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K L Mathis,E J Dozois,D W Larson,R R Cima,J M Sarmiento,B G Wolff,J K Heimbach,J H Pemberton BACKGROUND: The aim was to evaluate outcomes in patients with ulcerative colitis complicated by primary sclerosing cholangitis (PSC) who required ileal pouch-anal anastomosis (IPAA) and orthotopic liver transplantation (OLT). METHODS: A retrospective analysis was performed of 32 patients undergoing... ( view more ) both IPAA and OLT between 1980 and 2006. Data were collected regarding demographics, indication for surgery, postoperative complications, and outcome of IPAA and OLT. RESULTS: Thirty-day mortality after either procedure was nil. The median preoperative Model for End-stage Liver Disease (MELD) score for the group with initial IPAA was 8 (range 6-20) and the postoperative score was 11 (range 6-19). At 1 and 10 years, 32 and 26 of the 32 liver grafts had survived, and 31 and 30 of the 32 pouches, respectively. Fourteen patients require daily medical therapy for chronic pouchitis. At a median follow-up of 3.6 (range 0.2-16.2) years after the second of two procedures, responding patients reported a median of 5.5 stools per day and 2 stools per night. CONCLUSION: IPAA and OLT are feasible and safe in patients requiring both procedures for ulcerative colitis and PSC. Functional outcomes are stable over time, despite an increased risk of chronic pouchitis. ( view less ) Julie K Heimbach PURPOSE OF REVIEW: The purpose of this review is to present recent data demonstrating the success of neoadjuvant therapy followed by liver transplantation for hilar cholangiocarcinoma. RECENT FINDINGS: The most recent outcomes of a protocol involving neoadjuvant therapy followed by liver transplant... ( view more ) for hilar cholangiocarcinoma, placed in context with the most recent data regarding outcomes for surgical resection, are discussed. Data involving the observation and management of an increased rate of vascular complications following this aggressive protocol are described. Additionally, factors which may predict disease recurrence along with the implications of these data on organ allocation policy are reviewed. SUMMARY: For patients with early stage hilar cholangiocarcinoma which is unresectable or arising in the setting of primary sclerosing cholangitis, neoadjuvant chemoradiotherapy followed by liver transplantation provides excellent survival benefit. Outcomes are notably superior to other treatment options, including resection. The protocol, however, requires extensive involvement and expertise from multiple specialties to ensure success. ( view less ) J Leonard,J K Heimbach,M Malinchoc,K Watt,M Charlton The impact of obesity on outcomes following liver transplantation has been difficult to determine, in part due to the confounding effects of ascites on BMI. We evaluated the impact of pretransplant recipient obesity on outcomes following liver transplantation using the NIDDK Liver Transplantation D... ( view more )atabase. Pretransplant BMI, corrected for ascites, was categorized as underweight (BMI <18 kg/m(2)), normal weight (BMI 18-25 kg/m(2)), overweight (BMI 25.1-30 kg/m(2)), Class I obese (BMI 30.1-35 kg/m(2)), Class II obese (BMI 35.1-40 kg/m(2)) and Class III obese (BMI >40 kg/m(2)). Primary outcomes were patient and graft survival. Secondary outcomes included days in hospital and days in ICU. Data from 704 adult liver transplant recipients from the NIDDK LTD and a further 609 patients from the Mayo Clinic were analyzed. Early and late patient and graft survival was similar across all BMI categories. Correcting for ascites volume resulted in 11-20% of patients moving into a lower BMI classification. The relative risk for mortality increased by 7% for each liter of ascites removed. We conclude that corrected BMI is not independently predictive of patient or graft survival. Obesity, within the ranges observed in this study, should not be considered to be a contraindication to liver transplantation in the absence of other relative contraindications. ( view less ) P A Marone,J F Borzelleca,D Merkel,J T Heimbach,E Kennepohl A 28-day dietary study was conducted in Hsd:SD rats to evaluate the safety of PureLo, a non-caloric powdered concentrate of the Chinese fruit Luo Han Guo, which derives its sweetening properties from triterpene glycosides called mogrosides. Groups of 20 rats (10/sex/group) were fed diets containing... ( view more ) 0, 10,000, 30,000, or 100,000 ppm PureLo for 28 days (OECD, Redbook 2000). PureLo was well tolerated and produced no significant adverse effects. Reduced body weight and body weight gain in high-dose animals of both sexes were related to sporadic reductions in food consumption; there were no overall differences in feed efficiency. Statistically significant changes in clinical chemistry (decreased bilirubin, increased total protein) and relative organ weights of