Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation

FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[3H] fucose and [3H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-3H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a congenital glycosylation disorder characterized by a defective fucose-salvage pathway

Intermediate filament–membrane attachments function synergistically with actin-dependent contacts to regulate intercellular adhesive strength

By tethering intermediate filaments (IFs) to sites of intercellular adhesion, desmosomes facilitate formation of a supercellular scaffold that imparts mechanical strength to a tissue. However, the role IF–membrane attachments play in strengthening adhesion has not been directly examined. To address this question, we generated Tet-On A431 cells inducibly expressing a desmoplakin (DP) mutant lacking the rod and IF-binding domains (DPNTP). DPNTP localized to the plasma membrane and led to dissociation of IFs from the junctional plaque, without altering total or cell surface distribution of adherens junction or desmosomal proteins. However, a specific decrease in the detergent-insoluble pool of desmoglein suggested a reduced association with the IF cytoskeleton. DPNTP-expressing cell aggregates in suspension or substrate-released cell sheets readily dissociated when subjected to mechanical stress whereas controls remained largely intact. Dissociation occurred without lactate dehydrogenase release, suggesting that loss of tissue integrity was due to reduced adhesion rather than increased cytolysis. JD-1 cells from a patient with a DP COOH-terminal truncation were also more weakly adherent compared with normal keratinocytes. When used in combination with DPNTP, latrunculin A, which disassembles actin filaments and disrupts adherens junctions, led to dissociation up to an order of magnitude greater than either treatment alone. These data provide direct in vitro evidence that IF–membrane attachments regulate adhesive strength and suggest furthermore that actin- and IF-based junctions act synergistically to strengthen adhesion

VAMP8 is a vesicle SNARE that regulates mucin secretion in airway goblet cells

Mucin secretion in the lung is regulated by the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) exocytotic core, which has not been defined in airway goblet cells. In this study, the SNARE vesicle-associated membrane protein 8 (VAMP8) was found to be expressed in human airway epithelial goblet cells. VAMP8 knockdown by RNA interference techniques reduced airway epithelial mucin secretion induced by PAR agonists, neutrophil elastase and ATP. Basal (non-agonist elicited) mucin secretion was also reduced as a result of VAMP8 knockdown. Importantly, mucin secretion was reduced in the lungs of VAMP8 knockout mice compared to wild-type littermates. Our data suggest that VAMP8 is an essential SNARE in airway mucin granule exocytosis. Reduction of VAMP8 activity/expression may provide a novel therapeutic target to ameliorate airway mucus obstruction in lung diseases

Placebo response in binge eating disorder

Objective: Placebo response in studies of binge eating disorder (BED) has raised concern about its diagnostic stability. The aims of this study were (1) to compare placebo responders (PRs) with nonresponders (NRs); (2) to investigate the course of BED following placebo response; and (3) to examine attributions regarding placebo response. Method: The baseline placebo run-in phase (BL) was part of a RCT investigating sibutramine hydrochloride for BED; it included 451 participants, ages 19–63, diagnosed with BED. Follow-up (FU) included 33 PRs. Results: In this study, 32.6% of participants responded to placebo (PRs = 147; NRs = 304). PRs exhibited significantly less symptom severity. At FU (n = 33), many PRs reported continued symptoms. Conclusion: PRs exhibited significantly less severe pathology than NRs. Placebo response in BED may transitory or incomplete. The results of this study suggest variable stability in the BED diagnosis

Proceedings of the Working Group Session on Fertility Preservation for Individuals with Gender and Sex Diversity

Children and adolescents with gender and sex diversity include (1) gender-nonconforming and transgender individuals for whom gender identity or expression are incongruent with birth-assigned sex (heretofore, transgender) and (2) individuals who have differences in sex development (DSD). Although these are largely disparate groups, there is overlap in the medical expertise necessary to care for individuals with both gender and sex diversity. In addition, both groups face potential infertility or sterility as a result of desired medical and surgical therapies. The Ann and Robert H. Lurie Children's Hospital of Chicago (Lurie Children's) gender and sex development program (GSDP) provides specialized multidisciplinary care for both transgender and DSD patients. In response to patient concerns that recommended medical treatments have the potential to affect fertility, the Lurie Children's GSDP team partnered with experts from the Oncofertility Consortium at Northwestern University to expand fertility preservation options to gender and sex diverse youth. This article summarizes the results of a meeting of experts across this field at the annual Oncofertility Consortium conference with thoughts on next steps toward a unified protocol for this patient group.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140296/1/trgh.2016.0008.pd

