A new isoleucine substitution of Val-20 in transthyretin tetramers selectively impairs dimer-dimer contacts and causes systemic amyloidosis.

The most frequent form of inherited amyloidoses is associated with mutations in the transthyretin (TTR) gene coding for 127-amino acid residues of four identical, noncovalently linked subunits that form a pair of dimers in the plasma protein complex. Amyloid fibrils containing the variant and to a lesser extent the wild-type form of the TTR molecule are deposited in various organs, including peripheral nerves and the myocardium, with polyneuropathy and cardiomyopathy as major clinical manifestations. So far, more than 40 distinct amino acid substitutions distributed throughout the TTR sequence over 30 positions have been found to be correlated with an increased amyloidogenicity of TTR. Most of these amyloidogenic amino acid substitutions are suspected to alter the conformation and stability of the monomer. Here we identify and characterize by protein and DNA analysis a novel amyloidogenic Val-20 to Ile mutation in a German three-generation family. The index patient suffered from severe amyloid cardiomyopathy at the age of 60. Conformational stability and unfolding behavior of the Ile-20 monomer in urea gradients was found to be almost indistinguishable from that of wild-type TTR. In contrast, tetramer stability was significantly reduced in agreement with the expected change in the interactions between the two opposing dimers via the side chain of Ile-20. Our observations provide strong evidence for the view that amyloidogenic amino acid substitutions in TTR facilitate the conversion of tetrameric TTR complexes into those conformational intermediates of the TTR folding pathway that have an intrinsic amyloidogenic potential.

Choroidal Thickness And Volume In Healthy Young Whites And Their Relationship With Axial Length, Ammetropy And Sex

Purpose: To evaluate choroidal thickness in young subjects using Enhanced Depth Imaging Spectral Domain Optical Coherence Tomography (EDI SD-OCT) describing volume differences between all the defined areas of the Early Treatment Diabetic Retinopathy Study (ETDRS). Design: Prospective, clinical study. Methods: Seventy-nine eyes of 95 healthy, young (23.8±3.2years), adult volunteers were prospectively enrolled. Manual choroidal segmentation on a 25-raster horizontal scan protocol was performed. The measurements of the nine subfields defined by the ETDRS were evaluated. Results: Mean subfoveal choroidal thickness was 345.67±81.80μm and mean total choroidal volume was 8.99±1.88mm3. Choroidal thickness and volume were higher at the superior and temporal areas compared to inferior and nasal sectors of the same diameter respectively. Strong correlations between subfoveal choroidal thickness and axial length (AL) and myopic refractive error were obtained, r = -0.649, p<0.001 and r = 0.473, p<0.001 respectively. Emmetropic eyes tended to have thicker subfoveal choroidal thickness (381.94±79.88μm versus 307.04±64.91μm) and higher total choroidal volume than myopic eyes (9.80± 1.87mm3 versus 8.14±1.48mm3). The estimation of the variation of the subfoveal choroidal thickness with the AL was-43.84μm/mm. In the myopic group, the variation of the subfoveal choroidal thickness with the myopic refractive error was -10.45μm/D. Conclusions: This study establishes for the first time a normal database for choroidal thickness and volume in young adults. Axial length, and myopic ammetropy are highly associated with choroidal parameters in healthy subjects. EDI SD-OCT exhibited a high degree of intraobserver and interobserver repeatability.

Modélisation de l’activité électrique des oreillettes avant et après ablation par cathéter

- Réalisé au centre de recherche de l'hospital du Sacré-Coeur de Montréal. - Programme conjoint entre Université de Montréal et École Polytechnique de Montréal.

The Sovereign Debt Crisis: Placing a curb on growth (updated edition). CEPS Paperbacks. September 2013

This book provides an update to the major 2012 study by the same authors on the dual role of the public sector as the provider of the ultimate riskless asset and, at the same time, the source of a potential major systemic risk. In this second edition, Brender and his colleagues concentrate again on the tension between the need for the public sector to sustain demand in the face of a deleveraging private sector and the longer-term challenges of sustainability for fiscal policy in the major developed economies of the US, Japan and the euro area. In short, their principal thesis is that sovereign debt is in crisis. This crisis is apparent in the euro area, but it is also real, if at present only latent, in the US and Japan. The book shows how this process has evolved in these three big developed economies – and how their policy choices impact on global financial markets.

