Glucose,glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathy

Receptor for advanced glycation endproducts (RAGE) is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. Driven by rapid accumulation and expression of key ligands such as advanced glycation endproducts (AGE) and S100/calgranulins in diabetic tissues, upregulation and activation of RAGE magnifies cellular perturbation in tissues affected by hyperglycemia, such as the large blood vessels and the kidney. In the diabetic glomerulus, RAGE is expressed principally by glomerular visceral epithelial cells (podocytes). Blockade of RAGE in the hyperglycemic db/db mouse suppresses functional and structural alterations in the kidney, in the absence of alterations in blood glucose. Recent studies in homozygous RAGE null mice support a key role for RAGE in glomerular perturbation in diabetes. Importantly, beyond diabetes, studies in other settings of glomerulopathies support a critical RAGE-dependent pathway in podocytes linked to albuminuria, mesangial expansion, and glomerular sclerosis. A new paradigm is proposed in glomerular injury, and it is suggested that blockade of the RAGE axis may provide a novel means to prevent irreparable glomerular injury in diabetes and other sclerosing glomerulopathies.     

Early changes in functional dynamic magnetic resonance imaging predict for pathologic response to neoadjuvant chemotherapy in primary breast cancer

PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows noninvasive, in vivo measurements of tissue microvessel perfusion and permeability. We examined whether DCE-MRI done after two cycles of neoadjuvant chemotherapy could predict final clinical and pathologic response in primary breast cancers. EXPERIMENTAL DESIGN: Thirty-seven patients with primary breast cancer, due to receive six cycles of neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy, were examined using DCE-MRI before neoadjuvant chemotherapy and after two cycles of treatment. Changes in DCE-MRI kinetic parameters (K(trans), k(ep), v(e), MaxGd, rBV, rBF, MTT) were correlated with the final clinical and pathologic response to neoadjuvant chemotherapy. Test-retest variability was used to determine individual patient response. RESULTS: Twenty-eight patients were evaluable for response (19 clinical responders and 9 nonresponders; 11 pathologic responders and 17 nonresponders). Changes in the DCE-MRI kinetic parameters K(trans), k(ep), MaxGd, rBV, and rBF were significantly correlated with both final clinical and pathologic response (P < 0.01). Change in K(trans) was the best predictor of pathologic nonresponse (area under the receiver operating characteristic curve, 0.93; sensitivity, 94%; specificity, 82%), correctly identifying 94% of nonresponders and 73% of responders. Change in MRI-derived tumor size did not predict for pathologic response. CONCLUSION: Changes in breast tumor microvessel functionality as depicted by DCE-MRI early on after starting anthracycline-based neoadjuvant chemotherapy can predict final clinical and pathologic response. The ability to identify nonresponders early may allow the selection of patients who may benefit from a therapy change.     

Inadequate internal mammary artery graft as a cause of postoperative ischemia: incidence, diagnosis and management.

Inadequate left internal mammary artery (LIMA) graft to the left anterior descending artery (LAD) was encountered in 10 of 3,076 patients between 1984 and July 1990. The mean number of bypass grafts was 2.9 per patient. All patients with inadequate LIMA grafts were stable preoperatively with normal to moderately reduced left ventricular function. No technical difficulties were encountered during surgery. All patients were weaned off cardiopulmonary bypass with minimal or no inotropic support. Each patient developed myocardial ischemia of the LAD territory and/or circulatory collapse or recurrent ventricular dysrhythmia during the first 24 h postoperatively. Six patients, who were immediately re-operated on and had an additional saphenous graft to the LAD, recovered with no infarction and good functional results. Four patients, who were medically treated, developed myocardial infarction. In cases of refractory circulatory collapse and/or ventricular dysrhythmia, inadequate LIMA flow should be suspected. We recommend urgent re-operation with additional saphenous vein graft to the LAD.     

Oral cancer in southern India: the influence of smoking, drinking, paan-chewing and oral hygiene

Between 1996 and 1999 we carried out a case-control study in 3 areas in Southern India (Bangalore, Madras and Trivandrum) including 591 incident cases of cancer of the oral cavity (282 women) and 582 hospital controls (290 women), frequency-matched with cases by age and gender. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained from unconditional multiple logistic regressions and adjusted for age, gender, center, education, chewing habit and (men only) smoking and drinking habits. Low educational attainment, occupation as a farmer or manual worker and various indicators of poor oral hygiene were associated with significantly increased risk. An OR of 2.5 (95% CI 1.4-4.4) was found in men for smoking > or = 20 bidi or equivalents versus 0/day. The OR for alcohol drinking was 2.2 (95% CI 1.4-3.3). The OR for paan chewing was more elevated among women (OR 42; 95% CI 24-76) than among men (OR 5.1; 95% CI 3.4-7.8). A similar OR was found among chewers of paan with (OR 6.1 in men and 46 in women) and without tobacco (OR 4.2 in men and 16.4 in women). Among men, 35% of oral cancer is attributable to the combination of smoking and alcohol drinking and 49% to pan-tobacco chewing. Among women, chewing and poor oral hygiene explained 95% of oral cancer.     