liver, adrenals, ovaries and/or testes, and epididymides were not correlated with any histopathological findings and were not considered adverse. Although a few clinical and pathological findings suggest possible treatment-related effects, particularly in the high-dose group, these findings were transient, not dose-dependent, non-adverse, inconsistent, occurred only in one sex, and/or not supported by histopathological findings. Under the conditions of this study and based on the toxicological endpoints evaluated, the NOAEL for PureLo was 100,000 ppm in the diet, the highest level tested, equivalent to 7.07 and 7.48 g/kg bw/day for male and female rats, respectively. ( view less ) Jarkko Rautio,Hanna Kumpulainen,Tycho Heimbach,Reza Oliyai,Dooman Oh,Tomi Järvinen,Jouko SavolainenProdrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for ... ( view more )improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials. ( view less ) Ramona Thieme,Elena Rakosy-Tican,Tatjana Gavrilenko,Olga Antonova,Jörg Schubert,Marion Nachtigall,Udo Heimbach,Thomas Thieme Solanum tarnii, a wild diploid, tuber-bearing Mexican species belonging to the series Pinnatisecta is highly resistant to Potato virus Y (PVY) and Colorado potato beetle and shows a strong hypersensitive reaction to Phytophthora infestans. Therefore, it could be a potential source of resistance to ... ( view more )pathogens for potato breeders. S. tarnii (2n=2x=24) is reproductively isolated from tetraploid Solanum tuberosum and hence difficult to include in potato breeding programmes. In this study, interspecific somatic hybrids were produced for the first time by protoplast electrofusion of the cells of potato cv. Delikat (Solanum tuberosum L.) and Solanum tarnii. The hybrid nature of the regenerants was confirmed by simple sequence repeat (SSR) and amplified fragment length polymorphism (AFLP) markers and by morphological analysis and flow cytometry. Selected somatic hybrids were successfully backcrossed with cv. Delikat. Parental lines, primary somatic hybrids and BC1 progeny were assessed for resistance to PVY by mechanical inoculation, grafting and exposure to viruliferous aphid vectors in the field, and resistance to late blight (P. infestans) by detached leaflet and whole tuber tests. The somatic hybrids showed no symptoms of viral infection and most of them displayed high levels of resistance to foliage blight. The BC1 progenies were highly resistant to PVY and a few were resistant to foliage blight. Selected hybrids and BC1 clones were evaluated in the field for tuber quality and tuber yield. Some BC1 clones produced yields of good quality tubers. The results confirm that both the resistance to PVY and to late blight of S. tarnii is expressed in somatic hybrids, and PVY resistance is transferred to BC1 progeny, whereas blight resistance is harder to transfer. Somatic hybridization again proved to be a valuable tool for producing pre-breeding material with increased genetic diversity. ( view less ) James T Heimbach Manufacturers wish to communicate the benefits of probiotics in advertising and labeling with lawful and adequately substantiated claims. Regulatory and substantiation requirements differ for products intended to cure, treat, prevent, or mitigate a disease; to reduce a healthy individual's risk of ... ( view more )developing a disease; or to affect the structure or function of the body. Food labeling is regulated by the US Food and Drug Administration, and advertising is regulated by the Federal Trade Commission; the standards and methods used by these agencies differ. Food manufacturers must design their claims regarding the benefits of probiotics with the regulatory environment in mind and must develop their research plans to provide evidence that satisfies the agencies' substantiation requirements. This article offers an overview of the applicable laws and regulations, what they mandate regarding legitimate claims, and the issues regarding the design of research to substantiate such claims. ( view less ) Hendrik T J Mantel,Charles B Rosen,Julie K Heimbach,Scott L Nyberg,Michael B Ishitani,James C Andrews,Michael A McKusick,Michael G Haddock,Steven R Alberts,Gregory J Gores Liver transplantation after neoadjuvant chemoradiotherapy has emerged as an effective treatment for patients with localized, node-negative, unresectable hilar cholangiocarcinoma (CCA) or CCA arising in the setting of primary sclerosing cholangitis (PSC). However, concern has arisen regarding the po... ( view more )tential for vascular complications due to high-dose neoadjuvant therapy before transplantation. We reviewed our experience with specific aims to determine the incidences of arterial, portal, and hepatic venous complications in patients transplanted for CCA compared with patients who undergo transplantation for other indications, and to describe patient outcome as a result of these vascular