High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele.

For over 10,000 years, Andeans have resided at high altitude where the partial pressure of oxygen challenges human survival. Recent studies have provided evidence for positive selection acting in Andeans on the HIF2A (also known as EPAS1) locus, which encodes for a central transcription factor of the hypoxia-inducible factor pathway. However, the precise mechanism by which this allele might lead to altitude-adaptive phenotypes, if any, is unknown. By analyzing whole genome sequencing data from 46 high-coverage Peruvian Andean genomes, we confirm evidence for positive selection acting on HIF2A and a unique pattern of variation surrounding the Andean-specific single nucleotide variant (SNV), rs570553380, which encodes for an H194R amino acid substitution in HIF-2α. Genotyping the Andean-associated SNV rs570553380 in a group of 299 Peruvian Andeans from Cerro de Pasco, Peru (4,338 m), reveals a positive association with increased fraction of exhaled nitric oxide, a marker of nitric oxide biosynthesis. In vitro assays show that the H194R mutation impairs binding of HIF-2α to its heterodimeric partner, aryl hydrocarbon receptor nuclear translocator. A knockin mouse model bearing the H194R mutation in the Hif2a gene displays decreased levels of hypoxia-induced pulmonary Endothelin-1 transcripts and protection against hypoxia-induced pulmonary hypertension. We conclude the Andean H194R HIF2A allele is a hypomorphic (partial loss of function) allele.

The Legacy of Infectious Disease Exposure on the Genomic Diversity of Indigenous Southern Mexicans.

To characterize host risk factors for infectious disease in Mesoamerican populations, we interrogated 857,481 SNPs assayed using the Affymetrix 6.0 genotyping array for signatures of natural selection in immune response genes. We applied three statistical tests to identify signatures of natural selection: locus-specific branch length (LSBL), the cross-population extended haplotype homozygosity (XP-EHH), and the integrated haplotype score (iHS). Each of the haplotype tests (XP-EHH and iHS) were paired with LSBL and significance was determined at the 1% level. For the paired analyses, we identified 95 statistically significant windows for XP-EHH/LSBL and 63 statistically significant windows for iHS/LSBL. Among our top immune response loci, we found evidence of recent directional selection associated with the major histocompatibility complex (MHC) and the peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling pathway. These findings illustrate that Mesoamerican populations' immunity has been shaped by exposure to infectious disease. As targets of selection, these variants are likely to encode phenotypes that manifest themselves physiologically and therefore may contribute to population-level variation in immune response. Our results shed light on past selective events influencing the host response to modern diseases, both pathogenic infection as well as autoimmune disorders.

Identification and determination of phenyl methyl carbamate released from adducted hemoglobin for methyl isocyanate exposure verification.

Methyl isocyanate (MIC), an intermediate in the synthesis of carbamate pesticides, is a toxic industrial chemical that causes irritation and damage to the eyes, respiratory tract, and skin. Due to the high reactivity of MIC, it binds to proteins to form protein adducts. While these adducts can be used as biomarkers to verify exposure to MIC, methods to detect MIC adducts are cumbersome, typically involving enzymatic (pronase) or strong acid (Edman degradation) hydrolysis of hemoglobin. Hence, in this study, a simple method was developed which utilizes base hydrolysis of MIC-tyrosine adducts from isolated hemoglobin to form phenyl methyl carbamate (PMC), followed by rapid liquid-liquid extraction, and liquid chromatography tandem mass spectrometry analysis. The hydrolysis chemistry is the first report of base hydrolysis of a tyrosine-ß-C-hydroxo phenol bond in aqueous solution. The method produced excellent sensitivity (detection limit of 0.02 mg/kg), linearity (R2 = 0.998, percent residual accuracies > 96), and dynamic range (0.06‒15 mg/kg). The accuracy and precision (100 ± 9% and < 10% relative standard deviation, respectively) of the method were outstanding compared to existing techniques. The validated method was able to detect significantly elevated levels of PMC from hemoglobin isolated from MIC-exposed rats.

Elucidating the Biomechanics of Leukocyte Transendothelial Migration by Quantitative Imaging.

