Effectiveness of anti-osteoporotic drugs to prevent secondary fragility fractures: systematic review and meta-analysis.

Patients with osteoporotic fractures have an increased risk for secondary fractures. However, a rigorous study that assesses the effectiveness of individual osteoporotic drugs in preventing subsequent fractures is lacking. The purpose of this review was to analyze the effectiveness of anti-osteoporotic drugs in preventing secondary fractures. We searched for randomized controlled trials that showed the incidence of secondary fractures while using anti-osteoporotic drugs (bisphosphonates, selective estrogen receptor modulators, parathyroid hormone (PTH), or calcitonin) in MEDLINE, Embase.com , and Cochrane Central Register databases. We estimated risk ratios (RR) and numbers needed to treat (NNT) to prevent secondary fractures. Twenty-six studies met our eligibility criteria. There was a significant reduction in RR (0.38-0.77) after the use of anti-osteoporotic drugs for secondary vertebral fractures. Bisphosphonates and PTH significantly reduced the risk of a secondary non-vertebral fracture (RR 0.59 and 0.64). PTH needed the fewest number of patients to be treated to prevent a secondary vertebral fracture (NNT: 56). Our study demonstrated the effectiveness of anti-osteoporotic agents included in our systematic review in preventing secondary vertebral fractures. Bisphosphonates and PTH were most effective in preventing non-vertebral fractures. We suggest that clinicians should prescribe these drugs to prevent secondary vertebral/non-vertebral fractures.

Health resource utilisation associated with skeletal-related events in patients with bone metastases secondary to solid tumours: regional comparisons in an observational study.

Skeletal-related events (SREs) including spinal cord compression, pathologic fracture, and radiation or surgery to bone, occur frequently due to bone metastases in advanced cancer. This analysis of a multicentre, observational study was designed to describe cross-regional differences in health resource utilisation (HRU) of SREs in Western Europe and the US. Patients with bone metastases due to breast, lung or prostate cancer, or multiple myeloma who had experienced a SRE within the past 97 days were enrolled. Investigators recorded HRU associated with SREs, including hospitalisation and length of stay (LOS), outpatient visits, procedures and bisphosphonate use. This subanalysis includes 668 patients with solid tumours (US, n = 190 with 354 SREs; EU, n = 478 with 893 SREs). The rate of SREs associated with hospitalisation(s) was higher in the EU vs. the US (30% vs. 15%, P < 0.001) and LOS was longer in the EU [mean (SD) days/SRE: 19.87 (17.31) vs. 10.61 (9.39)]. However, the US was associated with higher rate of SREs with outpatient visits than the EU (88% vs. 74%, P < 0.0001) and more procedures [mean (SD)/SRE: 11.26 (7.94) vs. 6.91 (6.48)]. Bisphosphonates were less often used in the EU (65% vs. 76% of US, P = 0.0033). In patients experiencing SREs due to bone metastases, HRU patterns reflect regional diversity with a substantial burden in both regions.

The effect of pre-procedure anxiety on sedative requirements for sedation during colonoscopy.

This study investigated the effects of pre-procedural anxiety (assessed using the Beck Anxiety Inventory) on sedative requirements in 135 patients undergoing sedation for colonoscopy. Deep sedation was defined as loss of consciousness and no response to colonoscopy, and was achieved by target-controlled infusion of propofol. Patients' characteristics, baseline haemodynamic profiles, Beck Anxiety Inventory scores, effect-site propofol concentration at loss of consciousness and characteristics of recovery were recorded. No correlations were found between Beck Anxiety Inventory scores and effect-site propofol concentration at loss of consciousness or baseline haemodynamic profiles. There was no statistical difference in the characteristics of recovery among patients with different levels of anxiety. In conclusion, in patients receiving deep sedation for colonoscopies, the level of pre-procedural anxiety did not relate to the sedative requirement or post-procedural recovery characteristics.

Comparison of clinical outcome of single-incision laparoscopic surgery using a simplified access system with conventional laparoscopic surgery for malignant colorectal disease.