complications. We reviewed data for all patients who underwent liver transplantation for CCA between January 1993 and April 2006 and compared the incidences of vascular complications to whole organ and living donor recipient control groups. Sixty-eight patients underwent neoadjuvant therapy and subsequent liver transplantation. Arterial complications arose in 21%; portal venous complications arose in 22%; and overall, 40% developed vascular complications. Late hepatic artery complications occurred more often in living donor recipients transplanted for CCA compared with the living donor control group (P=0.047). Late portal vein complications occurred more often in both whole organ and living donor recipients transplanted for CCA compared with the control groups (P=0.01 and P=0.009). Hepatic venous complications were rare. Patient and graft survival were not different between CCA and control patients. Liver transplantation with neoadjuvant therapy is associated with far higher rates of late arterial and portal venous complications, but these complications do not adversely affect patient and graft survival. ( view less ) Paul J Van den Brink,J M Hans Baveco,Jana Verboom,Fred Heimbach In the present study we present a population model (Metapopulation model for Assessing Spatial and Temporal Effects of Pesticides [MASTEP]) describing the effects on and recovery of the waterlouse Asellus aquaticus after exposure to a fast-acting, nonpersistent insecticide as a result of spray drif... ( view more )t in pond, ditch, and stream scenarios. The model used the spatial and temporal distribution of the exposure in different treatment conditions as an input parameter. A dose-response relation derived from a hypothetical mesocosm study was used to link the exposure with the effects. The modeled landscape was represented as a lattice of 1- by 1-m cells. The model included processes of mortality of A. aquaticus, life history, random walk between cells, density dependence of population regulation, and, in the case of the stream scenario, medium-distance drift of A. aquaticus due to flow. All parameter estimates were based on expert judgment and the results of a thorough review of published information on the ecology of A. aquaticus. In the treated part of the water body, the ditch scenario proved to be the worst-case situation, due to the absence of drift of A. aquaticus. Effects in the pond scenario were smaller because the pond was exposed from one side, allowing migration from the other, less contaminated side. The results of the stream scenario showed the importance of including drift for the population recovery in the 100-m stretch of the stream that was treated. It should be noted, however, that the inclusion of drift had a negligible impact on numbers in the stream as a whole (600 m). ( view less ) Roman Perri,Maha Assi,Jayant Talwalkar,Julie Heimbach,William Hogan,S Breanndan Moore,Charles B RosenGraft-vs.-host disease (GVHD) is a rare, serious complication of orthotopic liver transplantation (OLT). We have treated 5 patients to date with GVHD after OLT. A total of 78 patients worldwide have been reported to have experienced this complication. The means by which GVHD after OLT has been mana... ( view more )ged is guided by experience with the more common GVHD that occurs after stem cell transplantation. However, despite the use of various treatment modalities, the mortality of GVHD after OLT remains high. This case series and review of the literature demonstrates that successful resolution of GVHD after OLT cannot be expected with the use of those modalities that have been tried to date. It is imperative that new treatments be applied to GVHD after OLT in order to improve the prognosis of patients with this diagnosis. ( view less ) Claas Falldorf,Yvonne Heimbach,Christoph von Kopylow,Werner JüptnerWe present a method that allows the reconstruction of smooth phase distributions from their laterally sheared representation. The proposed approach is efficient in the sense that only one sheared distribution is needed to completely restore the signal. A mandatory requirement is that the phase dist... ( view more )ribution is spatially limited. The method is exemplified by means of a synthetic signal, and in addition a practical algorithm is given. Finally, experimental results are presented. The deformation of a metallic surface is investigated by both speckle shearography and electronic speckle pattern interferometry (ESPI) respectively. To give proof of the proposed technique, the phase distribution reconstructed from the shearographic measurement is shown to match the results obtained by the ESPI. ( view less ) Christopher Seadeek,Howard Ando,Shobha N Bhattachar,Tycho Heimbach,Jason L Sonnenberg,Anthony C Blackburn The design and validation of a novel high-throughput system for thermodynamic solubility determination requiring only 5 mg of sample is