The compliance function in banking: Perspective and future in the age of globalization

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA – School of Business and Economics

Humoral response towards high density lipoprotein : a new mechanism for atherogenesis

RESUMO:Aterosclerose é uma das principais causas de morbilidade e mortalidade no mundo ocidental. É responsável, direta ou indiretamente, pela maior percentagem de gastos com a saúde na maioria dos países europeus. A “teoria lipídica” da aterosclerose, que se baseia na dislipidemia como causa primária para a doença vascular tem algumas implicações práticas importantes: permite a definição de linhas de orientação e protocolos simples e ainda estabelece alvos terapêuticos que podem ser atingidos na maior parte dos casos com a atual intervenção farmacológica. A associação da aterosclerose com o sistema imunológico (a “teoria imunológica”), forneceu por sua vez novas formas de explorar os mecanismos envolvidos e abriu novas perspetivas para um conhecimento mais completo da doença. No entanto, levanta dificuldades evidentes no que diz respeito às possibilidades terapêuticas. De todos os intervenientes no processo aterosclerótico (bioquímicos, imunológicos e anatómicos), as lipoproteínas de elevada densidade (HDL) são atualmente reconhecidas como um dos fatores mais importantes na aterogénese. Isto é baseado no reconhecimento das múltiplas propriedades anti-aterogénicas das HDL como por exemplo: a anti-oxidante, a anti-inflamatória e a antitrombótica, bem como o seu importante papel na melhoraria da função endotelial. Atualmente, é consensual que as funções anti-aterogénicas das HDL vão além do seu papel no transporte reverso do colesterol (RCT) e a importância das HDL no processo aterosclerótico baseia-se não apenas no seu papel protetor impedindo a formação da placa de ateroma, mas também na estabilização destas, prevenindo a sua ruptura e, consequentemente o evento trombótico. Como fundamentais no processo aterosclerótico estão reconhecidos dois principais conjuntos de eventos: um caracterizado por alterações no metabolismo das lipoproteínas que resultam em lipoproteínas pró-inflamatórias e pró-oxidantes que interagem com os componentes celulares da parede arterial e que conduzem à formação da placa de ateroma; o outro evento é a resposta imunológica desencadeada contra um novo conjunto de antigénios que por sua vez leva à produção de citoquinas pró-inflamatórias. Dada a complexidade da HDL e das suas múltiplas funções estas lipoproteínas tornaram-se um potencial alvo para a resposta auto-imune, e cujas consequências podem explicar algumas das associações identificados em estudos clínicos e epidemiológicos. Contudo esta interação entre o sistema imunológico e HDL nunca foi exaustivamente estudada. Portanto, pomos a hipótese de que em condições oxidativas e pró-inflamatórias, um aumento do antigénio (HDL) conduz a um consequente acréscimo na produção de anticorpos anti-HDL (aHDL) responsáveis pela alteração quantitativa e / ou qualitativa das HDL. O conceito de que estes anticorpos podem contribuir tanto para a evolução a longo prazo do processo aterosclerótico, como para o desencadeamento de eventos clínicos pode também explicar a heterogeneidade encontrada em cada doente e nos grandes estudos clínicos, no que diz respeito aos fatores de risco e outcomes clínicos. Para além disso, a confirmação desta hipótese pode permitir explicar porque é que as intervenções terapêuticas atualmente em desenvolvimento para aumentar os níveis de HDL, não conseguem mostrar a tão esperada redução do risco vascular. O objetivo geral desta tese foi identificar e caracterizar a resposta humoral contra os componentes da HDL, e avaliar possíveis mecanismos que possam contribuir para a modificação das propriedades anti-aterogénicas das HDL. Para alcançar este objetivo investigou-se: 1) A presença de anticorpos aHDL em doentes com lúpus eritematoso sistémico (SLE) e em doentes com manifestações clínicas de aterosclerose, como os doentes com doença arterial coronária (CAD), acidente vascular cerebral isquémico (IS) e diabetes tipo 2; 2) Os principais alvos antigénicos dentro do complexo das HDL e a associação entre os títulos de anticorpos aHDL e diferentes características clínicas destas doenças; 3) As modificações das funções normais associadas às HDL, em particular da função anti-oxidante e anti-inflamatória; 4) A atividade biológica dos anticorpos aHDL isolados do soro de doentes através de um conjunto de experiências in vitro de inibição da atividade da paraoxonase 1 (PON1) e da expressão de moléculas de adesão em culturas de células endoteliais. Para tal foi necessário estabelecer um método de isolamento dos anticorpos. Os anticorpos aHDL isolados do soro de doentes foram utilizados de forma a identificar as potenciais alterações dos sistemas celulares utilizados; 5) O efeito de fármacos usados no tratamento das dislipidemias, em