Mice lacking the transcription factor T-bet in the innate immune system develop microbiota-dependent colitis. Here, we show that interleukin-17A (IL-17A)-producing IL-7Rα+ innate lymphoid cells ...(ILCs) were potent promoters of disease in Tbx21−/−Rag2−/− ulcerative colitis (TRUC) mice. TNF-α produced by CD103−CD11b+ dendritic cells synergized with IL-23 to drive IL-17A production by ILCs, demonstrating a previously unrecognized layer of cellular crosstalk between dendritic cells and ILCs. We have identified Helicobacter typhlonius as a key disease trigger driving excess TNF-α production and promoting colitis in TRUC mice. Crucially, T-bet also suppressed the expression of IL-7R, a key molecule involved in controlling intestinal ILC homeostasis. The importance of IL-7R signaling in TRUC disease was highlighted by the dramatic reduction in intestinal ILCs and attenuated colitis following IL-7R blockade. Taken together, these data demonstrate the mechanism by which T-bet regulates the complex interplay between mucosal dendritic cells, ILCs, and the intestinal microbiota.
► Chronic colitis in TRUC mice was mediated by IL-17-producing innate lymphoid cells ► TNF-α synergized with IL-23 to induce innate IL-17 production ► Helicobacter typhlonius triggered intestinal pathology in TRUC mice ► T-bet regulated IL-7R transcription, a key checkpoint in intestinal ILC homeostasis
Introduction: The purpose of this study was to develop an evidence‐based guideline for the use of neuromuscular ultrasound in the diagnosis of carpal tunnel syndrome (CTS). Methods: Two questions ...were asked: (1) What is the accuracy of median nerve cross‐sectional area enlargement as measured with ultrasound for the diagnosis of CTS? (2) What added value, if any, does neuromuscular ultrasound provide over electrodiagnostic studies alone for the diagnosis of CTS? A systematic review was performed, and studies were classified according to American Academy of Neurology criteria for rating articles of diagnostic accuracy (question 1) and for screening articles (question 2). Results: Neuromuscular ultrasound measurement of median nerve cross‐sectional area at the wrist is accurate and may be offered as a diagnostic test for CTS (Level A). Neuromuscular ultrasound probably adds value to electrodiagnostic studies when diagnosing CTS and should be considered in screening for structural abnormalities at the wrist in those with CTS (Level B). Muscle Nerve 46: 287–293, 2012
We previously demonstrated that MnCl2 induces double-stranded DNA breaks in sperm in a process that we term as sperm chromatin fragmentation. Here, we tested if the levels of double-stranded DNA ...breaks were corelated to the concentration of MnCl2, and we compared this to another agent that causes single-stranded DNA breaks, H2O2. We found that both methods have the advantage of inducing DNA breaks in a concentration-dependent manner. Mouse sperm were treated with varying concentrations of either H2O2 or MnCl2, and the DNA damage was assessed by pulse-field gel electrophoresis, and the alkaline and neutral comet assays. Oocytes were injected with either treated sperm and the resulting embryos analyzed with an embryoscope to detect subtle changes in embryonic development. We confirmed that H2O2 treatment induced primarily single-stranded DNA breaks and MnCl2 induced primarily double-stranded DNA breaks, indicating different mechanisms of damage. These sperm were injected into oocytes, and the development of the resulting embryos followed with an embryoscope equipped with time lapse recording. We found that aberrations in early embryonic development by day 2 with even the lowest levels of DNA damage and that the levels of embryonic aberrations correlated to the concentration of either H2O2 or MnCl2. Low levels of H2O2 caused significantly more aberrations in embryonic development than low levels of MnCl2 even though the levels of DNA damage as measured by comet assays were similar. These data demonstrate that even low levels of sperm DNA damage cause delays and arrests in embryonic development. Summary Sentence Treatment of mouse sperm with doses of DNA damaging agents that are too low to cause easily visualized DNA breaks cause significant embryonic development problems when used to fertilize untreated eggs. Graphical Abstract
Introduction
We evaluated whether better cardiovascular health at midlife and improvement of cardiovascular health within midlife were associated with dementia risk.
