Background Higher muscle mass is associated with better outcomes and longevity in patients with chronic disease states. Imaging studies such as dual‐energy X‐ray absorptiometry (DEXA) are among the gold standard methods for assessing body fat and lean body mass (LBM), approximately half of which is comprised of skeletal muscle mass. Elaborate imaging devices, however, are not commonly available in routine clinical practice and therefore easily accessible and cost‐effective, but reliable muscle mass biomarkers are needed. One such marker is serum creatinine, derived from muscle‐based creatine, which is inexpensive and ubiquitously available, and it can serve as a biomarker of skeletal muscle mass in human subjects. Methods and results In 118 hemodialysis patients, we found that the 3‐month averaged serum creatinine concentration correlated well with DEXA‐measured LBM. The recent literature regarding serum creatinine as a surrogate of muscle mass is summarized, as is the literature concerning the use of other measures of muscle mass, such as plasma gelsolin and actin, and urinary creatinine excretion. We have also reviewed the role of dietary meat intake in serum creatinine variability along with several biomarkers of dietary meat intake (creatine, carnitine, carnosine, ophidine, anserine, 3‐methyl‐ l‐histidine and 1‐methylhistidine). Conclusion In summary, none of these biomarkers was studied in CKD patients. We advance the hypothesis that in both health and disease, under steady state, serum creatinine can serve as a reliable muscle mass biomarker if appropriate adjustment for full or residual kidney function and dietary meat intake is undertaken.

Mechanisms of ligand binding and activation of G protein-coupled receptors are particularly important, due to their ubiquitous expression and potential as drug targets. Molecular interactions between ligands and these receptors are best defined for small molecule ligands that bind within the transmembrane helices. Extracellular domains seem to be more important for peptide ligands, based largely on effects of receptor mutagenesis, where interference with binding or activity can reflect allosteric as well as direct effects. We now take the more direct approach of photoaffinity labeling the active site of the cholecystokinin (CCK) receptor, using a photolabile analogue of CCK having a blocked amino terminus. Guanine nucleotide-binding protein (G protein) 1 -coupled receptors are the largest group of plasma membrane receptors, representing a superfamily with a remarkable diversity of activating ligands. Our best understanding of the molecular basis for ligand binding to members of this superfamily is the binding of the chromophore to rhodopsin and the binding of biogenic amines to adrenergic receptors. These insights come from complementary studies of receptor mutagenesis, photoaffinity labeling, and reciprocal chemical modification of ligand and receptor (1-6). All available data focus the relevant interactions to sites at the core of the coalescence of transmembrane helices, in the outer third of the bilayer. Even with this extensive information, the constrained nature of the ligands, and the relatively confined space for ligand docking, the debate continues regarding the specific siting of the agonist ligands in some of these receptor systems (7,8).Understanding the interactions between peptide ligands and their G protein-coupled receptors represents an even greater challenge. By first principles, these ligands are quite flexible and can achieve many conformations. Whereas some peptides appear to have some preferred conformation in solution (9), there is little information regarding how such structures relate to the receptor-bound states of these ligands. Most of our insights into binding domains for peptide ligands have come from receptor mutagenesis studies, which have focused attention on receptor domains predicted to be outside the membrane (7,8). Given the extended size of the pharmacophoric domains and the solubilities of the peptide ligands, these regions of interaction seem plausible. We know, however, that receptor mutagenesis can modify receptor function nonspecifically, interfering with biosynthetic processing or trafficking or having an allosteric effect, rather than necessarily directly interfering with a site of ligand-receptor interaction. For a very limited number of peptide receptors in this family, direct sites of contact have been recently described using photoaffinity labeling approaches (10 -13).Cholecystokinin (CCK) is a peptide hormone and neurotransmitter that has a wide spectrum of physiologic actions (14). These relate largely to control of nutrient assimilation, through regulation of...

Muscle mass reflected in serum Cr level may be associated with survival even in PD patients. However, the serum Cr-mortality association is attenuated in the early period of PD treatment, suggesting competing effect of muscle mass versus residual renal function on mortality.

Background The Metabolic syndrome (MetS) and/or its individual components have been linked to the development of cancer. Recent studies have suggested a similar link to hepatocellular carcinoma (HCC). The aim of this study was to evaluate the direction and magnitude of the association between the MetS and HCC. Methods Two reviewers independently conducted a systemic search to identify available evidence from databases from January 1980 to June 2012. Search terms included ‘Metabolic syndrome’, ‘insulin resistance syndrome’, ‘metabolic abnormalities’ combined with ‘hepatocellular carcinoma’ and ‘liver cancer’. No language restriction was applied to the search. Only studies reporting an effect measure for the association between MetS and HCC were eligible for inclusion. Publication bias was assessed using the Begg and Egger’s tests, with a visual inspection of funnel plot. All analyses were performed using Comprehensive Meta-Analysis version 2 software. Results Four studies (3 cohort and 1 case-control) with a total of 829,651 participants were included in the analysis. The age range of participants was between 30 and 84 years. The combined analysis showed an overall 81% increase risk of HCC in cases with MetS (RR: 1.81, 95% CI: 1.37–2.41). After excluding the single case-control study from analysis, the overall risk ratio remained statistically significant (RR: 1.49, 95% CI: 1.27–1.74). Funnel plot inspection, Begg and Egger’s tests showed no evidence of publication bias for combined analysis. Conclusions Though studies are scarce, currently available epidemiologic data is suggestive of significantly higher risk of hepatocellular carcinoma among patients with metabolic syndrome.

