Human PXR-mediated induction of intestinal CYP3A4 attenuates 1α,25-dihydroxyvitamin D₃ function in human colon adenocarcinoma LS180 cells

Oxidative catabolism of 1α,25-dihydroxyvitamin D(3) [1α,25(OH)(2)D(3)] is mediated by either CYP24A1 or CYP3A4. In this paper, we tested whether induction of CYP3A4 in the LS180 intestinal cell model enhances clearance of 1α,25(OH)(2)D(3) and blunts its hormonal effect on expression of the apical membrane calcium transport protein, TRPV6. Treatment with the hPXR agonist rifampin significantly increased CYP3A4 mRNA content and catalytic activity, but had no effect on CYP24A1 or TRPV6 mRNA content. Pre-treating cells with rifampin for 48h, prior to a 24h 1α,25(OH)(2)D(3) treatment phase, was associated with a subsequent 48% increase in the elimination of 1α,25(OH)(2)D(3) and a 35% reduction of peak TRPV6 mRNA. Introduction of the CYP3A4 inhibitor, 6',7'-dihydroxybergamottin, an active inhibitor in grapefruit juice, reversed the effects of rifampin on 1α,25(OH)(2)D(3) clearance and TRPV6 expression. Over-expression of hPXR in LS180 cells greatly enhanced the CYP3A4 responsiveness to rifampin pretreatment, and elicited a greater relative suppression of TRPV6 expression and an increase in 1α,25(OH)(2)D(3) disappearance rate, compared to vector expressed cells, following hormone administration. Together, these results suggest that induction of CYP3A4 in the intestinal epithelium by hPXR agonists can result in a greater metabolic clearance of 1α,25(OH)(2)D(3) and reduced effects of the hormone on the intestinal calcium absorption, which may contribute to an increased risk of drug-induced osteomalacia/osteoporosis in patients receiving chronic therapy with potent hPXR agonists. Moreover, ingestion of grapefruit juice in the at-risk patients could potentially prevent this adverse drug effect.     

Physical functioning is related to both an impaired physical ability and ADL disability: A ten year follow-up study in middle-aged and older persons

ObjectiveIdentification of measures of physical function that mediate or link impaired physical ability with disability in activities of daily living (ADL) is necessary to facilitate the development of interventions to prevent or delay the onset of ADL disability. We examined whether measures of physical function at baseline are determinants of the Short Physical Performance Battery, as measure of physical ability, and disability, at ten years follow-up.Study designProspective cohort study in 625 middle-aged and older persons.Main outcome measuresPhysical ability was measured by Guralniks Short Physical Performance Battery (impaired physical ability: score <6) and ADL ability by the KATZ questionnaire (ADL disability: score ≥1). Physical function was measured by lung function (in men only), handgrip strength, leg strength, and physical activity. The associations between physical function and the dichotomized impaired physical ability and disability-score were estimated using Poisson regression.ResultsBetter lung function and higher leg strength were associated with a lower risk of having impaired physical ability, RR = 0.98, 95% CI [0.96; 0.99] per 10 L/min and RR = 0.97, 95% CI [0.94; 0.99] per 10 Nm, respectively.Higher handgrip strength, leg strength and level of physical activity were associated with a lower risk of having ADL disability, RR = 0.72, 95% CI [0.57; 0.92] per 10 kg, RR = 0.95, 95% CI [0.92; 0.98] per 10 Nm, RR = 0.98, 95% CI [0.96; 0.99] per point-score, respectively.Additional adjustment for baseline ADL disability did not materially changed the point-estimates (except for handgrip strength).ConclusionOverall, leg extensor strength was associated with both an impaired physical ability and ADL disability. Other measures of physical functioning were either related to an impaired physical ability or ADL disability. ADL disability may be an intermediate factor for hand grip strength in the causal chain from impaired physical ability to ADL disability at follow-up. The results of this study show that leg strength might be a relevant parameter to consider for future intervention studies.     

Patient Blood Management in der Geburtsvorbereitung,Geburtshilfe und postpartalen Phase

Die Anaesthesiologie - Die Implementierung eines Patient Blood Management (PBM) wird zunehmender Standard in der operativen Medizin. Seit einiger Zeit gilt das Interesse auch den vulnerablen...     