Transactions of the sixth International congress on tuberculosis. Washington, September 28 to October 5, 1908.

v. 1, pt. 1. Proceedings of Section I: Pathology and bacteriology. Proceedings of joint session of Sections I and II: Opsonic index. Conjunctival and cutaneous tuberculin reactions. Serum diagnosis.--v. 1, pt. 2 Proceedings of Section II: Clinical study and therapy of tuberculosis, sanatoria, hospitals, and dispensaries.--v. 2. Proceedings of Section III: Surgery and orthopedics. Proceedings of Section IV: Tuberculosis in infancy.--v. 3. Proceedings of Section V: Hygienic, social, industrial, and economic aspects of tuberculosis.--v. 4, pt. 1. Proceedings of Section VI: State and municipal control of tuberculosis.--v. 4, pt. 2. Proceedings of Section VII: Tuberculosis in animals and its relations to man.--v. 5. The opening and closing ceremonies. Report of the Secretary-General. Officers, committees, and members.--[v. 6] A series of public lectures Specially prepared for the sixth International congress on tuberculosis, by A. Calmette...Louis Landouzy...[and others] Ed. by the secretary-general, and printed as a supplement to the Transactions of the Congress.

Treatment of eight dogs with nasal tumours with a alternating doses of doxorubicin and carboplatin in conjunction with oral piroxicam

Objective To determine the efficacy and toxicity of chemotherapy in the treatment of canine nasal tumours. Design Retrospective clinical study Procedure Eight dogs with histologically confirmed nasal tumours were staged by means of complete blood count, serum biochemical analysis, cytological analysis of fine needle aspirate of the regional lymph nodes, thoracic radiographs and computed tomography scan of the nasal cavity. All dogs were treated with alternating doses of doxorubicin, carboplatin and oral piroxicam. All dogs were monitored for side effects of chemotherapy and evaluated for response to treatment by computed tomography scan of the nasal cavity after the first four treatments. Results Complete remission was achieved in four dogs, partial remission occurred in two dogs and two had stable disease on the basis of computed tomography evaluation. There was resolution of clinical signs after one to two doses of chemotherapy in all dogs. Conclusions This chemotherapy protocol was efficacious and well tolerated in this series of eight cases of canine nasal tumours.

How common is comorbidity and why does it occur?

Comorbidity is most generally defined as the co-occurrence of two or more mental health problems. Comorbidity between drug and other psychological disorders has emerged as a major clinical, public health and research issue over the past few decades. The reasons for comorbidity are complex. Furthermore, comorbidity is often associated with poor treatment outcome, severe illness course, and high service utilisation. This presents a significant challenge with respect to the identification, prevention and management of people with comorbid disorders. The unmet need for treatment within this group is considerable and the lack of research is unacceptable. This paper will give a brief overview of epidemiological research into comorbidity; and examine the reasons why comorbidity might occur.

Therapeutic goals for otherwise healthy diabetic cats

The principle goals of treating diabetes in cats are to correct the major clinical signs of diabetes (weight loss, polydipsia / polyuria, and polyphagia or inappetence), and to prevent diabetic ketoacidosis. Additional goals are to minimize the risk of hypoglycaemia by appropriate dose adjustment of insulin or oral hypoglycaemic agents. Appropriate therapy of cats may also lead to diabetic remission, although currently it is not possible at diagnosis to predict which cats are more likely to go into remission. Treatment that is most effective in correcting hyperglycaemia is more likely to lead to remission by facilitating the recovery of the pancreatic cells from glucose toxicity.

A PSICOTERAPIA BREVE OPERACIONALIZADA DE MULHERES EM SITUAÇÃO DE VIOLÊNCIA DOMÉSTICA

A presente pesquisa foi realizada com duas mulheres em situação de violência doméstica e fundamentou-se nos pressupostos teóricos, técnicos e metodológicos da intervenção psicológica intitulada PBO- Psicoterapia Breve Operacionalizada. O objetivo foi analisar o processo da PBO de mulheres em situação de violência doméstica. Para a realização do diagnóstico adaptativo operacionalizado utilizou-se como instrumento a EDAO - Escala Diagnóstica Adaptativa Operacionalizada. O método utilizado foi o estudo clínico de abordagem psicanalítica que tem como base o estudo descritivo do tipo estudo de caso. As participantes realizaram cinco entrevistas diagnósticas e foram classificadas igualmente com adaptação ineficaz severa apresentando sintomas neuróticos mais limitadores, inibições restritivas e rigidez de traços caracterológicos. Elas foram encaminhadas para um atendimento em PBO. Após o final do processo realizou-se as entrevistas de Follow up que foram novamente avaliadas por meio da EDAO. Os dados obtidos nas entrevistas de follow up mostraram que houve mudança na eficácia adaptativa. As participantes foram classificadas igualmente com Adaptação Ineficaz Moderada. Elas apresentavam alguns sintomas neuróticos, inibição moderada, alguns traços caracterológicos. Conclui-se que nos casos estudados, na análise por setores, pôde-se perceber que o setor afetivo relacional constituiu-se como uma fonte de conflitos e insatisfações gerando soluções em sua maioria pouquíssimas adequadas, obviamente, influenciando decisivamente os demais setores da adaptação. Também, observou-se o fenômeno da reprodução de modelos do passado nas relações estabelecidas no presente. Nos dois casos estudados houve uma situação de violência física e de abuso sexual, que se configurava como uma herança provinda de uma dinâmica relacional da família de origem e se perpetuava livremente em suas famílias nucleares. Por último, cabe assinalar que as pacientes participaram de forma ativa durante o processo terapêutico. A partir das interpretações teorizadas foram capazes de reconsiderarem suas atitudes frente às situações-problema vividas e puderam, durante e após o processo psicoterapêutico, adotar algumas medidas concretas para enfrentá-las de forma mais adequada. Conclui-se que o processo de psicoterapia breve operacionalizado e a utilização das interpretações teorizadas parecem ter contribuído para a mudança na qualidade da eficácia adaptativa das duas mulheres que fizeram parte deste estudo.