AIM: Instrument crowding is encountered in single-incision laparoscopic surgery (SILS). Our aim was to compare the results of SILS with those of conventional laparoscopic surgery (CLS) for malignant colorectal disease. METHODS: The records of 27 patients who received SILS for the treatment of malignant disease using a home-made multiple-port system were compared with those of 68 patients who received CLS performed in a standard manner using four to five trocar sites. RESULTS: There were no significant differences in age, gender, disease stage, tumour location or tumour size between the SILS and CLS groups. The most common surgery was high anterior resection in both groups (SILS, 63.0%vs CLS, 58.8%). There were no significant differences between the groups in types of surgery performed, length of bowel resected, resection margin, blood loss, duration of surgery or postoperative complications. Postoperative pain scores were significantly higher in the SILS group than in the CLS group (3.07 ± 1.14 vs 2.41 ± 0.63, respectively, P < 0.001). CONCLUSIONS: SILS is as effective as CLS, and is not associated with increased duration of surgery, blood loss or complications.

Differentiation of central nervous system neuronal cells by fibroblast-derived growth factor requires at least two signaling pathways: roles for Ras and Src.

To evaluate the role of mitogen-activated protein (MAP) kinase and other signaling pathways in neuronal cell differentiation by basic fibroblast-derived growth factor (bFGF), we used a conditionally immortalized cell line from rat hippocampal neurons (H19-7). Previous studies have shown that activation of MAP kinase kinase (MEK) is insufficient to induce neuronal differentiation of H19-7 cells. To test the requirement for MEK and MAP kinase (ERK1 and ERK2), H19-7 cells were treated with the MEK inhibitor PD098059. Although the MEK inhibitor blocked the induction of differentiation by constitutively activated Raf, the H19-7 cells still underwent differentiation by bFGF. These results suggest that an alternative pathway is utilized by bFGF for differentiation of the hippocampal neuronal cells. Expression in the H19-7 cells of a dominant-negative Ras (N17-Ras) or Raf (C4-Raf) blocked differentiation by bFGF, suggesting that Ras and probably Raf are required. Expression of dominant-negative Src (pcSrc295Arg) or microinjection of an anti-Src antibody blocked differentiation by bFGF in H19-7 cells, indicating that bFGF also signals through a Src kinase-mediated pathway. Although neither constitutively activated MEK (MEK-2E) nor v-Src was sufficient individually to differentiate the H19-7 cells, coexpression of constitutively activated MEK and v-Src induced neurite outgrowth. These results suggest that (i) activation of MAP kinase (ERK1 and ERK2) is neither necessary nor sufficient for differentiation by bFGF; (ii) activation of Src kinases is necessary but not sufficient for differentiation by bFGF; and (iii) differentiation of H19-7 neuronal cells by bFGF requires at least two signaling pathways activated by Ras and Src.

Raf and fibroblast growth factor phosphorylate Elk1 and activate the serum response element of the immediate early gene pip92 by mitogen-activated protein kinase-independent as well as -dependent signaling pathways.

Previous studies have shown that a mitogen activated protein (MAP) kinase (MEK)-independent signaling pathway is required by activated Raf or fibroblast-derived growth factor (FGF) for the differentiation of rat hippocampal neuronal H19-7 cells. We now demonstrate that both Raf and FGF similarly induce prolonged transcription and translation of the immediate early gene pip92 in the absence of activation of the MAP kinases (MAPKs) ERK1 and ERK2. To determine the mechanism by which this occurs and to identify novel Raf-activated signaling pathways, we investigated the induction of the pip92 promoter by both FGF and an estradiol-activated Raf-1-estrogen receptor fusion protein (deltaRaf-1:ER) in H19-7 cells. Deletion analysis of the pip92 promoter indicated that activation by the MAPK-independent pathway occurs primarily within the region containing a serum response element (SRE). Further analysis of the SRE by using a heterologous thymidine kinase promoter showed that both an Ets and CArG-like site are required. Elk1, which binds to the Ets site, was phosphorylated both in vitro and in vivo by the MAPK-independent pathway, and phosphorylation of an Elk1-GAL4 fusion protein by this pathway was sufficient for transactivation. Finally, at least two Elk1 kinases were fractionated by gel filtration, and analysis by an in-gel kinase assay revealed at least three novel Raf-activated Elk1 kinases. These results indicate that both FGF and Raf activate MAPK-independent kinases that can stimulate Elk1 phosphorylation and immediate early gene transcription.

