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Introduction: Short-term fasting protects against renal ischemia reperfusion injury (IRI). mTOR signaling is downregulated and may be involved in its protective effect. Rapamycin is considered a possible mimetic as it inhibits the mTOR pathway. This study examines the effect of rapamycin on renal IRI. Material and Methods: Mice were divided into four groups: ad libitum (AL), fasted (F), AL treated with rapamycin (AL+R), and F treated with rapamycin (F+R). Rapamycin was administered intraperitoneally 24 h before bilateral renal IRI was induced. Survival was monitored for 7 days. Renal cell death, regeneration, and mTOR activity were determined 48 h after reperfusion. Oxidative stress resistance of human renal proximal tubular and human primary tubular epithelial cells after rapamycin treatment was determined. Results: All F and F+R mice survived the experiment. Although rapamycin substantially downregulated mTOR activity, survival in the AL+R group was similar to AL (10%). Renal regeneration was significantly reduced in AL+R but not in F+R. After IRI (48 h), pS6K/S6K ratio was lower in F, F+R, and AL+R groups compared to AL fed animals (p = 0.02). In vitro, rapamycin also significantly downregulated mTOR activity (p < 0.001) but did not protect against oxidative stress. Conclusion: Rapamycin pretreatment does not protect against renal IRI. Thus, protection against renal IRI by fasting is not exclusively mediated through inhibition of mTOR activity but may involve preservation of regenerative mechanisms despite mTOR downregulation. Therefore, rapamycin cannot be used as a dietary mimetic to protect against renal IRI. [ABSTRACT FROM AUTHOR]

We present an updated overview of the literature comparing normothermic with hypothermic machine perfusion in porcine kidneys. We conducted a systematic literature review in Embase, Medline Epub (Ovid), Cochrane Central, Web of Science, and Google Scholar on studies comparing normothermic (NMP) to hypothermic machine perfusion (HMP) in porcine kidneys. A meta‐analysis was judged inappropriate because of heterogeneity in study design and perfusion methods. The quality of evidence of each included study was assessed. We included 8 studies. One out of 5 studies reported a significant difference in peak renal blood flow in favor of NMP. Oxygen consumption was significantly higher in NMP kidneys in 2 out of 5 studies. Peak creatinine clearance in NMP was significantly higher than that in HMP in 1 out of 6 studies. Two out of 4 studies reported a higher degree of epithelial vacuolation in kidneys receiving NMP over HMP. None of the studies found a significant difference between NMP and HMP in peak serum creatinine or graft survival after autotransplantation. The results need to be interpreted with caution in view of the diversity in perfusion protocols, the low quality of evidence, and the limited sample sizes. [ABSTRACT FROM AUTHOR]

Morbid obesity is characterized by chronic, low-grade inflammation, which is associated with 'inflamm-aging'. The presence of metabolic syndrome (MetS) might accelerate this phenomenon of metaflammation. In this study, we assessed the effects of morbid obesity and MetS on the composition of a broad spectrum of immune cells present within the circulation. A total of 117 morbidly obese patients (MOP) without MetS (MetS-), 127 MOP with MetS (MetS+) and 55 lean controls (LC) were included in this study. Absolute numbers of T cell, B cell, NK cell and monocyte subsets were assessed within peripheral blood using flow cytometry. Both absolute cell numbers and proportion of cells were evaluated correcting for covariates age, body mass index and cytomegalovirus serostatus. Although the absolute number of circulating CD4+ T cells was increased in the MetS+ group, the CD4+ T cell composition was not influenced by MetS. The CD8+ T cell and B cell compartment contained more differentiated cells in the MOP, but was not affected by MetS. Even though the absolute numbers of NK cells and monocytes were increased in the MOP as compared to LC, there was no difference in proportions of NK and monocyte subsets between the three study groups. In conclusion, although absolute numbers of CD4+ and CD8+ T cells, B cells, NK cells and monocytes are increased in MOP, obesity-induced effects of the composition of the immune system are confined to a more differentiated phenotype of CD8+ T cells and B cells. These results were not affected by MetS. [ABSTRACT FROM AUTHOR]