described. The system uses a sintered nickel filter assembly to recover excess solids from saturated solutions for rapid crystallinity assessment via powder X-ray ... ( view more )diffraction (PXRD). Moreover, the system measures the pH of filtrates to provide a final pH value with the solubility measurement. The limit of detection for the UV-vis plate reader used on this system is approximately 0.001 mg/ml, while the practical upper limit is approximately 3 mg/mL. The solubility measurements of 60 proprietary Pfizer compounds were used to validate the nickel filter assembly against a more conventional polyvinylidenedifluoride (PVDF) filter. Additionally, a comparison was made between a subset of 10 compounds run on the automated system and a more traditional shake-flask method employing HPLC analysis. In both cases, a favorable comparison was obtained. ( view less ) Julie K Heimbach,Gregory J Gores,Michael G Haddock,Steven R Alberts,Rachel Pedersen,Walter Kremers,Scott L Nyberg,Michael B Ishitani,Charles B Rosen BACKGROUND: Sixty-five patients with unresectable hilar cholangiocarcinoma (CCA) have undergone orthotopic liver transplantation (OLT) after neoadjuvant chemoradiotherapy per a clinical care protocol developed in 1993. We reviewed our experience with the aim to identify clinicopathological predicto... ( view more )rs of disease recurrence. METHODS: All patients with CCA that underwent OLT at our institution between 1993 and January 1, 2006 were treated in accord with our published protocol. We analyzed multiple clinical and explant pathologic factors using Cox regression analysis. RESULTS: Sixty-five patients with CCA underwent OLT. Four patients died within six months due to postoperative complications. At last follow-up, 11 patients (17%) had developed recurrence seven to 64 months after OLT. Mean time to recurrence was 29 months, and eight patients had died from recurrent disease. Patient and disease-free survival were 76% and 60% five years after OLT. Predictors of recurrence were older age, pretransplant cancer antigen (CA) 19-9 >100 U/ml, prior cholecystectomy, mass on cross-sectional imaging, residual tumor in explant >2 cm, tumor grade and perineural invasion in explant. Underlying primary sclerosing cholangitis, percutaneous biliary intubation, gender, and other time points for CA 19-9 were not associated with recurrence. Prolonged staging-to-OLT intervals for patients transplanted after implementation of model for end-stage liver disease (MELD) showed a trend toward increased recurrence. CONCLUSIONS: Older patients and those with high CA-19.9 levels, and larger tumors are more likely to develop recurrent disease. Prolonged waiting time may emerge as a significant risk factor with longer follow-up. These findings may guide patient selection, applicability of live donor transplantation and MELD score exceptions for this aggressive protocol. ( view less ) Matthew B Klein,Avery B Nathens,David M Heimbach,Nicole S Gibran BACKGROUND: Optimal burn care is provided at specialized burn centers. Given the geographic location of these centers, many burn patients receive initial treatment at local emergency departments prior to transfer. The purpose of this study was to determine whether patients transferred from other fa... ( view more )cilities have worse outcomes than those admitted directly from the field. STUDY DESIGN: A retrospective cohort study was performed comparing the outcomes of patients admitted to our burn center directly from the field with patients requiring transfer from a preliminary care facility. The outcomes of interest were mortality, length of stay, length of stay/TBSA burned, number of operations and hospital charges. Poisson regression or Cox proportional hazards model was used to evaluate differences in outcomes after adjusting for potential confounders. RESULTS: From 2000 to 2003 a total of 1877 patients were admitted to our burn center and 953 (51%) were transferred from a preliminary care facility. No difference (p<0.05) was found in length of stay, number of operations, hospital charges and mortality between the two cohorts. CONCLUSIONS: This study demonstrates that patients transferred to a regional burn center from local hospitals have equivalent mortality, length of stay and hospital charges as those admitted directly from the field. ( view less ) X Qin,S Xiaojian,L Ronggan,W Yuxian,T Zhunian,G Shouji,J HeimbachA combined 28-day and 90-day oral (Gavage) study was conducted in male and female dogs to investigate the safety of PureLo, a non-caloric sweetener derived from the Chinese fruit Luo Han Guo, which achieves its sweetness from the presence of triterpene glycosides known as mogrosides. Three dogs of ... ( view more )each sex were administered 10 mL/kg bw/day of either an aqueous solution providing 3000 mg/kg bw/day of PureLo or distilled water for either 28 days or 90 days. Measurements included