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Purpose: Serotonin (5-HT) is implicated in the underlying mechanisms which mediate cell death following ionizing radiation exposure, however, effects appear to be cell type-dependent. We sought to further characterize the role of 5-HT and 5-HT receptors (5-HTRs) in the exacerbation of cell death following ionizing radiation exposure in human colon carcinoma cells. Materials and methods: We examined the clonogenic survival of colon carcinoma HCT116 cells treated with 5-HT and the selective 5-HTR antagonists ketanserin (5-HT 2A ) and ondansetron (5-HT 3 ), following exposure to direct ionizing radiation and irradiated cell-conditioned medium (ICCM). The relative expression of these target receptors was measured using western blotting. Results: Western blotting results revealed that relative protein levels of the 5-HT 2A and 5-HT 3 receptors were similar. 5-HT concentration-dependent increases in cell death that occurred following direct ionizing radiation exposure were abolished by both 5-HTR antagonists. Death of nonirradiated cells recipient of ICCM was increased in a concentration-dependent manner by 5-HT when present during donor cell irradiation. Both 5-HTR antagonists completely abolished the increases in bystander-induced cell death generated by 5-HT. Finally, we show that exposure of cells to 5-HT prior to receipt of ICCM can also dictate the degree of bystander-induced cell death. Conclusions: Our findings demonstrate a definitive role for 5-HT in the exacerbation of cell death following ionizing radiation exposure in colon carcinoma cells and highlight 5-HTRs as potential markers for predicting cellular radiosensitivity.

Ionizing radiation (IR) is an environmental carcinogen and the biological damages it elicits are mechanistically distinct between high and low doses. Non-targeted effects occurring in nonirradiated cells such as the radiation-induced bystander effect predominate at low doses of IR. However, the role of non-targeted effects in environmental radiation protection is often overlooked because the governing mechanisms are complex and multifactorial. An improved understanding of the signaling molecules and their capacity to sensitize specific cell types are essential in establishing environmental IR risks. In particular, serotonin (5-HT) has been identified to exacerbate both direct irradiation and bystander-induced cell death (CD) in certain cell types, although not all cell types are responsive to 5-HT in this respect. In this study, we further characterize the role of 5-HT and 5-HT receptors (5-HTR) in the amplification of CD following IR exposure in human keratinocytes. We examined the survival of HaCaT cells treated with 5-HT and the 5-HTR antagonists ketanserin (5-HT 2A ) and ondansetron (5-HT 3 ) following exposure to direct IR and irradiated cell condition medium (ICCM). Nonirradiated cell survival was consistent with the vehicle control among 5-HT concentrations ranging from 0.001 to 100 μM. Significant 5-HT concentration-dependent increases in CD occurred following direct IR exposure. Nonirradiated ICCM-recipient CD was not altered by 5-HT (0.001-100 μM) when present during donor cell irradiation among all IR doses. Increases in direct irradiation CD evoked by 5-HT were significantly attenuated by ondansetron, blocking the effect of 5-HT, whereas ketanserin did not alter CD. Western blotting of these target 5-HTRs revealed protein expression of the 5-HT 3 receptor, while the 5-HT 2A receptor was not detected. We have demonstrated a definitive role for 5-HT in the exacerbation of CD following direct IR exposure and identified the 5-HT 3 receptor as a potential target for ameliorating radiation damage in keratinocytes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The radiation-induced bystander effect is mechanistically complex, involving many different signaling components. Serotonin, present in fetal bovine serum (FBS), has been implicated in the modulation of cellular responses to radiation. However, the role of this ubiquitous signaling molecule has yet to be elucidated with regard to cell line-specific radiation responses. In this study, cell survival was measured in HCT116 p53 wild-type (HCT116 +/+ ) and HaCaT cell cultures treated with media containing serotonin-depleted FBS and compared to our standard FBS-supplemented media, using clonogenic assays. We utilized an enzyme-linked immunosorbent assay to quantify the difference (4.3 ± 1.3 ng/ml) in serotonin concentrations among the media. Serotonin-depleted media significantly reduced survival in both nonirradiated cell lines. Furthermore, we sought to determine the effects to cells in this media exposed to direct irradiation as well as bystander media from irradiated cells. Cell survival was significantly increased when HCT116 +/+ cells were directly irradiated in serotonin-depleted media, while HaCaT cells showed no significant difference in survival between the media. Bystander investigations demonstrated that HCT116 +/+ cells were only able to generate a bystander effect when cultured in standard media conditions containing greater serotonin levels. Conversely, HaCaT cells were unaffected by the different media in terms of producing a bystander response, generating bystander effects irrespective of the media. Previous research linking serotonin receptors to the bystander effect, together with our results, indicate that receptor heterogeneity among cell types may underlie serotonin sensitivity in direct irradiation and bystander responses through serotonin receptor-mediated cell signaling cascades.

