Sex differences in ethanol-induced hypothermia in ethanol-naïve and ethanol-dependent/withdrawn rats.

BACKGROUND: Human and animal findings indicate that males and females display major differences in risk for and consequences of alcohol abuse and alcoholism. These differences are in large part mediated by sex-specific hormonal environments. Gonadal and adrenal secretory products are known to modulate the neurobehavioral responses of ethanol (EtOH) dependence and withdrawal. However, the effects of these steroids on physiological adaptations, such as thermoregulation, are less well established. To study the role of sex-related hormones in mediating sex differences in the hypothermic response to acute challenge with EtOH, we compared the EtOH-induced hypothermic responses of EtOH-naïve male and female rats and EtOH-dependent (on the third day of withdrawal) male and female rats before (intact) and after depletion of all gonadal and adrenal steroids by gonadectomy (GDX) with or without adrenalectomy (ADX). METHODS: Intact and GDX male and female rats, with or without ADX, were fed an EtOH-containing liquid diet for 15 days while control (EtOH-naïve) rats were pairfed the isocaloric liquid diet without EtOH or fed normal rat chow and water. On the third day of withdrawal from the EtOH diet we tested the hypothermic response to EtOH challenge (1.5 g/kg BWt, ip). Blood alcohol content (BAC) and corticosterone (CORT) content were analyzed in a separate series of intact and GDX males and females with and without ADX in response to the EtOH challenge. RESULTS: Ethanol-induced hypothermia was significantly greater and its duration significantly longer in intact males than females when subjects were EtOH-naïve. EtOH-induced hypothermia was significantly greater in intact females than males by the third day of withdrawal from EtOH dependence. GDX in males significantly shortened the duration of the hypothermic response and tended to blunt EtOH-induced hypothermia while response duration was significantly extended by GDX in females that tended to enhance EtOH-hypothermia. EtOH-induced hypothermia was significantly enhanced and its duration significantly lengthened by combined GDX and ADX in EtOH-naïve and -withdrawn males and by combined GDX and ADX in EtOH-naïve but not EtOH-withdrawn females. These differential EtOH-induced hypothermic responses did not appear to be caused by differences in EtOH handling among the groups. The absence of adrenal activation by EtOH in the GDX-ADX males and females contributes to their enhanced EtOH-induced hypothermic responses. CONCLUSIONS: These results implicate the direct and indirect effects of removal of gonadal and adrenal secretory products as mediators of the thermoregulatory actions of EtOH.

Molecular epigenetics, chromatin, and NeuroAIDS/HIV: immunopathological implications.

Epigenetics studies factors related to the organism and environment that modulate inheritance from generation to generation. Molecular epigenetics examines non-coding DNA (ncdDNA) vs. coding DNA (cdDNA), and pertains to every domain of physiology, including immune and brain function. Molecular cartography, including genomics, proteomics, and interactomics, seeks to recognize and to identify the multi-faceted and intricate array of interacting genes and gene products that characterize the function and specialization of each individual cell in the context of cell-cell interaction, tissue, and organ function. Molecular cartography, epigenetics, and chromatin assembly, repair and remodeling (CARR), which, together with the RNA interfering signaling complex (RISC), is responsible for much of the control and regulation of gene expression, intersect.We describe current and ongoing studies aimed to apply these overlapping areas of research, CARR and RISC, to a novel understanding of the immuno-neuropathology of HIV-1 infection, as an example. Taken together, the arguments presented here lead to a novel working hypothesis of molecular immune epigenetics as it pertains to HIV/AIDS, and the immunopathology of HIV-1-infected CD4+ cells. Specifically, we discuss these views in the context of the structure-function relationship of chromatin, the cdDNA/ncdDNA ratio, and possible nucleotide divergence in the untranslated regions (UTRs) of mature mRNA intronic and intergenic DNA sequences, and putative catastrophic consequences for immune surveillance and the preservation of health in HIV/AIDS. Here, we discuss the immunopathology of HIV Infection, with emphasis on CARR in cellular, humoral and molecular immune epigenetics.

