A history of obesity leaves an inflammatory fingerprint in liver and adipose tissue.

BACKGROUND/OBJECTIVES: Dieting is a popular yet often ineffective way to lower body weight, as the majority of people regain most of their pre-dieting weights in a relatively short time. The underlying molecular mechanisms driving weight regain and the increased risk for metabolic disease are still incompletely understood. Here we investigate the molecular alterations inherited from a history of obesity. METHODS: In our model, male high-fat diet (HFD)-fed obese C57BL/6J mice were switched to a low caloric chow diet, resulting in a decline of body weight to that of lean mice. We measured body composition, as well as metrics of glucose, insulin and lipid homeostasis. This was accompanied by histological and gene expression analysis of adipose tissue and liver to assess adipose tissue inflammation and hepatosteatosis. Moreover, acute hypothalamic response to (re-) exposure to HFD was assessed by qPCR. RESULTS & CONCLUSIONS: Within 7 weeks after diet switch, most obesity-associated phenotypes, such as body mass, glucose intolerance and blood metabolite levels were reversed. However, hepatic inflammation, hepatic steatosis as well as hypertrophy and inflammation of perigonadal, but not subcutaneous, adipocytes persisted in formerly obese mice. Transcriptional profiling of liver and perigonadal fat revealed an upregulation of pathways associated with immune function and cellularity. Thus, we show that weight reduction leaves signs of inflammation in liver and perigonadal fat, indicating that persisting proinflammatory signals in liver and adipose tissue could contribute to an increased risk of formerly obese subjects to develop the metabolic syndrome upon recurring weight gain.

A paternal methyl donor-rich diet altered cognitive and neural functions in offspring mice.

Dietary intake of methyl donors, such as folic acid and methionine, shows considerable intra-individual variation in human populations. While it is recognized that maternal departures from the optimum of dietary methyl donor intake can increase the risk for mental health issues and neurological disorders in offspring, it has not been explored whether paternal dietary methyl donor intake influences behavioral and cognitive functions in the next generation. Here, we report that elevated paternal dietary methyl donor intake in a mouse model, transiently applied prior to mating, resulted in offspring animals (methyl donor-rich diet (MD) F1 mice) with deficits in hippocampus-dependent learning and memory, impaired hippocampal synaptic plasticity and reduced hippocampal theta oscillations. Gene expression analyses revealed altered expression of the methionine adenosyltransferase Mat2a and BK channel subunit Kcnmb2, which was associated with changes in Kcnmb2 promoter methylation in MD F1 mice. Hippocampal overexpression of Kcnmb2 in MD F1 mice ameliorated altered spatial learning and memory, supporting a role of this BK channel subunit in the MD F1 behavioral phenotype. Behavioral and gene expression changes did not extend into the F2 offspring generation. Together, our data indicate that paternal dietary factors influence cognitive and neural functions in the offspring generation.

Impact of Anesthesia on the Outcome of Acute Ischemic Stroke after Endovascular Treatment with the Solitaire Stent Retriever.

