World Alzheimer Report 2011 - The benefits of early diagnosis and intervention

Alzheimer's Disease International released the World Alzheimer Report 2011 - The benefits of early diagnosis and intervention on the 13th September 2011. Key Findings:As many as three-quarters of the estimated 36 million people worldwide living with dementia have not been diagnosed and hence cannot benefit from treatment, information and care. In high-income countries, only 20-50% of dementia cases are recognized and documented in primary care. In low- and middle-income countries, this proportion could be as low as 10%.Failure to diagnose often results from the false belief that dementia is a normal part of aging, and that nothing can be done to help. On the contrary, the new report finds that interventions can make a difference, even in the early stages of the illness.Drugs and psychological interventions for people with early-stage dementia can improve cognition, independence, and quality of life. Support and counseling for caregivers can improve mood, reduce strain and delay institutionalization of people with dementia.Governments, concerned about the rising costs of long-term care linked to dementia, should “spend now to save later.” Based on a review of economic analyses, the report estimates that earlier diagnosis could yield net savings of up to US$10,000 per patient in high-income countries.��World Alzheimer Report 2011 - Executive Summary (PDF, 36 pages, 1128KB)World Alzheimer Report 2011 (PDF, 72 pages, 1710KB)����

Diagnosis of Streptococcus pneumoniae meningitis by polymerase chain reaction amplification of the gene for pneumolysin

Diagnosis of bacterial meningitis has long been based on classical methods of Gram stain, serological tests, and culture of cerebrospinal fluid (CSF). The performance of these methods, especially culture and direct smear, is thwarted by failure to detect bacteria following administration of antimicrobial agents and reluctance to performance lumbar punctures at admission. Indeed, patients with meningitis frequently receive antibiotics orally or by injection before the diagnosis is suspected or established. Thus an alternative method has become necessary to help clinicians and epidemiologists to management and control of bacterial meningitis. We evaluate the application of a polymerase chain reaction-based (PCR) assay for amplification of pneumolysin gene (ply) to diagnosis of Streptococcus pneumoniae meningitis. The PCR assay sensitivity for CSF was 96% (95% confidence interval, CI, 90-99%) compared to a sensitivity of 59% for culture (95% CI 49-69%), 66% for Gram stain (95% CI 56-74%), and 78% for latex agglutination test (95% CI 69-86%); PCR specificity was 100% (95% CI 83-100%). PCR results were available within 4 h of the start of the assay. This molecular approach proved to be reliable and useful to identify this bacterium compared with other classical laboratory methods for identification of bacterial meningitis pathogens.

Director of Public Health annual report 2011 and core tables 2010

Too many children and young people are living in circumstances that make it difficult for them to thrive. That is the key message from the third Annual Report of the Director of Public Health (DPH) for Northern Ireland, which was published on 14th June 2012. This significant report highlights the many public health challenges that affect people in Northern Ireland.As Director of Public Health, Dr Carolyn Harper's report describes the main public health challenges across Northern Ireland, and details work being undertaken by the Public Health Agency (PHA) and its partners over the past year to improve the health and wellbeing of people here.A Core Tables report for 2010, available below, produced by the PHA in support of the Director of Public Health's Annual Report for 2011-2012, including information such as estimated home population figures and projections, births information, fertility rates, death rates, information on mortality, life expectancy, immunisation rates and screening uptake rates.

Assessment of a two-step nucleic acid amplification assay for detection of Neisseria meningitidis followed by capsular genogrouping

Immediate prevention of meningococcal disease relies in part on the prompt treatment with antibiotics of household and other close contacts of cases; however intervention with effective vaccination relies on identification of serogroup-causing strains. Parenteral antibiotic for patient with suspected meningococcal disease before hospital admission is currently recommended. Laboratory standard methods are hindered by failure to detect bacteria by this medical approach to improve patient prognosis. We assessed two polymerase chain reaction (PCR) assays to detect (crgA) and define the serogroups (siaD, orf-2, and ctrA) of Neisseria meningitidis in 120 cerebrospinal fluid (CSF) samples from positive cases (culture or antigen detection or direct smear). The PCR sensitivity for the identification of N. meningitidis was 100% (95% confidence interval, CI, 96-100%) compared to a sensitivity of 46% for culture (95% CI 37-55%), 61% for latex agglutination test (95% CI 52-70%), and 68% for Gram stain (95% CI 59-76%); PCR specificity was 97% (95% CI 82-100%). PCR correctly identified the serogroups A, B, C, W135, Y, and X in CSF samples with a sensitivity of 88% (95% CI 80-93%); the primer sets were 100% specific. The introduction of PCR-based assays shall increase laboratory confirmed cases, consequently enhancing surveillance of meningococcal disease.

