Mercury transfer in coastal and oceanic food webs from the Southwest Atlantic Ocean.

The dynamics of contaminants, such as mercury (Hg), in marine trophic webs is a critical topic in the scientific community due to the high concentrations encountered in organisms. In this study we attempted to provide information on total Hg accumulation patterns and possible pathways of trophic transfers assessed in combination with δ13C and δ15N to understand how this contaminant permeates three sub-Antarctic food webs: the Beagle Channel (BC), the Atlantic coast of Tierra del Fuego (AC-TDF) and Burdwood Bank (BB). We found a site-specific pattern of Hg transfer and biomagnification processes, while the oceanic BB showed major Hg transfer through the pelagic domain, coastal sectors (BC and AC-TDF) indicate a general biodilution process but with Hg concentrations incrementing with the benthivory grade. This represents a dissimilar Hg bioavailability for marine consumers that rely on different diet and forage in different habitats, and may become an issue of important conservation concern for these southern areas.

When the living and the deceased cannot agree on organ donation: a survey of US organ procurement organizations (OPOs).

The legal concept of first person authorization (FPA) is based on the principle that a decision by a person with decision-making capacity should be respected even after he or she dies. Although the transplant community largely supports this concept, its implementation has not been universal. We conducted a web-based survey of all 58 Organ Procurement Organization (OPO)executive directors in the United States to assess OPOs' procurement policies and practices in the context of family objections. All 58 respondents(100%) responded to our survey. All OPOs except one have an online donor registration website. Most OPOs(89%) (51 of 57 respondents) estimated that the frequency of family objecting to organ donation in cases of registered donors was <10%. No OPOs reported the frequency to be higher than 25%. Only 50% (27 of 54) of the OPOs have a written policy on handling family objections. Approximately 80% of the OPOs reported honoring FPA. However, in the past 5 years, 20 OPOs (35%) have not yet participated in organ procurement from a registered deceased donor over family objection. Further research to identify the barriers and possible solutions to implementing FPA is warranted.

Opportunities for shared decision making in kidney transplantation.

Health researchers and policy-makers increasingly urge both patient and clinician engagement in shared decision making (SDM) to promote patient-centered care. Although SDM has been examined in numerous clinical settings, it has received little attention in solid organ transplantation. This paper describes the application of SDM to the kidney transplantation context. Several distinctive features of kidney transplantation present challenges to SDM including fragmented patient-provider relationships, the time-sensitive and unpredictable nature of deceased organ offers, decision-making processes by transplant providers serving as both organ guardians (given the organ scarcity) versus advocates for specific patients seeking transplantation, variable clinical practices and policies among transplant centers, and patients' potentially compromised cognitive status and literacy levels. We describe potential barriers to and opportunities for SDM, and posit that SDM is feasible, warranting encouragement in kidney transplantation. We propose strategies to promote and overcome obstacles to SDM in kidney transplantation. We contend that engagement in SDM can be facilitated by re-organization of clinical care, communication and education of providers and patients.

Long-term pancreatic allograft survival after renal retransplantation in prior simultaneous pancreas-kidney recipients.

Over a 23-year period, our center performed 82 renal retransplants in prior simultaneous pancreas-kidney recipients with functioning pancreatic allografts. All patients were insulin-independent at retransplantation. We aimed to quantify the risk of returning to insulin therapy and to identify factors that predispose patients to pancreatic allograft failure after renal retransplantation. Among these 82 patients, pancreatic allograft survival after renal retransplantation was 78%, 49% and 40% at 1, 5 and 10 years. When analyzing risk factors, we unexpectedly found no clear relationship between the cause of primary renal allograft failure, hemoglobin A1c (HbA1c) or fasting C-peptide level at retransplant and subsequent pancreatic allograft failure. An elevated HbA1c in the month after renal retransplant correlated with subsequent pancreatic graft loss and patients experiencing pancreatic graft loss were more likely to subsequently lose their renal retransplant. Although it is difficult to prospectively identify those patients who will return to insulin therapy after repeat renal transplantation, the relatively high frequency of this event mandates that this risk be conveyed to patients. Nonetheless, the survival benefit associated with renal retransplantation justifies pursuing retransplantation in this population.

Incidence of and risk factors for posttransplant diabetes mellitus after pancreas transplantation.

