SGLT2 inhibition attenuates arterial dysfunction and decreases vascular F-actin content and expression of proteins associated with oxidative stress in aged mice

GeroScience - Aging of the vasculature is characterized by endothelial dysfunction and arterial stiffening, two key events in the pathogenesis of cardiovascular disease (CVD). Treatment with sodium...     

Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.     

Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium

Confluent cultures of endothelial cells from human umbilical cord were used to study the effect of activated human protein C (APC) on the production of plasminogen activators, plasminogen activator-inhibitor, and factor VIII-related antigen. Addition of APC to the cells in a serum-free medium did not affect the production of tissue-type plasminogen activator (t-PA) or factor VIII-related antigen; under all measured conditions, no urokinase activity was found. However, less plasminogen activator-inhibitor activity accumulated in the conditioned medium in the presence of APC. This decrease was dose dependent and could be prevented by specific anti-protein C antibodies. No decrease was observed with the zymogen protein C or with diisopropylfluorophosphate-inactivated APC. APC also decreased the t-PA inhibitor activity in endothelial cell-conditioned medium in the absence of cells, which suggests that the effect of APC is at least partly due to a direct effect of APC on the plasminogen activator- inhibitor. High concentrations of thrombin-but not of factor Xa or IXa-- had a similar effect on the t-PA inhibitor activity. The effect of APC on the plasminogen activator-inhibitor provides a new mechanism by which APC may enhance fibrinolysis. The data suggest that activation of the coagulation system may lead to a secondary increase of the fibrinolytic activity by changing the balance between plasminogen activator(s) and its (their) fast-acting inhibitor.     

Arthritis onset and worsening self-rated health: a longitudinal evaluation of the role of pain and activity limitations

OBJECTIVE: To longitudinally explore the hypothesized role of worsening pain and development of activity limitations as mediators in the relationship between arthritis onset and worsening self-rated health (SRH). METHODS: Data was obtained from the 1998/1999 and 2000/2001 cycles of the population-based Canadian longitudinal National Population Health Survey (n = 10,859; ages > or = 18; response rate: time 1 = 81.6%, time 2 = 89.2%). Respondents were asked about chronic conditions, pain, activity limitations, and self-perceived health; change over time was assessed. Change in effect of arthritis onset on worsening SRH upon considering potential mediators was assessed through multivariate logistic regression, controlling for sociodemographic characteristics and onset of other conditions. RESULTS: Worsening pain fully explained the effect of arthritis onset on worsening SRH; a portion of the effect of worsening pain was mediated by the development of activity limitation. Residual direct effect of arthritis onset was statistically insignificant. Worsening pain and development of activity limitations also mediated a portion of the effects of onset of other chronic conditions but to a lesser extent than arthritis onset. CONCLUSION: This is the first study to examine these relationships longitudinally. Identifying the role of mediators is necessary if target areas of prevention and/or management are sought, either at the individual or population level. Our results indicate that the development of arthritis has a significant impact on worsening SRH. Pain and development of activity limitations fully account for the relationship between arthritis onset and worsening SRH. High priority should be placed on prevention and management strategies for pain among people with arthritis.     

TEL gene is involved in myelodysplastic syndromes with either the typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13)

A t(5;12)(q33;p13) translocation is a recurrent chromosome abnormality in a subgroup of myeloid malignancies with features of both myeloproliferative disorders and myelodysplastic syndromes (MDSs). The molecular consequence of a t(5;12) is a fusion between the platelet- derived growth factor receptor-B gene on chromosome 5 and a novel ETS- like gene, TEL, on chromosome 12. We report on three patients with a t(5;12)(q33;p13) diagnosed as chronic myelomonocytic leukemia, and one case of a t(10;12)(q24;p13) in a progressive MDS, with eosinophilia and monocytosis. Involvement of the TEL gene in these chromosome translocations was investigated by fluorescence in situ hybridization (FISH) with cosmid probes containing selectively the 5' end or 3' end of TEL. Hybridization of these cosmids to the der(5)/der(10) or a der(12), respectively, demonstrated a rearrangement of TEL in both translocations, showing that the t(10;12) is a variant translocation of the t(5;12). Cloning of the fusion cDNA of one case of t(5;12) showed that the breakpoint occurred at the RNA level at exactly the same position as reported by Golub et al (Cell 77:307, 1994). In addition, the TEL gene on chromosome 12 could be localized between two probes previously mapped to 12p13, namely PRB1 and D12S178, leading to a better definition of the position of TEL in this chromosome region. Moreover, in the case involving chromosome 10, the breakpoint occurred between cKTN206 and cKTN312/LYT-10 at 10q24. Clinicohematological data in these studies as well as the restriction mapping of chromosomal breakpoints strongly suggest that (1) common features in MDSs involving the TEL gene are monocytosis and eosinophilia, (2) chromosomes other than no. 5 may be involved and at least a t(10;12)(q24;p13) variant chromosome translocation does exist in these MDSs, and (3) both standard and variant 12p/TEL translocations may be identified by FISH with appropriate probes.     

Priorities for Closing the Evidence-Practice Gaps in Poststroke Aphasia Rehabilitation: A Scoping Review

Objective

To identify implementation priorities for poststroke aphasia management relevant to the Australian health care context.

An evaluation of peer-led STD/HIV prevention work in a public sex environment

This paper describes an independent evaluation of a peer-led STD/HIV prevention intervention conducted by Gay Men Fighting AIDS (GMFA) in a public sex environment (PSE). A variety of quantitative and qualitative research methods were employed to collect data on the intervention process as well as its outcomes. The main aim of the intervention was the distribution of condoms and safer sex literature to PSE users. During a five-month period, over 100,000 condoms and 2,200 safer sex information packs were distributed by GMFA volunteers to the PSE users. Condom provision was identified as the most needed health promotion activity in PSEs in a survey of gay and bisexual men (n = 688) conducted by the evaluators. Data collected showed that condoms provided by GMFA, as well as from other sources, were being used in the PSE. The peer-led focus of the intervention was acceptable to the PSE users. In addition, high levels of commitment and input from the volunteers contributed considerable added value to the intervention. The evaluation found that GMFA was successful in reaching the target population and addressing their needs and demands.     

Productivity, consumers, and the structure of a river food chain

We tested models of food chain dynamics in experimentally manipulated channels within a natural river. As light levels increased, primary productivity and the biomass of algae and primary predators increased, but the biomass of grazers remained relatively constant. In the presence of a fourth trophic level, algae and primary predators decreased, but grazers increased. These results match predictions of food chain models based on classical predator-prey theory and suggest that simple models of multitrophic level interactions are sometimes sufficient to predict the responses of natural communities to changes in environmental productivity and predators.