The supply of donor organs has not increased as fast as has the number of patients awaiting kidney transplantation. Few organs are shared outside the areas of recovery. This trend has caused some ESRD patients to seek listing at multiple centers. We examined UNOS registry data and transplant registry data at the University of Alabama at Birmingham (UAB) for the 576 patients listed at multiple centers over an 8-year span ending December 31, 2005. We identified 72 multilisted patients who received a deceased-donor renal allograft at UAB and reviewed their records for demographics, HLA matching and transfer of listing time. The only predictors for transplantation at UAB were initial listing at UAB or transfer of waiting time. Fifty-one of the 72 patients had listed at UAB first; the other 21 had transferred waiting time. None of the 176 patients who listed elsewhere first and did not transfer waiting time had been transplanted at UAB. Aggregate cost of listing and evaluation for the 176 patients listed elsewhere first who did not transfer waiting time was $1 254 528. Secondary listing at UAB, with a large cohort awaiting transplantation, without transfer of waiting time from another center was an expensive and futile process.

Individuals waiting for a renal transplant experience excessive cardiovascular mortality, which is not fully explained by the prevalence of ischemic heart disease in this population. Overt heart failure is known to increase the mortality of patients with ESRD, but the impact of lesser degrees of ventricular systolic dysfunction is unknown. For examination of the association between left ventricular ejection fraction(LVEF) and mortality of renal transplant candidates, the records of 2718 patients evaluated for transplantation at one institution were reviewed. During 6355 patient-years (median 27 mo) of follow-up, 681 deaths occurred. Patients with systolic dysfunction (LVEF

Background: Gated single photon emission computed tomography (SPECT) provides information on myocardial perfusion and left ventricular ejection fraction (LVEF), which correlates with risk of cardiac events in patients with known or suspected coronary artery disease (CAD). We hypothesize that decreased LVEF at time of renal transplant evaluation is an independent risk factor for cardiac death and nonfatal events after transplant., Methods and Results: A total of 653 recipients of renal allografts between 1998 and 2005 had stress SPECT imaging before transplantation. One hundred and nineteen (18%) patients had left ventricular (LV) systolic dysfunction (LVEF

This counter view of protocol biopsy suggests that the widespread clinical use of this technique may be questionable. It may remain primarily a valuable research tool. Cost and risk remain as major issues. Be it screening by routine computed tomography scan for apparently normal people or routine biopsy of normal functioning kidneys there is always the risk that more harm than good might be done. The proof of benefit should be strong (scientifically strong), which requires confirmation and reproducibility of controlled trials. Patients need to know how protocol biopsy is to be used (research, management or both) and the strength of the scientific evidence concerning benefit in long-term management.

