Age-related alterations of active pumping mechanisms in rat thoracic duct

OBJECTIVE: To evaluate the age-related changes in active pumping in thoracic duct (TD) from 24-month-old Fisher-344 rats comparing with TD pumping in 9-month rats. METHODS: Lymphatic diameters, contraction amplitude and frequency, ejection fraction, and fractional pump flow were determined in isolated TD preparations. Western blot analyses were performed to evaluate relative levels of eNOS and iNOS in 9- and 24-month-old TD. RESULTS: Stretch-dependent regulation was altered in aged TD especially at higher levels of pressure: the negative inotropy, negative chronotropy and diminished minute pumping (2- to 3-fold decrease) were observed. Physiological NO/imposed-flow-dependent inhibition was completely abolished in aged TD, yet NO-synthase blockade by L-NAME (10(-4) M) increased pumping in a flow-independent manner. Western blot analyses indicated that the relative levels of eNOS were decreased approximately 7-fold in the 24-month-old TD when compared with 9-month-old TD; whereas iNOS levels were increased approximately 10-fold in 24-month-old TD. CONCLUSIONS: These data provide the first evidence that stretch- and imposed-flow-dependent regulatory mechanisms are greatly altered in aged TD. These alterations of active pumping mechanisms in TD appear to be related with age-related disturbances in NO-dependent regulatory pathways, and may reflect diminished lymphatic muscle contractility as well as altered lymphatic endothelium function.     

Arranging and negotiating the use of informal interpreters in general practice consultations: Experiences of refugees and asylum seekers in the west of Ireland

This paper focuses on the work involved for service users in arranging and negotiating the use of informal interpreters from their social networks for general practice consultations. The data are drawn from a participatory learning and action research study, carried out in the west of Ireland. Qualitative data were gathered using a peer researcher model from a ‘hard to reach’ community of Serbo-Croat and Russian refugees and asylum seekers (n = 26). The findings elucidate that there is a tension for service users between the experienced benefits of having a trusted friend/family member present to act as their interpreter and the burden of work and responsibility to manage the language barrier. Participants emphasize that, for them, the use of informal interpreters can be inadequate and problematic and can leave them worried, frustrated and with experiences of error and misdiagnosis. Overall, they state a clear preference for the use of professional, trained interpreters in general practice consultations which is currently unavailable to them in routine Irish general practice consultations.     

Assessing health diagnosis disclosure decisions in relationships: testing the disclosure decision-making model

Illness affects millions of Americans each year, and the disclosure of health conditions can facilitate access to social support, in addition to other physical and physiological benefits. This article tests the Disclosure Decision-Making Model (DD-MM; Greene, 2009 ) to predict factors that influence the likelihood of disclosing (and past disclosure of) nonvisible physical or mental health-related information. One hundred eighty-seven (n?=?187) people were recruited for a study to report on both disclosing and not disclosing a nonvisible health condition. Measured variables included information assessment, relational quality, anticipated reactions (support, relational consequences), confidence in response, disclosure efficacy, and disclosure (likelihood of disclosure and depth of disclosure). Structural equation modeling results supported many of the proposed hypotheses, with a great deal of similarity across models. Specifically, assessing information predicted efficacy, and to some extent relational outcomes. Closeness was related to response overall and to efficacy in one model. Response predicted outcome overall and likelihood of disclosure in one model. Finally, efficacy predicted likelihood of disclosure and depth of disclosure. The article discusses the implications of the findings for understanding information, relationship assessments, and efficacy in disclosing health diagnoses.     

Phenoxodiol, a novel isoflavone, induces G1 arrest by specific loss in cyclin-dependent kinase 2 activity by p53-independent induction of p21WAF1/CIP1

Phenoxodiol, an isoflavone derivative of genistein with unknown mechanism of action, is currently being evaluated in early human cancer clinical trials. To determine the mechanism of antiproliferative effects of phenoxodiol, we examined its effects in a battery of human cell lines. Although we observed caspase-dependent apoptosis in HN12 cells as early as 24 hours after exposure, clonogenic death occurred only after 48-hour exposure despite caspase blockade by the general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (ZVAD)-fmk. Moreover, clear evidence of cell death as determined by nuclear morphology and plasmatic membrane damage occur despite ZVAD, suggesting that another mechanism besides caspase-dependent apoptosis is required for clonogenic death induced by phenoxodiol. In search for other potential antiproliferative effects, we assessed the effects of phenoxodiol in the cell cycle progression of human carcinoma cell lines. A significant G(1)-S arrest was observed by 12 hours of exposure in HN12 cell lines at concentrations > or =5 microg/mL. Cell cycle arrest occurred several hours (approximately 12 hours) before induction of apoptosis. Analysis of in vitro purified cyclin-dependent kinase (cdk) activity showed that phenoxodiol did not inhibit cdk activity. In contrast, cellular cdk2 activity obtained from HN12 cell lines exposed to phenoxodiol for 12 hours decreased by 60%, whereas cdk6 activity remained unaltered, suggesting that the loss of cdk2 activity was specific. Loss in cdk2 activity was preceded by the accumulation of the endogenous cdk inhibitor p21(WAF1). To assess the role of p21(WAF1) induction by phenoxodiol, we used HCT116 isogenic cell lines and showed that phenoxodiol induced G(1) arrest together with p21(WAF1) expression in wild-type clones. In contrast, p21(-/-) variants failed to show G(1) arrest. Finally, induction of p21 by phenoxodiol is p53 independent, as phenoxodiol induced p21 in HCT116 lacking p53. These data therefore indicate that phenoxodiol promotes G(1)-S arrest by the specific loss in cdk2 activity due to p53-independent p21(WAF1) induction. This novel feature of phenoxodiol may have clinical implications, as the majority of human malignancies have aberrations in cell cycle progression regulation.