Docetaxel-induced Hand and Foot Syndrome in a Patient with Metastatic Breast Carcinoma

Hand and foot syndrome (HFS) is a well-known complication of chemotherapeutic drugs given in a dose-dense manner. Our patient was a 52-year-old female with metastatic breast carcinoma on salvage chemotherapy regimen with docetaxel at a dose of 60 mg/m². The patient had grade 3 HFS characterized by symmetrical, tender, and erythematous skin lesions over the palms and soles associated with dysesthesia necessitating interruption of treatment. She developed this syndrome at a much lower dose than previously described due to her altered hepatic function. An insight regarding this unique distressing side-effect and assessment of various contributing factors would help us identify and treat the patient at the earliest.     

Toward an understanding of the short bone phenotype associated with multiple osteochondromas

Individuals with multiple osteochondromas (MO) demonstrate shortened long bones. Ext1 or Ext2 haploinsufficiency cannot recapitulate the phenotype in mice. Loss of heterozygosity for Ext1 may induce shortening by steal of longitudinal growth into osteochondromas or by a general derangement of physeal signaling. We induced osteochondromagenesis at different time points during skeletal growth in a mouse genetic model, then analyzed femora and tibiae at 12 weeks using micro‐CT and a point‐distribution‐based shape analysis. Bone lengths and volumes were compared. Metaphyseal volume deviations from normal, as a measure of phenotypic widening, were tested for correlation with length deviations. Mice with osteochondromas had shorter femora and tibiae than controls, more consistently when osteochondromagenesis was induced earlier during skeletal growth. Volumetric metaphyseal widening did not correlate with longitudinal shortening, although some of the most severe shortening was in bones with abundant osteochondromas. Loss of heterozygosity for Ext1 was sufficient to drive bone shortening in a mouse model of MO, but shortening did not correlate with osteochondroma volumetric growth. While a steal phenomenon seems apparent in individual cases, some other mechanism must also be capable of contributing to the short bone phenotype, independent of osteochondroma formation. Clones of chondrocytes lacking functional heparan sulfate must blunt physeal signaling generally, rather than stealing growth potential focally. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 651–657, 2013     

Trends and relationship between chlorophyll-a and sea surface temperature in the central equatorial Indian Ocean

This work presents the trend analysis and relationship between chlorophyll-a (chl-a) concentration and sea surface temperature (SST) in the central equatorial Indian Ocean (CEIO) using Aqua MODIS chl-a Level-3 Standard Mapped Image (SMI) data for a period of 10 years (2002–2012). In order to understand the monsoonal variability of chl-a concentration and SST and to evaluate their relationships over the CEIO, trend analysis of chl-a values was carried out. The area average chl-a concentration in the region shows a weak annual cycle with high concentration during winter (October–December) and low in summer (June). High chl-a concentration (~0.22 mg m^?3) is observed during early winter in the region. Chl-a concentration starts decreasing from March onwards until the onset of summer monsoon. The data reveal low chl-a concentrations during summer period, i.e., from June to September, which is in accordance with several observations, and higher concentrations during October to December. The other reason is that satellite sensor may not capture chl-a variability more accurately because of cloud cover during summer monsoon time. A reasonably significant coefficient of determination (R² = 0.51; significant at p < 0.05 level) between SST and chl-a concentration is recorded. This study clearly suggests that the SST acts as a proxy for variables which cause high chl-a concentration in the CEIO.     

The role of nucleotides in apoptotic cell clearance: implications for disease pathogenesis

Apoptosis occurs in many tissues, during both normal and pathogenic processes. Normally, apoptotic cells are rapidly cleared, either by neighboring or recruited phagocytes. The prompt clearance of apoptotic cells requires that the apoptotic cells announce their presence through the release of chemotactic factors, known as “find-me” signals, to recruit phagocytes to the site of death, and through the exposure of so-called “eat-me” signals, which are ligands for phagocytic uptake. The importance of prompt apoptotic cell clearance is revealed by findings that decreasing the efficiency of engulfment results in the persistence of apoptotic cells, which is often associated with chronic inflammation and autoimmunity. Additionally, the proper clearance of apoptotic cells is actively anti-inflammatory, which is thought to play a crucial role in immunologic tolerance. Therefore, defects associated with clearance of apoptotic cells may contribute to the pathogenesis of several inflammatory diseases, including autoimmunity and atherosclerosis. Here, we review the role of nucleotides in the apoptotic cell clearance process and discuss their implications for disease pathogenesis.