CD4 T cells producing pro-inflammatory interleukin-17 mediate high pathology in schistosomiasis

In murine schistosomiasis mansoni, pronounced CD4 T cell-mediated, egg-induced, hepato-intestinal immunopathology and death, whether genetically determined or elicited experimentally, are associated with failure to down-regulate a net pro-inflammatory immune response. Important evidence contributing to this notion comes from the observation that immunization with schistosome egg antigens in CFA (SEA/CFA) causes low pathology C57BL/6 mice to develop an exacerbated form of disease and death in a cytokine milieu characterized by elevated interferon (IFN)-gamma levels. Since such a pro-inflammatory environment presumes a signaling pathway involving interleukin (IL)-12, the SEA/CFA immunization model was used to examine the extent of hepatic immunopathology in the absence of this cytokine. Surprisingly, the IL-12p40 subunit was an absolute requirement for the development of exacerbated disease, whereas the IL-12p35 subunit was not. Moreover, significantly elevated in vitro production of IL-17, but not of IFN-gamma, correlated with the high pathology, and neutralization of IL-17 in vivo resulted in a significant reduction of hepatic inflammation. Our findings clearly demonstrate the pathogenic potential of the novel IL-17-producing T cell subpopulation (ThIL-17), previously shown to mediate chronic inflammation in autoimmune disease. They also imply that IL-23, but not IL-12, is the critical signal necessary to support the pro-inflammatory ThIL-17 subset involved in high pathology schistosomiasis.

Collective Intelligence for OER Sustainability

To thrive, the Open Educational Resource (OER) movement, or a given initiative, must make sense of a complex, changing environment. Since "sustainability" is a desirable systemic capacity that our community should display, we consider a number of principles that sharpen the concept: resilience, sensemaking and complexity. We outline how these motivate the concept of collective intelligence (CI), we give examples of what OER-CI might look like, and we describe the emerging Cohere CI platform we are developing in response to these requirements.

Determinants of the educational use of digital learning materials: The mediating role of self-efficacy, perceived norm and attitude

Initiatives to stimulate the development and propagation of open educational resources (OER) need a sufficiently large community that can be mobilized to participate in this endeavour. Failure to achieve this could lead to underuse of OER. In the context of the Wikiwijs initiative a large scale survey was undertaken amongst primary and secondary school teachers to explore possible determinants of the educational use of digital learning materials (DLMs). Basing on the Integrative Model of Behaviour Prediction it was conjectured that self-efficacy, attitude and perceived norm would take a central role in explaining the intention to use DLMs. Several other predictors were added to the model as well whose effects were hypothesized to be mediated by the three central variables.All conjectured relationships were found using path analysis on survey data from 1484 teachers. Intention to DLMs was most strongly determined by self-efficacy, followed by attitude. ICT proficiency was in its turn the strongest predictor of self-efficacy. Perceived norm played only a limited role in the intention to use DLMs. Concluding, it seems paramount for the success of projects such as Wikiwijs to train teachers in the use of digital learning materials and ICT (e.g. the digital blackboard) and to impact on their attitude.

Ecological control of Triatoma dimidiata (Latreille, 1811): five years after a Costa Rican pilot project

An ecological pilot project for the control of Triatoma dimidiata allowed a new evaluation four and five years after environmental modifications in the peridomestic areas of 20 households. It was verified that the two groups of houses, 10 case-houses and 10 control-houses, were free of insects after those periods of time. In the first group, the owners started a chicken coop in the backyard and a colony of bugs was found there without infesting the house. In the second group, the inhabitants of one house once again facilitated the conditions for the bugs to thrive in the same store room, reaffirming that man-made ecotopes facilitates colonization. This ecological control method was revealed to be reliable and sustainable and it is recommended to be applied to those situations where the vectors of Chagas disease can colonize houses and are frequent in wild ecotopes.

