Protection From the Second Warm Ischemic Injury in Kidney Transplantation Using an Ex Vivo Porcine Model and Thermally Insulating Jackets

BackgroundKidney transplantation is the optimum treatment for kidney failure in carefully selected patients. Technical surgical complications and second warm ischemic time (SWIT) increase the risk of delayed graft function (DGF) and subsequent short- and long-term graft outcomes including the need for post-transplant dialysis and graft failure. Intraoperative organ thermal regulation could reduce SWIT, minimizing surgical complications due to time pressure, and limiting graft ischemia-reperfusion injury.MethodsA novel ischemic-injury thermal protection jacket (iiPJ) was designed and fabricated in silicone composite and polyurethane (PU) elastomer prototypes. Both were compared with no thermal insulation as controls. Time to reach ischemic threshold (15°C) and thermal energy transfer were compared. A water bath model was used to examine the thermal protective properties of porcine kidneys, as a feasibility study prior to in vivo translation.ResultsIn both iterations of the iiPJ, the time taken to reach the warm ischemia threshold was 35.2 ± 1.4 minutes (silicone) and 38.4 ± 3.1 minutes (PU), compared with 17.2 ± 1.5 minutes for controls (n = 5, P < .001 for both comparisons). Thermal energy transfer was also found to be significantly less for both iiPJ variants compared with controls. There was no significant difference between the thermal performance of the 2 iiPJ variants.ConclusionProtection from SWIT by using a protective insulation jacket is feasible. With clinical translation, this novel strategy could facilitate more optimal surgical performance and reduce transplanted organ ischemia-reperfusion injury, in particular the SWIT, potentially affecting delayed graft function and long-term outcomes.     

Comparison of renal function after open radical cystectomy,extracorporeal robot assisted radical cystectomy,and intracorporeal robot assisted radical cystectomy

PurposeRenal function outcomes following robot-assisted radical cystectomy (RARC) have not been well established. We sought to compare long-term renal function outcomes between open radical cystectomy, RARC with extracorporeal urinary diversion and intracorporeal urinary diversion at a high volume institution.Materials and MethodsWe retrospectively reviewed our institutional bladder cancer database for patients who underwent RC from 2010 to 2019 with pre-operative estimated glomerular filtration rate (eGFR) > 45 ml/min/1.73m². Changes in renal function were assessed through locally weighted scatter plot smoothing and comparison of median eGFR between surgical groups. Chronic Kidney Disease Stage 3B was defined as eGFR < 45 ml/min/1.73m². Renal function decline was defined as a ≥10 ml/min/1.73m² drop in eGFR. Kaplan Meier method with log-rank was used to compare CKD 3B-free survival and renal function decline. Cox Proportional Hazards model was used to identify predictors of CKD 3B.ResultsSix hundred and forty four patients were included with median follow-up of 32 months (IQR 12–56). Preoperative characteristics were similar among the groups with no differences in median pre-operative eGFR (ORC: 74.6, extracorporeal urinary diversion: 74.3, intracorporeal urinary diversion: 71.6 ml/min/1.73m², P = 0.15). Median postoperative eGFR on follow up was not different between groups (P = 0.56). 33% of patients developed CKD 3B. There were no differences in CKD 3B-free survival by surgical approach (P = 0.23) or urinary diversion (P = 0.09). 64% of patients experienced renal function decline with a median time of 2.4 years (P 0.23). Predictors of CKD were pathologic T3 disease or greater (HR: 1.77, P = 0.01), ureteroenteric anastomotic stricture (HR: 2.80, P < 0.001), preoperative CKD Stage 2 (HR: 1.81, P =0.02), and preoperative CKD Stage 3A (HR: 5.56, P < 0.001).ConclusionRenal function decline is common after RC. Tumor stage, pre-operative eGFR, and ureteral stricture development, not surgical approach, influence renal function decline.     

Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel,potent and selective inhibitor of dopamine-β-hydroxylase

1. Inhibitory modulation of sympathetic nerve function may have a favourable impact on the progression of congestive heart failure. Nepicastat is a novel inhibitor of dopamine-β-hydroxylase, the enzyme which catalyses the conversion of dopamine to noradrenaline in sympathetic nerves. The in vitro pharmacology and in vivo catecholamine modulatory effects of nepicastat were investigated in the present study.
2. Nepicastat produced concentration-dependent inhibition of bovine (IC₅₀=8.5±0.8 nM) and human (IC₅₀=9.0±0.8  nM)dopamine-β-hydroxylase. The corresponding R-enantiomer (RS-25560-198) was approximately 2–3 fold less potent than nepicastat. Nepicastat had negligible affinity (>10 μM) for twelve other enzymes and thirteen neurotransmitter receptors.
3. Administration of nepicastat to spontaneously hypertensive rats (SHRs) (three consecutive doses of either 3, 10, 30 or 100 mg kg⁻¹, p.o.; 12 h apart) or beagle dogs (0.05, 0.5, 1.5 or 5 mg kg⁻¹, p.o.; b.i.d., for 5 days) produced dose-dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery (mesenteric or renal), left ventricle and cerebral cortex. At the highest dose studied, the decreases in tissue noradrenaline were 47%, 35% and 42% (in SHRs) and 88%, 91% and 96% (in dogs) in the artery, left ventricle and cerebral cortex, respectively. When tested at 30 mg kg⁻¹, p.o., in SHRs, nepicastat produced significantly greater changes in noradrenaline and dopamine content, as compared to the R-enantiomer (RS-25560-198), in the mesenteric artery and left ventricle.
4. Administration of nepicastat (2 mg kg⁻¹, b.i.d, p.o.) to beagle dogs for 15 days produced significant decreases in plasma concentrations of noradrenaline and increases in plasma concentrations of dopamine and dopamine/noradrenaline ratio. The peak reduction (52%) in plasma concentration of noradrenaline and the peak increase (646%) in plasma concentration of dopamine were observed on day-6 and day-7 of dosing, respectively.
5. The findings of this study suggest that nepicastat is a potent, selective and orally active inhibitor of dopamine-β-hydroxylase which produces gradual modulation of the sympathetic nervous system by inhibiting the biosynthesis of noradrenaline. This drug may, therefore, be of value in the treatment of cardiovascular disorders associated with over-activation of the sympathetic nervous system, such as congestive heart failure.

