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.

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).

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.

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.

Gigantic jets between a thundercloud and the ionosphere.

Transient luminous events in the atmosphere, such as lighting-induced sprites and upwardly discharging blue jets, were discovered recently in the region between thunderclouds and the ionosphere. In the conventional picture, the main components of Earth's global electric circuit include thunderstorms, the conducting ionosphere, the downward fair-weather currents and the conducting Earth. Thunderstorms serve as one of the generators that drive current upward from cloud tops to the ionosphere, where the electric potential is hundreds of kilovolts higher than Earth's surface. It has not been clear, however, whether all the important components of the global circuit have even been identified. Here we report observations of five gigantic jets that establish a direct link between a thundercloud (altitude approximately 16 km) and the ionosphere at 90 km elevation. Extremely-low-frequency radio waves in four events were detected, while no cloud-to-ground lightning was observed to trigger these events. Our result indicates that the extremely-low-frequency waves were generated by negative cloud-to-ionosphere discharges, which would reduce the electrical potential between ionosphere and ground. Therefore, the conventional picture of the global electric circuit needs to be modified to include the contributions of gigantic jets and possibly sprites.

Germline transmission of exogenous genes in the chicken.

Difficulties associated with in vitro manipulation and culture of the early chicken embryo have restricted generation of transgenic chickens to approaches that use replication-competent retroviruses. The need to produce transgenic chickens in the absence of replicating virus prompted development of a new method of gene transfer into the chicken. Microinjection of the replication-defective reticuloendotheliosis virus (REV) vector ME111 beneath unincubated chicken embryo blastoderms results in infection of germline stem cells. This vector contains genetic information exogenous to the chicken genome, including both the herpes simplex virus type 1 thymidine kinase gene and the Tn5 neomycin phosphotransferase gene. About 8 percent of male birds hatched from injected embryos contained vector DNA in their semen. All four positive males tested passed vector sequences onto their progeny. Analysis of G1 offspring showed that gonads of G0 male birds were mosaic with respect to insertion of vector provirus. Thus, primordial germ cells present in the unincubated chicken embryo blastoderm are susceptible to infection by defective REV vectors.

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.

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.

Replication-defective chimeric helper proviruses and factors affecting generation of competent virus: expression of Moloney murine leukemia virus structural genes via the metallothionein promoter.

Two chimeric helper proviruses were derived from the provirus of the ecotropic Moloney murine leukemia virus by replacing the 5'long terminal repeat and adjacent proviral sequences with the mouse metallothionein I promoter. One of these chimeric proviruses was designed to express the gag-pol genes of the virus, whereas the other was designed to express only the env gene. When transfected into NIH 3T3 cells, these helper proviruses failed to generate competent virus but did express Zn2+-inducible trans-acting viral functions needed to assemble infectious vectors. One helper cell line (clone 32) supported vector assembly at levels comparable to those supported by the Psi-2 and PA317 cell lines transfected with the same vector. Defective proviruses which carry the neomycin phosphotransferase gene and which lack overlapping sequence homology with the 5' end of the chimeric helper proviruses could be transfected into the helper cell line without generation of replication-competent virus. Mass cultures of transfected helper cells produced titers of about 10(4) G418r CFU/ml, whereas individual clones produced titers between 0 and 2.6 X 10(4) CFU/ml. In contrast, defective proviruses which share homologous overlapping viral sequences with the 5' end of the chimeric helper proviruses readily generated infectious virus when transfected into the helper cell line. The deletion of multiple cis-acting functions from the helper provirus and elimination of sequence homology overlapping at the 5' ends of helper and vector proviruses both contribute to the increased genetic stability of this system.

Influence of everolimus on cyclosporine Neoral pharmacokinetics in Chinese de novo cardiac transplant recipients.

