Milk proteins,cytokines and intestinal epithelial functions in children

This paper discusses the relationship between food antigens, lymphocytes and the epithelial properties of the jejunum in children with cow's milk allergy. Experimental results indicate that increased protein permeability is not the primary cause of cow's milk allergy. Rather, results are interpreted as a secondary effect of an abnormal immunological response leading to mucosal inflammation and impairment of the endocytic process by the intestinal epithelial cells. Stimulation by cow's milk proteins caused the lymphocytes from infants with cow's milk allergy to release more tumor necrosis factor-α TNFα than those from control infants. After appropriate antigenic stimulation, the cytokines released by the activated lymphocytes from these infants perturbed epithelial function, in particular its barrier capacity. Tumor necrosis factor a, together with gamma interferon are involved in these adverse effects. It is thought that bovine β-lactoglobulin present in the intestinal lumen may be responsible for the secretory diarrhea observed in children with cow's milk allergy, as a consequence of stimulation of electrogenic chloride secretion. In addition, luminal foreign protein may stimulate the submucosal cells. As a consequence, the submucosal release of mediators, including lymphokines, might alter the intestinal epithelial barrier. In conclusion, in physiological conditions, the subepithelial tissue that comprises the immune system and many other systemic systems receive information on the antigenic content within the intestinal lumen via the intestinal epithelium.     

Validation of a Noninvasive Measure of Local Myocardial Repolarization in a Conscious Human Model:

INTRODUCTION: A commercial pacemaker sensor measure of the unipolar endocardial stimulus to T wave interval may accurately reflect changes in the monophasic action potential duration at 90% repolarization (APD90). This sensor system was used to study the kinetics of adaptation of repolarization duration to changes in heart rate in humans. METHODS AND RESULTS: Patients were studied using an external pacemaker capable of displaying all stimulus to T wave intervals for each paced beat. Right ventricular stimulation was delivered via the pacemaker and compared simultaneously to APD90. Steady-state pacing was simulated by 60 seconds of pacing at cycle lengths (CLs) 350 to 700 msec. Adaptation to a new ventricular rate was analyzed with a sudden 200-msec decrease in CL. The relation between repolarization measure and steady-state CL (n = 16) was linear with a slope of 0.16 and 0.19 for APD90 and stimulus to T wave interval, respectively (P = NS). The adaptation of both repolarization measures to a sudden change in rate were best modeled by a biexponential function. Stimulus to T wave interval exhibited a parallel course to APD90, and an analysis of normalized differences between APD90 and stimulus to T wave interval followed an approximately normal distribution, with 93.5% of the paired differences within 2 SD of the mean. CONCLUSION: A pacemaker sensor measure of stimulus to T wave interval accurately parallels APD90 during both steady-state and sudden changes in rate. Repolarization in human endocardium follows a linear relation to steady-state CL and adapts to a new rate with a biexponential function. This model represents a novel method for studying human cardiac repolarization.     

Transcutaneous T Wave Shock: A Universal Method for Ventricular Fibrillation Induction

Our objective was to develop a universal noninvasive method for VF induction. ICD implantation requires VF induction. Conventional rapid ventricular stimulation may fail to induce VF. Some ICDs can deliver low energy shocks on the T wave to induce VF. We hypothesized that an external dual chamber pacemaker and an external defibrillator could be configured to allow reliable VF induction with any ICD system. A surface ECC signal was delivered to the atrial channel of an external dual chamber DDD pacemaker. The 'AV' delay was adjusted so that the ventricular output of the pacemaker was delivered to an external defibrillator synchronized to deliver 5–50 J. Twenty-six patients at ICD implant or follow-up had VF induced in native rhythm (sinus rhythm or atrial fibrillation), or during a ventricular pacing train (3–8 beats at cycle length 500–880 ms). VF was successfully induced in 14 of 25 (56%) patients in native rhythm; and in 16 of 17 (94%) patients during pacing (P = 0.013). VF induction success rate was 36% in native rhythm (31/86 attempts) and 88% during pacing (69/78 attempts) (P < 0.001). The 'R' to shock interval was 269 ± 31 ms in native rhythm and 257 ± 48 ms during pacing. Energy delivered from the external defibrillator was 19 ± 3 J in native rhythm and 21 ± 6 J during pacing. We concluded that VF induction by synchronizing a small external shock to the T wave is a fast, effective way to reliably ensure arrhythmia induction with any ICD at implant or follow-up. This method is more successful during pacing than in sinus rhythm.     

