Blood coagulation, fibrinolytic and inhibitory profiles in renal transplant recipients: comparison of cyclosporine and azathioprine.

Renal transplant recipients treated with cyclosporine (CS) have been reported to be at increased risk of thrombotic complications. The present study was intended to examine the blood coagulation, fibrinolytic, and inhibitory systems in such patients. Eight transplant recipients on maintenance immunosuppression with CS and prednisone were studied. Five transplant recipients maintained on azathioprine (AZA) and prednisone and 32 normal volunteers served as controls. Plasma antigen concentrations and/or activities of various proteins in the above pathways were measured. Both the CS and AZA groups exhibited significant elevations of factor IX activity, von Willebrand factor (vWF), D-dimer, protein C and tissue type plasminogen activator (t-PA) levels when compared with the normal controls. In addition, CS group showed a significant elevation of alpha 2-macroglobulin activity and AZA group showed a significant reduction in factor XII activity when compared with the normal controls. Comparison of data from CS and AZA groups revealed higher factor XII activity and vWF concentration in the former group. In conclusion, transplant recipients treated with long-term cyclosporine and prednisone exhibited significant elevation of plasma vWF, D-dimer and protein C concentrations. In addition, both CS and AZA-treated transplant recipients showed increased plasma concentrations of D-dimer and t-PA. The latter observations suggest in vivo thrombin generation, fibrin formation and degradation.     

Gene expression of LDL receptor, HMG-CoA reductase, and cholesterol-7 alpha-hydroxylase in chronic renal failure

BACKGROUND: Chronic renal failure (CRF) is associated with an atherogenic lipid profile and an increased risk of ischaemic cardiovascular disease. The associated hyperlipidaemia is reportedly ameliorated by erythropoietin (Epo) therapy. According to a recent report, rats studied 3 weeks after 5/6 nephrectomy and fed a high- protein diet exhibited increased activities of hepatic HMG-CoA reductase (HMG-CoAR) and cholesterol 7 alpha-hydroxylase (Ch-7 alpha- H), despite normal corresponding mRNA values. DESIGN AND METHODS: This study was designed to examine the effects of naturally progressing CRF of longer duration as well as those of Epo therapy on gene expressions of the key factors involved in hepatic cholesterol metabolism, i.e., LDL receptor (LDLR), HMG-CoAR, and Ch-7 alpha-H. Sprague-Dawley rats were randomized to the CRF group (5/6 nephrectomy), Epo-treated CRF group (given Epo 150 U/kg/twice weekly) and sham-operated, placebo- treated normal controls. They were allowed free access to regular rat chow and studied 6 weeks after surgery. Liver mRNAs and protein mass or activities of the above factors were studied. RESULTS: Plasma cholesterol concentration was significantly increased in the CRF group (P < 0.001) and was modestly lowered (P < 0.05) by Epo therapy. However, microsomal cholesterol concentration and LDLR, HMG-CoAR, and Ch-7 alpha-H mRNA as well as HMG-CoAR activity, and Ch-7 alpha-H and LDLR protein mass measurements were virtually identical in the three groups. Thus, hepatic LDLR, HMG-CoAR, and Ch-7 alpha-H mRNA and protein measurements in rats with CRF were similar to those of the normal control group representing an inappropriate response to the associated hypercholesterolemia. Epo therapy led to partial amelioration of CRF- associated hypercholesterolaemia with no discernible effect on hepatic tissue expression of the above factors.      

Pancreatic pathology in chronic dialysis patients--an autopsy study of 78 cases

Autopsy data from 78 patients with end-stage renal disease (ESRD) treated with long-term hemodialysis were examined. Various pancreatic abnormalities were found in 47 (60%) patients. The most prevalent abnormality was pancreatitis which was seen in 22 patients (28%). Other lesions found with considerable frequency included fibrosis, hemosiderin deposits, calcification, cystic changes, amyloidosis and abscess formation. In addition hyalinization, atrophy or absence of islands of Langerhans and necrosis of peripancreatic fat were seen in several cases and inspissated secretions, focal ductular epithelial metaplasia and dilatation were noted in some patients. Comparison of the present data with those of a large survey of ESRD patients conducted prior to dialysis era indicates a considerable increase in the prevalence of pancreatic pathology in ESRD patients sustained by long-term hemodialysis treatment.     