Leukocyte transendothelial migration is crucial for innate immunity and inflammation. Upon tissue damage or infection, leukocytes exit blood vessels by adhering to and probing vascular endothelial cells (VECs), breaching endothelial cell-cell junctions, and transmigrating across the endothelium. Transendothelial migration is a critical rate-limiting step in this process. Thus, leukocytes must quickly identify the most efficient route through VEC monolayers to facilitate a prompt innate immune response. Biomechanics play a decisive role in transendothelial migration, which involves intimate physical contact and force transmission between the leukocytes and the VECs. While quantifying these forces is still challenging, recent advances in imaging, microfabrication, and computation now make it possible to study how cellular forces regulate VEC monolayer integrity, enable efficient pathfinding, and drive leukocyte transmigration. Here we review these recent advances, paying particular attention to leukocyte adhesion to the VEC monolayer, leukocyte probing of endothelial barrier gaps, and transmigration itself. To offer a practical perspective, we will discuss the current views on how biomechanics govern these processes and the force microscopy technologies that have enabled their quantitative analysis, thus contributing to an improved understanding of leukocyte migration in inflammatory diseases.

Radiosurgery treatment planning using conformal arc informed volumetric modulated arc therapy.

Linac based radiosurgery to multiple metastases is commonly planned with volumetric modulated arc therapy (VMAT) as it effectively achieves high conformality to complex target arrangements. However, as the number of targets increases, VMAT can struggle to block between targets, which can lead to highly modulated and/or nonconformal multi-leaf collimator (MLC) trajectories that unnecessarily irradiation of healthy tissue. In this study we introduce, describe, and evaluate a treatment planning technique called Conformal Arc Informed VMAT (CAVMAT), which aims to reduce the dose to healthy tissue while generating highly conformal treatment plans. CAVMAT is a hybrid technique which combines the conformal MLC trajectories of dynamic conformal arcs with the MLC modulation and versatility of inverse optimization. CAVMAT has 3 main steps. First, targets are assigned to subgroups to maximize MLC blocking between targets. Second, arc weights are optimized to achieve the desired target dose, while minimizing MU variation between arcs. Third, the optimized conformal arc plan serves as the starting point for limited inverse optimization to improve dose conformity to each target. Twenty multifocal VMAT cases were replanned with CAVMAT with 20Gy applied to each target. The total volume receiving 2.5Gy[cm3], 6Gy[cm3], 12Gy[cm3], and 16Gy[cm3], conformity index, treatment delivery time, and the total MU were used to compare the VMAT and CAVMAT plans. In addition, CAVMAT was compared to a broad range of planning strategies from various institutions (108 linear accelerator based plans, 14 plans using other modalities) for a 5-target case utilized in a recent plan challenge. For the linear accelerator-based plans, a plan complexity metric based on aperture opening area and perimeter, total monitor units (MU), and MU for a given aperture opening was utilized in the plan challenge scoring algorithm to compare the submitted plans to CAVMAT. After re-planning the 20 VMAT cases, CAVMAT reduced the average V2.5Gy[cm3] by 25.25 ± 19.23%, V6Gy[cm3] by 13.68 ± 18.97%, V12Gy[cm3] by 11.40 ± 19.44%, and V16Gy[cm3] by 6.38 ± 19.11%. CAVMAT improved conformity by 3.81 ± 7.57%, while maintaining comparable target dose. MU for the CAVMAT plans increased by 24.35 ± 24.66%, leading to an increased treatment time of 2 minutes. For the plan challenge case, CAVMAT was 1 of 12 linac based plans that met all plan challenge scoring criteria. Compared to the average submitted VMAT plan, CAVMAT increased the V10%Gy[%] of healthy tissue (Brain-PTV) by roughly 3.42%, but in doing so was able to reduce the V25%Gy[%] by roughly 3.73%, while also reducing V50%Gy[%], V75%Gy[%], and V100%Gy[%]. The CAVMAT technique successfully eliminated insufficient MLC blocking between targets prior to the inverse optimization, leading to less complex treatment plans and improved tissue sparing. Tissue sparing, improved conformity, and decreased plan complexity at the cost of slight increase in treatment delivery time indicates CAVMAT to be a promising method to treat brain metastases.

Proximate Composition, Cyanide Content, and Carotenoid Retention after Boiling of Provitamin A-Rich Cassava Grown in Ghana.

