Dietary Diversity on the Swahili Coast: The Fauna from Two Zanzibar Trading Locales.

Occupants of coastal and island eastern Africa-now known as the 'Swahili coast'-were involved in long-distance trade with the Indian Ocean world during the later first millennium CE. Such exchanges may be traced via the appearance of non-native animals in the archaeofaunal record; additionally, this record reveals daily culinary practises of the members of trading communities and can thus shed light on subsistence technologies and social organisation. Yet despite the potential contributions of faunal data to Swahili coast archaeology, few detailed zooarchaeological studies have been conducted. Here, we present an analysis of faunal remains from new excavations at two coastal Zanzibar trading locales: the small settlement of Fukuchani in the north-west and the larger town of Unguja Ukuu in the south-west. The occurrences of non-native fauna at these sites-Asian black rat (Rattus rattus) and domestic chicken (Gallus gallus), as well as domestic cat (Felis catus)-are among the earliest in eastern Africa. The sites contrast with one another in their emphases on wild and domestic fauna: Fukuchani's inhabitants were economically and socially engaged with the wild terrestrial realm, evidenced not only through diet but also through the burial of a cache of wild bovid metatarsals. In contrast, the town of Unguja Ukuu had a domestic economy reliant on caprine herding, alongside more limited chicken keeping, although hunting or trapping of wild fauna also played an important role. Occupants of both sites were focused on a diversity of near-shore marine resources, with little or no evidence for the kind of venturing into deeper waters that would have required investment in new technologies. Comparisons with contemporaneous sites suggest that some of the patterns at Fukuchani and Unguja Ukuu are not replicated elsewhere. This diversity in early Swahili coast foodways is essential to discussions of the agents engaged in long-distance maritime trade.

Silver nanoparticles in the environment: Sources, detection and ecotoxicology.

The environmental impact of silver nanoparticles (AgNP) has become a topic of interest recently, this is due to the fact that AgNPs have been included in numerous consumer products including textiles, medical products, domestic appliances, food containers, cosmetics, paints and nano-functionalised plastics. The production, use and disposal of these AgNP containing products are potential routes for environmental exposure. These concerns have led to a number of studies investigating the release of particles from nano-functionalised products, the detection of the particles in the aquatic environment and the potential environmental toxicology of these AgNPs to aquatic organisms. The overall aim of this review is to examine methods for the capture and detection of AgNPs, potential toxicity and transmission routes in the aquatic environment.

Critical needs in drug discovery for cessation of alcohol and nicotine polysubstance abuse.

Polysubstance abuse of alcohol and nicotine has been overlooked in our understanding of the neurobiology of addiction and especially in the development of novel therapeutics for its treatment. Estimates show that as many as 92% of people with alcohol use disorders also smoke tobacco. The health risks associated with both excessive alcohol consumption and tobacco smoking create an urgent biomedical need for the discovery of effective cessation treatments, as opposed to current approaches that attempt to independently treat each abused agent. The lack of treatment approaches for alcohol and nicotine abuse/dependence mirrors a similar lack of research in the neurobiology of polysubstance abuse. This review discusses three critical needs in medications development for alcohol and nicotine co-abuse: (1) the need for a better understanding of the clinical condition (i.e. alcohol and nicotine polysubstance abuse), (2) the need to better understand how these drugs interact in order to identify new targets for therapeutic development and (3) the need for animal models that better mimic this human condition. Current and emerging treatments available for the cessation of each drug and their mechanisms of action are discussed within this context followed by what is known about the pharmacological interactions of alcohol and nicotine. Much has been and will continue to be gained from studying comorbid alcohol and nicotine exposure.

Antithymocyte globulin induction and rapid steroid taper leads to excellent results in kidney transplantation with donation after cardiac death donors: importance of rejection and delayed graft function.