Association of renal injury with increased oxygen free radical activity and altered nitric oxide metabolism in chronic experimental hemosiderosis

Chronic iron (Fe) overload is associated with a marked increase in renal tissue iron content and injury. It is estimated that 10% of the American population carry the gene for hemochromatosis and 1% actually suffer from iron overload. The mechanism of iron overload-associated renal damage has not been fully elucidated. Iron can accelerate lipid peroxidation leading to organelle membrane dysfunction and subsequent cell injury/death. Iron-catalyzed generation of reactive oxygen species (ROS) is responsible for initiating the peroxidatic reaction. We investigated the possible association of oxidative stress and its impact on nitric oxide (NO) metabolism in iron-overload-associated renal injury. Rats were randomized into Fe-loaded (given 0.5 g elemental iron/kg body weight as iron dextran; i.v.), Fe-depleted (given an iron-free diet for 20 weeks), and control groups. Renal histology, tissue expression of endothelial and inducible nitric oxide synthases (eNOS and iNOS), renal tissue expression of nitrotyrosine, plasma, and renal tissue lipid peroxidation product, malondialdehyde (MDA), and plasma and urinary NO metabolites (NOx) were examined. Iron overload was associated with mild proteinuria, tissue iron deposition together with significant glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Rare focal glomerulosclerosis and tubulointerstitial changes were noted in normal controls. No renal lesions were observed in Fe-depleted rats. Iron deposits were seen in glomeruli, proximal tubules, and interstitium. The iron staining in the distal tubules was negligible. Both plasma and renal tissue MDA and renal tissue nitrotyrosine were increased significantly in Fe-loaded rats compared with control rats. In contrast, Fe-depleted animals showed a marked reduction in plasma and renal tissue MDA and nitrotyrosine together with significant elevation of urinary NOx excretion. In addition, iron-overload was associated with up-regulation of renal eNOS and iNOS expressions when compared with the control and Fe-depleted rats that showed comparable values. In conclusion, chronic iron overload resulted in iron deposition in the glomeruli and proximal tubules with various renal lesions and evidence of increased ROS activity, enhanced ROS-mediated inactivation, and sequestration of NO and compensatory up-regulation of renal eNOS and iNOS expressions. However, iron depletion was associated with reduced MDA and tissue nitrotyrosine abundance, increased urinary NOx excretion, normal nitric oxide synthase (NOS) expression, and absence of renal injury. These findings point to the possible role of ROS in chronic iron overload-induced renal injury.     

Pathology of digestive organs in renal transplant recipients

A necropsy study of the pathological findings in the digestive system of 19 renal transplant recipients revealed that gastrointestinal (GI), hepatobiliary, and pancreatic pathologies are common in renal transplant recipients. Fifteen of the 19 patients studied had GI pathology. Hepatobiliary pathology was the most common finding with all but one of the 19 cases exhibiting one or more abnormalities. Pancreatic abnormalities were less frequent with 11 patients demonstrating normal findings.     