Objective: We characterized the pharmacokinetics of tacrolimus and everolimus in a combined immunosuppressive regimen., Methods: This was an open-label exploratory trial in eight maintenance renal transplant patients with calcineurin inhibitor intolerance initially receiving mycophenolate mofetil (MMF) and tacrolimus. At enrollment, MMF was discontinued and replaced with everolimus 1.5 mg twice a day in study period 1 (days 1 to 10). In period 2 (day 11 to month 3), tacrolimus dose was reduced by half., Results: At study entry tacrolimus trough level (C0) was 7.9 +/- 3.9 ng/mL and area under the curve over a dosing interval (AUC) was 132 +/- 56 ng x h/mL. The addition of everolimus in period 1 did not change tacrolimus exposure: C0 8.4 +/- 4.0 ng/mL, AUC 134 +/- 70 ng x h/mL. Everolimus pharmacokinetics in the presence of tacrolimus in period 1 were: C0 3.3 +/- 1.2 ng/mL, Cmax 10.4 +/- 5.1 ng/mL, AUC 58 +/- 20 ng x h/mL. When compared to pharmacokinetic data from a previous study in 47 renal transplant patients receiving everolimus at the same fixed dose (1.5 mg twice a day) with cyclosporine, everolimus exposure was 2.5-fold higher with cyclosporine relative to the data in this study with tacrolimus. After tacrolimus dose reduction in period 2, there was no clinically relevant change in everolimus exposure: C0 3.0 +/- 1.1 ng/mL, Cmax 8.2 +/- 1.3 ng/mL, AUC 49 +/- 10 ng x h/mL., Conclusions: Tacrolimus appears to have a minimal effect on everolimus blood levels compared with the influence of cyclosporine. The dose of everolimus when combined with tacrolimus needs to be higher than when combined with cyclosporine in order to reach a given everolimus blood level.

The use of cyclosporine and tacrolimus therapy in nonrenal (heart, heart/lung, lung, and liver) transplantation has resulted in improved patient and graft survival. Nephrotoxicity is one of the major side effects of tacrolimus and cyclosporine therapy and may lead to ESRD. The trend of referral of nonrenal solid-organ transplant recipients for kidney transplant evaluation at a large multiorgan transplant center was examined. Records of all patients who were referred for renal transplantation at the University of Alabama between January 1, 1993, and June 30, 2004, were reviewed. Eighty (0.96%) of 8318 individuals had previously undergone a nonrenal solid-organ transplant and were included in the study. The majority (72%) of patients had their nonrenal transplants performed at the University of Alabama. Twenty-two patients had their nonrenal transplant performed elsewhere and had fewer data available for analysis. From the period 1993-1996 to 2001-2004, an 11-fold increase in the absolute number of referrals of patients with nonrenal transplants was noted. Of patients who were referred for transplant evaluation, 25 became recipients of kidney transplants with a predominance of living-donor transplants. Referral for kidney transplant evaluation among nonrenal solid-organ transplant recipients is increasing and will exacerbate the existing shortage of deceased-donor kidneys that are available for transplantation. There was a trend for liver transplant recipients compared with other solid-organ recipients to develop ESRD at a greater rate.

The growing shortage of deceased-donor kidneys and the rapid growth in the number of patients with end-stage renal failure aged 65 years and older is impacting the current policies for allocation of allografts. The utilitarian and egalitarian philosophies may clash in times of limited resources. Organ transplantation can be viewed as a microcosm concerning healthcare issues facing an aging population and limited resources. The limited resources in organ transplantation are not merely financial. The limits on supply of deceased-donor organs will force the transplant community to deal with allocation issues before the more general population faces other limits in health care. Our discussions may clarify some of the problems.

