Humoral and cellular immunity following severe head injury: review and current investigations.

Infection is a common and serious complication of severe head injury. Immunocompetence in 25 severely head injured patients was investigated by measuring: (1) delayed-type hypersensitivity (DTH) skin test responses to common antigens; (2) phytohaemagglutinin (PHA) stimulated peripheral blood lymphocyte (PBL): blastogenesis, phenotype expression, and lymphokine production; (3) lymphokine-activated killer (LAK) cytotoxicity, antibody dependent cellular cytotoxicity (ADCC) and natural killer (NK) cytotoxicity; and (4) immunoglobulin and complement levels. The incidence of anergy to DTH skin testing was 100%. There was a decrease in PHA stimulated: PBL blastogenesis (p = 0.002), T-cell expression (p = 0.018), helper T-cell expression (p less than 0.001), interleukin-2 receptor expression (p less than 0.001), interleukin-2 production (p = 0.035) and gamma-interferon production (p less than 0.001). LAK cytotoxicity was depressed following incubation with IL-2 (p less than 0.001). There was no significant decrease in immunoglobulin levels and all acute phase reactants tested increased. The results of this study indicate that the cellular arm of immune response, including lymphocyte activation and cytokine production, is suppressed following severe head injury. The lack of enhancement in LAK cytotoxicity following incubation of PBLs with interleukin-2 suggests that factors other than decreased interleukin-2 production, such as the inherent lymphocyte dysfunction, other soluble mediators or suppressor cells, may be responsible for the reduction in cellular immunity observed following severe head injury.     

In vivo PET imaging of cardiac presynaptic sympathoneuronal mechanisms in the rat.

The sympathetic nervous system of the heart plays a key role in the pathophysiology of various cardiac diseases. Small-animal models are valuable for obtaining further insight into mechanisms of cardiac disease and therapy. To determine the translational potential of cardiac neuronal imaging from rodents to humans, we characterized the rat sympathetic nervous system using 3 radiotracers that reflect different subcellular mechanisms: (11)C-meta-hydroxyephedrine (HED), a tracer of neuronal transport showing stable uptake and no washout in healthy humans; (11)C-phenylephrine (PHEN), a tracer of vesicular leakage and intraneuronal metabolic degradation with initial uptake and subsequent washout in humans; and (11)C-epinephrine (EPI), a tracer of vesicular storage with stable uptake and no washout in humans. METHODS: We used a small-animal PET system to study healthy male Wistar rats at baseline, after desipramine (DMI) pretreatment (DMI block), and with DMI injection 15 min after tracer delivery (DMI chase). The rats were kept under general isoflurane anesthesia while dynamic emission scans of the heart were recorded for 60 min after radiotracer injection. A myocardial retention index was determined by normalizing uptake at 40 min to the integral under the arterial input curve. Washout rates were determined by monoexponential fitting of myocardial time-activity curves. RESULTS: At baseline, HED showed high myocardial uptake and sustained retention, EPI showed moderate uptake and significant biphasic washout, and PHEN showed moderate uptake and monoexponential washout. The average (+/- SD) left ventricular retention index for HED, PHEN, and EPI was 7.38% +/- 0.82%/min, 3.43% +/- 0.45%/min, and 4.24% +/- 0.59%/min, respectively; the washout rate for HED, PHEN, and EPI was 0.13% +/- 0.23%/min, 1.13% +/- 0.35%/min, and 0.50% +/- 0.24%/min, respectively. The DMI chase resulted in increased washout only for HED. DMI block decreased myocardial uptake of all tracers by less than 90%. CONCLUSION: Kinetic profiles of HED in the rat myocardium were similar to those of HED in humans, suggesting comparable neuronal transport density. Unlike in humans, however, significant washout of EPI and faster washout of PHEN were encountered, consistent with high intraneuronal metabolic activity, high catecholamine turnover, and reduced vesicular storage. This evidence of increased neuronal activity in rodents has implications for translational studies of cardiac neuronal biology in humans.     