BACKGROUND AND PURPOSE: General anesthesia during endovascular treatment of acute ischemic stroke may have an adverse effect on outcome compared with conscious sedation. The aim of this study was to examine the impact of the type of anesthesia on the outcome of patients with acute ischemic stroke treated with the Solitaire stent retriever, accounting for confounding factors. MATERIALS AND METHODS: Four-hundred one patients with consecutive acute anterior circulation stroke treated with a Solitaire stent retriever were included in this prospective analysis. Outcome was assessed after 3 months by the modified Rankin Scale. RESULTS: One-hundred thirty-five patients (31%) underwent endovascular treatment with conscious sedation, and 266 patients (69%), with general anesthesia. Patients under general anesthesia had higher NIHSS scores on admission (17 versus 13, P < .001) and more internal carotid artery occlusions (44.6% versus 14.8%, P < .001) than patients under conscious sedation. Other baseline characteristics such as time from symptom onset to the start of endovascular treatment did not differ. Favorable outcome (mRS 0-2) was more frequent with conscious sedation (47.4% versus 32%; OR, 0.773; 95% CI, 0.646-0.925; P = .002) in univariable but not multivariable logistic regression analysis (P = .629). Mortality did not differ (P = .077). Independent predictors of outcome were age (OR, 0.95; 95% CI, 0.933-0.969; P < .001), NIHSS score (OR, 0.894; 95% CI, 0.855-0.933; P < .001), time from symptom onset to the start of endovascular treatment (OR, 0.998; 95% CI, 0.996-0.999; P = .011), diabetes mellitus (OR, 0.544; 95% CI, 0.305-0.927; P = .04), and symptomatic intracerebral hemorrhage (OR, 0.109; 95% CI, 0.028-0.428; P = .002). CONCLUSIONS: In this single-center study, the anesthetic management during stent retriever thrombectomy with general anesthesia or conscious sedation had no impact on the outcome of patients with large-vessel occlusion in the anterior circulation.

The Impact of Histological Clot Composition in Embolic Stroke.

PURPOSE: Thrombus composition has been suggested to have a decisive impact on the outcome of patients treated by mechanical thrombectomy because of embolic stroke. The recent development of stent retrievers allows collection and, hence, histopathological analysis of fresh thrombus material. Against this background, the aim of this prospective study was to assess the impact of thrombus composition on mechanical recanalization, clinical outcome and stroke etiology. METHODS: Thirty-four patients suffering from acute ischemic stroke due to occlusion of the distal internal carotid artery/carotid-T, anterior cerebral artery, or middle cerebral arteries were mechanically recanalized, and thrombus material was obtained. Histological thrombus composition was compared with imaging, clinical, and neurointerventional data. RESULTS: The main findings were that a higher percentage of white blood cells (WBCs) in the thrombus was associated with (i) cardioembolic etiology, (ii) extended mechanical recanalization time, and (iii) less favorable recanalization (Thrombolysis in Cerebral Infarction score) and clinical outcome (National Institute of Health Stroke Scale). CONCLUSION: Our results suggest that thrombi with a high WBC fraction are related to more organized thrombi of cardioembolic origin associated with less favorable recanalization and clinical outcome in acute ischemic anterior circulation stroke. WBC-mediated immunological and coagulatory processes may play a key role in thrombus formation and pathogenesis of stroke warranting further investigation.

Cardiovascular disease mortality of A-bomb survivors and the healthy survivor selection effect.

The latest A-bomb survivor data for cardiovascular diseases are analysed to investigate whether in the first years after the bombings the baseline rates of proximal survivors were markedly different compared with those of the distal survivors. This phenomenon relates to a healthy survivor selection effect. This question is important for the decision whether to include or exclude the early years of follow-up when analysing the biological effects from acute low and high dose exposures following the nuclear weapons explosions in Hiroshima and Nagasaki. The present study shows that for cerebrovascular diseases and heart diseases the baseline rates are not significantly different in the first two decades of follow-up. Thus, for these two detrimental health outcomes, there is no need to exclude distal survivors and the first decades of follow-up time when investigating the shapes of the related dose-responses.

Constitutive expression of murine c-FLIPR causes autoimmunity in aged mice.

