Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease.

We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35-75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state [Hoehn and Yahr stage 2-3 and Unified Parkinson's Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45] and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 µg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 ± 17.6% in the active group and 11.8 ± 15.8% in the placebo group (least squares mean difference: -4.9%, 95% CI: -16.9, 7.1, P = 0.41). Secondary endpoints did not show significant differences between the groups either. A post hoc analysis found nine (43%) patients in the active group but no placebo patients with a large clinically important motor improvement (≥10 points) in the OFF state (P = 0.0008). 18F-DOPA PET imaging demonstrated a significantly increased uptake throughout the putamen only in the active group, ranging from 25% (left anterior putamen; P = 0.0009) to 100% (both posterior putamina; P < 0.0001). GDNF appeared to be well tolerated and safe, and no drug-related serious adverse events were reported. The study did not meet its primary endpoint. 18F-DOPA imaging, however, suggested that intermittent convection-enhanced delivery of GDNF produced a putamen-wide tissue engagement effect, overcoming prior delivery limitations. Potential reasons for not proving clinical benefit at 40 weeks are discussed.

Global discovery of colonization determinants in the squid symbiont Vibrio fischeri.

Animal epithelial tissue becomes reproducibly colonized by specific environmental bacteria. The bacteria (microbiota) perform critical functions for the host's tissue development, immune system development, and nutrition; yet the processes by which bacterial diversity in the environment is selected to assemble the correct communities in the host are unclear. To understand the molecular determinants of microbiota selection, we examined colonization of a simplified model in which the light organ of Euprymna scolopes squid is colonized exclusively by Vibrio fischeri bacteria. We applied high-throughput insertion sequencing to identify which bacterial genes are required during host colonization. A library of over 41,000 unique transposon insertions was analyzed before and after colonization of 1,500 squid hatchlings. Mutants that were reproducibly depleted following squid colonization represented 380 genes, including 37 that encode known colonization factors. Validation of select mutants in defined competitions against the wild-type strain identified nine mutants that exhibited a reproducible colonization defect. Some of the colonization factors identified included genes predicted to influence copper regulation and secretion. Other mutants exhibited defects in biofilm development, which is required for aggregation in host mucus and initiation of colonization. Biofilm formation in culture and in vivo was abolished in a strain lacking the cytoplasmic chaperone DnaJ, suggesting an important role for protein quality control during the elaboration of bacterial biofilm in the context of an intact host immune system. Overall these data suggest that cellular stress responses and biofilm regulation are critical processes underlying the reproducible colonization of animal hosts by specific microbial symbionts.

Pathologic sequelae of allosensitization in liver transplantation.

The long-term impact of allosensitization between ABO compatible donor/recipient pairs in liver transplantation is unclear. Accumulating clinical evidence suggests that donor-specific antibody formation may lead to antibody-mediated rejection and is causally linked to pathologic injury, graft loss, and death. Although this immune-mediated graft dysfunction is increasingly being associated with poor outcomes, the specific pathologic sequelae are not defined. Herein, we examine the relationship between allosensitization, antibody-mediated rejection, and subsequent graft pathology.

Portal Steal Syndrome After Full-Size Deceased Donor Liver Transplantation.

Successful liver transplantation typically results in an immediate decrease in intrahepatic resistance accompanied by an initial increased hepatopedal portal flow. Within a short period of time, the portal hypertension resolves and the variceal shunts involute. However, in situations in which intrahepatic vascular resistance to venous flow remains elevated, significant hepatofugal portal flow may continue through persistent mesenteric shunts. This situation, portal steal, can result in decreased perfusion of the liver graft leading to graft dysfunction, failure, and potentially recipient death. This report details a case and the surrounding literature to highlight appropriate diagnosis and management in these patients.

Changing paradigms in organ preservation and resuscitation.

