Visceral fat measured by DXA is associated with increased risk of non-spine fractures in nonobese elderly women: a population-based prospective cohort analysis from the São Paulo Ageing & Health (SPAH) Study

Summary

The present study investigates the relationship between visceral fat measured by dual-energy X-ray absorptiometry (DXA) and the incidence of non-spine fractures in community-dwelling elderly women. We demonstrated a potential negative effect of visceral fat on bone health in nonobese women.

Introduction

The protective effect of obesity on bone health has been questioned because visceral fat has been demonstrated to have a deleterious effect on bone. The aim of this study was to investigate the association of visceral fat measured by DXA with the incidence of non-spine fractures in community-dwelling elderly women.

Methods

This longitudinal prospective population-based cohort study evaluated 433 community-dwelling women aged 65 years or older. A specific clinical questionnaire, including personal history of a fragility fracture in non-spine osteoporotic sites, was administered at baseline and after an average of 4.3 years. All incidences of fragility fractures during the study period were confirmed by affected-site radiography. Visceral adipose tissue (VAT) was measured in the android region of a whole-body DXA scan.

Results

The mean age was 72.8?±?4.7 years, and 28 incident non-spine osteoporotic fractures were identified after a mean follow-up time of 4.3?±?0.8 years. According to the Lipschitz classification for nutritional status in the elderly, 38.6 % of women were nonobese (BMI?≤?27 kg/m²) and 61.4 % were obese/overweight. Logistic regression models were used to estimate the relationship between VAT and non-spine fractures in elderly women. After adjusting for age, race, previous fractures, and BMD, VAT (mass, area, volume) had a significant association with the incidence of non-spine fractures only in nonobese elderly women (VAT mass: OR, 1.42 [95 % CI, 1.09–1.85; p?=?0.010]; VAT area: OR, 1.19 [95 % CI, 1.05–1.36; p?=?0.008]; VAT volume: OR, 1.40 [95 % CI, 1.09–1.80; p?=?0.009]).

Conclusion

This study suggests a potential negative effect of visceral adiposity on bone health in nonobese women.

     

Macroscopic portal vein tumor thrombi of liver metastasis from colorectal cancer

We present a case of multiple colorectal liver metastases with macroscopic portal vein thrombi. A 55-year-old woman presented to us with rectosigmoid cancer and presented with two liver metastases. The tumor in the posterior sector was associated with invasion of first order branches of the portal vein. We performed low anterior resection, hepatic posterior sectorectomy and partial left anterior sectorectomy. Both the colorectal cancer and liver tumors exhibited histological characteristics of moderately differentiated adenocarcinoma with a substantial amount of mucin production. The liver metastases were associated with prominent tumor thrombi in many branches of the portal vein. Stronger staining for endoglin (CD 105) than for Fas ligand (Fas L) and matrix metalloproteinase (MMP-2) was observed in both the colorectal cancer and metastatic liver tumor cells. Expression of the vascular endothelial growth factor within the tumor cells was seen in both the colorectal cancer as well as the metastatic liver tumor cells. Six months after the operation, she was diagnosed to have multiple, more than about 20 liver metastases, and in 9 months after the operation, the patient died. The colorectal cancer with liver metastases associated with portal vein tumor thrombosis was poor prognosis, found neoplastic microvessel formation.     

RNA interference for noggin enhances the biological activity of bone morphogenetic proteins in vivo and in vitro

