Type I signal peptidase from Leishmania is a target of the immune response in human cutaneous and visceral leishmaniasis.

The gene encoding type I signal peptidase (Lmjsp) has been cloned from Leishmania major. Lmjsp encodes a protein of 180 amino residues with a predicted molecular mass of 20.5 kDa. Comparison of the protein sequence with those of known type I signal peptidases indicates homology in five conserved domains A-E which are known to be important, or essential, for catalytic activity. Southern blot hybridisation analysis indicates that there is a single copy of the Lmjsp gene. A recombinant SPase protein and a synthetic peptide of the L. major signal peptidase were used to examine the presence of specific antibodies in sera from either recovered or active individuals of both cutaneous and visceral leishmaniasis. This evaluation demonstrated that sera from cutaneous and visceral forms of leishmaniasis are highly reactive to both the recombinant and synthetic signal peptidase antigens. Therefore, the Leishmania signal peptidase, albeit localised intracellularly, is a significant target of the Leishmania specific immune response and highlights its potential use for serodiagnosis of cutaneous and visceral leishmaniasis.

Affect-related synesthesias: A prospective view on their existence, expression and underlying mechanisms

The literature on developmental synaesthesia has seen numerous sensory combinations, with surprisingly few reports on synaesthesias involving affect. On the one hand, emotion, or more broadly affect, might be of minor importance to the synaesthetic experience (e.g. Sinke et al., 2012). On the other hand, predictions on how affect could be relevant to the synaesthetic experience remain to be formulated, in particular those that are driven by emotion theories. In this theoretical paper, we hypothesize that a priori studies on synaesthesia involving affect will observe the following. Firstly, the synaesthetic experience is not merely about discrete emotion processing or overall valence (positive, negative) but is determined by or even altered through cognitive appraisal processes. Secondly, the synaesthetic experience changes temporarily on a quantitative level according to i) the affective appraisal of the inducing stimulus or ii) the current affective state of the individual. These hypotheses are inferred from previous theoretical and empirical accounts on synaesthesia (including the few examples involving affect), different emotion theories, crossmodal processing accounts in synaesthetes and nonsynaesthetes, and the presumed stability of the synaesthetic experience. We hope that the current review will succeed in launching a new series of studies on "affective synaesthesias". We particularly hope that such studies will apply the same creativity in experimental paradigms as we have seen and still see when assessing and evaluating "traditional" synaesthesias.

Evaluation of C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as diagnostic parameters in sepsis-related fatalities.

The aims of this study were to investigate the usefulness of serum C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as postmortem markers of sepsis and to compare C-reactive protein and procalcitonin values in serum, vitreous humor, and cerebrospinal fluid in a series of sepsis cases and control subjects, in order to determine whether these measurements may be employed for the postmortem diagnosis of sepsis. Two study groups were formed, a sepsis group (eight subjects coming from the intensive care unit of two university hospitals, with a clinical diagnosis of sepsis in vivo) and control group (ten autopsy cases admitted to two university medicolegal centers, deceased from natural and unnatural causes, without elements to presume an underlying sepsis as the cause of death). Serum C-reactive protein and procalcitonin concentrations were significantly different between sepsis cases and control cases, whereas serum tumor necrosis factor alpha, interleukin-6, and interleukin-8 values were not significantly different between the two groups, suggesting that measurement of interleukin-6, interleukin-8, and tumor necrosis factor alpha is non-optimal for postmortem discrimination of cases with sepsis. In the sepsis group, vitreous procalcitonin was detectable in seven out of eight cases. In the control group, vitreous procalcitonin was clearly detectable only in one case, which also showed an increase of all markers in serum and for which the cause of death was myocardial infarction associated with multi-organic failure. According to the results of this study, the determination of vitreous procalcitonin may be an alternative to the serum procalcitonin for the postmortem diagnosis of sepsis.

Exotic taxa less related to native species are more invasive.

Some species introduced into new geographical areas from their native ranges wreak ecological and economic havoc in their new environment. Although many studies have searched for either species or habitat characteristics that predict invasiveness of exotic species, the match between characteristics of the invader and those of members of the existing native community may be essential to understanding invasiveness. Here, we find that one metric, the phylogenetic relatedness of an invader to the native community, provides a predictive tool for invasiveness. Using a phylogenetic supertree of all grass species in California, we show that highly invasive grass species are, on average, significantly less related to native grasses than are introduced but noninvasive grasses. The match between the invader and the existing native community may explain why exotic pest species are not uniformly noxious in all novel habitats. Relatedness of invaders to the native biota may be one useful criterion for prioritizing management efforts of exotic species.

