Genome-wide gene expression responses to experimental manipulation of Saccharomyces cerevisiae repressor activator protein 1 (Rap1) expression level.

Precise regulation of transcription in gene expression is critical for all aspects of normal organism form, fitness, and function and even minor alterations in the level, location, and timing of gene expression can result in phenotypic variation within and between species including evolutionary innovations and human disease states. Eukaryotic transcription is regulated by a complex interplay of multiple factors working both at a physical and molecular levels influencing this process. In Saccharomyces cerevisiae, the TF with the greatest number of putative regulatory targets is the essential gene Repressor Activator Protein 1 (RAP1). While much is known about the roles of Rap1 in gene regulation and numerous cellular processes, the response of Rap1 target genes to systematic titration of RAP1 expression level remains unknown. To fill this knowledge gap, we used a strain with a tetracycline-titratable promoter replacing wild-type regulatory sequences of RAP1 to systematically reduce the expression level of RAP1 and followed this with RNA sequencing (RNA-seq) to measure genome-wide gene expression responses. Previous research indicated that Rap1 plays a significant regulatory role in particular groups of genes including telomere-proximal genes, homothallic mating (HM) loci, glycolytic genes, DNA repair genes, and ribosomal protein genes; therefore, we focused our analyses on these groups and downstream targets to determine how they respond to reductions in RAP1 expression level. Overall, despite being known as both an activator and as a repressor of its target genes, we found that Rap1 acts as an activator for more target genes than as a repressor. Additionally, we found that Rap1 functions as an activator of ribosomal protein genes and a repressor for HM loci genes consistent with predictions from the literature. Unexpectedly, we found that Rap1 functions as a repressor of glycolytic enzyme genes contrary to prior reports of it having the opposite effect. We also compared the expression of RAP1 to five different genes related to DNA repair pathway and found that decreasing RAP1 downregulated four of those five genes. Finally, we found no effect of RAP1 depletion on telomere-proximal genes despite its functioning to silence telomeric repeat-containing RNAs. Together our results enrich our understanding of this important transcriptional regulator.

Risk of chronic kidney disease in people living with HIV by tenofovir disoproxil fumarate (TDF) use and baseline D:A:D chronic kidney disease risk score.

OBJECTIVES: To assess the risk of chronic kidney disease (CKD) associated with tenofovir disoproxil fumarate (TDF) use by baseline D:A:D CKD risk score. METHODS: Adult antiretroviral therapy (ART)-naïve people living with HIV (PLWH) initiating treatment, with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 , were identified in the OPERA cohort. CKD was defined as two or more consecutive eGFR < 60 mL/min/1.73 m2 , > 90 days apart. Associations between TDF use, baseline D:A:D CKD risk and incident CKD were assessed with incidence rates (IRs; Poisson regression) and adjusted pooled logistic regression. The impact of pharmacoenhancers on the observed association between TDF and CKD was also evaluated. RESULTS: Of 9802 PLWH included, 6222 initiated TDF and 3580 did not (76% and 79% low D:A:D CKD risk, respectively). Overall, 125 CKD events occurred over 24 382 person-years of follow-up. Within strata of D:A:D CKD risk score, IRs were similar across TDF exposure, with high baseline CKD risk associated with highest incidence. Compared with the low-risk group without TDF, there was no statistical difference in odds of incident CKD in the low-risk group with TDF (adjusted odds ratio = 0.55, 95% confidence interval: 0.19-1.54). Odds of incident CKD did not differ statistically significantly by pharmacoenhancer exposure, with or without TDF. CONCLUSIONS: In this large cohort of ART-naïve PLWH, incident CKD following ART initiation was infrequent and strongly associated with baseline CKD risk. TDF-containing regimens did not increase the odds of CKD in those with a low baseline D:A:D CKD risk, the largest group of ART-naïve PLWH, and may remain a viable treatment option in appropriate settings.

Examination of ionoregulatory characteristics of South American cichlids.