OBJECTIVE: This study sought to determine the influence of everolimus on cyclosporine Neoral (CsA) pharmacokinetics over the first 6 months after heart transplantation in Chinese recipients. METHODS: Six de novo cardiac recipients receiving a CsA-everolimus-based immunosuppressive regimen after rabbit antithymoglobulin sequential immuno-induction were compared with six age-matched recipients receiving a CsA-azathioprine-based regimen. We compared CsA 12-hour area-under-curve (AUC) of the first dose (PK-1) and steady state dose (PK-S) at 1 month after transplantation. The CsA trough concentrations (Cmin) were compared over the first 6 months after transplantation. RESULTS: There was no significant difference between the two groups in age, gender, and body weight. With respect to dose-normalized CsA AUC(0-infinity) of PK-1 and dose-normalized CsA AUC(0-12) of PK-S, the difference between the everolimus- and the azathioprine-based regimens was not significant. The dose-normalized CsA trough concentrations (Cmin/dose) were significantly lower in the everolimus-based group than in the azathioprine-based group during the first 5 months after heart transplantation, but the difference was not significant at posttransplantation month 6. CONCLUSIONS: When CsA pharmacokinetic profiles were considered, the CsA dose requirement was not lower in Chinese patients receiving everolimus than that in patients receiving azathioprine. The results differed from reports from Western countries.

Extracorporeal membrane oxygenation hybrid with various ventricular assist devices as double bridge to heart transplantation.

Ventricular assist devices (VAD) have benefitted patients with end-stage heart failure as a bridge to heart transplantation (HTx). We present our experience with HTx after an extracorporeal membrane oxygenation (ECMO) hybrid with various ventricular assist devices (VAD). From May 1996 to December 2003, mechanical circulatory support with a Biopump VAD was performed in eight patients, HeartMate left VAD in eight patients, and Thoratec VAD in eight patients. Before VAD implantation, 19 patients maintained their circulation with ECMO. Half of the 24 patients were implanted with VAD to await a suitable donor for HTx. We observed that half of the patients supported by ECMO hybrid with various VAD awaited a suitable donor for HTx. In our experience, we recommend the application of ECMO for short-term support within 1 week and the Biopump VAD, Thoractec VAD, or HeartMate VAD for medium-term or long-term support as a bridge to HTx.

Therapeutic drug monitoring of cyclosporine Neoral in de novo Chinese cardiac transplant recipients treated with an everolimus-cyclosporine immunosuppressive regimen.

UNLABELLED: This study determined cyclosporine Neoral (CsA) pharmacokinetics and the accuracy of a limited sampling strategy to predict the 12-hour CsA area-under-the-curve (AUC) to provide a practical method for more accurate therapeutic drug monitor of CsA among de novo Chinese heart transplant recipients treated with an everolimus-CsA immunosuppressive regimen. METHODS: Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after oral administration of CsA in six de novo heart recipients receiving a CsA, everolimus, and methylprenisolone immunosuppressive regimen after rabbit antithymoglobulin sequential immuno-induction. We analyzed the pharmacokinetics of the first dose (PK-1) and steady state dose (PK-2) at 1 month after transplantation. The accuracy of a single-point sampling method to predict the AUC was generated by linear regression analyses. RESULTS: The t(max) and dose-normalized C(max) of PK-1 and PK-2 were similar. The correlations in single-point blood levels of PK-1 to predict the AUC(0-infinity) were much lower than the corresponding sampling times in PK-2. In PK-2 study, C4 had the best correlation (r(2) = 0.913, P = .003) to predict AUC(0-12). In addition, the trough concentrations, C(0) (r(2) = 0.875, P = .006) and C(12) (r(2) = 0.783, P = .02) also showed good correlations. C2 had insufficient correlation to predict AUC(0-infinity) in PK-1 or AUC(0-12) in the PK-2 study. In conclusion, the absorption of CsA was similar during PK-1 and PK-2. At steady dose, C4 had the best single-point correlation to predict AUC(0-12). Trough blood levels may be more practical in clinical use to monitor CsA.

Simultaneous heart and kidney transplantation for combined cardiac and renal failure.

