stage 1, disease remission, and non-requirement of corticosteroid treatment. The alleles HLA-DRB1*11:01 and HLA-DQA1*05:05 are associated with more advanced disease represented by the CXR stages 2-4. HLA-DQB1*05:03 associated with sarcoidosis extrapulmonary manifestation. In our Czech cohort, we document some associations between sarcoidosis and HLA previously described in other populations. Further, we suggest novel susceptibility factors for sarcoidosis, such as HLA-DQB1*06:04, and characterize associations between HLA and sarcoidosis clinical phenotypes in Czech patients. Our study also extends the role of the 8.1 ancestral haplotype (HLA-A*01:01∼HLA-B*08:01∼HLA-C*07:01∼HLA-DRB1*03:01∼HLA-DQA1*05:01∼HLA-DQB1*02:01), already implicated in autoimmune diseases, as a possible predictor of better prognosis in sarcoidosis. The general translational application of our newly reported findings for personalized patient care should be validated by an independent study from another, international referral center.

PRRT2 benign familial infantile seizures (BFIS) with atypical evolution to encephalopathy related to status epilepticus during sleep (ESES).

Heterozygous variants in PRRT2 are mostly associated with benign phenotypes, being the major genetic cause of benign familial infantile seizures (BFIS), as well as in paroxysmal disorders. We report two children from unrelated families with BFIS that evolved to encephalopathy related to status epilepticus during sleep (ESES). Two probands presented with focal motor seizures at 3months of age, with a limited course. Both children presented, at around 5years of age, with centro-temporal interictal epileptiform discharges with a source in the frontal operculum, markedly activated by sleep, and associated with stagnation on neuropsychological development. Whole-exome sequencing and co-segregation analysis revealed a frameshift mutation c.649dupC in the proline-rich transmembrane protein 2 (PRRT2) in both probands and all affected family members. The mechanism leading to epilepsy and the phenotypic variability ofPRRT2variants remain poorly understood. However, its wide cortical and subcortical expression, in particular in the thalamus, could partially explain both the focal EEG pattern and the evolution to ESES. No variants in thePRRT2gene have been previously reported in patients with ESES. Due to the rarity of this phenotype, other possible causative cofactors are likely contributing to the more severe course of BFIS in our probands.

Risk factors for upper urinary tract uroliths and ureteral obstruction in cats under referral veterinary care in the United Kingdom.

Cats presenting with upper urinary tract uroliths (UUTUs) and ureteral obstruction ("obstructive UUTU") are typically younger than cats with idiopathic CKD that often have incidental nephroliths. Cats with upper urinary tract urolith have 2 clinical phenotypes; a more aggressive phenotype at risk of obstructive UUTU at a young age and a more benign phenotype in older cats, with reduced risk of obstructive UUTU. Identify risk factors for UUTU and for obstructive UUTU. Eleven thousand four hundred thirty-one cats were referred for care over 10 years; 521 (4.6%) with UUTU. Retrospective VetCompass observational cross-sectional study. Multivariable logistic regression models were performed to identify risk factors for a diagnosis of UUTU vs no UUTU and additionally, obstructive UUTU vs nonobstructive UUTU. Risk factors for UUTU included female sex (odds ratio [OR] 1.6, confidence interval [CI] 1.3-1.9; P < .001), British shorthair, Burmese, Persian, Ragdoll or Tonkinese (vs non-purebred ORs 1.92-3.31; P < .001) breed and being ≥4 years (ORs 2.1-3.9; P < .001). Risk factors for obstructive UUTU were female sex (OR 1.8, CI 1.2-2.6; P=.002), having bilateral uroliths (OR 2.0, CI 1.4-2.9; P=.002) and age, with the odds of obstructive UUTU increasing as age at diagnosis of UUTU decreased (≥12 years, reference category; 8-11.9 years, OR 2.7, CI 1.6-4.5; 4-7.9 years, OR 4.1, CI 2.5-7.0; 0-3.9 years, OR 4.3, CI 2.2-8.6; P < 0.001). Cats diagnosed with UUTU at a younger age have a more aggressive phenotype with higher risk of obstructive UUTU compared to cats over 12 years of age diagnosed with UUTU.