Identification of a silencer module which selectively represses cyclic AMP-responsive element-dependent gene expression.

The cyclic AMP (cAMP)-inducible promoter from the rat lactate dehydrogenase A subunit gene (LDH A) is associated with a distal negative regulatory element (LDH-NRE) that represses inherent basal and cAMP-inducible promoter activity. The element is of dyad symmetry, consisting of a palindromic sequence with two half-sites, 5'-TCTTG-3'. It represses the expression of an LDH A/chloramphenicol acetyltransferase (CAT) reporter gene in a dose-dependent, orientation- and position-independent fashion, suggesting that it is a true silencer element. Uniquely, it selectively represses cAMP-responsive element (CRE)-dependent transcription but has no effect on promoters lacking a CRE sequence. The repressing action of LDH-NRE could be overcome by cotransfection with LDH A/CAT vector oligonucleotides containing either the LDH-NRE or CRE sequence. This suggests that the reversal of repression was caused by the removal of functional active, limiting transacting factors which associate with LDH-NRE as well as with CRE. Gel mobility shift, footprinting, and Southwestern blotting assays demonstrated the presence of a 69-kDa protein with specific binding activity for LDH-NRE. Additionally, gel supershift assays with anti-CREB and anti-Fos antibodies indicate the presence of CREB and Fos or antigenically closely related proteins with the LDH-NRE/protein complex. We suggest that the LDH-NRE and CRE modules functionally interact to achieve negative modulation of cAMP-responsive LDH A transcriptional activity.

Augmentation of tumor metastasis by platelet-activating factor.

The effect of platelet-activating factor (PAF) on experimental pulmonary metastasis by the B16F10 murine melanoma and the possible involvement of PAF in the activities of tumor necrosis factor alpha (TNF-alpha) and interleukin 1alpha (IL-1alpha) in tumor metastasis were investigated. i.p. injection of PAF enhanced the lung colonization in a dose- and time-dependent manner. PAF enhanced lung colonization when it was administered after, but not before, B16F10 inoculation. Multiple injections of PAF were more effective than a single injection. Neutralization of endogenous PAF with PAF antagonist BN50739 decreased lung colonization, suggesting that endogenous PAF plays an important role in pulmonary metastases. A single i.p. injection of TNF-alpha or IL-1alpha caused a marked enhancement in lung colonization. TNF-alpha- and IL-1alpha-mediated enhancement in lung colonies was significantly inhibited by BN50739. These results demonstrate that PAF has a metastasis-enhancing effect and is a mediator of the metastatic activities of TNF-alpha and IL-1alpha.

The influence of androstadienone during psychosocial stress is modulated by gender, trait anxiety and subjective stress: An fMRI study.

Androstadienone (ANDR), a bodily secreted steroid compound, is a socially relevant chemosignal that modulates subjective and (neuro)physiological responses, predominantly in females. The impact of ANDR on stress responses in males and females has not been explored. Therefore, this fMRI study aimed to examine psychosocial stress reactions induced by mental arithmetic and social evaluation on behavioral and hormonal levels (46 participants: 15 naturally cycling females in their early follicular phase (EF), 15 females on hormonal contraceptives (HC) and 16 males); and on a neural level (40 participants: 13 EF-females, 13 HC-females and 14 males) in an ANDR and placebo treatment repeated-measures design. While no gender differences emerged in subjective ratings and performance during stress, neural activation patterns differed significantly. Besides, ANDR attenuated the post-stress increase of negative mood in all participants. Region of interest analyses showed that irrespective of treatment, males showed stronger activation of the dorsolateral prefrontal cortex (DLPFC) than females. At the whole brain level, gender differences emerged indicating stronger fronto-parietal activation in males compared to HC-females on both treatments. Males showed stronger visual and fusiform activation than EF-females under ANDR. Both female groups did not show stronger activation than males. Further, error ratio in the ANDR-stress condition was positively associated with their post-stress cortisol level and increase in subjective stress in males; and male DLPFC activity in the ANDR-stress condition was negatively associated with trait anxiety. Surprisingly, compared to HC-females, EF-female only showed stronger activation of arousal-related areas under placebo treatment. Taken together, these findings suggest that the male stress reaction under social evaluative threat was stronger than female stress reactions as a function of ANDR. More specifically, this effect on behavioral and neural stress reactions seems to depend on trait anxiety in males only. The study highlights the significance of a chemosignal in enhancing social threat that may facilitate adaptive stress responses.

