Search

Stakeholder engagement, specifically integration of patient and family perspectives about what matters, is increasingly recognized as a critical component of patient-centered healthcare delivery. This study describes a structured approach to and evaluation of stakeholder engagement in the development of novel sexual and reproductive health (SRH) educational resources for adolescent and young adult (AYA) women with cystic fibrosis (CF). Key stakeholders participated in a systematic series of steps to iteratively develop and adapt patient educational resources. Process measures (stakeholder recruitment, composition, co-learning, and transparency) and proximal outcomes of stakeholder involvement (impact on the development process and satisfaction) were measured via recorded stakeholder recommendations and a stakeholder survey. Seventeen stakeholders participated in seven group and two patient-only conference calls. The majority of stakeholders understood their roles, had their expectations met or exceeded, and were satisfied with the frequency and quality of engagement in the project. All stakeholders in attendance provided multiple concrete recommen-dations during the development process. Stakeholders explored the motivations of AYA women with CF related to SRH and agreed that the ideal resource should be online. After reviewing the design of existing resources, stakeholders decided by consensus to partner with a pre-existing young women’s health website and created 11 CF-specific SRH guides. This study illuminates a path for a formal process of stakeholder engagement and evaluation in educational resource development centered on the SRH care needs of AYA women with CF. Similar systematic, planned processes could be extended to other populations and aspects of healthcare.

The study goal was to evaluate the transplacental transfer of two corticosteroids, budesonide (BUD) and fluticasone propionate (FP), in pregnant mice and investigate whether P-glycoprotein (P-gp) might be involved in reducing BUD transplacental transfer. Pregnant mice (N = 18) received intravenously either low (104.9 μg/kg) or high (1049 μg/kg) dose of [3H]-BUD or a high dose of [3H]-FP (1590 μg/kg). In a separate experiment, pregnant mice (N = 12) received subcutaneously either the P-gp inhibitor zosuquidar (20 mg/kg) or vehicle, followed by an intravenous infusion of [3H]-BUD (104.9 μg/kg). Total and free (protein unbound) corticosteroid concentrations were determined in plasma, brain, fetus, placenta, kidney, and liver. The ratios of free BUD concentrations in fetus versus plasma K(fetus, plasma, u, u) 0.42 ± 0.17 (mean ± SD) for low-dose and 0.38 ± 0.18 for high-dose BUD were significantly different from K = 1 (P

Human polymorphonuclear leukocytes (PMN) have been reported to completely lack of DNA-dependent protein kinase (DNA-PK) which is composed of Ku protein and the catalytic subunit DNA-PKcs, needed for nonhomologous end-joining (NHEJ) of DNA double-strand breaks. Promyelocytic HL-60 cells express a variant form of Ku resulting in enhanced radiation sensitivity. This raises the question if low efficiency of NHEJ, instrumental for the cellular repair of oxidative damage, is a normal characteristic of myeloid differentiation. Here we confirmed the complete lack of DNA-PK in PMN protein extracts, and the expression of the truncated Ku86 variant form in HL-60. However, this degradation of DNA-PK was shown to be due to a DNA-PK-degrading protease in PMN and HL-60. In addition, by using a protease-resistant whole cell assay, both Ku86 and DNA-PKcs could be demonstrated in PMN, suggesting the previously reported absence in PMN of DNA-PK to be an artefact. The levels of Ku86 and DNA-PKcs were much reduced in PMN, as compared with that of the lymphocytes, whereas HL-60 displayed a markedly elevated DNA-PK concentration. In conclusion, our findings provide evidence of reduced, not depleted expression of DNA-PK during the mature stages of myeloid differentiation.