The gp 130 family cytokines IL-6, LIF and OSM but not IL-11 can reverse the anti-proliferative effect of dexamethasone on human myeloma cells

Summary. In order to understand the mechanisms supporting steroid escape in patients with multiple myeloma (MM), three IL-6 autocrine human myeloma cell lines, LP1, OPM2 and L363, have been treated with dexamethasone in the presence or absence of cytokines belonging to the gp 130 family: IL-6, LIF, OSM and IL-11. With pharmacological doses of dexamethasone, a dramatic growth arrest was observed in all the cell lines. IL-6 completely reversed this inhibition. Of note, this IL-6 induced reversion was still seen with very low amounts of IL-6 (12 pg/ml). Finally, whereas LIF and OSM had clear growth-promoting effects on OPM2 only, both cytokines (but not IL-11) reversed the dexa-methasone-induced growth arrest in all the cell lines. Therefore the high levels of IL-6 (ng/ml) observed in the MM intermediate milieu and the putative presence of LIF and OSM can easily counteract the effects of dexamethasone in vivo.     

Dual Device Therapy in the Setting of Changing ICD Technology: Device-Device Interaction Revisited

This case report concerns an adverse device-device interaction between a replacement ICD and a dual chamber rate responsive pacemaker. It was observed that subtle changes in the design of sensing circuits between an older first-generation ICD and the newer third-generation ICD device led to unexpected and dramatic changes in the interactive behavior of a dual device system. The new ICD was connected to chronically implanted hardware. The sensing behavior of the newer ICD included a shorter time constant in the decay of the automatic gain control function, resulting in triple sensing of both the atrial and ventricular paced stimuli and the evoked QRS complex. Physicians should be aware of new design changes in the future so as to anticipate such interactions. In the setting of rapidly changing technology, extra caution must be exercised when choosing to implant two devices in the same patient.     

Pharmacokinetics of Heterologous and Homologous Immunoglobulin G,F(ab‘)2 and Fab after Intravenous Administration in the Rat

Because few pharmacokinetic studies of antibodies and their fragments have compared the influence of species origin and antibody size, the plasma pharmacokinetics of a single intravenous dose (0.7 mg kg^?1) of ¹²⁵I-labelled mouse, rat and human immunoglobulin G (IgG), and mouse F(ab')₂ and Fab were investigated in the rat. IgG reached equilibrium after six distribution half-lives, i.e. only 36–50 h post-dosing, and the distribution volume was about four times the rat plasma volume. IgG elimination half-lives ranged from 5.33 to 8.10 days. Fragmentation of IgG into smaller fragments, F(ab')₂ and Fab, resulted in pharmacokinetics that were molecular-weight-dependent with volume of distribution and systemic clearance values inversely related to antibody size. We conclude that antibody variability in terms of species origin and size influences antibody pharmacokinetics and should be carefully studied before selection of the best antibody for a clinical application.     

APOPTOSIS PREVENTION AS A MECHANISM OF IMMUNE EVASION

When cells are infected with viruses, they may trigger their apoptosis programs. In unicellular organisms, this may have protected cell populations by limiting viral replication from infected cells. Multicellular organisms can also trigger the apoptosis program after viral infection. In response, viruses have evolved a wide variety of inhibitors of apoptosis. In higher organisms, the outcome of viral infections is largely determined by the immune system. Since apoptosis is intimately linked to the function and regulation of the immune system, the ability of viruses to inhibit apoptosis could profoundly alter the immune response. Viral antiapoptotic proteins could protect infected cells from apoptosis induced by cytotoxic lymphocytes, alter antigen cross-presentation and the priming of the immune response, or modulate the expression of danger signals from sites of infection. The virus/host interaction is likely to provide useful lessons regarding the workings of the mammalian immune system.