We examined ionoregulatory traits of four cichlid species from South America, oscars (Astronotus ocellatus), Tapajos cichlids (Geophagus sp.), Macmaster's dwarf cichlids (Apistogramma macmasteri), and keyhole cichlids (Cleithracara maronii), all inhabitants of ion-poor waters. Km values for Na+ transport in fish held in 100 µmol L-1 Na+ water ranged from 49 to 143 µmol L-1, and Jmax values spanned 450 to 1205 nmol g-1 h-1. After one month in 1000 µmol L-1 Na+ water, kinetic parameters for Na+ uptake in three of the four species acclimated, but only oscars displayed the "typical" pattern of higher Km and lower Jmax values. Low pH water inhibited Na+ uptake (JinNa) in all, and stimulated Na+ efflux (JoutNa) 2.5 to 3.5-fold in three of the four species. Oscars alone had had a measurable JinNa at pH 3.5 and no stimulation of JoutNa. We measured JinNa in oscars and keyhole cichlids during exposure to 100 µmol L-1 Ethoxzolemide (EZ), an inhibitor of carbonic anhydrase, and 1 mmol L-1 NH4Cl (HEA). EZ inhibited JinNa by about 50% and HEA reduced JinNa by 80-90%. These results suggest that Na+ uptake involves H+ extrusion. Acute exposure to 1 µmol L-1 CuSO4 and 60 nmol L-1 AgNO3 inhibited JinNa in both species by 30-85%. Exposure of oscars to 5-fold higher concentrations of both metals did not further inhibit JinNa, but it did stimulate JoutNa 50-150%. The response to metals of both species are similar to other species that have been examined.

Validation of the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) chronic kidney disease risk score in HIV-infected patients in the USA.

OBJECTIVES: The aim of the study was to assess the validity of an easy-to-calculate chronic kidney disease (CKD) risk score developed by the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) group in a longitudinal observational study of people living with HIV (PLWH) in the USA. METHODS: PLWH (2002-2016) without prior exposure to potentially nephrotoxic antiretroviral agents and with at least three estimated glomerular filtration rate (eGFR) test results were identified in the Observational Pharmaco-Epidemiology Research and Analysis (OPERA® ) cohort. Three samples were drawn independently using the same eligibility criteria but each using a different eGFR equation, specifically the Cockcroft-Gault (C-G), Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR estimation method. Full and short D:A:D risk scores were applied. CKD was defined as a confirmed decrease in eGFR to < 60 mL/min/1.73 m2 (stages 3-5). Poisson models estimated the association between CKD incidence and a one-point increase in the continuous risk score. The incidence rate ratio (IRR), adjusted IRR (aIRR), and Harrell's discrimination statistic were used to assess validity. RESULTS: There were 19 444, 22 727 and 22 748 PLWH in the OPERA C-G, CKD-EPI and MDRD samples, respectively. The median (minimum-maximum) follow-up duration was 6.1 (0.3-9.1) years in the D:A:D cohort and ranged from 3.2 to 3.5 (0.2-15.5) years in the OPERA validation samples. The observation time for the majority of PLWH in the D:A:D cohort began prior to 2006, in stark contrast to the OPERA validation samples, where the majority of PLWH were observed after 2011. The CKD incidence ranged from 7.3 per 1000 person-years [95% confidence interval (CI) 6.8, 7.9 per 1000 person-years] in OPERA C-G to 11.0 (95% CI 10.4, 11.6 per 1000 person-years) in OPERA MDRD. In OPERA samples, IRRs by risk group and adjusted IRRs (full risk score) were similar to those in the D:A:D derivation cohort (adjusted IRR 1.3; 95% CI 1.3, 1.3). Harrell's c-statistic ranged from 0.87 to 0.92 in the OPERA samples, comparable to that in the derivation cohort (0.92). Results for short scores were similar. CONCLUSIONS: The findings support the validity of the D:A:D risk scoring method for assessing CKD (stages 3-5) probability in an exclusively USA-based sample regardless of eGFR method.

Transcriptome analysis of osteoblasts in an ovariectomized mouse model in response to physical exercise.

