The metabolic sulphation of polyethyleneglycols by isolated perfused rat and guinea-pig livers

1. It is shown that isolated perfused rat and guinea-pig livers can sulphate polyethyleneglycol 200 at rates of about 5 and 10 nmol/g per min, respectively. 2. In the guinea-pig about equal amounts of sulphated polyethyleneglycol 200 appear in the bile and in the perfusate, while in the rat about 99% appears in the latter. 3. Polyethyleneglycols 400 and 1000 are also sulphated in perfused guinea-pig liver but polyethyleneglycol 6000 is not. 4. Polyethyleneglycols are therefore not suitable solvents for xenobiotics which may undergo sulphation because of the likelihood of competition for sulphate.     

Adenosine and anergy

T cells must integrate multiple environmental cues when deciding whether to mount an immunogenic or tolerogenic response. Since not all self-reactive T cells are eliminated during thymic development, mechanisms of peripheral tolerance such as T cell anergy contribute to preventing autoimmunity. Recent studies have implicated extracellular adenosine and the adenosine A(2A) receptor as playing an important role in inhibiting T cell effector function. Herein, we review the current literature regarding T cell anergy and the emerging literature implicating the A(2A) receptor as critical regulator of immune activation. Finally, we present evidence to suggest a possible role for adenosine A(2A) receptor signaling in T cell anergy.     

Expanding spectrum of congenital disorder of glycosylation Ig (CDG-Ig): sibs with a unique skeletal dysplasia, hypogammaglobulinemia, cardiomyopathy, genital malformations, and early lethality

In this report, we describe a brother and sister who presented at birth with short-limb skeletal dysplasia, polyhydramnios, prematurity, and generalized edema. Dysmorphic features included broad nose, thick ears, thin lips, micrognathia, inverted nipples, ulnar deviation at the wrists, spatulate fingers, fifth finger camptodactyly, nail hypoplasia, and talipes equinovarus. Other features included short stature, microcephaly, psychomotor retardation, B-cell lymphopenic hypogammaglobulinemia, sensorineural deafness, retinal detachment and blindness, intestinal malrotation with poor gastrointestinal motility, persistent hyponatremia, intermittent hypoglycemia, and thrombocytopenia. Cardiac anomalies included PDA, VSD, hypertrophic cardiomyopathy, and arrhythmias. The brother had a small penis with hypospadias, hypoplastic scrotum, and non-palpable testes. Skeletal findings included absent ossification of cervical vertebral bodies, pubic bones, knee epiphyses, and tali. Both sibs died before age 2 years, one of overwhelming sepsis and the other of cardiorespiratory failure associated with her cardiomyopathy. Metabolic studies showed a type 1 pattern of abnormal serum transferrin glycosylation. Fibroblasts synthesized truncated LLOs, primarily Man(7)GlcNAc(2), suggestive of CDG-Ig. Both sibs were compound heterozygotes for a novel 301 G > A (G101R) mutation and a previously described 437 G > A (R146Q) mutation in ALG12. Congenital disorders of glycosylation should be considered for children with undiagnosed multi-system disease including neurodevelopmental delay, skeletal dysplasia, immune deficiency, male genital hypoplasia, and cardiomyopathy.     

Stakeholder perspectives on the development of a virtual clinic for diabetes care: qualitative study

Background

The development of the Internet has created new opportunities for health care provision, including its use as a tool to aid the self-management of chronic conditions. We studied stakeholder reactions to an Internet-based “virtual clinic,” which would allow people with diabetes to communicate with their health care providers, find information about their condition, and share information and support with other users.

Objective

The aim of the study was to present the results of a detailed consultation with a variety of stakeholder groups in order to identify what they regard as the desirable, important, and feasible characteristics of an Internet-based intervention to aid diabetes self-management.

Methods

Three focus groups were conducted with 12 people with type 1 diabetes who used insulin pumps. Participants were recruited through a local diabetes clinic. One-on-one interviews were conducted with 5 health care professionals from the same clinic (2 doctors, 2 nurses, 1 dietitian) and with 1 representative of an insulin pump company. We gathered patient consensus via email on the important and useful features of Internet-based systems used for other chronic conditions (asthma, epilepsy, myalgic encephalopathy, mental health problems). A workshop to gather expert consensus on the use of information technology to improve the care of young people with diabetes was organized.

Results

Stakeholder groups identified the following important characteristics of an Internet-based virtual clinic: being grounded on personal needs rather than only providing general information; having the facility to communicate with, and learn from, peers; providing information on the latest developments and news in diabetes; being quick and easy to use. This paper discusses these characteristics in light of a review of the relevant literature. The development of a virtual clinic for diabetes that embodies these principles, and that is based on self-efficacy theory, is described.

Conclusions

Involvement of stakeholders is vital early in the development of a complex intervention. Stakeholders have clear and relevant views on what a virtual clinic system should provide, and these views can be captured and synthesized with relative ease. This work has led to the design of a system that is able to meet user needs and is currently being evaluated in a pilot study.     

Dietary microparticles and their impact on tolerance and immune responsiveness of the gastrointestinal tract

Dietary microparticles are non-biological bacterial-sized particles of the gastrointestinal lumen that occur due to endogenous formation (calcium phosphate) or following oral exposure (exogenous microparticle). In the UK, about 40 mg (10(12)) of exogenous microparticles are ingested per person per day, through exposure to food additives, pharmaceutical/supplement excipients or toothpaste constituents. Once ingested, exogenous microparticles are unlikely to pass through the gastrointestinal tract without adsorbing to their surfaces some ions and molecules of the intestinal lumen. Both entropy and ionic attraction drive such interactions. Calcium ions are especially well adsorbed by dietary microparticles which then provide a positively charged surface for the attraction (adsorption) of other organic molecules such as lipopolysaccharides, peptidoglycans or protein antigen from the diet or commensal flora. The major (but not only) sites of microparticle entry into intestinal tissue are the M-cell rich lymphoid aggregates (termed Peyer's patches in the small bowel). Indeed, it is well established that this is an efficient transport route for non-biological microparticles although it is unclear why. We hypothesise that this pathway exists for "endogenous microparticles" of calcium phosphate, with immunological and physiological benefit, and that "exogenous dietary microparticles", such as titanium dioxide and the silicates, hijack this route. This overview focuses on what is known of these microparticles and outlines their potential role in immune tolerance of the gut (endogenous microparticles) or immune activation (exogenous microparticles) and inflammation of the gut.     

Salvage of locally recurrent breast cancer with repeat breast conservation using 45 Gy hyperfractionated partial breast re-irradiation

Breast Cancer Research and Treatment - Mastectomy has long been the preferred approach for local salvage of recurrent breast cancer following breast-conservation therapy (BCT). Growing interest in...     

Use of Group Concept Mapping to Identify Patient Domains of Uncertainty That Contribute to Emergency Department Use

Introduction

Prior research suggests that uncertainty related to symptoms is a driver of emergency department (ED) use, and that patients often leave the ED with uncertainty not being addressed. Our objective was to engage patients to identify domains that contribute to feelings of uncertainty and decisions to use the ED.

RSV604, a novel inhibitor of respiratory syncytial virus replication

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease.