1,25-Dihydroxyvitamin D3 has been shown to play an important role in vitro in regulating osteoblast gene transcription and promoting osteoclast differentiation. To address the role of the vitamin D ...receptor (VDR) in skeletal homeostasis, formal histomorphometric analyses were performed in VDR null mice in the setting of impaired mineral ion homeostasis as well as in VDR null mice in whom normal mineral ion homeostasis had been preserved. In hypocalcemic VDR null mice, there was an increase in bone volume as a result of a dramatic increase in osteoid. There was also an increase in the number of osteoblasts without a significant change in the number of osteoclasts. Examination of the growth plate revealed marked disorganization, with an increase in vascularity and matrix. Biomechanical parameters demonstrated increased bone fragility in the hypocalcemic VDR null mice. In the VDR ablated mice in whom normal mineral ion homeostasis had been preserved, none of these measurements was significantly different from those in wild-type littermates raised under identical conditions. Notably, the morphology and width of the growth plate were indistinguishable from those in wild-type controls, demonstrating that a calcium/phosphorus/lactose-enriched diet started at 16 days of age in the VDR null mice permits the development of both normal morphology in the growth cartilage and adjacent metaphysis and normal biomechanical competence of cortical bone. Thus, the principle action of the VDR in skeletal growth, maturation, and remodeling is its role in intestinal calcium absorption. The skeletal consequences of VDR ablation are a result of impaired intestinal calcium absorption and/or the resultant secondary hyperparathyroidism and hypophosphatemia.
Mechanical loading and estrogen play important roles in bone homeostasis. The aim of this study was to evaluate the effects of mechanical loading on trabecular bone in the proximal femur of ...ovariectomized rats. We hypothesized that mechanical loading suppresses bone resorption and increases bone formation, which differs from the suppressive effects of estrogen on both resorption and formation. Furthermore, we expected to find changes in trabecular architecture elicited by the effects of mechanical loading and estrogen deficiency. Sixty female Wistar rats, 12 weeks old, were assigned to either the sedentary groups sham surgery (SED), ovariectomy (SED+OVX), and ovariectomy with estrogen replacement (SED+OVX+E2) or to the exercise groups EX, EX+OVX, EX+OVX+E2. Following ovariectomy, 5 microg 17beta-estradiol was given once weekly to the estrogen replacement groups. Exercise consisted of running with a backpack (load +/-20% of body weight) for 15 minutes/day, 5 days/week, for 19 weeks. Dual-energy X-ray absorptiometry (DXA) scans were performed before (T0), during (T6), and after (T19) the exercise period to obtain bone mineral content (BMC) and bone mineral density (BMD) data. After the exercise program, all rats were killed and right and left femora were dissected and prepared for micro-CT scanning and histomorphometric analysis of the proximal femoral metaphysis. After 19 weeks, increases in BMC (P = 0.010) and BMD (P = 0.031) were significant. At T19, mechanical loading had a significant effect on BMC (P = 0.025) and BMD (P = 0.010), and an interaction between mechanical loading and estrogen (P = 0.023) was observed. Bone volume and trabecular number decreased significantly after ovariectomy, while trabecular separation, mineralizing surface, bone formation rate, osteoclast surface, degree of anisotropy, and structure model index increased significantly after ovariectomy (P < 0.05). Trabecular bone turnover and structural parameters in the proximal femur were not affected by exercise. Estrogen deficiency resulted in a less dense and more oriented trabecular bone structure with increased marrow cavity and a decreased number of trabeculae. In conclusion, mechanical loading has beneficial effects on BMC and BMD of the ovariectomized rat. This indicates that the load in the backpack was high enough to elicit an osteogenic response sufficient to compensate for the ovariectomy-induced bone loss. The results confirm that estrogen suppresses both bone resorption and bone formation in the proximal metaphysis in the femoral head of our rat-with-backpack model. The effects of mechanical loading on the trabecular bone of the femoral head were not significant. This study suggests that the effect of mechanical loading in the rat-with-backpack model mainly occurs at cortical bone sites.