Recipients of primary transplants from donation after cardiac death (DCD) donors (n = 40) performed from January 2005 to December 2009 were retrospectively reviewed and compared with recipients of primary transplants from donation after brain death (DBD) donors (n = 142). Patients received rabbit antithymocyte globulin induction and rapid steroid taper (RST; steroids stopped 5 days after surgery). Maintenance immunosuppression included tacrolimus and mycophenolate mofetil. Protocol kidney biopsies, creatinine (Cr), and measured glomerular filtration rate (mGFR; determined by cold iothalamate or 24-h creatinine clearance) were obtained at 1, 4, 12, and 24 months. Kidney biopsies for cause were conducted for unexplained elevated Cr, decline in mGFR, or new proteinuria. Biopsies were graded for rejection according to the Banff criteria. Graft survival at 3 years was 90.0% for DCD recipients and 86.6% for DBD recipients (P = NS). Rejection of any grade diagnosed on any biopsy through the first 2 years occurred in 18 DCD (45%) and 50 DBD (35%) recipients. Rejection of a grade more than Banff borderline occurred in 12.5% DCD and 12.7% DBD recipients. At 2 years, the mean ± SEM Cr and mGFR for DCD recipients with rejection were 1.8 ± 0.29 mg/dL and 59.2 ± 8.5 mL/min versus 1.3 ± 0.11 mg/dL and 67.0 ± 7.8 ml/min for those without rejection. For DBD recipients with rejection, Cr and mGFR at 2 years were 1.7 ± 0.12 mg/dL and 54.0 ± 4.4 mL/min versus 1.4 ± 0.11 mg/dL and 66.6 ± 3.3 ml/min for those without rejection (P = NS). Comparing DCD to DBD, there was no statistical difference in mean Cr or mGFR outcomes. Regardless of group, grafts with delayed graft function had lower 3-year survival. DCD primary kidney transplant recipients treated with rabbit antithymocyte induction and RST have short-term graft survival and function equivalent to DBD recipients. RST appears to be acceptable immunosuppression for DCD recipients.

Temporal dependence of cysteine protease activation following excitotoxic hippocampal injury.

Excitotoxic insults can lead to intracellular signaling cascades that contribute to cell death, in part by activation of proteases, phospholipases, and endonucleases. Cysteine proteases, such as calpains, are calcium (Ca(2+))-activated enzymes which degrade cytoskeletal proteins, including microtubule-associated proteins, tubulin, and spectrin, among others. The current study used the organotypic hippocampal slice culture model to examine whether pharmacologic inhibition of cysteine protease activity inhibits N-methyl-D-aspartate- (NMDA-) induced excitotoxic (20 µM NMDA) cell death and changes in synaptophysin immunoreactivity. Significant NMDA-induced cytotoxicity (as measured by propidium iodide [PI] uptake) was found in the CA1 region of the hippocampus at all timepoints examined (24, 72, 120 h), an effect significantly attenuated by co-exposure to the selective NMDA receptor antagonist DL-2-Amino-5-phosphonopentanoic acid (APV), but not MDL-28170, a potent cysteine protease inhibitor. Results indicated sparing of NMDA-induced loss of the synaptic vesicular protein synaptophysin in all regions of the hippocampus by MDL-28170, though only at early timepoints after injury. These results suggest Ca(2+)-dependent recruitment of cysteine proteases within 24h of excitotoxic insult, but activation of alternative cellular degrading mechanisms after 24h. Further, these data suggest that synaptophysin may be a substrate for calpains and related proteases.

Can anti-erosion dentifrices also provide effective plaque control?

OBJECTIVE: While gingivitis and caries continue to be prevalent issues, there is growing concern about dental erosion induced by dietary acids. An oral hygiene product that protects against all these conditions would be beneficial. This study investigated the potential of two anti-erosion dentifrices to inhibit plaque. METHODS: This was a randomized, three-period, two-treatment, double-blind, crossover study evaluating a stannous chloride/sodium fluoride dentifrice (SnCl(2)/NaF, blend-a-med(®) Pro Expert) and a popular anti-erosion dentifrice (NaF, Sensodyne(®) ProNamel(™)). During Period 3, subjects were randomized to repeat one treatment to evaluate any product carryover effects. Each treatment period was 17 days. Test dentifrices were used with a standard manual toothbrush. Digital plaque image analysis (DPIA) was employed at the end of each period to evaluate plaque levels (i) overnight (am prebrush); (ii) post-brushing with the test product (am post-brush); and (iii) mid-afternoon (pm). Analysis was conducted via an objective computer algorithm, which calculated total area of visible plaque. RESULTS: Twenty-seven subjects completed the study. At all time points, subjects had statistically significantly (P ≤ 0.0001) lower plaque levels after using the SnCl(2)/NaF dentifrice than the NaF dentifrice. The antiplaque benefit for the SnCl(2)/NaF dentifrice versus the NaF dentifrice was: am prebrush = 26.0%; am post-brushing = 27.9%; pm = 25.7%. CONCLUSIONS: The SnCl(2)/NaF dentifrice provided significantly greater daytime and overnight plaque inhibition than the NaF toothpaste. When recommending dentifrice to patients susceptible to dental erosion, clinicians can consider one that also inhibits plaque.

