Search

Aim: Orexins/hypocretins (OX/Hcrt) are hypothalamic neuropeptides linking sleep-wakefulness, appetite and neuroendocrine control. Their role and mechanisms of action on higher brain functions, such as learning and memory, are not clear. Methods: We used field recordings of excitatory post-synaptic potentials (fEPSP) in acute mouse brain slice preparations to study the effects of orexins and pharmacological inhibitors of multiple kinases on long-term synaptic plasticity in the hippocampus. Results: Orexin-A (OX-A) but not orexin-B (OX-B) induces a state-dependent long-term potentiation of synaptic transmission (LTP OX ) at Schaffer collateral-CA1 synapses in hippocampal slices from adult (8- to 12-week-old) mice. In contrast, OX-A applied to slices from juvenile (3- to 4-week-old) animals causes a long-term depression (LTD OX ) in the same pathway. LTP OX is blocked by pharmacological inhibition of orexin receptor-1 (OX1R) and plasticity-related kinases, including serine/threonine- (CaMKII, PKC, PKA, MAPK), lipid- (PI3K), and receptor tyrosine kinases (Trk). Inhibition of OX1R, CaMKII, PKC, PKA and Trk unmasks LTD OX in adult animals. Conclusion: Orexins control not only the bistability of arousal states and threshold for appetitive behaviours but, in an age- and kinase-dependent manner, also bidirectional long-term synaptic plasticity in the hippocampus, providing a possible link between behavioural state and memory functions.

Cranial radiation therapy is commonly used in the treatment of childhood cancers. It is associated with cognitive impairments tentatively linked to the hippocampus, a neurogenic region of the brain important in memory function and learning. Hippocampal neurogenesis is positively regulated by voluntary exercise, which is also known to improve hippocampal-dependent cognitive functions. In this work, we irradiated the brains of C57/BL6 mice on postnatal day 9 and evaluated both the acute effects of irradiation and the effects of voluntary running on hippocampal neurogenesis and behavior 3 months after irradiation. Voluntary running significantly restored precursor cell and neurogenesis levels after a clinically relevant, moderate dose of irradiation. We also found that irradiation perturbed the structural integration of immature neurons in the hippocampus and that this was reversed by voluntary exercise. Furthermore, irradiation-induced behavior alterations observed in the open-field test were ameliorated. Together, these results clearly demonstrate the usefulness of physical exercise for functional and structural recovery from radiation-induced injury to the juvenile brain, and they suggest that exercise should be evaluated in rehabilitation therapy of childhood cancer survivors.

Background and aims: The importance of efficient and safe treatment of Crohns disease is highlighted by its chronicity. Both medical and surgical treatments have shown good results in the symptomatic control of limited ileocaecal Crohns disease. The aim of this study was to compare medical treatment with surgical treatment of ileocaecal Crohns disease. Methods: Thirty-six patients from seven hospitals with primary ileocaecal Crohns disease were randomized to either medical or surgical treatment. The medical treatment was induction of remission with budesonide and thereafter maintenance treatment with azathioprine. The surgical treatment was open ileocaecal resection. Crohns disease activity index over time, expressed as area under the curve at 1, 3 and 5 years, was the primary endpoint. Subjective health measured with the 36-item Short Form Survey Instrument (SF36) and a visual analogue scale (VAS) were secondary endpoints. Results: There were no differences between the treatment groups in Crohns disease activity index over time. General health, measured as SF36 score, was higher in patients receiving surgical treatment than in those receiving medical treatment at 1 year, but there was no corresponding difference in VAS. Due to the slow inclusion rate and changes in clinical practice, the study was t = erminated prematurely. Conclusion: The study ended up being underpowered and should be interpreted with caution, but there was no clinically significant difference between the two treatment arms. Further studies are needed to address this important clinical question.

The effects of hypoxia-ischemia (HI) on proliferation and differentiation in the immature (postnatal day 9) and juvenile (postnatal day 21) mouse hippocampus were investigated by injecting bromodeoxyuridine (50 mg/kg) daily for 7 days after the insult and evaluating the labeling 5 weeks after HI. Phenotypic differentiation was evaluated using NeuN, Iba1, APC, and S100β as markers of neurons, microglia, oligodendrocytes, and astrocytes, respectively. The basal proliferation, in particular neurogenesis, was higher in the immature than in the juvenile hippocampus. Hypoxia-ischemia did not increase neurogenesis significantly in the immature dentate gyrus (DG), but it increased several-fold in the juvenile brain, reaching the same level as in the normal, noninjured immature brain. This suggests that the immature hippocampus is already working at the top of its proliferative capacity and that even though basal neurogenesis decreased with age, the injury-induced generation of new neurons in the juvenile hippocampus could not increase beyond the basal level of the immature brain. Generation of glial cells of all three types after HI was significantly more pronounced in the cornu ammonis of the hippocampus region of the juvenile hippocampus. In the DG, only microglia production was greater in the juvenile brain. Increased microglia proliferation correlated with increased levels of the proinflammatory cytokines MCP-1 and IL-18 3 days after HI, indicating that the inflammatory response is stronger in the juvenile hippocampus. In summary, contrary to what has been generally assumed, our results indicate that the juvenile brain has a greater capacity for neurogenesis after injury than the immature brain.

Kupari M, Eriksson S, Turto H, Lommi J, Pettersson K (Helsinki University Central Hospital, Helsinki; and University of Turku, Turku; Finland). Leakage of cardiac troponin I in aortic valve stenosis. J Intern Med 2005; 258; 231-237. Objective. Degeneration and death of cardiomyocytes contribute to the genesis of heart failure (HF) in aortic valve stenosis (AS). We studied whether the ongoing myocyte damage in AS can be detected from circulating cardiac troponin I (cTnI) concentrations. Design and setting. A cross-sectional cohort study in a university hospital. Subjects and methods. We examined 131 adult patients undergoing echocardiography and cardiac catheterization for isolated AS. Blood was sampled from the aortic root and, in a subset of 49 patients, also from the coronary sinus for the determination of cTnI using a sensitive immunoanalysis. Results. Seventy-three patients (56%) had detectable aortic cTnI (≥5 ng L -1 ) with 30 of them (23% of the total group) having cTnI above the reference limit in healthy subjects (>14 ng L -1 ). Patients with detectable cTnI had a higher prevalence of HF than those with undetectable cTnI (42% vs. 19%, P = 0.004). Plasma cTnI rose from the aorta to the coronary sinus by ≥5 ng L -1 in 13 of 49 patients with AS (27%) versus in none of 12 control patients free of structural heart disease (P= 0.044). AS patients with transcardiac cTnI gradients >5 ng L -1 had lower left ventricular (LV) ejection fractions than AS patients with gradients

The hippocampal dentate gyrus (DG) is an area of active proliferation and neurogenesis within the adult brain. The molecular events controlling adult cell genesis in the hippocampus essentially remain unknown. It has been reported previously that adult male and female rats from the strains Sprague Dawley (SD) and spontaneously hypertensive (SHR) have a marked difference in proliferation rates of cells in the hippocampal DG. To exploit this natural variability and identify potential regulators of cell genesis in the hippocampus, hippocampal gene expression from male SHR as well as male and female SD rats was analyzed using a cDNA array strategy. Hippocampal expression of the gene-encoding glucose-dependent insulinotropic polypeptide (GIP) varied strongly in parallel with cell-proliferation rates in the adult rat DG. Moreover, robust GIP immunoreactivity could be detected in the DG. The GIP receptor is expressed by cultured adult hippocampal progenitors and throughout the granule cell layer of the DG, including progenitor cells. Thus, these cells have the ability to respond to GIP. Indeed, exogenously delivered GIP induced proliferation of adult-derived hippocampal progenitorsin vivoas well asin vitro, and adult GIP receptor knock-out mice exhibit a significantly lower number of newborn cells in the hippocampal DG compared with wild-type mice. This investigation demonstrates the presence of GIP in the brain for the first time and provides evidence for a regulatory function for GIP in progenitor cell proliferation.