CHIP-mediated degradation of transglutaminase 2 negatively regulates tumor growth and angiogenesis in renal cancer.

The multifunctional enzyme transglutaminase 2 (TG2) primarily catalyzes cross-linking reactions of proteins via (γ-glutamyl) lysine bonds. Several recent findings indicate that altered regulation of intracellular TG2 levels affects renal cancer. Elevated TG2 expression is observed in renal cancer. However, the molecular mechanism underlying TG2 degradation is not completely understood. Carboxyl-terminus of Hsp70-interacting protein (CHIP) functions as an ubiquitin E3 ligase. Previous studies reveal that CHIP deficiency mice displayed a reduced life span with accelerated aging in kidney tissues. Here we show that CHIP promotes polyubiquitination of TG2 and its subsequent proteasomal degradation. In addition, TG2 upregulation contributes to enhanced kidney tumorigenesis. Furthermore, CHIP-mediated TG2 downregulation is critical for the suppression of kidney tumor growth and angiogenesis. Notably, our findings are further supported by decreased CHIP expression in human renal cancer tissues and renal cancer cells. The present work reveals that CHIP-mediated TG2 ubiquitination and proteasomal degradation represent a novel regulatory mechanism that controls intracellular TG2 levels. Alterations in this pathway result in TG2 hyperexpression and consequently contribute to renal cancer.

Proteolytic degradation and potential role of onconeural protein cdr2 in neurodegeneration.

Cerebellar degeneration-related protein 2 (cdr2) is expressed in the central nervous system, and its ectopic expression in tumor cells of patients with gynecological malignancies elicits immune responses by cdr2-specific autoantibodies and T lymphocytes, leading to neurological symptoms. However, little is known about the regulation and function of cdr2 in neurodegenerative diseases. Because we found that cdr2 is highly expressed in the midbrain, we investigated the role of cdr2 in experimental models of Parkinson's disease (PD). We found that cdr2 levels were significantly reduced after stereotaxic injection of 1-methyl-4-phenylpyridinium (MPP(+)) into the striatum. cdr2 levels were also decreased in the brains of post-mortem PD patients. Using primary cultures of mesencephalic neurons and MN9D cells, we confirmed that MPP(+) reduces cdr2 in tyrosine hydroxylase-positive dopaminergic neuronal cells. The MPP(+)-induced decrease of cdr2 was primarily caused by calpain- and ubiquitin proteasome system-mediated degradation, and cotreatment with pharmacological inhibitors of these enzymes or overexpression of calcium-binding protein rendered cells less vulnerable to MPP(+)-mediated cytotoxicity. Consequently, overexpression of cdr2 rescued cells from MPP(+)-induced cytotoxicity, whereas knockdown of cdr2 accelerated toxicity. Collectively, our findings provide insights into the novel regulatory mechanism and potentially protective role of onconeural protein during dopaminergic neurodegeneration.

A systematic review of the management of acute pyogenic flexor tenosynovitis.

UNLABELLED: Pyogenic flexor tenosynovitis (PFT) is an aggressive closed-space infection that can result in severe morbidity. Although surgical treatment of pyogenic flexor tenosynovitis has been widely described, the role of antibiotic therapy is inadequately understood. We conducted a literature review of studies reporting on acute pyogenic flexor tenosynovitis management. A total of 28 case series articles were obtained, all of which used surgical intervention with varied use of antibiotics. Inconsistencies among the studies limited summative statistical analysis. Our results showed that use of antibiotics as a component of therapy resulted in improved range of motion outcomes (54% excellent vs. 14% excellent), as did using catheter irrigation rather than open washout (71% excellent vs. 26% excellent). These studies showed benefits of early treatment of pyogenic flexor tenosynovitis and of systemic antibiotic use. As broad-spectrum antibiotics have changed the management of other infectious conditions, we must more closely evaluate consistent antibiotic use in pyogenic flexor tenosynovitis management. LEVEL OF EVIDENCE: Therapeutic, Level III.