OBJECTIVES: Osteoporosis is a metabolic disease resulting in progressive loss of bone mass as measured by bone mineral density (BMD). Physical exercise has a positive effect on increasing or maintaining BMD in postmenopausal women. The contribution of exercise to the regulation of osteogenesis in osteoblasts remains unclear. We therefore investigated the effect of exercise on osteoblasts in ovariectomized mice. METHODS: We compared the activity of differentially expressed genes of osteoblasts in ovariectomized mice that undertook exercise (OVX+T) with those that did not (OVX), using microarray and bioinformatics. RESULTS: Many inflammatory pathways were significantly downregulated in the osteoblasts after exercise. Meanwhile, IBSP and SLc13A5 gene expressions were upregulated in the OVX+T group. Furthermore, in in vitro assay, IBSP and SLc13A5 mRNAs were also upregulated during the osteogenic differentiation of MC3T3-E1 and 7F2 cells. CONCLUSION: These findings suggest that exercise may not only reduce the inflammatory environment in ovariectomized mice, indirectly suppressing the overactivated osteoclasts, but may also directly activate osteogenesis-related genes in osteoblasts. Exercise may thus prevent the bone loss caused by oestrogen deficiency through mediating the imbalance between the bone resorptive activity of osteoclasts and the bone formation activity of osteoblasts.Cite this article: W-B. Hsu, W-H. Hsu, J-S. Hung, W-J. Shen, R. W-W. Hsu. Transcriptome analysis of osteoblasts in an ovariectomized mouse model in response to physical exercise. Bone Joint Res 2018;7:601-608. DOI: 10.1302/2046-3758.711.BJR-2018-0075.R2.

Meta-analysis of the prevalence of renal cancer detected by abdominal ultrasonography.

BACKGROUND: The potential for an ultrasound-based screening programme for renal cell carcinoma (RCC) to improve survival through early detection has been the subject of much debate. The prevalence of ultrasound-detected asymptomatic RCC is an important first step to establishing whether a screening programme may be feasible. METHODS: A systematic search of MEDLINE and Embase was performed up to March 2016 to identify studies reporting the prevalence of renal masses and RCC. Two populations of patients were chosen: asymptomatic individuals undergoing screening ultrasonography and patients undergoing ultrasonography for abdominal symptoms not related to RCC. A random-effects meta-analysis was performed. Study quality was evaluated using a validated eight-point checklist. RESULTS: Sixteen studies (413 551 patients) were included in the final analysis. The pooled prevalence of renal mass was 0·36 (95 per cent c.i. 0·23 to 0·52) per cent and the prevalence of histologically proven RCC was 0·10 (0·06 to 0·15) per cent. The prevalence of RCC was more than double in studies from Europe and North America than in those from Asia: 0·17 (0·09 to 0·27) versus 0·06 (0·03 to 0·09) per cent respectively. Data on 205 screen-detected RCCs showed that 84·4 per cent of tumours were stage T1-T2 N0, 13·7 per cent were T3-T4 N0, and only 2·0 per cent had positive nodes or metastases at diagnosis. CONCLUSION: At least one RCC would be detected per 1000 individuals screened. The majority of tumours identified are early stage (T1-T2).

Effect of shockwave therapy on plantar fasciopathy. A biomechanical prospective.

It has been suggested that extracorporeal shockwave therapy is a safe and effective treatment for pain relief from recalcitrant plantar fasciopathy (PF). However, the changes in gait and associated biomechanical parameters have not been well characterised. We recruited 12 female patients with recalcitrant PF who had a mean age of 59 years (50 to 70) and mean body mass index of 25 kg/m(2) (22 to 30). The patients reported a mean duration of symptoms of 9.3 months (6 to 15). Shockwave therapy consisting of 1500 impulses (energy flux density 0.26 mJ/mm(2)) was applied for three sessions, each three weeks apart. A pain visual analogue scale (VAS) rating, plantar pressure assessment and motion analysis were carried out before and nine weeks after first shock wave therapy. It was demonstrated that patients increased their walking velocity and cadence as well indicating a decrease in pain after shockwave therapy. In the symptomatic foot, the peak contact pressure over the forefoot increased and the contact area over the digits decreased. The total foot impulse also decreased as did stance duration. The duration the centre of pressure remained in the hindfoot increased in the symptomatic foot after shockwave therapy. The differences in centre of pressure trajectory at baseline decreased at final follow-up. In conclusion, shockwave therapy not only decreased the pain VAS rating but also improved the gait parameters of the symptomatic foot in PF patients.