Three-dimensional ultrasound fetal lung volumes and infant respiratory outcome: a prospective observational study.

OBJECTIVE: To determine if fetal lung volumes (FLVs), determined by three-dimensional rotational ultrasound and virtual organ computer-aided analysis software (vocal), correlated with neonatal respiratory outcomes in surviving infants who had a high risk [fetuses with congenital diaphragmatic hernia (CDH)], lower risk [fetuses with anterior wall defects (AWDs)] and no risk (controls) of abnormal antenatal lung growth. DESIGN: Prospective observational study. SETTING: Tertiary fetal medicine and neonatal intensive care units. POPULATION: Sixty fetuses (25 with CDH, 25 with AWDs and ten controls). METHODS: FLVs were measured and expressed as the percentage of the observed compared with the expected for gestational age. MAIN OUTCOME MEASURES: Neonatal respiratory outcome was determined by the duration of supplemental oxygen, mechanical ventilation and dependencies, and assessment of lung volume using a gas dilution technique to measure functional residual capacity (FRC). RESULTS: The infants with CDH had lower FLV results than both the infants with AWDs (P=0.05) and the controls (P<0.05). The infants with CDH had longer durations of mechanical ventilation (P<0.001) and supplementary oxygen (P<0.001) dependence, compared with infants with AWDs. The infants with CDH had a lower median FRC than both the infants with AWDs (P<0.001) and the controls (P<0.001). FLV results correlated significantly with the durations of dependency on ventilation (r= -0.744, P<0.01) and oxygen (r= -0.788, P<0.001), and with FRC results (r=0.429, P=0.001). CONCLUSIONS: These results suggest that FLVs obtained using three-dimensional rotational ultrasound might be useful in predicting neonatal respiratory outcome in surviving infants who had varying risks of abnormal lung growth. Larger and more comprehensive studies are needed to clarify the role that lung volume measurements have in assessing lung function and growth.

The importance of glucocorticoids in alcohol dependence and neurotoxicity.

Alterations in hypothalamo-pituitary adrenal (HPA) function have been described in alcoholics and in rodents after chronic alcohol consumption but the role of glucocorticoids in alcohol consumption, and the mechanisms involved, has received little attention until recently. Both alcohol consumption and withdrawal from chronic alcohol intake raise circulating glucocorticoid levels, and prolonged high concentrations of glucocorticoids are known to have detrimental effects on neuronal function and cognition. This minireview covers the ways in which glucocorticoids may be involved in drinking behavior, from social drinking to dependence, and the negative consequences of alcohol consumption seen during withdrawal which may have a detrimental effect on treatment outcome. Research shows prolonged increases in brain glucocorticoid concentrations and decreased brain glucocorticoid receptor availability (consistent with increased levels of endogenous ligand) after withdrawal from chronic alcohol treatment. Evidence suggests that increased glucocorticoid levels in the brain after chronic alcohol treatment are associated with the cognitive deficits seen during abstinence which impact on treatment efficacy and quality of life. Studies on organotypic cultures also demonstrate the importance of glucocorticoids in the neuropathological consequences of alcohol dependence.

Selective vulnerability of hippocampal cornu ammonis 1 pyramidal cells to excitotoxic insult is associated with the expression of polyamine-sensitive N-methyl-D-asparate-type glutamate receptors.