PURPOSE OF REVIEW: Shortage of donor organs has increased consideration for use of historically excluded grafts. Ex-vivo machine perfusion is an emerging technology that holds the potential for organ resuscitation and reconditioning, potentially increasing the quality and number of organs available for transplantation. This article aims to review the recent advances in machine perfusion and organ preservation solutions. RECENT FINDINGS: Flow and pressure-based machine perfusion has shown improved kidney graft function and survival, especially among expanded criteria donors. Pressure-based machine perfusion is demonstrating promising results in preservation and resuscitation of liver, pancreas, heart, and also lung grafts. August 2014 marked Food and Drug Administration approval of XPS XVIVO Perfusion System (XVIVO Perfusion Inc., Englewood, Colorado, USA), a device for preserving and resuscitating lung allografts initially considered unsuitable for transplantation. Although there is no consensus among physicians about the optimal preservation solution, adding antiapoptotic and cell protective agents to preservation solutions is an interesting research area that offers potential to improve preservation. SUMMARY: Ex-vivo machine perfusion of solid organs is a promising method that provides the opportunity for resuscitation and reconditioning of suboptimal grafts, expanding the number and quality of donor organs.

Anomalous hepatic vein anatomy of left lateral section grafts and customized unification venoplasty for pediatric living donor liver transplantation.

In liver transplantation, a left lateral section (LLS) graft may have an unusual variant left hepatic vein (LHV) anatomy. This study was designed to analyze the incidence of unusual LHV variants and to determine technical methods for effective reconstruction in infant recipients weighing approximately 10 kg or less. The study comprised 3 parts: an LHV variation analysis, a simulation-based design for the technical modification of graft LHV venoplasty, and its clinical application. The LHV anatomy of 300 potential LLS graft donors was classified into 4 types according to the number and location of the hepatic vein openings: (1) a single opening (n = 218 or 72.7%); (2) 2 large adjacent openings (n = 29 or 9.7%); (3) 2 adjacent openings, 1 large and 1 small (n = 34 or 11.3%); and (4) 2 widely spaced openings (n = 19 or 6.3%). Types 2 and 3 required wedged unification venoplasty, and type 4 required additional vein interposition. In a series of 49 cases using LLS grafts, the graft hepatic vein complication rate was 4.5% at 3 years; stenting was necessary for 1 of the 36 type 1 LHV grafts (2.8%) and for 1 of the 13 type 2-4 LHV grafts (7.7%, P = 0.46). A customized interposition-wedged unification venoplasty technique for coping with type 4 vein variations was developed with a simulation-based approach, and it was successfully applied to a 10-month-old male infant receiving an LLS graft with a type 4 LHV. In conclusion, nearly all LHV variations can be effectively managed with customized unification venoplasty. These venoplasty techniques represent beneficial surgical options as part of graft standardization for hepatic vein reconstruction in pediatric living donor liver transplantation.

New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney-liver complications.

Improved neonatal medical care and renal replacement technology have improved the long-term survival of patients with ARPKD. Ten-yr survival of those surviving the first year of life is reported to be 82% and is continuing to improve further. However, despite increases in overall survival and improved treatment of systemic hypertension and other complications of their renal disease, nearly 50% of survivors will develop ESRD within the first decade of life. In addition to renal pathology, patients with ARPKD develop ductal plate malformations with cystic dilation of intra- and extrahepatic bile ducts resulting in CHF and Caroli syndrome. Many patients with CHF will develop portal hypertension with resulting esophageal varices, splenomegaly, hypersplenism, protein losing enteropathy, and gastrointestinal bleeding. Management of portal hypertension may require EBL of esophageal varices or porto-systemic shunting. Complications of hepatic involvement can include ascending cholangitis, cholestasis with malabsorption of fat-soluble vitamins, and rarely benign or malignant liver tumors. Patients with ARPKD who eventually reach ESRD, and ultimately require kidney transplantation, present a unique set of complications related to their underlying hepato-biliary disease. In this review, we focus on new approaches to these challenging patients, including the indications for liver transplantation in ARPKD patients with severe chronic kidney disease awaiting kidney transplant. While survival in patients with ARPKD and isolated kidney transplant is comparable to that of age-matched pediatric patients who have received kidney transplants due to other primary renal diseases, 64-80% of the mortality occurring in ARPKD kidney transplant patients is attributed to cholangitis/sepsis, which is related to their hepato-biliary disease. Recent data demonstrate that surgical mortality among pediatric liver transplant recipients is decreased to <10% at one yr. The immunosuppressive regimen used for kidney transplant recipients is adequate for most liver transplant recipients. We therefore suggest that in a select group of ARPKD patients with recurrent cholangitis or complications of portal hypertension, combined liver-kidney transplant is a viable option. Although further study is necessary to confirm our approach, we believe that combined liver-kidney transplantation can potentially decrease overall mortality and morbidity in carefully selected ARPKD patients with ESRD and clinically significant CHF.