Objective: To study long and short term survival in patients aged 60 years or over admitted with a peptic ulcer bleeding and find out which factors influence outcome.Design: Cohort study with matched controls.Setting: Two emergency hospitals, SwedenPatients: 676 of the 687 patients aged 60 years or over admitted to the two emergency hospitals serving Gothenburg, Sweden during 1989&1993 who fulfilled the diagnostic criteria and whose case notes were available for study.Main outcome measures: Seven year survival rates and odds ratios for risk factors based on multiple logistic regression analyses.Results: 37 patients died and the timing was evenly distributed within the first 30 days of admission with a cumulated case-fatality rate of 5.5% at day 30. Mortality was increased among the patients compared with the control group during the subsequent years. Factors that influenced day 30 mortality were age and Forrest class.Conclusion: Mortality is increased among patients with peptic ulcer bleeding even long af...

Taurine, a major osmolyte in the brain evokes a long-lasting enhancement (LLETAU) of synaptic transmission in hippocampal and cortico-striatal slices. Hippocampal LLETAU was abolished by the GABA uptake blocker nipecotic acid (NPA) but not by the taurine-uptake inhibitor guanidinoethyl sulphonate (GES). Striatal LLETAU was sensitive to GES but not to NPA. Semiquantitative PCR analysis and immunohistochemistry revealed that taurine transporter expression is significantly higher in the striatum than in the hippocampus. Taurine transporter-deficient mice displayed very low taurine levels in both structures and a low ability to develop LLETAU in the striatum, but not in the hippocampus. The different mechanisms of taurine-induced synaptic plasticity may reflect the different vulnerabilities of these brain regions under pathological conditions that are accompanied by osmotic changes such as hepatic encephalopathy.

Dorsal raphe serotonin neurons fire tonically at a low rate during waking. In vitro, however, they are not spontaneously active, indicating that afferent inputs are necessary for tonic firing. Agonists of three arousal-related systems impinging on the dorsal raphe (orexin/hypocretin, histamine and the noradrenaline systems) caused an inward current and increase in current noise in whole-cell patch-clamp recordings from these neurons in brain slices. The inward current induced by all three agonists was significantly reduced in extracellular solution containing reduced sodium (25.6 mm). In extracellular recordings, all three agonists increased the firing rate of serotonin neurons; the excitatory effects of histamine and orexin A were occluded by previous application of phenylephrine, suggesting that all three systems act via common effector mechanisms. The dose–response curve for orexin B suggested an effect mediated by type II (OX(2)) receptors. Single-cell PCR demonstrated the presence of both OX(1) and OX(2)receptors in tryptophan hydroxylase-positive neurons. The effects of histamine and the adrenoceptor agonist, phenylephrine, were blocked by antagonists of histamine H(1) and α(1)receptors, respectively. The inward current induced by orexin A and phenylephrine was not blocked by protein kinase inhibitors or by thapsigargin. Three types of current–voltage responses were induced by all three agonists but in no case did the current reverse at the potassium equilibrium potential. Instead, in many cases the orexin A-induced current reversed in calcium-free medium at a value (−23 mV) consistent with the activation of a mixed cation channel (with relative permeabilities for sodium and potassium of 0.43 and 1, respectively).

Dysfunction of the orexin/hypocretin neurotransmitter system leads to the sleep disorder narcolepsy. Narcolepsy is characterized by excessive daytime sleepiness and the occurrence of cataplexy--a sudden loss of muscle tone triggered by emotionally arousing events. Both symptoms can be treated with drugs that act on dopaminergic systems. Here we have investigated the effect of orexins on the firing of dopaminergic and GABAergic neurons of the substantia nigra (SN) in brain slices. Surprisingly, dopaminergic neurons in pars compacta were unaffected by orexins. In contrast, bath application of orexin A (100 nM) or orexin B (5-300 nM) greatly increased the firing rate of GABAergic neurons in pars reticulata. The orexin B-mediated excitation was unaffected by blocking synaptic transmission (using low-Ca2+/high-Mg2+ solution). However, the effect of orexin B was reduced significantly by thapsigargin (1 microM) and inhibitors of protein kinase A. The presence of orexinergic fibres in the SN pars reticulata was demonstrated by immunohistochemical methods with the fibre density increasing in the rostrocaudal direction. The orexin excitation of SN reticulata cells may help to maintain their high firing rate during waking. Furthermore, the absence of orexin effects in narcolepsy may predispose affected individuals to attacks of cataplexy.

In a previous study it was shown that a nonsense mutation in the DMRT3 gene alters the pattern of locomotion in horses and that this mutation has a strong positive impact on trotting performance of Standardbreds. One aim of this study was to test if racing performance and trotting technique in the Nordic (Coldblood) trotters are also influenced by the DMRT3 genotype. Another aim was to further investigate the effect of the mutation on performance in Standardbreds, by using a within-family analysis and genotype-phenotype correlations in a larger horse material than in the previous study. We genotyped 427 Nordic trotters and 621 Standardbreds for the DMRT3 nonsense mutation and a SNP in strong linkage disequilibrium with it. In Nordic trotters, we show that horses homozygous for the DMRT3 mutation (A) had significantly higher EBV for trotting performance traits than heterozygous (CA) or homozygous wild-type (CC) horses (P = 0.001). Furthermore, AA homozygotes had a higher proportion of victories and top 3 placings than horses heterozygous or homozygous wild-type, when analyzing performance data for the period 3 to 6 yr of age (P = 0.06 and P = 0.05, respectively). Another finding in the Nordic trotters was that the DMRT3 mutation influenced trotting technique (P = 2.1 × 10(-8)). Standardbred horses homozygous AA had significantly higher EBV for all traits than horses with at least 1 wild-type allele (CA and CC; P = 1.6 × 10(-16)). In a within-family analysis of Standardbreds, we found significant differences in several traits (e.g., earnings, P = 0.002; number of entered races, P = 0.004; and fraction of offspring that entered races, P = 0.002) among paternal half-sibs with genotype AA or CA sired by a CA stallion. For most traits, we found significant differences at young ages. For Nordic trotters, most of the results were significant at 3 yr of age but not for the older ages, and for the Standardbreds most of the results for the ages 3 to 5 were significant. For Nordic trotters, the proportion of victories and placings were the only traits that were significant for other ages than 3 yr.

Patch-clamp whole-cell recordings were made in the hypothalamic tuberomammillary (TM) nucleus from isolated histaminergic neurons, identified by their expression of histidine decarboxylase. We compared strychnine-sensitive glycine-mediated currents with maximal currents activated by gamma-Aminobutyric acid (GABA, 0.5 mM) which were blocked by gabazine. The maximal glycine response (1 mM) in histaminergic cells with larger somata (25 microm) was about half of the maximal GABA response whereas in the cells with a smaller soma size (19.5 microm) the glycine response was absent or very small. We conclude that histaminergic cells are heterogeneous with respect to their sensitivity to glycine and this correlates with their size.