Photofrin binds to procaspase-3 and mediates photodynamic treatment-triggered methionine oxidation and inactivation of procaspase-3.

Diverse death phenotypes of cancer cells can be induced by Photofrin-mediated photodynamic therapy (PDT), which has a decisive role in eliciting a tumor-specific immunity for long-term tumor control. However, the mechanism(s) underlying this diversity remain elusive. Caspase-3 is a critical factor in determining cell death phenotypes in many physiological settings. Here, we report that Photofrin-PDT can modify and inactivate procaspase-3 in cancer cells. In cells exposed to an external apoptotic trigger, high-dose Photofrin-PDT pretreatment blocked the proteolytic activation of procaspase-3 by its upstream caspase. We generated and purified recombinant procaspase-3-D(3)A (a mutant without autolysis/autoactivation activity) to explore the underlying mechanism(s). Photofrin could bind directly to procaspase-3-D(3)A, and Photofrin-PDT-triggered inactivation and modification of procaspase-3-D(3)A was seen in vitro. Mass spectrometry-based quantitative analysis for post-translational modifications using both (16)O/(18)O- and (14)N/(15)N-labeling strategies revealed that Photofrin-PDT triggered a significant oxidation of procaspase-3-D(3)A (mainly on Met-27, -39 and -44) in a Photofrin dose-dependent manner, whereas the active site Cys-163 remained largely unmodified. Site-directed mutagenesis experiments further showed that Met-44 has an important role in procaspase-3 activation. Collectively, our results reveal that Met oxidation is a novel mechanism for the Photofrin-PDT-mediated inactivation of procaspase-3, potentially explaining at least some of the complicated cell death phenotypes triggered by PDT.

Potentially avoidable emergency department attendance: interview study of patients' reasons for attendance.

OBJECTIVES: To explore the reasons for attendance at the emergency department (ED) by patients who could have been managed in an alternative service and the rate of acute admissions to one acute hospital. DESIGN: Interview study. SETTING: One acute hospital (University Hospitals of Leicester) in the East Midlands. PARTICIPANTS: 23 patients and/or their carers. METHODS: A purposive sample of patients attending the ED and the linked urgent care centre was identified and recruited. Patients in the sample were approached by a clinician and a researcher and invited to take part in an interview. Patients of different ethnicities and from different age groups, arriving at the ED via different referral routes (self-referral, emergency ambulance, GP referral, out-of-hours services) and attending at different times of the day and night were included. The interviews were recorded and transcribed with the individuals' permission and analysed using the framework analysis approach. RESULTS: Patients' anxiety or concern about the presenting problem, the range of services available to the ED and the perceived efficacy of these services, patients' perceptions of access to alternative services including general practice and lack of alternative pathways were factors that influenced the decision to use the ED. CONCLUSIONS: Access to general practice, anxiety about the presenting problem, awareness and perceptions of the efficacy of the services available in the ED and lack of alternative pathways are important predictors of attendance rates.

The effect of early cardiac rehabilitation on health-related quality of life among heart transplant recipients and patients with coronary artery bypass graft surgery.

