Excitotoxicity in a chronic model of multiple sclerosis: Neuroprotective effects of cannabinoids through CB1 and CB2 receptor activation

Inflammation, autoimmune response, demyelination and axonal damage are thought to participate in the pathogenesis of multiple sclerosis (MS). Understanding whether axonal damage causes or originates from demyelination is a crucial issue. Excitotoxic processes may be responsible for white matter and axonal damage. Experimental and clinical studies indicate that cannabinoids could prove efficient in the treatment of MS. Using a chronic model of MS in mice, we show here that clinical signs and axonal damage in the spinal cord were reduced by the AMPA antagonist, NBQX. Amelioration of symptomatology by the synthetic cannabinoid HU210 was also accompanied by a reduction of axonal damage in this model. Moreover, HU210 reduced AMPA-induced excitotoxicity both in vivo and in vitro through the obligatory activation of both CB1 and CB2 cannabinoid receptors. Together, these data underline the implication of excitotoxic processes in demyelinating pathologies such as MS and the potential therapeutic properties of cannabinoids.     

Predicting outcomes of primary care patients with major depression: development of a depression prognosis index

OBJECTIVE: Depression research and practice focus increasingly on diverse patient populations with varying probabilities of response to clinical care. Prognostic indices use preexisting patient characteristics to estimate the probability of subsequent negative clinical outcomes and are useful tools for improving the study and care of diverse populations. Few such measures, however, have been developed for mental health conditions. This study developed and validated a depression prognosis measure for primary care patients with major depression. METHODS: Consecutive patients in 108 primary care practices were screened for depression, and 1,471 with major depression were enrolled. A Depression Prognosis Index (DPI) predicting persistent depression six months after baseline was developed for a random one-third subsample and validated with the remaining two-thirds. Models included prior treatment, demographic characteristics, comorbidities, and other physical, psychological, and social predictors. RESULTS: Sixty-four percent to 65% of patients classified by baseline DPI score as being in the sample quartile with the worst prognosis had probable major depression six months later, compared with 14% to 15% in the best-prognosis quartile. The DPI had an R2 of .40 in the development sample and .27 in the validation sample. Important predictors included severity of depression symptoms at baseline, social support, common physical symptoms, and having completed three months of antidepressants at sample entry. CONCLUSIONS: The ability of the DPI to predict six-month outcomes compares favorably to that of prognostic indices for general medical problems. These results validate the DPI and provide conceptual guidance for further development of depression risk stratification instruments for clinical and research use.     

De novo autoimmune hepatitis following liver transplantation: a case report

De novo autoimmune hepatitis (AIH), a rare disorder first described in 1998, appears in patients with liver transplants due to autoimmune and nonautoimmune etiologies. De novo AIH occurs in 2.5% to 3.4% of allografts; children seem to have a predilection for this syndrome. We have present herein a case of a liver allograft recipient who developed chronic hepatitis associated with autoimmune features outlining the clinical course, liver histology, and response to treatment.     

The physiological effects of thoracic epidural anesthesia and analgesia on the cardiovascular, respiratory and gastrointestinal systems

Studies of regional anesthesia are increasing in popularity not only for the purpose of technical advancement, but also to better understand the effects of neural deafferentation on the function of various organs. Thoracic epidural anesthesia (TEA) is one of the most versatile and widely utilized neural deafferentation techniques. The aim of this article is to critically review published data regarding the most relevant effects of TEA on the cardiovascular, respiratory and gastrointestinal systems. In the cardiovascular system, TEA modifies the electrical activity of the heart in addition to ventricular function and wall motion. Improvements in regional blood flow and a reduction of the major determinants of cardiac oxygen consumption lead to less severity of the ischemic injury. Although TEA negatively affects the performance of intercostal muscles, it spares diaphragmatic function and, when it is limited to the first five thoracic segments, affects pulmonary volumes to a lesser extent. TEA can be safely used in patients with compromised respiration. Splanchnic sympathetic block is achieved when thoracic fibers from T5 to T12 are affected in a dose-dependent manner. Improved gastrointestinal blood flow and motility are clear in animals, and in clinical studies, TEA has been shown to improve recovery after major abdominal surgery. TEA thus presents a powerful tool available to anesthesiologists for perioperative intervention, but its use alone cannot prevent postoperative morbidity and mortality. It is therefore necessary to address its use in the context of multimodal intervention.     