Death receptor-mediated apoptosis is a key mechanism for the control of immune responses and dysregulation of this pathway may lead to autoimmunity. Cellular FLICE-inhibitory proteins (c-FLIPs) are known as inhibitors of death receptor-mediated apoptosis. The only short murine c-FLIP splice variant is c-FLIPRaji (c-FLIPR). To investigate the functional role of c-FLIPR in the immune system, we used the vavFLIPR mouse model constitutively expressing murine c-FLIPR in all hematopoietic compartments. Lymphocytes from these mice are protected against CD95-mediated apoptosis and activation-induced cell death. Young vavFLIPR mice display normal lymphocyte compartments, but the lymphocyte populations alter with age. We identified reduced levels of T cells and slightly higher levels of B cells in 1-year-old vavFLIPR mice compared with wild-type (WT) littermates. Moreover, both B and T cells from aged vavFLIPR animals show activated phenotypes. Sera from 1-year-old WT and transgenic animals were analysed for anti-nuclear antibodies. Notably, elevated titres of these autoantibodies were detected in vavFLIPR sera. Furthermore, tissue damage in kidneys and lungs from aged vavFLIPR animals was observed, indicating that vavFLIPR mice develop a systemic lupus erythematosus-like phenotype with age. Taken together, these data suggest that c-FLIPR is an important modulator of apoptosis and enforced expression leads to autoimmunity.

Naturally occurring autoantibodies interfere with ß-amyloid metabolism and improve cognition in a transgenic mouse model of Alzheimer's disease 24 h after single treatment.

There is evidence that naturally occurring antibodies directed against Aß (nAbs-Aß) have a role in Aß-metabolism and Aß-clearance. The presence of nAbs-Aß leads to a reduction in amyloid fibrillation and thus a reduction in their toxicity. We investigated the effects of nAbs-Aß in respect to oligomerization and used the Tg2576 transgenic mouse model in order to investigate the rapid effect with a single-dose (24 h) on oligomer breakdown and cytokine secretion along with immunohistochemical characterization of synaptic plasticity. nAbs-Aß were able to reduce toxic oligomer concentration with an increase in Aß-monomers. Cytokine secretion was significantly reduced. Synaptic plasticity was also improved after administration of nAbs. Finally, single treatment lead to a significant improvement in cognition. This study demonstrates the efficacy of nAbs-Aß and presents evidence that several hallmarks of the disease are targeted by nAbs-Aß.

Inbred wild type mouse strains have distinct spontaneous morphological phenotypes.

The mouse is the most commonly used animal for modelling human disease. New approaches for generating genetically manipulated mouse models to represent human disease, as well as target the function of specific genes, has increased the importance of mice in biomedical science. For the correct interpretation of alterations in mouse phenotype the basic morphology of background mouse strains must be known. Despite on-going efforts to create publicly available baseline phenotypic data, the information concerning spontaneous lesions in wild-type mice is incomplete and scattered so far, and further studies are needed. We addressed this problem by screening haematoxylin-eosin stained sections of brain, reproductive organs, urinary bladder, kidney, thyroid, parathyroid, heart, lung, spleen, thymus, lymph nodes, adrenal glands, stomach, intestine, liver, skin and pancreas of six commonly used inbred mouse strains (C57BL6/J, C57BL6/NTac, C3HeB/FeJ, BALB/cByJ, 129P2/OlaHsd and FVB/N) for inherent spontaneous morphological lesions. Interesting spontaneous phenotypes were seen in morphology of the liver, pancreas, adrenal glands, lungs, intestines and heart. In conclusion, care should be taken when choosing the background mouse strain for genetic manipulations, since different mouse strains harbour different inherent lesions that can affect the function of targeted genes, interpretation of results and translation of results to model human disease.

[A million football fans in a city of 120,000 inhabitants--a nightmare for emergency medicine and disaster management? Euro 2008 and the "Orange wonder of Berne"]. / 1.000.000 Fussballfans in einer Stadt mit 120.000 Einwohnern--ein notfallmedizinischer Albtraum? Die Euro 2008 und das "Oranje-Wunder von Bern"