Significant efficiency findings while controlling for the frequent confounders of CAI research in the PlanAlyzer project's computer-based,self-paced,case-based programs in anemia and chest pain diagnosis

Richard E. Clark in his widely published comprehensive studies and meta-analyses of the literature on computer assisted instruction (CAI) has decried the lack of carefully controlled research, challenging almost every study which shows the computer-based intervention to result in significant post-test proficiency gains over a non-computer-based intervention. We report on a randomized study in a medical school setting where the usual confounders found by Clark to plague most research, were carefully controlled. PlanAlyzer is a microcomputer-based, self-paced, case-based, event-driven system for medical education which was developed and used in carefully controlled trials in a second year medical school curriculum to test the hypothesis that students with access to the interactive programs could integrate their didactic knowledge more effectively and/or efficiently than with access only to traditional textual “nonintelligent” materials. PlanAlyzer presents cases, elicits and critiques a student's approach to the diagnosis of two common medical disorders: anemias and chest pain. PlanAlyzer uses text, hypertext, images and critiquing theory. Students were randomized, one half becoming the experimental group who received the interactive PlanAlyzer cases in anemia, the other half becoming the controls who received the exact same content material in a text format. Later in each year there was a crossover, the controls becoming the experimentals for a similar intervention with the cardiology PlanAlyzer cases. Preliminary results at the end of the first two full trials shows that the programs have achieved most of the proposed instructional objectives, plus some significant efficiency and economy gains. 96 faculty hours of classroom time were saved by using PlanAlyzer in their place, while maintaining high student achievement. In terms of student proficiency and efficiency, the 328 students in the trials over two years were able to accomplish the project's instructional objectives, and the experimentals accomplished this in 43% less time than the controls, achieving the same level of mastery. However, in spite of these significant efficiency findings, there have been no significant proficiency differences (as measured by current factual and higher order multiple choice post-tests) between the experimental and control groups. Very careful controls were used to avoid what Clark has found to be the most common confounders of CAI research. Accordingly, this research proved Clark's rival hypothesis, that the computer, in itself, does not appear to contribute to proficiency gains, at least as measured by our limited post-testing. Clark's position is that the computer is primarily a vehicle—as is either a pill or a hypodermic needle for delivering a drug. The hypodermic needle can deliver the drug more efficiently than can the pill, (as can the computer deliver the subject matter content more efficiently, as our research indicates), but the same content is delivered. At the same time, we proved our own hypothesis, as far as efficiency gains resulting from the computer are concerned. However, going beyond Clark's research, we may be teaching processes both more effectively and efficiently with the computer (experience in problem-solving or clinical reasoning and pattern recognition) which our current post-tests do not adequately measure. Our on-going research suggests additional inquiry in several areas: better evaluation instruments to measure the clinical reasoning skills PlanAlyzer was designed to teach; the addition of more advanced cases to determine if this might transform efficiency gains of the computer group into proficiency gains; the addition of enhanced graphic decision support tools and other pedagogical enhancements including cognitive feedback to strengthen PlanAlyzer's power to teach complex concepts of medical decision-making.     

Reactive oxygen species: a breath of life or death?

New insights into cancer cell-specific biological pathways are urgently needed to promote development of rationally targeted therapeutics. Reactive oxygen species (ROS) and their role in cancer cell response to growth factor signaling and hypoxia are emerging as verdant areas of exploration on the road to discovering cancer's Achilles heel. One of the distinguishing and near-universal hallmarks of cancer growth is hypoxia. Unregulated cellular proliferation leads to formation of cellular masses that extend beyond the resting vasculature, resulting in oxygen and nutrient deprivation. The resulting hypoxia triggers a number of critical adaptations that enable cancer cell survival, including apoptosis suppression, altered glucose metabolism, and an angiogenic phenotype. Ironically, recent investigations suggest that oxygen depletion stimulates mitochondria to elaborate increased ROS, with subsequent activation of signaling pathways, such as hypoxia inducible factor 1alpha, that promote cancer cell survival and tumor growth. Because mitochondria are key organelles involved in chemotherapy-induced apoptosis induction, the relationship between mitochondria, ROS signaling, and activation of survival pathways under hypoxic conditions has been the subject of increased study. Insights into mechanisms involved in ROS signaling may offer novel avenues to facilitate discovery of cancer-specific therapies. Preclinical and clinical evaluation of agents that modify ROS signaling in cancer offers a novel avenue for intervention. This review will cover recent work in ROS-mediated signaling in cancer cells and its potential as a target for developmental therapeutics.     

Survey of psychiatric disorders in a Taiwanese village population six months after a major earthquake.