Australian blue-collar men's health and well-being: contextual issues for workplace health promotion interventions.

In Australia, blue-collar workers are predominantly male and form a unique and large (approximately 30%) subset of the Australian workforce. They exhibit particular health-related issues and, in comparison to other groups, often a lack of health promoting behavior. This article briefly discusses the Australian context and some of the key health issues blue-collar men face, in particular as it relates to construction workers. It reviews the impact of gender and socioeconomic factors in designing workplace health promotion interventions. This article considers practice strategies for health promoters in a specific workplace setting: it looks at meta-factors and industry-based contextual factors, including barriers to implementation and participation, while addressing common misconceptions about Australian blue-collar workers.

Draft genome sequence of Vibrio fischeri SR5, a strain isolated from the light organ of the Mediterranean squid Sepiola robusta.

Here, we describe the draft genome sequence of Vibrio fischeri SR5, a squid symbiotic isolate from Sepiola robusta in the Mediterranean Sea. This 4.3-Mbp genome sequence represents the first V. fischeri genome from an S. robusta symbiont and the first from outside the Pacific Ocean.

Incentives for organ donation: proposed standards for an internationally acceptable system.

Incentives for organ donation, currently prohibited in most countries, may increase donation and save lives. Discussion of incentives has focused on two areas: (1) whether or not there are ethical principles that justify the current prohibition and (2) whether incentives would do more good than harm. We herein address the second concern and propose for discussion standards and guidelines for an acceptable system of incentives for donation. We believe that if systems based on these guidelines were developed, harms would be no greater than those to today's conventional donors. Ultimately, until there are trials of incentives, the question of benefits and harms cannot be satisfactorily answered.

Anaphylaxis on reperfusion during liver transplantation with coagulopathy.

We present a case in which anaphylaxis on hepatic reperfusion during liver transplantation presented only with hypotension and coagulopathy. There were no cutaneous manifestations or clinical features distinguishing anaphylaxis from postreperfusion syndrome. The recipient regularly consumed seafood, and the organ donor died of anaphylaxis to shellfish. The trigger for anaphylaxis was postulated to be passive transfer of immunoglobulin to the recipient. Anesthesiologists should be notified of donor factors to anticipate anaphylaxis. In this report, we discuss coagulopathy of anaphylaxis and contrast it with disseminated intravascular coagulation.

The Future of CMC Regulatory Submissions: Streamlining Activities Using Structured Content and Data Management.