The impact of an intervention to increase uptake to structured self-management education for people with type 2 diabetes mellitus in primary care (the embedding package), compared to usual care, on glycaemic control: study protocol for a mixed methods study incorporating a wait-list cluster randomised controlled trial

Abstract: Background: Approximately 425 million people globally have diabetes, with ~ 90% of these having Type 2 Diabetes Mellitus (T2DM). This is a condition that leads to a poor quality of life and increased risk of serious health complications. Structured self-management education (SSME) has been shown to be effective in improving glycaemic control and patient related outcome measures and to be cost-effective. However, despite the demonstrated benefits, attendance at SSME remains low. An intervention has been developed to embed SSME called the ‘Embedding Package’. The intervention aims to address barriers and enhance enablers to uptake of SSME at patient, healthcare professional and organisational levels. It comprises a marketing strategy, user friendly and effective referral pathways, new roles to champion SSME and a toolkit of resources. Methods: A mixed methods study incorporating a wait-list cluster randomised trial and ethnographic study, including 66 UK general practices, will be conducted with two intervention start times (at 0 and 9 months), each followed by an active delivery phase. At 18 months, the intervention will cease to be actively delivered and a 12 month observational follow-up phase will begin. The intervention, the Embedding Package, aims to increase SSME uptake and subsequent improvements in health outcomes, through a clear marketing strategy, user friendly and effective referral pathways, a local clinical champion and an ‘Embedder’ and a toolkit of resources for patients, healthcare professionals and other key stakeholders. The primary aim is, through increasing uptake to and attendance at SSME, to reduce HbA1c in people with T2DM compared with usual care. Secondary objectives include: assessing whether there is an increase in referral to and uptake of SSME and improvements in biomedical and psychosocial outcomes; an assessment of the sustainability of the Embedding Package; contextualising the process of implementation, sustainability of change and the ‘fit’ of the Embedding Package; and an assessment of the cost-effectiveness of the Embedding Package. Discussion: This study will assess the effectiveness, cost-effectiveness and sustainability of the Embedding Package, an intervention which aims to improve biomedical and psychosocial outcomes of people with T2DM, through increased referral to and uptake of SSME. Trial registration: International Standard Randomised Controlled Trials Number ISRCTN23474120. Assigned 05/04/2018. The study was prospectively registered. On submission of this manuscript practice recruitment is complete, participant recruitment is ongoing and expected to be completed by the end of 2019

Plasmodium knowlesi in Human, Indonesian Borneo

Plasmodium knowlesi is now established as the fifth Plasmodium species to cause malaria in humans. We describe a case of P. knowlesi infection acquired in Indonesian Borneo that was imported into Australia. Clinicians need to consider this diagnosis in a patient who has acquired malaria in forest areas of Southeast Asia

Effects of Selective Matrix Metalloproteinase Inhibitor (PG-116800) to Prevent Ventricular Remodeling After Myocardial Infarction Results of the PREMIER (Prevention of Myocardial Infarction Early Remodeling) Trial

ObjectivesWe sought to determine whether matrix metalloproteinase (MMP) inhibitor, PG-116800, reduced left ventricular (LV) remodeling after myocardial infarction (MI).BackgroundPG-116800 is an oral MMP inhibitor with significant antiremodeling effects in animal models of MI and ischemic heart failure.MethodsIn an international, randomized, double-blind, placebo-controlled study, 253 patients with first ST-segment elevation MI and ejection fraction between 15% and 40% were enrolled 48± 24 h after MI and treated with placebo or PG-116800 for 90 days. Major efficacy end points were changes in LV volumes as determined by serial echocardiography, and clinical and safety outcomes were also collected.ResultsIn total, 203 patients (80%) completed 90 days of treatment and had evaluable baseline and 90-day echocardiograms. The proportion of patients with anterior MI (78% vs. 81%) and primary percutaneous coronary intervention (90% vs. 91%) along with baseline LV ejection fraction (35.5% vs. 36.8%) did not differ between PG-116800-treated and placebo-treated patients. There was no difference in the change in LV end-diastolic volume index from days 0 to 90 with PG-116800 versus placebo (5.09 ± 1.45 ml/m2vs. 5.48 ± 1.41 ml/m2, p = 0.42). Changes in LV diastolic volume, LV systolic volume, LV ejection fraction, sphericity index, plus rates of death or reinfarction were not significantly improved with PG-116800. PG-116800 was well tolerated; however, there was increased incidence of arthralgia and joint stiffness without significant increase in overall musculoskeletal adverse events (21% vs. 15%, p = 0.33).ConclusionsMatrix metalloproteinase inhibition with PG-116800 failed to reduce LV remodeling or improve clinical outcomes after MI