PURPOSE: To investigate the effect of an early postoperative outpatient cardiac rehabilitation program to health-related quality of life among heart transplantation recipients (HTR) and patients with coronary artery bypass graft (CABG) surgery. METHODS: The study included 45 clinically stable HTR (age: 47 ± 14 years; 36 men, 9 women) and 34 patients with CABG (age: 57.2 ± 12.5 years; 27 men, 7 women). HTR started rehabilitation 70 ± 33 days after transplantation; patients with CABG started training 36 ± 18 days after surgery. Patients participated in a 12-week supervised exercise training program three times per week. Each training session comprised 10 minutes of warm-up, 25 to 30 minutes of cycling or treadmill walking, and 10 minutes of cooldown. The exercise intensity was set at 50% to 80% of peak oxygen uptake (V̇O(2peak)) according to the patient's condition. The health-related quality of life of subjects was evaluated by the Medical Outcomes Trust 36-item health survey (SF-36) at baseline and upon the completion of rehabilitation. RESULTS: At baseline, the HTR group showed lower V̇O(2peak) than the CABG group, but the health-related quality of life was similar between the two groups. After training, both groups exhibited an increase of 3.6 mL·kg(-1)·min(-1) in V̇O(2peak) and improvement of physical component in health-related quality of life. The HTR group showed a significant increase of SF-36 scores in physical functioning (59.7 ± 18.9 to 77.0 ± 14.0), physical role (21.1 ± 34.1 to 38.3 ± 37.9), bodily pain (57.4 ± 24.3 to 73.6 ± 21.5), social functioning (63.6 ± 23.4 to 72.8 ± 22.1), emotional role (59.2 ± 43.7 to 76.3 ± 37.4), and mental health (67.1 ± 17.9 to 73.4 ± 14.6). The CABG group only exhibited increased scores in physical functioning (60.0 ± 22.9 to 73.4 ± 18.0), physical role (19.1 ± 24.9 to 27.9 ± 38.3), bodily pain (57.1 ± 20.0 to 70.3 ± 16.1), and social functioning (54.0 ± 21.3 to 69.9 ± 21.1). CONCLUSIONS: Early postoperative cardiac rehabilitation significantly improved physical capacity and quality of life among heart transplant recipients and patients with CABG. Additionally, HTR showed greater improvement in health-related quality of life than patients with CABG regardless of lower physical capacity.

The role of reactive oxygen species scavenging enzymes in the development of septic loosening after total hip replacement.

In this study of 41 patients, we used proteomic, Western blot and immunohistochemical analyses to show that several reactive oxygen species scavenging enzymes are expressed differentially in patients with primary osteoarthritis and those with non-loosening and aseptic loosening after total hip replacement (THR). The patients were grouped as A (n = 16, primary THR), B (n = 10, fixed THR but requiring revision for polyethylene wear) and C (n = 15, requiring revision due to aseptic loosening) to verify the involvement of the identified targets in aseptic loosening. When compared with Groups A and B, Group C patients exhibited significant up-regulation of transthyretin and superoxide dismutase 3, but down-regulation of glutathione peroxidase 2 in their hip synovial fluids. Also, higher levels of superoxide dismutase 2 and peroxiredoxin 2, but not superoxide dismutase 1, catalase and glutathione perioxidase 1, were consistently detected in the hip capsules of Group C patients. We propose that dysregulated reactive oxygen species-related enzymes may play an important role in the pathogenesis and progression of aseptic loosening after THR.

Characteristics of general practices associated with emergency-department attendance rates: a cross-sectional study.

BACKGROUND: Strategies are needed to contain emergency-department attendance. Quality of care in general practice might influence the use of emergency departments, including management of patients with chronic conditions and access to consultations. AIM: The aim was to determine whether emergency-department attendance rates are lower for practices with higher quality and outcomes framework performance and lower for practices with better patient reported access. DESIGN: A cross-sectional study. SETTING: Two English primary-care trusts, Leicester City and Leicestershire County and Rutland, with 145 general practices. METHOD: Using data on attendances at emergency departments in 2006/2007 and 2007/2008, a practice attendance rate was calculated for each practice. In a hierarchical negative binomial regression model, practice population characteristics (deprivation, proportion of patients aged 65 or over, ethnicity, gender) and practice characteristics (total list size, distance from the emergency department, quality and outcomes framework points, and variables measuring satisfaction with access) were included as potential explanatory variables. RESULTS: In both years, greater deprivation, shorter distance from the central emergency department, lower practice list size, white ethnicity and lower satisfaction with practice telephone access were associated with higher emergency-department attendance rates. CONCLUSIONS: Performance as indicated by the quality and outcomes framework did not predict rates of attendance at emergency departments, but satisfaction with telephone access did. Consideration should be given to improving access to some general practices to contain the use of emergency departments.

