Motor excitability measurements in early stage familial amyloid polyneuropathy: The influence of tafamidis treatment.

OBJECTIVE: To test motor fiber excitability in early affected patients with transthyretin (TTR)-type familial amyloid polyneuropathy (TTR-FAP) before and during tafamidis treatment. METHODS: We examined the left median nerve of 21 healthy-matched controls and 10 early affected TTR-FAP patients using the automated threshold-tracking program, QTRAC. TTR-FAP patients were tested one day before the initiation of tafamidis treatment, 3 and 6 months later. RESULTS: The drug was well-tolerated in all patients; there was no drop-out. No statistical difference was found between healthy controls and TTR-FAP patients at study entry. On treatment, both stimulus intensity for 50% of the maximal motor response and rheobase increased significantly from entry to the last evaluation at 6 months (P<0.05). Strength duration time constant decreased significantly from the 3rd to the 6th month of evaluation (P<0.05). There was also a "fanning-out" effect on the late depolarization phase (TEd 90-100ms) as well as a shortened relative refractory period from study entry to the 6th month of evaluation. CONCLUSIONS: Threshold-tracking of median nerve motor fibers is not a helpful technique for the early diagnosis of TTR-FAP patients. Tafamidis was well-tolerated. We observed possible membrane hyperpolarization during treatment. Threshold tracking can contribute to documenting the action of new drugs to treat neuropathies. Tafamidis may change nerve electrical properties by reducing the burden of amyloid fibrils.

VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.

Several vascular disorders, such as aberrant angiogenesis, atherosclerosis and pulmonary hypertension, have been linked to dysfunctional BMP signaling. Vascular hyperpermeability via distortion of endothelial cell adherens junctions is a common feature of these diseases, but the role of BMPs in this process has not been investigated. BMP signaling is initiated by binding of ligand to, and activation of, BMP type I (BMPRI) and type II (BMPRII) receptors. Internalization of VE-cadherin as well as c-Src kinase-dependent phosphorylation have been implicated in the loosening of cell-cell contacts, thereby modulating vascular permeability. Here we demonstrate that BMP6 induces hyperpermeabilization of human endothelial cells by inducing internalization and c-Src-dependent phosphorylation of VE-cadherin. Furthermore, we show BMP-dependent physical interaction of VE-cadherin with the BMP receptor ALK2 (BMPRI) and BMPRII, resulting in stabilization of the BMP receptor complex and, thereby, the support of BMP6-Smad signaling. Our results provide first insights into the molecular mechanism of BMP-induced vascular permeability, a hallmark of various vascular diseases, and provide the basis for further investigations of BMPs as regulators of vascular integrity, both under physiological and pathophysiological conditions.

Specific regulation of the chemokine response to viral hemorrhagic septicemia virus at the entry site.

The fin bases constitute the main portal of rhabdovirus entry into rainbow trout (Oncorhynchus mykiss), and replication in this first site strongly conditions the outcome of the infection. In this context, we studied the chemokine response elicited in this area in response to viral hemorrhagic septicemia virus (VHSV), a rhabdovirus. Among all the rainbow trout chemokine genes studied, only the transcription levels of CK10 and CK12 were significantly upregulated in response to VHSV. As the virus had previously been shown to elicit a much stronger chemokine response in internal organs, we compared the effect of VHSV on the gills, another mucosal site which does not constitute the main site of viral entry or rhabdoviral replication. In this case, a significantly stronger chemokine response was triggered, with CK1, CK3, CK9, and CK11 being upregulated in response to VHSV and CK10 and CK12 being down-modulated by the virus. We then conducted further experiments to understand how these different chemokine responses of mucosal tissues could correlate with their capacity to support VHSV replication. No viral replication was detected in the gills, while at the fin bases, only the skin and the muscle were actively supporting viral replication. Within the skin, viral replication took place in the dermis, while viral replication was blocked within epidermal cells at some point before protein translation. The different susceptibilities of the different skin layers to VHSV correlated with the effect that VHSV has on their capacity to secrete chemotactic factors. Altogether, these results suggest a VHSV interference mechanism on the early chemokine response at its active replication sites within mucosal tissues, a possible key process that may facilitate viral entry.

A modified vaccinia Ankara virus (MVA) vaccine expressing African horse sickness virus (AHSV) VP2 protects against AHSV challenge in an IFNAR -/- mouse model.

African horse sickness (AHS) is a lethal viral disease of equids, which is transmitted by Culicoides midges that become infected after biting a viraemic host. The use of live attenuated vaccines has been vital for the control of this disease in endemic regions. However, there are safety concerns over their use in non-endemic countries. Research efforts over the last two decades have therefore focused on developing alternative vaccines based on recombinant baculovirus or live viral vectors expressing structural components of the AHS virion. However, ethical and financial considerations, relating to the use of infected horses in high biosecurity installations, have made progress very slow. We have therefore assessed the potential of an experimental mouse-model for AHSV infection for vaccine and immunology research. We initially characterised AHSV infection in this model, then tested the protective efficacy of a recombinant vaccine based on modified vaccinia Ankara expressing AHS-4 VP2 (MVA-VP2).