Interdisciplinary intervention for work-related musculoskeletal disorders

The proposed research aims to address the work-related MSD management issue through an interdisciplinary intervention involving clinical and occupational health competencies (rheumatology, occupational medicine, ergonomics). Workers enduring MSD (especially back-pain) and absent from work are selected from volunteering companies (construction, hospitals, public transport, delivery networks). The workers are randomly placed into two groups : the control group benefits from an usual MSD management strategy and the intervention group benefits from a case-management strategy including workhardening treatment (work oriented reeducation) and ergonomic intervention in the workplace. The comparison of health and work-related variables prior and after intervention in the two groups will be used to assess the intervention efficiency and its economic benefits. We expect to produce new strategies for the management of MSD and workplace rehabilitation as well as guidelines for both authorities and companies.

Reducing the clinical burden of ranibizumab treatment for neovascular age-related macular degeneration using an individually planned regimen.

AIMS: The purpose of this study was to clinically validate an individually planned treatment regimen for neovascular age-related macular degeneration (nAMD), termed, observe and plan. This regimen was based on the predictability of an individual's need for retreatment and aimed to reduce the clinical burden, while obtaining good functional results. METHODS: This was a prospective case series that included 104 patients (115 eyes) with treatment-naive nAMD. Following three loading doses of ranibizumab, monthly observation visits allowed the disease recurrence interval to be determined. The recurrence interval was reduced by 2 weeks to give the retreatment interval for the next three injections. Periodical control visits (at least every 6 months) allowed the effectiveness of the treatment to be assessed and individual intervals adjusted. RESULTS: Mean visual acuity (VA) improved by 8.7 and 9.8 letters in months 3 and 12, respectively. The mean number of injections during the 12-month study was 7.8, while the mean number of ophthalmic examinations between months 3 and 12 was 3.97. The mean treatment interval after the loading doses was 1.97 months. CONCLUSIONS: The observe-and-plan regimen significantly improved VA. This was obtained with fewer clinic visits compared with other regimens, which could ease the burden of nAMD treatment. TRIAL REGISTRATION NUMBER: Commission cantonale (VD) d'éthique de la recherché Clinique, Université de Lausanne, Protocole 351/11.

Long-term cerebral plasticity-related gene expression : a study of the respective role of CBP and CRTC1 in CREB transcriptional activation