ESTUDO DOS EFEITOS DE PROGRAMA DE APOIO NA AGRESSIVIDADE REACIONAL DE POLICIAIS ENVOLVIDOS EM OCORRÊNCIAS GRAVES

O objetivo do presente trabalho é estudar os efeitos de programa de apoio na agressividade reacional de policiais envolvidos em ocorrências graves, considerando-se como tal aquelas em que há confronto armado ou acidentes de trânsito com viaturas em atividade operacional, qualquer que seja o resultado do evento. Esse estudo é composto pela verificação da modificação da resposta agressiva reacional de 77 policiais militares envolvidos em ocorrências graves, utilizando-se, para esse fim, o Psicodiagnóstico Miocinético antes e depois da execução do programa de apoio. Compõem, ainda, o estudo a caracterização sóciodemográfica da amostra e a identificação dos níveis de agressividade nela existentes no início do programa e após o seu encerramento, além da definição do perfil de cinco categorias distintas, em função do tipo de resposta apresentada após o programa: agressividade ampliada, reduzida, inalterada, estável e instável. É ainda objeto da presente pesquisa o estudo clínico de um caso de cada uma das categorias definidas, de acordo com o perfil apurado, utilizando-se, além dos dados do Psicodiagnóstico Miocinético, outros levantados por intermédio de ficha de cadastro, de entrevista individual, do Teste Palográfico e da Escala de Personalidade de Comrey. Os resultados demonstram a modificação da resposta agressiva reacional na maioria dos policiais militares envolvidos no estudo, após o programa de apoio.

ASPECTOS PSICODINÂMICOS E ADAPTATIVOS DE PAIS E MÃES DE CRIANÇAS DIAGNOSTICADAS COM PARALISIA CEREBRAL

Diante do sofrimento e das questões enfrentadas por pais e mães de crianças diagnosticadas com paralisia cerebral, o presente trabalho estudou aspectos psicodinâmicos e adaptativos. Para tanto, foi realizado estudo clínico, de recorte diagnóstico, em que participaram dois pais e duas mães de crianças com paralisia cerebral que contavam de 1 a 5 anos de idade. Os pais e mães passaram por entrevistas clínicas preventivas orientadas pela EDAO e pela técnica de Desenho-Estória com Tema. A análise do material obtido indicou que todos eles passaram por período de crise após a notícia do diagnóstico da criança e, na atualidade, foram classificados como tendo Adaptação Ineficaz, sendo que os dois pais e uma mãe tinham Adaptação Ineficaz Severa, uma mãe Adaptação Ineficaz Moderada. Com relação aos aspectos intra-píquicos, foram identificadas defesas primitivas nessa lida com o sofrimento ocasionado pela deficiência da criança. Concluiu-se que os recursos internos anteriores ao nascimento da criança e à própria personalidade de cada pai/mãe foi preponderante em sua adaptação e que a paralisia cerebral da criança afetou todos os setores adaptativos dos pais e mães.(AU)