Biofortified yellow-fleshed cassava is important in countries with high cassava consumption, to improve the vitamin A status of their populations. Yellow- and white-fleshed cassava were evaluated over three locations for proximate composition and cyanide content as well as retention of carotenoids after boiling. There was significant variation in the crude fiber, fat, protein and ash content of the genotypes. All but one of the yellow-fleshed cassava genotypes recorded higher protein values than the white-fleshed local genotypes across locations. The cyanide content of the genotypes varied between locations but was within the range of sweet cassava genotypes, but above the maximum acceptable recommended limit. Micronutrient retention is important in biofortified crops because a loss of micronutrients during processing and cooking reduces the nutritional value of biofortified foods. Total carotenoid content (TCC) ranged from 1.18-18.81 µg.g-1 and 1.01-13.36 µg.g-1 (fresh weight basis) for fresh and boiled cassava, respectively. All the yellow-fleshed cassava genotypes recorded higher TCC values in both the fresh and boiled state than the white-fleshed genotypes used as checks.

Analysis of TRPA1 antagonist, A-967079, in plasma using high-performance liquid chromatography tandem mass-spectrometry.

The noxious effects from exposure to toxic inhalation hazards (TIHs, such as isocyanates, chlorine, etc.) are known to be triggered by the activation of transient receptor potential ankyrin 1 (TRPA1) ion channel. Antagonists of TRPA1 have shown near complete attenuation of the noxious effects from TIH exposure. One of the TRPA1 antagonists, (1E,3E)-1-(4-fluorophenyl)-2-methyl-1-pentene-3-one oxime (A-967079), has shown impressive efficacy, high selectivity, high potency, and oral bioavailability. Although a validated method to quantify A-967079 in biological matrices is vital for the further development of A-967079 as a therapeutic agent, no method for its analysis from any matrix is currently available. Hence, a rapid and simple HPLC-MS/MS method was developed and validated to quantify A-967079 in rabbit plasma. The method presented here features an excellent LOD of 25 nM and a wide linear range (0.05-200 µM), with good accuracy and precision (100 ± 10.5% and <14.2% relative standard deviation, respectively). The stability of A-967079 in plasma was excellent for most of the storage conditions evaluated. The method was successfully applied to determine A-967079 from treated animals and it may facilitate the development of this TRPA1 antagonist as a therapeutic agent against the noxious effects of TIH exposure.

Diagnosis of cyanide poisoning using an automated, field-portable sensor for rapid analysis of blood cyanide concentrations.

Cyanide (both HCN and CN- are represented by CN) has multiple industrial applications, is commonly found in some foods, and is a component of fire smoke. Upon exposure, CN blocks production of adenosine triphosphate, causing cellular hypoxia and cytotoxic anoxia, which can eventually result in death. Considering CN's quick onset of action and the long analysis times associated with current techniques, the objective of this study was to develop and validate a rapid and field-portable sensor to detect blood CN concentrations focusing on both concentration and diagnostic accuracy. The sensor takes advantage of the chemical properties of CN by converting it exclusively to HCN via acidification of whole blood. High-speed headspace transfer is used to deliver HCN to a capture solution where it is reacted with naphthalene dialdehyde and taurine to produce a fluorescent ß-isoindole product. Simple spectrofluorometric analysis of the product provides quantitative analysis of CN from whole blood in 60 s and requires only 25 µL of blood (obtainable via fingerstick). A limit of detection of 5 µM, a linear range of 10-200 µM (with ≥15 µM considered CN exposed), and excellent accuracy (100 ± 15%) and precision (≤15.2% relative standard deviation) were obtained. To evaluate the diagnostic accuracy of the sensor, rabbit blood samples (N = 190, including 24 blinded samples) were analyzed by both the sensor and a lab-based spectrophotometric method. An excellent positive correlation was obtained between the sensor and the lab-based method (R2 ˃ 0.995) confirming the concentration accuracy of the CN sensor. Moreover, the sensor produced no false positives or negatives when diagnosing CN poisoning.

Metabolism of Cyanide by Glutathione To Produce the Novel Cyanide Metabolite 2-Aminothiazoline-4-oxoaminoethanoic Acid.