     

An Approach for Widening the Bioequivalence Acceptance Limits in the Case of Highly Variable Drugs

Purpose. Highly variable drugs pose a problem in bioequivalence assessment because they often fail to meet current regulatory acceptance criteria for average bioequivalence (80–125%). This paper examines alternative approaches to establishing bioequivalence. Methods. Suggested solutions have included alternate study designs, e.g., replicate and multiple dose studies, reducing the level of the confidence interval, and widening the acceptance limits. We focus on the latter approach. Results. A rationale is presented for defining wider acceptance limits for highly variable drugs. Two previously described methods are evaluated, and a new method having more desirable properties is proposed. Conclusions. We challenge the one size fits all current definition of bioequivalence acceptance limits for highly variable drugs, proposing alternative limits or goal posts which vary in accordance with the intrasubject variability of the reference product.     

Native Hawaiian Birth Weight and Infant Mortality: Is Birth in Hawai'i Protective?

PURPOSE OF THE PAPER: This study provides baseline information on the characteristics of Native Hawaiian mothers and the health status of their infants, comparing residents of Hawaii with those of the continental U.S. The impact of Hawaii residence on low birth weight and infant mortality among Native Hawaiians is assessed. SUMMARY OF METHODS UTILIZED: Data from the National Center for Health Statistics 1983­1987 Linked U.S. Live Birth and Infant Death file were used to examine parental characteristics, prenatal care use and infant outcomes using chi­square and logistic regression procedures. PRINCIPAL FINDINGS: Despite a higher sociodemographic risk profile among Hawaii resident mothers, preterm birth, low and very low birth weight percentages were similar. Continental infants had significantly highter percentages of very pre­term birth and macrosomia. Mortality rates in both the neonatal and post­neonatal periods, and for SIDS and perinatal causes were elevated among continental infants. Hawaii residence had a borderline protective effect on infant mortality, wehn sociodemographic and prenatal care differences were controlled. CONCLUSIONS: This study suggests a possibly protective effect of Hawaii residence on the health of Native Hawaiian infants during the period of following employer­mandated health insurance coverage but before the initiation of "gap­group" coverage and the Native Hawaiian Health Care Systems in Hawaii. RELEVANCE TO ASIAN PACIFIC ISLANDER AMERICAN POPULATIONS. This is the first report documenting the sociodemographic and health status of the growing number of Native Hawaiian mothers and their infants residing outside of Hawaii. Expanded health insurance coverage and culturally appropriate and accessible health care may contribute to improved infant health status in Hawaii. Their absence, along with possible barriers of sociocultural isolation, may account for the poorer than expected outcomes of continental infants and predict a widening gap between them and their counterparts in Hawaii. A follow­up study of the health status of Native Hawaiian mothers and infants, and their access to appropriate care in Hawaii and thei continental U.S. is recommended.     

Cowden syndrome and Lhermitte-Duclos disease.

BACKGROUND. Cowden syndrome (CS) is a rare but underdiagnosed autosomal dominant condition also known as "multiple hamartoma-neoplasia syndrome." Patients have multiple tricholemmomas (a type of benign skin appendage tumor) and oral papillomatosis and cutaneous keratoses. They often have goiter, gastrointestinal polyps, and hamartomatous soft tissue lesions. Breast cancer affects approximately one third of women with CS. Lhermitte-Duclos disease (LDD) is a peculiar proliferation of abnormal neuronal elements of the cerebellum that has features of a hamartoma and of a neoplasm. METHODS. The authors described two patients who have both CS and LDD. Also reviewed were 50 of approximately 62 previously described cases of LDD (identified through literature searches) in an effort to find patients with LDD who had other associated lesions. RESULTS. Only one other patient in whom both LDD and CS were recognized has been reported. In addition, a number of patients with LDD who had other neoplasms and/or thyroid lesions have been described. CONCLUSIONS. Given the rarity of these two entities, we believe that their association is not fortuitous. LDD fits into the concept of CS as a hamartoma-neoplasia syndrome. In addition, a number of patients with LDD who had other neoplasms or thyroid lesions have been reported, raising the possibility that CS and LDD are more closely linked than is generally appreciated. We suspect that there are more patients with LDD who have unrecognized CS. Patients with either of the two diseases should be examined and followed up for evidence of the other.     

Chemoelectronic mobilization of chemical species in low-conductivity fluids: new electrokinetic effect.

An electrokinetic phenomenon is reported here which differs from its classical counterparts most distinctively by nonlinear conductivity and mobility. Neither purely electrolytic nor electrostatic in nature, this phenomenon is presumed to involve subtle charge transfer effects and association reactions permitting a controlled "chemoelectric" mobilization. In its electrokinetic manifestation, this phenomenon can be used to mobilize chemical species commonly with migration rates orders of magnitude greater than can be achieved electrophoretically and is shown to induce the movement of nonpolar molecules, such as aromatic hydrocarbons, at rates exceeding several centimeters per minute in easily achievable voltage gradients. The operational technique, developed as a separations method used for demonstrating the effect, is called "electromolecular propulsion".