Flotillin-1 interacts with the serotonin transporter and modulates chronic corticosterone response.

Aberrant serotonergic neurotransmission in the brain is considered at the core of the pathophysiological mechanisms involved in neuropsychiatric disorders. Gene by environment interactions contribute to the development of depression and involve modulation of the availability and functional activity of the serotonin transporter (SERT). Using behavioral and in vivo electrophysiological approaches together with biochemical, molecular-biological and molecular imaging tools we establish Flotillin-1 (Flot1) as a novel protein interacting with SERT and demonstrate its involvement in the response to chronic corticosterone (CORT) treatment. We show that genetic Flot1 depletion augments chronic CORT-induced behavioral despair and describe concomitant alterations in the expression of SERT, activity of serotonergic neurons and alterations of the glucocorticoid receptor transport machinery. Hence, we propose a role for Flot1 as modulatory factor for the depressogenic consequences of chronic CORT exposure and suggest Flotillin-1-dependent regulation of SERT expression and activity of serotonergic neurotransmission at the core of the molecular mechanisms involved.

Long-term effects of maternal immune activation on depression-like behavior in the mouse.

Depression is a debilitating mental disease affecting a large population worldwide, the pathophysiological mechanisms of which remain incompletely understood. Prenatal infection and associated activation of the maternal immune system (MIA) are prominently related to an increased risk for the development of several psychiatric disorders including schizophrenia and autism in the offsprings. However, the role of MIA in the etiology of depression and its neurobiological basis are insufficiently investigated. Here we induced MIA in mice by challenge with polyinosinic:polycytidylic phosphate salt-a synthetic analog of double-stranded RNA, which enhances maternal levels of the cytokine interleukin-6 (IL-6)-and demonstrate a depression-like behavioral phenotype in adult offsprings. Adult offsprings additionally show deficits in cognition and hippocampal long-term potentiation (LTP) accompanied by disturbed proliferation of newborn cells in the dentate gyrus and compromised neuronal maturation and survival. The behavioral, neurogenic and functional deficiencies observed are associated with reduced hippocampal expression of vascular endothelial growth factor (VEGF)A-VEGFR2. IL-6-STAT3-dependent aberrant VEGFA-VEGFR2 signaling is proposed as neurobiological mechanism mediating the effects of MIA on the developing fetal brain and ensuing consequences in adulthood.

Strain-dependent regulation of neurotransmission and actin-remodelling proteins in the mouse hippocampus.

Individual mouse strains differ significantly in terms of behaviour, cognitive function and long-term potentiation. Hippocampal gene expression profiling of eight different mouse strains points towards strain-specific regulation of genes involved in neuronal information storage. Protein expression with regard to strain- dependent expression of structures related to neuronal information storage has not been investigated yet. Herein, a proteomic approach based on two-dimensional gel electrophoresis coupled with mass spectrometry (MALDI-TOF/TOF) has been chosen to address this question by determining strain-dependent expression of proteins involved in neurotransmission and activity-induced actin remodelling in hippocampal tissue of five mouse strains. Of 31 spots representing 16 different gene products analysed and quantified, N-ethylmaleimide-sensitive fusion protein, N-ethylmaleimide-sensitive factor attachment protein-alpha, actin-like protein 3, profilin and cofilin were expressed in a strain-dependent manner. By treating protein expression as a phenotype, we have shown significant genetic variation in brain protein expression. Further experiments in this direction may provide an indication of the genetic elements that contribute to the phenotypic differences between the selected strains through the expressional level of the translated protein. In view of this, we propose that proteomic analysis enabling to concomitantly survey the expression of a large number of proteins could serve as a valuable tool for genetic and physiological studies of central nervous system function.

Strain-dependent expression of signaling proteins in the mouse hippocampus.