Characteristics of the transport of oxalate and other ions across rabbit proximal colon

In order to characterize oxalate handling by the P2 segment of the rabbit proximal colon, the fluxes of [¹⁴C]oxalate, ²²Na⁺, and ³⁶Cl^– were measured in vitro using conventional short-circuiting techniques. In standard buffer the proximal colon exhibited net secretion of Na⁺ (–2.31±0.64 equiv cm^–2 h^–1), negligible net Cl^– transport, and net secretion of oxalate (–12.7±1.6 pmol cm^–2 h^–1). Replacement of buffer Na⁺ or Cl^– abolished net oxalate secretion, while HCO ₃ ^– -free media revealed a net absorption of oxalate (19.3±4.2 pmol cm^–2 h^–1) and stimulated NaCl absorption. Mucosal amiloride and dimethylamiloride (1 mM) significantly reduced the unidirectional fluxes of oxalate and enhanced sodium secretion by decreasing J _ms ^Na . The anion exchange inhibitor 4,4-diisothiocyanatostilbene-2,2-disulfonic acid (DIDS; 0.1 mM, both sides) reduced the unidirectional fluxes of oxalate and chloride. Serosal epinephrine (50 M) stimulated oxalate absorption (21.3±6.3 pmol cm^–2 h^–1) and sodium absorption (5.71±1.20 equiv cm^–2 h^–1), whereas dibutyryl-cAMP enhanced oxalate secretion (–43.4±6.9 pmol cm^–2 h^–1) and stimulated chloride secretion (–7.27 ±0.64 equiv cm^–2 h^–1). These results indicate that the P2 segment of the proximal colon possesses (a) secretory as well as absorptive capacities, (b) oxalate fluxes that are mediated by pathways involving Na⁺, Cl^–, HCO ₃ ^– transport and (c) a net oxalate flux that is sensitive to absorptive and secretory stimuli.     

Intraoperative small bowel length measurements and analysis of demographic predictors of increased length

Few studies have measured small bowel length (SBL) in live humans and many textbooks base their “normal” SBL values on cadaver data. Here, we present a series of intraoperative SBL measurements and analyze predictors of increased length. SBL from ligament of Treitz to ileocecal valve was measured in patients undergoing laparotomy for colorectal resection. Patients with Crohn's disease and those who had undergone prior bowel resections were excluded. In the 240 patients studied, mean SBL was 506 ± 105 (285–845) cm. Height was positively associated with increased SBL (P < 0.001) and men had longer SBL than women (533 vs. 482 cm, P < 0.001). A multivariate linear regression model using patient sex, age, height and weight was significant (P = 0.001) and the predictors explained 8% of the variance in SBL. In this model, only height was independently predictive of increased SBL (P = 0.03). Correlation results differed between sexes. In men, height correlated with increased SBL (r = 0.20; P = 0.03), whereas in women it did not. In men, age had a positive correlation with SBL at a trend level (r = 0.17; P = 0.08), whereas in women age had a negative correlation with SBL (r = ?0.18; P = 0.04). The mean SBL was 506 cm in live patients, as compared with the 600–700 cm range derived from prior cadaver studies. Male sex and height had positive correlations with SBL. SBL may decrease with age in women but not in men. Clin. Anat. 26:827–832, 2013. © 2013 Wiley Periodicals, Inc.     

Treatment of chronic diarrhoea

The treatment of chronic diarrhoea can be challenging. While Oral Rehydration Solution is an important step in treating diarrhoeal illnesses, various medications can be used to alleviate the symptoms while the patient is undergoing diagnostic work up or to target the underlying mechanism responsible for their diarrhoea. Medications are also being prescribed in cases when there is a strong suspicious about a diagnosis or when there is no specific treatment for an underlying aetiology. This chapter discusses the treatment options for diarrhoeal disorders.     

An introduction for the special issue on environmental health and genome integrity

Environmental exposures and genome maintenance mechanisms that respond to environmentally-induced genotoxicity have a profound impact on human health. Eight review articles in this Special Issue (SI) titled “Environmental Health and Genome Integrity” describe emerging new mechanisms by which distinct forms of environmentally-induced DNA damage are remediated, and explain how DNA repair pathway choices impact genome integrity and disease propensity. Here, we provide an introduction to reviews from this SI. Our expanding knowledge of how genotoxic exposures impact the genome will allow us to better predict, prevent and treat environmentally-induced human diseases such as cancer and neurodegenerative disorders.