Seasonal evolution of Titan's stratosphere during the Cassini mission.

Titan's stratosphere exhibits significant seasonal changes, including break-up and formation of polar vortices. Here we present the first analysis of mid-infrared mapping observations from Cassini's Composite InfraRed Spectrometer (CIRS) to cover the entire mission (Ls=293-93°, 2004-2017) - mid-northern winter to northern summer solstice. The north-polar winter vortex persisted well after equinox, starting break-up around Ls∼60°, and fully dissipating by Ls∼90°. Absence of enriched polar air spreading to lower latitudes suggests large-scale circulation changes and photochemistry control chemical evolution during vortex break-up. South-polar vortex formation commenced soon after equinox and by Ls∼60° was more enriched in trace gases than the northern mid-winter vortex and had temperatures ∼20 K colder. This suggests early-winter and mid-winter vortices are dominated by different processes - radiative cooling and subsidence-induced adiabatic heating respectively. By the end of the mission (Ls=93°) south-polar conditions were approaching those observed in the north at Ls=293°, implying seasonal symmetry in Titan's vortices.

Nucleophosmin is a novel Bax chaperone that regulates apoptotic cell death.

The proapoptotic B-cell lymphoma-2 family protein Bax is a key regulatory point in the intrinsic apoptotic pathway. However, the factors controlling the process of Bax activation and translocation to mitochondria have yet to be fully identified and characterized. We performed affinity chromatography using peptides corresponding to the mitochondrial-targeting region of Bax, which is normally sequestered within the inactive structure. The molecular chaperone nucleophosmin was identified as a novel Bax-binding protein by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Reciprocal co-immunoprecipitation and proximity assays confirmed the Bax-nucleophosmin protein-protein interaction and verified that nucleophosmin only bound to activated conformationally altered Bax. Confocal microscopy in a cell-based apoptosis model, demonstrated that nucleophosmin translocation from nucleolus to cytosol preceded Bax movement. Specific knockdown of nucleophosmin expression using RNAi attenuated apoptosis as measured by mitochondrial cytochrome c release and activation of the caspase cascade. In a mouse model of ischaemic stroke, subcellular fractionation studies verified that nucleophosmin translocation occurred within 3 h, at a time before Bax translocation but after Bax conformational changes have occurred. Thus, we have elucidated a novel molecular mechanism whereby Bax becomes activated and translocates to the mitochondria to orchestrate mitochondrial dysfunction and apoptotic cell death, which opens new avenues for therapeutic intervention.

Association of resident, facility, and geographic characteristics with chronic undernutrition in a nationally represented sample of older residents in U.S. nursing homes.

BACKGROUND: Undernutrition (also known as protein-calorie malnutrition or energy-deficiency) is associated with exacerbation of health conditions, increased frailty, and decline in physical, cognitive, and affective function. This is a critical problem for older adults who reside in nursing homes and have many limitations that contribute to reduced food intake. OBJECTIVE: To determine the relationship of chronic undernutrition [body mass index (BMI) < 18.5 kg/m2] to resident, facility, and geographical characteristics in a national sample of nursing home residents aged 60 y or older in the U.S. DESIGN: A cross-sectional, secondary analysis of a 10% nationally representative random sample of annual assessments of nursing home residents in the U.S. (n = 128,514), using the Minimum Data Set (MDS). Data included measured weight and height, resident characteristics, facility characteristics, and geographic location. RESULTS: More than 12% (n = 15,566) were chronically undernourished (energy-deficient), with more than 27% of those being severely undernourished (BMI < 16). Independent correlates of chronic undernutrition (multivariate analysis) included resident characteristics (ADL, having chewing or swallowing problems, or leaving at least 25% of the meal uneaten), facility characteristics (% Medicare and for-profit status), and geographic characteristics (living in nursing home in urban or large towns). CONCLUSION: This study found a high percentage of chronic undernutrition in this nationally representative sample of U.S. nursing home residents. Furthermore, resident, facility, and geographic characteristics were associated with chronic undernutrition. Strategies need to be developed and documented that ensure nutritional health to residents with a variety of health problems.

Retinal detachment repair and cataract surgery in patients with atopic dermatitis.