Posttransplant diabetes mellitus (PTDM) after pancreas transplantation (PTX) has not been extensively examined. This single center, retrospective analysis of 674 recipients from 1994 to 2005 examines the incidence of and risk factors for PTDM after PTX. PTDM was defined by fasting plasma glucose level > or =126 mg/dL, confirmed on a subsequent measurement or treatment with insulin or oral hypoglycemic agent for > or =30 days. The incidence of PTDM was 14%, 17% and 25% at 3, 5 and 10 years after PTX, respectively and was higher (p = 0.01) in solitary pancreas (PAN) versus simultaneous kidney pancreas (SPK) recipients (mean follow-up 6.5 years). In multivariate analysis, factors associated with PTDM were: older donor age (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.03-1.06, p < 0.001), higher recipient body mass index (HR 1.07,CI 1.01-1.13, p = 0.01), donor positive/recipient negative CMV status (HR 1.65,CI 1.03-2.6, p = 0.04), posttransplant weight gain (HR 4.7,CI 1.95-11.1, p < 0.001), pancreas rejection (HR 1.94.CI 1.3-2.9, p < 0.001) and 6 month fasting glucose (HR 1.01,CI 1.01-1.02, p < 0.001), hemoglobin A(1)c, (HR 1.12,CI 1.05-1.22, p = 0.002) and triglyceride to high-density lipoprotein (TG/HDL) ratio (HR 0.94,CI 0.91-0.96, p < 0.001). This study delineates the incidence and identifies risk factors for PTDM after PTX.

Nonadherence consensus conference summary report.

This report is a summary of a 'Consensus Conference' on nonadherence (NA) to immunosuppressants. Its aims were: (1) to discuss the state-of-the-art on the definition, prevalence and measurement of NA, its risk factors and impact on clinical and economical outcomes and interventions and (2) to provide recommendations for future studies. A two-day meeting was held in Florida in January 2008, inviting 66 medical and allied health adherence transplant and nontransplant experts. A scientific committee prepared the meeting. Consensus was reached using plenary and interactive presentations and discussions in small break-out groups. Plenary presenters prepared a summary beforehand. Break-out group leaders initiated discussion between the group members prior to the meeting using conference calls and e-mail and provided a summary afterward. Conclusions were that NA: (a) is more prevalent than we assume; (b) is hard to measure accurately; (c) tends to confer worse outcomes; (d) happens for a number of reasons, and system-related factors including the patient's culture, the healthcare provider and the setting and (e) it is not currently known how to improve adherence. This consensus report provided some roadmaps for future studies on this complicated, multifaceted problem.

A comparison of alemtuzumab with basiliximab induction in simultaneous pancreas-kidney transplantation.

Alemtuzumab is a humanized, rat monoclonal antibody directed against the CD52 antigen. After binding, alemtuzumab causes profound and durable depletion and has been successfully used as immune induction therapy for organ transplantation. This was a single center, retrospective review of patients who underwent simultaneous pancreas-kidney transplantation at the University of Wisconsin using alemtuzumab induction therapy compared with historical controls that received induction with basiliximab. There were no differences in donor or recipient demographics, rates of patient survival, renal or pancreas allograft survival, renal allograft delayed graft function, EBV infection, BKV infection, PTLD or sepsis. There was a statistically significant increase in the incidence of cytomegalovirus (CMV) infection in the alemtuzumab-treated group. Given the significantly higher incidence of CMV infections, we have since altered our induction protocol to consist of a single 30 mg dose of alemtuzumab instead of two doses. The long-term effects of this change remain to be seen. Due to the results seen in this study, the low initial cost of the drug and the absence of any severe, short-term side effects, alemtuzumab has been selected as the induction drug of choice at our center for patients undergoing SPK.

Kidney function after solitary pancreas transplantation.

Preserving kidney function in patients after solitary pancreas transplantation (SPTx) is an important consideration, yet various factors may negatively impact long-term function of the native kidneys or kidney allograft. To determine changes in kidney function over time in a series of patients receiving SPTx, we conducted a retrospective analysis and tracked changes in serum creatinine (SCr) and calculated glomerular filtration rate (GFR) from baseline to 6 months, 1 year, or 3 years after SPTx in a series of pancreas after kidney transplants PAK; (n = 61) and pancreas transplants alone PTA; (n = 27) performed at our institution. The mean follow-up for the PAK and PTA groups was 3.4 and 2.7 years, respectively. In this series, 8% of patients after SPTx developed significant kidney failure, defined by either initiation of dialysis or receiving a kidney transplant (PAK-6, PTA-1). Twenty seven percent of SPTx patients with a baseline GFR < 60 suffered either an elevated SCr > 2.2, dialysis, or kidney transplant, whereas no patients with a baseline GFR > 60 developed significant kidney dysfunction. In the PAK group, the GFR did not show significant deterioration over time. In contrast to relatively stable kidney function in PAK patients, PTA patients experienced overall significantly greater rates of decline over time. GFR in PTA patients decreased from 78 +/- 19 (40 to 114) mL/min/1.73 m2 at baseline to 65 +/- 20 at 1 year (P = .006), while SCr increased from 1.03 +/- 0.25 mg/dL to 1.28 +/- 0.43 over the same time period (P = .012). These data show that kidney function may deteriorate after SPTx and proper patient selection may reduce the frequency of this complication.