Individual mouse strains may differ significantly in terms of behavior and cognitive function. Hippocampal gene expression profiling on several mouse strains has been carried out and points toward substantial strain-specific variation of more than 200 genes including components of major signaling pathways involved in neuronal information storage. Strain-specific hippocampal protein expression, however, has not been investigated yet. A proteomic approach based on two-dimensional gel electrophoresis coupled with mass spectrometry has been chosen to address this question by determining strain-dependent expression of signaling proteins in hippocampi of four inbred and one outbred mouse strain. Forty-six spots corresponding to 37 different signaling proteins have been analyzed and quantified. Statistical analysis revealed strain-dependent expression of serine/threonine protein phosphatase 1, serine/threonine protein phosphatase 2A, large GTP binding protein OPA1, guanine nucleotide-binding protein beta, putative GTP-binding protein Ran, receptor of activated protein kinase C1, WASP-family protein member 1, voltage-dependent anion channel 2 and 14-3-3 protein gamma. Differential expression of signaling proteins in the hippocampus may contribute to the molecular understanding of strain-dependent behavioral and cognitive performance. Moreover, these data highlight the importance of the genetic background for the analysis of signaling pathways in the hippocampus in wild-type mice as well as in gene-targeting experiments.

Cytoskeleton derangement in brain of patients with Down syndrome, Alzheimer's disease and Pick's disease.

Although cytoskeleton derangement has been reported in brain of patients with neurodegenerative disorders, basic information on integral constituents forming this network including stoichiometric composition is missing. It was therefore the aim of the study to qualitatively and quantitatively evaluate individual proteins of the three major classes representing the cytoskeleton of human brain. Cytoskeleton proteins beta-actin (betaA), alpha-actinin (Act), tubulin beta-III (betaIII), microtubule associated protein 1 (MAP1), neurofilaments NF-L, NF-M and NF-H and neuron specific enolase (NSE), a marker for neuronal density, were determined by immunoblotting. Brain samples (frontal cortex) of controls (CO), patients with Down Syndrome (DS), Alzheimer's disease (AD) and Pick's disease (PD) were used for the study. In DS brain betaIII, NF-H and NF-M, in AD brain NF-M and NF-H and in PD brain NF-L, NF-M and NF-H were significantly reduced. Stoichiometry of cytoskeleton proteins in control brain revealed the following relations: betaA:Act:betaIII:MAP1:NF-L:NF-M:NF-H = 1.0:0.8:3.8:2.4:3.2:2.2. This stoichiometrical ratios were aberrant in DS, AD and PD with the main outcome that ratios of members of the neurocytoskeleton (betaIII, NF's) in relation to betaA were remarkably decreased. This finding confirms data of decreased neuronal density using NSE in DS and AD. We propose stoichiometry of cytoskeleton elements in normal brain and confirm and extend knowledge on cytoskeleton defects in neurodegenerative diseases. The finding of significantly decreased individual elements may well lead to or represent disassembly of the neurocytoskeleton observed in neurodegenerative diseases.

Cimetidine decreases indomethacin induced duodenal mucosal damage in patients with acute musculoskeletal disorders.

The effect of two doses of cimetidine, 400 mg at night and 400 mg bd, on the protection of indomethacin (50 mg tid) induced mucosal damage was evaluated in a double blind study in patients with acute musculoskeletal disorders. Endoscopic mucosal lesions were scored before and after five to seven days of treatment. One hundred and ninety one patients were endoscoped before the trial, 34 (17.8%) had greater than one erosion and were not recruited. Forty patients were excluded for non-compliance, or lost to follow up. At the second endoscopy, oesophageal, and fundic damage was negligible. Gastric and duodenal lesion score in patients treated with cimetidine 400 mg bd: 2.7 (0.5) (SE); n = 42) was significantly lower (p less than 0.0122) than in placebo treated patients: 6.1 (0.9) (n = 50) or in patients treated with cimetidine 400 mg at night 7.1 (0.8) (n = 21). Cimetidine 400 mg bd provided significant protection for the duodenum, but its protection of antral mucosa did not reach statistical significance. There was no correlation between upper gastrointestinal symptoms and endoscopic findings.