Noggin is a major extracellular antagonist to bone morphogenetic proteins (BMPs) which binds to BMPs and blocks binding of them to BMP-specific receptors and negatively regulates BMP-induced osteoblastic differentiation. In this study, we investigated the effect of noggin silencing by transfection of small interfering RNA (siRNA) on BMP-induced osteoblastic differentiation in vitro and ectopic bone formation in vivo induced by recombinant human BMP-2 (rhBMP-2). Noggin mRNA expression was up-regulated in response to rhBMP-2 in C2C12 cells, a myoblastic cell line, in dose- and time-dependent fashion as determined by real-time RT-PCR assay. Silencing of noggin expression by transfection of noggin siRNA suppressed BMP-stimulated noggin expression, resulting in acceleration of BMP-induced osteoblastic differentiation. For in vivo noggin silencing, siRNA was injected locally into back muscles and transfected into local cells by electroporation, where rhBMP-2-retaining (5 μg) collagen disks had been surgically placed. The implants were harvested at 2 weeks after surgery from experimental and control group mice and analyzed by radiological and histological methods. As a result, bone mineral content of ossicles ectopically induced by rhBMP-2 was significantly increased by silencing of noggin. Our findings suggest that silencing of noggin enhances the osteoblastic differentiation of BMP-responding cells in vitro and new bone formation induced by rhBMP-2 in vivo by eliminating negative regulation of the effects of BMP. RNA interference might be useful for intensifying the effects of BMP in promoting new bone (callus) formation in repair of damaged bone.     

Simultaneous resection for colorectal cancer and synchronous liver metastases

Purposes

The correct timing of hepatectomy in patients with synchronous colorectal liver metastases is unclear. The aim of this study was to assess the clinical value of simultaneous resection (SR) for patients with colorectal cancer and synchronous liver metastases.

Methods

Between January 2006 and December 2013, 158 patients underwent resection of primary colorectal cancer and liver metastases. Sixty-three patients possessed synchronous colorectal liver metastases. Of those with synchronous colorectal liver metastases, 41 patients (65 %) underwent SR, and 22 (35 %) underwent delayed resection (DR). The clinicopathologic and operative data and the surgical outcomes of the patients in the SR and DR groups were retrospectively analyzed.

Results

The type of primary/liver resection, liver resection time, total blood loss volume, R0 resection rate, and morbidity rate were similar between the two groups. The SR group was associated with a shorter total postoperative hospital stay (21 vs 32 days, p < 0.001). However, the overall survival rate was similar between the two groups (3-year survival, 65.6 % in the SR group versus 66.8 % in the DR group, p = 0.054).

Conclusion

Simultaneous resection of colorectal cancer and synchronous liver metastases is associated with a comparable morbidity rate and shorter hospital stay, even when following rectal resection and major hepatectomy.

     

Work stress and workload of full-time anesthesiologists in acute care hospitals in Japan

Purpose  The number of anesthesiologists per population in Japan is small compared with that in Europe and North America. While there is a growing concern that hard work causes anesthesiologists’ fatigue and may compromise patient safety, the workload and physical stress, as well as the impact of staff support on physicians’ stress have not been assessed in detail. The goal of this study was to evaluate the working environment, anesthesia workload, and occupational stress of anesthesiologists in Japan. Methods  A questionnaire survey was performed targeting 1010 members of the Japanese Society of Anesthesiologists working as anesthesiologists affiliated with acute care hospitals in Japan. Data on background information, working environment, operation anesthesia duties, and stress were collected, and the relationship of work stress with background, environment, and anesthesia duties was evaluated by linear regression analysis. Results  Responses were obtained from 383 full-time anesthesiologists (response rate, 43.9%). The total anesthesia time per week was 23.6 h on average. The work stress score was 114.3 ± 30.2 (mean ± SD) when the average workers’ work stress score in Japan was 100. The work stress score was significantly associated with “years of experience” (with experience < 10 years considered as the reference; 10–19 years: β = −0.18, P = 0.02, ≥20 years: β = −0.15, P = 0.04), “hospital with ≥500 beds” (with a hospital with ≤ 299 beds considered as the reference; β = 0.15, P = 0.04), “total time of anesthesia per week” (β = 0.18, P.02), “estimated annual cases managed by an anesthesiologist” (β = 0.12, P = 0.04) and “no-support stress” (β = 0.21, P < 0.01) on linear regression analysis (R² = 0.12). Conclusion  Our results provide a quantitative assessment of the duties of anesthesiologists and show that work stress among anesthesiologists is related to workload and other factors. Summaries of this study were presented at the 53rd and 54th General Meetings of the Japanese Society of Anesthesiologists (JSA) at Kobe (2006) and Sapporo (2007).     

