A complementarity-determining region peptide of an anti-desmosome autoantibody may interact with the desmosomal plaque through molecular mimicry with a cytoplasmic desmoglein 1 sequence

The sera of patients with pemphigus, a group of autoimmune blistering skin diseases, contain autoantibodies directed against components of adhering junctions termed desmosomes. F12, a human monoclonal antibody derived from a pemphigus patient, recognizes an unknown polypeptide of the desmosomal and hemidesmosomal plaques. The third complementarity-determining region of the F12 heavy chain (VH-CDR3) was shown to share a four-amino-acid sequence (GSSG) with the intracellular domains of desmoglein 1 and bullous pemphigoid antigen 2 which interact with components of, respectively, the desmosomal and hemidesmosomal plaques. Computer modeling of F12 showed that the GSSG sequence protudes inside the antigen-combining site and thus might be involved in antigen interactions. The GSSG sequence is essential to F12 function, since a peptide containing the VH-CDR3 inhibited its binding to target antigens while VH-CDR3 peptides with specific modifications of the GSSG sequence did not. These data allow us to hypothesize that certain autoantibodies produced during the course of an autoimmune disease can behave as adhesion molecules, through the molecular mimicry of the motif involved in protein/protein adhesion, and to propose a new self-antigen binding mechanism for some autoantibodies.     

Increased risk of pneumococcal infections in cardiac transplant recipients

We observed 5 episodes of pneumococcal infection among 129 cardiac transplant patients between March 1985 and December 1987, giving an estimated incidence of 36 cases per 1000 patient-years. Infections occurred a mean of 58 days after transplantation and included bacteremia with empyema, bacteremia alone, and pneumonia. All patients recovered from their infections. There was no correlation between infection and age, sex, immunosuppression, or rejection episodes. We also measured antibody levels to 12 pneumococcal antigens in 6 unvaccinated, uninfected patients before and after cardiac transplantation, to see if baseline antibody levels decreased. Protective levels of antibody were defined as greater than or equal to 300 ng of anticapsular antibody nitrogen per milliliter serum. Before transplantation patients had protective antibody levels to a mean of 8.7 +/- 1.2 pneumococcal serotypes; after transplantation, the number of presumably protective antibody levels decreased to 6.5 +/- 1.4 (P = 0.021). One of these patients subsequently developed pneumococcal pneumonia. Cardiac transplant patients are at increased risk of pneumococcal infections. Vaccinating transplant candidates prior to transplantation may provide protection after transplantation.     

Identification and characterization of insulin receptors in basolateral membranes of dog intestinal mucosa

Little is known about hormonal regulation of substrate transport and metabolism in the mucosal lining of the small intestine. Because insulin regulates these functions in other tissues by binding to its receptor, we have investigated the presence of insulin receptors in canine small intestinal mucosa with basolateral membranes (BLM) and brush border membranes (BBM) prepared by sorbitol density centrifugation. A14-[125I]iodoinsulin was used to study binding and structural characteristics of specific insulin receptors in BLM. Analysis of receptors in BLM identified binding sites with high affinity (Kd 88 pM) and low capacity (0.4 pmol/mg protein) as well as with low affinity (Kd 36 nM) and high capacity (4.7 pmol/mg protein). Binding was time, temperature, and pH dependent, and 125I-labeled insulin dissociation was enhanced in the presence of unlabeled insulin. Cross-reactivity of these receptors to proinsulin, IGF-II, and IGF-I was 4, 1.8, and less than 1%, respectively. Covalent cross-linking of labeled insulin to BLM insulin receptors with disuccinimidyl suberate revealed a single 135,000-Mr band that was completely inhibited by unlabeled insulin. There was a 16-fold greater specific binding of insulin to BLM (39.0 +/- 2.4%) than to BBM (2.5 +/- 0.6%). These results demonstrate the presence of a highly specific receptor for insulin on the vascular, but not the luminal, surface of the small intestinal mucosa in dogs, and suggest that insulin may play an important role in the regulation of gastrointestinal physiology.     

Almitrine bismesylate disposition in the human digestive tract

Summary The absorption of almitrine from the upper gastrointestinal tract has been evaluated in 6 healthy volunteers by an intubation technique. Almitrine bismesylate dissolved in malic acid was introduced into the stomach after homogenization with a meal containing the marker¹⁴C-polyethylene glycol (PEG) 4000. Unlabeled PEG 4000 was infused into the second part of duodenum throughout the experiment. Samples of the luminal content were collected every 15 min for four hours from the stomach and at the ligament of Treitz. Blood was also collected.Almitrine was neither absorbed from nor metabolized in the stomach. About 37% of the quantity of drug emptied from the stomach was absorbed from the duodenum. Almitrine was detected in plasma 50 min after ingestion of the meal and its plasma concentration-time profile reflected the cumulative gastric emptying rate. The metabolite tetrahydroxy almitrine was found in intestinal samples as soon as unchanged drug was detected in plasma. The intraluminal rate of formation of the metabolite increased with time.The results suggest hepatic metabolism of almitrine followed by rapid excretion of the metabolite in the bile.     