BACKGROUND: Quercetin is a flavonoid with reported antioxidant, anti-inflammatory and anti-aging effects, and may limit muscle wasting in cancer cachexia. OBJECTIVE: To investigate the effect of quercetin on muscle wasting in the murine C26 cancer-cachexia model and assess the feasibility of non-invasive micro-CT analysis of skeletal muscle. MATERIALS AND METHODS: Custom CRM(P) diets supplemented with 250 mg/kg quercetin (Q) were obtained. Thirty CD2F1 mice were equally randomized to non-tumor-bearing (NTB), C26 tumor-bearing (TB), TB + Q. All groups started their allocated diet and underwent hindlimb micro-CT. Bodyweight, food intake, and grip-strength were recorded periodically. After 21 days, repeat micro-CT was performed. Gastrocnemius (GCM) and tibialis anterior (TA) muscles were resected. mRNA expression of MuRF1, Atrogin-1, myogenin, and MyoD was determined. RESULTS: NTB and TB + Q gained 9.4% and 5.3% bodyweight respectively, TB lost 3.9%. Hind limb skeletal muscle volume remained stable for NTB and TB + Q, whereas TB decreased from 242.0 mm3 to 212.8 mm3. Mean GCM muscle weight was 175.2 mg (NTB), 171.3 mg (TB + Q) versus 125.5 mg (TB). A tendency towards decreased expression of atrogin-1 and MuRF1 was observed in TB + Q. CONCLUSION: Dietary quercetin supplementation limits bodyweight loss and muscle wasting in the C26-cancer-associated cachexia model. [ABSTRACT FROM AUTHOR]

Background/objectives: Currently, there are no widely accepted cut-off points to categorize patients as sarcopenic (low skeletal muscle mass) or myosteatotic based on computed tomography (CT) measurements. Moreover, little is known about skeletal muscle mass in healthy subjects, particularly in a Western-European population.Subjects/methods: Skeletal muscle mass (skeletal muscle index, cm2/m2) and density (Hounsfield units, HU) at the level of the third lumbar vertebra were measured on contrast-enhanced CT images in live kidney donors with an age range of 18-86 years, who may be considered as healthy subjects, from 2010 to 2015. Differences between sex, body mass index (BMI), age groups, and American Society of Anesthesiologists (ASA) classification were assessed. Mann-Whitney U and Kruskal-Wallis tests were used to compare groups.Results: Of the 1073 included patients, 499 (46.5%) were male and the median age and BMI were 51 years and 25.4 kg/m2, respectively. Male gender, increased age, and increased BMI were significantly associated with both skeletal muscle mass and density. Nomograms including these parameters were developed to calculate the estimated skeletal muscle mass and density of a healthy subject and the lower bound of the 90% prediction interval (p5) values were provided.Conclusions: Skeletal muscle density and mass were significantly associated with sex, age, and BMI in a large cohort of healthy Western-European subjects. The newly developed nomograms may be used to calculate the estimated healthy skeletal muscle mass for individuals in patient populations. [ABSTRACT FROM AUTHOR]

Background: Low skeletal muscle mass is associated with increased postoperative morbidity and worse survival following resection for perihilar cholangiocarcinoma (PHC). We investigated the predictive value of skeletal muscle mass and density for overall survival (OS) of all patients with suspected PHC, regardless of treatment. Methods: Baseline characteristics and parameters regarding disease and treatment were collected from all patients with PHC from 2002 to 2014. Skeletal muscle mass and density were measured at the level of the third lumbar vertebra on CT. The association between skeletal muscle mass and density with OS was investigated using the Kaplan-Meier method and Cox survival. Results: Median OS in 233 included patients did not differ between those with and without low skeletal muscle mass (p = 0.203), whereas a significantly different median OS (months) was observed between patients with low (HR 7.0, 95% CI 4.7–9.3) and high (HR 12.1, 95% CI 8.1–16.1) skeletal muscle density (p = 0.004). Low skeletal muscle density was independently associated with decreased OS (HR 1.78, 95% CI 1.03–3.07, p = 0.040) within the first 6 months but not after 6 months (HR 0.68, 95% CI 0.44–1.07, p = 0.093), after adjusting for age, tumour size and suspected peritoneal or other distant metastases on imaging. Conclusion: A time-dependent effect of skeletal muscle density on OS was found in patients with PHC, regardless of subsequent treatment. Low skeletal muscle density may identify patients at risk for early death. [ABSTRACT FROM AUTHOR]

Summary: Low skeletal muscle mass (sarcopenia) is associated with increased morbidity and mortality in liver transplant candidates. We investigated the association between sarcopenia and hospital costs in patients listed for liver transplantation. Consecutive patients with cirrhosis listed for liver transplantation between 2007 and 2014 in a Eurotransplant centre were identified. The skeletal muscle index (SMI, cm2/m2) was measured on CT performed within 90 days from waiting list placement. The lowest sex‐spe cific quartile represented patients with sarcopenia. In total, 224 patients were included. Median time on the waiting list was 170 (IQR 47–306) days, and median MELD score was 16 (IQR 11–20). The median total hospital costs in patients with sarcopenia were €11 294 (IQR 3570–46 469) compared with €6878 (IQR 1305–20 683) in patients without sarcopenia (P = 0.008). In multivariable regression analysis, an incremental increase in SMI was significantly associated with a decrease in total costs (€455 per incremental SMI, 95% CI 11–900, P = 0.045), independent of the total time on the waiting list. In conclusion, sarcopenia is independently associated with increased health‐related costs for patients on the waiting list for liver transplantation. Optimizing skeletal muscle mass may therefore lead to a decrease in hospital expenditure, in addition to greater health benefit for the transplant candidate. [ABSTRACT FROM AUTHOR]

Background: Low skeletal muscle mass is associated with poor postoperative outcomes in cancer patients. Furthermore, it is associated with increased healthcare costs in the United States. We investigated its effect on hospital expenditure in a Western-European healthcare system, with universal access. Methods: Skeletal muscle mass (assessed on CT) and costs were obtained for patients who underwent curative-intent abdominal cancer surgery. Low skeletal muscle mass was defined based on pre-established cut-offs. The relationship between low skeletal muscle mass and hospital costs was assessed using linear regression analysis and Mann-Whitney U-tests. Results: 452 patients were included (median age 65, 61.5% males). Patients underwent surgery for colorectal cancer (38.9%), colorectal liver metastases (27.4%), primary liver tumours (23.2%), and pancreatic/periampullary cancer (10.4%). In total, 45.6% had sarcopenia. Median costs were €2,183 higher in patients with low compared with patients with high skeletal muscle mass (€17,144 versus €14,961; P<0.001). Hospital costs incrementally increased with lower sex-specific skeletal muscle mass quartiles (P = 0.029). After adjustment for confounders, low skeletal muscle mass was associated with a cost increase of €4,061 (P = 0.015). Conclusion: Low skeletal muscle mass was independently associated with increased hospital costs of about €4,000 per patient. Strategies to reduce skeletal muscle wasting could reduce hospital costs in an era of incremental healthcare costs and an increasingly ageing population. [ABSTRACT FROM AUTHOR]

Introduction. Surgery-induced oxidative stress increases the risk of perioperative complications and delay in postoperative recovery. In mice, short-term preoperative dietary and protein restriction protect against oxidative stress. We investigated the feasibility of a calorie- and protein-restricted diet in two patient populations. Methods. In this pilot study, 30 live kidney donors and 38 morbidly obese patients awaiting surgery were randomized into three groups: a restricted diet group, who received a synthetic liquid diet with 30% fewer calories and 80% less protein for five consecutive days; a group who received a synthetic diet containing the daily energy requirements (DER); and a control group. Feasibility was assessed using self-reported discomfort, body weight changes, and metabolic parameters in blood samples. Results. Twenty patients (71%) complied with the restricted and 13 (65%) with the DER-diet. In total, 68% of the patients reported minor discomfort that resolved after normal eating resumed. The mean weight loss on the restricted diet was significantly greater (2.4 kg) than in the control group (0 kg, p = 0.002), but not in the DER-diet (1.5 kg). The restricted diet significantly reduced levels of serum urea and plasma prealbumin (PAB) and retinol binding protein (RBP). Conclusions. A short-term preoperative calorie- and protein-restricted diet is feasible in kidney donors and morbidly obese patients. Compliance is high and can be objectively measured via changes in urea, PAB, and RBP levels. These results demonstrate that this diet can be used to study the effects of dietary restriction on surgery-induced oxidative stress in a clinical setting. [ABSTRACT FROM AUTHOR]

Background: The main limitation to the use of irinotecan in the treatment of colorectal cancer is the severity of side effects, including neutropaenia and diarrhoea. Here, we explored the effects of 3 days of fasting on irinotecan-induced toxicities, on plasma, liver and tumour pharmacokinetics and on anti-tumour activity in mice.Experimental Approach: Male BALB/c mice received C26 colon carcinoma cells subcutaneously. They were randomized 1:1 into equally sized ad libitum fed and fasted groups after which they were treated with irinotecan. Weight and adverse side effects were recorded daily. At the end of the experiment, tumours were resected and weighed, and concentrations of irinotecan and its active metabolite SN-38 were determined in plasma and tumour.Key Results: Fasting prevented the diarrhoea and visible signs of discomfort induced by irinotecan. Ad libitum fed animals developed leucopenia compared with untreated controls, whereas fasted mice did not. Irinotecan suppressed tumour growth equally in both treated groups, compared with untreated controls. Levels of the active irinotecan metabolite SN-38 9 (calculated as AUC values) were significantly lower in fasted mice in both plasma and liver, but not in tumour tissue.Conclusions and Implications: Fasting protected against irinotecan-induced side effects without interfering with its anti-tumour efficacy. Fasting induced a lower systemic exposure to SN-38, which may explain the absence of adverse side effects, while tumour levels of SN-38 remained unchanged. These data offer important new approaches to improve treatment with irinotecan in patients. [ABSTRACT FROM AUTHOR]