Bone mineral and other bone components in vertebrae evaluated by QCT and MRI

To evaluate the usefulness of assessing bone components using magnetic resonance imaging (MRI), the contributions of bone components, including mineral, fat and collagen, to bone mineral density (BMD) and T1 relaxation time (T1) were studied using phantoms. Excised human vertebrae were also evaluated by quantitative computed tomography (QCT) and MRI. T1 was shortened with increasing quantities of fat and collagen. In water, T1 was significantly affected by bone density, while in oil, T1 became slightly longer as bone density increased. The presence of fat and collagen caused under- and overestimations of BMD, respectively. There was good correlation between T1 and BMD in osteoporotic vertebrae and the vertebrae with long T1 showed an increased content of hematopoietic marrow and/or abnormally increased bone mineral. It was concluded that the experimental data showed that MRI can contribute to the assessment of bone quality.     

Development of a therapeutic adenoviral vector for cholangiocarcinoma combining tumor-restricted gene expression and infectivity enhancement

Cholangiocarcinoma is an invasive malignancy that is most often unresectable upon diagnosis and unresponsive to chemotherapy and radiation. While adenoviral gene therapy has shown promise in treating many tumors, systemic toxicity and low tumor transduction efficiency have hampered its application in many gastrointestinal cancers. To overcome these difficulties, we have constructed an adenoviral vector utilizing a tumor-specific promoter (TSP) for selective transgene expression and a vector with an RGD-motif in the fiber-knob region for infectivity enhancement. In seeking a TSP for cholangiocarcinoma, Secretory Leukoprotease Inhibitor, Midkine, Gastrin Releasing Peptide, VEGF, Cox-2M, and Cox-2L promoters were configures in adenoviral vectors, and evaluated in cholangiocarcinoma cells lines (Oz and SkChA-1). Luciferase assays demonstrated that Cox-2 promoters (M and L) showed the highest promoter activity, with Cox-2M appearing slightly stronger than Cox-2L. Infectivity enhanced vectors with RGD-motif in the fiber-knob region were also constructed with the luciferase transgene driven by a CMV control and the Cox-2M and Cox-2L promoters. Subsequent luciferase assays comparing the unmodified vectors to the RGD-modified versions demonstrated higher levels of luciferase activity than the RGD-infected cells. This paradigm was then applied to a therapeutic HSV-TK/GCV model by constructing RGD-enhanced HSV-TK vectors driven by Cox-2M and Cox-2L promoters. In vitro cytocidal effect analysis confirmed that the RGD-modified, cox-2 (M and L) driven vectors showed a stronger cytocidal effect upon gancyclovir administration than the vectors with wild-type fiber. The Cox-2 promoter demonstrates a favorable selectivity profile for cholangiocarcinoma, and RGD-modification further enhances transduction efficiency. This combination has potential to overcome the obstacles to clinical application of adenoviral gene therapy in cholangiocarcinoma. Presented at the Forty-Third Annual Meeting of The Society for Surgery of The Alimentary Tract, San Francisco, California, May 19–22, 2002 (oral presentation).     

ADC value and diffusion tensor imaging of prostate cancer: changes in carbon-ion radiotherapy

PURPOSE: To assess the apparent diffusion coefficient (ADC) value and diffusion tensor image (DTI) including fractional anisotropy (FA) of the noncancerous prostate and prostate cancer before and after carbon-ion radiotherapy (CIRT). MATERIALS AND METHODS: Nine patients with biopsy-proven prostate cancer underwent 1.5T magnetic resonance (MR) examinations. One patient with benign prostatic hypertrophy and one healthy volunteer were also examined as references. The changes in ADC values and DTI of the entire prostate calculated from b-values of 0 and 700 (s/mm(2)) were estimated between before and after CIRT. RESULTS: ADC values of prostate cancer significantly increased after CIRT by paired t-test (P < 0.01) but those of noncancerous inner gland (IG) and peripheral zone (PZ) showed no significant change. By analysis of variance, significant differences in ADC values were observed among prostate cancer and noncancerous IG and PZ before CIRT (P < 0.05). After CIRT, those significant differences had disappeared. FAs showed no significant differences in any comparisons. DTI showed changes in the direction of the main axis of the tensor in prostate cancer after CIRT. CONCLUSION: There were changes in ADC and DTI in prostate cancer after CIRT. They may be useful for monitoring prostatic structural changes under radiotherapy.     