Mortality after distal radial fractures in the Medicare population.

The occurrence of a low energy fracture of the distal radius increases the risk for another, more serious fracture, such as a proximal femoral fracture. Early mortality after a proximal femoral fracture has been widely studied, but the association between a distal radial fracture and mortality is unknown. The date of death for all Medicare beneficiaries who sustained an isolated distal radial fracture in 2007 was determined using Medicare Vital Statistics files. The adjusted mortality rate for each age-sex group was calculated and compared with published US mortality tables. Distal radial fractures were not associated with an increased mortality rate. In fact, beneficiaries had a significantly lower mortality rate after distal radial fractures than the general population. This may be related to the injured beneficiaries' involvement in the healthcare system. Mortality rate did not vary significantly based on time from injury. Our results indicate that any mortality is unlikely to be attributable to the distal radial fracture or its treatment. Level of evidence: III.

Magnetocaloric properties of TbN, DyN and HoN nanopowders prepared by the plasma arc discharge method.

We report for the first time the synthesis of nanopowders of TbN, DyN and HoN crystallized in a cubic structure by the plasma arc discharge (PAD) method and investigate their magnetocaloric properties for magnetic refrigeration applications. The nitridization of terbium, dysprosium and holmium was obtained using a mixture of nitrogen and argon gas inside a discharge chamber with 4 kPa pressure. The structural and microstructural properties of these rare earth nitrides were investigated by using X-ray diffraction and transmission electron microscopy. The studied nitrides undergo a second-order ferromagnetic to paramagnetic phase transition at Curie temperatures of 35.7, 19.9 and 14.2 K for TbN, DyN and HoN, respectively. The magnetocaloric effects were estimated by calculating the magnetic entropy changes from the magnetization data sets measured at the different applied magnetic fields and temperatures. The changes in entropy -ΔSM were found to be 12.0, 13.6 and 24.5 J kg(-1) K(-1) at an applied magnetic field of 5 T.

Frequent allelic loss on chromosomes 4q and 16q associated with human hepatocellular carcinoma in Taiwan.

To define the critical region of liver-specific tumor suppressor genes in human hepatocellular carcinoma (HCC), we analyzed 30 cases of hepatocellular carcinoma using nine 4q and six 16q microsatellite polymorphic DNA markers. We observed one major common deleted region which was flanked by D4S175-D4S1625 and there may be two tumor suppressor genes on chromosome 16q associated with HCC. An extensive study of allelotyping of human HCC was therefore carried out in the candidate region on arms of chromosome 4q with additional tumor tissues and more informative microsatellite DNA markers. These data imply that at least one putative tumor suppressor gene is located in the human chromosome 4q26-q27 region and provides very useful information for further construction of a long-range physical restriction map and thereafter cloning of the putative tumor suppressor gene.

Multiple ligand interaction of alpha-synuclein produced various forms of protein aggregates in the presence of Abeta25-35, copper, and eosin.

Various protein aggregates of alpha-synuclein developed by way of the common protein self-oligomerization in the presence of Abeta25-35, copper, and eosin were examined. All the aggregates exhibited congo red birefringence although the actual amounts of the aggregates were varied as determined by thioflavin T binding fluorescence. When their morphologies were analyzed in relation to in vitro cytotoxicity, the smallest granular aggregates obtained with copper exhibited the highest cytotoxicity, while the fibrous structures by eosin did not affect the cell.

Expression of immediate early gene cyr61 during the differentiation of immortalized embryonic hippocampal neuronal cells.