Injury severity differentially affects short- and long-term neuroendocrine outcomes of traumatic brain injury.

Having reported that traumatic brain injury (TBI), produced by moderate lateral controlled cortical impact (CCI), causes long-term dysregulation of the neuroendocrine stress response, the aim of this study was to assess short- and long-term effects of both moderate and mild CCI on stress-induced hypothalamic-pituitary-adrenal (HPA) function. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths to produce either a moderate or mild CCI. Controls underwent sham surgery without injury. Commencing at one week after recovery from surgery, rats were exposed to stressors: 30-min restraint (days 7, 34, and 70) or 15-min forced swim (days 21 and 54). Tail vein blood was analyzed for corticosterone (CORT) content by radioimmunoassay. On days 7 and 21, the stress-induced HPA responses were significantly attenuated by both mild and moderate CCI. Significant attenuation of the CORT response to stress persisted through day 70 after moderate CCI. In contrast, stress-induced CORT levels on days 34, 54, and 70 were significantly enhanced after mild CCI. Differential effects of injury severity were also observed on motor function in a forelimb test on post-injury day 12 and on cortical lesion volume and hippocampal cell loss at day 70, but not on working memory in a radial maze on day 15. The differing short- and long-term stress-induced HPA responses may be mediated by differential effects of moderate and mild CCI on the efficiency of glucocorticoid negative feedback or signaling among hypothalamic and extrahypothalamic components of the neuroendocrine stress-response system.

Neuroendocrine immunity in patients with Alzheimer's disease: toward translational epigenetics.

The emerging domain of epigenetics in molecular medicine finds application for a variety of patient populations. Here, we present fundamental neuroendocrine immune evidence obtained in patients with senile dementia of the Alzheimer's type (sDAT), and discuss the implications of these data from the viewpoint of translational epigenetics of Alzheimer's disease. We followed 18 subjects with mild sDAT treated with acetylcholinesterase inhibitors, and 10 control subjects matched for age in a repeated measure design every six months for 18 months. We monitored psychosocial profile (Mini-Mental State Examination, Functional Assessment Staging, Independence in Activities of Daily Living, Depression, Profile of Moods States) in parallel to immunophenotypic parameters of T cell subpopulations by flow cytometry. Based on change in the mini-mental state score at entry and at 18 months, patients with sDAT were assigned to a "fast progression" (delta greater than 2 points) or to a "slow progression" group (delta less than or equal to 2 points). The change in circulating activated T cells (CD3+Dr+) with time in patients with sDAT was significantly inversely correlated with the change in time in natural killer (NK) cytotoxic activity to cortisol modulation in these patients, which was greater in patients with fast progression, compared to slow progression sDAT. These data indicate underlying neuroendocrine immune processes during progression of sDAT. Our observations suggest that psychoimmune measures such as those we have monitored in this study provide relevant information about the evolving physiological modulation in patients with sDAT during progression of Alzheimer's disease, and point to new or improved translational epigenetic treatment interventions.

Aluminium blunts the proliferative response and increases apoptosis of cultured human cells: putative relationship to Alzheimer's disease.

Aluminium (Al) has been investigated as a neurotoxic substance. Al ranks among the potential environmental risk factors for Alzheimer's disease (AD). Epidemiological studies tested the relationship between Al in drinking water and AD, showing a significant correlation between elevated levels of monomeric Al in water and AD, although data to date remain inconclusive with respect to total Al. The aim of this study was to test whether or not Al exacerbates cellular toxicity mediated by the amyloid beta (Abeta) peptide. We evaluated the role of Al in modulating programmed cell death (apoptosis) in human cell cultures. We used the osteosarcoma cell line monolayer (SaOs-2) to demonstrate that treatment of SaOs-2 cultures with the Abeta peptide mid-fragment (25 to 35) at nano M, followed by co-incubation with physiological concentrations of aluminium chloride, which release monomeric Al in solution, led to marked expression of caspase 3, but not caspase 9, key markers of the apoptotic process. The same experimental conditions were shown to blunt significantly the proliferative response of normal human peripheral blood mononuclear cells (PBMC) to phytohemagglutinin (PHA) stimulation. Our observations support the hypothesis that Al significantly impairs certain cellular immune responses, and confirm that Al-mediated cell toxicity may play an important role in AD.