particular o ácido nicotínico e as estatinas, na variação dos títulos de anticorpos aHDL através de ensaios clínicos randomizados, controlados com placebo e em dupla ocultação. Os métodos utilizados neste trabalho incluíram: técnicas imunológicas (como por exemplo, enzyme-linked immunoabsorbent assay - ELISA, ensaio imunoturbidimetrico e cromatografia de imuno-afinidade) técnicas bioquímicas (tais como a quantificação de atividade enzimática por espectrofotometria e por luminescência), experiências com cultura de células e citometria de fluxo. Os nossos resultados mostram que: 1) A presença de anticorpos aHDL, e mais especificamente anticorpos contra alguns do seus principais componentes como a apolipoproteína A-I (ApoA-I, principal apolipoproteína presente nas HDL) e a PON1 (o enzima que mais contribui para a propriedade anti-oxidante das HDL), quer em doentes com doenças auto-imunes, como o SLE, quer em doentes com manifestações clínicas de aterosclerose, como CAD, IS e diabetes tipo 2. Os doentes apresentaram títulos de anticorpos IgG aHDL, aApoA-I e aPON1 significativamente mais elevados do que controlos saudáveis com a mesma idade e sexo. 2) A correlação positiva estatisticamente significativa entre os títulos de aHDL e aApoA-I e aPON1 sugere que estes sejam dois dos principais alvos antigénicos dentro do complexo das HDL. Os anticorpos encontrados nestes doentes estão associados com a diminuição da atividade da PON1 e a uma redução da capacidade anti-oxidante total (TAC) do soro, um aumento dos biomarcadores de disfunção endotelial (como por exemplo dos metabolitos do óxido nítrico - NO2- e NO3-, as moléculas de adesão vascular e intracelular - VCAM-1 e ICAM-1 e os níveis de 3-nitrotirosina). Nos doentes com SLE os títulos destes estão associados a um aumento do dano cardiovascular e à atividade global da doença avaliados pelas escalas SLICC/ACR DI e BILAG score, respetivamente. Enquanto que nos doentes com diabetes tipo 2 estes anticorpos estão associados com um aumento dos níveis de glicemia em jejum (FGP) e hemoglobina glicada (HbA1c). 3) Após se ter estabelecido um método de isolamento dos anticorpos que permite isolar quantidades significativas de anticorpos do soro de doentes sem perder a sua especificidade, foi identificada a capacidade dos anticorpos isolados do soro de doentes inibirem de uma forma dependente da concentração a atividade da PON1 até um máximo de 70% no caso dos doentes com SLE e ente 7-52% no caso dos anticorpos isolados de doentes com CAD e IS. 4) O efeito anti-inflamatório das HDL na inibição da produção de VCAM-1 induzida por citoquinas (como o TNF-) foi revertido em mais de 80% pelos anticorpos aHDL isolados do soro de doentes. 5) A angiogenesis induzida por HDL através do aumento do fator de crescimento do endotélio vascular (VEGF) foi anulada em 65% pelos anticorpos aHDL isolados do soro de doentes. 6) Os atuais agentes farmacológicos disponíveis para aumentar as concentrações de HDL-C estão associados a um aumento dos títulos de anticorpos.-------- ABSTRACTAtherosclerosis is the major cause of morbidity and mortality in the western world. It is also responsible, directly or indirectly, for the highest percentage of health costs in most European countries. Despite the use of new technologies for the diagnosis of vascular disease and regardless of the major advances in treatment, the atherosclerosis-related clinical burden is still raising. The “lipid theory” of atherogenesis, which identifies dyslipidemia as the primary cause of this vascular disease has some important practical implications: it allows the definition of simple guidelines and establishes therapeutic targets which can be generally met with current pharmacologic intervention. The association between atherosclerosis an the immune system (the immune concept) has in turn provided new ways of exploring the mechanisms involved in this condition and has opened new perspectives in the understanding of the disease. However, it raises obvious difficulties when it comes to treatment options. Of all the players (biochemical, immunological and anatomical) involved in this matter, high-density lipoproteins (HDL) are currently recognised as one of the most important factors in atherogenesis. This is based on the recognition of HDL's multiple anti-atherogenic properties: anti-oxidant, anti-inflammatory and antithrombotic, as well as its capacity to improve endothelial function. Nowadays, it is widely recognized that the anti-atherogenic functions of HDL go beyond reverse cholesterol transport (RCT), and the importance of HDL is based not just on its ability to reduce atheroma formation but also on its ability to stabilise plaques, therefore preventing their rupture and ultimately thrombosis. Two main set of events have been recognised as fundamental in atherogenesis: one, characterized by lipoprotein metabolism alterations, resulting in pro-inflammatory and pro-oxidative