Recent advancements in data engineering, data science, and secure cloud storage can transform the current state of global Chemistry, Manufacturing, and Controls (CMC) regulatory activities to automated online digital processes. Modernizing regulatory activities will facilitate simultaneous global submissions and concurrent collaborative reviews, significantly reducing global licensing timelines and variability in globally registered product details. This article describes advancements made within the pharmaceutical industry from theoretical concepts to utilization of structured content and data in CMC submissions. The term Structured Content and Data Management (SCDM) outlines the end-to-end scientific data lifecycle from capture in source systems, aggregation into a consolidated repository, and transformation into semantically structured blocks with metadata defining relationships between scientific data and business contexts. Automation of regulatory authoring (termed Structured Content Authoring) is feasible because SCDM makes data both human and machine readable. It will offer health authorities access to the digital data beyond the current standard of PDF documents and, for a review process, SCDM would "enrich the effectiveness, efficiency, and consistency of regulatory quality oversight" (Yu et al., 2019). SCDM is a novel solution for content and data management in regulatory submissions and can enable faster access to critical therapies worldwide.

Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson's Disease.

BACKGROUND: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson's disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [18F]DOPA uptake throughout the entire putamen. OBJECTIVE: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks. METHODS: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson's Disease Rating Scale (UPDRS) motor score. RESULTS: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7±20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6±23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI: -13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week 80 and placebo/GDNF at Week 40 showed significant differences for mean OFF state UPDRS motor (-9.6±6.7 vs. -3.8±4.2 points, p = 0.0108) and activities of daily living score (-6.9±5.5 vs. -1.0±3.7 points, p = 0.0003). No treatment-emergent safety concerns were identified. CONCLUSIONS: The aggregate study results, from the parent and open-label extension suggest that future testing with GDNF will likely require an 80- rather than a 40-week randomized treatment period and/or a higher dose.

Patient access to transplantation with an Internet-identified live kidney donor: a survey of U.S. centers.

BACKGROUND: To investigate legitimate transplantation in the United States with an Internet-identified live donor organ, from the patient's perspective, kidney centers were contacted by a researcher posing as an ideal patient and recipient pair seeking to find a center to perform their transplant. METHODS: Responses were obtained with fewer than three phone calls and within less than 2 wk from 100 of 206 UNOS listed centers; 42 pediatric or inactive centers were excluded. RESULTS: A total of 37% (76 of 100) indicated a willingness to consider such a transplant. Eight centers acknowledged having previously performed one, with 100% (8/8) of these indicating that they would still consider future participation. CONCLUSION: Large numbers of Internet-facilitated transplants are not yet being performed in the United States. Because it was possible to elicit a definite answer with 3 or fewer calls at only 49% of centers, we conclude that a significant proportion of centers are not providing easy access to potential donors and recipients. Agreeable centers were clustered geographically, suggesting that multiple factors may be influencing opinions. 100% of agreeable centers required their own standard evaluation of the donor and recipient and indicated that financial exchange between the pair was illegal. We conclude that Internet-based live donor kidney transplants are occurring and have received cautious acceptance at a significant number of legitimate centers. The utility of asking "How did the recipient-donor pair present to our institution" may no longer be relevant. We suggest that every pair seeking access to legitimate transplantation should undergo standardized evaluation with open acknowledgment of the relationship as a modifier.

Probabilistic risk assessment of accidental ABO-incompatible thoracic organ transplantation before and after 2003.

BACKGROUND: A widely reported ABO-mismatch accident in March of 2003 raised concerns about the reliability of the transplantation system. Because this type of failure is rare and significant, we performed a probabilistic risk assessment (PRA) of the donor-recipient matching processes for thoracic organ transplantation. METHODS: A probabilistic risk assessment was performed. RESULTS: The likelihood of accidental incompatible implantation was already low in 2003. The PRA model indicates that the likelihood of such an event was 1.38x10 per donated organ. This estimate correlates closely with the observed rate of these accidents. Based on this model, process changes put in place shortly after the accident reduced the probability to approximately 3.08x10 and changes put in place in October 2004 further reduced the probability to approximately 2.22x10 per organ donated. CONCLUSIONS: The observed and predicted likelihoods of accidental incompatible thoracic organ transplantation are comparable. These likelihoods are several orders of magnitude smaller than other hazards associated with solid organ transplantation. The PRA model indicates that changes that followed the March 2003 accident further reduced the likelihood of accidental incompatible implantation by roughly two orders of magnitude. Quantitative estimates from PRA can be used to assess risks in healthcare and to gauge the impact of system changes on these risks.