Characterization of 23S rRNA domain V mutations in gastric biopsy patients from the eastern Amazon

Resistance of Helicobacter pylori to clarithromycin is characterised by simple point mutations in the 23S ribosomal RNA (rRNA) gene and is responsible for the majority of cases of failure to eradicate this bacterium. In this paper, we characterised the variability of the 23S rRNA gene in biopsies of patients with gastric pathologies in the eastern Amazon (Northern Region of Brazil) using PCR and sequencing. A total of 49 sequences of H. pylori strains were analysed and of those, 75.6% presented nucleotide substitutions: A2142G (3.3%), T2182C (12.9%), G2224A (6.45%), T2215C (61.3%), A2192G (3.3%), G2204C (6.4%) and T2221C (6.4%). Of the mutations identified, four are known mutations related to cases of resistance and 16.1% are not yet described, revealing a high prevalence of mutations in the H. pylori 23S rRNA gene among the strains circulating in the in the eastern Amazon. The high prevalence in individuals with gastric pathologies in the Northern Region of Brazil demonstrates the need for characterising the profile of these strains to provide correct therapy for patients, considering that mutations in this gene are normally associated with resistance to the primary medication used in controlling H. pylori infection.

Genetic variations in drug-induced liver injury (DILI): resolving the puzzle.

Despite stringent requirements for drug development imposed by regulatory agencies, drug-induced liver injury (DILI) is an increasing health problem and a significant cause for failure to approve drugs, market withdrawal of commercialized medications, and adoption of regulatory measures. The pathogenesis is yet undefined, though the rare occurrence of idiosyncratic DILI (1/100,000–1/10,000) and the fact that hepatotoxicity often recurs after re-exposure to the culprit drug under different environmental conditions strongly points toward a major role for genetic variations in the underlying mechanism and susceptibility. Pharmacogenetic studies in DILI have to a large extent focused on genes involved in drug metabolism, as polymorphisms in these genes may generate increased plasma drug concentrations as well as lower clearance rates when treated with standard medication doses. A range of studies have identified a number of genetic variants in drug metabolism Phase I, II, and III genes, including cytochrome P450 (CYP) 2E1, N-acetyltransferase 2, UDP-glucuronosyltransferase 2B7, glutathione S-transferase M1/T1, ABCB11, and ABCC2, that enhance DILI susceptibility (Andrade et al., 2009; Agundez et al., 2011). Several metabolic gene variants, such as CYP2E1c1 and NAT2 slow, have been associated with DILI induced by specific drugs based on individual drug metabolism information. Others, such as GSTM1 and T1 null alleles have been associated with enhanced risk of DILI development induced by a large range of drugs. Hence, these variants appear to have a more general role in DILI susceptibility due to their role in reducing the cell's antioxidative capacity (Lucena et al., 2008). Mitochondrial superoxide dismutase (SOD2) and glutathione peroxidase 1 (GPX1) are two additional enzymes involved in combating oxidative stress, with specific genetic variants shown to enhance the risk of developing DILI

Transmitted human immunodeficiency virus-1 drug resistance in a cohort of men who have sex with men in Belo Horizonte, Brazil - 1996-2012

The presence of transmitted human immunodeficiency virus (HIV)-1 drug-resistance (TDR) at the time of antiretroviral therapy initiation is associated with failure to achieve viral load (VL) suppression. Here, we report TDR surveillance in a specific population of men who have sex with men (MSM) in Belo Horizonte, Brazil. In this study, the rate of TDR was evaluated in 64 HIV-infected individuals from a cohort of MSM between 1996-June 2012. Fifty-four percent had a documented recent HIV infection, with a seroconversion time of less than 12 months. The median CD4+T lymphocyte count and VL were 531 cells/mm3and 17,746 copies/mL, respectively. Considering the surveillance drug resistance mutation criteria, nine (14.1%) patients presented TDR, of which three (4.7%), five (7.8%) and four (6.2%) had protease inhibitors, resistant against nucleos(t)ide transcriptase inhibitors and against non-nucleoside reverse-transcriptase inhibitors mutations, respectively. Two of the patients had multi-drug-resistant HIV-1. The most prevalent viral subtype was B (44, 68.8%), followed by subtype F (11, 17.2%). This study shows that TDR may vary according to the population studied and it may be higher in clusters of MSM.