lipoproteins, which interact with the normal cellular elements of the arterial wall leading to atheroma formation; the other, the immune cellular response towards new sets of antigens which lead to the production of pro-inflammatory cytokines. Given to HDL complexity and multiple functions this lipoprotein has became a potential target for an auto-immune response, the consequences of which may explain some of the association identified in epidemiological and clinical studies, though the interaction between the immune system and HDL has never been thoroughly addressed. Therefore, we hypothesized that under oxidative and pro-inflammatory conditions, the increase in the antigen (HDL) would lead to a consequent increase in the production of anti-HDL (aHDL) antibodies be responsible for quantitative and/or qualitative changes of HDL. The concept that these antibodies may contribute either to the long-term evolution of atherosclerosis or to the triggering of clinical events may also explain the heterogeneity found in individual patients and in large cohorts regarding risk factors and clinical outcomes. Moreover this may be a major breakthrough in understanding why therapeutic interventions that increase HDL levels, failed to show the anticipated reduction in vascular risk. The overall aims of this thesis were to identified and characterize the humoral response towards HDL components and to evaluate the possible mechanisms that may contribute to the modifications of the anti-atherogenic properties of HDL. To achieve this objective we investigated: 1) the presence of aHDL antibodies in patients with systemic lupus erythematosus (SLE) and in patients with atherosclerosis-related clinical events, such as coronary artery disease (CAD), ischemic stroke (IS) and type 2 diabetes; 2) the association between the titres of aHDL antibodies and different clinical features of these diseases; 3) the modifications of the anti-atherogenic properties of HDL; 4) the biologic effect of aHDL antibodies isolated from serum of patients on the anti-oxidant and anti-inflammatory properties of HDL; 5) the effect of different pharmacologic treatments for dyslipidemia on the prevalence and activity of aHDL antibodies. The methodologies used in this work included immunologic-related techniques (e.g. enzyme-linked immunoabsorbent assay – ELISA, immunoturbidimetric immunoassay and immunoaffinity chromatography), biochemical techniques (enzymatic assays with quantification by spectrophotometry and luminescence methods), cell culture experiments and flow cytometry. Our results indicate that: 1) The titres of IgG aHDL, anti-apolipoprotein A-I (aApoA-I) and anti-paraoxonase 1 (aPON1) antibodies were higher in patients with SLE, CAD, IS and type 2 diabetes when compared with age and sex matched healthy controls. 2) The antibodies found in these patients were associated with decreased PON1 activity, (the enzyme responsible for most of the anti-oxidant effect of HDL), reduced total anti-oxidant capacity (TAC) of serum and increased biomarkers of endothelial dysfunction (nitric oxide metabolites, adhesion molecules, nitrotyrosine). In patients with SLE the antibody titres were associated with an increase in disease-related cardiovascular damage and activity whereas in patients with type 2 diabetes they were directly related with the fasting glucose plasma (FGP) levels and the glycosylated haemoglobin (HbA1c). 3) The antibodies isolated from serum of our patients, directly inhibited HDL-associated PON1 activity in a dose dependent way ranging from 7 to 52%. 4) The anti-inflammatory effect of HDL, measured by the percentage of inhibition of the cytokine-induced production of vascular adhesion molecules (VCAM-1), was reduced in more than 80% by aHDL antibodies isolated from our patients. 5) The HDL-induced angiogenesis by increasing vascular endothelial growth factor (VEGF) levels was abrogated in 65% by the antibodies isolated from serum of patients. 6) The current available pharmacologic agents for increasing HDL-C concentrations were associated with an increase in the titres of IgG aApoA-I antibodies. This increase was higher in the extended release niacin when compared to statins probably due to their dampening effect on oxidative stress. In conclusion, aHDL antibodies are present in different pathologic conditions. aHDL antibodies represent a family of self-reacting immunoglobulins, of which ApoA-I and PON1 might be the most relevant targets. These antibodies are biologically active, interfering with the HDL anti-oxidant and anti-inflammatory properties and, consequently, with the atherosclerotic process. The pathogenic potential of these antibodies may lead to the identification of a new biomarker for vascular disease, whilst presenting itself as a novel target for a different treatment approach which may redefine the treatment strategies and clinical trials design for HDL interventions in the future.