Excess glutamate release and stimulation of post-synaptic glutamatergic receptors have been implicated in the pathophysiology of many neurological diseases. The hippocampus, and the pyramidal cell layer of the cornu ammonus 1 (CA1) region in particular, has been noted for its selective sensitivity to excitotoxic insults. The current studies examined the role of N-methyl-D-aspartate (NMDA) receptor subunit composition and sensitivity to stimulatory effects of the polyamine spermidine, an allosteric modulator of NMDA NR2 subunit activity, in hippocampal CA1 region sensitivity to excitotoxic insult. Organotypic hippocampal slice cultures of 8 day-old neonatal rat were obtained and maintained in vitro for 5 days. At this time, immunohistochemical analysis of mature neuron density (NeuN); microtubule associated protein-2(a,b) density (MAP-2); and NMDA receptor NR1 and NR2B subunit density in the primary cell layers of the dentate gyrus (DG), CA3, and CA1 regions, was conducted. Further, autoradiographic analysis of NMDA receptor distribution and density (i.e. [(125)I]MK-801 binding) and spermidine (100 microM)-potentiated [(125)I]MK-801 binding in the primary cell layers of these regions was examined. A final series of studies examined effects of prolonged exposure to NMDA (0.1-10 microM) on neurodegeneration in the primary cell layers of the DG, CA3, and CA1 regions, in the absence and presence of spermidine (100 microM) or ifenprodil (100 microM), an allosteric inhibitor of NR2B polypeptide subunit activity. The pyramidal cell layer of the CA1 region demonstrated significantly greater density of mature neurons, MAP-2, NR1 and NR2B subunits, and [(125)I]MK-801 binding than the CA3 region or DG. Twenty-four hour NMDA (10 microM) exposure produced marked neurodegeneration (approximately 350% of control cultures) in the CA1 pyramidal cell region that was significantly reduced by co-exposure to ifenprodil or DL-2-Amino-5-phosphonopentanoic acid (APV). The addition of spermidine significantly potentiated [(125)I]MK-801 binding and neurodegeneration induced by exposure to a non-toxic concentration of NMDA, exclusively in the CA1 region. This neurodegeneration was markedly reduced with co-exposure to ifenprodil. These data suggest that selective sensitivity of the CA1 region to excitotoxic stimuli may be attributable to the density of mature neurons expressing polyamine-sensitive NR2B polypeptide subunits.

Intra-cornu ammonis 1 administration of the human immunodeficiency virus-1 protein trans-activator of transcription exacerbates the ethanol withdrawal syndrome in rodents and activates N-methyl-D-aspartate glutamate receptors to produce persisting spatial learning deficits.

Human immunodeficiency virus-1 (HIV-1) infection may produce neurological deficits, such as cognitive decline, that may be worsened by concurrent ethanol (EtOH) abuse. Among the many biochemical cascades likely mediating HIV-1-associated neuronal injury is enhancement of N-methyl-d-aspartate (NMDA) receptor function and progression to excitotoxicity, an effect that may be directly or indirectly related to accumulation in brain of the HIV-1 trans-activator of transcription (Tat) factor. The present studies were designed to examine the hypothesis that binge-like EtOH pre-exposure would enhance effects of Tat on NMDA receptor function. These studies employed a modified in vivo binge EtOH exposure regimen designed to produce peak blood EtOH levels (BEL) of <200 mg/dl in adult male rats and were designed to examine effects of intra-hippocampal injection of Tat (0.5 microl/500 pM/2 min) on EtOH withdrawal-related behavior, spatial learning, and histological measures. Unilateral cannulae were implanted into the cornu ammonis 1 (CA1) pyramidal cell layer of animals prior to beginning a 4-day binge EtOH regimen. EtOH was administered via intragastric intubation ( approximately 3.0-5.0 g/kg) with dose determined by behavioral ratings of intoxication daily for 4 days (at 08:00, 16:00, and 24:00 h). EtOH withdrawal behaviors were monitored 12 h after the last administration of EtOH. Morris water maze learning was assessed during the following 4 days, at which times brains were harvested for autoradiographic measurement of NMDA receptor density and neuroinflammation. Maximal BELs of 187.69 mg/dl were observed 60 min after EtOH administration on day 2 of the regimen. In contrast, peak BELs of approximately 100 mg/dl were observed 60 min after EtOH administration on day 4 of the regimen, suggesting development of metabolic tolerance. Significant behavioral abnormalities were observed in EtOH withdrawn animals, including tremor and seizures. Intra-CA1 region injection of Tat significantly potentiated EtOH withdrawal behavioral abnormalities, an effect that was reduced by MK-801 pre-exposure. While EtOH withdrawn animals showed learning similar to control animals, EtOH withdrawn animals that received intra-CA1 Tat injection demonstrated persisting deficits in spatial learning on days 3 and 4 of training, effects that were markedly reduced by administration of the competitive NMDA receptor antagonist MK-801 30 min prior to Tat injection. No changes in [(3)H]MK-801 binding were observed. Binding density of [(3)H]PK11195, a ligand for peripheral benzodiazepine receptors expressed on activated microglia, was elevated proximal to cannula tracks in all animals, but was not altered by EtOH or Tat exposure. These findings suggest that EtOH abuse and/or dependence in HIV-positive individuals may promote HIV-1-associated cognitive deficits by altering NMDA receptor function in the absence of microglial activation or neuroinflammation.