Internalization of antibodies by endothelial cells via fibronectin implicating a novel mechanism in lupus nephritis

BACKGROUND: One of the crucial events in lupus nephritis is the glomerular deposition of immunoglobulins (Igs), of which pathogenic properties have been proposed mostly to be either type IIor type III allergic reactions. Some of IgG3-producing hybridoma clones established from an MRL/MpTn-gld/gld (MRL/gld) lupus mouse generate wire loop-like lesions in glomeruli resembling lupus nephritis when injected into SCID mice. These clones are useful for analyzing the mechanisms of glomerular deposition of antibodies in lupus nephritis at the monoclonal level. METHODS: Glomerular lesions of SCID mice injected with the hybridoma clones, 17H8a or 1G3 as control were analyzed by light and electron microscopy. Interaction of the antibodies with human glomerular endothelial cells (HGECs) and human umbilical vein endothelial cells (HUVECs) in vitro was studied by fluorescence microscopy, electron microscopy, and flow cytometry. RESULTS: Both antibodies did not show any antigen specificity for mouse glomeruli. The glomerular lesions generated by 17H8a, but not by 1G3, contained electron-dense deposits not only in subendothelial regions but also in the cytoplasm of endothelial cells, suggesting internalization of the 17H8a antibodies by endothelial cells. In cell culture studies, internalization of only 17H8a antibodies by HGECs and HUVECs was observed, but the antibodies did not have antigen specificity for both types of endothelial cells. The internalization by HUVECs was mediated by actin polymerization, and it was inhibited by RGDS (Arg-Gly-Asp-Ser) tetrapeptide, antihuman fibronectin and antihuman integrin beta1 monoclonal antibodies. CONCLUSION: The interaction between particular antibodies and endothelial cell surface integrins via fibronectin may be involved in their subsequent internalization by endothelial cells leading to antibody deposition in glomeruli. This may be one of the mechanisms of glomerular injury in lupus nephritis.     

CD27/CD70, CD134/CD134 ligand, and CD30/CD153 pathways are independently essential for generation of regulatory cells after intratracheal delivery of alloantigen

BACKGROUND: We investigated whether blockade of tumor necrosis factor receptor-ligand pathways could generate regulatory cells induced by intratracheal delivery of alloantigen. METHODS: CBA (H-2k) mice were pretreated with intratracheal delivery of splenocytes (1x10(7)) from C57BL/10 (H-2b) mice and intraperitoneal administration of monoclonal antibody (mAb) specific for CD70, CD134 ligand (CD134L), CD153, or CD137L. Seven days later, C57BL/10 hearts were transplanted into pretreated CBA mice. Some naive CBA mice underwent adoptive transfer of splenocytes (5x10(7)) from pretreated CBA mice and transplantation of a C57BL/10 heart on the same day. RESULTS: Untreated CBA mice rejected C57BL/10 cardiac grafts acutely (median survival time [MST] 12 days). Pretreatment with intratracheal delivery of C57BL/10 donor splenocytes prolonged graft survival significantly (MST 84 days). Mice given intratracheal delivery of alloantigen plus anti-CD70, anti-CD134L, or anti-CD153 mAb, but not those given intratracheal delivery of alloantigen plus anti-CD137L mAb, rejected their graft acutely (MST 16, 14, 10, and 65 days, respectively). Adoptive transfer of splenocytes from mice pretreated with intratracheal delivery of alloantigen plus anti-CD70, CD134L, or CD153 mAb did not prolong survival of C57BL/10 cardiac grafts in naive secondary CBA recipients (MST 14, 11, and 11 days, respectively), whereas adoptive transfer of splenocytes from mice given intratracheal delivery of alloantigen plus anti-CD137L mAb did (MST 75 days). CONCLUSION: The CD27/CD70, CD134/CD134L, and CD30/CD153 pathways are independently required for generation of regulatory cells in our model.