Methods
Two longitudinal ...population‐based studies were used: Atherosclerosis Risk in Communities (ARIC) (n = 11,460/visits at ages 54 and 60), and Age, Gene/Environment Susceptibility (AGES)‐Reykjavik (n = 3907/visit at age 51). A cardiovascular health score (range 0–12/0–14, depending on diet availability) including six/seven items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Cardiovascular health was defined as low (score 0–4/0–5), intermediate (5–7/6–9), or high (8–12/10–14). Incident dementia was ascertained through linkage to health records and with neuropsychological examinations.
Results
Midlife high compared to low cardiovascular health (hazard ratios HRs: for ARIC: 0.60 95% confidence interval: 0.52, 0.69); for AGES‐Reykjavik: 0.83 0.66, 0.99 and improvement of cardiovascular health score within midlife (HR per one‐point increase: ARIC: 0.94 0.92, 0.96) were associated with lower dementia risk.
Discussion
Better cardiovascular health at midlife and improvement of cardiovascular health within midlife are associated with lower dementia risk.
Highlights
Cardiovascular health and dementia were studied in two large cohort studies.
Better cardiovascular health at midlife relates to lower dementia risk.
Improvement of cardiovascular health within midlife relates to lower dementia risk.
Promotion of cardiovascular health at midlife can help to reduce dementia risk.
Purpose
This retrospective observational study compares how different classes of blastocyst genotypes from egg donor cycles differentially blastulate and expand using a standard assay.
Methods
...Quantitative measurements of expansion utilized a customized neural network that segments all sequential time-lapse images during the first 10 h of expansion.
Results
Analyses were performed using two developmental time perspectives using time-lapse imaging. The first was the time to blastocyst formation (tB), which broadly reflects variations in developmental rate. Euploidy peaked at 100–115 h from fertilization. In contrast, aneuploidy peaks flanked this interval bi-modally. These distributions limit ploidy discrimination based upon traditional standard grading features when assessed in real time. In contrast, from the second perspective of progressive blastocyst expansion that is normalized to each individual blastocyst’s tB time, euploidy was significantly increased at expansion values > 20,000µ
2
across all tB intervals studied. A Cartesian coordinate plot graphically summarizes information useful to rank order blastocysts within cohorts for transfer. Defined aneuploidy subgroups, distinguished by the number and complexity of chromosomes involved, also showed distributive differences from both euploids and from each other. A small subset of clinically significant trisomies did not show discriminating features separating them from other euploids.
Conclusion
A standard assay of blastocyst expansion normalized to each individual blastocyst’s time of blastocyst formation more usefully discriminates euploidy from aneuploidy than real-time expansion comparisons using absolute developmental time from fertilization.
This study reviews contemporary management and follow-up of pediatric ovarian torsion.
This is a retrospective series of patients from birth to 19 years undergoing operative management of ovarian ...torsion from 2012 to 2016.
We studied 43 girls who underwent 51 operations for ovarian torsion. The median age was 8.3 years. Ultrasound was utilized for diagnosis in 24/29 patients (83%) evaluated in a children's hospital. In contrast, computed tomography was used initially in 7 cases (50%) in children imaged at non–children's hospitals before transfer. Initial operation for ovarian torsion was completed laparoscopically in 38 (88%). Overall, ovarian preservation was performed in 37 (86%) patients, while 6 (13%) underwent oophorectomy. Indications for oophorectomy included 5 infants with in utero torsion and an 18-year-old with a suspected malignancy. In girls with acute ovarian torsion, the oophorectomy rate was reduced to 2%. Postoperatively, 1 patient developed a small bowel obstruction requiring operation after laparoscopic ovarian detorsion. Recurrent torsion occurred in 3 patients (7%). In total, 34 patients underwent postoperative ovarian imaging. A total of 25 (74%) had follicles visualized in the previously torsed ovary.
Ovarian-sparing operations for acute torsion are safe and result in ovarian salvage and preservation of follicular development in more than 70% of children and adolescents.
