Abnormal response of costal chondrocytes to acidosis in patients with chest wall deformity.

Costal cartilage is much understudied compared to the load bearing cartilages. Abnormally grown costal cartilages are associated with the inherited chest wall deformities pectus excavatum and pectus carinatum resulting in sunken or pigeon chest respectively. A lack of understanding of the ultrastructural and molecular biology properties of costal cartilage is a major confounder in predicting causes and outcomes of these disorders. Due to the avascular nature of cartilage, chondrocytes metabolize glycolytically, producing an acidic environment. During physical activity hydrogen ions move within cartilage driven by compressive forces, thus at any one time, chondrocytes experience transient changes in pH. A variety of ion channels on chondrocytes plasma membrane equip them to function in the rapidly changing conditions they experience. In this paper we describe reduced expression of the ASIC2 gene encoding the acid sensing ion channel isoform 2 (previously referred to as ACCN1 or ACCN) in patients with chest wall deformities. We hypothesized that chondrocytes from these patients cannot respond normally to changes in pH that are an integral part of the biology of this tissue. Activation of ASICs indirectly creates a cascade ultimately dependent on intracellular calcium transients. The objective of this paper was to compare internal calcium signaling in response to external pH changes in costal chondrocytes from patients with chest wall deformities and healthy individuals. Although the molecular mechanism through which chondrocytes are regulated by acidosis remains unknown, we observed reduced amplitudes of calcium rise in patient chondrocytes exposed to low pH that become further impaired upon repeat exposure.

The blunted effect of glucose-dependent insulinotropic polypeptide in subcutaneous abdominal adipose tissue in obese subjects is partly reversed by weight loss.

BACKGROUND: Glucose-dependent insulinotropic polypeptide (GIP) appears to have impaired effect on subcutaneous abdominal adipose tissue metabolism in obese subjects. The aim of the present study was to examine whether weight loss may reverse the impaired effect of GIP on subcutaneous abdominal adipose tissue in obese subjects. METHODS: Five obese males participated in a 12-week weight loss program, which consisted of caloric restriction (800 Cal day(-)(1)) followed by 4 weeks of weight-maintenance diet. Before and after weight loss, subcutaneous adipose tissue lipid metabolism was studied by conducting regional measurements of arterio-venous plasma concentrations of metabolites and blood flow (adipose tissue blood flow, ATBF) across a segment of the abdominal adipose tissue in the fasting state and during GIP infusion (1.5 pmol kg(-)(1 )min(-)(1)) in combination with a hyperinsulinemic-hyperglycemic clamp. RESULTS: After weight loss (7.5±0.8 kg), glucose tolerance and insulin sensitivity increased significantly as expected. No significant differences were seen in basal ATBF before (1.3±0.4 ml min(-1) 100 g tissue(-1)) and after weight loss (2.1±0.4 ml min(-1) 100 g tissue)(-1); however, a tendency to increase was seen. After weight loss, GIP infusion increased ATBF significantly (3.2±0.1 ml min(-1) 100 g tissue(-1)) whereas there was no increase before weight loss. Triacylglycerol (TAG) uptake did not change after weight loss. Baseline free fatty acid (FFA) and glycerol output increased significantly after weight loss, P<0.001. During the clamp period, FFA and glycerol output declined significantly, P<0.05, with no differences before and after weight loss. Weight loss increased glucose uptake and decreased FFA/glycerol ratio during the clamp period, P<0.05. CONCLUSIONS: In obese subjects, weight loss, induced by calorie restriction, improves the blunted effect of GIP on subcutaneous abdominal adipose tissue metabolism.

Membrane channel gene expression in human costal and articular chondrocytes.

