Distinct seasonal patterns in the onset of adult idiopathic inflammatory myopathy in patients with anti-Jo-1 and anti-signal recognition particle autoantibodies

In idiopathic inflammatory myopathy (IIM; or, polymyositis/dermatomyositis), the myositis-specific autoantibodies anti-Jo-1 and anti-signal recognition particle (anti-SRP), appear to define clinically and immunogenetically distinct groups of patients. We show here that the month during which the onset of weakness occurs is not random in patients with anti-Jo-1 auto-antibodies (average month April, P less than 0.02) and in those with anti-SRP autoantibodies (average month November, P less than 0.02); both groups of patients also experience rapid onset of disease. By contrast, patients classified into the traditional categories of polymyositis and dermatomyositis do not have recognizable seasonal patterns and do not differ in the rate of onset of disease. These findings suggest that searches for seasonal patterns in the onset of autoimmune disorders characterized by disease-specific autoantibodies may provide useful clues to etiology.     

Ternary complex formation of AFN‐1252 with Acinetobacter baumannii FabI and NADH: Crystallographic and biochemical studies

Acinetobacter baumannii is an opportunistic Gram‐negative bacterial pathogen, associated mostly with hospital‐acquired infections. The emergence of drug resistance strains made it necessary to explore new pathways for the development of more effective antibiotics. Enoyl CoA reductase (FabI), a key enzyme in the fatty acid biosynthesis (FAS) pathway, has emerged as a potential target for antibacterial drug development. Earlier reports show that the lead SaFabI inhibitor AFN‐1252 can inhibit FabI from other organisms including Escherichia coli and Burkholderia pseudomallei, but with differential potency. In the present work, we show that AFN‐1252 is a moderate inhibitor of AbFabI with an IC₅₀ of 216 nM. AFN‐1252 stabilized AbFabI with a 4.2°C increase in the melting temperature (T_m) and, interestingly, the stabilization effect was significantly increased in presence of the cofactor NADH (?T_m = 17°C), suggesting the formation of a ternary complex AbFabI: AFN‐1252: NADH. X‐ray crystallography studies of AbFabI co‐crystalized with AFN‐1252 and NADH confirmed the ternary complex formation. The critical interactions of AFN‐1252 with AbFabI and NADH identified from the co‐crystal structure may facilitate the design and development of new drugs against A. baumannii infections by targeting the FAS pathway.     

Altered striatal function in a mutant mouse lacking D1A dopamine receptors.

Of the five known dopamine receptors, D1A and D2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thought to result from imbalanced activity in these pathways. Dopamine regulates movement through its differential effects on D1A receptors expressed by direct output neurons and D2 receptors expressed by indirect output neurons. To further examine the interaction of D1A and D2 neuronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D1A receptors (D1A-/-). D1A-/- mutants are growth retarded and die shortly after weaning age unless their diet is supplemented with hydrated food. With such treatment the mice gain weight and survive to adulthood. Neurologically, D1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striatum revealed changes associated with the altered phenotype of these mutants. D1A receptor binding was absent in striatal sections from D1A-/- mice. Striatal neurons normally expressing functional D1A receptors are formed and persist in adult homozygous mutants. Moreover, substance P mRNA, which is colocalized specifically in striatal neurons with D1A receptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D2 receptors, are unaffected. These findings show that D1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway.     

Zinc absorption in alcoholics using zinc-65

Alcoholism is occasionally complicated by zinc deficiency. We have assessed the possibility that malabsorption of zinc may be a potential cause. Using a dual isotope absorption technique the absorption of 65Zn in 18 alcoholic patients was 37% (13 +/- SD) and 56% (10 +/- SD) in a normal control group (p less than 0.001). The mean serum zinc in 55 alcoholic patients was 11.6 mumol/l (3.0 +/- SD) and in 36 normal volunteers the mean serum zinc was 13.6 mumol/l (1.8 +/- SD; p less than 0.001). This study suggests that chronic alcohol abuse will decrease the absorption of zinc and this may contribute towards the zinc deficiency occasionally associated with alcoholism.     

Foodborne botulism in a six-month-old infant caused by home-canned baby food

Previously reported cases of botulism in infants have been diagnosed as infant botulism; that is, botulism caused by intestinal colonization by Clostridium botulinum with intraluminal production and absorption of toxin. Foodborne botulism is caused by ingestion of preformed toxin. We describe an unusual case of foodborne botulism in a 6-month-old infant caused by the ingestion of improperly prepared home-canned baby food. This represents the youngest age of onset for foodborne botulism in the United States of which we are aware and illustrates the need to rule out foodborne botulism, which represents a public health emergency, regardless of the patient's age. The diagnosis could have been readily missed or delayed in this case because the weakness was rapidly progressive rather than insidious, as is typical of infant botulism.     