PurposeThe aim of this study is to report a case series of ocular complications including retinal detachment (RD) and cataract in atopic dermatitis (AD) and surgical management involving a majority of Caucasian patients.Patients and methodsThis study is an observational case series, originally designed as an audit. It involves detailed discussion of history, clinical features, and surgical management of patients presenting with retinal detachment and cataracts secondary to severe AD. Six consecutive patients with diagnosis of severe AD requiring posterior segment and cataract surgery were included in the study.ResultsEight eyes of six patients had retinal detachment. Most of them involved the temporal retina. The retinal breaks were located anteriorly close to the ora serrata in six eyes and Giant tear retinal (GRT) detachment was found in two eyes. Five eyes had proliferative vitreo-retinopathy (PVR) at presentation. All six patients had bilateral cataracts and cataract surgery was performed in eleven eyes. Bilateral simultaneous surgery was essential in two patients. Three eyes had secondary intra-ocular lens (IOL) implantation with pars plana vitrectomy for subluxed lens implant.ConclusionsAnterior retinal breaks and temporal RD are common in retinal detachment secondary to AD. PVR is often present, which makes surgical management difficult. Cataract formation is quite often and late subluxation of IOL may occur.

Caspase 6 activity initiates caspase 3 activation in cerebellar granule cell apoptosis.

Using a well documented ex vivo system consisting of rodent cerebellar granule cells (CGCs) the activation of caspases 3 and 6 during apoptosis induced by withdrawal of trophic support was analyzed. At the time of deprivation, the addition of the irreversible, broad-spectrum caspase inhibitor zVADfmk or the cell permeable, caspase 6 inhibitor CP-VEID-cho can transiently suppress the appearance of apoptosis, including the early appearance of DNA fragmentation. Using immunoblotting and fluorogenic peptide assays we observe deprivation-induced activation of caspases 3 and 6, but not caspase 9. Furthermore, active caspase 6 is capable of processing and activating procaspase 3 in cellular extracts prepared from non-apoptotic CGCs, whereas caspase 3 failed to activate caspase 6. In consonant with this, the cell permeable caspase 6 inhibitor prevented deprivation-induced caspase 3 activation whereas a cell permeable caspase 3 inhibitor, CP-DEVD-cho, had no effect on caspase 6 activation. This would indicate that caspase 6 is a significant inducer of the early caspase 3 activity in apoptotic CGCs.

Mice overexpressing human caspase 3 appear phenotypically normal but exhibit increased apoptosis and larger lesion volumes in response to transient focal cerebral ischaemia.

Caspase 3 activation has been implicated in cell death following a number of neurodegenerative insults. To determine whether caspase genes can affect the susceptibility of cells to neurodegeneration, a transgenic mouse line was created, expressing human caspase 3 under control of its own promoter. The human gene was regulated by the murine homeostatic machinery and human procaspase 3 was expressed in the same tissues as mouse caspase 3. These novel transgenic mice appeared phenotypically and developmentally normal and survived in excess of 2 years. Behavioural assessment using the 5-choice serial reaction time task found no differences from wild-type littermates. Caspase activity was found to be tightly regulated under physiological conditions, however, significantly larger lesions were obtained when transgenic mice were subjected to focal cerebral ischaemia/reperfusion injury compared to wild-type littermates. These data demonstrate that mice overexpressing human caspase 3 are essentially normal, however, they have increased susceptibility to degenerative insults.

Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury.

Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.

Changes in plasma leptin during the treatment of diabetic ketoacidosis.

To test the hypothesis that insulin regulates leptin, we measured the plasma leptin concentration before and during treatment of diabetic ketoacidosis (DKA), a condition characterized by extreme insulin deficiency. The study included 17 patients with type 1 diabetes (7 males and 10 females), aged 10+/-1 yr (mean +/- SE), with a body mass index of 17.6+/-1.9 kg/m2. Patients were treated with continuous insulin infusion and fluid and electrolyte replacement. Plasma leptin was measured every 6 h in the first 24 h, during which patients received a total insulin dose of 0.6-2.0 U/kg. Plasma leptin concentrations were also measured in a control group of 29 stable type 1 diabetic children (12 males and 17 females) and 25 healthy children (11 males and 14 females), aged 11+/-1 yr, with a body mass index of 18.5+/-1.1 kg/m2. Before treatment, plasma leptin concentrations were significantly lower in patients with DKA than those in diabetic and healthy controls (4.9+/-1.2 vs. 9.0+/-1.8 and 11.2+/-2.1 ng/mL, respectively; P < 0.05). In the DKA patients, plasma leptin increased to 6.4+/-1.5, 7.5+/-1.9, 9.1+/-2.7, and 8.9+/-2.5 at 6, 12, 18, and 24 h, respectively, after starting treatment (P = 0.001). Thus, leptin levels increased by 38+/-10% and 92+/-38% within 6 and 24 h of starting treatment. There was no difference in the change in plasma leptin by 24 h between subjects who could eat (n = 7) and those who could not (n = 10). The plasma leptin increase was paralleled by a rise in insulin level and a decline in glucose and cortisol levels at 6 and 24 h. In conclusion, DKA was associated with decreased plasma leptin concentrations. Treatment resulted in a significant increase in plasma leptin, which may be due to the effect of insulin on leptin production. Our data lend support to the hypothesis that insulin is the link between caloric intake and plasma leptin.