We have studied the effects of nociceptin/orphanin FQ on the histaminergic neurons in the tuberomammillary (TM) nucleus and compared them with the actions of opioid agonists. Intracellular recordings of the membrane potential were made with sharp electrodes from superfused rat hypothalamic slices. Nociceptin strongly inhibited the firing of the TM neurons. In the concentration range 10-300 nM, nociceptin hyperpolarized the neurons in a dose-dependent and reversible manner. Insensitivity to tetrodotoxin indicated a postsynaptic effect which was associated with decreased input resistance. Voltage-current plots suggested the involvement of a potassium conductance which was highly sensitive to Ba(2+) and decreased by Cs(+), in keeping with the activation of an inwardly rectifying potassium channel. Morphine (20-100 microM) depolarized the TM neurons and increased their firing, and this effect was blocked by tetrodotoxin. Dynorphin A(1-13) at 100-300 nM did not affect the TM neurons. Nociceptin and morphine modulate the activity of the TM neurons, and most likely histamine release, in opposite ways. Histamine has an antinociceptive effect in the brain and may be involved in opioid-induced analgesia. Nociceptin might therefore influence pain transmission by inhibiting opioid-induced histamine release from the TM nucleus and also modulate other physiological mechanisms which have been ascribed to the histaminergic system.

In several species, including humans, the dentate granule cell layer (GCL) of the hippocampus exhibits neurogenesis throughout adult life. The ability to regulate adult neurogenesis pharmacologically may be of therapeutic value as a mechanism for replacing lost neurons. Insulin-like growth factor-I (IGF-I) is a growth-promoting peptide hormone that has been shown to have neurotrophic properties. The relationship between IGF-I and adult hippocampal neurogenesis is to date unknown. The aim of this study was to investigate the effect of the peripheral administration of IGF-I on cellular proliferation in the dentate subgranular proliferative zone, which contains neuronal progenitor cells, and on the subsequent migration and differentiation of progenitor cells within the GCL. Using bromodeoxyuridine (BrdU) labeling, we found a significant increase of BrdU-immunoreactive progenitors in the GCL after 6 d of peripheral IGF-I administration. To determine the cell fate in progenitor progeny, we characterized the colocalization of BrdU-immunolabeled cells with cell-specific markers. In animals treated with IGF-I for 20 d, BrdU-positive cells increased significantly. Furthermore, the fraction of newly generated neurons in the GCL increased, as evaluated by the neuronal markers Calbindin D28K, microtubule-associated protein-2, and NeuN. There was no difference in the fraction of newly generated astrocytes. Thus, our results show that peripheral infusion of IGF-I increases progenitor cell proliferation and selectively induces neurogenesis in the progeny of adult neural progenitor cells. This corresponds to a 78 ± 17% (p< 0.001) increase in the number of new neurons in IGF-I-treated animals compared with controls.

BACKGROUND—Bile tolerant helicobacter species such as H hepaticus and H bilis have frequently been reported to cause hepatitis in mice and other rodents. AIMS—To investigate the possible pathogenic role of these and other helicobacter species in chronic liver disease in humans. METHODS—Serum samples from 144 patients with various chronic liver diseases, 30 patients with primary sclerosing cholangitis (PSC), and 48 healthy blood donors were analysed for antibodies against H hepaticus murine strain CCUG 33637 and H pylori strain CCUG 17874. Cell surface proteins of H hepaticus were extracted by acid glycine buffer and used in an enzyme immunoassay (EIA) and immunoblot (IB). RESULTS—56 of 144 (39%) patients with chronic liver diseases and six of 30 (20%) with PSC showed increased antibody concentrations in the H hepaticus EIA; in the H pylori EIA the numbers were 58% and 13% respectively. Compared with the healthy blood donors the antibody reactivity against the two helicobacter species was not increased (46% and 48% respectively). Patient serum samples retested by the H hepaticus EIA after absorption with sonicated H pylori cells remained positive in 12 of 37 (33%) serum samples. Distinct antibody reactivity to 55-65 kDa proteins was observed by H hepaticus IB, after the absorption step, and was considered specific for H hepaticus. These 12 serum samples were from patients with chronic alcoholic liver disease. CONCLUSIONS—Antibodies to H hepaticus, often cross reacting with H pylori, occur frequently in patients with chronic liver diseases, with no clear cut relation to specific diagnostic groups. The pathogenic significance of these findings is not known. Keywords: Helicobacter hepaticus; Helicobacter pylori; chronic liver diseases; primary sclerosing cholangitis; enzyme immunoassay; immunoblot

Severe alpha1-antitrypsin (AAT) deficiency predisposes to emphysema development. Highly variable rates of decline in lung function are reported in PiZZ individuals. The annual decline in forced expiratory volume in one second (FEV1; delta FEV1) was analysed in relation to smoking status in a cohort of 608 adult PiZZ individuals included in the Swedish national AAT deficiency register. Delta FEV1 was analysed in 211 never-smokers, in 351 exsmokers, and in 46 current smokers after performing at least two spirometries during a follow-up time of 1 yr or longer (median 5.5 yrs, range 1-31). The adjusted mean delta FEV1 in never-smokers was 47 mL x yr(-1) (95% confidence interval (CI) 41-53 mL x yr(-1)), 41 mL x yr(-1) (95% CI 36-48 mL x yr(-1)) in exsmokers, and 70 mL x yr(-1) (95% CI 58-82 mL x yr(-1)) in current smokers. A dose-response relationship was found between cigarette consumption and delta FEV1 in current smokers and exsmokers. In never-smokers, a greater delta FEV1 was found after 50 yrs of age than before. No sex differences were found in delta FEV1. In conclusion, among PiZZ individuals, the change in forced expiratory volume in one second is essentially the same in never-smokers and exsmokers. Smoking is associated with a dose-dependent increase in the change in forced expiratory volume in one second.

BACKGROUND: Although the eradication ofHelicobacter pyloriis of primary importance when initiating treatment, it is also important to have a strategy for patients who areH pylori-negative, fail to demonstrate eradication or have a tendency to become re-infected or relapse.PATIENTS AND METHODS: In a double-blind, parallel-group clinical trial of 928 patients (from 70 centres in 16 countries) with duodenal ulcers who after a short term study had relief of symptoms and healed ulcers proved endoscopically, 308 were randomly assigned to receive omeprazole 10 mg in the morning, 308 to receive omeprazole 20 mg in the morning and 312 to receive ranitidine 150 mg at bedtime for up to 12 months. Symptoms were assessed every three months and endoscopy repeated at three, six and 12 months, or more often if indicated by recurrence of symptoms. The safety screening included basal serum gastrin concentrations and gastric mucosal histopathology.RESULTS: The remission rates up to 12 months were 87% for the omeprazole 20 mg group, 71% for the omeprazole 10 mg group and 63% for the ranitidine group. Omeprazole 20 mg differed significantly from both omeprazole 10 mg (P=0.0001, 95% CI 9 to 23) and ranitidine (P=0.0001, 95% CI 17 to 31). There was no statistically significant difference between omeprazole 10 mg and ranitidine over the 12-month period, but the 95% confidence interval allowed differences between 0% and 16% in favour of omeprazole at 12 months. A Cox regression analysis revealed that longer treatment courses to heal, smoking, a long ulcer history and young age negatively contributed to the odds of staying in remission. The treatments were well tolerated. There was a slight increase in basal serum gastrin concentrations, reflecting the different degrees of acid inhibition induced by the three treatments. No dysplastic or neoplastic lesions were found in any biopsies.CONCLUSIONS: More duodenal ulcer patients are maintained in remission with omeprazole 20 mg daily than with omeprazole 10 mg daily or with ranitidine 150 mg at bedtime.