Fluoroscopically guided vs modified traditional placement of tunneled hemodialysis catheters: clinical outcomes and cost analysis.

Tunneled cuffed internal jugular vein catheters are widely used to provide short to medium-term vascular access for hemodialysis. The NKF-K/DOQI guidelines state that fluoroscopy is mandatory for insertion of all cuffed dialysis catheters. The KDOQI recommendation makes it difficult for Nephrologists to perform this procedure without access to fluoroscopy. This results in unnecessary waiting times and the inappropriate use of acute, non-tunneled catheters. The purpose of this study is: 1) to compare the outcomes of fluoroscopically guided vs modified traditional catheter placement technique, and 2) to perform a cost analysis of the two techniques. We performed a retrospective investigation of 202 tunneled hemodialysis catheters performed at our tertiary care hospital. Procedural data were obtained from the University of Wisconsin Department of Medicine, Nephrology Section Interventional Nephrology procedural database. Patient demographics, laboratory tests were obtained from the University of Wisconsin Hospital electronic medical record (EMR). Logistic regression was used to evaluate the effect of blind vs fluoro-guided placement on clinical outcomes, corrected for side of procedure, age, gender, previous history of catheter placement, diabetes mellitus (DM), and pre-procedural coagulation parameters. Baseline characteristics of 'blind' vs fluoro-guided groups differed with respect to side of procedure and DM (91.0% vs 79.6%, p = 0.02 and 43.30% vs 58.40%, p = 0.02, respectively). Non-fluoroscopic placement of catheters was associated with a decreased odds ratio of immediate success (OR = 0.1298, CI = 0.02 - 0.71). No difference in major or minor bleeding complications was discovered between the blind vs fluoro-guided group. Cost analysis revealed that performing the non-fluoroscopic technique as the preferred initial procedure would represent a substantial reduction in total bills submitted to third-party payers, including Medicare.

Oleic acid, a skin penetration enhancer, affects Langerhans cells and corneocytes.

Permeation enhancers (PE) are frequently used in the field of dermal research and for the development of transdermal delivery products. However, their influence on skin epidermal Langerhans cells (LC) has not yet been investigated. In this work we studied the effect of four PE, oleic acid (OA), propylene glycol (PG), ethanol, and diethylene glycol monoethyl ether (DGME), and an iontophoretic treatment on the morphometric parameters of epidermal Langerhans cells (LC). Retinoic acid (RA) was used as a positive control. Test solutions were applied to the footpad of Sabra mice. The area, perimeter, density and shape factor (SF) were the morphometric parameters evaluated following ATPase staining of LC. Application of RA led to a large decrease in cell density (-50.2%, P<0.01) and dendritic shape (19.8%, P<0.01). Treatment with 10% OA in ethanolic solution caused a severe decrease in LC density (-69.0%, P<0.01), accompanied by a decrease in dendricity as measured by the changes in SF. Ethanol had no statistically significant effect on the LC morphologic parameters tested. All other PE had a mild, if any, effect on LC morphology. SEM micrographs of the skin of IOPS hairless rats demonstrated that 24 h in vivo treatment with 10% OA in ethanolic solution resulted in the generation of pores on the surface of epidermal corneocytes.

Simultaneous pancreas-kidney and pancreas transplantation.

The best available method currently for achieving steady normoglycemia in individuals with type 1 diabetes mellitus (DM) is replacing the pancreas, e.g. whole pancreas transplantation. Pancreatic transplantation, as either simultaneous pancreas-kidney (SPK) or solitary pancreas transplantation alone (PTA), has moved beyond simple metabolic or quality-of-life goals. It is now an effective treatment to reverse or minimize metabolic abnormalities and complications of type 1 DM as well as potentially extend the life span of those afflicted by type 1 DM and its many co-morbid complications. Candidates for SPK and PTA transplantation need to meet various criteria even to undergo the transplant procedure and receive a pancreatic allograft that is deemed suitable. SPK and PTA recipients, though free from insulin use, still may encounter common post-transplant medical complications, e.g. cardiovascular disease, high blood pressure, as well as complications unique to SPK and PTA transplantation. The advantages of PTA and SPK transplantation are frankly now more obvious as improvements in surgical technique and new immunosuppression have made an increasing number of PTA and SPK transplants viable and functional long-term. The idea of pancreas transplantation can be touted as a therapeutic advance for type 1 DM. It can improve survival and limit many diabetic-related complications, while improving quality of life, especially in those individuals also afflicted with diabetic-related kidney disease.

Small molecules that dramatically alter multidrug resistance phenotype by modulating the substrate specificity of P-glycoprotein.