Characteristics of general practices associated with emergency admission rates to hospital: a cross-sectional study.

OBJECTIVES: To identify characteristics of general practices associated with emergency hospital admission rates, and determine whether levels of performance and patient reports of access are associated with admission rates. DESIGN: A cross-sectional study. SETTING: Two primary care trusts (Leicester City and Leicestershire County and Rutland) in the East Midlands of England. PARTICIPANTS: 145 general practices. METHODS: Hospital admission data were used to calculate the rate of emergency admissions from 145 practices, for two consecutive years (2006/7 and 2007/8). Practice characteristics (size, distance from principal hospital, quality and outcomes framework performance data, patient reports of access to their practices) and patient characteristics (deprivation, ethnicity, gender and age), were used as predictors in a two-level hierarchical model, developed with data for 2007/8, and evaluated against data for 2006/7. RESULTS: Practice characteristics (shorter distance from hospital, smaller list size) and patient characteristics (higher proportion of older people, white ethnicity, increasing deprivation, female gender) were associated with higher admission rates. There was no association with quality and outcomes framework domains (clinical or organisation), but there was an association between patients reporting being able to see a particular general practitioner (GP) and admission rates. As the proportion of patients able to consult a particular GP increased, emergency admission rates declined. CONCLUSIONS: The patient characteristics of deprivation, age, ethnicity and gender are important predictors of admission rates. Larger practices and greater distance from a hospital have lower admission rates. Being able to consult a particular GP, an aspect of continuity, is associated with lower emergency admission rates.

Total knee replacement in patients with significant femoral bowing in the coronal plane: a comparison of conventional and computer-assisted surgery in an Asian population.

We conducted a retrospective study to investigate the effect of femoral bowing on the placement of components in total knee replacement (TKR), with regard to its effect on reestablishing the correct mechanical axis, as we hypothesised that computer-assisted total knee replacement (CAS-TKR) would produce more accurate alignment than conventional TKR. Between January 2006 and December 2009, 212 patients (306 knees) underwent TKR. The conventional TKR was compared with CAS-TKR for accuracy of placement of the components and post-operative alignment, as determined by five radiological measurements. There were significant differences in the reconstructed mechanical axes between the bowed and the non-bowed group after conventional TKR (176.2° (SD 3.4) vs 179.3° (SD 2.1), p < 0.001). For patients with significant femoral bowing, the reconstructed mechanical axes were significantly closer to normal in the CAS group than in the conventional group (179.2° (SD 1.9) vs 176.2° (SD 3.4), p < 0.001). Femoral bowing resulted in inaccuracy when a conventional technique was used. CAS-TKR provides an effective method of restoring the mechanical axis in the presence of significant femoral bowing.

End-stage renal disease after orthotopic heart transplantation: a single-institute experience.

Orthotopic heart transplantation is the treatment of choice for end-stage heart failure, and calcineurin inhibitor agents allow for better allograft survival. However, pretransplantation low cardiac output status and posttransplantation immunosuppressants contribute toward deterioration of renal function. From 1987 to 2008, 350 patients underwent orthotopic heart transplantation in our hospital. Most of them received anti-thymocyte globulin (ATG) as the induction immunosuppressant. The introduction of mycophenolate mofetil (MMF) reduced the maintenance level of cyclosporine. The 26 patients who developed end-stage renal disease required dialysis. We reviewed the patient characteristics, including pretransplantation status, immunosuppressant regimens and drug levels, time and type of dialysis, and mortality rate. The mean age of these 26 patients was 53 years. Three patients underwent peritoneal dialysis. The overall 1-year survival rate was 96%, and the 5-year survival rate was 80%. The duration from heart transplantation to chronic dialysis correlated with the presence of a pretransplantation diagnosis of diabetes (P<.05) and an elevated pretransplantation blood creatinine level (P=.01), but there was no significant effect of the initial level of cyclosporine. In addition, the pretransplantation blood creatinine level was also related to the necessity of immediate postoperative hemodialysis (P=.01). There was no significant risk factor in relation to mortality. Regardless of modification of immunosuppressant regimens and initial drug levels, pretransplantation kidney function played an important inverse role in the duration from transplantation to dialysis: the higher the pretransplantation blood creatinine, the shorter the duration. While awaiting a heart transplant, more effort should be spent on protecting renal function to avoid early chronic dialysis.