Background and Method: In a retrospective study 2,351 records from patients who underwent surgery for acute appendicitis during 1986–1993 were analysed. During this period, there were 362 patients with perforated appendicitis. The aim of this study was to analyse the complication rate, the period of antibiotic treatment and whether the complication rate decreased when intravenous treatment was followed by oral antibiotic treatment. Results: The complication frequency was 18% which was significantly higher than that for non-perforated appendicitis of 10%. The complication rate was 15% in the group receiving additional oral antibiotics compared to 19% in the group receiving only intravenous antibiotics. This difference is not significant. Conclusion: Perforated appendicitis is however still associated with increased mortality and morbidity.

Background: Ursodeoxycholic acid (UDCA) has been shown to improve serum levels of liver enzymes and bilirubin in primary biliary cirrhosis (PBC). However, it is still uncertain whether UDCA treatment also improves symptoms, liver histology, and survival without liver transplantation. Methods: We randomized 116 patients with PBC to receive 0.5 g UDCA (n = 60) or placebo (n = 56) daily for 2 years. During the next 2 years, 80% of the UDCA-treated patients and 65% of the placebo-treated patients continued to take UDCA. Results: UDCA improved serum enzyme values but not survival, symptoms, serum bilirubin levels, or liver histology. There was no significant difference in response between initially symptomatic and asymptomatic patients. Conclusions: UDCA in a dosage of 7.7 mg/kg body weight is of little benefit in PBC. This does not exclude the possibility that larger doses have beneficial effects.

Oxidative stress plays an important role in the development of tissue damage following transient focal cerebral ischaemia. Glutathione is a central component in the antioxidant defence of cells. We have previously shown a close association between mitochondrial glutathione loss and cell death following middle cerebral artery (MCA) occlusion. Glutathione monoethyl ester increases cellular glutathione and is particularly effective in increasing the mitochondrial pool. In the present investigation, we infused glutathione monoethyl ester into the third ventricle during 2 h of MCA occlusion and 48 h of reperfusion. Infarct size was reduced from 46% of the total ischaemic hemisphere in saline-treated animals to 16% following ester treatment. Thus, glutathione monoethyl ester provides neuroprotection following transient focal cerebral ischaemia.

The incidence and prevalence of collagenous colitis are unknown. An epidemiological study was undertaken between 1984-93. All patients living in the immediate catchment area of Orebro Medical Center Hospital with the diagnosis collagenous colitis were identified. Biopsy specimens classified as unspecific intestinal fibrosis were re-examined to identify cases not correctly diagnosed at first. Medical records were scrutinised and colorectal biopsy specimens re-evaluated. Thirty patients with collagenous colitis were diagnosed during the study period. The female:male ratio was 9:1. The median age at diagnosis was 64 (28-78) years. The prevalence at 31 December 1993, was 15.7/10(5) inhabitants (95% CI; 9.8 to 21.6/10(5)). The mean annual incidence during the period 1984-93 was 1.8/10(5) inhabitants (95% CI; 1.2 to 2.4/10(5)). A peak incidence was found in women 70-79 years old. Collagenous colitis occurs mainly in middle aged women, and the frequency is higher than earlier anticipated. The prevalence and incidence is similar to primary biliary cirrhosis. In women 70-79 years of age, the incidence for collagenous colitis approaches the incidence for ulcerative colitis.

In a retrospective study comprising 88 patients operated upon with curative intent a number of histopathological parameters of possible prognostic value regarding local recurrence and long-time survival were analysed. Local recurrence within 5 years was found in 28 patients (32%) of which 17 (61%) were diagnosed within the first 2 years. Crude survival rates at 5 and 10 years were 25% and 15%. According to Lauren's classification the results indicated better, but not significant, 5-and 10-year survival for the diffuse type (36% vs 25%). The probability of 10-year survival suggested a better ( P = 0.06) prognosis for tumours in the middle third of the stomach, and for patients operated with total gastrectomy ( P = 0.025). The probability of recurrence in relation to lymph node involvement suggested a more favourable prognosis ( P = 0.06) for patients without lymph node metastases, and in relation to tumour fibrosis a less favourable prognosis for pronounced fibrosis ( P = 0.001).

The aim of this study was to evaluate the long-term results of resective surgery on children with difficult-to-treat epilepsy in Norway.In the period 1995-2004, 64 surgical procedures (54 resections and 10 functional hemispherotomies) were performed in 54 children. The children's medical records were retrospectively reviewed at a minimum of 2 years after surgery. We sent a questionnaire regarding their epilepsy (seizures, usage of antiepileptic drugs) and general functioning (social situation, motor, language, cognition, behavioural or emotional problems, any remedial action) to the children/parents after a mean follow-up period of 7 years.55.5% of the children were seizure-free. The success rate varied according to the type of surgery. Best results were found after functional hemispherotomies and temporal lobe resections, as nine of 10 (90%) and 10 of 19 (53%) of these patients, respectively, became seizure-free. In addition to a better seizure control, 71% of the children/parents reported of a better cognitive and psychosocial functioning.The results of epilepsy surgery in this paediatric cohort are very edifying, and it is our impression that this treatment option is underused in Norway.

The genetic evaluation of Icelandic horses is currently based on results from breeding field tests of riding ability and conformation. The effect of integrating competition traits and/or test status into the genetic evaluation was studied concerning estimation bias, predictive ability, accuracy, correlations between breeding values and ranking of sires. Breeding field test data included 19 954 records from horses assessed in 11 countries during 1994-2008. Competition data included 44 160 records from 7687 horses competing in Iceland and Sweden in 1998-2008. Test status was defined as attendance of horses born in Iceland at breeding field tests and/or in competition. Overall, there were trivial differences between different genetic evaluation models regarding estimation bias and predictive ability. Very strong correlations were estimated between breeding values for combined indexes of conformation, riding ability and total score from different models. Higher accuracy was achieved for most of the traits when competition traits and/or test status were added to the model. Sires ranked differently when the new traits were added to the genetic evaluation model. It was concluded that competition traits should be integrated into the genetic evaluation. Further analyses on genetic parameters for test status and its relationship with the other traits are needed for future inclusion of test status in the genetic evaluation.

Genetic evaluation of Icelandic horses is currently based on results from breeding field tests where riding ability and conformation of the horses are evaluated over the course of 1-2 days. Only a small part of registered horses attend these field tests, and it can be assumed that these are not a random sample of the population. In this study, the trait test status was introduced, describing whether a horse was assessed in a breeding field test. This trait was analysed to find out whether it has a genetic variation and how it correlates genetically to other traits in the breeding goal. Breeding field test data included 39,443 mares born in Iceland in 1990-2001, of which 7431 were assessed in the period 1994-2007. The trait was defined in relation to age, gender and stud of horses. Variance and covariance components were estimated using the Markov Chain Monte Carlo method by applying the Gibbs sampler procedure in the DMU program. Three multivariate analyses were performed where the test status trait was analysed with breeding field test traits. Animal models and sire models were applied. Based on estimated heritabilities (0.51-0.67) and genetic correlations (0.00-0.87), the test status trait showed significant genetic variation and was strongly correlated to some traits. The test status trait reflects preselection in the breeding field test traits and should be included in the genetic evaluation to enhance the procedure, reduce selection bias and increase accuracy of the estimation.