Mental health care assessed based on structure, process and outcome : a retrospective cohort study

RESUMO: As doenças mentais são comuns, universais e associadas a uma significativa sobrecarga pessoal, familiar, social e económica. Os Serviços de Saúde Mental devem abordar de forma adequada as necessidades dos pacientes e familiares tanto ao nível clínico como também ao nível social. O presente estudo foi realizado num período de grande transformação nos sistemas de saúde primário e de saúde mental em Portugal, num Departamento de Psiquiatria desenvolvido com base nos princípios da OMS. Os objectivos incluem a caracterização: 1) das Unidades Funcionais do Departamento; 2) dos pacientes internados pela primeira vez no internamento de agudos; 3) da utilização dos serviços nas equipas comunitárias após a alta; e 4) da avaliação de alguns dos indicadores de qualidade do departamento, com recurso ao modelo de Donabedian sobre a articulação entre a Estrutura-Processo-Resultados. Metodologia: Foi escolhido um estudo de coorte retrospectivo. Todos os pacientes internados pela primeira vez entre 2008 e 2010 foram incluídos no estudo. Os seus processos clínicos e a base de dados do hospital onde são registados todos os contactos que estes tiveram com os profissionais de saúde mental foram revistos de forma a obter dados sociodemográficos e clínicos, durante o período do estudo e após a alta. Os instrumentos utilizados foram o WHO-ICMHC (Classificação Internacional de Cuidados de Saúde Mental), para caracterizar o Departamento, o AIESMP (Avaliação Inicial de Enfermagem em Saúde Mental e Psiquiatria) para recolha dos dados sociodemográficos, e o VSSS (Escala de Satisfação com os Serviços de Verona) de forma a avaliar a satisfação dos pacientes em relação aos cuidados recebidos. A análise estatística incluiu a análise descritiva, quantitativa e qualitativa dos dados. Resultados: As Unidades Funcionais do Departamento revelaram níveis elevados de articulação e consistência com as necessidades de cuidados psiquiátricos e reabilitação psicossocial dos pacientes. Os 543 pacientes admitidos pela primeira vez eram maioritariamente (56.9%) mulheres, caucasianas (81.2%), com diagnóstico de perturbações do humor (66.3%), internadas voluntariamente (59.7%), e uma idade média de 45.1 anos. Estas eram significativamente mais velhas, mais frequentemente empregadas, casadas/coabitar e tinham uma prevalência mais elevada de perturbações do humor, comparativamente aos homens. O internamento compulsivo era mais significativo nos homens (54.7%). A taxa de abandono no pós-alta (4.2%) e a taxa de reinternamentos (2.9%) na quinzena após a alta revelaram-se inferiores aos padrões na literatura internacional. De forma global, a satisfação dos pacientes com os cuidados de saúde mental foi positiva. Conclusões: Os cuidados prestados mostraram-se eficazes, adaptados e baseados nas necessidades e problemas específicos dos pacientes. A continuidade e a abrangência de cuidados foram difundidos e mantidos ao longo do processo de cuidados. Este Departamento pode ser considerado um exemplo de como proporcionar tratamento digno e eficiente, e uma referência para futuros serviços de psiquiatria.-------------- ABSTRACT: Mental health disorders are common, universal, and associated with heavy personal, family, social and economic burden. Mental health services should be aimed at adequately addressing patients’ and families’ needs at clinical and social level. The current study was carried out at a time of great transformation in the health and mental health systems in Portugal, in a Psychiatric Department developed taking in consideration the WHO principles. The objectives included characterizing: 1) the Psychiatric Department’s different units; 2) the patients admitted for the first time to the inpatient unit; 3) their use of community mental health services after discharge; and 4) assessing some of the department’s quality indicators, with resource to Donabedian’s Structure-Process-Outcome model. Methodology: A retrospective cohort design was chosen. All the firstly admitted patients in the period between 2008 and 2010 were included in the study. Their clinical records and the hospital’s database which registers all of the contacts the patients had with the mental health professionals during the study period, were reviewed to retrieve sociodemographic and clinical data and information on follow-up. The instruments used were the WHO International Classification of Mental Health Care (ICMHC) to characterize the department, the Initial Nurses’ Assessment in Mental Health and Psychiatry (AIESMP) for patients’ sociodemographic data, and the Verona Service Satisfaction Scale (VSSS) to assess patients’ satisfaction with care received. Statistical analysis included descriptive, quantitative and qualitative analysis of the data. Results: The Department’s Functional units revealed high levels of articulation, and were consistent with patients’ needs for psychiatric care and psychosocial rehabilitation. The 543 patients firstly admitted were mainly (56.9%) female, Caucasian (81.2%), diagnosed with mood disorders (66.3%), voluntarily admitted (59.7%), and with a mean age of 45.1 years. Female patients were significantly older, more frequently employed, married/cohabiting and had a higher prevalence of mood disorders when compared to males. Involuntary admission was more significant in males (54.7%). Dropout rates during follow-up (4.2%) and readmission rates (2.9%) in the fortnight following discharge were lower than standards in international literature. Overall patients’ satisfaction with mental health care was positive. Conclusions: The care delivered was effective, adapted and based on the patients’ specific needs and problems. Continuity and comprehensiveness of care was endorsed and maintained throughout the care process. This department may be considered an example of both humane and effective treatment, and a reference for future psychiatric care.