Genetic dissection of c-Myc function during mouse organogenesis

Résumé Le gène c-myc est un des oncogènes les plus fréquemment mutés dans les tumeurs humaines. Même si plus de 70 % des cancers humains montrent une dérégulation de c-Myc, les connaissances sur son rôle physiologique pendant le développement, et dans la souris adulte restent très peu connus. Récemment, notre laboratoire a pu montrer que c-Myc contrôle l'équilibre entre le renouvellement et la différenciation des cellules souches hématopoïetiques (CSH) dans la souris adulte. Ceci est probablement dû à lacapacité de c-Myc de contrôler l'entrée et la sortie des CSH de leur niche de la moelle osseuse, en régulant plusieurs molécules d'adhésion, parmi lesquelles la cadhérine-N (Wilson et al., 2004; Wilson and Trumpp, 2006). Des études utilisant un mutant d'inactivation ont demontré que la protéine c-Myc est essentielle pour le développement au delà du jour embryonnaire E9.5. Les embryons c-Myc déficients sont plus petits que la normale et possèdent de nombreux défauts; en particulier ils ne peuvent établir un système hématopoietique embryonnaire primitif (Trumpp et al., 2001). Nous avons récemment découvert que le développement du placenta dépend de la présence de cMyc. Ceci permet de proposer que certains, sinon tous, les défauts embryonnaires puorraient dériver indirectement d'un défaut nutritionnel causé par la défaillance du placenta. Afin de répondre à cette question de manière génétique, nous avons utilisé l'allele conditionel c-mycflox (Trumpp et al., 2001) en combinaison avec l'allele Sox2-Cre (Hayashi et al., 2002). Celui-ci détermine l'expression de la récombinase Cre spécifiquement dans les cellules de l'épiblaste à partir de E6.5, tandis qu'il n'y a pas, ou seulement très peu, d'activité de la récombinase Cre dans les tissus extraembryonnaires.Alnsi, cette stratégie nous permet de générer des embryons sans c-Myc qui se développent en présence d'un compartment extraembryonnaire ou c-Myc est exprimé normalement (Sox2Cre;c-mycflox2) Ces embryons, Sox2Cre;c-mycflox2 se développent et grandissent normalement tout en formant un système vasculaire normal, mais meurent à E11.5 à cause d'un sévère manque de cellules hématopoïetiques. De façon très intéressante, la seule population qui semble être présente en nombre à peu près normal dans ces embryons est celle des précurseurs et des cellules souches. Les cellules qui forment cette population prolifèrent normalement mais ne peuvent pas former des colonies in vitro, ce qui montre que ces cellules ont perdu leur activité de cellules souches. Cependant, lorsque nous avons analysé ces cellules plus en détail en éxaminant l'expression des molécules d'intégrine nous avons découvert que l'integrine ß est sur-éxprimée à la surface des cellules c-Myc déficientes. Ceci pourrait indiquer un mécanisme par lequel c-Myc régule des molécules d'adhésion sur les cellules du sang. En conséquence, en absence de c-Myc, l'adhésion et la migration des cellules du sang de l'AGM (Aorte-Gonade-Mésonéphros) vers le foie de l'embryon, à travers le système vasculaire, est compromise. En outre, nous avons pu montrer que les hépatocytes du foie, qui constitue le site principal de formation des cellules hématopoïetiques pendant le développement, est sévèrement atteint dans des Sox2Cre;c-mycflox2 embryons. Ceci n'est pas du à un défaut