Immunologic status of hemophilia patients treated with cryoprecipitate or lyophilized concentrate

We evaluated 37 patients with moderate or severe hemophilia A and six patients with severe factor IX deficiency for clinical or laboratory evidence of immune abnormalities. Patients were assigned to one of four groups according to the type of clotting factor replacement. Twenty patients had received only cryoprecipitate during the two years preceding the evaluation (group I); 11 additional patients were treated predominantly with cryoprecipitate but had also received up to nine bottles of factor VIII concentrate (group II); six patients received factor VIII concentrate (group III); six patients received factor IX concentrate (group IV). There was no clinical or laboratory evidence of immunodeficiency among the 43 patients. The mean absolute number of Th cells was normal in all patient groups, but the mean absolute number of Ts cells was increased compared with controls, both in patients treated with cryoprecipitate and in patients treated with factor VIII or factor IX concentrate. There was no correlation between the Th/Ts ratio and patient age, alanine aminotransferase level, hepatitis serology, in vitro lymphocyte function, or amount of clotting factor administered. Our observations demonstrate that the volunteer or commercial origin of clotting factor replacement cannot fully explain the alterations in lymphocyte subset distribution previously described in patients with hemophilia A.     

Establishing and managing a periodontal biobank for research: the sharing of experience

Periodontal bio‐repositories, which allow banking of clinically validated human data and biological samples, provide an opportunity to derive biomarkers for periodontal diagnosis, prognosis and therapeutic activities which are expected to improve patient management. This article presents the establishing of the Malaysian Periodontal Database and Biobank System (MPDBS) which was initiated in 2011 with the aim to facilitate periodontal research. Partnerships were established with collaborating centres. Policies on specimen access, authorship and acknowledgement policies were agreed upon by all participating centres before the initiation of the periodontal biobank. Ethical approval for the collection of samples and data were obtained from institutional ethics review boards. A broad‐based approach for informed consent was used, which covered areas related to quality of life impacts, genetics and molecular aspects of periodontal disease. Sample collection and processing was performed using a standardized protocol. Biobanking resources such as equipment and freezers were shared with the Malaysian Oral Cancer Database and Tissue Bank System (MOCDTBS). In the development of the MPDBS, challenges that were previously faced by the MOCDTBS were considered. Future challenges in terms of ethical and legal issues will be faced when international collaborations necessitate the transportation of specimens across borders.     

Outcomes Among Diabetic Patients Undergoing Percutaneous Coronary Intervention With Contemporary Drug-Eluting Stents: Analysis From the BIONICS Randomized Trial

Objectives

The authors sought to investigate the impact of diabetes mellitus (DM) on outcomes following contemporary drug-eluting stent (DES) implantation in the BIONICS (BioNIR Ridaforolimus Eluting Coronary Stent System in Coronary Stenosis) trial.

Convection‐Enhanced Drug Delivery to the Brain: Therapeutic Potential and Neuropathological Considerations

Convection‐enhanced delivery (CED) describes a direct method of drug delivery to the brain through intraparenchymal microcatheters. By establishing a pressure gradient at the tip of the infusion catheter in order to exploit bulk flow through the interstitial spaces of the brain, CED offers a number of advantages over conventional drug delivery methods—bypass of the blood–brain barrier, targeted distribution through large brain volumes and minimization of systemic side effects. Despite showing early promise, CED is yet to fulfill its potential as a mainstream strategy for the treatment of neurological disease. Substantial research effort has been dedicated to optimize the technology for CED and identify the parameters, which govern successful drug distribution. It seems likely that successful clinical translation of CED will depend on suitable catheter technology being used in combination with drugs with optimal physicochemical characteristics, and on neuropathological analysis in appropriate preclinical models. In this review, we consider the factors most likely to influence the success or failure of CED, and review its application to the treatment of high‐grade glioma, Parkinson's disease (PD) and Alzheimer's disease (AD).     

Changes in physical activity,diet, and body weight across the education and employment transitions of early adulthood: A systematic review and meta‐analysis

Early adulthood is a time when individuals go through important life transitions, such as moving from high school into higher education or employment, but the impact of these life transitions on changes in body weight, diet, and physical activity is not known. We searched six electronic databases to July 2019 for longitudinal observational studies providing data on adiposity, diet, and/or physical activity across education or employment transitions in young people aged between 15 and 35 years. We found 19 studies, of which 17 assessed changes in physical activity, three body weight, and five diet or eating behaviours. Meta‐analysis (n=9) found that leaving high school was associated with a decrease of ?7.04 (95% CI, ?11.26, ?2.82) min/day of moderate‐to‐vigorous physical activity. Three studies reported increases in body weight on leaving high school. A small number of studies suggested decreases in diet quality on leaving high school (n=2/4 papers) and leaving university (n=1) but not on starting employment (n=1). Studies suggested no change in physical activity on leaving university (n=4) but decreases in physical activity on starting employment (n=2/3). The transition of leaving high school is an important time to support individuals to prevent decreases in physical activity and gains in body weight.