Association between the degree of physical impairment from leprosy and dependence in activities of daily living among the elderly in a health unit in the State of Minas Gerais

Introduction In addition to the common alterations and diseases inherent in the aging process, elderly persons with a history of leprosy are particularly vulnerable to dependence because of disease-related impairments. Objective determine whether physical impairment from leprosy is associated with dependence among the elderly. Methods An analytical cross-sectional study of elderly individuals with a history of leprosy and no signs of cognitive impairment was conducted using a database from a former leprosy colony-hospital. The patients were evaluated for dependence in the basic activities of daily living (BADL) and instrumental activities of daily living (IADL), respectively) and subjected to standard leprosy physical disability grading. Subsequently, descriptive and univariate analyses were conducted, the latter using Pearson's chi-squared test. Results A total of 186 elderly persons were included in the study. Of these individuals, 53.8% were women, 49.5% were older than 75 years of age, 93% had four or less years of formal education, 24.2% lived in an institution for the long-term care of the elderly (ILTC), and 18.3% had lower limb amputations. Among those evaluated, 79.8% had visible physical impairments from leprosy (grade 2), 83.3% were independent in BADL, and 10.2% were independent in IADL. There was a higher impairment grade among those patients who were IADL dependent (p=0.038). Conclusion s: The leprosy physical impairment grade is associated with dependence for IADL, creating the need for greater social support and systematic monitoring by a multidisciplinary team. The results highlight the importance of early diagnosis and treatment of leprosy to prevent physical impairment and dependence in later years.

