The association of concurrent vitamin D and sex hormone deficiency with bone loss and fracture risk in older men: The osteoporotic fractures in men (MrOS) study

Low 25‐hydroxyvitamin D (VitD), low sex hormones (SH), and high sex hormone binding globulin (SHBG) levels are common in older men. We tested the hypothesis that combinations of low VitD, low SH, and high SHBG would have a synergistic effect on bone mineral density (BMD), bone loss, and fracture risk in older men. Participants were a random subsample of 1468 men (mean age 74 years) from the Osteoporotic Fractures in Men Study (MrOS) plus 278 MrOS men with incident nonspine fractures studied in a case‐cohort design. “Abnormal” was defined as lowest quartile for VitD (<20 ng/mL), bioavailable testosterone (BioT, <163 ng/dL), and bioavailable estradiol (BioE, <11 pg/mL); and highest quartile for SHBG (>59 nM). Overall, 10% had isolated VitD deficiency; 40% had only low SH or high SHBG; 15% had both SH/SHBG and VitD abnormality; and 35% had no abnormality. Compared to men with all normal levels, those with both SH/SHBG and VitD abnormality tended to be older, more obese, and to report less physical activity. Isolated VitD deficiency, and low BioT with or without low VitD, was not significantly related to skeletal measures. The combination of VitD deficiency with low BioE and/or high SHBG was associated with significantly lower baseline BMD and higher annualized rates of hip bone loss than SH abnormalities alone or no abnormality. Compared to men with all normal levels, the multivariate‐adjusted hazard ratio (95% confidence interval [CI]) for incident nonspine fracture during 4.6‐year median follow‐up was 1.2 (0.8–1.8) for low VitD alone; 1.3 (0.9–1.9) for low BioE and/or high SHBG alone; and 1.6 (1.1–2.5) for low BioE/high SHBG plus low VitD. In summary, adverse skeletal effects of low sex steroid levels were more pronounced in older men with low VitD levels. The presence of low VitD in the presence of low BioE/high SHBG may contribute substantially to poor skeletal health. © 2012 American Society for Bone and Mineral Research.     

Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss

Osteoporosis is characterized by enhanced differentiation of bone‐resorbing osteoclasts, resulting in a rapid loss of functional trabecular bone. Bone‐forming osteoblasts and osteoblast‐derived osteocytes perform a key role in the regulation of osteoclast development by providing both the pro‐osteoclastogenic cytokine receptor activator of NF‐κB ligand (RANKL) and its natural decoy receptor osteoprotegerin (OPG). By regulating the RANKL/OPG ratio, osteoblasts hence determine the rate of both osteoclast differentiation and bone turnover. Here, we describe a novel role for liver X receptors (LXRs) during the crosstalk of bone‐forming osteoblasts and bone‐resorbing osteoclasts. By using a system of osteoblast/osteoclast cocultures, we identify LXRs as regulator of RANKL expression and the RANKL/OPG ratio in osteoblasts. Activation of LXRs drastically reduced the RANKL/OPG ratio and interfered with osteoblast‐mediated osteoclast differentiation in vitro. During an ovariectomy (OVX)‐induced model of postmenopausal osteoporosis, the application of an LXR agonist shifted the RANKL/OPG ratio in vivo, ameliorated the enhanced osteoclast differentiation, and provided complete protection from OVX‐induced bone loss. These results reveal an unexpected involvement of LXRs in the regulation of bone turnover and highlight a potential role for LXRs as novel targets in the treatment of osteoporosis and related diseases. © 2012 American Society for Bone and Mineral Research.     

Does hostile neck anatomy preclude successful endovascular aortic aneurysm repair?