The 2008 European Football Championship 2008 (Euro 08) is the largest sporting event ever organized in Switzerland. One million visitors came to the city of Berne during the event and the local airport in Bern/Belp registered 261 extra flights. For each football game there were 33,000 fans in the stadium and 100,000 fans in the public viewing zones.The ambulance corps and the Department of Emergency Medicine (ED) at Inselspital, University Hospital Berne, were responsible for basic medical care and emergency medical management. Injuries and illnesses were analyzed by a standardized score (NACA score). The preparation strategy as well as costs and patient numbers are presented in detail.A total of 30 additional ambulance vehicles were used, 4,723 additional working days (one-third medical professionals) were accumulated, 662 ambulance calls were registered and 240 persons needed medical care (62% Swiss, 28% Dutch and 10% other nationalities). Among those needing treatment 51 were treated in 1 of the 4 city hospitals. No injuries with NACA grades VI and VII occurred (NACA I: 4, NACA II: 17, NACA III: 16, NACA IV: 10 and NACA V: 4 patients). The city of Berne compensated the Inselspital Bern with a total of 112,603 Euros for extra medical care costs. The largest amount was spent on security measures (50,300 Euros) and medical staff (medical doctors 22,600 Euros, nurses 29,000 Euros). Because of the poor weather and the exemplary behavior of the fans, the course of events was rather peaceful.

[Characterization of ENU-mutant mice. Animal models for human diseases using morphological and molecular methods]. / Charakterisierung von ENU-Mausmutanten. Tiermodelle für menschliche Erkrankungen mittels morphologischer und molekularer Methoden.

Following sequencing of the human genome there are new challenges to decipher the knowledge concerning gene function and the role of gene interactions and pathways leading to disease. Mouse models have proven to be an ideal tool for this purpose. Point mutations induced by chemical mutagenesis by N-ethyl-N-nitrosourea (ENU) offer possibilities for the analysis of the phenotypic outcome of a single base pair exchange on the entire organism. The Munich ENU mouse mutagenesis project is part of the worldwide efforts to obtain mutations for each gene. The generation of new alleles or allelic series offers relevant insights into the relevance of single gene sections. Various mouse models for human diseases have been generated by a systematic large-scale genome-wide phenotyping screen in the last decade. This work illustrates how the implementation of the ENU mouse mutagenesis project with gene identification and parallel high-throughput screening is taking advantage of local cooperation with experienced phenotyping groups at the Helmholtz Zentrum München, leading to major advances in the functional analysis of the mammalian genome.

[Doppler sonography suggesting fulminant aortic dissection in initial middle cerebral artery infarction]. / Dopplersonographie mit Hinweis auf fulminante Aortendissektion bei initialem Mediainfarkt.

Acute aortic dissection is a cardiovascular emergency with a wide spectrum of clinical symptoms making the diagnosis difficult if the leading symptom of thoracic pain is not present. In up to 10% of cases an ischemic stroke may be the first clinical sign. We report a patient with a middle cerebral artery infarction in whom an abnormal signal in the extracranial Doppler sonography revealed the first hint of an aortic dissection. Before the diagnosis could be verified, the patient died due to electromechanical decoupling; autopsy showed an extensive aortic dissection with cardiac tamponade. Based on this case report, we review special problems of diagnosis and therapy in aortic dissection with primary cerebrovascular manifestation.

[Porcine malignant catarrhal fever: diagnostic findings and first detection of the pathogenic agent in diseased swine in Switzerland]. / Porcines Bösartiges Katarrhalfieber: Diagnostische Befunde und erstmaliger Nachweis des Erregers bei erkrankten Schweinen in der Schweiz.

For the first time Ovine Herpesvirus 2 (OvHV-2) was identified in Swiss pigs as the causative agent of Porcine Malignant Catarrhal Fever (MCF). Diseased animals from two farms were observed to show weakness, anorexia, fever up to 41 degrees C, and neurological symptoms, i.e. ataxia, convulsions and hyperesthesia, erosion on the snout and in the oral and nasal mucosa, as well as multiple skin lesions. Histopathological findings included severe non-purulent inflammation with mononuclear cell infiltration in several organs. Most dominant were meningo-encephalitis, disseminated nephritis as well as purulent catarrhalic bronchopneumonia. The findings were quite reminiscent of the lesions due to MCF in cattle and give therefore substantial proof to use Porcine Malignant Catarrhal Fever as the term for the disease. Identification of the causative agent was done with a quantitative PCR specific for OvHV-2. Different tissues from diseased animals were positive. Furthermore, one animal which had been ill for more than five days tested positive for antibodies against an epitope conserved among MCF viruses. Serum samples from diseased animals reacted negative towards Classical Swine Fever- and Pseudorabies virus antigen. A weakly positive reaction against porcine enterovirus type I argued against the involvement of enteroviruses in the observed disease. Moreover, by means of different conventional PCRs, we detected the newly discovered porcine lymphotropic herpesviruses for the first time in Switzerland and could at the same time exclude their involvement in Porcine Malignant Catarrhal Fever.