Density-dependent morphological plasticity and trade-offs among vegetative traits in Eichhornia crassipes (Pontederiaceae)

Density-dependent responses are an important component of the organism life-history, and the resource allocation theory is a central concept to the life-history theory. When resource allocation varies due to environmental changes, a plant may change its morphology or physiology to cope with the new conditions, a process known as phenotypic plasticity. Our study aimed to evaluate how plant density affects Eichhornia crassipes allocation patterns. A total of 214 individuals in high and low density were collected. The density effect was observed in all plant traits examined including biomass accumulation. All traits of E. crassipes demonstrated higher values in high density conditions, except for biomass of leaves. Density exhibited a high influence on vegetative traits of E. crassipes, but did not influence allocation pattern, since a trade-off among the vegetative traits was not found. The morphological plasticity and the absence of trade-offs were discussed as strategies to overcome neighbor plants in competition situations. In high density conditions, there were clear changes in the morphology of the plants which probably allows for their survival in a highly competitive environment.

Alcohol-dependent patients receiving specialised outpatient care: an overview of gender issues

OBJECTIVE: The objective of the present study, with focus on gender, was aimed at evaluating alcohol-dependent individual in terms of socio-demographic variables related to alcohol consumption and therapeutic interventions. METHODS: This is a retrospective cross-sectional study of 1,051 patients (833 men and 218 women), with diagnosis of alcohol dependence syndrome, according to ICD-10 criteria, who had sought treatment for the first time at a specialised health centre between 2000 and 2006. RESULTS: The results showed that women, compared to men, are more likely to be unemployed and without partner, in addition to having higher educational level, latter age of alcohol initiation, needing less outpatient alcohol detoxification program, consuming more fermented beverage, presenting less psychiatric comorbidities, and using less coadjutant medications during treatment. CONCLUSION: We can state that some peculiarities exist permeating both gender and alcohol consumption. A further focus on the characteristics of each population is needed to facilitate the adequate use of therapeutic interventions according to gender specificities.

Ambulatory blood pressure monitoring and microalbuminuria in normotensive subjects with insulin-dependent diabetes mellitus

OBJECTIVE: To assess the association between microalbuminuria with ambulatory blood pressure monitoring in normotensive individuals with insulin-dependent diabetes mellitus. METHODS: Thirty-seven patients underwent determination of the rate of urinary excretion of albumin through radioimmunoassay and ambulatory blood pressure monitoring. Their mean age was 26.5±6.7 years, and the mean duration of their disease was 8 (1-34) years. Microalbuminuria was defined as urinary excretion of albumin > or = 20 and <200µg/min in at least 2 out of 3 urine samples. RESULTS: Nine (24.3%) patients were microalbuminuric. Ambulatory blood pressure monitoring in the microalbuminuric patients had higher mean pressure values, mainly the systolic pressure, during sleep as compared with that in the normoalbuminuric patients (120.1±8.3 vs 110.8±7.1 mmHg; p=0.007). The pressure load was higher in the microalbuminuric individuals, mainly the systolic pressure load during wakefulness [6.3 (2.9-45.9) vs 1.6 (0-16%); p=0.001]. This was the variable that better correlated with the urinary excretion of albumin (rS=0.61; p<0.001). Systolic pressure load >50% and diastolic pressure load > 30% during sleep was associated with microalbuminuria (p=0.008). The pressure drop during sleep did not differ between the groups. CONCLUSION: Microalbuminuric normotensive insulin-dependent diabetic patients show greater mean pressure value and pressure load during ambulatory blood pressure monitoring, and these variables correlate with urinary excretion of albumin.

Chronic Stress Improves NO- and Ca2+ Flux-Dependent Vascular Function: A Pharmacological Study

Background: Stress is associated with cardiovascular diseases. Objective: This study aimed at assessing whether chronic stress induces vascular alterations, and whether these modulations are nitric oxide (NO) and Ca2+ dependent. Methods: Wistar rats, 30 days of age, were separated into 2 groups: control (C) and Stress (St). Chronic stress consisted of immobilization for 1 hour/day, 5 days/week, 15 weeks. Systolic blood pressure was assessed. Vascular studies on aortic rings were performed. Concentration-effect curves were built for noradrenaline, in the presence of L-NAME or prazosin, acetylcholine, sodium nitroprusside and KCl. In addition, Ca2+ flux was also evaluated. Results: Chronic stress induced hypertension, decreased the vascular response to KCl and to noradrenaline, and increased the vascular response to acetylcholine. L-NAME blunted the difference observed in noradrenaline curves. Furthermore, contractile response to Ca2+ was decreased in the aorta of stressed rats. Conclusion: Our data suggest that the vascular response to chronic stress is an adaptation to its deleterious effects, such as hypertension. In addition, this adaptation is NO- and Ca2+-dependent. These data help to clarify the contribution of stress to cardiovascular abnormalities. However, further studies are necessary to better elucidate the mechanisms involved in the cardiovascular dysfunction associated with stressors. (Arq Bras Cardiol. 2014; [online].ahead print, PP.0-0)

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice.