propre aux cellules hépatiques qui ont perdu c-Myc, mais résulte plutôt de l'absence de cellules hématopoietïques qui normalement colonisent le foie à ce stade du développement. Ces résultats représentent la première preuve directe que le développement des hépatoblastes est dépendant de signaux provenant des cellules du sang. Summary The myc gene is one of the most frequently mutated oncogenes in human tumors. It is found to be mis-regulated in over 70% of all human cancers. However, our knowledge about its physiological role in mammalian development and adulthood remains limited. Recent work in our laboratory showed that c-Myc controls the balance between hematopoietic stem cell (HSC) self-renewal and differentiation in the adult mouse. This is likely due to the capacity of c-Myc to control entry and exit of HSCs from the bone marrow niche by regulating a number of cell adhesion molecules including N-cadherin (Wilson et al., 2004; Wilson and Trumpp 2006). During development knockout studies showed that c-Myc is required for embryonic development beyond embryonic day (E) 9.5. c-Myc deficient embryos are severely reduced in size and show multiple defects including the failure to establish a primitive hematopoietic system (Trumpp et al., 2001). Importantly, we recentry uncovered that placental development also seems to depend on normal c-Myc function, raising the possibility that some if not all of the embryonic defects observed could be mediated indirectly by a nutrition defect caused by placental failure. To address this possibility genetically, we took advantage of the conditional c-mycflox allele (Trumpp et al., 2001) in combination with the Sox2-Cre allele (Hayashi et al., 2002), in which Cre expression is specifically targeted to all epiblast cells by E6.5, while there is little or no Cre activity inextra-embryonic lineages. Thus, this strategy allows the generation of c-Myc deficient embryos, which develop within a normal c-Myc expressing extra-embryonic compartment (Sox2Cre;c-mycflox2) Such Sox2Cre;c-mycflox2 embryos develop and grow appropriately and form a normal vascular system but die at E11.5 due to a severe lack of blood cells. Interestingly, the only hematopoietic population that seems to be present in almost normal numbers in the embryo is the stem/progenitor cell population. Cells within this populatíon proliferate normal but can not give rise to hematopoietic colonies in vitro showing that functional hematopoietic stem cell (HSC) activity is lost. However, when we analyzed these phenotypic HSCs in more detail and examined integrin expression in mutant stem/progenitor cells, we observed that ß1-integrin is upregulated. This may point to a potential mechanism whereby c-Myc regulates adhesíon molecules on hematopoietic cells and thereby disturbs adhesion and migration from the AGM (aorta-gonads-mesonephros) through the vascular system to the liver. Furthermore, we uncovered that the fetal liver, the main site of hematopoietic expansion at that stage, is severely affected in Sox2Cre;c-mycflox2 embryos and that this is not due to a cell intrinsic defect of c-Myc deficient hepatocytes but rather due to the lack of hematopoietic cells that normally colonize the fetal liver at that stage of development. This provides first direct evidence that hepatoblast development depends on signals derived from blood cells.