1.1 AbstractThe treatment of memory disorders and cognitive deficits in various forms of mental retardation may greatly benefit from a better understanding of the molecular and cellular mechanisms of memory formation. Different forms of memory have distinct molecular requirements.Short-term memory (STM) is thought to be mediated by covalent modifications of existing synaptic molecules, such as phosphorylation or dephosphorylation of enzymes, receptors or ion channels. In contrast, long-term memoiy (LTM) is thought to be mediated by growth of new synapses and restructuring of existing synapses. There is extensive evidence that changes in gene expression and de novo protein synthesis are key processes for LTM formation. In this context, the transcription factor CREB (cAMP-response element-binding protein) was shown to be crucial. Activation of CREB requires phosphorylation of a serine residue (Ser-133), and the subsequent recruitment of a coactivator called CREB-binding protein (CBP). Moreover, we have recently shown that another coactivator called CREB Regulated Transcription Coactivator 1 (CRTC1) functions as a calcium- and cAMP-sensitive coincidence detector in neurons, and is involved in hippocampal long-term synaptic plasticity. Given the importance of cAMP and calcium signaling for plasticity-related gene expression in neurons and in astrocytes, we sought to determine the respective involvement of the CREB coactivators CBP and CRTC1 in CREB-mediated transcription.We developed various strategies to selectively interfere with these CREB coactivators in mouse primary neurons and in astrocytes in vitro. However, despite several pieces of evidence implicating CBP and/or CRTC1 in the regulation of neuronal plasticity genes, we could not clearly determine the respective requirement of these coactivators for the activation of these genes. Nevertheless, we showed that calcineurin activity, which is important for CRTC1 nuclear translocation, is necessary for the expression of some CREB-regulated plasticity genes. We associated this phenomena to physiopathological conditions observed in Down's syndrome. In addition, we demonstrated that in astrocytes, noradrenaline stimulates CREB-target gene expression through β-adrenergic receptor activation, intracellular cAMP pathway activation, and CRTC-induced CREB transactivation.Defining the respective role of CREB and its coactivators CBP and CRTC1 in neuronal and astrocytic cultures in vitro sets the stage for future in vivo studies and for the possible development of new therapeutic strategies to improve the treatment of memoiy and cognitive disorders.1.2 RésuméUne meilleure connaissance des mécanismes moléculaires et cellulaires responsables de la formation de la mémoire pourrait grandement améliorer le traitement des troubles de la mémoire ainsi que des déficits cognitifs observés dans différentes formes de pathologies psychiatriques telles que le retard mental. Les différentes formes de mémoire dépendent de processus moléculaires différents.La mémoire à court terme (STM) semble prendre forme suite à des modifications covalentes de molécules synaptiques préexistantes, telles que la phosphorylation ou la déphosphorylation d'enzymes, de récepteurs ou de canaux ioniques. En revanche, la mémoire à long terme (LTM) semble être due à la génération de nouvelles synapses et à la restructuration des synapses existantes. De nombreuses études ont permis de démontrer que les changements dans l'expression des gènes et la synthèse de protéine de novo sont des processus clés pour la formation de la LTM. Dans ce contexte, le facteur de transcription CREB (cAMP-response element-binding protein) s'est avéré être un élément crucial. L'activation de CREB nécessite la phosphorylation d'un résidu sérine (Ser-133), et le recrutement d'un coactivateur nommé CBP (CREB binding protein). En outre, nous avons récemment démontré qu'un autre coactivateur de CREB nommé CRTC1 (CREB Regulated Transcription Coactivator 1) agit comme un détecteur de coïncidence de l'AMP cyclique (AMPc) et du calcium dans les neurones et qu'il est impliqué dans la formation de la plasticité synaptique à long terme dans l'hippocampe. Etant donné l'importance des voies de l'AMPc et du calcium dans l'expression des gènes impliqués dans la plasticité cérébrale, nous voulions déterminer le rôle respectif des coactivateurs de CREB, CBP et CRTC1.Nous avons développé diverses stratégies pour interférer de façon sélective avec les coactivateurs de CREB dans les neurones et dans les astrocytes chez la souris in vitro. Nos résultats indiquent que CBP et CRTC1 sont tous deux impliqués dans la transcription dépendante de CREB induite par l'AMPc et le calcium dans les neurones. Cependant, malgré plusieurs évidences impliquant CBP et/ou CRTC1 dans l'expression de gènes de plasticité neuronale, nous n'avons pas pu déterminer clairement leur nécessité respective pour l'activation de ces gènes. Toutefois, nous avons montré que l'activité de la calcineurine, dont dépend la translocation nucléaire de CRTC1, est nécessaire à l'expression de certains de ces gènes. Nous avons pu associer ce phénomène à une condition physiopathologique observée dans le syndrome de Down. Nous avons également montré que dans les astrocytes, la noradrénaline stimule l'expression de gènes cibles de CREB par une activation des récepteurs β- adrénergiques, l'activation de la voie de l'AMPc et la transactivation de CREB par les CRTCs.Définir le rôle respectif de CREB et de ses coactivateurs CBP et CRTC1 dans les neurones et dans les astrocytes in vitro permettra d'acquérir les connaissances nécessaires à de futures études in vivo et, à plus long terme d'éventuellement développer des stratégies thérapeutiques pour améliorer les traitements des troubles cognitifs.

Acquired form of angioedema of the head and neck related to a deficiency in c1-inhibitor: a case report with a review of the literature.

Angioedema related to a deficiency in the C1-inhibitor protein is characterized by its lack of response to therapies including antihistamine, steroids, and epinephrine. In the case of laryngeal edema, mortality rate is approximately 30 percent. The first case of the acquired form of angioedema related to a deficiency in C1-inhibitor was published in 1972. In our paper, we present a case of an acquired form of angioedema of the oropharyngeal region secondary to the simultaneous occurrence of two causative factors: neutralization of C1-inhibitor by an autoantibody and the use of an angiotensin convertin enzyme inhibitor.

TBS (trabecular bone score) and diabetes-related fracture risk.

CONTEXT: Type 2 diabetes is associated with increased fracture risk but paradoxically greater bone mineral density (BMD). Trabecular bone score (TBS) is derived from the texture of the spine dual x-ray absorptiometry (DXA) image and is related to bone microarchitecture and fracture risk, providing information independent of BMD. OBJECTIVE: This study evaluated the ability of lumbar spine TBS to account for increased fracture risk in diabetes. DESIGN AND SETTING: We performed a retrospective cohort study using BMD results from a large clinical registry for the province of Manitoba, Canada. Patients: We included 29,407 women 50 years old and older with baseline DXA examinations, among whom 2356 had diagnosed diabetes. MAIN OUTCOME MEASURES: Lumbar spine TBS was derived for each spine DXA examination blinded to clinical parameters and outcomes. Health service records were assessed for incident nontraumatic major osteoporotic fractures (mean follow-up 4.7 years). RESULTS: Diabetes was associated with higher BMD at all sites but lower lumbar spine TBS in unadjusted and adjusted models (all P < .001). The adjusted odds ratio (aOR) for a measurement in the lowest vs the highest tertile was less than 1 for BMD (all P < .001) but was increased for lumbar spine TBS [aOR 2.61, 95% confidence interval (CI) 2.30-2.97]. Major osteoporotic fractures were identified in 175 women (7.4%) with and 1493 (5.5%) without diabetes (P < .001). Lumbar spine TBS was a BMD-independent predictor of fracture and predicted fractures in those with diabetes (adjusted hazard ratio 1.27, 95% CI 1.10-1.46) and without diabetes (hazard ratio 1.31, 95% CI 1.24-1.38). The effect of diabetes on fracture was reduced when lumbar spine TBS was added to a prediction model but was paradoxically increased from adding BMD measurements. CONCLUSIONS: Lumbar spine TBS predicts osteoporotic fractures in those with diabetes, and captures a larger portion of the diabetes-associated fracture risk than BMD.