A role for the gastro-intestinal tract in controlling bone remodeling is suspected since serum levels of bone remodeling markers are affected rapidly after a meal. Glucose-dependent insulinotropic polypeptide (GIP) represents a suitable candidate in mediating this effect. The aim of the present study was to investigate the effect of total inhibition of GIP signaling on trabecular bone volume, microarchitecture and quality. We used GIP receptor (GIPR) knockout mice and investigated trabecular bone volume and microarchitecture by microCT and histomorphometry. GIPR-deficient animals at 16 weeks of age presented with a significant (20%) increase in trabecular bone mass accompanied by an increase (17%) in trabecular number. In addition, the number of osteoclasts and bone formation rate was significantly reduced and augmented, respectively in these animals when compared with wild-type littermates. These modifications of trabecular bone microarchitecture are linked to a remodeling in the expression pattern of adipokines in the GIPR-deficient mice. On the other hand, despite significant enhancement in bone volume, intrinsic mechanical properties of the bone matrix was reduced as well as the distribution of bone mineral density and the ratio of mature/immature collagen cross-links. Taken together, these results indicate an increase in trabecular bone volume in GIPR KO animals associated with a reduction in bone quality.

Pathfinding of corticothalamic axons relies on a rendezvous with thalamic projections.

Major outputs of the neocortex are conveyed by corticothalamic axons (CTAs), which form reciprocal connections with thalamocortical axons, and corticosubcerebral axons (CSAs) headed to more caudal parts of the nervous system. Previous findings establish that transcriptional programs define cortical neuron identity and suggest that CTAs and thalamic axons may guide each other, but the mechanisms governing CTA versus CSA pathfinding remain elusive. Here, we show that thalamocortical axons are required to guide pioneer CTAs away from a default CSA-like trajectory. This process relies on a hold in the progression of cortical axons, or waiting period, during which thalamic projections navigate toward cortical axons. At the molecular level, Sema3E/PlexinD1 signaling in pioneer cortical neurons mediates a "waiting signal" required to orchestrate the mandatory meeting with reciprocal thalamic axons. Our study reveals that temporal control of axonal progression contributes to spatial pathfinding of cortical projections and opens perspectives on brain wiring.

Male dominance linked to size and age, but not to 'good genes' in brown trout (Salmo trutta).

BACKGROUND: Males that are successful in intra-sexual competition are often assumed to be of superior quality. In the mating system of most salmonid species, intensive dominance fights are common and the winners monopolise most mates and sire most offspring. We drew a random sample of mature male brown trout (Salmo trutta) from two wild populations and determined their dominance hierarchy or traits linked to dominance. The fish were then stripped and their sperm was used for in vitro fertilisations in two full-factorial breeding designs. We recorded embryo viability until hatching in both experiments, and juvenile survival during 20 months after release into a natural streamlet in the second experiment. Since offspring of brown trout get only genes from their fathers, we used offspring survival as a quality measure to test (i) whether males differ in their genetic quality, and if so, (ii) whether dominance or traits linked to dominance reveal 'good genes'. RESULTS: We found significant additive genetic variance on embryo survival, i.e. males differed in their genetic quality. Older, heavier and larger males were more successful in intra-sexual selection. However, neither dominance nor dominance indicators like body length, weight or age were significantly linked to genetic quality measured as embryo or juvenile survival. CONCLUSION: We found no evidence that females can improve their offspring's genetic viability by mating with large and dominant males. If there still were advantages of mating with dominant males, they may be linked to non-genetic benefits or to genetic advantages that are context dependent and therefore possibly not revealed under our experimental conditions - even if we found significant additive genetic variation for embryo viability under such conditions.