Perivascular microapplication of endothelin-1: a new model of focal cerebral ischaemia in the rat.

In the present study, we describe the effects of perivascular microapplication of the potent vasoconstrictor peptide endothelin-1 (ET-1; (120 pmol in 3 microliters), delivered via a guide cannula stereotaxically positioned above the left cerebral artery (MCA) of the conscious male Sprague-Dawley rat. Ten minutes after the administration of Et-1, mean arterial blood pressure had increased by 20% and profound reductions in local cerebral blood flow (up to 93%) were observed within those brain areas supplied by the MCA. In addition, significant increases in local cerebral blood flow were observed within the globus pallidus (100%), substantia nigra pars reticulata (48%), ventrolateral thalamus (65%), and dorsal hippocampus (74%) ipsilateral to the insult. Twenty-four hours following the insult, the pattern of ischaemic damage was similar to that reported previously following permanent occlusion of the rat MCA. It is suggested that perivascular microapplication of Et-1 may provide a useful model for the study of the functional disturbances associated with focal cerebral ischaemia in the conscious rat.

Enhanced cerebrovascular responsiveness to hypercapnia following depletion of central serotonergic terminals.

Serotonin-containing nerve fibres innervate cerebral blood vessels, but the source of this innervation and the physiological effects of perivascular serotonin release remain controversial. The purpose of the present study was to examine the effects of central serotonergic depletion upon the relationship between CBF and glucose utilization under both normo- and hypercapnic conditions. To induce the loss of serotonergic terminals, rats were injected twice daily for 4 consecutive days with 20 mg/kg of the specific serotonergic neurotoxin methylenedioxyamphetamine (MDA). Between 4 and 6 weeks later, local CBF and glucose utilization were measured using the fully quantitative [14C]iodoantipyrine and [14C]2-deoxyglucose autoradiographic techniques, respectively, and the efficacy of the lesioning protocol was assessed using [3H]paroxetine radioligand binding analysis. In all animals treated with MDA, there was a significant decrease in serotonin uptake sites throughout the brain, falling from 223 +/- 20 to 40 +/- 16 fmol/mg tissue in parietal cortex, for example, although the raphe nuclei themselves were unaffected (300 +/- 20 fmol/mg tissue in controls and 291 +/- 18 in MDA-treated rats). In normocapnic rats, the effects of MDA pretreatment upon blood flow and glucose use were slight and focally concentrated. However, when the animals were rendered hypercapnic, CBF was significantly higher in MDA-treated rats than in normal controls, for example, increasing from 356 +/- 22 ml 100 g-1 min-1 in frontal cortex of hypercapnic controls to 700 +/- 81 ml 100 g-1 min-1 in MDA-pretreated rats with similar levels of hypercapnia. In some brain areas of hypercapnic MDA-pretreated rats, blood flows were too high (> 800 ml 100 g-1 min-1) to be accurately quantified.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoradiographic determination of glucose content and estimation of the lumped constant in intracerebral neuronal tissue transplants.