The influence of insulin on lipolysis and glucose metabolism in abdominal adipose tissue was studied in situ with the microdialysis technique during a euglycaemic insulin clamp (1 mU kg-1 min-1) in nine cirrhotic patients and 10 controls. The cirrhotic patients displayed a 50% decrease in glucose utilization rate during the clamp (P < 0.001). Dialysate glucose levels decreased similarly by 20-30%., in patients and controls, which in the presence of unchanged local blood flow in the adipose tissue in response to insulin, is at hand with a glucose uptake into the adipocytes of similar magnitude in both groups. Before and during the clamp, the arterial and dialysate levels of glycerol were higher in the patients than in the control subjects (ANOVA P = 0.001 and 0.048 in arterial blood and dialysate, respectively). In relative terms, however, insulin induced a 70% reduction of arterial and dialysate glycerol in both groups. The concentrations of lactate and pyruvate in the dialysate and blood increased in a similar way in both groups during hyperinsulinaemia. The results suggest an increased rate of lipolysis in cirrhotic patients. Insulin cannot lower it to normal, although it is still capable of achieving a relative reduction. No explanation was found in the adipose tissue to the insulin resistance to whole-body glucose utilization that was noted in the patients with cirrhosis.

It has been the purpose of this study to examine possible differences in the amount of stimulatory (Gs) and inhibitory (Gi) G-protein α-subunits (measured with a quantitative enzyme-linked immunosorbent assay in fat cell membrane preparation) between subcutaneous and intra-abdominal regions in rats. The lipolytic response to isoproterenol and the number of β-adrenergic binding sites were also examined. These parameters were all evaluated simultaneously in subcutaneous (inguinal), epididymal and perirenal fat samples collected from six male Sprague-Dawley rats. The membrane contents of the Gs and Gi α-subunits were similar in the three depots. Moreover, no difference was found among the different regions with regard to isoproterenol-stimulated glycerol release and β-adrenoceptor number, expressed per cell number. In conclusion, the present study shows for the first time in rats that the abundance of inhibitory and stimulatory G-protein α-subunits is similar in subcutaneous and in visceral adipocytes. Moreover, the number ofβ-adrenoceptors and the lipolytic response to isoproterenol do not show significant variations with the anatomical site. As the present results are apparently in contrast with those obtained previously in human adipocytes, there is a possibility that the different results observed in rat and in human fat cells could be explained by species differences.

As the prevalence of hepatitis C virus (HCV) antibodies has been reported to be high among alcohol-dependent individuals, we screened prospectively 310 consecutive non-selected alcoholic outpatients for HCV and possible routes of transmission. Using a second-generation enzyme-linked immunosorbent assay test and retesting all positive sera with a second-generation recombinant immunoblot assay, we found the prevalence of anti-HCV to be 14.5% (45 of 310). Of the 45 anti-HCV-positive individuals, 39 (88.7%) had a history of intravenous drug abuse, 2 had received blood transfusions, and only 4 lacked an identifiable source of infection. The magnitude of alcohol consumption, number of hospital admissions, duration of alcohol dependence, or presence of tattooing could not be shown to be factors of importance for the transmission of HCV infection. Our results suggest that a history of intravenous drug abuse is a common phenomenon and the predominant route of HCV transmission among alcoholics. True community-acquired infection would appear to be rare.

Energy expenditure was determined using continuous indirect calorimetry in the basal state and during 3 h of total parenteral nutrition (TPN) in 8 patients with cirrhosis and 8 healthy volunteers. TPN consisted of glucose, fat and amino acids and had a glucose/fat ratio of 50:50. The infusion rate was set to provide energy corresponding to 62.5% of the individually measured 24-h resting energy expenditure. In the basal state energy expenditure was similar in patients and controls while the respiratory quotient (RQ) was lower in the patients (0.78 +/- 0.01 vs. 0.82 +/- 0.01, mean +/- SEM, p0.05). During TPN, energy expenditure increased progressively during the 3-h infusion period. The average rise in energy expenditure was similar in patients (19.1 +/- 1.2%) and in controls (21.4 +/- 1.6%, n.s.). The RQ rose in both groups, but more in the patients with cirrhosis. At the end of the study, RQ was higher in patients (0.89 +/- 0.01) than in controls (0.85 +/- 0.01, p0.05). It is concluded that the nutrient-induced rise in energy expenditure during TPN is not significantly different in patients with cirrhosis and control subjects. Furthermore, the results indicate that the increased fat utilization in overnight fasting cirrhotic patients is rapidly shifted to an augmented carbohydrate oxidation during TPN, possibly as a consequence of marked hyperinsulinemia.

Purpose: Acute appendicitis is often difficult to diagnose and a negative laparotomy rate of about 25% is common. At Danderyd Hospital we started routine US in these patients, the aim being to estimate the sensitivity and the specificity for US when compared with the body mass index (BMI) of the patient. Material and Methods: All patient records were examined: During a period of 6 months 142 patients over 14 years of age were investigated with US. Their height and weight were noted and the BMI was calculated. Results: The sensitivity for US examination was 0.76 in patients with a BMI Conclusion: US is a good method for examination of patients with BMI less than 25 but not in patients with BMI over 25.

Background The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression. Methodology/Principal Findings We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and co-expressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decreased hypocretin promotor activity in the presence of excessive IGFBP3. Although we found no IGFBP3 autoantibodies nor a genetic association with IGFBP3 polymorphisms in human narcolepsy, we found that an IGFBP3 polymorphism known to increase serum IGFBP3 levels was associated with lower CSF hypocretin-1 in normal individuals. Conclusions/Significance Comparison of the transcriptome in narcolepsy and narcolepsy model mouse brains revealed a novel dysregulated gene which colocalized in hypocretin cells. Functional analysis indicated that the identified IGFBP3 is a new regulator of hypocretin cell physiology that may be involved not only in the pathophysiology of narcolepsy, but also in the regulation of sleep in normal individuals, most notably during adolescence. Further studies are required to address the hypothesis that excessive IGFBP3 expression may initiate hypocretin cell death and cause narcolepsy.

Glucose uptake by the intestine and its conversion into 3-carbon compounds in the human intestine in the basal state and after an oral glucose load are not understood. Consequently, we studied the arterial and portal venous concentration differences (A-PV) for glucose and glucogenic substrates in the basal state and 3 h after the ingestion of a 100-g glucose load with the catheter technique. Five patients were studied 3-11 days after surgery for gallbladder disease or cancer of the colon or liver. A-PV for glucose in the basal state was 0.12 +/- 0.02 mM (P less than 0.01), indicating net glucose uptake by extrahepatic splanchnic tissues. No net exchange of lactate or pyruvate was detected, but there was release of alanine and uptake of glutamine. After glucose ingestion, glucose was released by the gut, reflecting absorption of the load (mean A-PV for glucose -2.10 +/- 0.04 mM, P less than 0.01). The arterial glucose concentration rose gradually from 4.6 +/- 0.1 mM before glucose ingestion to a plateau at 9.5 +/- 0.7 mM from 90 to 180 min. Glucose ingestion was accompanied by net lactate and alanine release (A-PV -0.16 +/- 0.06 mM and -48 +/- 7 microM, respectively), whereas A-PV for pyruvate did not change. We conclude that, in postoperative patients, there is a significant net glucose uptake by the gastrointestinal tract in the basal state. Glucose ingestion is accompanied by a small release of lactate and alanine from the intestine. However, the estimated net gut formation of lactate and alanine can play only a minor role in the disposal of an oral glucose load.