Synchronized mechanical ventilation for respiratory support in newborn infants.

BACKGROUND: During synchronized mechanical ventilation, positive airway pressure and spontaneous inspiration coincide. If synchronous ventilation is provoked, adequate gas exchange should be achieved at lower peak airway pressures, potentially reducing baro/volutrauma, air leak and bronchopulmonary dysplasia. Synchronous ventilation can potentially be achieved by manipulation of rate and inspiratory time during conventional ventilation and employment of patient triggered ventilation. OBJECTIVES: To compare the efficacy of: (i) synchronized mechanical ventilation, delivered as high frequency positive pressure ventilation (HFPPV) or patient triggered ventilation - assist control ventilation (ACV) or synchronous intermittent mandatory ventilation (SIMV)) with conventional ventilation (CMV) (ii) different types of triggered ventilation (ACV, SIMV, pressure regulated volume control ventilation (PRVCV) and SIMV plus pressure support (PS) SEARCH STRATEGY: Searches from 1985-2007 of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007),Oxford Database of Perinatal Trials, MEDLINE, previous reviews, abstracts and symposia proceedings; hand searches of journals in the English language and contact with expert informants. SELECTION CRITERIA: Randomised or quasi-randomised clinical trials comparing synchronized ventilation delivered as high frequency positive pressure ventilation (HFPPV) or triggered ventilation (ACV/SIMV) to conventional mechanical ventilation (CMV) in neonates. Randomised trials comparing different triggered ventilation modes (ACV, SIMV, SIMV plus PS and PRVCV) in neonates. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including mortality, air leaks (pneumothorax or pulmonary interstitial emphysema (PIE)), severe intraventricular haemorrhage (grades 3 and 4), bronchopulmonary dysplasia (BPD) (oxygen dependency beyond 28 days), moderate/severe BPD (oxygen/respiratory support dependency beyond 36 weeks postmenstrual age (PMA) and duration of weaning/ventilation. Four comparisons were made: (i) HFPPV vs. CMV; (ii) ACV/SIMV vs. CMV; (iii) ACV vs. SIMV or PRVCV vs. SIMV (iv) SIMV plus PS vs. SIMV. Data analysis was conducted using relative risk for categorical outcomes, weighted mean difference for outcomes measured on a continuous scale. MAIN RESULTS: Fourteen studies were eligible for inclusion. The meta-analysis demonstrates that HFPPV compared to CMV was associated with a reduction in the risk of air leak (typical relative risk for pneumothorax was 0.69, 95% CI 0.51, 0.93). ACV/SIMV compared to CMV was associated with a shorter duration of ventilation (weighted mean difference -34.8 hours, 95% CI -62.1, -7.4). ACV compared to SIMV was associated with a trend to a shorter duration of weaning (weighted mean difference -42.4 hours, 95% CI -94.4, 9.6). Neither HFPPV nor triggered ventilation was associated with a significant reduction in the incidence of BPD. There was a non-significant trend towards a lower mortality rate using HFPPV vs. CMV and a non-significant trend towards a higher mortality rate using triggered ventilation vs. CMV. No disadvantage of HFPPV or triggered ventilation was noted regarding other outcomes. Since the last review, two new patient triggered modes have been included: pressure regulated volume control ventilation (PRVCV) and SIMV plus pressure support. Each of these methods of ventilation has only been tested in single randomised trials with no significant advantages in important outcomes. AUTHORS' CONCLUSIONS: Compared to conventional ventilation, benefit is demonstrated for both HFPPV and triggered ventilation with regard to a reduction in air leak and a shorter duration of ventilation, respectively. In none of the trials was complex respiratory monitoring undertaken and thus it is not possible to conclude that the mechanism of producing those benefits is by provocation of synchronized ventilation. Further trials are needed to determine whether synchronized ventilation is associated with other benefits, but optimisation of trigger and ventilator design with respect to respiratory diagnosis is encouraged before embarking on further trials. It is essential newer forms of triggered ventilation are tested in adequately powered randomised trials with long-term outcomes before they are incorporated into routine clinical practice.