Simultaneous heart and kidney transplantation (SHKT) is feasible for combined cardiac and renal failure. Herein we reviewed our 10-year experience in SHKT. Six patients underwent SHKT from June 1995 to December 2004. Their ages ranged from 13 to 63 years old with a mean of 45.5 +/- 15.8 years. They were all men except one girl, who was the youngest (aged 13) who suffered from dilated cardiomyopathy with congestive heart failure and chronic renal failure due to systemic lupus erythematosus. Because of aggravating heart failure, she changed from hemodialysis to peritoneal dialysis. Because of intractable heart failure, she underwent SHKT from a 24-year-old female donor. All received hemodialysis before SHKT. The indications for heart transplantation included dilated cardiomyopathy (n = 3), ischemic cardiomyopathy (n = 1), cardiac allograft vasculopathy (n = 1), and cardiac allograft failure (n = 1). The immunosuppressive protocol and rejection surveillance were these employed for heart transplantation. No operative mortality was noted in this study. The 1-year and 5-year survival rates were the same, 83%. The 10-year survival rate was 55%. No cardiac or renal allograft rejection was noted. No renal allograft loss was noted. There were two late mortalities: the one, who underwent redo heart transplantation for coronary artery vasculopathy died of cardiac allograft failure 1 year after SHKT. The other patient died of massive ischemic necrosis of the intestine at 6 years after SHKT. Our experience showed that SHKT had good short- and long-term results without increasing immunosuppressive doses. End-stage failure of either the heart or the kidney did not preclude heart plus kidney transplantation.

Successful treatment of hepatitis B virus infection with Lamivudine after heart transplantation.

Patients with hepatitis B virus (HBV) infection have a higher morbidity and mortality after heart transplantation (HT). HBV infection is endemic in Taiwan. We studied the effect of lamivudine treatment of HBV infection after HT. From July 1987 to July 2005, 252 patients underwent HT. All recipients and donors underwent routine screening of hepatitis B surface antigen (HBsAg), hepatitis B e antigen, antibody to hepatitis B surface antigen, antibody to hepatitis B core antigen, antibody to hepatitis B e antigen, and an alanine aminotransferase (ALT) level before HT. When ALT was two times greater than the upper limit of normal or serum bilirubin was higher than 3 mg/dL in HBsAg-positive patients, HBV-DNA were checked by a branched DNA assay or polymerase chain reaction. When HVB-DNA was greater than 100,000 copies/mL, lamivudine (100 mg per day) was prescribed indefinitely. There were 14 patients under lamivudine treatment after HT, among whom, none suffered severe adverse reactions from lamivudine. Four patients died: one due to end-stage cirrhosis while awaiting liver transplantation at 14 months after HT. Two died of sudden death at 54 months and 138 months after HT. Another died of diffuse B cell lymphoma at 62 months after HT. All the survivors have normal ALT and undetectable HBV-DNA after lamivudine treatment. But the YMDD mutant was detected in two patients. With successful treatment of HBV infection in HT, it is not necessary to exclude HBV infection patients from HT.

Sparing immunosuppression in heart transplant recipients with severe sepsis.

This study described an analysis of severe sepsis among heart transplantation recipients who were treated by sparing all immunosuppressants. Sepsis leading to multiple organ failure (MOF) in heart transplantation has a high mortality. This retrospective study of 190 patients who underwent heart transplantation from 1993 to 2004 included 12 who had severe sepsis with MOF who were treated by sparing all immunosuppressants. Half of them survived after sparing all immunosuppressants with intensive endomyocardial biopsy. Only one case needed pulse therapy for an acute rejection episode. The most common bacterial infectious episodes were caused by methicillin-resistant Staphylococcus aureus (n = 3). All sepsis episodes occurred in the first month after heart transplantation except in one case, which occurred 6 years after heart transplantation. There was a 50% survival rate of heart transplantation recipients who experienced MOF due to severe sepsis and were treated by sparing all immunosuppressants under a program of intensive endomyocardial biopsy.

Heart retransplantation for heart allograft failure in Chinese heart transplant recipients: NTUH experience.

We investigated the short- and long-term results after heart retransplantation in terms of different causes of heart allograft failure. We sought to establish the data of heart retransplantation in Chinese compared with Western counterparts due to differences in heart allograft vasculopathy. From March 1995 to May 2005, eight heart transplantation recipients with allograft failure underwent retransplantation. Heart allograft failure was due to coronary vasculopathy (CAV) in six patients (75%) and acute rejection in two patients (25%). The mean interval to retransplantation was 32 to 84 months (mean 54.3 months). There were five patients who survived after heart retransplantation for CAV and no patient survived after an earlier diagnosis of acute rejection. Heart retransplantation is a feasible method with acceptable long-term survival rate for heart allograft failure. After careful pretransplant evaluation, retransplantation is acceptable. The survival after retransplantation for CAV is notably great than that after acute rejection. Heart retransplantation is the only way for patients who have cardiac allograft failure to achieve long-term survival.