Evolutionary conservation of drug action on lipoprotein metabolism-related targets.

Genetic analysis has shown that the slower than normal rhythmic defecation behavior of the clk-1 mutants of Caenorhabditis elegans is the result of altered lipoprotein metabolism. We show here that this phenotype can be suppressed by drugs that affect lipoprotein metabolism, including drugs that affect HMG-CoA reductase activity, reverse cholesterol transport, or HDL levels. These pharmacological effects are highly specific, as these drugs affect defecation only in clk-1 mutants and not in the wild-type and do not affect other behaviors of the mutants. Furthermore, drugs that affect processes not directly related to lipid metabolism show no or minimal activity. Based on these findings, we carried out a compound screen that identified 190 novel molecules that are active on clk-1 mutants, 15 of which also specifically decrease the secretion of apolipoprotein B (apoB) from HepG2 hepatoma cells. The other 175 compounds are potentially active on lipid-related processes that cannot be targeted in cell culture. One compound, CHGN005, was tested and found to be active at reducing apoB secretion in intestinal Caco-2 cells as well as in HepG2 cells. This compound was also tested in a mouse model of dyslipidemia and found to decrease plasma cholesterol and triglyceride levels. Thus, target processes for pharmacological intervention on lipoprotein synthesis, transport, and metabolism are conserved between nematodes and vertebrates, which allows the use of C. elegans for drug discovery.

[GUTI-VAL apparatus: respiratory deficiency and non-invasive ventilation]. / Dispositivo GUTI-VAL. Insuficiencia respiratoria con ventilación no invasiva.

Mechanical non-invasive ventilation provides a useful therapeutic option to treat some types of respiratory deficiencies. This apparatus improves the morbid mortality rate and shortens hospital stays especially since it prevents tracheotomy, but it can produce some inconveniences. The authors evaluate the efficiency of the GUTI-VAL Connection Apparatus in the treatment of patients suffering from a respiratory deficiency used along with a CPAP mask in terms of the degree of comfort and acceptance patients have, the prevention of a tracheotomy and of cutaneous lesions. This study, run over a 13 month period, dealt with patients checked into our Intensive Care Unit, a multidimensional unit in a county hospital, suffering from acute respiratory deficiencies or chronic acute deficiencies to whom treatment with mechanical non-invasive ventilation type CPAP with a GUTI-VAL apparatus was applied. The authors conclude that this apparatus proved to have a low mortality rate, few complications and good patient tolerance.

Biological monitoring of organochlorine pesticides using Anodontites trapesialis (Lam, 1819), (Bivalvia: Mycetopodidae) in a lotic environment-urban sewage

The contribution of domestic and industrial waste to the discharge of organochlorine compounds into the Pardo river, the major body of water in the northeast region of the state of São Paulo, was studied through the biological monitoring of the limnal bivalve anodontites trapesialis. The method used was gas-phase chromatography using a CG 35370 chromatograph. The results showed the abscense of organochlorine pesticide waste from the urban sewage of the city of Ribeirão Preto.

Biological monitoring of organochlorides using the limnic bisalves anodontites trapesialis: (Lam., 1819)

The mussel Anodontites trapesialis (Lam, 1819) was used as an indicator of organochloride pollutans in the Canoas River, located in the municpality of Mococa (21-25'08"S and 47W), State of Säo Paulo, Brazil. Biological monitoring was performed for one year at the site of an orange grove on the left bank of the river. Forty-five animals were placed in aluminum enclosures on the river bottom at this site and 4 animals were sacrificed for pesticide analysis at 3-month intevals, each corrsponding to one season of the year. Pesticides were extracted by the method of Bedford et al., (1968), modified, and the analyses were performed bay gas phase chromatography equipped with an elelctron capture detector. The aninals were found to have been exposed to DDT. Lindane and Heptachlor. Variation in Aldrin and Dieldrin levels was not significant enough to permit inferences. Endrin was not detected in any of the analyses

Praguicidas organoclorados no leite humano / Organoclorine pesticides in human milk

Analisam-se amostras de leite humano de sete trabalhadoras rurais do município de Jaboticabal, Säo Paulo. Identificaram-se traços de lindane em três amostras e níveis bastantes baixos de heptacloro, que näo excederam 0,001 mg/kg. Constataram-se DDT total em 100% das amostras, com níveis variando entre 0,008 a 0,455 mg/kg. Níveis de p.p'-DDT foram mais elevados do que os de p.p'-DDE, em todas as amostras, demonstrando uma exposiçäo recente ao DDT.

Variaçäo dos níveis de DDT no leite materno no transcurso da lactaçäo: estudo de caso / Variation of DDT levels in human milk durign lactation: case study

Estudo realizado em lactante com comprovada exposiçäo ocupacional, mostrando a queda dos níveis de DDT total desde o início da amamentaçäo até o retorno às suas atividades, quando se constatou elevaçäo, principalmente do p,p'-DDT, indicando uma contaminaçäo recente a essas susbstâncias