Evidence for the involvement of CD44 in endothelial cell injury and induction of vascular leak syndrome by IL-2.

At sites of chronic inflammation seen during infections, autoimmunity, graft-vs-host response, and cytokine therapy, endothelial cell injury is known to occur, the exact mechanism of which is unknown. In the current study we used IL-2-induced vascular leak syndrome (VLS) as a model to investigate whether cytotoxic lymphocytes use CD44 in mediating endothelial cell injury. Administration of IL-2 to wild-type mice triggered significant VLS in the lungs and liver. In contrast, in CD44 knockout (KO) mice, IL-2-induced VLS was markedly reduced in the lungs and liver. IL-2-treated wild-type and CD44 KO mice had similar levels of perivascular infiltration with lymphocytes in the lungs and liver. This suggested that the decrease in VLS seen in CD44 KO mice was not due to the inability of lymphocytes to migrate to these organs. Ultrastructural studies demonstrated extensive endothelial cell damage in the lungs and liver of IL-2-treated wild-type, but not CD44 KO, mice. Moreover, CD44-KO mice exhibited a marked decrease in IL-2-induced lymphokine-activated killer cell activity. The induction of VLS was dependent on the expression of CD44 on immune cells rather than endothelial cells because adoptive transfer of CD44+, but not CD44- spleen cells along with IL-2 into CD44 KO mice triggered VLS. The IL-2-induced VLS was blocked by administration of F(ab')2 of Abs against CD44. The current study demonstrates that CD44 plays a key role in endothelial cell injury. Blocking CD44 in vivo may offer a novel therapeutic approach to prevent endothelial cell injury by cytotoxic lymphocytes in a variety of clinical disease models.

Posttraumatic headache: neuropsychological and psychological effects and treatment implications.

Posttraumatic headache (PTHA) is a frequent occurrence following trauma to the head, brain, and/or neck. Estimates of persistence for 6 months are as high as 44%. Review of available studies examining the effect of headache on neuropsychological test findings reveals that chronic headache pain, and chronic pain generally, exerts a significant and negative effect that poses a challenge to differential diagnostic efforts in the evaluation of mild brain injury. Given that PTHA is the most common postconcussive symptom and most frequent type of posttraumatic pain associated with mild traumatic brain injury (TBI), it follows that resolution of the postconcussion syndrome, and successful posttraumatic adaptation, may frequently rely on success in coping with PTHA symptomatology. Viewing PTHA from a biopsychosocial perspective, a general outline is offered for improving both assessment and treatment of PTHA. In addition, the most promising psychology-based treatment interventions are reviewed.

Evidence for the involvement of Fas ligand and perforin in the induction of vascular leak syndrome.

Endothelial cell injury resulting in vascular leak syndrome (VLS) is one of the most widely noted phenomenons in a variety of clinical diseases. In the current study we used IL-2-induced VLS as a model to investigate the role of cytolytic lymphocytes in the cytotoxicity of endothelial cells. Administration of IL-2 (75,000 U/mouse, three times a day for 3 days) into BL/6 wild-type mice triggered significant VLS in the lungs, liver, and spleen. Interestingly, perforin-knockout (KO) mice exhibited a marked decrease in IL-2-induced VLS in all three organs tested. Also, Fas ligand-defective (gld) mice and Fas-deficient (lpr) mice exhibited decreased VLS in the liver and spleen, but not in the lungs. The decreased VLS seen in perforin-KO, gld, and lpr mice was not due to any defect in lymphocyte migration or homing to various organs because histopathologic studies in these mice demonstrated significant and often greater perivascular infiltration of lymphocytes compared with the IL-2-treated wild-type mice. Ultrastructural studies of the lungs demonstrated significant damage to the endothelial cells in IL-2-treated wild-type mice and decreased damage in perforin-KO mice. IL-2 administration caused up-regulation of CD44 in all strains of mice tested and triggered increased LAK activity against an endothelial cell line in wild-type and gld mice, but not in perforin-KO mice. The current study demonstrates for the first time that perforin and Fas ligand may actively participate in endothelial cell injury and induction of VLS in a variety of organs.