Preoperative fasting and dietary restriction offer robust protection against renal ischemia/reperfusion injury (I/RI) in mice. We recently showed that Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, plays a pivotal role in renal I/RI. Based on these findings, we investigated the effect of short-term DR (30% reduction of total food intake) or three days of water only fasting on MBL in 10–12 weeks old male C57/Bl6 mice. Both dietary regimens significantly reduce the circulating levels of MBL as well as its mRNA expression in liver, the sole production site of MBL. Reconstitution of MBL abolished the protection afforded by dietary restriction, whereas in the fasting group the protection persisted. These data show that modulation of MBL is involved in the protection against renal I/RI induced by dietary restriction, and suggest that the mechanisms of protection induced by dietary restriction and fasting may be different. [ABSTRACT FROM AUTHOR]

Since the discovery of microRNAs, ample research has been conducted to elucidate their involvement in an array of (patho)physiological conditions. Ischemia reperfusion injury is a major problem in kidney transplantation and its mechanism is still not fully known, nor is there an effective therapy. Furthermore, no biomarker is available to specifically measure (ischemic) damage after kidney transplantation or predict transplantation outcome. In this review, we summarize studies conducted on microRNAs in renal ischemia reperfusion injury and kidney transplantation. Although the number of publications on miRNAs in different areas of nephrology is increasing every year, only a limited number of reports that address the role of miRNAs in relation to ischemia reperfusion injury or kidney transplantation are available. All reports up to June 2014 on microRNAs in renal IRI, kidney transplantation, and renal allograft status were included. Design of the studies was highly variable and there was limited overlap between microRNAs found in these reports. No single microRNA expression pattern could be found, although multiple microRNAs involved in the immune response seem to be altered after ischemia reperfusion injury and kidney transplantation. Although there is a growing interest in microRNA research in kidney transplantation aiming to identify biomarkers and therapeutical targets, to date, no specific microRNA has been demonstrated to be applicable as either one, mostly because of lack of specificity. More systematical research is needed to determine whether microRNAs can be applied as biomarker, therapeutic target, or therapeutic agent in kidney transplantation. [ABSTRACT FROM AUTHOR]

Circadian clock genes regulate 10-15% of the transcriptome, and might function as tumor suppressor genes. Relatively little is known about the circadian clock in tumors and its effect on surrounding healthy tissues. Therefore, we compared the 24-hr expression levels of key circadian clock genes in liver and kidney of healthy control mice with those of mice bearing C26 colorectal tumor metastases in the liver. Metastases were induced by injection of C26 colorectal carcinoma cells into the spleen. Subsequently, tumor, liver and kidney tissue was collected around the clock to compare circadian rhythmicity. Expression levels of five clock genes ( Rev-Erbα, Per1, Per2, Bmal1 and Cry1) and three clock-controlled genes (CCGs; Dbp, p21 and Wee1) were determined by qRT-PCR. Liver and kidney tissue of healthy control mice showed normal 24-hr oscillations of all clock genes and CCGs, consistent with normal circadian rhythmicity. In colorectal liver metastases, however, 24-hr oscillations were completely absent for all clock genes and CCGs except Cry1. Liver and kidney tissue of tumor-bearing mice showed a shift in clock periodicity relative to control mice. In the liver we observed a phase advance, whereas in the kidney the phase was delayed. These data show that hepatic metastases of C26 colon carcinoma with a disrupted circadian rhythm phase shift liver and kidney tissue clocks, which strongly suggests a systemic effect on peripheral clocks. The possibility that tumors may modify peripheral clocks to escape from ordinary circadian rhythms and in this way contribute to fatigue and sleep disorders in cancer patients is discussed. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injury (IRI) is inevitable during kidney transplantation leading to oxidative stress and inflammation. We previously reported that preoperative fasting in young-lean male mice protects against IRI. Since patients are generally of older age with morbidities possibly leading to a different response to fasting, we investigated the effects of preoperative fasting on renal IRI in aged-overweight male and female mice. Male and female F1-FVB/C57BL6-hybrid mice, average age 73 weeks weighing 47.2 grams, were randomized to preoperative ad libitum feeding or 3 days fasting, followed by renal IRI. Body weight, kidney function and survival of the animals were monitored until day 28 postoperatively. Kidney histopathology was scored for all animals and gene expression profiles after fasting were analyzed in kidneys of young and aged male mice. Preoperative fasting significantly improved survival after renal IRI in both sexes compared with normal fed mice. Fasted groups had a better kidney function shown by lower serum urea levels after renal IRI. Histopathology showed less acute tubular necrosis and more regeneration in kidneys from fasted mice. A mRNA analysis indicated the involvement of metabolic processes including fatty acid oxidation and retinol metabolism, and the NRF2-mediated stress response. Similar to young-lean, healthy male mice, preoperative fasting protects against renal IRI in aged-overweight mice of both genders. These findings suggest a general protective response of fasting against renal IRI regardless of age, gender, body weight and genetic background. Therefore, fasting could be a non-invasive intervention inducing increased oxidative stress resistance in older and overweight patients as well. [ABSTRACT FROM AUTHOR]