Physiologic modulation of natural killer cell activity as an index of Alzheimer's disease progression.

Patients with Alzheimer's disease (AD) are characterized by an altered sensitivity to cortisol-mediated modulation of circulating lymphocytes. Longitudinal studies are needed to address the clinical applicability of these abnormalities as prognostic factors. Therefore, we designed a longitudinal study to address the clinical applicability of physiologic modulation of Natural Killer (NK) cell activity as a prognostic factor in AD. NK activity was assessed as baseline measurement and in response to modulation by cortisol at 10(-6)M. To verify the immunophysiological integrity of the NK cell population, we tested augmentation of NK cytotoxicity by human recombinant interleukin (IL)-2 (100 IU/ml) as control. The response to modulation by cortisol or by IL-2 was significantly greater in patients with AD. Based on change in the Mini-Mental State score at entry and at 18 months, patients with AD could be assigned to a "fast progression" (Delta > 2 points) or to a "slow progression" group (Delta

Evidence-Based Research in Complementary and Alternative Medicine III: Treatment of Patients with Alzheimer's Disease.

This paper presents the novel domain of evidence-based research (EBR) in the treatment of patients with Alzheimer's disease (AD) from the perspective of traditional medicine and of complementary and alternative medicine. In earlier lectures we have described the process of evidence-based medicine as a methodological approach to clinical practice that is directed to aid clinical decision-making. Here, we present a practical example of this approach with respect to traditional pharmacological interventions and to complementary and alternative treatments for patients with AD.

Lasting neuroendocrine-immune effects of traumatic brain injury in rats.

Traumatic brain injury (TBI) is a principal cause of long-term physical, cognitive, behavioral, and social deficits in young adults, which frequently coexist with a high incidence of substance abuse disorders. However, few studies have examined the long-term effects of TBI on the neuroendocrine-immune system. TBI was induced in adult male rats under isoflurane anesthesia by cortical contusion injury with a pneumatic piston positioned stereotaxically over the left parietal cortex. Controls underwent sham surgery without injury. At 4 weeks post-injury, the plasma corticosterone response to 30-min restraint stress was significantly blunted in TBI rats compared to the sham controls. One week later, transmitters were implanted for continuous biotelemetric recording of body temperature and spontaneous locomotor activity. At 6 weeks post-injury, the febrile response to i.p. injection of the bacterial endotoxin, lipopolysaccharide (LPS; 50 microg/kg), was significantly lower in TBI than in sham rats. At 8 weeks, swimming in the forced swim test was significantly less in TBI than sham rats. At 9 weeks, rats were rendered ethanol (EtOH) dependent by feeding an EtOH-containing liquid diet for 14 days. Cosine rhythmometry analysis of circadian body temperature Midline Estimating Statistic of Rhythm (MESOR), amplitudes, and acrophases indicated differential effects of EtOH and withdrawal in the two groups. Light- and dark-phase activity analysis indicated that TBI rats were significantly more active than the sham group, and that EtOH and withdrawal differentially affected their activity. Given the extensive interactions of the neuroendocrine-immune systems, these results demonstrate that TBI produces lasting dysregulation amidst the central substrates for allostasis and circadian rhythmicity.

Evidence-based dentistry: a clinician's perspective.

Evidence-based dentistry is a discipline that provides best, explicit-based evidence to dentists and their patients in shared decision-making. Currently, dentists are being trained and directed to adopt the role of translational researchers in developing evidence-based dental practices. Practically, evidence-based dentistry is not usable in its current mode for the provision of labor-intensive services that characterize current dental practice. The purpose of this article is to introduce a model of evidence-based dental practice. This model conceptualizes a team approach in explaining problems and solutions to change current dental practice. These changes constitute an evidence-based dental practice that involves the electronic chart, centralized database, knowledge management software, and personnel in optimizing effective oral health care to dental patients.