Growth factor-mediated signal transduction is a process that is of fundamental importance in understanding cellular growth and differentiation. In order to elucidate the signaling pathways leading to neuronal differentiation, we have tried to identify intermediates that are selectively induced in the differentiation of immortalized neuronal hippocampal cell line H19-7. In the present study we found that immediate early gene cyr61 is expressed in a rapid and transient manner by bFGF during the differentiation of H19-7 cells. To clarify the signal transduction pathway for the induction of cyr61 by bFGF, we checked whether Raf-1 and mitogen-activated protein kinase (MAPK) is activated during the induction of cyr61. It is identified that cyr61 is induced by bFGF via at least two signaling pathways; MAPK-dependent as well as MAPK-independent signaling pathways. This study suggested that cyr61 is likely to play an important role in neuronal differentiation process.

Kinematics of cervical spine discectomy with and without bone grafting: quantitative evaluation of late fusion in a sheep model.

OBJECTIVE: This study was conducted to evaluate the kinematic response of late fusion results for cervical spine discectomies with and without bone grafting. MATERIALS AND METHODS: Fifteen Barbados Black Belly sheep underwent sham operations (Group A, n = 5), C2-C3 discectomies only (Group B, n = 5), and C2-C3 discectomies with autologous iliac bone grafting (Group C, n = 5). Ten months after surgery, the animals were killed. Fresh ligamentous spines (C1-C5) were subjected to the relevantly applied loads through a loading frame attached to the C1. Each vertebra (from C2 to C4) was attached with a set of three infrared light-emitting diodes to record the spatial location relating to each load application using a Selspot II system (Selcom Selective Electronics, Inc., Valdese, NC). The load-deformation data of the C2-C3 and C3-C4 motion segments were recorded and analyzed for the three groups. RESULTS: At the C2-C3 motion segment, the results indicated that Group B displayed larger motion ranges of rotation and lateral bending loads than did the other two groups. Significantly larger motion ranges of rotation loads were found in Group B than in Group C (P<0.05, for both comparisons). In contrast, Group C had the smallest motion ranges of flexion, lateral bending, and rotation loads. At the C3-C4 motion segment, both groups that had undergone discectomies had a significantly larger motion range of flexion load compared with Group A (P<0.05, for both comparisons). A significant increase in the motion range of right axial rotation was found in Group B (P<0.05), but not in Group C, compared with Group A. Group B exhibited larger motion ranges responding to all six tested loads than did Group C. CONCLUSION: The results indicate that anterior fusion after C2-C3 cervical discectomies, regardless of the presence or absence of bone grafting, decreases the motion range of flexion load at the C2-C3 motion segment, and contrary data were seen at the C3-C4 motion segment. For axial rotation loads, discectomies without bone grafting resulted in increased motion ranges of both C2-C3 and C3-C4 motion segments whereas discectomies with bone grafting did not. The data may have clinical relevance regarding the role of bone grafting in cases of cervical spine disease.

Adriamycin-inducible proteins associated with drug sensitivity in resistant immunoblastic B lymphoma cells.

We have previously established an immunoblastic B lymphoma cell line, designated HOB1. This cell line is hypersensitive to a wide spectrum of chemotherapeutic agents. Two co-regulated polypeptides around 64 kDa (termed p64) were induced 10-30-fold in response to adriamycin and some other drugs at the IC50 (the concentration inhibiting cell growth by 50%). These inducible proteins are localized as monomeric forms in the cytosolic fraction, with isoelectric points of pH = 6.2 (major protein) and pH = 7.0 (minor protein). An adriamycin-resistant cell line was established from HOB1 cells. The p64 inducibility was dramatically reduced in resistant HOB1 cells or unrelated cell lines which show phenotypic resistance to adriamycin toxicity. The loss of p64 inducibility in resistant cells is not due to a failure of cells to take up adriamycin since drug accumulation kinetics remained the same as in the parental cells.

Seat support surface optimization using force feedback.

The development, implementation and evaluation of an algorithm designed to find optimal seat support surfaces is presented. The algorithm has been developed and implemented on an active contour measurement device. The device consists of an array of positioning elements equipped with force sensors for feedback. With a patient seated on the array, the algorithm is designed to find a seat contour that optimally satisfies given performance criteria. The performance criteria are based on measured stiffness of the soft tissues. A theoretical development of the algorithm is presented along with the modifications made to the algorithm during implementation. The results from several tests using man-made test bodies and a prototype contour gage are presented to verify the algorithm's performance.