The MUTYH hotspot mutations p.G396D and p.Y179C do not cause substantial genetic susceptibility to biliary cancer

Inflammation-associated oxidative stress and DNA damage are involved in malignant transformation of cholangiocytes. Defective DNA repair mechanisms may predispose to cholangiocarcinoma (CCA) formation, and an elevated CCA risk for MutY human homologue (MUTYH) germline mutation carriers has been proposed previously. The aim of this study was to re-evaluate the MUTYH hotspot mutations p.Y179C (rs34612342) and p.G396D (rs36053993) as genetic susceptibility factors in a large CCA cohort. The study population consisted of 219 Caucasian CCA patients (66.2 ± 11.9 years, 130 males, 89 females; 43 intrahepatic and 176 extrahepatic tumours; tissue diagnosis in 77.6 %) and 355 healthy controls (61.0 ± 11.0 years; 158 males, 197 females). MUTYH hotspot variants were genotyped using TaqMan assays. Four CCA patients were monoallelic mutation carriers (3 p.G396D; 1 p.Y179C) whereas 6 control subjects were heterozygotes (5 p.G396D; 1 p.Y179C). None of the patients carried a biallelic hotspot mutation. The observed allele frequencies did not differ significantly between cases and controls (p > 0.05) and association tests did not provide evidence for an involvement of p.Y179C (OR 1.6 [95 % CI 0.1–26.0]) or p.G396D (OR 1.0 [95 % CI 0.2–4.1]) in the susceptibility to CCA. Power analysis identified a sufficient power only for large effect sizes (>90 % for OR > 5.8 for p.G396D and OR > 18.5 for p.Y179C). Monoallelic MUTYH hotspot mutations do not act as major genetic susceptibility factors causing a substantial CCA risk in the Caucasian population. Due to the low statistical power for the identification of small effect sizes, much larger studies will be needed to detect such effects of minor clinical significance.     

Clinical and prognostic value of advanced glycation end-products in chronic heart failure.

AIMS: Advanced glycation end-products (AGEs) have been proposed as a novel factor involved in the development and progression of chronic heart failure (CHF). We aimed to determine whether plasma levels of N(epsilon)-(carboxymethyl)lysine (CML) and N(epsilon)-(carboxyethyl)lysine (CEL), two well-known AGEs, are related to the severity and prognosis of CHF. METHODS AND RESULTS: A total of 102 CHF patients, aged 58 +/- 12 years, with an average left ventricular ejection fraction of 28 +/- 9% were followed for 1.7 (1.2-1.9) years. NYHA functional class and NT-pro-BNP were used as estimates of the severity of CHF. CML and CEL were determined by LC-MS/MS. CML levels were associated with NYHA functional class (P < 0.001) and NT-pro-BNP levels (P < 0.001). Survival analysis for the combined end-point of death, heart transplantation, ischaemic cardiovascular event, and hospitalization for heart failure revealed that CML levels predicted outcome, even after adjustment for age, gender, aetiology of CHF, identified risk modifiers, and several known predictors of outcome in CHF. The predictive value of CML subsided after correction for renal function. CEL was not associated with the severity or prognosis of CHF. CONCLUSION: Plasma AGEs, in particular CML levels, are related to the severity and prognosis of CHF. The fact that the relation between CML and prognosis subsided after correction for renal function may suggest that AGE accumulation in renal failure explains part of the prognostic value of renal function in CHF. However, further investigation is warranted to exclude the possibility that CML is just an innocent marker of renal function.     

Renal Effects of Aliskiren Compared With and in Combination With Irbesartan in Patients With Type 2 Diabetes, Hypertension, and Albuminuria

OBJECTIVE

We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination.

RESEARCH DESIGN AND METHODS

This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR).

RESULTS

Placebo geometric mean albuminuria was 258 mg/day (range 84–2,361), mean ± SD 24-h blood pressure was 140/73 ± 15/8 mmHg, and GFR was 89 ± 27 ml/min per 1.73 m². Aliskiren treatment reduced albuminuria by 48% (95% CI 27–62) compared with placebo (P < 0.001), not significantly different from the 58% (42–79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59–79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3–8.8) ml/min per 1.73 m² by aliskiren, 8.0 (3.6–12.3) ml/min per 1.73 m² by irbesartan, and 11.7 (7.4–15.9) ml/min per 1.73 m² by the combination.

CONCLUSIONS

The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.Albuminuria is the best available surrogate parameter in the treatment of diabetic nephropathy. Degree of proteinuria is associated with risk of renal and cardiovascular events (1). Proteinuria reduction is associated with a slowing of the decline in renal function (2). Blockade of the renin-angiotensin-aldosterone system (RAAS) is the cornerstone treatment of incipient and overt diabetic nephropathy, and in type 2 diabetes angiotensin II receptor blockers (ARBs) such as irbesartan are considered standard treatment after the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA) 2 Study (3) and Irbesartan Diabetic Nephropathy Trial (IDNT) (1).Aliskiren represents a new principle of blocking the RAAS, inhibiting renin directly and acting at the rate-limiting step. The drug is approved for treatment of hypertension but has also shown renoprotective potential in patients with type 2 diabetes and albuminuria (4,5).Combining an ARB and a direct renin inhibitor could offer improved RAAS blockade by acting both at the receptor level and at the first step of the cascade. We compared the antiproteinuric effect of maximal recommended doses of aliskiren, irbesartan, and the combination in patients with type 2 diabetes and albuminuria. We also assessed the impact of the treatments on RAAS components and biomarkers of inflammation, endothelial dysfunction, and cardiovascular risk.     

Renal function after endovascular aortic aneurysm repair: a single-center experience with transrenal versus infrarenal fixation.