Background: Patients infected with hepatitis C virus (HCV) frequently develop renal failure after liver transplantation., Objective: To describe renal histologic characteristics and concomitant clinical features in HCV-infected patients with end-stage cirrhosis., Design: Case series., Setting: Single-center liver transplant program in the United States., Patients: 30 patients who received liver transplants for HCV-induced cirrhosis., Intervention: Kidney biopsy during liver engraftment., Measurements: Clinical data and laboratory tests of renal function within 6 months before liver transplantation., Results: Twenty-five patients had immune-complex glomerulonephritis: membranoproliferative glomerulonephritis type 1 (n = 12), IgA nephropathy (n = 7), and mesangial glomerulonephritis (n = 6). Of these patients, 10 had normal serum creatinine levels, normal urinalysis results, and normal quantitative proteinuria. For 5 others, the only renal abnormality was an increased serum creatinine level. No patient had cryoglobulins in the blood or kidney., Limitations: This small observational study did not include patients with nonviral cirrhosis and did not document post-transplantation outcomes., Conclusions: Immune-complex glomerulonephritis was common in patients with end-stage HCV-induced cirrhosis and was often clinically silent. Its potential to cause renal failure after liver transplantation may be underappreciated.

With the recent focus of monitoring cyclosporine (CsA) therapy using measures of CsA absorption, it is important to understand published reports of diurnal variation in CsA exposure. In 10 renal transplant patients, CsA concentrations were measured 0, 1, 2, 3, and 4 h after both the morning and the evening doses and in a repeat session at least 1 wk later. Both area under the curve for the final 4 h after cyclosporine dose and cyclosporine concentrate 2 h after the cyclosporine dose were more than two-fold higher after the morning dose in both sessions. Because the morning levels were collected in a fasted condition and the evening ones in a fed condition, the study was extended to collect evening levels after fasting. The area under the curve for the final 4 h after cyclosporine dose and cyclosporine concentrate 2 h after the cyclosporine dose values observed now were comparable to the morning fasted values. That the large diurnal variation was due to variation in food consumption, as opposed to a biologic circadian rhythm affecting CsA absorption, has significant implications for therapeutic drug monitoring.

Cyclosporine ended the azathioprine-prednisone era of transplantation. For years prior to cyclosporine, regimens in transplant centers were relatively fixed and all patients received the same two drugs in nearly the same doses with adjustments made primarily for toxicities. Transplant physicians became expert in the side effects of steroids and azathioprine. Cyclosporine changed everything. Change is never easy, however, and initial resistance to changing protocols (especially for a new nephrotoxic drug) was only overcome by randomized, controlled trials. Cyclosporine increased allograft and patient survival rates without increasing opportunistic infections. However, as important were the changes in thinking that came about. It can be argued that cyclosporine contributed to expanding multicenter controlled trials in the transplant community. It also helped bring about concepts such as tailoring drugs to individual patients, drug minimization or elimination, use of polypharmacy, and focus on the first few weeks after transplant. Understanding of T-cell function and causes of renal dysfunction were brought into clearer focus by this exciting new agent.

Pericardial cystic lesions (PCLs) occur infrequently but are significant for their varying clinical presentation and pathological multitude. A review of the literature (including Medline and Current Contents database searches, and search of existing bibliographies) finds confusion in nomenclature and an absence of appropriate classification. A new classification system is proposed based on exo- or endophytic growth, presence of adhesions, and compression of myocardium or great vessels. A multitude of pathological entities with diverse pathogenesis, disease courses, and prognoses may present as PCLs. Detailed knowledge of lesion types and alternatives among diagnostic and therapeutic options permits a selective approach to patient management. The usefulness of a unified classification system should be evaluated in a substantial patient population, with detailed statistical analysis.