Optimal latent period in a bacteriophage population model structured by infection-age

We study the lysis timing of a bacteriophage population by means of a continuously infection-age-structured population dynamics model. The features of the model are the infection process of bacteria, the natural death process, and the lysis process which means the replication of bacteriophage viruses inside bacteria and the destruction of them. We consider that the length of the lysis timing (or latent period) is distributed according to a general probability distribution function. We have carried out an optimization procedure and we have found the latent period corresponding to the maximal fitness (i.e. maximal growth rate) of the bacteriophage population.

Macrophages induce neutrophil apoptosis through membrane TNF, a process amplified by Leishmania major.

Neutrophils are recruited to the site of parasite inoculation within a few hours of infection with the protozoan parasite Leishmania major. In C57BL/6 mice, which are resistant to infection, neutrophils are cleared from the site of s.c. infection within 3 days, whereas they persist for at least 10 days in susceptible BALB/c mice. In the present study, we investigated the role of macrophages (MPhi) in regulating neutrophil number. Inflammatory cells were recruited by i.p. injection of either 2% starch or L. major promastigotes. Neutrophils were isolated and cultured in the presence of increasing numbers of MPhi. Extent of neutrophil apoptosis positively correlated with the number of MPhi added. This process was strictly dependent on TNF because MPhi from TNF-deficient mice failed to induce neutrophil apoptosis. Assays using MPhi derived from membrane TNF knock-in mice or cultures in Transwell chambers revealed that contact with MPhi was necessary to induce neutrophil apoptosis, a process requiring expression of membrane TNF. L. major was shown to exacerbate MPhi-induced apoptosis of neutrophils, but BALB/c MPhi were not as potent as C57BL/6 MPhi in this induction. Our results emphasize the importance of MPhi-induced neutrophil apoptosis, and membrane TNF in the early control of inflammation.

Dose-dependent positive association between cigarette smoking, abdominal obesity and body fat: cross-sectional data from a population-based survey.

ABSTRACT: BACKGROUND: Although smokers tend to have a lower body-mass index than non-smokers, smoking may favour abdominal body fat accumulation. To our knowledge, no population-based studies have assessed the relationship between smoking and body fat composition. We assessed the association between cigarette smoking and waist circumference, body fat, and body-mass index. METHODS: Height, weight, and waist circumference were measured among 6,123 Caucasians (ages 35-75) from a cross-sectional population-based study in Switzerland. Abdominal obesity was defined as waist circumference>=102 cm for men and >=88 cm for women. Body fat (percent total body weight) was measured by electrical bioimpedance. Age- and sex-specific body fat cut-offs were used to define excess body fat. Cigarettes smoked per day were assessed by self-administered questionnaire. Age-adjusted means and odds ratios were calculated using linear and logistic regression. RESULTS: Current smokers (29% of men and 24% of women) had lower mean waist circumference, body fat percentage, and body-mass index compared with non-smokers. Age-adjusted mean waist circumference and body fat increased with cigarettes smoked per day among smokers. The association between cigarettes smoked per day and body-mass index was non-significant. Compared with light smokers, the adjusted odds ratio (OR) for abdominal obesity in men was 1.28 (0.78-2.10) for moderate smokers and 1.94 (1.15-3.27) for heavy smokers (P=0.03 for trend), and 1.07 (0.72-1.58) and 2.15 (1.26-3.64) in female moderate and heavy smokers, respectively (P<0.01 for trend). Compared with light smokers, the OR for excess body fat in men was 1.05 (95% CI: 0.58-1.92) for moderate smokers and 1.15 (0.60-2.20) for heavy smokers (P=0.75 for trend) and 1.34 (0.89-2.00) and 2.11 (1.25-3.57), respectively in women (P=0.07 for trend). CONCLUSION: Among smokers, cigarettes smoked per day were positively associated with central fat accumulation, particularly in women.

A general multiserver state-dependent queueing system

The work studies a general multiserver queue in which the service time of an arriving customer and the next interarrival period may depend on both the current waiting time and the server assigned to the arriving customer. Stability of the system is proved under general assumptions on the predetermined distributions describing the model. The proof exploits a combination of the Markov property of the workload process with a regenerative property of the process. The key idea leading to stability is a characterization of the limit behavior of the forward renewal process generated by regenerations. Extensions of the basic model are also studied.