Variable Nav1.5 Protein Expression from the Wild-Type Allele Correlates with the Penetrance of Cardiac Conduction Disease in the Scn5a+/− Mouse Model

BACKGROUND: Loss-of-function mutations in SCN5A, the gene encoding Na(v)1.5 Na+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a(+/-) mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A. METHODOLOGY/PRINCIPAL FINDINGS: Based on ECG, 10-week-old Scn5a(+/-) mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a(+/-) mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A-mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a(+/-) mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a(+/-) mice had similar Na(v)1.5 mRNA but higher Na(v)1.5 protein expression, and moderately larger I(Na) current than severely affected Scn5a(+/-) mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a(+/-) mice than in mildly affected ones. CONCLUSIONS: Scn5a(+/-) mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a(+/-) mice, phenotype severity correlates with wild-type Na(v)1.5 protein expression

The unsupported upper limb exercise test in people without disabilities: assessing the within-day test–retest reliability and the effects of age and gender

Purpose: To estimate the within-day test–retest reliability and standard error of measurement (SEM) of the unsupported upper limb exercise test (UULEX) in adults without disabilities and to determine the effects of age and gender on performance of the UULEX. Method: A cross-sectional study was conducted with 100 adults without disabilities (44 men, mean age 44.2 [SD 26] y; 56 women, mean age 38.1 [SD 24.1] y). Participants performed three UULEX tests to establish within-day reliability, measured using an intra-class correlation coefficient (ICC) model 2 (two-way random effects) with a single rater (ICC[2,1]) and SEM. The effects of age and gender were examined using two-factor mixed-design analysis of variance (ANOVA) and one-way repeated-measures ANOVA. For analysis purposes, four sub-groups were created: younger adults, older adults, men, and women. Results: Excellent within-day reliability and a small SEM were found in the four sub-groups (younger adults: ICC[2,1]=0.88; 95% CI: 0.82, 0.92; SEM∼40 s; older adults: ICC[2,1]=0.82; 95% CI: 0.72, 0.90; SEM∼50 s; men: ICC[2,1]=0.93; 95% CI: 0.88, 0.96; SEM∼30 s; women: ICC[2,1]=0.85; 95% CI: 0.78, 0.91; SEM∼45 s). Younger adults took, on average, 308.24 seconds longer than older adults to perform the test; older adults performed significantly better on the third test (p0.05). Conclusion: The within-day test–retest reliability and SEM values of the UULEX may be used to define the magnitude of the error obtained with repeated measures. One UULEX test seems to be adequate for younger adults to achieve reliable results, whereas three tests seem to be needed for older adults.Objectif : évaluer la fiabilité d'un test-retest en une même journée et l'erreur type de mesure (ETM) du test d'exercice des membres supérieurs sans appui (UULEX) chez des adultes sans incapacités et déterminer les effets de l'âge et du sexe sur leur exécution. Méthodologie : les chercheurs ont réalisé une étude transversale auprès de 100 adultes sans incapacités (44 hommes, d'un âge moyen de 44,2 ans [ÉT 26], et 56 femmes, d'un âge moyen de 38,1 ans [ÉT 24,1]). Les participants ont effectué trois UULEX pour établir la fiabilité du test-retest en une même journée, mesurés à l'aide du modèle 2 de coefficient de corrélation intraclasse (ICC, effets aléatoires bilatéraux) comportant un ICC(2,1) et une ETM à un seul évaluateur. Les chercheurs ont examiné les effets de l'âge et du sexe à l'aide d'une analyse de variance bifactorielle à mesures mixtes et d'une analyse de variance unifactorielle à mesures répétées. Pour les besoins de l'analyse, les chercheurs ont créé quatre sous-groupes: jeunes adultes, adultes plus âgés, hommes et femmes. Résultats : les quatre sous-groupes affichaient une excellente fiabilité en une même journée et une petite ETM (jeunes adultes: ICC[2,1]=0,88 [IC 95% : 0,82, 0,92] et ETM∼40 secondes; adultes plus âgés : ICC[2,1]=0,82 [IC 95 % : 0,72, 0,90] et ETM∼50 secondes; hommes: ICC[2,1]=0,93 [IC 95% : 0,88, 0,96] et ETM∼30 secondes; femmes: ICC[2,1]=0,85 [IC 95 % : 0,78, 0,91] et ETM∼45 secondes). En moyenne, les jeunes adultes ont effectué le test pendant 308,24 secondes de plus que les adultes plus âgés; ceux-ci ont obtenu un résultat nettement meilleur au troisième test (p0,05). Conclusion : il est possible d'utiliser la fiabilité de test-retest en une même journée et les valeurs d'ETM de l'UULEX pour définir l'importance de l'erreur obtenue lors de mesures répétées. Un UULEX semble suffire pour que les jeunes adultes obtiennent des résultats fiables, tandis que trois tests semblent nécessaires chez les adultes plus âgés

Xenopus Pkdcc1 and Pkdcc2 Are Two New Tyrosine Kinases Involved in the Regulation of JNK Dependent Wnt/PCP Signaling Pathway