Chondrocytes are the uniquely resident cells found in all types of cartilage and key to their function is the ability to respond to mechanical loads with changes of metabolic activity. This mechanotransduction property is, in part, mediated through the activity of a range of expressed transmembrane channels; ion channels, gap junction proteins, and porins. Appropriate expression of ion channels has been shown essential for production of extracellular matrix and differential expression of transmembrane channels is correlated to musculoskeletal diseases such as osteoarthritis and Albers-Schönberg. In this study we analyzed the consistency of gene expression between channelomes of chondrocytes from human articular and costal (teenage and fetal origin) cartilages. Notably, we found 14 ion channel genes commonly expressed between articular and both types of costal cartilage chondrocytes. There were several other ion channel genes expressed only in articular (6 genes) or costal chondrocytes (5 genes). Significant differences in expression of BEST1 and KCNJ2 (Kir2.1) were observed between fetal and teenage costal cartilage. Interestingly, the large Ca(2+) activated potassium channel (BKα, or KCNMA1) was very highly expressed in all chondrocytes examined. Expression of the gap junction genes for Panx1, GJA1 (Cx43) and GJC1 (Cx45) was also observed in chondrocytes from all cartilage samples. Together, this data highlights similarities between chondrocyte membrane channel gene expressions in cells derived from different anatomical sites, and may imply that common electrophysiological signaling pathways underlie cellular control. The high expression of a range of mechanically and metabolically sensitive membrane channels suggest that chondrocyte mechanotransduction may be more complex than previously thought.

Fluid balance and conventional and novel biomarkers of acute kidney injury in cardiovascular surgery.

AIM: Fluid balance (FB) is an emerging predictor of acute kidney injury (AKI). We investigated the comparative utility of FB with conventional and novel biomarkers to predict AKI in cardiovascular surgery patients. METHODS: Data collected in a prospective, observational study designed to investigate the relationship between FB and AKI in an academic medical center were utilized for analyses. FB, routine clinical parameters, conventional and novel biomarkers in 100 consecutive cardiovascular surgery patients was analyzed. RESULTS: Each variable studied was divided into quartiles and the lowest quartile served as the referent quartile. The adjusted OR for AKI for the highest vs. lowest quartile of FB was 4.98 (CI95%1.38-24.10, P=0.046), serum creatinine (SCr) 11.54 (CI95% 1.37-97.18, P=0.024), urine NGAL 2.76 (CI95% 0.48-15.93, P=0.255) and IL-18 2.31 (CI95% 0.41-13.16, P=0.346, and serum MCP-1 4.93 (CI95% 0.81-30.09, P=0.084) and TNF-alpha 15.59 (CI95% 1.19-204.19, P=0.036). Comparison of ROC curves demonstrated that the diagnostic performance of FB and SCr to predict AKI were comparable, as were FB with urine NGAL and IL-18 and serum MCP-1 and TNF-alpha.. While there was a graded relationship with the risk for AKI according to quartiles for FB, SCr and serum TNF-alpha, the remaining biomarkers including urine NGAL were not independent predictors of AKI. CONCLUSION: At 24 hours postoperatively, the performance of FB to predict AKI was comparable to that of preoperative conventional and postoperative 24-hour novel biomarkers.

The value of FDG-PET/CT in the diagnostic work-up of extra cardiac infectious manifestations in infectious endocarditis.

Infectious endocarditis (IE) is a serious condition with a high morbidity and mortality. The optimal management of IE depends not only on correct antibiotic therapy and surgery when needed, but involves identification of the portal of entry and detection of extracardiac infectious manifestations. To discover the latter an (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET)/CT examination has been proposed. However, the diagnostic value of a PET/CT in this setting remains unresolved. Thus, we wished to assess the usefulness of a PET/CT study in patients with IE as a supplemental method to standard work-up in evaluating primary and distant infective foci. A retrospective cohort study of 72 IE patients admitted from 2008 to 2010, which had an (18)F-FDG-PET/CT performed. Findings were assessed in relation to the routine work-up, which served as the "gold standard". One hundred-fifty-nine infectious lesions were identified. (18)F-FDG-PET identified 64 of these, and suggested another 50. Overall sensitivity and positive predictive value was 40 and 56 %, respectively, in detecting both cardiac and extracardiac infective foci. When excluding lungs and organs with high physiological FDG-uptake/secretion, the corresponding values increased to 87 and 52 %, respectively. (18)F-FDG-PET/CT may be an important diagnostic tool in detecting extra cardiac infections in patients with IE, particularly in organs with low physiological glucose uptake.

Renal support in acute kidney injury.

Acute kidney injury requiring renal replacement therapy (RRT) is associated with an unacceptably high mortality rate. Despite the identification of the modality, timing and intensity of dialysis, membrane biocompatibility, hollow fiber and catheter properties as potential modifying factors, there is little convincing evidence for the superiority of one over the other. However, the available data suggest that the early initiation of RRT may be beneficial. A focused review of clinical trials and meta-analysis of clinical trials of RRT is provided.