BACKGROUND AND PURPOSE: The catastrophic Chi-Chi earthquake of September 21, 1999 in Taiwan provided a unique opportunity to study the disaster's psychiatric impact on survivors. This study assessed the development of psychiatric disorders among residents in a Taiwanese village near the epicenter of the earthquake within 6 months of the disaster. METHODS: A total of 442 of the 602 actual living residents of Tong-Chi village who were over 16 years of age and were present in the community at the time of the earthquake were included in this population survey. Subjects were interviewed by psychiatrists using the Mini-International Neuropsychiatric Interview and questionnaires to collect demographic information and risk factors for psychiatric disorders 4 to 6 months after the earthquake. RESULTS: The prevalence rates were 9.5% for current major depression, 2.8% for past major depressive episode, and 7.9% for post-traumatic stress disorder (PTSD). Females had significantly higher rates of most psychiatric disorders. After controlling for covariates, the significant risk factors for PTSD were female gender and having sought medical service after the earthquake. Significant risk factors for major depressive episode were divorced/widowed status, education level equal to or below primary school, and prominent house damage. CONCLUSION: This population survey of earthquake disaster survivors found an increased prevalence of psychiatric disorders after exposure to a catastrophic earthquake. These results highlight the need for prompt therapeutic attention to residents of earthquake disaster areas after the event.     

Is herpes zoster a marker for occult or subsequent malignancy?

BACKGROUND: It has been suggested that herpes zoster may be a marker for occult malignancy. AIM: To examine the emergence of a subsequent cancer diagnosis in patients with and without herpes zoster. DESIGN OF STUDY: Retrospective cohort study. SETTING: Results were based on the database of Intego, an ongoing Belgian general practice-based morbidity registry, covering 37 general practitioners and including about 311 000 patient years between the years 1994 and 2000. METHOD: Survival analysis comparing the emergence of malignancy in patients with and without herpes zoster. RESULTS: The number of patients below the age of 65 years with herpes zoster, cancer or both was too low to draw any sensible conclusions. Above the age of 65 years we identified a significant increase of cancer emergence in the whole group and in females (hazard ratio = 2.65, 95% confidence interval = 1.43 to 4.90), but not in males. No difference could be identified in the first year after the herpes zoster infection. CONCLUSION: Our results do not justify extensive testing for cancer in herpes zoster patients. The association we identified, however, leaves open a number of questions with respect to the physiopathology behind it.     

Current status of colorectal cancer chemoprevention

Chemoprevention refers to suppression or reversal of the carcinogenic process using pharmacologic or nutritional agents. Colorectal carcinogenesis is a protracted, multistep process that offers opportunities for prevention. Aspirin and selective cyclooxygenase-2 inhibitors (coxibs) have been evaluated for the prevention of sporadic adenoma recurrence. Aspirin was shown to reduce adenoma recurrence rates in patients with prior colorectal neoplasms; however, the optimal dosage remains unclear. Recent studies of coxibs indicate that these agents are effective in reducing sporadic adenoma recurrence, but chronic use can result in serious cardiovascular toxicity. These data underscore the need for chemopreventive agents with acceptable risk-to-benefit ratios. In this regard, nitric-oxide-releasing aspirin shows chemopreventive efficacy in preclinical models and holds promise for reduced toxicity in humans. Furthermore, ongoing chemoprevention trials are evaluating nutritional supplements, such as folic acid and selenium, and results are eagerly awaited.     

The effects of severe visual challenges on steering performance in visually healthy young drivers.

PURPOSE: Two experiments explored the extent to which induced blur, reduced luminance, and reduced visual fields affect drivers' steering performance in a driving simulator. METHODS: In experiment 1, ten young participants (M = 21.2 years) drove at approximately 89 km/h (55 mph) along a curvy roadway while being exposed to blur (0 to + 10 D), luminance (0.003 to 16.7 cd/m), and visual field (1.7 and 150 degrees) manipulations. In experiment 2, a new group of ten young participants (M = 18.5 years) drove while exposed to seven visual field sizes (1.7 to 150 degrees). RESULTS: Steering was sensitive to a reduced field size but not to the blur and luminance challenges. Acuity, on the other hand, was sensitive to the blur and luminance challenges but not to reduced field size. DISCUSSION: In healthy young drivers, steering performance is remarkably robust to severe blur and to extremely low luminances. These results support a key element of the selective degradation hypothesis advanced by Leibowitz and colleagues--that steering abilities are preserved at night even when the ability to recognize objects and hazards is not. Additional research should address the other element of this hypothesis--that drivers fail to appreciate the extent to which their visual abilities are degraded at night.