Schedule-induced masseter EMG in facial pain subjects vs. no-pain controls.

Empirical reports suggest that oral habits (e.g., teeth clenching) may be behavioral mediators linking stress to muscle hyperreactivity and the development of facial pain. Another report suggests that excessive behavioral adjuncts develop in conjunction with fixed-time stimulus presentation. The present study assessed the extent to which the oral habits exhibited by facial pain patients are schedule-induced. Subjects with Temporomandibular Disorder (TMD) symptomatology (n = 15) and pain-free controls (n = 15) participated in a 4-phase experiment (adaptation, baseline, task, recovery) designed to elicit schedule-induced behaviors. Self-report of oral habits and negative affect were recorded after each phase. Objective measures of oral habits were obtained via behavioral observation and masseter EMG recordings. Results revealed that negative arousal significantly increased during the fixed-time (FT) task and was also associated with increased oral habits among the TMD subjects. Moreover, 40% of the TMD subjects and none of the controls exhibited a pattern of EMG elevations in the early part of the inter-stimulus interval that met a strict criteria for scheduled-induced behavior per se. Taken together, these results suggest that the TMD subjects were engaging in schedule-induced oral habits. The adjunctive behavior literature seems to provide a plausible explanation as to how oral habits develop and are maintained in TMD patients, despite their painful consequences.

Cerebral glucose utilization in polysubstance abuse.

Regional cerebral glucose metabolism in subjects with histories of polysubstance abuse was compared to that in control subjects who were drawn from the same community. The substance abuse group showed lower absolute metabolic rates for glucose in lateral occipital gyrus and higher normalized metabolic rates in temporal and frontal areas, including orbitofrontal cortex. It is suggested that some patterns of brain function associated with polysubstance abuse may represent consequences of drug exposure, or they could reflect pre-existing differences that may be relevant to the etiology and maintenance of polysubstance abuse.

Growth, nutrient utilization and intestinal morphology of pigs fed high-fiber diets.

Two trials (24 and 48 pigs; 9.7 kg initial body weight) were conducted to determine the effects of dietary fiber on growth, nutrient utilization and intestinal morphology of young pigs. The four diets fed were: basal corn-soybean meal (B), 15% oat hulls (OH), 15% soybean hulls (SH), and 20% alfalfa meal (AM). Fiber source did not have major effects on performance in a 35-d feeding trial. Balance trials (7-d duration) were conducted 32 d (Trial 1) or 6 d (Trial 2) after completion of the feeding trials. Feed intakes were equalized at 8.7% (Trial 1) or 10.3% (Trial 2) of initial body weight (kg.75). All fiber sources decreased apparent digestibilities of N, energy and dry matter (P less than .05) with no effect on N retention. Apparent digestibilities of neutral and acid detergent fiber, cellulose, and hemicellulose were reduced by OH and AM (P less than .01), but not by SH. Fiber sources did not affect apparent Ca, P, Zn or Mn absorption or retention, or Mg absorption, but decrease Mg retention (P less than .05). Apparent Na absorption was decreased by OH and increased by AM (P less than .05) but was unaffected by SH. All fiber sources increased K intake, but only SH and AM increased apparent K absorption (P less than .05). Fiber sources did not affect Na or K retention. The OH increased Cu intake and balance (P less than .05). All fiber sources increased Fe intake, but only SH and AM increased (P less than .05) Fe balance. Villus shape and surface morphology in jejunum and ileum examined by scanning electron microscopy (Trial 1 only) appeared to be independent of diet. However, jejunum villus morphologies of two pigs fed AM were characterized by loss of epithelial cells and microvilli at the villus apex, and ileum villi were blunted and frequently folded in one pig fed SH. Fiber sources at the levels included in a corn-soybean meal diet fed in this study had only a minimal impact on performance and utilization of minerals and N and intestinal structure, although apparent energy utilization was decreased.