OBJECTIVES: Poor outcomes have been reported with endovascular aneurysm repair (EVAR) in patients with hostile neck anatomy. Unsupported endografts with active fixation may offer certain advantages in this situation. We compared EVAR results using the Ancure (Guidant) endograft in patients with and without hostile neck anatomy. METHODS: Records of EVAR patients from October 1999 to July 2002 at a tertiary care hospital were retrospectively reviewed from a division database. Patients with elective open abdominal aortic aneurysm (AAA) repair during the same period were reviewed to determine those unsuitable for EVAR. Hostile neck anatomy, assessed by computer tomography (CT) scans and angiograms, was defined as one or more of the following: (1) neck length 3 mm, (3) >2-mm reverse taper within 1 cm below the renal arteries, (4) neck thrombus > or =50% of circumference, and (5) angulation > or =60 degrees within 3 cm below renals. RESULTS: Three hundred and twenty-two patients underwent EVAR with an average follow-up of 18 months. Patients in Phase II trials (n = 41), repaired with other graft types (n = 48), or without complete anatomic records (n = 27) were excluded. Demographics and co-morbidities were similar in the 115 good-neck (GN) and 91 bad-neck (BN) patients except for age (mean, 72.9 years GN vs 75.7 BN; P = 0.13), gender (11% female GN vs 22% BN; P =.04); neck length (mean, 21.8 mm GN vs 14.4 mm BN: P <.001), and angulation (mean, 22 degrees GN vs 40 degrees BN; (P <.001). Perioperative mortality (0 GN vs 1.1% BN), late mortality (5.2% GN vs 4.4% BN), all endoleaks (19.1% GN vs 17.6% BN), proximal endoleaks (0.8% GN vs 2.1% BN), and graft migration (0 for both groups) did not reach statistical significance. Neck anatomy precluded EVAR in 106 of 165 (64%) patients with open AAA. CONCLUSIONS: Unsupported endografts with active fixation can yield excellent results in treating many medically compromised patients with hostile neck anatomy. Nonetheless, an unsuitable neck remains the most frequent cause for open abdominal AAA.     

Microvessel density and vascular endothelial growth factor expression in infiltrating lobular mammary carcinoma

Angiogenesis is an important prognostic factor in infiltrating ductal carcinoma (IDC). Vascular endothelial growth factor (VEGF) stimulates angiogenesis in vivo. VEGF expression has been correlated with high vascularity in IDC. However, little is known about the prognostic significance of microvessel density (MVD) and its correlation with the expression of VEGF in infiltrating lobular carcinoma (ILC). We analyzed tumor samples from 51 patients with primary classic ILC to determine the relationship between tumoral MVD and VEGF expression. Cases of pleomorphic lobular carcinoma and tubulolobular carcinoma were excluded. Five-micron thick sections obtained from formalin-fixed, paraffin-embedded tissue blocks were immunostained with antibodies to factor VIII-related antigen (Dako, Carpenteria, CA) and VEGF (Calbiochem, Boston, MA). The former was used for MVD analysis. The vessel counts from the three most vascular fields (x200 magnification) were recorded and the highest of the vessel counts of the three fields was designated as the MVD. The intensity of VEGF staining and the proportion of cells staining were scored. Both the vessel counts and the scoring of VEGF staining were evaluated by two independent pathologists. The Student's t-test and Wilcoxon rank sum test were used to compare mean MVD and VEGF scores according to various clinical and pathologic features. All significance tests were two-sided with an alpha-level of 0.05. There was good correlation between the MVD of each observer (correlation coefficient 0.775, p < 0.001). There was no correlation of MVD or VEGF score with the size or stage of the tumor. In addition, the MVD or VEGF score was not significantly different between axillary lymph node-positive cases and node-negative cases, between patients with recurrence and those without, and between patients who survived and those who died of disease. There was, however, a weak negative correlation between the MVD and VEGF expression (Spearman correlation coefficient -0.08). Neither MVD or VEGF immunoscore were associated with tumor recurrence or vital status in patients with ILC. The absence of a statistically significant positive correlation between MVD and VEGF expression suggests that other factors may play a more important role in the angiogenesis of ILC.     

The role of human glandular kallikrein 2 for prediction of pathologically organ confined prostate cancer

BACKGROUND: In recent studies serum levels of human glandular kallikrein 2 (hK2) demonstrated significant differences in pathologically organ-confined versus non-organ-confined prostate cancer (PCa). In this study we investigated whether hK2 adds independent information when considered together with traditionally used parameters to predict organ confined (pT2a/b) PCa. METHODS: Serum levels of hK2, total and free prostate-specific antigens (PSA) were obtained one day before radical prostatectomy in 245 consecutive men. These were included with clinical stage and biopsy Gleason grade into univariate analysis and multivariate logistic regression models. RESULTS: pT2a/b PCa was found in n = 148 patients. In univariate analysis all preoperative parameters demonstrated significant association with the presence of pT2a/b PCa. Using multivariate logistic regression model hK2 (P = 0.022), clinical stage (P < 0.0001), and Gleason grade (P < 0.0001) were independent predictors of pT2a/b PCa whereas PSA (P = 0.3) was not. In bootstrap corrected logistic regression based nomograms the addition of hK2 density marginally enhanced predictive accuracy when PSA, PSA density, clinical stage, and Gleason grade were considered (AUC = 0.879 without hK2 density and 0.883 with hK2 density). CONCLUSIONS: hK2 and hK2 density could independently predict pT2a/b PCa. However, improvement in predictive accuracy was marginal when nomograms based on traditional variables were complemented with this serum marker.     