1. The oral and intravenous kinetics of morphine were investigated in seven cirrhotic patients with a history of encephalopathy. The plasma concentrations of morphine and its metabolites morphine-3 (M3G) and morphine-6 (M6G) were measured by h.p.l.c. 2. The mean terminal elimination half-life of morphine was 4.2 h (95% CI 3.6-4.8) the mean volume of distribution was 4.1 l kg-1 (95% CI 2.9-5.4) and the mean plasma clearance was 11.4 ml min-1 kg-1 (95% CI 8.1-14.7). The mean oral bioavailability was 101% (95% CI 56-147). 3. The plasma clearance of morphine was significantly lower, its terminal elimination half-life longer and its oral bioavailability greater in the cirrhotic patients compared with patients with normal liver function. The metabolic ratio M3G/morphine was significantly lower in the cirrhotic patients than in control subjects after oral dosing, but did not differ after intravenous dosing. 4. The average urinary recoveries of morphine plus M3G and M6G were 49.9% after i.v. and 57.7% after oral administration. There were no statistically significant differences in the urinary recovery between the two routes of administration or between the cirrhotic patients and controls. 5. Specific changes in the EEG pattern could not be detected after intravenous dosage. 6. The metabolism of morphine is impaired significantly in patients with severe cirrhosis. Clinically important findings were a high oral bioavailability and a long elimination half-life. These findings call for cautious dosing of oral and intravenous morphine in patients with severe end stage liver disease.

We demonstrate that X chromosome-linked inhibitor of apoptosis protein (XIAP) counteracts oxidative stress in two essentially different disease-related models of brain injury, hypoxia-ischemia and irradiation, as judged by lower expression of nitrotyrosine (5-fold) and 4-hydroxy-2-nonenal (10-fold) in XIAP-overexpressing compared with wild-type mice. XIAP overexpression induced up-regulation of at least three antioxidants residing in mitochondria, superoxide dismutase 2, thioredoxin 2 and lysine oxoglutarate reductase. Cytochrome c release from mitochondria was reduced in XIAP-overexpressing mice. Hence, in addition to blocking caspases, XIAP can regulate reactive oxygen species in the brain, at least partly through up-regulation of mitochondrial antioxidants. XIAP-induced prevention of oxidative stress was not secondary to tissue protection because although XIAP overexpression provides tissue protection after hypoxia-ischemia, it does not prevent tissue loss after irradiation. This is a previously unknown role of XIAP and may provide the basis for development of novel protective strategies for both acute and chronic neurodegenerative diseases, where oxidative stress is an integral component of the injury mechanisms involved.

We have previously demonstrated that glucose-dependent insulinotropic polypeptide (GIP; gastric inhibitory polypeptide) is present in the adult rat hippocampus. This finding leads to the conclusion that all members of the secretin-glucagon family of gastrointestinal regulatory polypeptides can be found in the brain. To investigate the localization of GIP-producing cells, we used immunohistochemistry on sections of the adult rat brain. High levels of GIP immunoreactivity were observed in the olfactory bulb, hippocampus, and Purkinje cells in the cerebellum. Moreover, a moderate but distinct GIP immunoreactivity was observed in the cerebral cortex, amygdala, substantia nigra, and lateral septal nucleus as well as in several nuclei in the thalamus, hypothalamus, and brainstem. GIP immunoreactivity was frequently found to colocalize with the neuronal marker NeuN but never with the glial marker glial fibrillary acidic protein. Thus, GIP appears to be mainly neuronal to its distribution. This widespread distribution of GIP-immunoreactive cells suggests the involvement of GIP in various neuronal functions and suggests that GIP may act as a neurotransmitter or neuromodulator. This is the first characterization of the anatomical distribution of GIP-immunoreactive cells in the rat brain providing an anatomical framework for future investigations regarding the functions of GIP in the central nervous system.

Nine-day-old harlequin (Hq) mice carrying the hypomorphic apoptosis-inducing factor (AIF)(Hq) mutation expressed 60% less AIF, 18% less respiratory chain complex I and 30% less catalase than their wild-type (Wt) littermates. Compared with Wt, the infarct volume after hypoxia-ischemia (HI) was reduced by 53 and 43% in male (YX(Hq)) and female (X(Hq)X(Hq)) mice, respectively (P

Histaminergic neurons located in the posterior hypothalamus (tuberomamillary nucleus, TMN) project widely through the whole brain controlling arousal and attention. They are tonically active during wakefulness but cease firing during sleep. As a homeostatic theory of sleep involves ATP depletion and adenosine accumulation in the brain, we investigated the role of ATP and its analogues as well as adenosine on neuronal activity in the TMN. We show increased firing of rat TMN neurons by ATP, ADP, UTP and 2meSATP, indicating activation of receptors belonging to the P2Y family. Adenosine affected neither membrane potential nor firing of these cells. Single-cell reverse transcriptase-polymerase chain reaction revealed that P2Y1 and P2Y4 are prevailing receptors in TMN neurons. P2Y1 receptor mRNA was detected with a higher frequency in 2-week-old than in 4-week-old rats; in accordance, 2meSATP was more potent than ATP. Semi-quantitative real-time polymerase chain reaction revealed a developmental downregulation of mRNA levels for P2Y1 and P2Y4 receptors. Immunocytochemistry demonstrated neuronal and glial localization of the P2Y1 receptor protein. Network activity measured with multielectrode arrays in primary cultures made from the posterior hypothalamus was enhanced by UTP and 2meSATP (P2Y4 and P2Y1 agonists, respectively). ATP caused an inhibition of firing, which was reversed in the presence of suramin or gabazine [gamma-aminobutyric acid (GABA)A receptor antagonist], indicating that GABAergic neurons are preferentially activated by ATP in this network. Excitation of the wake-active TMN neurons by nucleotides and the lack of adenosine action may be important factors in sleep-wake regulation.

Environmental enrichment (EE) alleviates sensorimotor deficits after brain infarcts but the cellular correlates are not well-known. This study aimed to test the effects of postischemic EE on neocortical cell genesis. A neocortical infarct was caused by distal ligation of the middle cerebral artery in adult spontaneously hypertensive rats, subsequently housed in standard environment or EE. Bromodeoxyuridine (BrdU) was administered during the first postischemic week to label proliferating cells and BrdU incorporation was quantified 4 weeks later in the periinfarct, ipsilateral medial and contralateral cortex. Immunohistochemistry and confocal microscopy were used to analyze co-localization of BrdU with neuronal (calbindin D28k, calretinin, parvalbumin, glutamic acid decarboxylase, tyrosine hydroxylase), astrocytic (glial fibrillary acidic protein, glutamine synthetase, vimentin, nestin), microglia/macrophage (CD11b/Ox-42, CD68/ED-1), oligodendrocyte progenitor/polydendrocyte (NG2, platelet-derived growth factor alpha receptor) or mature oligodendrocyte (myelin basic protein) markers. BrdU positive cells were increased in all analyzed cortical regions in stroke EE rats compared with stroke standard environment rats. Newly born cells in the periinfarct cortex were mostly reactive astroglia. Occasionally, BrdU positive cells in the periinfarct cortex that were negative for glial or microglia/macrophage markers co-expressed markers typical for interneurons but did not express appropriate functional markers. The majority of BrdU positive cells in intact cortical regions, ipsi- and contralaterally, were identified as NG2 positive polydendrocytes. Perineuronally situated newly born cells and polydendrocytes were found to be brain-derived neurotrophic factor immunoreactive. In conclusion, EE enhanced newborn glial scar astroglia and NG2+ polydendrocytes in the postischemic neocortex which might be beneficial for brain repair and poststroke plasticity.