Because of the infrequent application of cardiac assist devices for postcardiotomy heart failure, most published reports include the results of learning curves from multiple surgeons. Between October 1986 and June 2001, a single surgeon used 35 Sarns Centrifugal Pumps as ventricular assist devices in 21 patients with severe hemodynamic compromise after open heart surgery (0.88% incidence). Patients' ages ranged from 39 to 77 (mean, 59.6 years). Three patients required right ventricular assist devices, 4 left ventricular assist devices, and 14 had biventricular assist devices. For all, the indication for application was inability to wean from cardiopulmonary bypass despite multiple inotropes and intraaortic balloon pumping. All were expected to be intraoperative deaths without further mechanical assistance. Patients were assisted from 2 to 434 h (median, 48 h). Fifteen patients (71.4%) were weaned from device(s), and 11 patients (52.4%) were hospital survivors. Actuarial survival in those dismissed from the hospital was 78% at 5 years and 39% at 10 years. Patients facing certain demise after cardiac surgery can be salvaged with temporary centrifugal mechanical assist. Results are competitive with that achieved with more sophisticated devices. Hospital survivors enjoy reasonable longevity.

Paraplegia from ischemic injury of the spinal cord and renal failure from inadequate perfusion of the kidneys may occur from aortic cross-clamping during repair of traumatic thoracic aortic injuries. After Institutional Review Board approval, we retrospectively reviewed the charts of 26 patients surgically treated for traumatic transection of the descending thoracic aorta during a 14 year period (1987-2001), using centrifugal pump (Sarns) support for distal aortic perfusion. The study group comprised 19 males and 7 females, whose ages ranged from 15 to 69 years. For all but 1 patient, who fell from a flagpole, the injuries were incurred in motor vehicle accidents. Aortic cross-clamp time lasted between 5 to 78 min (median = 40 min). Mean arterial pressure ranged from 50 to 80 mm Hg (median = 70 mm Hg). All patients survived operation without developing paraplegia or renal failure. Distal centrifugal pump perfusion during repair of traumatic injury of the descending thoracic aorta is a valuable adjunct during surgical treatment and aids in preservation of spinal cord and renal function.

Kidney transplantation has seen a remarkable improvement in allograft survival rates and patient survival rates, and an equally remarkable reduction in acute rejection rates. Most attribute these changes to the introduction and widespread use of calcineurin inhibitors as part of the standard immunosuppressive regimen. Cyclosporine and tacrolimus are ideal immunosuppressive agents, much more effective and safe than the previous agents used. Especially ironic, however, for those caring for kidney transplant patients has been the finding that these breakthrough agents are toxic to the kidney and can cause hypertension. We can protect the transplanted kidney from rejection, but still damage it paradoxically by the protecting agent. Moreover, the prevalence of hypertension in transplant clinics has increased (from 40%-50% to up to 90%-100%) as these newer agents have gained widespread use. We remain uncertain of the mechanism whereby these agents cause hypertension, and therefore remain uncertain of the ideal treatment; however, the search for a mechanism has taken us from the organ level to intracellular effects of the agents. The fact that both agents cause nephrotoxicity suggests that a renal mechanism is at the heart of the hypertension.

Patients with high transthoracic impedance are reported to be at higher risk of poor outcomes when treated by present defibrillators. This study evaluates the defibrillation efficacy of biphasic truncated exponential (BTE), quadriphasic truncated exponential (QTE), and Edmark waveforms at simulated low, average, and high impedance levels. Waveforms were tested at 2 energy levels in random order in anesthetized dogs (n = 15, 16.9 +/- 1.2 kg), and a supplemental study estimated the ED50 peak current for BTE and QTE at a simulated high impedance level. Overall, BTE and QTE were equivalent, and both were superior to Edmark at equal delivered energies (P<.0001). However, in simulated high impedance patients at 24 J, QTE was superior to BTE (71% vs. 49%, P =.011 (borderline significance-see text)). Supplemental study, QTE mean ED50 peak current was lower than BTE (7.9 vs. 8.9 A, P =.0049). QTE and BTE waveforms were superior to Edmark at all studied conditions, but QTE appears to be superior to BTE in simulated high impedance patients.