Off-pump coronary artery bypass grafting: a case-matched comparison of hemodynamic outcome.

OBJECTIVE: The objective of this study was to assess improved myocardial protection by performing coronary artery bypass grafting (CABG) on the beating heart. A case-matched study was conducted among patients who underwent CABG either on-pump (group 1), or off-pump (group 2). METHODS: Forty-five pairs of patients, having a similar clinical profile, were selected on the basis of five variables: age, gender, body surface area, ejection fraction, extent of coronary disease. Operative risk predicted by the The Society of Thoracic Surgeons national database was 1.80+/-0.35% in group 1, and 1.89+/-0.37% in group 2 (NS). Cold blood cardioplegia and 28 degrees C cardiopulmonary bypass were used in group 1. In group 2, beating heart coronary grafting was achieved with the Octopus 1 and 2 stabilizers. The average number of distal anastomoses was 2.8+/-0.1 in group 1 and 2.3+/-0.1 in group 2 (P=0.015). RESULTS: There was no significant difference among the groups regarding the trend in cardiac index, left and right ventricular stroke work indexes, and systemic and pulmonary vascular resistance indexes. However, heart rate trend was slower in group 2 (P=0.05). Pharmacological support was required in 65% of the patients in group 1, and in 33% in group 2 (P<0.001). The total amount of Dobutamine and/or Dopamine administered during the first 48 h was 3914+/-1306 gamma/kg in group 1 and 1645+/-697 gamma/kg in group 2 (P=0.049). Release of creatine kinase MB mass isoenzyme (CK-MB mass) was markedly reduced in group 2 (P<10(-4)). CONCLUSIONS: Hemodynamic outcome following off-pump CABG is similar to on-pump CABG but the need for inotropic support is significantly reduced and CPK-MB mass release is markedly lower.     

Good outcome after liver transplantation for ALD without a 6 months abstinence rule prior to transplantation including post‐transplant CDT monitoring for alcohol relapse assessment – a retrospective study

Alcoholic liver disease (ALD) is the second most common indication for liver transplantation (LT). The utility of fixed intervals of abstinence prior to listing is still a matter of discussion. Furthermore, post‐LT long‐term observation is challenging, and biomarkers as carbohydrate‐deficient transferrin (CDT) may help to identify alcohol relapse. We retrospectively analyzed data from patients receiving LT for ALD from 1996 to 2012. A defined period of alcohol abstinence prior to listing was not a precondition, and abstinence was evaluated using structured psychological interviews. A total of 382 patients received LT for ALD as main (n = 290) or secondary (n = 92) indication; median follow‐up was 73 months (0–213). One‐ and five‐year patient survival and graft survival rates were 82% and 69%, and 80% and 67%, respectively. A total of 62 patients (16%) experienced alcohol relapse. Alcohol relapse did not have a statistically significant effect on patient survival (P = 0.10). Post‐transplant CDT measurements showed a sensitivity and specificity of 84% and 85%, respectively. In conclusion, this large single‐center analysis showed good post‐transplant long‐term results in patients with ALD when applying structured psychological interviews before listing. Relapse rates were lower than those reported in the literature despite using a strict definition of alcohol relapse. Furthermore, post‐LT CDT measurement proved to be a useful supplementary tool for detecting alcohol relapse.     

Focal nodular hyperplasia occurring after blunt abdominal trauma

Focal nodular hyperplasia of the liver is a benign neoplasm. The pathogenesis is unknown, but it was hypothesized that focal nodular hyperplasia may be a response to a vascular abnormality. We report on a case of focal nodular hyperplasia that developed in a young patient 1 year after a blunt hepatic injury.