Background Combination therapy with budesonide and formoterol reduces exacerbations of asthma, which are closely associated with human rhinovirus (RV) infections in both children and adults. These data suggest that budesonide and formoterol inhibit virus-induced inflammatory responses of airway epithelial cells. Methods To test this hypothesis, bronchial epithelial (BE) cells were obtained from airway brushings of 8 subjects with moderate-to-severe allergic asthma and 9 with neither asthma nor respiratory allergies. Cultured BE cells were incubated for 24 hours with budesonide (1.77 μM), formoterol (0.1 μM), both, or neither, and then inoculated with RV-16 (5×106 plaque forming units [PFU]/mL). After 24 hours, viral replication (RV RNA), cytokine secretion (CXCL8, CXCL10, TNFα, IFN-β, IL-28) and mRNA expression (CXCL8, CXCL10, TNF, IFNB1, IL28A&B) were analyzed. Results RV infection induced CXCL10 protein secretion and IFNB1 and IL28 mRNA expression. Drug treatments significantly inhibited secretion of CXCL10 in mock-infected, but not RV-infected, BE cells, and inhibited secretion of TNFα under both conditions. Neither budesonide nor formoterol, alone or in combination, significantly affected viral replication, nor did they inhibit RV-induced upregulation of IFNB1 and IL28 mRNA. Overall, RV replication was positively related to CXCL10 secretion and induction of IFNB1 and IL28 mRNA, but the positive relationship between RV RNA and CXCL10 secretion was stronger in normal subjects than in subjects with asthma. Conclusions Budesonide and formoterol can inhibit BE cell inflammatory responses in vitro without interfering with viral replication or production of interferons. These effects could potentially contribute to beneficial effects of budesonide/formoterol combination therapy in preventing RV-induced asthma exacerbations.

Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies. GC-induced apoptosis involves an intrinsic mitochondria-dependent pathway. BIM (BCL-2-interacting mediator of cell death), a BCL-2 homology 3-only pro-apoptotic protein, is upregulated by dexamethasone (Dex) treatment in acute lymphoblastic leukemia cells and has an essential role in Dex-induced apoptosis. It has been indicated that Dex-induced BIM is regulated mainly by transcription, however, the molecular mechanisms including responsible transcription factors are unclear. In this study, we found that Dex treatment induced transcription factor Runx2 and c-Jun in parallel with BIM induction. Dex-induced BIM and apoptosis were decreased in cells harboring dominant-negative c-Jun and were increased in cells with c-Jun overexpression. Cells harboring short hairpin RNA for Runx2 also decreased BIM induction and apoptosis. On the Bim promoter, c-Jun bound to and activated the AP-1-binding site at about -2.7 kb from the transcription start site. Treatment with RU486, a GC receptor antagonist, blocked Dex-induced Runx2, c-Jun and BIM induction, as well as apoptosis. Furthermore, pretreatment with SB203580, a p38-mitogen-activated protein kinase (MAPK) inhibitor, decreased Dex-induced Runx2, c-Jun and BIM, suggesting that p38-MAPK activation is upstream of the induction of these molecules. In conclusion, we identified the critical signaling pathway for GC-induced apoptosis, and targeting these molecules may be an alternative approach to overcome GC-resistance in leukemia treatment.

Background Prevention of mother-to-child transmission of HIV (PMTCT) is a major public health challenge in Zimbabwe. Methods Using trained peer counselors, a nevirapine (NVP)-based PMTCT program was implemented as part of routine care in urban antenatal clinics. Results Between October 2002 and December 2004, a total of 19,279 women presented for antenatal care. Of these, 18,817 (98%) underwent pre-test counseling; 10,513 (56%) accepted HIV testing, of whom 1986 (19%) were HIV-infected. Overall, 9696 (92%) of women collected results and received individual post-test counseling. Only 288 men opted for HIV testing. Of the 1807 HIV-infected women who received posttest counseling, 1387 (77%) collected NVP tablet and 727 (40%) delivered at the clinics. Of the 1986 HIV-infected women, 691 (35%) received NVPsd at onset of labor, and 615 (31%) infants received NVPsd. Of the 727 HIV-infected women who delivered in the clinics, only 396 women returned to the clinic with their infants for the 6-week follow-up visit; of these mothers, 258 (59%) joined support groups and 234 (53%) opted for contraception. By the end of the study period, 209 (53%) of mother-infant pairs (n = 396) came to the clinic for at least 3 follow-up visits. Conclusion Despite considerable challenges and limited resources, it was feasible to implement a PMTCT program using peer counselors in urban clinics in Zimbabwe.

The radial variability of extracellular single muscle fibre action potential (SFAP) field was studied on the basis of an SFAP theoretical model originally constructed by Rosenfalck (1969). Amplitude and time parameters of the SFAP as a function of the radial distance r less than or equal to 10 mm from the fibre were described by simple mathematical expressions. The results obtained were compared with existing experimental data from different authors and discussed in detail.