Making clinical decisions using a clinical practice guideline.

Clinical practice guidelines are statements developed from best evidence about clinically relevant appropriate care. A simulated patient case is presented to demonstrate how to use a CPG in decision-making in determining a clinical decision. Conceptualized knowledge management software templates are provided to explain a process by which best evidence is retrieved from a primary, centralized network database. Templates describe the process of converting a clinical question into a research question, retrieving best evidence, and performing data analysis for the outcome of individualizing and optimizing a clinical decision. Templates also describe the reciprocation of information to update CPGs by translational researchers who manage and build the primary, centralized network database.

Evidence-based dentistry: fundamentals for the dentist.

This article explains the fundamentals of evidence-based dentistry for the dentist. Evidence-based dentistry is a discipline whose primary participant is the translational researcher. Recent developments have emphasized the importance of this discipline (clinical and translational research) for improving health care. The process of evidence-based dentistry is the reciprocation of new and existing evidence between dentists and quantitative and qualitative researchers, facilitated by the translational researcher. The product of this reciprocation is the clinical practice guideline, or best evidence, that provides the patient options in choosing treatments or services. These options are quantified and qualified by decision, utility, and cost data. Using shared decision-making, the dentist and patient arrive at a mutual understanding of which option best meets an acceptable and preferred treatment course that is cost effective. This option becomes the clinical decision.

Clinical evidence and evidence-based dental treatment of special populations: patients with Alzheimer's disease.

This paper presents the novel domain of evidence-based research in the context of treating the dental needs of patients with special needs. A contrast is made between evidence-based dentistry and traditional dentistry, which is based on the evidence obtained by the dentist, with respect to the needs and the wants of the patient, and from the pertinent and accessible literature. By contrast, evidence-based dentistry is focused on integrating traditional dentistry with "the best available" research evidence. The aim of evidence-based dentistry is to improve clinical decision-making by its reliance on a critical analysis of the entire body of the published pertinent literature. It is a system of information management, and a system of data integration that assist clinicians in the process of meshing systemic clinical expertise, evidence provided by the patient, and the best literature evidence to enhance treatment outcomes. Evidence-based dentistry emphasizes rigorous analysis of evidence from clinical research, as the basis of sound dental practice, while discouraging intuitive and unsystematic approaches and promoting the systematic analysis and appraisal of the literature to determine the best treatment alternatives. In the case of patients with special needs, it is critical whether the dentist practices traditional dentistry or evidence-based dentistry to evaluate whether or not the patient is capable of expressing his or her needs/wants, unless, as in the more severe cases, he/she is accompanied by the caregiver. The purpose of this paper is to demonstrate the use of a simple in-house questionnaire for evaluating the patient's ability to tell the dentist his or her needs and wants accurately. In this context, the paper examines the dental needs of patients with dementia of the Alzheimer's type, DAT.

Cellular immunology in HIV-1 positive African American women using alcohol and cocaine.

Co-use of illicit drugs, in particular cocaine and alcohol, is common among HIV-1(+) men and women of different ethnic groups. We compared cohorts of alcohol and cocaine co-users HIV-1(+) African American women and in cohorts of drug-free, or methamphetamine users HIV-1(+) men. We monitored clinical cellular immune parameters at repeated regular intervals. We found that significant inverse correlations between (CD8+)CD38+ cells and subpopulations of CD4+ cells distinguished by the expression of CD45RA in HIV-1(+) alcohol and cocaine co- users but not in drug-free HIV-1(+) patients. Following stratification for CD4+ cell number, we found the (CD4+)CD45RA+ subpopulation to be significantly higher (p < 0.05) in the drug user compared to drug-free HIV-1(+). Drug abuse may alter the change from the (CD4+)CD45RA+ to the (CD4+)CD45RA- phenotype selectively, which recovers in HIV-1+ methamphetamine abusers during treatment from baseline to 4-weeks, as manifested by improved IL-2 production in vitro. of TH1 and TH2 cytokines during progression to AIDS.