Ethical issues of organ transplantation in Chinese community: perspectives of health professionals, legal professionals, and religious experts in Taiwan and mainland china.

OBJECTIVE: This study aimed to compare the perspectives of leading ethical issues related to organ transplantation as perceived by health professionals (HP), legal professionals (LP), and religious experts (RE) from Taiwan (TW) and Mainland China (MC). MATERIALS AND METHODS: A purposive sample including TW's organ transplant health professionals (OTHP), LP, and RE and MC's HP was obtained in this qualitative research. Data were analyzed by content analysis. RESULTS: A total of 127 subjects participated in this project (n = 119 in TW, 8 in MC). They were HP (n = 92), RE (n = 25 TW), and LP (n = 10 TW). Seven ethical dilemmas were reported: (1) difficulties in touching the hearts of the public (HP 100%, LP 100%, RE 100%); (2) challenges in helping donors and their families (HP 96%, RE 80%, LP 50%); (3) competence and availability of HP (HP 93%, RE 72%, LP 50%); (4) questionable social farewell (HP 92%, RE 20%, LP 100%); (5) questionable legitimacy of prisoners' motivations (LP 90%, RE 64%, HP 60%); (6) worry about public discrimination (LP 90%, HP 50%, RE 20%); and (7) challenges to families in taking care of the recipients (HP 87%, LP 70%, RE 52%). CONCLUSIONS: To provide holistic care, HP need to invite RE to provide spiritual support for the donors of cadaveric organs, recipients, and their families. Reliable LP can help them to complete the sophisticated legal procedures. With help from this triangulated collaborative team, the value of organ transplantation will be appreciated by the public.

Concerns regarding organ donation from prisoners with death penalties: perspectives of health professionals in Taiwan and Mainland China.

OBJECTIVE: This study aimed to compare the dilemmas of using organs from prisoners with death penalties (PDP) from the perspectives of organ transplant health professionals (OTHP) from Taiwan (TW) and Mainland China (MC). MATERIALS AND METHODS: A purposive sample including TW's OTHP (including transplant surgeons, nurses, researchers, social workers, and medical religious and legal experts), and MC's OTHP (including surgeons and nurses) was obtained in this qualitative research. TW's subjects received face-to-face interviews, and MC's subjects received telephone interviews due to limited communication opportunities. Data were analyzed by content analysis. RESULTS: A total of 105 subjects participated in this project (TW n = 99, MC n = 6). They were surgeons (n = 18: TW n = 14, MC n = 4), registered nurses (n = 42: TW n = 40, MC n = 2), OT coordinating nurses (n = 10 TW), OT researchers (n = 5 TW), social workers (n = 10 TW), medical religious experts (n = 15 TW), and medical legal experts (n = 5 TW). The following 8 ethical dilemmas were reported: (1) questionable legitimacy of PDP motivation (TW 100%, MC 100%); (2) recipients' worries about public discrimination (TW 89%, MC 50%); (3) difficulties in approaching PDP (TW 100%); (4) hesitation of HP and volunteers in helping PDP (TW 37%); (5) questionable social contribution of PDP as donor sources (TW 32%); (6) complex legal details of PDP issues (TW 26%); (7) potential threat from PDP families (TW 23%); and (8) difficulties in helping PDP families cope with post-organ donation syndrome (TW 11%). CONCLUSIONS: Five suggestions were developed in managing these challenges: (1) TW OTHP may empower their basic social science knowledge and empirical competence; (2) TW government may form a task force wherein OTHP leaders are encouraged to foster interdisciplinary collaborations with the public within short-, mid-, and long-term time frames; (3) TW and MC may establish evidence-based center(s) to provide systematic literature reviews for clinical guidance, policy making, and educational resources; (4) TW and MC may try to improve the quality of PDP organ harvesting and donation practice in jails/health institutes; and (5) TW and MC may develop reliable communication systems to share experiences of quality care for PDP, and to evaluate the appraisals both pro and con from multidisciplinary societies and the public, if available.