The direct analysis of cyanide (HCN or CN- inclusively symbolized as CN) to confirm exposure has major limitations due to cyanide's volatility, reactivity, and short half-life in biological fluids. These limitations have led to the exploration of cyanide detoxification products for indirect verification of cyanide exposure. Although cyanide interacts strongly with sulfur-containing molecules, to date, biomarkers resulting from the interaction of cyanide with glutathione (GSH; i.e., a biologically abundant sulfur-donating biomolecule) have yet to be discovered. In this study, we studied the interaction of CN and GSH to produce 2-aminothiazoline-4-oxoaminoethanioc acid (ATOEA). An LC-MS/MS method was developed and validated to analyze ATOEA from plasma, producing a linear range of 0.5-50 µM, a limit of detection of 200 nM, and excellent precision and accuracy. ATOEA concentrations were significantly elevated in the plasma of animals following cyanide exposure. Moreover, the production of ATOEA from cyanide exposure was confirmed by detection of both ATOEA and ATOEA-13C15N in rabbit plasma ( N = 11 animals) following administration of NaCN:K13C15N (1:1), with a similar amount of ATOEA and ATOEA-13C15N formed ( R2 = 0.9924, p < 0.05). The concentration of ATOEA increased with cyanide dose and then decreased rapidly when an antidote was administrated. This study definitively showed that ATOEA is produced from interaction of CN and GSH and can serve as a biomarker of cyanide exposure.

The inflammatory gene pathway is not a major contributor to polycystic ovary snydrome.

CONTEXT: Although inflammation is clearly associated with obesity, diabetes, and insulin resistance, the role of chronic inflammation in the etiology of polycystic ovary syndrome (PCOS) is unclear. OBJECTIVE: To determine whether chronic inflammation plays a causal role in the etiology of PCOS, we tested for an association between PCOS and genetic markers mapping to 80 members of the inflammatory pathway. DESIGN: This was a case-control association study. SETTING: The setting was an academic medical center. PATIENTS OR PARTICIPANTS: A total of 905 index case patients with PCOS and 955 control women (108 intensively phenotyped subjects with normal androgen levels and regular menses and 847 minimally phenotyped subjects with regular menses and no history of PCOS). INTERVENTIONS: Subjects were genotyped at single nucleotide polymorphisms mapping to 80 inflammatory genes. Logistic regression was used to test for an association between 822 single nucleotide polymorphisms and PCOS after adjustment for population stratification, body mass index, and/or age. In the index patients, we also tested for association with 11 quantitative traits (body mass index and testosterone, fasting insulin, fasting glucose, 2-hour postchallenge glucose, LH, FSH, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels). MAIN OUTCOME MEASURES: The evidence for an association with PCOS and with 11 quantitative traits was investigated. RESULTS: Nominally significant evidence for an association was observed with MAP3K7, IKBKG, TNFRS11A, AKT2, IL6R, and IRF1, but no results remained statistically significant after adjustment for multiple testing. CONCLUSIONS: Genetic variation in the inflammatory pathway is not a major contributor to the etiology of PCOS or related quantitative traits in women with PCOS.

Maternal deaths attributable to hypertensive disorders in a tertiary hospital in Ghana.

OBJECTIVE: To determine the contribution of hypertensive disorders of pregnancy to maternal deaths at Korle Bu Teaching Hospital (KBTH) in Accra, Ghana. METHODS: The retrospective descriptive study conducted at KBTH during 2010-2011 involved a comprehensive review of all maternal deaths attributable to hypertensive disorders. RESULTS: There were 21 385 deliveries, 21742 live births, and 199 maternal deaths, resulting in a maternal mortality ratio of 915.3 per 100000 live births. In total, 63 (31.7%) maternal deaths were attributable to hypertensive disorders with a case fatality rate of 3.9%. The incidence of hypertensive disorders of pregnancy was 7.6%. Hypertensive disorders were the most common direct cause of maternal death followed by obstetric hemorrhage (26.6%), unsafe abortion (11.1%), and puerperal sepsis (3.5%). Most (38.1%) hypertension-related maternal deaths occurred within 24hours of admission and the majority (79.4%) had been referred. Eclampsia was the leading immediate cause of hypertension-related death (23.8%), followed by acute renal failure (20.6%), intracerebral hemorrhage (15.9%), and pulmonary edema (12.7%). CONCLUSION: Hypertensive diseases are the leading cause of maternal death at KBTH, having overtaken obstetric hemorrhage, with eclampsia, acute renal failure, intracerebral hemorrhage, and pulmonary edema representing the major immediate causes of hypertension-related maternal death.

Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry.

CONTEXT: A previous genome-wide association study in Chinese women with polycystic ovary syndrome (PCOS) identified a region on chromosome 2p16.3 encoding the LH/choriogonadotropin receptor (LHCGR) and FSH receptor (FSHR) genes as a reproducible PCOS susceptibility locus. OBJECTIVE: The objective of the study was to determine the role of the LHCGR and/or FSHR gene in the etiology of PCOS in women of European ancestry. DESIGN: This was a genetic association study in a European ancestry cohort of women with PCOS. SETTING: The study was conducted at an academic medical center. PARTICIPANTS: Participants in the study included 905 women with PCOS diagnosed by National Institutes of Health criteria and 956 control women. INTERVENTION: We genotyped 94 haplotype-tagging single-nucleotide polymorphisms and two coding single-nucleotide polymorphisms mapping to the coding region of LHCGR and FSHR plus 20 kb upstream and downstream of the genes and test for association in the case control cohort and for association with nine quantitative traits in the women with PCOS. RESULTS: We found strong evidence for an association of PCOS with rs7562215 (P = 0.0037) and rs10495960 (P = 0.0046). Although the marker with the strongest association in the Chinese PCOS genome-wide association study (rs13405728) was not informative in the European populations, we identified and genotyped three markers (rs35960650, rs2956355, and rs7562879) within 5 kb of rs13405728. Of these, rs7562879 was nominally associated with PCOS (P = 0.020). The strongest evidence for association mapping to FSHR was observed with rs1922476 (P = 0.0053). Furthermore, markers with the FSHR gene region were associated with FSH levels in women with PCOS. CONCLUSIONS: Fine mapping of the chromosome 2p16.3 Chinese PCOS susceptibility locus in a European ancestry cohort provides evidence for association with two independent loci and PCOS. The gene products LHCGR and FSHR therefore are likely to be important in the etiology of PCOS, regardless of ethnicity.

Calcineurin inhibitor sparing with mycophenolate mofetil in liver transplantion: a systematic review of randomized controlled trials.

Liver transplant recipients are at high risk of developing acute and chronic renal failure. Moreover, introduction of the model for end-stage liver disease (MELD) score for primary allocation of liver grafts favors patients with pretransplant kidney dysfunction, which in turn have a higher risk of posttransplant renal failure. Calcineurin inhibitors (CNI) further increase the risk of renal failure and therefore sparing CNI with the use of mycophenolate mofetil (MMF) may improve renal function. MMF may either be used de novo in the immediate posttransplant period in combination with low-dose CNI (scenario 1) or patients that receive immunosuppression based on CNI may be converted to MMF in combination with minimization or elimination of CNI (scenario 2). Although many retrospective cohort studies and nonrandomized trials have implicated efficacy of this approach the evidence from randomized controlled studies has not been summarized. In the current review we report the results of a systematic review and meta-analysis of randomized controlled trials.

Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterised by hyperandrogenaemia and irregular menses. A recent genome-wide association study (GWAS) of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinising hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined. METHODS AND RESULTS: The study tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European derived PCOS cohorts (cohort A = 939 cases and 957 controls; cohort B = 535 cases and 845 controls). Cases fulfilled the National Institute of Child Health & Human Development criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in the study cohort (p(combined cohorts)=10(-8)); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. The present study had >80% power to detect an effect of similar size as was observed by Chen et al for DENND1A and THADA, but reduced power (at <40%) for LHCGR at p=0.0001. The study had sufficient power (57-88%) for LHCGR at p=0.01. CONCLUSIONS: At least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European derived populations, and are therefore likely to be important in the aetiology of PCOS regardless of ethnicity. The analysis of the LHCGR gene was not sufficiently powered to detect modest effects.

[Localisation of hepatic lesions to liver segments according to sonography (US), computed tomography (CT) and surgery (OP): a comparative study]. / Untersuchung der Segmentzugehörigkeit von Leberraumforderungen in Sonografie (US), Computertomografie (CT) und intraoperativ (OP): eine Vergleichsstudie.