•An artificial intelligence platform is applied to the analysis of blastocyst expansion•This platform can be used for single blastocyst selection for transfer•Such selection can result in high ...sustained implantation rates both with and without PTG-A
Can artificial intelligence (AI) discriminate a blastocyst's cellular area from unedited time-lapse image files using semantic segmentation and a deep learning optimized U-Net architecture for use in selecting single blastocysts for transfer?
This platform was retrospectively applied to time-lapse files from 101 sequentially transferred single blastocysts that were prospectively selected for transfer by their highest expansion ranking within cohorts using a 10 h expansion assay rather than standard grading.
The AI platform provides expansion curves and raw data files to classify and compare blastocyst phenotypes within both cohorts and populations. Of 35 sequential unbiopsied single blastocyst transfers, 23 (65.7%) resulted in a live birth. Of 66 sequential single euploid blastocyst transfers, also selected for their most robust expansion, 49 (74.2%) resulted in live birth. The AI platform revealed that the averaged expansion rate was significantly (P = 0.007) greater in euploid blastocysts that resulted in live births compared with those resulting in failure to give a live birth. The platform further provides a framework to analyse fragmentation phenotypes that can test new hypotheses for developmental regulation during the preimplantation period.
AI can be used to quantitatively describe blastocyst expansion from unedited time-lapse image files and can be used to quantitatively rank-order blastocysts for transfer. Early clinical results from such single blastocyst selection suggests that live birth rates without biopsy may be comparable to those found using single euploid blastocysts in younger, good responder patients.
The purpose of this cross-sectional study was to examine the influence of subthreshold posttraumatic stress disorder (PTSD) and full PTSD on quality of life following mild traumatic brain injury ...(mTBI).
Participants were 734 service members and veterans (SMV) classified into two injury groups: uncomplicated mild TBI (MTBI; n = 596) and injured controls (IC, n = 139). Participants completed a battery of neurobehavioral measures, 12-or-more months post-injury, that included the PTSD Checklist Civilian version, Neurobehavioral Symptom Inventory, and select scales from the TBI-QOL and MPAI. The MTBI group was divided into three PTSD subgroups: No-PTSD (n = 266), Subthreshold PTSD (n = 139), and Full-PTSD (n = 190).
There was a linear relationship between PTSD severity and neurobehavioral functioning/quality of life in the MTBI sample. As PTSD severity increased, significantly worse scores were found on 11 of the 12 measures (i.e., MTBI: Full-PTSD > Sub-PTSD > No-PTSD). When considering the number of clinically elevated scores, a linear relationship between PTSD severity and neurobehavioral functioning/quality of life was again observed in the MTBI sample (e.g., 3-or-more elevated scores: Full-PTSD = 92.1 %, Sub-PTSD = 61.9 %, No-PTSD = 19.9 %).
Limitations included the use of a self-report measure to determine diagnostic status that may under/overcount or mischaracterize individuals.
PTSD symptoms, whether at the level of diagnosable PTSD, or falling short of that because of the intensity or characterization of symptoms, have a significant negative impact on one's quality of life following MTBI. Clinicians' treatment targets should focus on the symptoms that are most troubling for an individual and the individual's perception of quality of life, regardless of the diagnosis itself.