The effect of protein malnutrition and nutritional support on the mechanical properties of fracture healing in the injured rat.

We investigated the effect of different nutritional regimens on fracture healing in the injured rat model. Four groups, each consisting of 12 male rats (307 +/- 16 g), were subjected to anesthesia, laparotomy (injury), and tibial osteotomy with internal fixation. Group I received 23% protein, group II received 23% protein and high caloric feed, group III received 5% protein, and group IV received 38% protein. After 8 weeks, calluses were x-rayed and the tibia was removed, fixed in a special block of methyl-metacrylate, and tested at tension up to failure in a mechanical testing apparatus. The distraction force at failure was measured, and callus stiffness and energy absorbed to failure were calculated. The low protein diet resulted in significantly lower tensile strength and stiffness of calluses compared to the other three dietary regimens, this despite adequate caloric intake. In addition, the low protein diet resulted in a callus with "rubbery" mechanical properties compared to the "rigid" calluses of the other three groups. The high protein diet did not result in any significant improvement in fracture healing. These results gain clinical significance in the face of a high incidence of protein calorie malnutrition in injured orthopedic surgery patients.

Hypobaric spinal anesthesia in the operative management of orthopedic emergencies in geriatric patients.

Hypobaric spinal anesthesia was administered to 40 patients undergoing lower limb surgery. Twenty-nine of the patients were debilitated geriatric patients who presented with orthopedic emergencies, in most cases a fractured hip. Hypobaric spinal anesthesia was found to be a simple and safe procedure that provided adequate analgesia. Due to its inherent nature, hypobaric spinal anesthesia does not necessitate positioning of the patient on the injured, painful side (unlike hyperbaric spinal or epidural anesthesia) and, therefore, facilitates a smooth and painless transfer of the patient to the operating table. Complications encountered were similar to those following hyperbaric anesthesia.

Condrocalcinose: comprometimento extra-articular. / Chondrocalcinosis: extra-articular involvement

Os autores apresentam dois casos de comprometimento extra-articular da condrocalcinose (bursa do olecrano), um fazendo parte de um acometimento generalizado e outro isolado, isto e, tomando apenas a bursa do olecrano, fato este ainda nao relatado na literatura

Doenca de Kawasaki. / Kawasaki's disease

Os autores descrevem um caso da doenca de Kawasaki acometendo uma crianca de 10 anos, tratada com aspirina e tendo boa evolucao. Os autores chamam a atencao para esta doenca ainda nao descrita entre nos, em razao de sua predilecao pela raca amarela e negra, contingente este importante entre nos

Artropatia associada a by pass intestinal? Artrite reativa. / Arthropathy associated with intestinal by pass. Reactive arthritis?

Os autores descrevem pela primeira vez, na literatura nacional, um caso apresentando artropatia secundaria a um by pass intestinal realizado para tratamento de obesidade morbida. Fazem uma revisao da literatura e discutem os possiveis mecanismos etiopatogenicos. Conceituam ainda as artrites reativas, enquadram esta patologia entre as mesmas, bem como propoem uma classificacao para estas artrites reativas

Dermatite herpetiforme e lupus eritematoso sistemico (LES). / Dermatitis herpetiformis and systemic lupus erythematosus

Os autores apresentam um caso de dermatite herpetiforme, associada a LES. Discutem a infrequencia deste achado,dando enfase aos achados histologicos e a importancia da imunefluorescencia.Salientam a boa resposta a sulfona, bem como o nao agravamento do LES com esta droga

Artropatia de lues secundaria. / Secondary lues joint disease

Os autores assinalam a relativa infrequencia da artropatia luetica e apresentam 4 casos com esta complicacao. Todos os pacientes tinham sinais e sintomas do secundarismo, bem como sorologia positiva. Assinalam a raridade de vasculite em 1 caso.Todos os casos reponderam bem, com remissao clinica, articular, bem como sorologica, com o classico tratamento com a penicilina