Protein Kinase Domain Containing, Cytoplasmic (PKDCC) is a protein kinase which has been implicated in longitudinal bone growth through regulation of chondrocytes formation. Nevertheless, the mechanism by which this occurs remains unknown. Here, we identified two new members of the PKDCC family, Pkdcc1 and Pkdcc2 from Xenopus laevis. Interestingly, our knockdown experiments revealed that these two proteins are both involved on blastopore and neural tube closure during gastrula and neurula stages, respectively. In vertebrates, tissue polarity and cell movement observed during gastrulation and neural tube closure are controlled by Wnt/Planar Cell Polarity (PCP) molecular pathway. Our results showed that Pkdcc1 and Pkdcc2 promote the recruitment of Dvl to the plasma membrane. But surprisingly, they revealed different roles in the induction of a luciferase reporter under the control of Atf2 promoter. While Pkdcc1 induces Atf2 expression, Pkdcc2 does not, and furthermore inhibits its normal induction by Wnt11 and Wnt5a. Altogether our data show, for the first time, that members of the PKDCC family are involved in the regulation of JNK dependent Wnt/PCP signaling pathway.Fundacao Ciencia e Tecnologia - IP; IBB/CBME, LA [PTDC/BIA-BCM/69912/2006, Pest-OE/EQB/LA0023/2013]; FCTinfo:eu-repo/semantics/publishedVersio

EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), 2013. Scientific Opinion on the public health hazards to be covered by inspection of meat (bovine animals).

A risk ranking process identified Salmonella spp. and pathogenic verocytotoxin-producing Escherichia coli (VTEC) as current high-priority biological hazards for meat inspection of bovine animals. As these hazards are not detected by traditional meat inspection, a meat safety assurance system for the farm-to-chilled carcass continuum using a risk-based approach was proposed. Key elements of the system are risk-categorisation of slaughter animals for high-priority biological hazards based on improved food chain information, as well as risk-categorisation of slaughterhouses according to their capability to control those hazards. Omission of palpation and incision during post-mortem inspection for animals subjected to routine slaughter may decrease spreading and cross-contamination with the high-priority biological hazards. For chemical hazards, dioxins and dioxin-like polychlorinated biphenyls were ranked as being of high potential concern; all other substances were ranked as of medium or lower concern. Monitoring programmes for chemical hazards should be more flexible and based on the risk of occurrence, taking into account the completeness and quality of the food chain information supplied and the ranking of chemical substances, which should be regularly updated to include new hazards. Control programmes across the food chain, national residue control programmes, feed control and monitoring of environmental contaminants should be better integrated. Meat inspection is a valuable tool for surveillance and monitoring of animal health and welfare conditions. Omission of palpation and incision would reduce detection effectiveness for bovine tuberculosis and would have a negative impact on the overall surveillance system especially in officially tuberculosis free countries. The detection effectiveness for bovine cysticercosis, already low with the current meat inspection system, would result in a further decrease, if palpation and incision are removed. Extended use of food chain information could compensate for some, but not all, the information on animal health and welfare lost if only visual post-mortem inspection is applied

A actividade física e o internamento por exacerbação da DPOC Physical activity and hospitalization for exacerbation of COPD

As exacerbações são eventos com um impacto negativo na qualidade de vida relacionada com a saúde, na função pulmonar, na utilização dos recursos de saúde e na sobrevida dos doentes com DPOC. Contudo, ainda não é conhecido o impacto dos internamentos por exacerbação na actividade física dos doentes. O presente estudo teve como objectivos: 1. Investigar o grau de inactividade dos doentes com DPOC durante e após um internamento por exacerbação, através da utilização de um monitor de actividade de elevada precisão; 2. Pesquisar se os doentes com internamentos no último ano por exacerbação da DPOC revelam uma recuperação mais lenta da sua actividade física quando comparados com doentes que não foram internados no último ano; 3. Investigar se os doentes com baixo nível de actividade física durante ou após o internamento por exacerbação têm maior probabilidade de serem reinternados no ano seguinte. Os autores avaliaram a actividade física através de um monitor de actividade que mediu de forma precisa o tempo que os doentes despendem na marcha, a andar de bicicleta, de pé, sentados e deitados. Estas medições foram efectuadas no 2º e 7º dias de internamento, bem como um mês após a alta. Foram ainda avaliadas a função pulmonar, as pressões máximas respiratórias, a força do quadricípite femoral, a massa isenta de gordura (por bioimpedância), a gasometria arterial, a prova de marcha e o índice de BODE (índice de massa corporal, obstrução das vias aéreas, dispneia e capacidade para o exercício). Resultados: Verificou-se uma redução importante do tempo despendido em actividades com sustentação do peso corporal (de pé e a andar) no 2º e no 7º dia de internamento, bem como um mês após a alta. O tempo despendido com estas actividades correlacionou-se de forma positiva com a força muscular (do quadricípite femoral). Os doentes com internamentos no último ano apresentaram uma redução ainda mais acentuada da actividade física quando comparados com os doentes sem internamentos recentes. Os doentes que apresentaram uma redução marcada da actividade um mês após a alta tiveram maior probabilidade de serem reinternados no ano seguinte. Conclusão: Os autores concluem que os doentes com DPOC apresentam uma redução acentuada da actividade física durante e após os internamentos por agudização da doença. Nos doentes com exacerbações frequentes, a inactividade é ainda mais acentuada. Por sua vez, a inactividade física torna o doente mais vulnerável a novos episódios de internamentos. As exacerbações da DPOC são eventos que têm um impacto negativo em vários aspectos da progressão da doença. Um tratamento apropriado das agudizações é um aspecto importante no controlo da doença. Os resultados do presente trabalho indicam que devem ser desenvolvidos todos os esforços e estratégias para aumentar a actividade física durante os internamentos por exacerbações e após a alta