Difficult extubation in low birthweight infants.

Randomised trials have demonstrated that ventilation techniques which support every spontaneous breath are the most efficacious weaning modes. Nasal continuous positive airway pressure after extubation reduces the likelihood of incidents leading to the need for reintubation in very low birthweight infants; further work is needed to determine if there are advantages of particular delivery techniques. Both methylxanthines and dexamethasone facilitate weaning and extubation; the efficacy of low-dose dexamethasone merits further investigation. Assessments of the efficacy of respiratory efforts and hence the balance of respiratory drive, muscle performance and respiratory load appear to best predict weaning and extubation success. Essential to the success of weaning and extubation are dedicated staff, whether this will be assisted by computerised decision-making tools requires testing. The above approaches are not mutually exclusive and those indicated by this review as appropriately evidence based should be considered by practitioners for current use to reduce difficult/unsuccessful extubation.

Asthma knowledge amongst paediatric trainees and parents.

To achieve asthma control adequate knowledge of the disease is required. Knowledge levels of thirty five specialist registrars and one hundred and sixty parents of children attending an asthmatic clinic, prior to entry into a formalised asthma educational program, were assessed utilising a twenty stem questionnaire with eighty five statements. Three out of thirty five specialist registrars had adequate knowledge levels whilst the other thirty two had potentially adequate knowledge levels. Sixty two out of one hundred and sixty parents had potentially adequate knowledge levels and the other ninety eight had inadequate knowledge levels. Parental knowledge can be improved by formal educational programs. Deficiencies in doctors' knowledge should be addressed through a similar program rather than rely on experiential learning.

Microtubule-associated targets in chlorpyrifos oxon hippocampal neurotoxicity.

Prolonged exposure to organophosphate (OP) pesticides may produce cognitive deficits reflective of hippocampal injury in both humans and rodents. Recent work has indicated that microtubule trafficking is also adversely affected by exposure to the OP pesticide chlorpyrifos, suggesting a novel mode of OP-induced neurotoxicity. The present studies examined effects of prolonged exposure to chlorpyrifos oxon (CPO) on acetylcholinesterase (AChE) activity, immunoreactivity (IR) of microtubule-associated proteins, neuronal injury, and tubulin polymerization using in vitro organotypic slice cultures of rat hippocampus and bovine tubulin. Cultures were exposed to CPO (0.1-10 microM) in cell culture medium for 1-7 days, a regimen producing progressive reductions in AChE activity of 15-60%. Cytotoxicity (somatic uptake of the non-vital marker propidium iodide), as well as IR of alpha-tubulin and microtubule-associated protein-2 (a/b) [MAP-2], was assessed 1, 3, and 7 days after the start of CPO exposure. As early as 24 h after the start of exposure, CPO-induced deficits in MAP-2 IR were evident and progressive in each region of slice cultures at concentrations as low as 0.1 microM. CPO exposure did not alter alpha-tubulin IR at any time point. Concentration-dependent injury in the cornu ammonis (CA)1 pyramidal cell layer and to a lesser extent, CA3 and dentate cells, was evident 3 days after the start of CPO exposure (>or=0.1 microM) and was greatest after 7 days. Tubulin polymerization assays indicated that CPO (>or=0.1 microM) markedly inhibited the polymerization of purified tubulin and MAP-rich tubulin, though effects on MAP-rich tubulin were more pronounced. These data suggest that exposure to CPO produces a progressive decrease in neuronal viability that may be associated with impaired microtubule synthesis and/or function.

Thiamine deficiency in the pathogenesis of chronic ethanol-associated cerebellar damage in vitro.