Background and Purpose— The subventricular zone in the adult brain is identified as an endogenous resource of neuronal precursors that can be recruited to adjacent lesioned areas. The hypothesis was tested that postischemic environmental enrichment might enhance subventricular zone cell genesis. Methods— A cortical infarct was induced in adult spontaneously hypertensive rats by ligating the middle cerebral artery distal to the striatal branches, after which animals were housed in either standard or enriched environment and allowed to survive for 5 weeks. The thymidine analogue bromodeoxyuridine was administered during the first postischemic week. The generation of neural stem/progenitor cells and neuronal precursors in the subventricular zone were studied with cell specific markers such as Ki67 and phosphorylated histone H3 (cell proliferation), Sox-2 (neural stem/progenitor cells), bromodeoxyuridine (slowly cycling, nonmigratory putative neural stem cells), and doublecortin (newborn immature neurons). Results— Proliferating cells in the subventricular zone were identified as chiefly neural progenitors but also putative neural stem cells and neuronal precursors. Five weeks after stroke, proliferation in the subventricular zone was lower in stroke-lesioned rats housed in standard environment compared with nonlesioned rats. Postischemic environmental enrichment normalized cell proliferation levels, increased the numbers of putative neural stem cells as assessed with bromodeoxyuridine, and increased doublecortin-positive neuroblasts, which extended in migratory chains toward the infarct. Conclusions— Enriched environment increased the neural stem/progenitor cell pool and neurogenesis in the adult subventricular zone 5 weeks after a cortical stroke. This might be of potential importance for tissue regeneration.

The objective of this study was to estimate genetic correlations between calving difficulty score and carcass traits in Charolais and Hereford cattle, treating first and later parity calvings as different traits. Genetic correlations between birth weight and carcass traits were also estimated. Field data on 59,182 Charolais and 27,051 Hereford calvings, and carcass traits of 5,260 Charolais and 1,232 Hereford bulls, were used in bivariate linear animal model analyses. Estimated heritabilities were moderate to high (0.22 to 0.50) for direct effects on birth weight, carcass weight, and (S)EUROP (European Community scale for carcass classification) grades for carcass fleshiness and fatness. Heritabilities of 0.07 to 0.18 were estimated for maternal effect on birth weight, and for direct and maternal effects on calving difficulty score at first parity. Lower heritabilities (0.01 to 0.05) were estimated for calving difficulty score at later parities. Carcass weight was positively genetically correlated (0.11 to 0.53) with both direct and maternal effects on birth weight and with direct effects on calving difficulty score. Carcass weight was, however, weakly or negatively (-0.70 to 0.07) correlated with maternal calving difficulty score. Higher carcass fatness grade was genetically associated with lower birth weight, and in most cases, also with less difficult calving. Genetic correlations with carcass fleshiness grade were highly variable. Moderately unfavorable correlations between carcass fleshiness grade and maternal calving difficulty score at first parity were estimated for both Charolais (0.42) and Hereford (0.54). This study found certain antagonistic genetic relationships between calving performance and carcass traits for both Charolais and Hereford cattle. Both direct and maternal calving performance, as well as carcass traits, should be included in the breeding goal and selected for in beef breeds.

Liver cirrhosis, described as the endstage of a necroinflammatory process, is often accompanied by ascites formation. The rationale for this study was the hypothesis that patients with liver cirrhosis have a low-grade chronic inflammatory response, which leads to an increased amount of proinflammatory cytokines accumulated in ascites. Twenty-five patients with liver cirrhosis complicated by ascites and twelve healthy volunteers were prospectively included in the study.Ascites and blood samples from the patients were obtained for analysis of inflammatory cytokines using enzyme-linked immunosorbent assay methodology. Blood samples were taken from the healthy volunteers to obtain reference values.Plasma and ascites concentrations of interleukin-1alpha, interleukin-6, and tumor necrosis factor-alpha were significantly elevated in the patients compared with plasma levels in the group of healthy controls. Significant elevation of interleukin-10 concentrations was found in ascites but not in plasma in the patients. There was no significant difference in interleukin-10 levels between patient and control plasma.The findings suggest that elevated cytokine concentrations in ascites and serum could perpetuate an inflammatory reaction that may be a source of preservation of an ongoing systemic inflammatory reaction. This may contribute to the maintenance, and even progress, of the liver dysfunction, leading to exaggerated ascites development.

High activity of the histaminergic neurons in the tuberomammillary (TM) nucleus increases wakefulness, and their firing rate is highest during waking and lowest during rapid eye movement sleep. The TM neurons receive a prominent innervation from sleep-active gamma-aminobutyric acidergic (GABAergic) neurons in the ventrolateral preoptic nucleus, which inhibits them during sleep. They also receive an excitatory input from the orexin- and dynorphin-containing neurons in the lateral hypothalamus, which are critically involved in sleep regulation and whose dysfunction causes narcolepsy. We have used intracellular recordings and immunohistochemistry to study if orexin neurons exert control over the GABAergic inputs to TM neurons in rat hypothalamic slices. Dynorphin suppressed GABAergic inputs and thus disinhibits the TM neurons, acting in concert with orexin to increase the excitability of these neurons. In contrast, both orexin-A and orexin-B markedly increased the frequency of GABAergic potentials, while co-application of orexin and dynorphin produced responses similar to dynorphin alone. Thus, orexins excite TM neurons directly and by disinhibition, gated by dynorphin. These data might explain some of the neuropathology of narcolepsy.

The histaminergic tuberomamillary (TM) nucleus, a center for the regulation of wakefulness, is excited by glutamatergic, aminergic and peptidergic inputs. AMPA receptor properties in relation to their expression were investigated in acutely isolated TM neurons with the help of whole-cell patch-clamp recordings combined with single-cell RT-PCR. The mRNAs encoding for the AMPA receptor GluR2 (100% of the neurons) and GluR1 (75%) were the most frequently detected, followed by the mRNA for GluR4 (56%), whereas GluR3 cDNA amplification did not yield a PCR product in any neuron. Flip splice variants prevailed over flop, in keeping with a strong glutamate-response potentiation by cyclothiazide. The expression pattern of AMPA subunits in their two splice variants was correlated with the different subtypes of Na+/Ca2+ (NCX) and Na+/Ca2+/K+ (NCKX) exchangers: glutamate receptor subunits GluR1-4 displayed no coordinated pattern with NCX. However, NCKX2 mRNA occurred only in TM cells with a fast desensitizing glutamate response, where it was coexpressed with the GluR4 subunit in the flop splice variant. NCKX3 mRNA was detected in neurons with fast or slow desensitization of glutamate responses. AMPA receptors in TM neurons were Ca2+-impermeable. As reverse Na+/Ca2+ exchange contributes to the immediate rise in intracellular calcium resulting from glutamate receptor activation, we suggest that the coordinated expression of NCKX2 with the fast desensitizing AMPA receptor-type reflects either a receptor-exchanger coupling or separate mechanisms for maintaining calcium homeostasis in neurons with fast or slow glutamate responses.