Evidence-based research in complementary and alternative medicine II: the process of evidence-based research.

It is a common practice in contemporary medicine to follow stringently the scientific method in the process of validating efficacy and effectiveness of new or improved modes of treatment intervention. It follows that these complementary or alternative interventions must be validated by stringent research before they can be reliably integrated into Western medicine. The next decades will witness an increasing number of evidence-based research directed at establishing the best available evidence in complementary and alternative medicine (CAM). This second paper in this lecture series examines the process of evidence-based research (EBR) in the context of CAM. We outline the fundamental principles, process and relevance of EBR, and its implication to CAM. We underscore areas of future development in EBR. We note that the main problem of applying EBR to CAM at present has to do with the fact that the contribution of EBR can be significant only to the extent to which studies used in the process of EBR are of good quality. All too often CAM research is not of sufficient quality to warrant the generation of a consensus statement. EBR, nevertheless, can contribute to CAM by identifying current weaknesses of CAM research. We present a revised instrument to assess quality of the literature.

Differential effects of alcohol consumption and withdrawal on circadian temperature and activity rhythms in Sprague-Dawley, Lewis, and Fischer male and female rats.

BACKGROUND: Hypothalamic synthesis and secretion of corticotropin-releasing hormone (CRH), a putative mediator of various behavioral and physiological responses to ethanol (EtOH), is defective in inbred Lewis (LEW) rats in comparison with their genetically related inbred Fischer 344 (F344) and outbred Sprague-Dawley (S-D) strains. We aimed to characterize the effects of continuous EtOH consumption and withdrawal on circadian patterns of body temperature and spontaneous locomotor activity in males and females of these 3 strains. METHODS: Adult LEW, F344, and S-D males and randomly cycling females were fed an EtOH-containing liquid diet or the control (pair-fed or lab chow and water) diet for 14 days. Biotelemetric body temperature data for the last 3 days of EtOH diet feeding and the first 3 days of withdrawal were subjected to cosinor analysis of the circadian rhythm parameters of midline-estimating statistic of rhythm (MESOR), amplitude, and acrophase. Mean dark-phase activity during these periods was also computed. RESULTS: In the control diet condition, the MESORs and amplitudes of LEW males were lower than those of F344 males. MESORs of rhythms of LEW females were lower than those of both F344 and S-D females. Ethanol consumption caused hypothermia with reduced MESORs and amplitudes of LEW and F344 males and amplitudes of F344 and S-D females. Upon withdrawal, MESORs of the males increased during each day as the amplitudes decreased, reflective of their initial withdrawal-induced dark-phase hypothermia, which was most pronounced in the LEW males, followed by light-phase hyperthermia. MESORs of females were not affected by withdrawal; their amplitudes were differentially affected. Acrophase of LEW males shifted from dark to light on the first day of withdrawal. All rats responded to EtOH exposure with a reduction of dark-phase spontaneous locomotor activity and an immediate increase upon withdrawal. CONCLUSIONS: Body temperature rhythms of the males were generally more affected by EtOH consumption and withdrawal than the females; within each sex, LEW and F344 rats differed significantly. The specific hormonal factors that mediate the differential temperature responses remain to be defined.

Salivary biomarkers in psychobiological medicine.

The value of salivary biomarkers for diagnostic and prognostic assessments has become increasingly well established in medicine, pharmacology, and dentistry. Certain salivary components mirror the neuro-endocrine status of the organism. Other saliva products are protein in nature, and can serve to reflect immune surveillance processes. The autonomic nervous system regulates the process of salivation, and the concentration of yet other salivary components, such as alpha-amylase, which provide a reliable outcome measure of the sympathetic response. Here, we discuss molecular technologies that have permitted giant steps in the utilization of salivary samples and micro-fluidics for the benefit of diagnostic medicine and dentistry, and their putative role in springing forward research in psychobiology.