Nutritional deficiencies associated with long-term ethanol consumption may cause neuronal damage in ethanol-dependent individuals. Thiamine deficiency, in particular, is thought to contribute to ethanol-associated cerebellar degeneration, although damage may occur in adequately nourished alcoholics. Thus, the present study examined the effects of thiamine depletion and ethanol exposure on cytotoxicity in rat cerebellum. Organotypic cerebellar slice cultures were treated starting at 25 days in vitro with 100 mM ethanol for 11 days or 10 days followed by a 24-h withdrawal period. This exposure paradigm has previously been shown in hippocampal slice cultures to result in spontaneous cytotoxicity upon ethanol withdrawal. Additional cerebellar cultures were exposed to the thiamine depleting agent pyrithiamine (10-500 microM) for 10 or 11 days, some in the presence of ethanol exposure or withdrawal. Other cultures were co-exposed to thiamine (1-100 microM), 500 microM pyrithiamine, and ethanol for 10 or 11 days. The results demonstrated that neither 11-day ethanol treatment nor withdrawal from 10-day exposure significantly increased cerebellar cytotoxicity, as measured by propidium iodide fluorescence. The 11-day treatment with 100 or 500 microM pyrithiamine significantly increased propidium iodide fluorescence approximately 21% above levels observed in control tissue. Cultures treated with both ethanol (11 days or 10 days plus withdrawal) and 500 microM pyrithiamine displayed a marked increase in cytotoxicity approximately 60-90% above levels observed in control cultures. Pyrithiamine and ethanol-induced cytotoxicity was prevented in cultures co-exposed to thiamine (10-100 microM) for the duration of pyrithiamine treatment. Findings from this report suggest that the cerebellum may be more sensitive to the toxic effects of thiamine deficiency, as compared with alcohol withdrawal, associated with alcohol dependence.

Corticosterone and dexamethasone potentiate cytotoxicity associated with oxygen-glucose deprivation in organotypic cerebellar slice cultures.

Many patients display elevated levels of serum cortisol following acute ischemic stroke. Given that glucocorticoids may potentiate some forms of insult, these studies examined the effects of corticosterone or dexamethasone exposure on cytotoxicity following oxygen-glucose deprivation in the cerebellum, a brain region susceptible to stroke. In organotypic cerebellar slice cultures prepared from neonatal rat pups, 90-min of oxygen-glucose deprivation at 15 days in vitro resulted in significant cytotoxicity at 24-, 48-, and 72-h post-oxygen-glucose deprivation, as measured by uptake of propidium iodide. Exposure of cultures following oxygen-glucose deprivation to the antioxidant trolox (500 microM), but not to the glucocorticoid receptor antagonist RU486 (10 microM), completely blocked oxygen-glucose deprivation-induced cytotoxicity. Corticosterone (1 microM) or dexamethasone (10 microM) exposure alone did not significantly increase propidium iodide uptake above levels observed in control cultures. However, corticosterone or dexamethasone exposure after oxygen-glucose deprivation potentiated oxygen-glucose deprivation-mediated propidium iodide uptake at each time point. Trolox, as well as RU486, co-exposure of cultures to corticosterone or dexamethasone after oxygen-glucose deprivation abolished all cytotoxicity. In conclusion, these data demonstrated that glucocorticoid exposure modulated oxygen-glucose deprivation-mediated propidium iodide uptake, which likely involved glucocorticoid receptor activation and pro-oxidant effects.

Effects of surgery on the acute phase response in clinically normal and diseased horses.

The serum concentrations of serum amyloid A, haptoglobin and fibrinogen were measured in a group of horses before and at intervals after elective and non-elective surgery, and in a control group of normal horses. There was a significant, rapid and repeatable increase in the concentration of serum amyloid A in response to both elective and non-elective surgery. In the control horses its serum concentration was within the normal range, from 0 to 0.2 microg/ml. Twenty-four hours after elective surgery its mean peak concentration was 16.4 microg/ml, and after non-elective surgery it was 27.3 microg/ml. In contrast, the serum concentrations of haptoglobin and fibrinogen increased more slowly after surgery and had not decreased by 72 hours after surgery.

(-)-nicotine ameliorates corticosterone's potentiation of N-methyl-d-aspartate receptor-mediated cornu ammonis 1 toxicity.

