Helicobacter pylori infection and gastric emptying of solids in humans

Helicobacter pylori has been implicated in a number of upper gastrointestinal illnesses. In a controlled study, we have investigated the relationship between H. pylori infection and gastric emptying of solids in two groups of patients with chronic symptoms of dyspepsia. In the first group, 19 patients with non-ulcer dyspepsia and H. pylori infection underwent a standard test of gastric emptying after ingestion of 500 μCi of Tc-labelled chicken liver. The results were compared to a control group of 16 uninfected volunteers. We also studied a second group of 20 patients with previously diagnosed idiopathic gastroparesis for the prevalence of H. pylori infection and its relationship to symptom severity and rates of gastric emptying. In the first group of patients, the half-time of gastric emptying was significantly less among the infected patients compared to the uninfected volunteers (108 ± 9 vs. 142 ± 14 min, P < 0.05). In the second group of patients with gastroparesis, the prevalence of H. pylori was not significantly different among these patients than among 21 age and sex matched controls (20% vs. 38%, P = 0.32). Gastric emptying was markedly slow in all 20 patients in the second group but less so among the four with H. pylori infection. Symptom scores were no different between infected and uninfected patients. We conclude that H. pylori infection is not associated with abnormally slow gastric emptying. On the contrary, gastric H. pylori infection appears to be associated with mildly accelerated emptying of solids compared to normal controls. Idiopathic gastroparesis and dyspepsia related H. pylori infection are separate but sometimes overlapping disorders.     

Mechanisms whereby Lytic Granules from Cytotoxic T Lymphocytes Damage Guinea Pig Ventricular Myocytes

During immunological rejection of the transplanted heart, cytoloxic T lymphocytes (CTL) infiltrate the myocardium and by damaging the myocytes contribute to loss of function. To address one important aspect of heart transplant rejection, we investigated in guinea pig ventricular myocytes how CTL-derived lytic granules containing the pore-forming protein perform reduce the membrane potential ( V m) and cause cell damage. The reduction in V_M was biphasic; within 8.4 × 1.9 min V _M was reduced from a control value of -78.4 × 1.9 mV to -69.9 × 3.5 mV. Subsequently, within 6.7 × 2.1 min V _M declined to - 3.4 × 1.2 mV. associated with a progressive contracture. Under whole cell voltage clamp, in myocytes held at their resting potential (V_M= -76.2 × 0.9 mV), granules induced discrete inward current steps (resembling "single channel'activity), with a mean amplitude of - 86.8 × 1.4 pA and open times lasting from seconds up to several minutes. The mean conductance and reversal potential calculated from the linear regression analysis of the I-V relations were 1390 pS and - 6.8 mV. respectively. The probable non-selectivity of these "channels" and the resultant loss of membrane K⁺ selectivity can account for the reduction in V _M. At the same time, opening of these pores leads to Ca-⁺ overload, resulting in contracture and cell damage.     

Prophylactic immune tolerance induced by changing the ratio of antigen-specific effector to regulatory T cells

Summary.  Background : Gene and protein replacement therapies for inherited protein deficiencies such as hemophilia or lysosomal storage disorders are limited by deleterious immune responses directed against their respective therapeutic proteins. Therefore, the development of protocols preventing such responses is key to providing successful long-term therapy. Objectives : We sought to develop a protocol, utilizing a drug/peptide cocktail, that would effectively shift the antigen-specific CD4+ T-cell population, tipping the balance from effector T cells (Teffs) towards regulatory T cells (Tregs). Methods : Treg-deficient (DO11.10-tg Rag2^−/−) BALB/c mice were used to screen for an optimal protocol addressing the aforementioned goal and to study the mechanisms underlying in vivo changes in T-cell populations. Muscle-directed gene transfer to hemophilia B mice was also performed in order to test the optimal protocol in a therapeutically relevant setting. Results: Specific antigen administration (4-week repeated dosing) combined with rapamycin and interleukin-10 led to substantial reductions in Teffs, via activation-induced cell death, and induced CD4+CD25+FoxP3+ Tregs to a large extent in multiple organs. The proportion of apoptotic T cells also increased over time, whereas Teffs and Tregs were differentially affected. When applied to a model of protein deficiency (gene therapy for hemophilia B), the protocol successfully prevented inhibitor formation, whereas non-specific immunosuppression was only marginally effective. Conclusions : It is feasible to provide a short-term, prophylactic protocol allowing for the induction of immune tolerance. This protocol may provide a marked advance in efforts seeking to improve clinical outcomes in disorders involving therapeutic protein replacement.     

TIME-DEPENDENCY OF NEUROHYPOPHYSEAL PEPTIDE ATTENUATION OF PUROMYCIN AMNESIA IN MICE

[Ile³, Arg⁸]. vasopressin (arginine-vasotocin), as well as the C-terminal tripeptides of the neurohypophyseal hormones arginine and lysine vasopressin, Pro-Arg-Gly-NH₂ and Pro-Lys-Gly-NH₂, were protective against puromycin-induced amnesia in mice when administered 24h before training. The N-protected tripeptide derivative, Z-Pro-Lys-Gly-NH₂, was effective when given 5 days before training. The effectiveness of all peptides to attenuate puromycin-induced amnesia decreased as the interval between training and peptide treatment increased, indicating that the peptides influence memory processes, rather than general arousal. Z-Pro-Lys-Gly-NH₂ was active at 24h after training, when the other peptides were no longer effective. Although it seems clear that neurohypophyseal hormones per se can attenuate puromycin-induced amnesia, these results are in line with the possibility that some portion of hormone action may be mediated via formation of longer-lived hormone fragments in the CNS.     

Animal models of bleeding and tissue repair

Summary.  While a number of animal models have been developed for human haemophilia, it has been difficult to develop reproducible measures of bleeding in these models. They have also not been extensively utilized to study the complications of haemophilia beyond blood loss. Poor haemostatic function also leads to local haematomas, joint damage and poor wound healing. Some of the abnormalities related to bleeding are because of the deleterious effects of iron deposition in the tissues. Evidence from mouse skin wound and joint haemorrhage models suggests that bleeding and iron deposition initiate a vicious cycle of inflammation, angiogenesis and renewed bleeding. However, there is much yet to be learned about the effects of bleeding on tissue responses, including validating the results of animal studies in clinical trials.