Atomic force microscopy characterization of collagen 'nanostraws' in human costal cartilage.

Costal cartilage, a type of hyaline cartilage that bridges the bony ribs and sternum, is relatively understudied compared to the load bearing cartilages. Deformities of costal cartilage can result in deformation of the chest wall, where the sternum is largely pushed toward or away from the spine, pectus excavatum and pectus carinatum, respectively, with each condition having significant clinical impact. In the absence of extensive literature describing morphological features of costal cartilage, we characterized a sample from the costal margin immunohistologically and through atomic force microscopy. We had previously observed the presence of collagen 'nanostraws' running the length of costal cartilage. Hypothesizing that these structures may be responsible for fluid flow within this thick, avascular tissue, and prior to microfluidic analysis, we estimated the diameters and measured Young's modulus of elasticity of the collagen nanostraws. We found significant differences in results between treatment type and fixation. Significant differences in nanostraw elasticity and diameter obviously affect nano-fluidic transport calculations, and therefore, we consider these results of importance to the scientific community relying upon measurements in the nanoscale.

Decorin expression, straw-like structure, and differentiation of human costal cartilage.

Costal cartilage is much understudied compared with the load-bearing cartilages. Abnormally grown costal cartilages are associated with the inherited chest wall deformities pectus excavatum and pectus carinatum resulting in sunken and pigeon chests, respectively. A lack of understanding of the ultrastructural and molecular biology of costal cartilage is a major confounder in predicting causes and outcomes of these disorders. This study analyzed the structure of marginal human costal cartilage (ribs 6-10) through scanning electron and atomic force microscopes and identified the presence of straw-like structures running longitudinally. We also demonstrated that chondrocytes tend to occur singly or as doublets and that centrally located cells produce high levels of aggrecan compared with more peripherally located cells measured using immunohistochemistry. Gene expression from mRNA extracted from cartilage showed high levels of decorin expression, likely associated with the large, complex tubular structures running through this cartilage type. COL2A1, ACAN, and TIMP1 also showed higher levels of expression compared with ACTB. Analysis of gene expression ratios demonstrate that costal cartilage is under differentiated compared with published ratios for articular cartilage, likely due to the vastly different biomechanical environments of each cartilage type. Further studies need to establish whether findings described here from the costal margins are significantly different than the cartilage of the "true ribs" and how these values change with age.

[Vitamin D status in aged subjects. Study of a Lebanese population]. / Statut vitaminique D des sujets âgés. Etude de la population libanaise.

OBJECTIVES: To evaluate vitamin D status in two subgroups of the Lebanese aged population. To compare results with reference values observed in healthy young volunteers. METHODS: Fifty aged institutionalized patients (25 men and 25 women) and 51 aged ambulatory subjects (25 men and 26 women) underwent the following explorations during winter: serum 25-OH vitamin D, parathyroid hormone, corrected serum calcium, phosphorus, creatinine, and alkaline phosphatases and urinary calcium/creatinine. Serum 25-OH vitamin D and urinary calcium/creatinine were also measured in 34 healthy young volunteers. RESULTS: Serum 25-OH vitamin D levels in 25 ambulatory subjects (49%) and 30 institutionalized patients (60%) were below 10 ng/ml. There was non significant difference in 25-OH vitamin D levels between the ambulatory and institutionalized aged populations, nor between aged women and aged men. Parathyroid hormone, alkaline phosphatases and urinary calcium/creatinine levels were higher in the institutionalized population than in the ambulatory population (p = 0.07; p = 0.0001; p = 0.0001 respectively). Aged women had higher parathyroid hormone and calcium/creatine levels than aged men (p = 0.005; p = 0.005 respectively). Finally, in the young population, 25-OH vitamin D was higher than in the aged institutionalized and ambulatory populations (p = 0.0001 and p = 0.0009 respectively). An inverse non-significant correlation (r = -0.16) was found between parathyroid hormone and 25-OH vitamin D. CONCLUSION: Our results show that even in a sunny country like Lebanon, vitamin D deficiency is often observed. The degree of deficiency probably lies between that observed in Europe and the United States. It could be related to low vitamin D diet.