clinical observations, body weight, food consumption, hematology, blood chemistry, urinalysis, gross necropsy, organ weight, and histopathology. There were no significant adverse effects on any of these measures. Based on the lack of toxicological effects in the study, the NOAEL for PureLo is 3000 mg/kg bw/day when administered to dogs by Gavage for 90 consecutive days. ( view less ) Pornprom Muangman,Heike Deubner,Shari Honari,David M Heimbach,Loren H Engrav,Matthew B Klein,Nicole S Gibran BACKGROUND: Integra, a dermal replacement template consisting of bovine collagen, chondroitin-6-sulfate, and a silastic sheet is a postexcisional treatment for deep partial to full thickness burns where autograft is limited. This study correlates Integra histology and quantitative microbiology cult... ( view more )ures with clinical outcomes after autografting. METHODS: Charts of 29 burn patients who underwent Integra treatment and neodermis biopsy at the time of ultra thin autografting were reviewed. We analyzed microbial contamination, inflammatory reaction, and autograft take. RESULTS: The mean burn size and age were 43% total body surface area and 39 years old, respectively. In quantitative neodermis cultures, 90% of samples had bacterial growth; nine samples (31%) had > 10(5) colony forming units per gram. The most common organism was Staphylococcus aureus (31%). Patients with quantitative bacterial counts >10(5) CFU/g received targeted systemic antibiotics. Integra take (83%) and autograft take (92%) were acceptable even in patients with high bacterial counts (78% Integra take; 86% autograft take). More than 50% of biopsies had dermal regeneration similar to normal dermis; foreign body reactions were unusual. Histologic evidence of inflammation, especially polymorphonuclear cells, was increased in biopsies with high bacterial counts. CONCLUSION: Integra and autograft take can be acceptable even with high bacterial counts if wounds are treated with appropriate targeted topical and systemic antibiotics in the presence of microbial contamination. Neodermis biopsies showed fibrous in-growth congruent with existing Integra fibers with minimal foreign body reaction. These data support Integra use as a safe and effective treatment modality in patients with major burns. ( view less ) D J Rea,J K Heimbach,J P Grande,S C Textor,S J Taler,M Prieto,T S Larson,F G Cosio,M D Stegall The link between obesity and renal disease is unclear, and there is no consensus as to whether obese individuals are at increased risk for kidney disease after living kidney donation if they otherwise meet acceptance criteria. We retrospectively studied time-zero (implantation) biopsies in 49 obese... ( view more ) (body mass index (BMI) > or = 30 kg/m2) and 41 non-obese (BMI < 30 kg/m2) renal donors that met acceptance criteria. We found that our obese donor population had higher systolic blood pressure (P < 0.001 vs non-obese) and higher absolute iothalamate clearance (P = 0.001 vs non-obese) before donation. The obese donors had larger glomerular planar surface area compared to non-obese controls (P = 0.017), and this parameter correlated with patient weight and urinary microalbumin excretion. Detailed examination of the biopsies revealed that although most histologic findings were similar between groups, the obese donors had more tubular dilation (P = 0.01), but less tubular vacuolization (P = 0.02) than the non-obese controls. There was also a trend toward more arterial hyalinosis in the obese patients than controls (P = 0.08). From these data, our studies detected subtle differences in donor organs obtained from obese compared to non-obese individuals. Further studies should be carried out to quantify the long-term impact of these findings. ( view less ) Alfredo Ramirez,André Heimbach,Jan Gründemann,Barbara Stiller,Dan Hampshire,L Pablo Cid,Ingrid Goebel,Ammar F Mubaidin,Abdul-Latif Wriekat,Jochen Roeper,Amir Al-Din,Axel M Hillmer,Meliha Karsak,Birgit Liss,C Geoffrey Woods,Maria I Behrens,Christian Kubisch Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders. Although the complex molecular pathophysiology of neurodegeneration is largely unknown, major advances have been achieved ... ( view more )by elucidating the genetic defects underlying mendelian forms of these diseases. This has led to the discovery of common pathophysiological pathways such as enhanced oxidative stress, protein misfolding and aggregation and dysfunction of the ubiquitin-proteasome system. Here, we describe loss-of-function mutations in a previously uncharacterized, predominantly neuronal P-type ATPase gene, ATP13A2, underlying an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia (PARK9, Kufor-Rakeb syndrome). Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. Our findings link a class of proteins with unknown function and substrate specificity to the protein networks implicated in neurodegeneration and parkinsonism. ( view less ) Pornprom Muangman,Loren H Engrav,David M Heimbach,Nobuyuki Harunari,Shari Honari,Nicole S Gibran,Matthew B Klein The benefits of the Integra Dermal Regeneration Template in the management of extensive burn injuries have been well documented. Integra can reduce donor- and graft-site scarring and has been reported to be capable of vascularizing over small areas of exposed bone and tendon. Given these potential ... ( view more )advantages, we have used Integra for a variety of other reconstruction applications. We performed a retrospective review of patients with complex wounds treated with Integra at our burn center. Integra was used in the management of a variety of wounds, including necrotizing fasciitis, extremity degloving injury, meningococcemia, Marjolin ulcer, postburn lip reconstruction, and fourth-degree burns with exposed bone or tendon. Engraftment rates of Integra and autograft were 98% +/- 4% and 97% +/- 4%, respectively. All areas of graft loss healed without need for regrafting. The benefits of Integra in the management of acute burn wounds can be extended to other traumatic and complex wounds. ( view less ) Joshua C Anthony,Todd N Merriman,James T Heimbach A 90-day oral (gavage) study was conducted in male and female Sprague Dawley rats to investigate the safety of Vivinal galactooligosaccharides (GOS) syrup at 2500 or 5000 mg/kg bw/day. A reference control containing fructooligosaccharides (FOS) was used to match the oligosaccharide and digestible s... ( view more )ugars in the test material (approximately 45% and 30%, respectively) and to assess if these had an impact on food consumption. Measurements included clinical observations, body weights, food consumption, hematology, clotting parameters, blood chemistries, urinalysis, ophthalmologic examinations, gross necropsies, organ weights, and histological examinations. There were no effects of feeding GOS syrup at either concentration on any parameter except food consumption. Statistically significant decreases (7-13%) in food consumption were seen in both sexes in the GOS syrup-treated animals at 5000 mg/kg bw/day and animals treated with the FOS control when compared to the reverse osmosis deionized (RODI) water controls. Based on the lack of toxicological effects in the study, the NOAEL for Vivinal GOS syrup is 5000 mg/kg bw/day when administered by gavage for 90 consecutive days. ( view less ) Amal Kaddoumi,David Fleisher,Tycho Heimbach,Lilian Y Li,Susan Cole The objective of this study was to evaluate potential contributions of intestinal export and metabolism to the oral dose-dependent pharmacokinetics of the human cGMP-specific phosphodiesterase type 5 inhibitor, UK-343,664. Differences between jejunal and ileal handling of this CYP3A and P-gp substr... ( view more )ate were investigated. CYP3A and P-gp display differing activities in the upper and lower mammalian small intestine and their impact on variable drug absorption can be mechanistically assessed for individual compounds with in situ perfusion of rat's small intestine. Isolated segments of rat jejunum and ileum were perfused with UK-343,664 solution and measurements were made as a function of drug concentration for dose dependence and in the presence of CYP3A and P-gp inhibitors. Intestinal permeability and metabolism were measured by total drug disappearance and major metabolite, UK-347,334 (N-desethyl metabolite), appearance in the intestinal lumen. Intestinal tissue and mesenteric blood measurements of drug and metabolite were also determined. The effective permeability (P(eff)) of UK-343,664 and metabolite formation (F(met)) increased as a function of concentration. Regional differences in P(eff) and F(met) were observed with low-intestinal metabolism of UK-343,664 in both regions (<10%). P-gp inhibition caused significant increase in P(eff) and F(met) in jejunum and ileum while ketoconazole, a P-gp and CYP3A inhibitor, has only limited effect on metabolism. In conclusion, UK-343,664 absorption is mainly regulated by P-gp in jejunum and ileum while CYP3A intestinal metabolism has minimal effect. This role of P-gp could explain the dose-dependent pharmacokinetics of UK-343,664 and its unusual behavior of t(max) as a function of dose. ( view less ) Michael Brands,Jens-Kerim Ergüden,Kentaro Hashimoto,Dirk Heimbach,Thomas Krahn,Christian Schröder,Stephan Siegel,Johannes-Peter Stasch,Hideki Tsujishita,Stefan Weigand,Nagahiro H Yoshida Inhibition of the metalloprotease ECE-1 may be beneficial for the treatment of coronary heart disease, cancer, renal failure, and urological disorders. A novel class of indole-based ECE inhibitors was identified by high throughput screening. Optimization of the original screening lead structure 6 l... ( view more )ed to highly potent inhibitors such as 11, which bears a bisaryl amide moiety linked to the indole C2 position through an amide