A pharmacokinetic/pharmacodynamic study comparing arformoterol tartrate inhalation solution and racemic formoterol dry powder inhaler in subjects with chronic obstructive pulmonary disease.

BACKGROUND: Arformoterol is a single-isomer (R,R-formoterol) nebulized long-acting beta(2)-agonist approved for use in patients with chronic obstructive pulmonary disease (COPD). Exposure (plasma concentrations of (R,R)-formoterol) and forced expiratory volume in 1s (FEV(1)) were compared for 15 microg nebulized arformoterol and 12 and 24 microg racemic formoterol (containing 6 and 12 microg (R,R)-formoterol, respectively) delivered by dry powder inhaler (DPI). METHODS: An open-label, randomized, three-way crossover study in 39 subjects with COPD (FEV(1) 1.4L, 44.4% predicted). Twice-daily treatments included nebulized arformoterol (15 microg) and racemic formoterol DPI (12 and 24 microg) for 14 days. Plasma concentrations of (R,R)- and (S,S)-formoterol were determined on days 1 and 14 of each treatment period. Airway function efficacy endpoints included the percent change in trough FEV(1) from baseline on day 14 of each treatment period. RESULTS: At steady state, exposure to (R,R)-formoterol was similar following nebulized 15 microg arformoterol (C(max): 6.5 pg/mL; AUC(0-tau): 56.5 pgh/mL) and 12 microg racemic formoterol DPI (C(max): 6.2 pg/mL; AUC((0-)(tau)()): 46.3 pgh/mL). The geometric mean ratios between these two treatments (90% confidence intervals) for C(max) and AUC((0-)(tau)()) were 0.91 (0.76, 1.09) and 1.16 (1.00, 1.35), respectively. Treatment with 24 microg racemic formoterol DPI resulted in dose proportionally higher (R,R)-formoterol: C(max) (10.8 pg/mL) and AUC((0-)(tau)()) (83.6 pgh/mL). Detectable (S,S)-formoterol was consistently measured only after treatment with racemic formoterol. The mean percent increase in trough FEV(1) was 19.1% in the arformoterol group, and 16.0% and 18.2% in the 12 and 24 microg racemic formoterol groups, respectively. Changes in (R,R)-formoterol concentrations over time paralleled changes in FEV(1). CONCLUSIONS: In this study, plasma exposure to (R,R)-formoterol was similar for nebulized 15 microg arformoterol and 12 microg racemic formoterol DPI, and 40% lower than 24 microg racemic formoterol DPI. There was no evidence of chiral interconversion following treatment with arformoterol. Finally, temporal changes in airway function in all treatment groups corresponded to changes in (R,R)-formoterol plasma concentrations.

Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development.

The generation and homeostasis of bone tissue throughout development and maturity is controlled by the carefully balanced processes of bone formation and resorption. Disruption of this balance can give rise to a broad range of skeletal pathologies. Lethal osteosclerotic bone dysplasia (or, Raine syndrome) is an autosomal recessive disorder characterized by generalized osteosclerosis with periosteal bone formation and a distinctive facial phenotype. Affected individuals survive only days or weeks. We have identified and defined a chromosome 7 uniparental isodisomy and a 7p telomeric microdeletion in an affected subject. The extent of the deleted region at the 7p telomere was established by genotyping microsatellite markers across the telomeric region. The region is delimited by marker D7S2563 and contains five transcriptional units. Sequence analysis of FAM20C, located within the deleted region, in six additional affected subjects revealed four homozygous mutations and two compound heterozygotes. The identified mutations include four nonsynonymous base changes, all affecting evolutionarily conserved residues, and four splice-site changes that are predicted to have a detrimental effect on splicing. FAM20C is a member of the FAM20 family of secreted proteins, and its mouse orthologue (DMP4) has demonstrated calcium-binding properties; we also show by in situ hybridization its expression profile in mineralizing tissues during development. This study defines the causative role of FAM20C in this lethal osteosclerotic disorder and its crucial role in normal bone development.