Hypercortisolemia, long-term exposure of the brain to high concentrations of stress hormones (i.e. cortisol), may occur in patients suffering from depression, alcoholism, and other disorders. This has been suggested to produce neuropathological effects, in part, via increased function or sensitivity of N-methyl-d-aspartate (NMDA)-type glutamate receptors. Given that cigarette smoking is highly prevalent in some of these patient groups and nicotine has been shown to reduce toxic consequences of NMDA receptor function, it may be suggested that nicotine intake may attenuate the neurotoxic effects of hypercortisolemia. To investigate this possibility, organotypic hippocampal slice cultures derived from rat were pre-treated with corticosterone (0.001-1 microM) alone or in combination with selective glucocorticoid receptor antagonists for 72-h prior to a brief (1-h) NMDA exposure (5 microM). Pre-treatment with corticosterone (0.001-1 microM) alone did not cause hippocampal damage, while NMDA exposure produced significant cellular damage in the cornu ammonis (CA)1 subregion. No significant damage was observed in the dentate gyrus or CA3 regions following NMDA exposure. Pre-treatment of cultures with corticosterone (0.1-1 microM) markedly exacerbated NMDA-induced CA1 and dentate gyrus region damage. This effect in the CA1 region was prevented by co-administration of the glucocorticoid receptor antagonist RU486 (>or=1 microM), but not spironolactone (1-10 microM), a mineralocorticoid receptor antagonist. In a second series of studies, both acute and pre-exposure of cultures to (-)-nicotine (1-10 microM) significantly reduced NMDA toxicity in the CA1 region. Co-administration of cultures to (-)-nicotine (1-10 microM) with 100 nM corticosterone prevented corticosterone's exacerbation of subsequent CA1 insult. This protective effect of (-)-nicotine was not altered by co-exposure of cultures to 10 microM dihydro-beta-erythroidine but was blocked by co-exposure to 100 nM methyllycaconitine, suggesting the involvement of nicotinic acetylcholine receptors possessing the alpha7* subunit. The present studies suggest a role for hypercortisolemia in sensitizing the hippocampal NMDA receptor system to pathological activation and indicate that prolonged nicotine exposure attenuates this sensitization. Thus, it is possible that one consequence of heavy smoking in those suffering from hypercortisolemia may be a reduction of neuronal injury and sparing of cellular function.

Hippocampal CA1 region neurodegeneration produced by ethanol withdrawal requires activation of intrinsic polysynaptic hippocampal pathways and function of N-methyl-D-aspartate receptors.

Long-term intake of ethanol produces adaptive alterations in multiple transmitter systems in the hippocampal formation that likely contribute to ethanol withdrawal-induced seizure and excitotoxicity. The present studies were designed to examine the role of N-methyl-d-aspartate receptor activation and cytosolic Ca(2+) accumulation in the neurotoxic effects of ethanol withdrawal. Further, these studies investigated the role of hippocampal network excitation in promoting both Ca(2+) accumulation and neurotoxicity during ethanol withdrawal. Chronic, continuous (11 day) exposure to ethanol (91 mM starting concentration) did not produce neurotoxicity in any region of organotypic hippocampal explants, as measured by uptake of the non-vital fluorescent marker propidium iodide. Withdrawal from chronic (10 day) ethanol exposure was associated with rapid (30 min) and significant increases in intracellular Ca(2+), assessed by visualization of Calcium-Orange fluorescence, in each region of hippocampal explants. However, neurotoxicity was observed 24 h after initiation of withdrawal and was only seen in the cornu ammonis 1 (CA1) region. Exposure to MK-801 (20 microM) at the start of ethanol withdrawal markedly attenuated Ca(2+) entry in all regions, as well as, CA1 region neurodegeneration. Further, treatment of explants with tetrodotoxin (500 nM) as well as surgical transection of mossy fiber or Schaffer collateral projections immediately prior to ethanol withdrawal blocked both regional increases in Ca(2+) accumulation and CA1 neurotoxicity. These data suggest that neurodegeneration observed during ethanol withdrawal is dependent upon polysynaptic propagation of action potentials ("network excitation") and whole-hippocampal excitation of glutamatergic systems.