group. Docking of 11 into a model structure of ECE revealed a unique binding mode in which the Zn center of the enzyme is not directly addressed by the inhibitor, but key interactions are suggested for the central amide group. Testing of the lead compound 6 in hypertensive Dahl S rats resulted in a decrease in blood pressure after an initial period in which the blood pressure remained unchanged, most probably the result of ET-1 already present. Indole derivative 6 also displays a cardio-protective effect in a mouse model of acute myocardial infarction after oral administration. The more potent chloropyridine derivative 9 antagonizes big-ET-1-induced increase in blood pressure in rats at intravenous administration of 3 mg kg-1. All ECE inhibitors of the indole class showed high selectivity for ECE over related metalloproteases such as NEP and ACE. Therefore, these compounds might have further potential as drugs for the treatment of coronary heart diseases. ( view less ) Pornprom Muangman,Stephen R Sullivan,Shari Honari,Lorenz H Engrav,David M Heimbach,Nicole S Gibran INTRODUCTION: Early excision and grafting (E&G) drastically changed burn care in America by reducing morbidity, mortality and hospital length of stay (LOS). The present study was intended to determine whether an optimal time window exists between resuscitation and wound sepsis for the first E&G in ... ( view more )a patient with a large burn. MATERIAL AND METHOD: The authors conducted a retrospective study of patients admitted between January 1994 and December 2000 with > or = 40% TBSA burns and at least 1 E&G procedure. Patients were grouped according to the day of their first operation. Patients allowed to heal indeterminate burns prior to excision and grafting of deep partial or full thickness burns were grouped as > or = d7 and were excluded from the present study. The authors correlated the time of first excision with infection, mortality and LOS. RESULTS: Seventy-five patients were identified and 12 patients allowed to heal indeterminate burn prior to excision and grafting of deep partial or full thickness burns were excluded. Sixty-three remaining patients included 51 males and 12 females. Mean burn size was 49% of total body surface area (TBSA) (44% deep partial or full thickness) and the mean age was 36 years. There were 61 flame (2 combined with electrical injuries), 1 scald and 1 chemical burn. Twelve died (19%) and 52 patients developed 121 infections. Whereas there was no statistical difference in mortality for patients operated on different days (p > 0.2), 60% of patients operated within the first 48 hours after injury died; this was not significant due to a small patient number CONCLUSIONS: The present data suggest that patients who undergo early excision and grafting within seven days following a major burn > or = 40% TBSA have equivalent infection or mortality rates regardless of when the first operation occurs between post burn day(PBD) 2 and PBD 7 (p > 0.2). ( view less ) Michael Brands,Jens-Kerim Ergüden,Kentaro Hashimoto,Dirk Heimbach,Christian Schröder,Stephan Siegel,Johannes-Peter Stasch,Stefan WeigandA novel class of indole-based endothelin-converting enzyme (ECE) inhibitors was identified by high throughput screening. We report systematic optimization of this compound class by means of classical and solid-phase chemistry. Optimized compounds with a bisarylamide side chain at the 2-position of ... ( view more )the indole skeleton exhibit low-nanomolar activity on ECE. ( view less ) M H Greenstone,D L Rowley,U Heimbach,J G Lundgren,R S Pfannenstiel,S A Rehner Identification of arthropod predators is challenging when closely related species are found at a given locality. Identification of the immature stages is especially problematic, because distinguishing morphological features are difficult to use or have not been described. We used polymerase chain r... ( view more )eaction (PCR) to distinguish closely related carabids and spiders, and to match eggs and larvae (or nymphs) with identified adult parents. Within the Carabidae, we amplified species-specific mitochondrial cytochrome oxidase I (COI) fragments for three species each in the genera Poecilus and Harpalus, and two each in Chlaenius and Bembidion. Within the Araneae, we amplified species-specific COI fragments for two Hibana species (Anyphaenidae), Pardosa milvina and Rabidosa rabida (Lycosidae), Frontinella communis and Grammonota texana (Linyphiidae), and Cheiracanthium inclusum (Miturgidae). We are able to correctly identify all immature stages tested--eggs, larvae (or nymphs) and pupae--by comparison of the amplified fragments with those of the adults. Using COI markers as species identifiers is a tenet of the Barcode of Life initiative, an international consortium to provide a molecular identifier for every animal species. ( view less )
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