Immunomodulatory effects of blood transfusions: the synergic role of soluble HLA Class I free heavy-chain molecules detectable in blood components

BACKGROUND: Over the past decades, the weight of the published literature demonstrates that blood transfusions can induce clinically significant immunosuppression in recipients. Several studies showed significant improved clinical outcomes in the patients receiving leukoreduced transfusions, compared with control patients who received nonleukoreduced transfusions. Moreover, the immunosuppressive potential of blood products grows with the time of their storage and becomes highest in nonleukoreduced blood products stored for a long time. STUDY DESIGN AND METHODS: The interest was previously focused on the determination of immunomodulatory soluble molecules such as soluble HLA Class I (sHLA-I) and soluble Fas ligand (sFasL) in different blood components and on the evaluation of their immunomodulatory activities. On this basis, whether soluble beta2-microglobulin free HLA Class I heavy chains (sHLA-beta2fHC) could be detected and immunochemically characterized in different blood components was evaluated. Immunomodulatory activity of detectable sHLA-beta2fHC molecules was evaluated by apoptosis inducing capacity in interleukin-2-activated antigen-specific cytotoxic T lymphocytes (CTL). RESULTS: Double-determinant immunoenzymatic assay indicates that sHLA-beta2fHC levels in red blood cells stored for up to 30 days and in random-donor platelets are significantly (p < 0.001) higher than in other blood components, and the immunochemical characterization suggests that the major source of sHLA-beta2fHC molecules might be the residual white cells that undergo membrane damage during storage. Finally, allogeneic CD8+ CTL apoptosis induction confirmed biofunctionality of sHLA-beta2fHC molecules. CONCLUSION: These data are comparable with those previously reported dealing with contaminant soluble molecules in allogeneic and autologous blood components, suggesting that sHLA-beta2fHC molecules could contribute to the immunosuppressive effects of blood transfusions.     

Sleep and behavioral/emotional problems in children: a population-based study

BackgroundThe potential relationships between sleep–wake behaviors and emotional/disruptive problems in otherwise healthy school-aged children are unclear.MethodsA parental questionnaire was developed for the epidemiologic survey of children’s sleep and wake behavioral patterns. The questions covered a wide range of features including sleep length (school days, weekends), time to fall asleep, night awakenings, bedtime and nighttime sleep-related behaviors, daytime sleepiness, irritability, and tiredness. To assess psychiatric symptomatology, the Rutter Scale B2 was completed by teachers. In addition to the total score, sub-scores of emotional, hyperactivity, and conduct problems were obtained. The representative population sample comprised 779 children (403 girls), with an age range of 6–11 years.ResultsHyperactivity and conduct problems at school in boys were both associated with parental reports of bedtime resistance. Hyperactivity was also associated with longer sleep duration during weekends. Conduct and emotional problems in girls were associated with earlier bedtime during school days. Emotional problems in girls were also associated with longer sleep durations in school days and weekends.ConclusionBedtime resistance was the only sleep behavior associated with either hyperactivity or conduct problems in children, and longer sleep durations appear to occur more frequently in children with both hyperactive or emotional problems. Information about good sleep hygiene at bedtime may help parents setting sleep limits.     

A multicentre follow-up of clinical aspects of traumatic spinal cord injury

STUDY DESIGN: Prospective, multicentred follow-up (FU) observational study. OBJECTIVES: Prospectively evaluate survival, complications, re-admissions and maintenance of clinical outcome in people experiencing traumatic spinal cord injury (SCI). SETTING: Seven spinal units and 17 rehabilitation centres participating in the previous GISEM (ie Italian Group for the Epidemiological Study of Spinal Cord Injuries) study. METHOD: A total of 511 persons with SCI, discharged between 1997 and 1999 after their first hospitalisation, were enrolled. A standardised questionnaire was administered via telephone. RESULTS: Of the 608 persons originally enrolled, 36 died between discharge and follow-up (mean 3.8+/-0.64 years). Of the remainder, 403 completed telephone interviews, 72 refused to participate and 97 could not be contacted. More than half of the patients interviewed (53.6%) experienced at least one SCI-related clinical problem in the 6 months preceding interview; the most frequent being urological complications (53.7%). At least one re-admission was recorded in 56.8% of patients between discharge and FU interview. Of the patients interviewed, 70.5% reported bowel autonomy and 86% bladder management autonomy. On multivariate analysis, lack of bowel/bladder autonomy was the most common variable with a strong predicting value for mortality, occurrence of complications and re-admissions. CONCLUSION: Re-admission and major complications seem common after SCI and should be considered when planning facilities. Failure to obtain bowel/bladder autonomy upon discharge from rehabilitation proved to be the most common predictive factor of poor outcome during the period between discharge and FU interview.