Signaling pathways mediate the neuroprotective effects of GDNF.

We show that the glial cell line-derived neurotrophic factor (GDNF) activates the PI3K/Akt-signaling pathway in human neuroblastoma cells that express functional Ret-receptor complexes. Consistent with this finding we show PI3K-dependent Bad-inactivation by binding to 14-3-3 proteins in response to GDNF. Using differential display techniques we detected several cDNA clones differentially expressed after treatment with GDNF or 6-OHDA.

[Surgical vs. conservative therapy of diacapitular and high condylar fractures with dislocation. A comparison between MRI and axiography]. / Operative vs. konservative Therapie diakapitulärer und hoher Kollumluxationsfrakturen. Vergleich mit MRT und Achsiographie.

AIMS: At present the discussion about the correct management of high condylar and diacapitular fractures has been reopened. The aim of the present prospective study was to evaluate the role of condylar mobility, disk mobility, and vertical dimension regarding the postoperative functional outcome after open reduction and osteosynthesis compared to nonsurgical treatment. METHODS: Since 1993 a total of 130 high condylar and diacapitular fractures have been treated by open reduction and osteosynthesis. Thirty-nine subjects with 51 fractures classes V and VI according to Spiessl and Schroll (surgical treatment, ST) were assessed postoperatively (mean 24 months) including magnetic resonance imaging (MRI) and axiography. Sixteen conservatively treated fractures served as a reference (conservative treatment, CT). RESULTS: Surgically treated temporomandibular joints presented a better condylar mobility (11.4 mm after ST, 5.9 mm after CT) and a less remarked loss of vertical ramus height (1.6 mm after ST, 5.4 mm after CT). Conservatively treated high condylar fractures formed a nearthrosis with the articular eminence in an anteromedial malposition (x axis 6.9 mm, y axis 10.3 mm). Disk mobility was reduced in both groups (3.8 mm after CT, 5.8 mm after ST), with major interindividual variations after ST. Significant correlations were found in the surgically treated group between axiographic limitations and limitations of disk mobility (p < 0.01) or periarticular scar formations (p < 0.01). Helkimo indices after ST (31% symptom free, 67% light symptoms < 5 points) were clearly superior (p < 0.01) to conservative treatment, with 63% of the subjects presenting craniomandibular symptoms > 5 points. CONCLUSIONS: According to the functional results observed, high condylar and diacapitular fractures will profit by open reduction and osteosynthesis. Only effective surgical procedures can preserve both disk mobility and vertical ramus height.

[Serological survey of Sarcoptes scabies var. suis infection using colostrum samples: preliminary results]. / Serologische Bestandesuntersuchung der Sarcoptes scabiei var. suis Infektion mit Kolostralmilchproben: vorläufige Resultate.

Pig mange was investigated serologically in colostral samples with ELISA using Chekit Sarcoptest. This test has already been using to investigate sera samples from swine in veterinary practice. A total of 684 sow colostral samples were collected from 24 mange free breeding units and 6 units with clinical manifestation of mange infestation. The specificity of the test was more than 99% and the mean seroprevalence 30% (range 6% to 100%). This simple method will allow in the future not only the rapid and certain diagnosis of pig mange but also the screening of pig breeding units after eradication of the disease.