Dietary restriction (DR) delays ageing and extends life span. Both long- and short-term DR, as well as short-term fasting provide robust protection against many “neuronal and surgery related damaging phenomena” such as Parkinson’s disease and ischemia-reperfusion injury. The exact mechanism behind this phenomenon has not yet been elucidated. Its anti-inflammatory actions prompted us to thoroughly investigate the consequences of DR and fasting on B and T cell compartments in primary and secondary lymphoid organs of male C57Bl/6 mice. In BM we found that DR and fasting cause a decrease in the total B cell population and arrest early B cell development, while increasing the number of recirculating mature B cells. In the fasting group, a significant reduction in peripheral B cell counts was observed in both spleen and mesenteric lymph nodes (mLN). Thymopoiesis was arrested significantly at double negative DN2 stage due to fasting, whereas DR resulted in a partial arrest of thymocyte development at the DN4 stage. Mature CD3+ T cell populations were increased in BM and decreased in both spleen and mLN. Thus, DR arrests B cell development in the BM but increases the number of recirculating mature B cells. DR also arrests maturation of T cells in thymus, resulting in depletion of mature T cells from spleen and mLN while recruiting them to the BM. The functional relevance in relation to protection against organ damage needs to be determined. [ABSTRACT FROM AUTHOR]

Focal segmental glomerulosclerosis (FSGS) is a kidney disease with progressive glomerular scarring and a clinical presentation of nephrotic syndrome. FSGS is a common primary glomerular disorder that causes renal dysfunction which progresses slowly over time to end-stage renal disease. Most cases of FSGS are idiopathic Although kidney transplantation is a potentially curative treatment, 40% of patients have recurrence of FSGS after transplantation. In this review a brief summary of the pathogenesis causing FSGS in humans is given, and a variety of animal models used to study FSGS is discussed. These animal models include the reduction of renal mass by resecting 5/6 of the kidney, reduction of renal mass due to systemic diseases such as hypertension, hyperlipidemia or SLE, drug-induced FSGS using adriamycin, puromycin or streptozotocin, virus-induced FSGS, genetically-induced FSGS such as via Mpv-17 inactivation and α-actinin 4 and podocin knockouts, and a model for circulating permeability factors. In addition, an animal model that spontaneously develops FSGS is discussed. To date, there is no exact understanding of the pathogenesis of idiopathic FSGS, and there is no definite curative treatment. One requirement facilitating FSGS research is an animal model that resembles human FSGS. Most animal models induce secondary forms of FSGS in an acute manner. The ideal animal model for primary FSGS, however, should mimic the human primary form in that it develops spontaneously and has a slow chronic progression. Such models are currently not available. We conclude that there is a need for a better animal model to investigate the pathogenesis and potential treatment options of FSGS. [ABSTRACT FROM AUTHOR]

van Ginhoven TM, de Bruin RWF, Timmermans M, Mitchell JR, Hoeijmakers JHJ, IJzermans JNM. Preoperative dietary restriction is feasible in live kidney donors. Clin Transplant 2011: 25: 486-494. © 2010 John Wiley & Sons A/S. Dietary restriction (DR), defined as reduced energy intake without malnutrition, confers protection against renal ischemia and reperfusion injury in animal models. This pilot study investigates for the first time the feasibility of pre-operative DR in the clinical setting. Live-kidney donors were randomized between pre-operative DR or ad libitum intake. Seventeen participants were instructed to follow a 30% calorie-restricted diet, followed by one day of water-only fasting prior to surgery. Thirteen participants were allowed to eat ad libitum pre-operatively. Ninety-four percent of the donors adhered to the diet, 31.4% reduction in caloric intake was achieved. Post-operative well-being, appetite and ability to perform daily tasks were not different between both groups. There was no difference in post-transplant graft function of kidneys obtained from DR donors or control donors as determined by serum creatinine levels during the first post-operative month and renograms at post-operative day one. This study shows that mild dietary restriction is feasible in the setting of live-kidney donation. No effect was observed regarding post-operative graft function. Additional studies are warranted to investigate the appropriate regimen of dietary restriction to protecting against ischemia and reperfusion injury, such as increasing the magnitude and/or duration of the reduction in daily caloric intake. [ABSTRACT FROM AUTHOR]