Community introduction of practice parameters for autistic spectrum disorders: Advancing early recognition.

OBJECTIVES: Within a strong interdisciplinary framework, improvement in the quality of care for children with autistic spectrum disorders through a 2 year implementation program of Practice Parameters, aimed principally at improving early detection and intervention. METHOD: We developed Practice Parameters (PPs) for Pervasive Developmental Disorders and circulated the PPs to all child and adolescent psychiatrists practicing in the region. RESULTS: PP development and parallel information strategies resulted in a significant decrease of 1.5 years in the mean-age-at-diagnosis. However, further analysis indicated that improvement was only transient. CONCLUSION: Despite the encouraging improvement in mean-age-at-diagnosis 2 years after PP implementation, other indicators showed a failure to maintain the improvements. A systematic screening program would be the most reliable method to reinforce the PPs.

Behavioural Flexibility: evolutionary past and its role in a changing world

A través de la historia de la vida, gran parte de los organismos han desarrollado estrategias para responder a un mundo en constante cambio. Hoy en día, las actividades humanas producen cambios ambientales a una velocidad sin precedentes, lo cual se traduce en grandes desafíos para la persistencia de biodiversidad. Esta investigación evalúa las respuesta de los animales a los cambios ambientales enfocándose en la flexibilidad del comportamiento como estrategia adaptativa. En una primera aproximación a una escala evolutiva, se otorgan evidencias del vínculo hasta ahora tenue entre la cognición e historias de vida, entregando un claro apoyo a la relación entre longevidad, vida reproductiva y el tamaño del cerebro en mamíferos. La longevidad es el centro de muchas hipótesis respecto a las ventajas de desarrollar un cerebro grande, como por ejemplo en la hipótesis del buffer cognitivo y las respuestas flexibles frente a nuevos ambientes. En un segundo nivel, se abordan factores extrínsecos e intrínsecos que podrían explicar las diferencias individuales en innovación, un componente clave en la flexibilidad del comportamiento. Por medio de una aproximación experimental, se evalúan potenciales escenarios que podrían conducir a consistentes diferencias individuales en uno de los principales factores subyacentes a la innovación (i.e. la motivación), y el potencial control endocrino sobre estos escenarios. Posteriormente, con el objetivo de evaluar la respuesta de los animales frente a los cambios ambientales actuales, se explora la respuesta de los animales frente a una de las actividades humanas mas disruptivas sobre los ecosistemas, la urbanización. Por medio de un analisis filogenetico comparativo a nivel global en aves se abordan los mecanismos implicados en la perdida de biodiversidad observada en ambientes urbanos. Los resultados entregan evidencias sobre la importancia de procesos de dispersión local junto con el papel clave de los rasgos de historia de vida, pero en un sentido diferente al clasicamente pensado. Finalmente por medio de una revisión bibliográfica se entregan evidencias teóricas y empíricas que respaldan el rol clave de la flexibilidad del comportamiento en confrontar los desafíos de una vida urbana. La integración de estos resultados muestra cómo el pasado evolutivo contribuye a hacer frente a los retos ambientales actuales, y pone de relieve posibles consecuencias ante un planeta más cambiante que nunca.

Monotherapy with darunavir/ritonavir is effective and safe in clinical practice.

INTRODUCTION Monotherapy against HIV has undoubted theoretical advantages and has good scientific fundaments. However, it is still controversial and here we will analyze the efficacy and safety of MT with darunavir with ritonavir (DRV/r) on patients who have received this treatment in our hospitals. MATERIALS AND METHODS Observational retrospective study that includes patients from 10 Andalusian hospitals that have received DRV/r in MT and that have been followed over a minimum of 12 months. We carried out a statistical descriptive analysis based on the profile of patients who had been prescribed MT and the efficacy and safety that were observed, paying special attention to treatment failure and virological evolution. RESULTS DRV/r was prescribed to 604 patients, of which 41.1% had a CD4 nadir <200/mmc. 33.1% had chronic hepatitis caused by HCV, had received an average of five lines of previous treatment and had a history of treatment failure to analogues in 33%, to non-analogues 22 and protease inhibitors (PI) in 19.5%. 76.6% proceeded from a previous treatment with PI. The simplification was the main criteria for the instauration of MT in the 81.5% and the adverse effects in the 18.5%. We managed to maintain MT in 84% of cases, with only 4.8% of virological failure (VF) with viral load (VL) >200 c/mL and 3.6% additional losses due to VF with VL between 50 and 200 copies/mL. Thirty three genotypes were performed after failure without findings of resistance mutations to DRV/r or other IPs. Only 23.7% of patients presented some blips during the period of exposition to MT. Eighty seven percent of all determinations of VL had <50 copies/mL, and only 4.99% had >200 copies/mL. Although up to 14.9% registered at some point an AE, only 2.6% abandoned MT because of AE and 1.2% because of voluntary decision. Although the average of total and LDL cholesterol increases 10 mg/dL after 2 years of follow-up, so did HDL cholesterol in 3mg/dL and the values of triglycerides (-14 mg/dL) and GPT (-6 UI/mL) decreased. The average count of CD4 lymphocytes increased from 642 to 714/mm(3) at 24 weeks. CONCLUSIONS In a very broad series of patients obtained from clinical practice, data from clinical trials was confirmed: MT with DRV as a de-escalation strategy is very safe, it's associated to a negligible rate of adverse effects and maintains a good suppression of HIV replication. VF (with >50 or >200 copies/mL) is always under 10% and in any case without consequences.