Aberrant p21 regulation in radioresistant primary glioblastoma multiforme cells bearing wild-type p53.

OBJECT: A clearer understanding of the cellular mechanisms involved in the response to ionizing radiation is pivotal to the development of new therapeutic strategies for glioblastoma multiforme (GBM). To gain insight into dynamic functional aspects of cell cycle regulation and the control of apoptosis in GBMs, the authors investigated the molecular changes induced by ionizing radiation in genetically characterized primary GBMs in vitro compared with secondary GBMs, Grades II and III gliomas, and three GBM cell lines. METHODS: Irradiation of primary GBMs bearing wild-type (wt) p53 invariably fails to invoke the G, checkpoint and apoptosis in vitro. In approximately half of these primary GBMs a defect lies at or above the level of p53 because transcriptional activation of p21 and bax after irradiation does not occur. The failure of a p21 response to irradiation is invariably accompanied by overexpression of p21 mRNA under nonirradiated conditions. In all remaining primary GBMs transcriptional activation of p21 after irradiation does occur, suggesting that a defect downstream from p21 prevents G, arrest. CONCLUSIONS: These results show that the G, checkpoint and the p53 pathway are dysfunctional in primary GBMs in vitro, despite the presence of an intact p53 gene. The data also suggest that primary GBMs may be divided into two categories on the basis of their p21 response to irradiation.

The Akt/protein kinase B-dependent anti-apoptotic pathway and the mitogen-activated protein kinase cascade are alternatively activated in human glioblastoma multiforme.

We investigated the activation of two important signal transduction pathways in human glioblastoma cells and found a constitutive phosphorylation of either Akt or mitogen-activated protein kinase (MAPK) under serum free conditions. In all but one cell line Wortmannin-sensitive activation of Akt could be attributed to the loss of functional PTEN protein. All cell lines with Akt activation exhibited only weak phosphorylation of the MAPK signal pathway, whereas those without constitutive Akt activation demonstrated high levels of phosphorylated MAPK under serum free conditions. Our data might indicate the presence of two functional subtypes of glioblastoma multiforme, since Akt and MAPK are involved in cellular survival and proliferation signalling, respectively.

Expression of alternatively spliced mdm2 transcripts correlates with stabilized wild-type p53 protein in human glioblastoma cells.

A puzzling finding in various human tumors, including glioblastoma multiforme (GBM), is the stabilization of wild-type (wt) p53 protein. The biological significance of this phenomenon and the mechanism by which it occurs are unexplained. Recent reports have revealed that mdm2 exerts its negative regulation on the p53 signal by directly binding p53 protein and thereby instigating its proteasomal degradation. mdm2 has been shown to exist in alternatively spliced forms in human ovarian and bladder carcinomas, and recently in GBM, with loss or disruption of its p53 binding domain. Here we report that alternatively spliced transcripts of mdm2 are present in 7 of 16 human GBM primary cell cultures and in the established GBM cell lines LN 229 and LN 18. Sequencing demonstrated loss of the amino terminal p53 binding domain in these alternatively spliced mdm2 transcripts, and an out-of-frame splicing in the majority of cases. A significant correlation between the presence of mdm2 splice variants and increased expression of wt p53 protein was observed. Furthermore, in the presence of an mdm2 splice variant, wt p53 stabilization occurred despite coincident MDM2 amplification. Our findings suggest that wt p53 protein stabilization may arise as a consequence of alternative splicing of mdm2. Such a mechanism might account for wt p53 protein accumulation in GBM cells, even in the presence of MDM2 gene amplification.

Epidemiologia das doenças respiratórias obstrutivas em relaçäo com o hábito de fumar / Epidemiology of obstructive respiratory diseases related to the smoking habit

Realizou-se uma amostragem entre a populaçäo de Porto Alegre, Brasil, com a finalidade de se conhecer a relaçäo do hábito tabágico com o fluxo respiratório de fumantes, ex-fumantes e näo fumantes