INTRODUCTION: The localisation of focal liver lesions is usually performed according to the Couinaud classification system. The exact description of localisation and size of liver lesions is especially important for surgical procedures. The aim of this prospective study was the evaluation of differences and agreements in the localisation and size of hepatic lesions as found by ultrasound (US), computed tomography (CT) and according to the intraoperative status (OP). MATERIAL AND METHODS: 32 patients (21 male, 11 female) were enrolled in the study. The results obtained from sonography, computed tomography and surgery were classified into 5 categories for localisation and for size, respectively. RESULTS: According to the agreement between sonography and computed tomography, 25 % of all hepatic lesions were classified into category 1 (exact agreement), whereas 40.6 % were ranked into category 2 (almost exact agreement). Correlating sonography and intraoperative results, 31.3 % of the lesions were classified into category 1 and 46.9 % into category 2. In the comparison of CT with OP, 34.4 % of the lesions were found to be in category 1 and 43.8 % in category 2. Concerning the size of the lesions, almost half of the tumours (46.9 %) were classified into category 1 on the basis of the correlation between US and CT and 21.9 % on the basis of the correlation between US and OP. DISCUSSION: The localisation and description of the size of hepatic lesions is mainly similar or even identical on the basis of the different methods. Further improvements might be achieved by the introduction of a consistent nomenclature.

Pre-existent portal vein thrombosis in liver transplantation: influence of pre-operative disease severity.

BACKGROUND: Portal vein thrombosis (PVT) is a surgical challenge in liver transplantation (LTx). In contrast to LTx in decompensated liver disease, which are associated with a higher morbidity and mortality, PVT influence on outcome is still under debate. To evaluate this influence at different stages of liver decompensation, we compared the outcome of patients suffering from PVT to patients with patent portal vein within different score ranges. METHODS: We included 193 LTx (24 with PVT) in our study, transplanted between 2004 and 2007 at our institution. Patients were divided into four Model of End-Stage Liver Disease (MELD) score groups, and outcome was compared between PVT- and non-PVT patients. RESULTS: In non-decompensated liver disease (MELD <15), we found a significantly decreased survival in patients suffering from PVT (one-yr survival 57% vs. 89%). By contrast, MELD score >15 (decompensated liver disease) leads to an equal or even better survival in PVT-patients compared with patients without PVT (one-yr survival 91% vs.75%), with an only slightly increased morbidity. CONCLUSION: Outcome in patients with PVT seems to be dependent on pre-operative disease severity. In contrast to compensated liver disease, no influence of PVT on outcome could be found in decompensated liver disease, and should therefore not be considered as a contraindication in LTx.

The impact of "high-producer" interleukin-6 haplotypes on cardiovascular morbidity and mortality in a kidney transplant population.

BACKGROUND: At present, inflammation is considered to be one of the key players in the development and maintenance of atherosclerosis, with ample impact on renal transplant outcomes. Interleukin-6 (IL-6) levels and the underlying genetically determined "high-producer" status impact cardiovascular morbidity and mortality. In end-stage renal disease (ESRD) patients, the role of genetically determined IL-6 differences in cardiovascular and renal outcomes of kidney transplantation is controversial. In this study, we sought to clarify the influence of IL-6 haplotypes on cardiovascular and renal outcomes among kidney transplant recipients. METHODS: Three hundred fifty-two first kidney transplant patients were genotyped for the two "clade" IL-6 polymorphisms ((-174)G/C and (1888)G/T) and two missense polymorphisms (Pro32Ser, Asp162Val), which are known to influence IL-6 levels and outcome. RESULTS: We observed four IL-6 haplotypes among our population: CCAG: 57.0%, CCAT: 2.8%, GCAT: 39.2%, GCTT: 1.0%. After stratifying the haplotypes into diplotypes in three different models, we failed to observe associations with early or late graft outcomes, or with all-cause or cardiovascular mortality. These findings were also confirmed when we separately analyzed each polymorphism. CONCLUSION: Despite evidence of associations in other transplant and ESRD cohorts, we could not confirm any association between IL-6 haplotypes/diplotypes and cardiovascular or graft-related outcomes among our population at high risk for inflammatory diseases.

Nanohybrids of nylon 6 with multi-walled carbon nanotubes: solvent-free polymerization of epsilon-caprolactam under variable experimental conditions.