Background: We studied whether tracheostomy after coronary artery bypass grafting (CABG) is associated with higher incidence of mediastinitis and mortality, and whether shorter intervals between median sternotomy and tracheotomy are associated with higher incidence of mediastinitis., Methods: Patients (n = 6,057) undergoing CABG since March 1977 were reviewed. Patients requiring tracheostomy and those developing mediastinitis were identified. Mediastinitis diagnosis required positive culture of mediastinal tissue or fluid., Results: After CABG, 88 patients had tracheostomy performed (1.45%). Seven patients receiving tracheostomy after developing mediastinitis were excluded. Of the remaining 81 patients, 7 developed mediastinitis (8.6%) compared with 44 of 5,969 (0.7%) who did not require tracheostomy (p < 0.001). Mortality in tracheostomy patients was 24.7% (20 of 81) compared with 5.2% in patients not requiring tracheostomy (316 of 5,969; p < 0.001). Patients not developing mediastinitis had tracheostomy placement an average of 25 days after CABG compared with 18.7 days for those developing mediastinitis (p = 0.141)., Conclusions: Tracheostomy after CABG is associated with increased incidence of mediastinitis and mortality. In this review, the time interval between CABG and tracheostomy was not predictive of mediastinitis. A larger sample size would be required to be confident that there is no correlation.

Previous studies of renal transplant recipients have suggested that weight gain after transplantation is relatively common, especially among certain populations. We conducted a retrospective review of 977 renal transplant recipients at the University of Alabama at Birmingham to identify patterns of weight change (as mean percentage of body weight at transplantation) attributed to race, sex, income, age at transplantation, pretransplantation time on dialysis, incidence of diabetes, rejection episode(s), and/or obesity (body mass index >/= 30 kg/m(2)) at transplantation. Patients were evaluated at 3, 6, 9, and 12 months posttransplantation and at 2 and 3 years, when available. Univariate analysis at 1 year showed that blacks achieved a greater weight change than whites (P = 0.0004), women had greater gains than men (P = 0.0001), and low-income patients had greater mean gains versus medium- (P = 0.0001) and high-income patients (P = 0.0001). Advancing age and weight gain were inversely correlated (P = 0.0002). Having one or more rejection episode indicated less weight gain than having no rejection episode (P = 0.0220). Incidence of diabetes or time on dialysis was not a significant predictor of weight gain. Black race, female sex, low income, younger age, and no incidence of rejection episodes were significantly associated with weight gain at 1 year in the multivariate analysis.

Despite significant advancements in clinical transplantation, very few reports describe the long-term acceptance of transplanted solid organs without indefinite immunosuppression. The immunosuppressive agents used are nonspecific and have serious potential side effects. We present a patient who received a living-donor renal allograft from the same person who had donated bone marrow to her several years earlier. Tolerance was expected based on previous acceptance of full-thickness skin grafts from the donor. Indeed, there has been no evidence of rejection during a 6-year follow-up period, and no induction or maintenance immunosuppression has been given. All noninvasive parameters of graft function remain normal. This and similar reports prove that genetically disparate solid organs can coexist without pharmacological immunosuppression.

Circulatory support devices are frequently required in postcardiotomy shock, postmyocardial infarction shock, and acute myocarditis. A panel of cardiac surgeons addressed the use of these devices in 4 patients. Cardiogenic shock after mitral valve replacement was considered best served by a left ventricular assist device (VAD) with apical rather than atrial cannulation. A left VAD should be placed first and a right VAD only if needed. Acute myocardial infarction shock was considered best treated with a left VAD with left ventricular cannulation to avoid thrombosis. If cardiac transplantation is an option, a long-term device must be considered. Young patients with acute fulminant myocarditis should be implanted with VADs in anticipation of recovery, and transplantation should be delayed. Patients with severe heart failure after coronary bypass grafting were considered best served by an extracorporal membrane oxygenation (ECMO) system or a VAD. Current postcardiotomy survival rates of postcardiotomy patients of 20% to 40% are worthwhile, but can be improved. Temporary devices such as ECMO can be changed to more long-term devices when necessary.