Nuclei of the brainstem involved in behavioral state control are mutually interconnected. Histaminergic neurons of the posterior hypothalamus receive inputs from brainstem noradrenergic cell groups as well as from the locus coeruleus. The role of adrenergic inputs in histaminergic function is unclear. We examined the actions of adrenergic agonists on histaminergic neurons of the tuberomamillary nucleus (TM) using electrophysiological methods in a brain slice preparation. Evoked GABAergic inhibitory postsynaptic potentials (IPSPs) in histaminergic neurons were reduced in amplitude following the application of norepinephrine (NE) (2-20 microM) or clonidine (10 microM) but were not affected by isoproterenol (10 microM). Norepinephrine application caused no changes in membrane properties of TM neurons. Responses to exogenously applied GABA were unaffected by adrenergic agonists. Clonidine reduced the frequency of spontaneous IPSPs, an action that was blocked by yohimbine. Norepinephrine did not alter the amplitude distribution of bicuculline-sensitive miniature inhibitory postsynaptic currents (mIPSCs). Thus, GABA release onto TM neurons is modulated presynaptically by adrenergic alpha(2)-receptors. Inputs from noradrenergic neurons of the brainstem will reduce the inhibitory actions of GABAergic inputs resulting in disinhibition of histaminergic neurons.

Orexins (OX), also called hypocretins, are bioactive peptides secreted from glucose-sensitive neurons in the lateral hypothalamus linking appetite, arousal and neuroendocrine-autonomic control. Here, OX-A was found to cause a slow-onset long-term potentiation of synaptic transmission (LTPOX) in the hippocampus of young adult mice. LTPOX was induced at Schaffer collateral-CA1 but not mossy fiber-CA3 synapses, and required transient sharp wave-concurrent population field-burst activity generated by the autoassociative CA3 network. Exogenous long θ-frequency stimulation of Schaffer collateral axons erased LTPOX in intact hippocampal slices but not mini slices devoid of the CA3 region. Pharmacological analysis revealed that LTPOX requires co-activation of ionotropic and metabotropic glutamatergic, GABAergic, as well as noradrenergic and cholinergic receptors. Together these data indicate that OX-A induces a state-dependent metaplasticity in the CA1 region associated with sharp-wave and θ rhythm activity as well as glutamatergic, GABAergic, aminergic, and cholinergic transmission. Thus, orexins not only regulate arousal threshold and body weight but also threshold and weight of synaptic connectivity, providing a molecular prerequisite for homeostatic and behavioral state-dependent control of neuronal plasticity and presumably memory functions.

To correlate the preoperative findings, perforation rate and the mortality rate after appendicectomy in the elderly age.Retrospective study.Teaching hospital, Sweden.Forty-seven patients over 80 years of age who have undergone acute appendicectomy.Operative and postoperative outcome after acute appendicectomy in the elderly.The complication rate after appendicectomy was statistically significantly increased to 28% as well as the mortality increased to 8.5% in the elderly patients when compared to the other age group. The perforation rate was also statistically significantly increased to 64% when compared to the same group.Our study shows that at the time of clinical symptoms, inflammatory parameters in acute appendicitis in the elderly do not differ from the young patient, but patients older than 80 years of age have a high risk of perforation, morbidity and mortality.

Orexins/hypocretins are involved in mechanisms of emotional arousal and short-term regulation of feeding. The dense projection of orexin neurons from the lateral hypothalamus to mesocorticolimbic dopaminergic neurons in the ventral tegmental area (VTA) is likely to be important in both of these processes. We used single-unit extracellular and whole-cell patch-clamp recordings to examine the effects of orexins (A and B) and melanin-concentrating hormone (MCH) on neurons in this region. Orexins caused an increase in firing frequency (EC(50) 78 nm), burst firing, or no change in firing in different groups of A10 dopamine neurons. Neurons showing oscillatory firing in response to orexins had smaller afterhyperpolarizations than the other groups of dopamine neurons. Orexins (100 nm) also increased the firing frequency of nondopaminergic neurons in the VTA. In the presence of tetrodotoxin (0.5 microm), orexins depolarized both dopaminergic and nondopaminergic neurons, indicating a direct postsynaptic effect. Unlike the orexins, MCH did not affect the firing of either group of neurons. Single-cell PCR experiments showed that orexin receptors were expressed in both dopaminergic and nondopaminergic neurons and that the calcium binding protein calbindin was only expressed in neurons, which also expressed orexin receptors. In narcolepsy, in which the orexin system is disrupted, dysfunction of the orexin modulation of VTA neurons may be important in triggering attacks of cataplexy.

Histaminergic neurons of the tuberomamillary nucleus display pacemaker properties; their firing rate is regulated according to behavioural state by gabaergic inhibition. Whole-cell recordings and single-cell RT-PCR from acutely isolated rat tuberomamillary neurons were used to characterize GABA -evoked currents and to correlate them with the expression pattern of 12 GABAA receptor subunits. We report differences in sensitivity to GABA and zinc as well as in the modulation of IPSC-decay times by zolpidem in histaminergic neurons expressing gamma-subunits at different levels. Immunocytochemistry and pharmacological analysis of whole-cell GABA-currents in these neurons revealed that all carry the gamma2-subunit protein and that all receptors contain at least one gamma-subunit. Neurons with different expression levels of gamma-subunits displayed a difference in cooperativity of GABA and zolpidem binding which we explain by the presence of one vs. two gamma-subunits in one receptor. Thus, we describe here native GABAA receptor function in relation to its stoichiometry.

The study aimed to elucidate the effects of cortical ischemia and postischemic environmental enrichment on hippocampal cell genesis. A cortical infarct was induced by a permanent ligation of the middle cerebral artery distal to the striatal branches in 6-month-old spontaneously hypertensive rats. Bromodeoxyuridine (BrdU) was administered as 7 consecutive daily injections starting 24 hours after surgery and animals were housed in standard or enriched environment. Four weeks after completed BrdU administration, BrdU incorporation and its co-localization with the neuronal markers NeuN and calbindin D28k, and the astrocytic marker glial fibrillary acidic protein in the granular cell layer and subgranular zone of the hippocampal dentate gyrus were determined with immunohistochemistry and were quantified stereologically. Compared with sham-operated rats, rats with cortical infarcts had a five-to sixfold ipsilateral increase in BrdU-labeled cells. About 80% of the new cells were neurons. Differential postischemic housing did not influence significantly the total number of surviving BrdU-labeled cells or newborn neurons. However, postischemic environmental enrichment increased the ipsilateral generation of astrocytes normalizing the astrocyte-to-neuron ratio, which was significantly reduced in rats housed in standard environment postischemically.

We investigated histamine concentration in post-mortem brain samples of patients with Parkinson's disease (PD, n = 24), multiple system atrophy (MSA, n = 8) and age-matched controls (n = 27). Histamine concentrations were significantly increased in the putamen (to 159% of the control mean), substantia nigra pars compacta (to 201%), internal globus pallidus (to 234%) and external globus pallidus (to 200%), i.e. in areas which play a crucial role in the motor behaviour and which show typical functional alterations in PD. In MSA no significant differences were seen. Tele-methylhistamine (histamine metabolite) concentrations were unchanged in PD. These results indicate that histamine concentration, but not its metabolism is increased in PD, but not in MSA. This finding may have implications in developing new drug therapies for PD and in differential diagnosis between PD and MSA.