The quasi-steady-state distribution volume of brain glucose was measured using 3-O-[14C]methylglucose quantitative autoradiography in a group of rats (n = 5) which 12-15 weeks previously had undergone unilateral ibotenic acid-induced lesion of the nucleus basalis magnocellularis, followed by implantation into ipsilateral neocortex of primordial basal forebrain cell suspensions. The effects of the lesion and the presence of transplanted tissue in neocortex were visualized by acetylcholinesterase histochemistry. The 3-O-[14C]methylglucose tracer was distributed homogeneously throughout the host brain areas analysed, with no side-to-side differences, despite a marked unilateral depletion of acetylcholinesterase activity ipsilateral to the lesion site. Whilst the transplants were indistinguishable from the homogeneity of surrounding host frontal cortex, there was a 70% increase in the apparent distribution volume of methylglucose localized around the ibotenate injection site and associated needle tract. Brain glucose content is an important experimental variable affecting the lumped constant of the 2-deoxyglucose technique. There was no evidence of any significant difference in the lumped constant between transplant and host tissue which might compromise the validity of the 2-deoxyglucose technique when used together with intracerebral implantation of fetal neuronal cell suspensions.

Normal cerebrovascular regulatory mechanisms are present in intracerebral neuronal transplants.

Local cerebral blood flow and local cerebral glucose utilization were measured using quantitative autoradiography in parallel groups of rats (n = 5-7) which 12-15 weeks previously had undergone limited unilateral ibotenate-induced lesion of the nucleus basalis magnocellularis, followed by implantation into ipsilateral neocortex of primordial basal forebrain cell suspensions. Surviving transplants were visualized by acetylcholinesterase histochemistry. Neither lesion alone nor the presence of a transplant produced significant side-to-side differences in either blood flow or glucose use in any of the 20 brain areas measured. Glucose use within the transplant was independent of the site of implantation. When sited in neocortex, glucose use in the transplant (66 +/- 4 mumol/100 g per min) was significantly lower than in the corresponding contralateral site (113 +/- 3 mumol/100 g per min), whereas when sited in subcortical white matter, glucose use (53 +/- 3 mumol/100 g per min) was significantly higher than in the contralateral side (29 +/- 4 mumol/100 g per min). In the host brain as a whole, the ratio of blood flow to glucose use ipsilateral to the transplant (m = 1.27, r = 0.88) was not significantly different from that of the contralateral side (m = 1.30, r = 0.94). This relationship was also observed within the transplanted tissue itself despite the fact that alkaline phosphatase histochemistry revealed a relative hypervascularization associated with the implantation site.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in local cerebral blood flow in mature rats following prenatal exposure to cocaine.

Time-mated female Sprague-Dawley rats were injected subcutaneously with either 40 mg/kg cocaine-HCl or saline once daily on gestational days 13 through to 16. Local cerebral blood flow and glucose use were measured in the mature male offspring from these dams using the fully quantitative [14C]2-deoxyglucose and [14C]iodoantipyrine autoradiographic techniques, respectively. The effects of the treatment upon the integrity of central serotonergic terminals was assessed using [3H]paroxetine radioligand binding autoradiography. There were no significant changes in glucose use in any of the 40 brain areas analysed in this study, and although there was a generalized tendency towards increases, these never exceeded +15% of control values. In contrast, significant increases in local cerebral blood flow were measured in more than one-third of the areas examined in cocaine-treated rats, ranging from +20% in dorsal raphe nucleus to +95% in some parts of the neocortex. In all but three brain areas, the ratio of cerebral blood flow to metabolic demand was found to increase following cocaine exposure, resetting the relationship from an overall ratio of 1.6 in controls to 2.5 in treated rats. This relative hyperaemia, which must result from excessive dilatation of the cerebrovascular bed under normal physiological conditions, could not be explained by a direct effect of the treatment on serotonergic constrictor neurons as there was no evidence for any changes in [3H]paroxetine binding. Whatever the underlying cause, we conclude that the effects upon cerebrovascular control mechanisms of prenatal exposure to cocaine identified here, might present a further source of difficulty in the management of "crack babies".

Chronic 3,4-methylenedioxymethamphetamine administration decreases glucocorticoid and mineralocorticoid receptor, but increases 5-hydroxytryptamine1C receptor gene expression in the rat hippocampus.