The tear film and contact lens wear

Contact lenses have become a popular method of vision correction for millions of people globally. As with all devices designed for use within the body, interactions occur between the implanted material and the surrounding biological fluid. A common complaint of lens wearers is that they often experience symptoms of dry eye whilst wearing lenses. This sensation is often heightened towards the end of the day. Through the course of this study, various analytical techniques have been utilised including one dimensional electrophoresis and Western Blotting to study the protein profiles of tear samples. By studying the tears of non-contact lens wearers, it was possible to analyse what could be considered normal, healthy, individuals. A clinical study was also undertaken which followed a population of individuals from the neophyte stage to one whereby they were accustomed lens wearers. Tears were monitored at regular intervals throughout the course of this study and worn contact lenses were also analysed for proteins that had been deposited both on and within the lens. Contact lenses disrupt the tear film in a physical manner by their very presence. They are also thought to cause the normal protein profile to deviate from what would be considered normal. The tear film deposits proteins and lipids onto and within the lens. The lens may therefore be depriving the tear film of certain necessary components. The ultimate aim of this thesis was to discover how, and to what extent, lenses affected tear proteins and if there were any proteins in the tear fluid that had the potential to be used as biochemical markers. Should this be achievable it may be possible to identify those individuals who were more likely to become intolerant lens wearers. This study followed the changes taking place to the tear film as an effect of wearing contact lenses. Twenty-eight patients wore two different types of silicone hydrogel lenses in both a daily wear and a continuous wear regime. The tear protein profiles of the lens-wearers were compared with a control group of non-lens wearing individuals. The considerable amount of data that was generated enabled the clearly observable changes to the four main tear proteins to be monitored.

Quantitative assessment of the pharmacotherapy of biopolar disorder and schizophrenia

The work present in this thesis was aimed at assessing the efficacy of lithium in the acute treatment of mania and for the prophylaxis of bipolar disorder, and investigating the value of plasma haloperidol concentration for predicting response to treatment in schizophrenia. The pharmacogenetics of psychotropic drugs is critically appraised to provide insights into interindividual variability in response to pharmacotherapy, In clinical trials of acute mania, a number of measures have been used to assess the severity of illness and its response to treatment. Rating instruments need to be validated in order for a clinical study to provide reliable and meaningful estimates of treatment effects, Eight symptom-rating scales were identified and critically assessed, The Mania Rating Scale (MRS) was the most commonly used for assessing treatment response, The advantage of the MRS is that there is a relatively extensive database of studies based on it and this will no doubt ensure that it remains a gold standard for the foreseeable future. Other useful rating scales are available for measuring mania but further cross-validation and validation against clinically meaningful global changes are required. A total of 658 patients from 12 trials were included in an evaluation of the efficacy of lithium in the treatment of acute mania. Treatment periods ranged from 3 to 4 weeks. Efficacy was estimated using (i) the differences in the reduction in mania severity scores, and (ii) the ratio and difference in improvement response rates. The response rate ratio for lithium against placebo was 1.95 (95% CI 1.17 to 3.23). The mean number needed to treat was 5 (95% CI 3 to 20). Patients were twice as likely to obtain remission with lithium than with chlorpromazine (rate ratio = 1.96, 95% CI 1.02 to 3.77). The mean number needed to treat (NNT) was 4 (95% CI 3 to 9). Neither carbamazepine nor valproate was more effective than lithium. The response rate ratios were 1.01 (95% CI 0.54 to 1.88) for lithium compared to carbarnazepine and 1.22 (95% CI 0.91 to 1.64) for lithium against valproate. Haloperidol was no better than lithium on the basis of improvement based on assessment of global severity. The differences in effects between lithium and risperidone were -2.79 (95% CI -4.22 to -1.36) in favour of risperidone with respect to symptom severity improvement and -0.76 (95% CI -1.11 to -0,41) on the basis of reduction in global severity of disease. Symptom and global severity was at least as well controlIed with lithium as with verapamil. Lithium caused more side-effects than placebo and verapamil, but no more than carbamazepine or valproate. A total of 554 patients from 13 trials were included in the statistical analysis of lithium's efficacy in the prophylaxis of bipolar disorder. The mean follow-up period was 5-34 months. The relapse risk ratio for lithium versus placebo was 0.47 (95% CI 0.26 to 0.86) and the NNT was 3 (95% CI 2 to 7). The relapse risk ratio for lithium versus imipramine was 0.62 (95% CI 0.46 to 0.84) and the NNT was 4 (951% Cl 3 to 7), The combination of lithium and imipramine was no more effective than lithium alone. The risk of relapse was greater with lithium alone than with the lithium-divalproate combination. A risk difference of 0.60 (95% CI 0.21 to 0.99) and an NNT of 2 (95% CI 1 to 5) were obtained. Lithium was as effective as carbamazepine. Based on individual data concerning plasma haloperidol concentration and percent improvement in psychotic symptoms, our results suggest an acceptable concentration range of 11.20-30.30 ng/mL A minimum of 2 weeks should be allowed before evaluating therapeutic response. Monitoring of drug plasma levels seems not to be necessary unless behavioural toxicity or noncompliance is suspected. Pharmacokinetics and pharmacodynamics, which are mainly determined by genetic factors, contribute to interindividual and interethnic variations in clinical response to drugs. These variations are primarily due to differences in drug metabolism. Variability in pharmacokinetics of a number of drugs is associated with oxidation polymorphism. Debrisoquine/sparteine hydroxylase (CYP2D6) and the S-mephenytoin hydroxylase (CYP2C19) are polymorphic P450 enzymes with particular importance in psychopharmacotherapy. The enzymes are responsible for the metabolism of many commonly used antipsychotic and antidepressant drugs. The incidence of poor metabolisers of debrisoquine and S-mephenytoin varies widely among populations. Ethnic variations in polymorphic isoenzymes may, at least in part, explain ethnic differences in response to pharmacotherapy of antipsychotics and antidepressant drugs.