Summary Three days of fasting protects mice against lethal renal ischemia-reperfusion (I/R) injury. We hypothesize that the protection imposed by fasting is mediated by increased levels of corticosterone, induced by the stress of food deprivation. C57Bl/6 mice were fasted for 3 days after which serum corticosterone levels were determined. Mice underwent a bilateral adrenalectomy (ADX). Ten days later, they were either fasted or given a corticosterone receptor antagonist while fasting. Bilateral renal I/R injury was induced by clamping the artery and vein of the left and right kidney simultaneously for 37 min. Survival and kidney function were determined. Fasting significantly increased corticosterone levels. Only 8% of the ADX mice which were fasted prior to I/R injury survived, whereas all sham-ADX operated mice survived I/R injury after fasting. After ADX and fasting, 70% of the mice subjected to sham I/R succumbed to the surgical procedure. After fasting with concomitant blockade of the glucocorticoid receptor all animals survived renal I/R. Three days of fasting protects against I/R injury and increases serum corticosterone levels. ADX renders mice incapable of withstanding subsequent abdominal surgery. Glucocorticoid receptor blockade does not interfere with the protective effects of fasting. Thus, the protection against renal I/R injury induced by preoperative fasting is mediated by corticosterone-independent mechanisms. [ABSTRACT FROM AUTHOR]

Dietary restriction (DR) extends lifespan and increases resistance to multiple forms of stress, including ischemia reperfusion injury to the brain and heart in rodents. While maximal effects on lifespan require long-term restriction, the kinetics of onset of benefits against acute stress is not known. Here, we show that 2–4 weeks of 30% DR improved survival and kidney function following renal ischemia reperfusion injury in mice. Brief periods of water-only fasting were similarly effective at protecting against ischemic damage. Significant protection occurred within 1 day, persisted for several days beyond the fasting period and extended to another organ, the liver. Protection by both short-term DR and fasting correlated with improved insulin sensitivity, increased expression of markers of antioxidant defense and reduced expression of markers of inflammation and insulin/insulin-like growth factor-1 signaling. Unbiased transcriptional profiling of kidneys from mice subject to short-term DR or fasting revealed a significant enrichment of signature genes of long-term DR. These data demonstrate that brief periods of reduced food intake, including short-term daily restriction and fasting, can increase resistance to ischemia reperfusion injury in rodents and suggest a rapid onset of benefits of DR in mammals. [ABSTRACT FROM AUTHOR]

Background. We have previously reported that small synthetic oligopeptides related to human β-chorionic gonadotropin (β-hCG) can reduce inflammation. Here we investigated whether such oligopeptides can reduce renal ischaemia-reperfusion injury in the mouse. [ABSTRACT FROM PUBLISHER]

Angiotensin (Ang) II mediates pathophysiologial changes in the kidney. Ang-(1-7) by interacting with the G protein-coupled receptor Mas may also have important biological activities. In this study, renal deficiency for Mas diminished renal damage in models of renal insufficiency as unilateral ureteral obstruction and ischemia/reperfusion injury while the infusion of Ang-(1-7) to wild-type mice pronounced the pathological outcome by aggravating the inflammatory response. Mas deficiency inhibited NF-κB activation and thus the elevation of inflammation-stimulating cytokines, while Ang-(1-7) infusion had proinflammatory properties in experimental models of renal failure as well as under basal conditions. The Ang-(1-7)-mediated NF-κB activation was Mas dependent but did not involve Ang II receptors. Therefore, the blockade of the NF-κB-activating properties of the receptor Mas could be a new strategy in the therapy of failing kidney. [ABSTRACT FROM AUTHOR]

Cockayne syndrome and other segmental progerias with inborn defects in DNA repair mechanisms are thought to be due in part to hypersensitivity to endogenous oxidative DNA damage. The accelerated aging-like symptoms of this disorder include dysmyelination within the central nervous system, progressive sensineuronal hearing loss and retinal degeneration. We tested the effects of congenital nucleotide excision DNA repair deficiency on acute oxidative stress sensitivity in vivo. Surprisingly, we found mouse models of Cockayne syndrome less susceptible than wild type animals to surgically induced renal ischemia reperfusion injury, a multifactorial injury mediated in part by oxidative damage. Renal failure-related mortality was significantly reduced in Csb−/– mice, kidney function was improved and proliferation was significantly higher in the regenerative phase following ischemic injury. Protection from ischemic damage correlated with improved baseline glucose tolerance and insulin sensitivity and a reduced inflammatory response following injury. Protection was further associated with genetic ablation of a different Cockayne syndrome-associated gene, Csa. Our data provide the first functional in vivo evidence that congenital DNA repair deficiency can induce protection from acute stress in at least one organ. This suggests that while specific types of unrepaired endogenous DNA damage may lead to detrimental effects in certain tissues, they may at the same time elicit beneficial adaptive changes in others and thus contribute to the tissue specificity of disease symptoms. [ABSTRACT FROM AUTHOR]