The effect of apical foramen patency on condensation stresses

Abstract Mathematical models and computer-based engineering tools were used to evaluate the effect of a patent or closed apical foramen on stresses that are produced within gutta-percha during condensation. We examined a mathematical model of a tapered canal with a definite constriction and compared the results when the apical foramen was closed or open. When the canal was closed an almost constant stress was seen throughout the gutta-percha. When the foramen was open a sharp increase in lateral stress was observed in the apical portions of the canal. The constriction near the foramen caused the gutta-percha to be squeezed together and the stress was increased. This increases the likelihood that the gutta-percha is well adapted to the apical constriction. However, the stresses are also transferred to the surrounding dentin, resulting in a stress concentration near the apical foramen where the bulk of dentin is minimal.     

Pyrethroids and enhanced inhibition in the hippocampus of the rat

The pyrethroid insecticides have been divided into two classes on the basis of their biochemical actions and behavioral indices of toxicity. Both types of pyrethroids have effects on sodium conductance, and Type II pyrethroids have been reported to antagonize gamma-aminobutyric acid (GABA) by interacting with the t-butyl-bicyclophosphorothionate (TBPS)/picrotoxinin binding site. The dentate gyrus of the hippocampus is equipped with GABAergic recurrent inhibitory circuits. The present experiment was designed to demonstrate dissociation in the biochemistry of pyrethroids by activating the perforant path with pairs of stimulus pulses and monitoring the recurrent inhibition in this circuit. Antagonism of GABA leads to a reduction in inhibition, measured as an increase in the size of the population spike in response to the second pulse of the pair. The GABAergic properties of the pyrethroids were assessed by examining paired pulse inhibition before and after oral treatment with 20 mg/kg of cismethrin (Type I), 20 mg/kg of fenvalerate, or 10 mg/kg of deltamethrin (Type IIs). Input/output (I/O) functions revealed a reduction in excitatory postsynaptic potential (EPSP) following cismethrin and deltamethrin. Population spike height was unaffected. Fenvalerate had no effect on I/O functions. In contrast to the prediction of reduced inhibition following treatment with Type II pyrethroids, deltamethrin and fenvalerate increased inhibition up to 500 and 150 ms interpulse intervals, respectively. Cismethrin was without effect on paired pulse inhibition. These findings fail to provide evidence of GABA antagonistic properties of Type II pyrethroids and may be best explained by a differential effect of these three pyrethroids on sodium channel kinetics.     

Stereoselective disposition of (+/-)-sotalol at steady-state conditions.

The objective of this study was to assess, under steady-state conditions, the stereoselective disposition of (+/-)-sotalol in man. In all patients studied (n = 7) values of oral clearance (137 +/- 51 ml min-1), renal clearance (96 +/- 42 ml min-1) and nonrenal clearance (41 +/- 25 ml min-1) of (-)-sotalol were greater than those for (+)-sotalol (123 +/- 45 ml min-1, 89 +/- 39 ml min-1 and 34 +/- 23 ml min-1, respectively; P < 0.05, Student's paired t-test). Binding to plasma proteins was greater for (+)-sotalol (38 +/- 9% vs 35 +/- 9% for the (-)-enantiomer; P < 0.05) such that unbound oral clearance (+)/(-) ratio (0.95 +/- 0.06) and unbound renal clearance (+)/(-) ratio (0.97 +/- 0.06) were not stereoselective. In contrast, estimated unbound nonrenal clearance, which represents approximately 25% of the total unbound clearance of the drug, was greater for the (-)-enantiomer (64 +/- 42 ml min-1) compared with (+)-sotalol (57 +/- 42 ml min-1; P < 0.05). The difference in the pharmacokinetics of sotalol enantiomers is mainly related to stereoselectivity in plasma protein binding.     

The Development and Teaching of the Ethical Principles and Guidelines for Family Scientists*

This article describes the development of the Ethical Principles and Guidelines for Family Scientists that the National Council on Family Relations Board of Directors unanimously approved. Furthermore, it discusses the importance of ethics education for family professionals and provides suggestions for educators. Finally, the ethical principles and guidelines are delineated. We argue that the development of a scholarship on ethics education is important for current and future family scientists.     

Trial of an intervention to reduce chronic benzodiazepine use among residents of aged-care accommodation

Abstract Background: Many residents of aged-care accommodation are chronic users of benzodiazepines. This pattern of use contradicts current guidelines and may adversely affect residents. It was hypothesised that a lasting reduction in benzodiazepine use could be achieved through a programme which involved prescribers, residents and caregivers in the change process. Aim: To demonstrate that an intervention which involved education and relaxation training for patients, and education of prescribers and caregivers, could reduce levels of chronic benzodiazepine use among residents of an aged-care facility. Methods: Two aged-care facilities from metropolitan Adelaide were chosen; one received the intervention, the other was a no-intervention comparison. Pre-test, post-test and follow-up interviews were conducted with 60 residents: 27 from the intervention setting and 33 from the comparison setting. Residents at the intervention setting were provided with relaxation skills training, and their medical practitioners and caregivers were provided with information about alternative strategies for managing sleep disturbance. Outcome measures were: the proportion of residents using benzodiazepines, total medication use, cognitive performance, emotional responsiveness, subjective health and sleep ratings and an index of well-being. Results: The proportion of participants in the intervention condition who used benzodiazepines declined significantly (from 70% to 35%); the reduction was maintained over the subsequent three months. No adverse consequences were associated with cessation of benzodiazepine use; there was improvement in emotional responsiveness among those who ceased benzodiazepine use. This structured intervention strategy is a useful approach for reducing levels of chronic benzodiazepine use among residents of aged-care accommodation.