By screening a chemical library for the compounds protecting cells from adriamycin (Adr), a series of small molecules was isolated that interfered with the accumulation of Adr in mouse fibroblasts by enhancing efflux of the drug. Isolated compounds also stimulated efflux of Rhodamine 123 (Rho-123), another substrate of multidrug transporters. Stimulation of drug efflux was detectable in the cells expressing P-glycoprotein (P-gp), but not in their P-gp-negative variants, and was completely reversible by the P-gp inhibitors. A dramatic stimulation of P-gp activity against Adr and Rho-123 by the identified compounds was accompanied by suppression of P-gp-mediated efflux of other substrates, such as Taxol (paclitaxel) or Hoechst 33342, indicating that they act as modulators of substrate specificity of P-gp. Consistently, P-gp modulators dramatically altered the pattern of cross-resistance of P-gp-expressing cells to different P-gp substrates: an increase in resistance to Adr, daunorubicin, and etoposide was accompanied by cell sensitization to Vinca alkaloids, gramicidin D, and Taxol with no effect on cell sensitivity to colchicine, actinomycin D, puromycin, and colcemid, as well as to several non-P-gp substrates. The relative effect of P-gp modulators against different substrates varied among the isolated compounds that can be used as fine tools for analyzing mechanisms of drug selectivity of P-gp. These results raise the possibility of a rational control over cell sensitivity to drugs and toxins through modulation of P-gp activity by small molecules.

Gene gun-mediate DNA vaccination against foot-and-mouth disease virus.

Foot-and-mouth disease (FMD) is one of the most dangerous diseases of cloven-hoofed animals and is a constant threat in the Middle-East and other regions throughout the world despite intensive vaccination programs. In this work, we describe the ability of FMDV expression constructs to protect pigs from FMDV challenge when used as a vaccine. The construct consists of encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES), the entire P1 and 2A together with 3CD sequences, all in the same reading frame. Another plasmid that was tested, carries the serotype O1 (G) VP1, Asia1 VP1 and O1 (G) 3C. Between each of the genes the 3C cleavage sequences were inserted. All constructs carried the cytomegalo virus (CMV) promoter. Using immunofluorescent and immunoblot techniques, we could show the expression and processing of viral proteins. Following the application of FMDV expression constructs into pigs skin by 'Gene Gun', pigs were partially protected from FMDV challenge.

Calcitonin gene related peptide in familial dysautonomia.

Familial dysautonomia (FD) patients have diminished sensory C-fibers. Calcitonin gene related peptide (CGRP) is a widely distributed neuropeptide and prominent neurotransmitter in C-fibers. We show that plasma CGRP levels measured by radioimmunoassay is significantly lower in 51 FD patients compared to controls (P<0.001). In 11/51 FD patients with FD crisis and in 19/51 FD patients with pneumonia, the mean CGRP levels rose significantly as compared to their baseline (P<0.003, P<0.001, respectively). The deficiency of CGRP in FD patients is consistent with their depletion of C-fibers, and may explain some of their symptoms, either directly or via modulation of sympathetic activity.

Living-unrelated renal transplantation at the University of Wisconsin.

Since 1984, we have performed 243 living-unrelated renal transplants at the University of Wisconsin. Rejection occurred in 47% of the patients. Graft loss occurred in 59 patients and 39 patients died. Graft survival in LURD transplants at 10 years is 54% and 43% at 15 years. Patient survival is 68% at 10 years and 54% at 15 years. These long-term results demonstrate that LURD is equivalent to haploidentical renal transplantation and superior to cadaveric transplantation. Husband-to-wife donation demonstrated improved graft survival when compared with wife-to-husband and nonspousal donation. Living-unrelated renal transplantation has been utilized successfully at the University of Wisconsin and may help to alleviate the donor shortage.

Liver transplantation from controlled non-heart-beating donors.

BACKGROUND: The use of organs from non-heart-beating donors (NHBDs) has been proposed as one way to increase the donor pool. However, few centers have transplanted livers from NHBDs. We report here the results of 19 liver transplants from controlled NHBDs. METHODS: From January 1993 through August 1999, 364 liver transplantations were performed from heart-beating donors (HBDs) and 19 liver transplantations were performed from NHBDs. Donor and recipient characteristics, posttransplant complications, and patient and allograft survival were compared. RESULTS: No differences in hepatic artery, portal vein, or biliary complications were noted between the groups. However, the rate of primary nonfunction was higher in recipients of livers from NHBDs (10.5% vs. 1.3%; P = .04). No difference in patient survival was seen between recipients of NHBDs or HBDs (72.6% vs. 84.8%; P =.36); however, allograft survival was lower in recipients who received livers from NHBDs (53.8% vs. 80.9%; P =.007). CONCLUSIONS: Liver transplantation from controlled NHBDs results in similar patient survival and post-transplant complications. However, primary nonfunction was higher and allograft survival was less in recipients of livers from NHBDs. The results of liver transplantation from controlled NHBDs are encouraging and should continue to be cautiously pursued as one way to help alleviate the current shortage of donor livers.