The presence of phased protoporphyrin IX (PpIX) bleach kinetics has been shown to correlate with esophageal response to 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) in animal models. Here we confirm the existence of phased PpIX photobleaching by increasing the temporal resolution of the fluorescence measurements using the therapeutic illumination and long wavelength fluorescence detection. Furthermore fluorescence differential pathlength spectroscopy (FDPS) was incorporated to provide information on the effects of PpIX and tissue oxygenation distribution on the PpIX bleach kinetics during illumination. ALA at a dose of 200 mg kg−1 was orally administered to 15 rats, five rats served as control animals. PDT was performed at an in situ measured fluence rate of 75 mW cm−2 using a total fluence of 54 J cm−2. Forty-eight hours after PDT the esophagus was excised and histologically examined for PDT-induced damage. Fluence rate and PpIX photobleaching at 705 nm were monitored during therapeutic illumination with the same isotropic probe. A new method, FDPS, was used for superficial measurement on saturation, blood volume, scattering characteristics and PpIX fluorescence. Results showed two-phased PpIX photobleaching that was not related to a (systematic) change in esophageal oxygenation but was associated with an increase in average blood volume. PpIX fluorescence photobleaching measured using FDPS, in which fluorescence signals are only acquired from the superficial layers of the esophagus, showed lower rates of photobleaching and no distinct phases. No clear correlation between two-phased photobleaching and histologic tissue response was found. This study demonstrates the feasibility of measuring fluence rate, PpIX fluorescence and FDPS during PDT in the esophagus. We conclude that the spatial distribution of PpIX significantly influences the kinetics of photobleaching and that there is a complex interrelationship between the distribution of PpIX and the supply of oxygen to the illuminated tissue volume. [ABSTRACT FROM AUTHOR]

Background: Lung ischemia-reperfusion injury (LIRI) is suggested to be a major risk factor for development of primary acute graft failure (PAGF) following lung transplantation, although other factors have been found to interplay with LIRI. The question whether LIRI exclusively results in PAGF seems difficult to answer, which is partly due to the lack of a long-term experimental LIRI model, in which PAGF changes can be studied. In addition, the long-term effects of LIRI are unclear and a detailed description of the immunological changes over time after LIRI is missing. Therefore our purpose was to establish a long-term experimental model of LIRI, and to study the impact of LIRI on the development of PAGF, using a broad spectrum of LIRI parameters including leukocyte kinetics. Methods: Male Sprague-Dawley rats (n = 135) were subjected to 120 minutes of left lung warm ischemia or were sham-operated. A third group served as healthy controls. Animals were sacrificed 1, 3, 7, 30 or 90 days after surgery. Blood gas values, lung compliance, surfactant conversion, capillary permeability, and the presence of MMP-2 and MMP-9 in broncho-alveolar-lavage fluid (BALf) were determined. Infiltration of granulocytes, macrophages and lymphocyte subsets (CD45RA+, CD5+CD4+, CD5+CD8+) was measured by flowcytometry in BALf, lung parenchyma, thoracic lymph nodes and spleen. Histological analysis was performed on HE sections. Results: LIRI resulted in hypoxemia, impaired left lung compliance, increased capillary permeability, surfactant conversion, and an increase in MMP-2 and MMP-9. In the BALf, most granulocytes were found on day 1 and CD5+CD4+ and CD5+CD8+-cells were elevated on day 3. Increased numbers of macrophages were found on days 1, 3, 7 and 90. Histology on day 1 showed diffuse alveolar damage, resulting in fibroproliferative changes up to 90 days after LIRI. Conclusion: The short-, and long-term changes after LIRI in this model are similar to the changes found in both PAGF and ARDS after clinical lung transplantation. LIRI seems an independent risk factor for the development of PAGF and resulted in progressive deterioration of lung function and architecture, leading to extensive immunopathological and functional abnormalities up to 3 months after reperfusion. [ABSTRACT FROM AUTHOR]