Evidence-based research in complementary and alternative medicine I: history.

Contemporary Western medicine has witnessed a fragmentation of our conceptualization of the medical endeavor into 'traditional medicine' and 'non-traditional medicine'. The former is meant to refer to the Western medical tradition, the latter encompasses both 'complementary' and 'alternative' medical practices. Complementary medicine complements conventional medical treatments, and alternative modes of medical interventions are meant to replace traditional Western medicine. Evidence-based research must be directed at establishing the best available evidence in complementary and alternative medicine. This paper is the first of a set of four 'lectures' that reviews the process of evidence-based research, and discusses its implications and applications for the early decades of the 21st century. The purpose of this paper is to introduce the series by examining some of the historical and philosophical foundations of this research endeavor.

Post-traumatic stress disorder: evidence-based research for the third millennium.

The stress that results from traumatic events precipitates a spectrum of psycho-emotional and physiopathological outcomes. Post-traumatic stress disorder (PTSD) is a psychiatric disorder that results from the experience or witnessing of traumatic or life-threatening events. PTSD has profound psychobiological correlates, which can impair the person's daily life and be life threatening. In light of current events (e.g. extended combat, terrorism, exposure to certain environmental toxins), a sharp rise in patients with PTSD diagnosis is expected in the next decade. PTSD is a serious public health concern, which compels the search for novel paradigms and theoretical models to deepen the understanding of the condition and to develop new and improved modes of treatment intervention. We review the current knowledge of PTSD and introduce the role of allostasis as a new perspective in fundamental PTSD research. We discuss the domain of evidence-based research in medicine, particularly in the context of complementary medical intervention for patients with PTSD. We present arguments in support of the notion that the future of clinical and translational research in PTSD lies in the systematic evaluation of the research evidence in treatment intervention in order to insure the most effective and efficacious treatment for the benefit of the patient.

Neuro-immunity in stress-related oral ulcerations: a fractal analysis.

By testing archival paraffinized biopsy blocks obtained from the oral pathology library with immunohistochemistry, we tested the hypothesis that substantial alterations are demonstrable in the cross-talk between sympathetic (VMAT) and para-sympathetic innervation (VAchT), and resident CD3+ T cells in the mucosa from oral lichen planus (OLP), compared to recurrent aphthous stomatitis (RAS) and control biopsies. We quantified fractal dimension and Euclidean dimension of CD3+ cells between the two pathologies, and across the set of CD3+ cells proximal to the vesicles of monoamines transport (VMAT)+ or the vesicles of acetylcholine transport (VAchT)+ innervation, compared to cells relatively distal to the nerve endings. The data show exquisite organization of the punctuate sympathetic and para-sympathetic staining about the resident CD3+ T cells in the OLP lesions, but not in the aphthous lesions or in control mucosa. Fractal analysis reveals that aphthous lesions are characterized by CD3+ T cells of larger size (Euclidean dimensional map), compared to control mucosa. CD3+ T cells in OLP lesions are also found to be significantly larger than those found in control lesions, when they are not proximal to sympathetic or para-sympathetic vesicles. The membrane of CD3+ T cells is overall more complex (fractal dimension) in aphthous lesions, compared to control sections. A similar trend is apparent, albeit not statistically significant, in CD3+ T cells resident in OLP lesions, whether or not they are located proximal to nerve endings. An overall decrease in the ratio of fractal dimension-over-topological dimension was also observed across the pathological lesions, compared to control. Taken together, these data indicate that as CD3+ T cells grow larger in the pathological conditions, they, in effect, stretch their plasma membrane, and that the cells may be at different stage of the cell cycle, relative to their position vis a' vis nerve endings. Because fractal analysis is performed on individual cells, it has the potential of being developed in a novel diagnostic test, as well as a prognostic tool for monitoring the etiology and the course of treatment at the individual cellular level. Our findings also open new frontiers of fundamental, clinical and translational biosciences of OLP.