Age-related differences in the use of guideline-recommended medical and interventional therapies for acute coronary syndromes: a cohort study.

OBJECTIVES: To compare the use of guideline-recommended medical and interventional therapies in older and younger patients with acute coronary syndromes (ACSs). DESIGN: Prospective cohort study. SETTING: Fifty-five hospitals in Switzerland. PARTICIPANTS: Eleven thousand nine hundred thirty-two patients with ACS enrolled between March 1, 2001, and June 30, 2006. ACS definition included ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina pectoris (UA). MEASUREMENTS: Use of medical and interventional therapies was determined after exclusion of patients with contraindications and after adjustment for comorbidities. Multivariate logistic regression models were used to calculate odds ratios (ORs) per year increase in age. RESULTS: Elderly patients were less likely to receive acetylsalicylic acid (OR=0.976, 95% confidence interval (CI)=0.969-0.980) or beta-blockers (OR=0.985, 95% CI=0.981-0.989). No age-dependent difference was found for heparin use. Elderly patients with STEMI were less likely to receive percutaneous coronary intervention (PCI) or thrombolysis (OR=0.955, 95% CI=0.949-0.961). Elderly patients with NSTEMI or UA less often underwent PCI (OR=0.943, 95% CI=0.937-0.949). CONCLUSION: Elderly patients across the whole spectrum of ACS were less likely to receive guideline-recommended therapies, even after adequate adjustment for comorbidities. Prognosis of elderly patients with ACS may be improved by increasing adherence to guideline-recommended medical and interventional therapies.

Aging effects on selective attention-related electroencephalographic patterns during face encoding.

Previous electrophysiological studies revealed that human faces elicit an early visual event-related potential (ERP) within the occipito-temporal cortex, the N170 component. Although face perception has been proposed to rely on automatic processing, the impact of selective attention on N170 remains controversial both in young and elderly individuals. Using early visual ERP and alpha power analysis, we assessed the influence of aging on selective attention to faces during delayed-recognition tasks for face and letter stimuli, examining 36 elderly and 20 young adults with preserved cognition. Face recognition performance worsened with age. Aging induced a latency delay of the N1 component for faces and letters, as well as of the face N170 component. Contrasting with letters, ignored faces elicited larger N1 and N170 components than attended faces in both age groups. This counterintuitive attention effect on face processing persisted when scenes replaced letters. In contrast with young, elderly subjects failed to suppress irrelevant letters when attending faces. Whereas attended stimuli induced a parietal alpha band desynchronization within 300-1000 ms post-stimulus with bilateral-to-right distribution for faces and left lateralization for letters, ignored and passively viewed stimuli elicited a central alpha synchronization larger on the right hemisphere. Aging delayed the latency of this alpha synchronization for both face and letter stimuli, and reduced its amplitude for ignored letters. These results suggest that due to their social relevance, human faces may cause paradoxical attention effects on early visual ERP components, but they still undergo classical top-down control as a function of endogenous selective attention. Aging does not affect the face bottom-up alerting mechanism but reduces the top-down suppression of distracting letters, possibly impinging upon face recognition, and more generally delays the top-down suppression of task-irrelevant information.

Diabetes mellitus, a microRNA-related disease?

Diabetes mellitus is a complex disease resulting in altered glucose homeostasis. In both type 1 and type 2 diabetes mellitus, pancreatic β cells cannot secrete appropriate amounts of insulin to regulate blood glucose level. Moreover, in type 2 diabetes mellitus, altered insulin secretion is combined with a resistance of insulin-target tissues, mainly liver, adipose tissue, and skeletal muscle. Both environmental and genetic factors are known to contribute to the development of the disease. Growing evidence indicates that microRNAs (miRNAs), a class of small noncoding RNA molecules, are involved in the pathogenesis of diabetes. miRNAs function as translational repressors and are emerging as important regulators of key biological processes. Here, we review recent studies reporting changes in miRNA expression in tissues isolated from different diabetic animal models. We also describe the role of several miRNAs in pancreatic β cells and insulin-target tissues. Finally, we discuss the possible use of miRNAs as blood biomarkers to prevent diabetes development and as tools for gene-based therapy to treat both type 1 and type 2 diabetes mellitus.