Acute psycho-physiological responses to perceptually regulated hypoxic and normoxic interval walks in overweight-to-obese adults

ObjectivesWe investigated psycho-physiological responses to perceptually regulated interval walks in hypoxia versus normoxia in obese individuals.DesignWithin-participants repeated measures.MethodsTen obese adults (BMI = 32 ± 3 kg/m^?2) completed a 60-min interval session (15 × 2 min walking at a rating of perceived exertion of 14 on the 6–20 Borg scale with 2 min of rest) either in hypoxia (FiO₂ = 13.0%, HYP) or normoxia (NOR). A third trial replicating the HYP speed pattern was carried out in normoxia as a control (CON). Exercise responses were analysed comparing the average of 1st to 3rd exercise bouts to those of the 4th–6th, 7th–9th, 10th–12th and 13th–15th exercise bouts (block 1 versus 2, 3, 4 and 5).ResultsTreadmill speed was slower during block 4 (6.14 ± 0.67 versus 6.24 ± 0.73 km/h^?1) and block 5 (6.12 ± 0.64 versus 6.25 ± 0.75 km/h^?1) in HYP compared to NOR or CON (p = 0.009). Compared to NOR and CON, heart rate was +6–10% higher (p = 0.001), whilst arterial oxygen saturation (?12–13%) was lower (p < 0.001) in HYP. Perceived limb discomfort was lower in HYP and CON versus NOR (?21 ± 4% and ?34 ± 6%; p = 0.004).ConclusionsIn overweight-to-obese adults, perceptually regulated interval walks in hypoxia versus normoxia leads to progressively slower speeds along with lower limb discomfort and larger physiological stress than normoxia. Walking at the speed adopted in hypoxia produces similar psycho-physiological responses at the same absolute intensity in normoxia.     

Clinical use of the Kessler psychological distress scales with culturally diverse groups

The Kessler 10 (K10) and embedded Kessler 6 (K6) was developed to screen for non‐specific psychological distress and serious mental illness in mental health surveys of English‐speaking populations, but has been adopted in Western and non‐Western countries as a screening and outcome measure in primary care and mental health settings. This review examines whether the original K6/K10's validity for culturally diverse populations was established, and whether the cultural equivalence, and sensitivity to change of translated or culturally adapted K6/K10s, has been demonstrated with culturally diverse client groups. Evidence for the original K6/K10's validity for culturally diverse populations is limited. Questions about the conceptual and linguistic equivalence of translated/adapted K6/K10s arise from reports of changes in item connotation and differential item functioning. Evidence for structural equivalence is inconsistent, as is support for criterion equivalence, with the majority of studies compromising on accuracy in case prediction. Research demonstrating sensitivity to change with culturally diverse groups is lacking. Inconsistent evidence for the K6/K10's cultural appropriateness in clinical settings, and a lack of clinical norms for either majority or culturally diverse groups, indicate the importance of further research into the psychological distress construct with culturally diverse clients, and the need for caution in interpreting K6/K10 scores. Copyright © 2014 John Wiley & Sons, Ltd.     

Tumour necrosis factor-α impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: Role of Hes1

Tumour necrosis factor-α (TNFα) is a pro-inflammatory cytokine, which influences neuronal survival and function yet there is limited information available on its effects on hippocampal neural precursor cells (NPCs). We show that TNFα treatment during proliferation had no effect on the percentage of proliferating cells prepared from embryonic rat hippocampal neurosphere cultures, nor did it affect cell fate towards either an astrocytic or neuronal lineage when cells were then allowed to differentiate. However, when cells were differentiated in the presence of TNFα, significantly reduced percentages of newly born and post-mitotic neurons, significantly increased percentages of astrocytes and increased expression of TNFα receptors, TNF-R1 and TNF-R2, as well as expression of the anti-neurogenic Hes1 gene, were observed. These data indicate that exposure of hippocampal NPCs to TNFα when they are undergoing differentiation but not proliferation has a detrimental effect on their neuronal lineage fate, which may be mediated through increased expression of Hes1.     

Delivering Child Community Psychology Services in the Community: Experiences from the NIPPERS Project

Background: The NIPPERS (Nursery Intervention Project for Parents & Education Related Services) was a novel community psychology service based in nursery settings in socio‐economically disadvantaged, inner‐city areas in London. Method: The service included consultation work with nursery staff, structured parenting groups and individual sessions for parents. Results: The delivery of the clinical service and research evaluation underwent several changes in the first phase of the project, in particular to ensure that the service was acceptable and accessible to families and staff. Although take‐up of community services was higher than in the local clinic‐based services, it was not taken up by some 40% of parents. Due to the allocation design, it was not possible to measure the effectiveness of the intervention. Conclusions: The NIPPERS service was successful in delivering a community child psychology service to families with high levels of early child behavioural problems at high risk for continuing difficulties.