Both glucocorticoids and serotonin have been implicated in the regulation of mood and neuroendocrine control. In this study we have examined the effects of the psychomotor stimulant, 3,4-methylenedioxymethamphetamine on corticosteroid and 5-hydroxytryptamine receptor subtype gene expression within the hippocampal formation using in situ hybridization histochemistry. Animals were injected subcutaneously with 3,4-methylenedioxymethamphetamine (20 mg/kg) twice daily for four days. Two weeks following this dosage regimen, shown to markedly reduce 5-hydroxytryptamine terminals, both glucocorticoid receptor and mineralocorticoid receptor messenger RNA expression were significantly decreased (30-47% fall) in the granule cells of the dentate gyrus and pyramidal cells of CA1-CA4 fields of Ammon's horn, but not in parietal cortex neurons. In the same rats, 5-hydroxytryptamine1C receptor messenger RNA expression was significantly increased in CA3 pyramidal neurons (133% rise), but neither 5-hydroxytryptamine1A or 5-hydroxytryptamine2 receptor messenger RNA levels were altered in any dorsal hippocampal subfield. 3,4-Methylenedioxymethamphetamine treatment was associated with modest hypersecretion of coricosterone during the diurnal nadir, without other peripheral evidence of chronic glucocorticoid excess (unchanged thymic and adrenal weights and corticosterone-binding globulin levels). These results emphasize the importance of the serotonergic innervation in maintaining hippocampal corticosteroid receptor gene expression. It is suggested that 5-hydroxytryptamine1C receptors may be involved in mediating the effects of serotonin on hippocampal glucocorticoid receptor and mineralocorticoid receptor expression and perhaps mood.

Chronic effects of the selective serotoninergic neurotoxin, methylenedioxyamphetamine, upon cerebral function.

The amphetamine derivative methylenedioxyamphetamine selectively destroys serotoninergic terminals in the brain. We have studied the effects of this toxin upon resting cerebral function, as reflected in rates of glucose utilization. Rats were injected subcutaneously with either 1 ml/kg saline (n = 5) or 20 mg/kg methylenedioxyamphetamine (n = 5) twice daily for four days. Local cerebral glucose utilization was measured between six and nine weeks after treatment using [14C]2-deoxyglucose quantitative autoradiography. Samples of frontal cortex taken from these animals for in vitro [3H]paroxetine binding showed a 64% reduction in 5-hydroxytryptamine uptake sites. In the majority of the 31 functionally diverse brain areas analysed, no significant changes were measured, but significant (P less than 0.05) increases in glucose use were found in neocortical regions e.g. anterior cingulate cortex (+16%) and sensorimotor cortex (+21%). However, the most profound increases were found in globus pallidus (+30%) and hippocampus molecular layer (+34%). It would appear, therefore, that treatment with methylenedioxyamphetamine results in long-lasting alterations in cerebral functional activity.

Advanced glycation end products in vitreous: Structural and functional implications for diabetic vitreopathy.

PURPOSE: Advanced glycation end products (AGEs) form irreversible cross-links with many macromolecules and have been shown to accumulate in tissues at an accelerated rate in diabetes. In the present study, AGE formation in vitreous was examined in patients of various ages and in patients with diabetes. Ex vivo investigations were performed on bovine vitreous incubated in glucose to determine AGE formation and cross-linking of vitreous collagen. METHODS: By means of an AGE-specific enzyme-linked immunosorbent assay (ELISA), AGE formation was investigated in vitreous samples obtained after pars plana vitrectomy in patients with and without diabetes. In addition, vitreous AGEs were investigated in bovine vitreous collagen after incubation in high glucose, high glucose with aminoguanidine, or normal saline for as long as 8 weeks. AGEs and AGE cross-linking was subsequently determined by quantitative and qualitative assays. RESULTS: There was a significant correlation between AGEs and increasing age in patients without diabetes (r = 0.74). Furthermore, a comparison between age-matched diabetic and nondiabetic vitreous showed a significantly higher level of AGEs in the patients with diabetes (P < 0.005). Collagen purified from bovine vitreous incubated in 0.5 M glucose showed an increase in AGE formation when observed in dot blot analysis, immunogold labeling, and AGE ELISA. Furthermore, there was increased cross-linking of collagen in the glucose-incubated vitreous, when observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and protein separation. This cross-linking was effectively inhibited by coincubation with 10 mM aminoguanidine. CONCLUSIONS: This study suggests that AGEs may form in vitreous with increasing age. This process seems to be accelerated in the presence of diabetes and as a consequence of exposure to high glucose. Advanced glycation and AGE cross-linking of the vitreous collagen network may help to explain the vitreous abnormalities characteristic of diabetes.

Vasomotor responses of cerebral arterioles in situ to putative dopamine receptor agonists.