Background-Alcoholic hepatitis (AH) is the most florid manifestation of alcoholic liver disease which accounts for significant morbidity, mortality and financial burden. Aim of this study is to evaluate temporal trend of hospitalizations from alcoholic hepatitis and evaluate its financial impact. Methods-The National Inpatient Sample (NIS) databases (from 2002 to 2010) which are collected as part of Healthcare Cost and Utilization Project by Agency for Healthcare Research and Quality were utilized. Individuals with age ≥ 21 years were included. The hospitalizations with primary diagnosis of AH were captured by ICD-9 codes. The national estimates of hospitalization were derived using sample weights provided by NIS. Simple linear regression method was used to assess trends in mortality and length of stay over time. Results-We observed the increased in total cases of AH-related hospitalization from 249,884 (0.66% of total admission in 2002) to 326,403 (0.83% of total admission in 2010). The significant increase in the total admission rate was attributable mainly to the rise in inpatient hospitalization for secondary diagnosis of AH (0.48% in 2002 to 0.67% in 2010). Most of the AH related hospitalization were males. Hepatic encephalopathy was found to be the most common admitting diagnosis for individuals hospitalized with secondary diagnosis of AH (8.9% in 2002 and 8.6% in 2010). There was a significant decrease in inpatient mortality for primary diagnosis of AH from 10.07 % (in 2002) to 5.76% (in 2010) (absolute risk reduction: 4.3%).

ObjectiveMedication adherence is impacted by regimen complexity. The SIMPLE (Simple basal Insulin titration, Metformin Plus Liraglutide for type 2 diabetes with very Elevated HbA1c) study compared GLP1RA plus basal insulin (GLP1RA+BI) to basal-bolus insulin (BBI) regimen in participants with very uncontrolled type 2 diabetes mellitus (T2DM). This analysis aimed to evaluate medication adherence to GLP1RA+BI compared with BBI, the effect of adherence on clinical and patient-reported outcomes, and baseline predictors of adherence.Research design and methodsThis was an analysis of the SIMPLE study based on prespecified outcome. The study took place in pragmatic, real-world setting. A total of 120 adults with T2DM and HgbA1c≥10% were randomized to detemir plus liraglutide, or detemir plus aspart before each meal; 6-month follow-up. The main outcomes evaluated were: adherence, HgbA1c, weight, quality of life, and hypoglycemia. Adherence rate was calculated for each study medication at each follow-up visit; participants were classified as ≥80% or <80% adherent.ResultA higher percentage of participants in the GLP1RA+BI compared with the BBI group had ≥80% adherence to detemir (59.3% vs 35.7%, p=0.02) as well as liraglutide versus aspart (57.4% vs 30.4%, p=0.007). Higher age was predictive of ≥80% adherence (OR per 5-year increment=1.48, 95% CI 1.09 to 2.0, p=0.01). Higher adherence led to greater improvement in HbA1c and weight in both groups. Treatment with GLP1RA+BI compared with BBI led to greater improvement in HbA1c, weight, and quality of life and lower risk of hypoglycemia even after adjusting for the difference in adherence between groups.ConclusionsAdherence was higher with the simplified regimen of GLP1RA+BI compared with BBI. Greater adherence to the simpler regimen amplified the treatment effect on HbA1c, weight, quality of life, and risk of hypoglycemia, yet statistically significant greater benefits were noted even when adjusted for adherence.Trial registration numberNCT01966978

Systemic vascular endothelial growth factor (VEGF) inhibitions can induce worsening hypertension, proteinuria and glomerular diseases of various types. These agents can also be used to treat ophthalmic diseases like proliferative diabetic retinopathy, diabetic macular edema, central retinal vein occlusion and age-related macular degeneration. Recently, pharmacokinetic studies confirmed that these agents are absorbed at levels that result in biologically significant suppression of intravascular VEGF levels. There have now been 23 other cases published that describe renal sequela of intravitreal VEGF blockade, and they unsurprisingly mirror known systemic toxicities of VEGF inhibitors. We present three cases where stable levels of proteinuria and chronic kidney disease worsened after initiation of these agents. Two of our three patients were biopsied. The first patient’s biopsy showed diabetic nephropathy and focal and segmental glomerulosclerosis (FSGS) with collapsing features and acute interstitial nephritis (AIN). The second patient’s biopsy showed AIN in a background of diabetic glomerulosclerosis. This is the second patient seen by our group, whose biopsy revealed segmental glomerulosclerosis with collapsing features in the setting of intravitreal VEGF blockade. Though FSGS with collapsing features and AIN are not the typical lesions seen with systemic VEGF blockade, they have been reported as rare case reports previously. In addition to reviewing known elements of intravitreal VEGF toxicity, the cases presented encompass renal pathology data supporting that intravitreal VEGF blockade can result in deleterious systemic and renal pathological disorders.

Fibrous dysplasia is a noninherited bone disease in which abnormal differentiation of osteoblasts leads to replacement of normal marrow and cancellous bone by immature bone with fibrous stroma. Monostotic fibrous dysplasia accounts for 28% in the ribs. It is often asymptomatic and incidentally detected on radiographs. As with many bone abnormalities, it can be superimposed by the formation of aneurysmal bone cysts. We report a case of a 70-year-old lady who presented with swelling on the chest wall of 20-ear duration and sudden increase in size for 8 months. Radiologically, X-ray and CT scan showed an expansible lesion of the medullary cavity with a ground-glass centre and thinning of cortex of the 5th rib. The resected lesion was a firm, well-defined solid, grey-white expansile mass replacing the medullary cavity. Histopathologically, benign fibrous spindle areas with disorganized irregular bony trabeculae were seen. Hemorrhagic spaces lined by osteoclast-like multinucleated giant cells were also noted. The diagnosis was fibrous dysplasia with aneurysmal bone cyst changes. Although fibrous dysplasia with aneurysmal bone cyst is rare, it should be taken into account in differential diagnosis of the rapidly growing solitary rib lesion.