The solvent-free polymerization of epsilon-caprolactam on 1,8-diaminooctane-functionalized multi-walled carbon nanotubes (DA-MWNTs) is proposed as a simple and ecologically friendly approach to the preparation of carbon nanotubes/nylon 6 hybrid materials. The main goal of the present study was to find a minimum temperature resulting in an efficient epsilon-caprolactam polymerization, along with the optimization of the weight ratio of DA-MWNTs to epsilon-caprolactam and reaction time. The effect of temperature was studied in the range of 170 degrees C to 210 degrees C. After the reaction at 170 degrees C, the nanotubes functionalized contained a large amount of unreacted monomer along with ca. 14% of polyamide. Increasing the reaction temperature dramatically reduced the content of epsilon-caprolactam impurity and increased the nylon 6 content to ca. 20%. The reaction time tested was 1, 2, 4, 6 and 8 h. Exposures at less than 4 h were insufficient, where the infrared spectral bands of nylon 6 were barely seen. The reaction time of 6 h was found to be optimal since a more prolonged heating for 8 h did not provide an evident further increase in polyamide content. The effect of stoichiometry was studied by varying the weight ratio of DA-MWNTs to epsilon-caprolactam from 1:0.1 to 1:1. The ratios 1:0.1 and 1:0.2 were too high, since they did not provide the amount of epsilon-caprolactam necessary to form the composites with at least 20% content of nylon 6. Starting with the ratio of 1:0.3, the infrared band intensities qualitatively stabilized and did not show dramatic variations. The use of reagent ratios of 1:0.3 to 1:0.7 might be especially appropriate for preparing the composites targeted to biomedical applications, whereas higher weight ratios are expected to increase the content of undesirable monomer impurities.

Percutaneous transluminal angioplasty as first-line treatment of transplant renal artery stenosis.

BACKGROUND: Transplant renal artery stenosis (TRAS) is a frequent complication after renal transplantation, however long-term follow-up data after interventional treatment are rare. PATIENTS: In our transplant center 11 of 264 consecutive renal transplant recipients (4.17%) were diagnosed with TRAS. In addition, TRAS occurred in 2 renal transplant recipients that had been transplanted at other centers but who had their follow-up examinations in our center. Either a rise of the serum creatinine level and/or worsened systemic hypertension or routine examination with color Doppler sonography were indications for further diagnostic workup. METHODS: Direct angiography of the transplant renal artery was performed followed by percutaneous transluminal angioplasty (PTA) after the diagnosis of TRAS was confirmed in all of these patients. RESULTS: The immediate success rate for PTA was 92.3% (12/13). Only 1 patient with a severe kinking of the transplant renal artery had to undergo surgery to restore renal function. No complications occurred after the interventions. Thereafter the patients were monitored for a mean observation period of 33.15 months. Serum creatinine levels were significantly lower after the intervention, and estimated glomerular filtration rate (eGFR) increased accordingly. With regard to blood pressure there was only a trend for lower blood pressure levels and less antihypertensive use, whereas the dose of the prescribed drugs decreased significantly with time after interventional treatment of TRAS. In addition, a long-lasting rise of the hemoglobin levels could also be demonstrated. CONCLUSION: In summary, the beneficial effect of PTA of TRAS on renal function is long-lasting. Therefore, PTA, usually combined with stent placement, should be first-line treatment in TRAS in all patients. Surgical revascularization is only warranted, if PTA fails.

[Case report--surgical therapy of a retroperitoneal liposarcoma weighing 45 kg]. / Fallbericht - Chirurgische Therapie eines 45 kg schweren retroperitonealen Liposarkoms.

Due to the late onset of symptoms, retroperitoneal liposarcoma are often diagnosed in advanced stages when adjacent organs have been infiltrated and the tumours have reached extensive sizes. Surgery remains the first choice of therapy. We report on the primary resection of a 45-kg liposarcoma that was removed en-bloc including the left kidney and descending colon with -tumour-free margins. Nine months later, the follow-up revealed a right-sided recurrence of the tumour, which was surgically removed including the right ureter. Since then, the patient has been without any signs of tumour recurrence or metastases. This report demonstrates that even extreme-ly large tumours can be removed safely and that the size is not a contraindication for primary surgical treatment. Local recurrence is common as seen in our case, and occurs even after R0 resection up to 10 years after the first operation. Recurrences should be surgically removed as this is the only treatment which has been shown to increase survival in even R1 and R2 situations.