The vasomotor responses of individual cerebral pial arterioles on the convexity of the cerebral cortex to subarachnoid perivascular micro-injections of dopamine and the putative dopamine receptor agonists, apomorphine, SKF 38393 and LY 141865, have been examined in 38 anaesthetized cats. The perivascular microapplication of dopamine (10(-9)-10(-3)M) effected dose-dependent reductions in pial arteriolar calibre, with the maximum reductions in calibre (22 +/- 2% from preinjection levels: mean +/- s.e.) being observed at 10(-3)M. The cerebrovascular constriction produced by dopamine (10(-5)M) could be significantly attenuated by the concomitant perivascular administration of phentolamine (10(-6)M) or methysergide (10(-6)M). The perivascular microapplication of apomorphine (10(-8)-10(-4)M) effected dose-dependent increases in arteriolar calibre, with the maximum increase (31 +/- 6%) being observed with apomorphine (10(-5)M). The perivascular administration of the putative dopamine D1-receptor agonist, SKF 38393 (10(-9)-10(-4)M) increased arteriolar calibre, with the maximum response (24 +/- 3%) being observed with injection of 10(-7)M. The putative dopamine D2-receptor agonist, LY 141865, also increased cerebral arteriolar calibre, but only at high concentrations (maximum calibre increase 25 +/- 6.1 with 10(-4)M). The cerebrovascular dilatations elicited by apomorphine and by SKF 38393 were markedly attenuated by the concomitant perivascular microapplication of the putative dopamine D1-receptor antagonist, SCH 23390 (10(-8)M). The perivascular administration of SCH 23390 (10(-9)-10(-5)M) per se did not alter arteriolar calibre nor the arteriolar dilatation provoked by microinjections of acidic cerebrospinal fluid. These results point to the presence on cat cerebral arterioles of dopamine receptors (probably of D1 subtype) mediating dilation.

Assessment of sensorimotor neglect after occlusion of the middle cerebral artery in the rat.

Evaluating the efficacy of neuroprotective drugs in rat models of focal cerebral ischemia has involved histological and behavioral batteries to examine treatment outcome. However, the behavioral tests used to date provide little insight into the nature of the neurological impairments. To provide an analysis of a possible "neglect" syndrome after occlusion of the middle cerebral artery, M. I. Posner's (1980) visual attentional paradigm was adapted for use in the rat. A paw-reaching task and a test of somatosensory "neglect" also were used to assess forelimb sensorimotor function. The lesion group displayed unilateral deficits; however, there was no evidence of attentional dysfunction. Results are consistent with the conclusion that the behavioral deficits identified arise from a somatosensory deficit rather than hemineglect due to dysfunctional spatial attention.

Alterations in hippocampal function following repeated exposure to the amphetamine derivative methylenedioxymethamphetamine ("Ecstasy").

The effect of the psychomotor stimulant, 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), upon integrated cerebral function was measured in rats using the quantitative [14C]deoxyglucose autoradiographic technique. Animals were injected with MDMA (20 mg/kg sc) twice daily for 4 days. Fourteen days after the final administration, [3H]-paroxetine binding to 5HT uptake sites was reduced by 89% in membranes prepared from tissue samples of frontal cortex. In the same rats [3H]-paroxetine binding autoradiography revealed heterogeneity in the regional distribution of 5-HT uptake site depletion within neocortex (0-92%) and hippocampus (30-95%). Despite these profound reductions in 5-HT uptake sites no significant alterations were found in glucose utilisation in any area of neocortex examined. However, significant increases in glucose use were found in subregions of the hippocampus, most notably within the pyramidal cell layer of CA2 and CA3 (25-35%). This study provides direct evidence that the loss of 5-HT innervation caused by exposure to MDMA results in lasting functional changes in hippocampus.

Glycyrrhetinic acid, an inhibitor of 11 beta-hydroxysteroid dehydrogenase, alters local cerebral glucose utilization in vivo.

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) metabolizes corticosterone (B) to inactive 11-dehydrocorticosterone and thus protects the non-specific renal mineralocorticoid receptor from exposure to B in vivo. There is regional 11 beta-OHSD mRNA expression and bioactivity in brain in vitro, but any in vivo function is unknown. We used the [14C]2-deoxyglucose technique in conscious rats to investigate whether 11 beta-OHSD inhibition with glycyrrhetinic acid alters local cerebral metabolic activity. We found increased glucose use in subregions of the hypothalamus, hippocampus, neocortex and subthalamus. Thus, 11 beta-OHSD may play a role in regulating the effects of B in the brain, in vivo.