Infection with the tick-borne encephalitis virus (TBEV) can result in various neurological complications. At present, there are little data available on laboratory findings that might help predict ...the clinical course and prognosis of tick-borne encephalitis (TBE). In the present study 100 patients with TBE were examined in respect to various laboratory parameters potentially characteristic for the disease and indicative for the prognosis in TBE. Pleocytosis, impairment of the blood-CSF barrier and intrathecal synthesis of immunoglobulins (IgM > IgG, IgA) were common findings in most patients. On admission to the hospital, 84% of the patients presented with an intrathecal synthesis of TBEV-specific IgM and/or IgG antibodies in the CSF. At follow-up, intrathecal synthesis of TBEV-specific antibodies was demonstrated in all patients studied within 15 days after the first examination, but changes of CSF parameters did not correlate with the clinical course of disease. In contrast to those with moderate course of disease, patients with severe courses of TBE displayed higher cell counts in the CSF and lower concentrations of neutralizing antibodies in serum, and more frequently revealed an intrathecal synthesis of total IgG. TBE-specific oligoclonal IgG antibodies in the CSF were demonstrated only in three patients with prior, incomplete, vaccination against TBE. The severe course of disease in individual patients with TBE may result from a slow or low production of neutralizing antibodies. In these patients, the more intense damage of the CNS tissue is reflected by higher cell counts in the CSF. At onset of disease the presence of a low concentration of neutralizing antibodies in serum and a high cell count in the CSF might indicate an unfavorable course of TBE.
Colorectal cancer is one of the leading causes of cancer deaths in the Western world. A better understanding of the development and progression of colorectal carcinoma is needed to define novel ...targets and strategies for treatment.
Gene expression profiles were determined for primary tumors of 10 locally restricted (T3N0M0), 8 lymphatically metastasized (T3N+M0), 7 systemically metastasized (T3N+M1) colorectal carcinomas, and 6 specimens of normal colorectal tissue by histology-guided oligonucleotide microarray analysis.
A total of 1,995 genes were differently regulated in primary tumors of colorectal carcinoma compared with normal colorectal tissue. Besides common features of dedifferentiation and different expression of genes involved in cell division, cell adhesion, angiogenesis, signal transduction and metabolism we observed a deregulation of genes with an as yet unclear function. We identified 126 genes that were subsequently up- and 204 genes down-regulated during tumor progression. Furthermore, we found a cluster of five genes exclusively up-regulated in primary tumors of systemically metastasized colorectal carcinomas. A comparison of locally restricted (T3N0M0) and systemically metastasized (T3N+M1) primary tumors showed 50 deregulated genes with a massive down-regulation of immune-modulatory genes in primary tumors of systemically metastasized carcinomas. Primary tumors of lymphatically (T3N+M0) and systemically metastasized (T3N+M1) carcinomas differed in the expression of 19 genes.
These results provide an additional step toward the identification of crucial genes for the progression of colorectal cancer and the identification of novel treatment targets or strategies.
Injecting drug users (IDU) are at risk of parenterally transmitted diseases such as hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infection. We investigated ...whether a history of syringe sharing in prison is a risk factor for these infections. In the longitudinal part of the study, HBV, HCV, and HIV seroincidence rates were determined.
The participants were recruited by multisite-sampling at different agencies for IDU. Data on risk behaviour were obtained by a standardized questionnaire. Serological markers for HBV, HCV, and HIV were determined. Logistic regression analysis was performed to adjust for confounding effects.
A history of syringe sharing in prison was significantly associated with HBV (adjusted prevalence odds ratio POR = 3.9, 95% confidence interval CI: 2-10), HCV (POR = 9.7, 95% CI: 3-33), and HIV infection (POR = 10.4, 95% CI: 4-29). The HIV seroincidence rate was 5.9 per 100 person-years. None of the IDU receiving methadone maintenance treatment (MMT) seroconverted whereas the HIV incidence was 8.5 among IDU not in MMT (P = 0.01).
The increased risk of HBV, HCV, and HIV infection among IDU who had shared syringes in prison warrants specific preventive action. The longitudinal data suggest that IDU in MMT have a lower risk of HIV infection.