Background. Chronic allograft nephropathy (CAN) is the single most important cause of late graft loss. Histologic signs of CAN overlap with the histology of normally ageing kidneys. Clinical observations show an inverse relationship between either donor age or ischemia time and long-term graft survival. The mechanisms by which donor age or ischemia lead to reduced functional lifespan are currently unknown. Material and methods. A review of the current literature on renal transplantation, ageing mechanisms and advances in the molecular pathogenesis of CAN was performed. Results and conclusions. Ischemia time and donor age have been identified as major allo-antigen-independent risk factors. Following transplantation, reactive oxygen species cause oxidative DNA and telomeric damage. Evidence for a molecular connection between oxidative DNA damage and ageing has increased, and suggests that the mechanisms causing normal ageing and long-term organ dysfunction may be fundamentally the same. The accelerated appearance of ageing phenotypes in transplanted organs has been shown in several studies. Together with the deleterious ongoing allogeneic immune response of the recipient, this leads to accelerated exhaustion of the regenerative capacity of the kidney, and eventually to dysfunction of the renal allograft. [ABSTRACT FROM AUTHOR]

Background: The insufflation of cold gas during laparoscopic surgery exposes patients to the risk for hypothermia. The objectives of this study were to investigate whether heating or humidification of insufflation gas could prevent peroperative hypothermia in a rat model, and to assess whether the peritoneum was affected by heating or humidification of the insufflation gas. Methods: Rats were exposed to insufflation with either cold, dry carbon dioxide (CO[sub 2]) (group I); cold, humidified CO[sub 2] (group II); warm, dry CO[sub 2] (group III); or warm, humidified CO[sub 2] (group IV); another group underwent gasless laparoscopy (group V). Core temperature and intraperitoneal temperature were registered in all animals during 120 minutes. Specimens of the parietal peritoneum were taken directly after desufflation and 2 and 24 hours after the procedure. All specimens were analyzed with scanning electron microscopy (SEM). Results: During the 120-minute study period, core temperature and intraperitoneal temperature were significantly reduced in groups I, II, and III. In the animals that underwent warm, humidified insufflation (group IV) and the gasless controls (group V), intraoperative hypothermia did not develop. At SEM, retraction and bulging of mesothelial cells and exposure of the basal lamina were seen in the four insufflation groups (groups I-IV) and also in the gasless controls (group V). Conclusion: Insufflation with cold, dry CO[sub 2] may lower the body temperature during laparoscopic surgery. Hypothermia can be prevented by both heating and humidifying the insufflation gas. Changes of the peritoneal surface occur after CO[sub 2] insufflation, despite heating or humidifying, and also after gasless surgery. [ABSTRACT FROM AUTHOR]

Compares the efficacy of human decay-accelerating factor (hDAF) transgenesis in preventing hyperacute xenografts rejection (HAR). Transplantation of hDAF rat hearts into cynomolgus monkeys; Effect of high serum concentrations on the perfusion of mouse hearts; Inhibition of HAR.

Long-term survival of small bowel transplants ishampered by chronic rejection. Epidermal growth factor(EGF) and transforming growth factor β (TGF-β)have opposing, regulatory roles in normal intestinal physiology and may be involved in thepathogenesis of chronic intestinal rejection. Our aimwas to investigate the expression of EGF andTGF-β1 in chronically rejecting smallbowel transplants. Orthotopic small bowel transplantation was performed inthe allogeneic DA-to-AS rat combination; Cyclosporin wasadministered temporarily to prevent acute rejection.Controls were DA isografts and normal DA rats. PreproEGF and TGF-β1 geneexpression was evaluated by northern blot analysis ofthe ileum RNA and standardized againstglyceraldehyde-3-phosphate-dehydrogenase expression.Allografts demonstrated functional impairment and histological features of chronicrejection, whereas isografts appeared normal. Allograftsdemonstrated a significant reduction of EGF mRNA whencompared to DA isografts. No significant changes were detected in TGF-β1expression in either allogeneic or syngeneic grafts. Inconclusion, this study demonstrates reduced preproEGFand preserved TGF-β1 gene expression inchronically rejecting small bowel transplants. [ABSTRACT FROM AUTHOR]

Besides esophagectomy and antireflux therapy with intensive endoscopic surveillance, endoscopic ablation therapy is a new treatment modality for Barrett's esophagus (BE) with high-grade dysplasia (HGD). Endoscopic surgical ablation can be performed by either a thermal, chemical, or mechanical method. This article describes the current management of patients with BE and HGD and the various methods of endoscopic ablation, including multipolar electrocoagulation, argon plasma beam coagulation, contact laser photoablation, and photodynamic therapy. It also summarizes the results of 37 patient studies, case reports, and abstracts on experimental endoscopic therapies for BE. The advantages and disadvantages of the various treatment possibilities are considered, and the future direction of the management of BE is discussed. [ABSTRACT FROM AUTHOR]