PURPOSE: To describe the short-term consequences of endovascular aortic aneurysm repair (EVAR) on renal function after infrarenal (IR) versus transrenal (TR) stent-graft fixation. METHODS: Between December 1996 and January 2006, 369 consecutive patients were treated with EVAR. All patients had an AneuRx or a Talent stent-graft implanted using IR (AneuRx) or transrenal (Talent) fixation. Post-EVAR, a standardized follow-up scheme included computed tomography (CT) scanning and serum creatinine measurements at 2 days, 3 months, and 12 months. Postoperative renal dysfunction was defined as a >20% decrease in serum creatinine clearance compared to baseline, the presence of new-onset dialysis, or both. Of the 369 patients, 309 (291 men; mean age 71+/-7 years, range 63-82) had complete 1-year follow-up and were included in this study. An IR stent-graft was placed in 190 patients, and a TR stent-graft was placed in the remaining 119 patients. RESULTS: At discharge, renal dysfunction occurred in 3.7% of the patients in the IR group versus 5.9% in the TR group (p = NS) and rose significantly to 13.7% in the IR group (p = 0.001) and 15.1% in the TR group (p = 0.02) at the 1-year follow-up. However, no significant difference was noted between the IR and TR groups at either time point. At the 1-year follow-up, at least 50% of renal dysfunction was caused by obstructions of (accessory) renal arteries and renal infarctions. During the follow-up interval, 3 (0.97%) of 309 patients underwent new-onset dialysis. CONCLUSION: Both infrarenal and transrenal fixation techniques in EVAR will lead to a significant rise in renal dysfunction during the first year. A few patients with dysfunction will require dialysis.     

Clinical impact of the updated international postoperative pancreatic fistula definition in distal pancreatectomy

Background

Postoperative pancreatic fistula (POPF) remains the most common complication after distal pancreatectomy. The International Study Group on Pancreatic Surgery definition of POPF is used worldwide. Recently, an update of the definition was published. The aim of this study was to determine the clinical impact of the update.

Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis

OBJECTIVE: Age is an important risk factor for osteoarthritis (OA). During aging, nonenzymatic glycation results in the accumulation of advanced glycation end products (AGEs) in cartilage collagen. We studied the effect of AGE crosslinking on the stiffness of the collagen network in human articular cartilage. METHODS: To increase AGE levels, human adult articular cartilage was incubated with threose. The stiffness of the collagen network was measured as the instantaneous deformation (ID) of the cartilage and as the change in tensile stress in the collagen network as a function of hydration (osmotic stress technique). AGE levels in the collagen network were determined as: Nepsilon-(carboxy[m]ethyl)lysine, pentosidine, amino acid modification (loss of arginine and [hydroxy-]lysine), AGE fluorescence (360/460 nm), and digestibility by bacterial collagenase. RESULTS: Incubation of cartilage with threose resulted in a dose-dependent increase in AGEs and a concomitant decrease in ID (r = -0.81, P < 0.001; up to a 40% decrease at 200 mM threose), i.e., increased stiffness, which was confirmed by results from the osmotic stress technique. The decreased ID strongly correlated with AGE levels (e.g., AGE fluorescence r = -0.81, P < 0.0001). Coincubation with arginine or lysine (glycation inhibitors) attenuated the threose-induced decrease in ID (P < 0.05). CONCLUSION: Increasing cartilage AGE crosslinking by in vitro incubation with threose resulted in increased stiffness of the collagen network. Increased stiffness by AGE crosslinking may contribute to the age-related failure of the collagen network in human articular cartilage to resist damage. Thus, the age-related accumulation of AGE crosslinks presents a putative molecular mechanism whereby age is a predisposing factor for the development of OA.     

Link between the X4 phenotype in human immunodeficiency virus type 1-infected mothers and their children,despite the early presence of R5 in the child

Coreceptor use was determined for human immunodeficiency virus type 1 (HIV-1) isolates of various subtypes from 11 women during pregnancy and their infected children. Isolates from peripheral blood mononuclear cells (n=79) and from plasma (n=59) were available. The clinical and immunological stages of HIV-1 infection were recorded. Coreceptor use was tested on human cell lines expressing CD4 and different chemokine receptors. The R5 virus predominated, and only 9 isolates from 2 mothers used CXC chemokine receptor 4. All children carried the R5 virus at the time of diagnosis of HIV-1 infection. In 2 children of mothers carrying the X4 virus, the virus switched from R5 to X4 or to R5X4 by age 18 months (child no. 9) and age 48 months (child no. 10), whereas no children followed up to a similar age whose mothers were carrying the R5 virus experienced such a switch (P=.048). This points to a link between the presence of X4 virus in the mother and the emergence of X4 virus in her child.     

Selectively filtering short wavelengths attenuates the disruptive effects of nocturnal light on endocrine and molecular circadian phase markers in rats

Various physiological processes exhibit a circadian rhythm synchronized to the geophysical light/dark cycle. Our study using a rat model demonstrated that exposure to light at night suppressed the expected nocturnal rise in melatonin, increased plasma corticosterone, and disrupted core clock gene expression in the hypothalamus and the adrenal gland. These effects were prevented by filtration of a 10-nm bandwidth of light between 470 and 480 nm, whereas filtration of light between 452 and 462 nm prevented the rise of corticosterone without restoring normal melatonin secretion or hypothalamic clock gene expression. This is the first demonstration of a wavelength dependency of glucocorticoid secretion and clock gene expression. Our results in an animal model suggest that filtering a narrow bandwidth of light from nocturnal lighting may efficiently attenuate overall disruption of circadian endocrine rhythms and clock gene expression in the hypothalamus and adrenal gland. Because a narrow bandwidth of light is filtered, the color distribution of the illumination source is not altered, and this may be of practical importance for potential future studies in shift workers.