Hardware and software systems will inevitably grow in scale and functionality. Because of this increase in complexity, the likelihood of subtle errors is much greater. A major goal of software ...engineering is to enable developers to construct systems that operate reliably despite this complexity. One way of achieving this goal is by using formal methods, which are mathematically based languages, techniques, and tools for specifying and verifying such systems. The state of the art in specification and verification is assessed. For verification, advances are highlighted in model checking and theorem proving. The future directions in fundamental concepts, new methods and tools, integration of methods, and education and technology transfer are outlined.
Abstract Background/Purpose Surgical wound class (SWC) is used to risk-stratify surgical site infections (SSI) for quality reporting. We previously demonstrated only 8% agreement between ...hospital-based SWC and diagnosis-based SWC for acute appendicitis. We hypothesized that education and process-based interventions would improve hospital-based SWC reporting and the validity of SSI risk stratification. Methods Patients (< 18 years old) who underwent appendectomies for acute appendicitis between January 2011 and December 2013 were included. Interventions entailed educational workshops regarding SWC for perioperative personnel and inclusion of SWC as a checkpoint in the surgical safety checklist. Thirty-day postoperative SSIs were recorded. Chi-square, Fisher’s exact test, and kappa statistic were utilized. Results 995 cases were reviewed (pre-intervention = 478, post-intervention = 517). Weighted interrater agreement between hospital-based and diagnosis-based SWC improved from 50% to 81% (p < 0.01), and weighted kappa increased from 0.16 (95% CI 0.004–0.03) to 0.29 (95% CI 0.25–0.34). Hospital-based dirty wounds were significantly associated with SSI in the post-intervention period only (p < 0.01). Conclusions Agreement between hospital-based SWC and diagnosis-based SWC significantly improved after simple interventions, and SSI risk stratification became consistent with the expected increase in disease severity. Despite these improvements, there were still substantial gaps in SWC knowledge and process.
To enable detailed analyses of cell interactions in tumour development, new epithelial and mesenchymal cell lines were established from human hepatocellular carcinoma by spontaneous outgrowth in ...culture. We obtained several hepatocarcinoma (HCC)-, B-lymphoblastoid (BLC)-, and myofibroblastoid (MF)-lines from seven cases. In-depth characterisation included cell kinetics, genotype, tumourigenicity, expression of cell-type specific markers, and proteome patterns. Many functions of the cells of origin were found to be preserved. We studied the impact of the mesenchymal lines on hepatocarcinogenesis by in vitro assays. BLC- and MF-supernatants strongly increased the DNA replication of premalignant hepatocytes. The stimulation by MF-lines was mainly attributed to HGF secretion. In HCC-cells, MF-supernatant had only minor effects on cell growth but enhanced migration. MF-lines also stimulated neoangiogenesis through vEGF release. BLC-supernatant dramatically induced death of HCC-cells, which could be largely abrogated by preincubating the supernatant with TNFbeta-antiserum. Thus, the new cell lines reveal stage-specific stimulatory and inhibitory interactions between mesenchymal and epithelial tumour cells. In conclusion, the new cell lines provide unique tools to analyse essential components of the complex interplay between the microenvironment and the developing liver cancer, and to identify factors affecting proliferation, migration and death of tumour cells, neoangiogenesis, and outgrowth of additional malignancy.
We deployed 72 sensors of 10 modalities in 15 wireless and wired networked sensor systems in the environment, in objects, and on the body to create a sensor-rich environment for the machine ...recognition of human activities. We acquired data from 12 subjects performing morning activities, yielding over 25 hours of sensor data. We report the number of activity occurrences observed during post-processing, and estimate that over 13000 and 14000 object and environment interactions occurred. We describe the networked sensor setup and the methodology for data acquisition, synchronization and curation. We report on the challenges and outline lessons learned and best practice for similar large scale deployments of heterogeneous networked sensor systems. We evaluate data acquisition quality for on-body and object integrated wireless sensors; there is less than 2.5% packet loss after tuning. We outline our use of the dataset to develop new sensor network self-organization principles and machine learning techniques for activity recognition in opportunistic sensor configurations. Eventually this dataset will be made public.
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