Pre-Hepatectomy Assessment of Bile Transporter Expression by Gadoxetic Acid-Enhanced MRI in a Rat Model of Liver Cirrhosis.

BACKGROUND: Gadoxetic acid is a liver-specific intravenous T1 magnetic resonance (MR) contrast agent that is excreted via the hepatobiliary system. We hypothesize that hepatocyte expressions of bile transporters (OATP1 and MRP2) correlate with dynamic profile of Gadoxetic acid enhanced (GE)-MR imaging (MRI). METHODS: Two groups of rats, control (n = 6) and cirrhosis (n = 12), received gadoxetic acid enhanced MRI followed by 70% hepatectomy. The change in MR signal intensity from the baseline before the contrast injection (ΔSI) was analyzed every minute for 30 min. Dynamic signal intensity retention ratio (DSR) was defined as the mean ΔSI of the third 10-minmin period divided by the first 10-minmin period. Real-time PCR was utilized to quantify mRNA expressions. RESULTS: Compared to the control, cirrhosis group demonstrated lower mRNA levels of OATP1 (0.038 ± 0.020 vs. 0.232 ± 0.0979; p = 0.004), MRP2 (0.201 ± 0.084 vs. 0.7567 ± 0.254; p = 0.002), and OATP1/MRP2 mRNA ratio (0.193 ± 0.065 vs. 0.342 ± 0.206; p = 0.032). DSR was higher in the cirrhosis group (0.678 ± 0.554 vs -0.125 ± 0.839; p = 0.033). In the cirrhosis group, there was an inverse correlation between the ratios of OATP1/MRP2 mRNA and DSR (R = -0.709, p = 0.01). CONCLUSION: Bile transporters OATP1/MRP2 mRNA expression ratio in rat liver tissue decreased with DMN-induced liver injury. The expressions of bile transporters correlated with GE-MRI DSR. The GE-MRI DSR has potential utility in qualifying OATP1/MRP2 mRNA expression.

Living donor liver transplantation for pediatric and adult recipients.

Living donor liver transplantation (LDLT) was initially developed to provide suitable liver grafts for pediatric patients with end-stage liver disease. This innovation was remarkable for the prospective nature of its development and the public discussions that resolved the ethical dilemma of removing a portion of a liver from a healthy donor for the benefit of another person. Since its inception, this procedure has been uniformly adopted by most pediatric transplant centers, with excellent results. Unfortunately, liver grafts obtained from this procedure did not provide sufficient hepatocyte mass for use in adult recipients. An adult donor procedure was, therefore, developed to provide larger liver grafts, which were derived from the right lobe of the liver. Much of the driving force for adult-to-adult LDLT has been in countries that lack the health-care infrastructure for obtaining deceased donors or have cultural objections to deceased donor transplantation. In developed countries, the initial growth of adult-to-adult LDLT has been tempered by notable donor complications, including death, but it continues to have an important role in providing life-saving liver grafts for recipients who are unable to compete for deceased donor grafts in the current organ-allocation system.

Ethical tensions in solid organ transplantation: the price of success.

Solid organ transplantation has rapidly developed into the therapy a choice for end-stage organ failure. The expansion of its use has resulted is a large deficiency in organ supply. To address this, the field of organ transplantation has attempted to develop new strategies that would increase the availability of organs for transplant. Some of these strategies include expansion of the donor pool by increasing the number of living donors or using deceased donor organs that may be marginal or "expanded". The intent is to bring life-saving therapy to individuals in need; however, much of this expansion has been brought forward without clear prospective guidelines. This article focuses on the current disparity between organ supply and demand, and how this has impacted the use of living donors and development of the "expanded donor" concept.