Background & Aims Innate lymphoid cells (ILCs) are a heterogeneous group of mucosal inflammatory cells that participate in chronic intestinal inflammation. We investigated the role of interleukin 6 ...(IL6) in inducing activation of ILCs in mice and in human beings with chronic intestinal inflammation. Methods ILCs were isolated from colons of Tbx21-/- × Rag2-/- mice (TRUC), which develop colitis; patients with inflammatory bowel disease (IBD); and patients without colon inflammation (controls). ILCs were characterized by flow cytometry; cytokine production was measured by enzyme-linked immunosorbent assay and cytokine bead arrays. Mice were given intraperitoneal injections of depleting (CD4, CD90), neutralizing (IL6), or control antibodies. Isolated colon tissues were analyzed by histology, explant organ culture, and cell culture. Bacterial DNA was extracted from mouse fecal samples to assess the intestinal microbiota. Results IL17A- and IL22-producing, natural cytotoxicity receptor–negative, ILC3 were the major subset of ILCs detected in colons of TRUC mice. Combinations of IL23 and IL1α induced production of cytokines by these cells, which increased further after administration of IL6. Antibodies against IL6 reduced colitis in TRUC mice without significantly affecting the structure of their intestinal microbiota. Addition of IL6 increased production of IL17A, IL22, and interferon-γ by human intestinal CD3-negative, IL7-receptor–positive cells, in a dose-dependent manner. Conclusions IL6 contributes to activation of colonic natural cytotoxicity receptor–negative, CD4-negative, ILC3s in mice with chronic intestinal inflammation (TRUC mice) by increasing IL23- and IL1α-induced production of IL17A and IL22. This pathway might be targeted to treat patients with IBD because IL6, which is highly produced in colonic tissue by some IBD patients, also increased the production of IL17A, IL22, and interferon-γ by cultured human colon CD3-negative, IL7-receptor–positive cells.
As a consequence of the genomic revolution, a large number of publications describing paroxysmal movement disorders have been published in the last few years, shedding light on their molecular ...pathology. Routine gene testing is not necessary to guide treatment for typical forms of paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and episodic ataxia type 1 or 2. It can, however, be helpful in the management of atypical or complex cases, especially for genetic counselling, treatment strategies, and the offer of preimplantation genetic diagnosis. Antiepileptic drugs remain the treatment of choice for PKD and episodic ataxia type 1, benzodiazepines are often useful for PNKD, and episodic ataxia type 2 benefits from acetazolamide regardless of the genetic etiology.
What the paper adds
A growing number of genes have been associated with classic and newly described paroxysmal movement disorders.
Paroxysmal movement disorders share common mechanisms and clinical features with other neurological paroxysmal phenomena including epilepsy and migraine.
Resumen
Fenotipos, genotipos, y el manejo de trastornos de movimientos paroxísticos
Como consecuencias de la revolución genómica, en los últimos años se han presentado un gran número de publicaciones describiendo los trastornos de movimientos paroxísticos, arrojando luz sobre su patología molecular. Los estudios de genes rutinarios no son necesarios para la guiar el tratamiento para la forma típica de disquinesia quinesigénica paroxística (DQP), disquinesia noquinesigénica paroxística (DNQP), y ataxia episódica tipo 1 o 2. Sin embargo, puede ser de ayuda para el manejo de casos atípicos o complejos, especialmente para consejo genético, estrategias de tratamiento, y el ofrecimiento de diagnóstico genético pre implante. Las drogas anticonvulsivantes continúan siendo el tratamiento de elección para DQP y ataxia episódica tipo 1, las benzodiacepinas son útiles con frecuencia para DNQP, y la ataxia episódica tipo 2 se beneficia con acetazolamida independientemente de la etiología genética.
Resumo
Fenótipos, genótipos, e o manejo de desordens motoras paroxísticas
Como consequência da revolução genômica, um grande número de publicações descrevendo desordens motoras paroxísticas tem sido publicado nos últimos anos, esclarecendo sua patologia molecular. O teste genético de rotina não é necessário para guiar o tratamento de formas típicas de discinesia paroxística cinesigênica (DPC), discinesia paroxística não‐cinesigênica (DPNC), e ataxia episódica tipo 1 ou 2. Pode, no entanto, ser útil no manejo de casos atípicos ou complexos, especialmente para aconselhamento genético, estratégias de tratamento, e oferta de diagnóstico genético pré‐implantação. Drogas anti‐epilépticas permanecem como o tratamento de escolha da DPC e ataxia episódica tipo 1, benzodiazepínicos são frequentemente úteis para DPNC, e a ataxia episódica tipo 2 se beneficia de acetazolamida independente da etiologia genética.
What the paper adds
A growing number of genes have been associated with classic and newly described paroxysmal movement disorders.
Paroxysmal movement disorders share common mechanisms and clinical features with other neurological paroxysmal phenomena including epilepsy and migraine.
This invited review is commented on by Babiker on page 533 of this issue.
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