Antibacterial activity of low amperage and low voltage electric current (DC)

Infection is a major clinical problem associated with the use of intravenous catheters.The efficacy of a direct electric current (10µA, 9V) via electrode-conducting carbon impregnated catheters to prevent colonisation of catheters by micro-organisms was investigated. The range of organisms susceptible to 10µA was determined by a zone of inhibition test. The catheters acting as the anode and the cathode were inserted into a nutrient agar plate inoculated with a lawn of bacteria. There was no zone of inhibition observed around the anode. Organisms susceptible to 10µA at the cathode were Staphylococcus aureus (2 strains), Staphylococcus epidermidis (5 strains), Escherichia coli and Klebsiella pneumoniae (2 strains each), and one strain of the following micro-organisms: Staphylococcus hominis, Proteus mirabilis, Pseudomonas aeruginosa and Candida albicans. The zones ranged from 6 to 16 mm in diameter according to the organisms under test. The zone size was proportional to the amperage (10 - 100 µA) and the number of organisms on the plate. Ten µA did not prevent adhesion of staphylococci to the cathode nor did it affect their growth in nutrient broth. However, it was bactericidal to adherent bacteria on the cathodal catheter and significantly reduced the number of bacteria on the catheter after 4 to 24 h application of electricity. The antimicrobial activity of low amperage electric current under anaerobic conditions and in the absence of chloride ions against bacteria attached to the surface of a current carrying electrode was also investigated.The mechanisms of the bactericidal activity associated with the cathode were investigated with S. epidermidis and S. aureus. The inhibition zone was greatly reduced in the presence of catalase. There was no zone around the cathode when the test was carried out under anaerobic conditions. Hydrogen peroxide was produced at the cathode surface under aerobic conditions, but not in the absence of oxygen. A salt-bridge apparatus was used to demonstrate further that hydrogen peroxide was produced at the cathode, and chlorine at the anode. The antimicrobial activity of low amperage electric current under anaerobic conditions and in the absence of chloride ions against bacteria attached to the surface of a current carrying electrode was also investigated. Antibacterial activity was reduced under anaerobic conditions, which is compatible with the role of hydrogen peroxide as a primary bactericidal agent of electricity associated with the cathode. A reduction in chloride ions did not significantly reduce the antibacterial activity suggesting chlorine plays only a minor role in the bactericidal activity against organisms attached to anodal electrode surfaces. The bactericidal activity of electric current associated with the cathode and H202 was greatly reduced in the presence of 50 μM to 0.5 mM magnesium ions in the test menstrum. Ten μA applied via the catheters did not prevent the initial biofilm growth by the adherent bacteria but reduced the number of bacteria in the biofilm by 2 log order aiter 24 h. The results suggested that 10 μA may prevent the colonisation of catheters by both the extra~ and intra-luminal routes. The localised production of hydrogen peroxide and chlorine and the intrinsic activity due to electric current may offer a useful method for the eradication of bacteria from catheter surfaces.

The language of female leadership

Could language be a reason why women are under-representedat senior level in the business world? The Language of Female Leadership investigates how female leaders actually use language to achieve their business and relational goals. The author proposes that the language of women leaders is shaped by the type of corporation they work for. Based on the latest research, three types of ‘gendered corporation’ appear to affect the way women interact with colleagues: the male-dominated,the gender-divided and the gender-multiple. This book shows that senior women have to carry out extra ‘linguistic work’ to make their mark in the boardroom. In male-dominated and gender-divided corporations, women must develop an extraordinarylinguistic expertise just to survive. In gender-multiple corporations, this linguistic expertise helps them to be highly regarded and effective leaders.Judith Baxter lectures in Applied Linguistics at the University of Aston. She has written and edited many publications in the field of language and gender, language and education and the language of leadership. She won a government award to conduct a major research study in the language of female leadership.