In an in vitro model of human tuberculosis, monocyte-microglial networks regulate matrix metalloproteinase-1 and -3 gene expression and secretion via a p38 mitogen activated protein kinase-dependent pathway.

BACKGROUND: Tuberculosis (TB) of the central nervous system (CNS) is characterized by extensive tissue inflammation, driven by molecules that cleave extracellular matrix such as matrix metalloproteinase (MMP)-1 and MMP-3. However, relatively little is known about the regulation of these MMPs in the CNS. METHODS: Using a cellular model of CNS TB, we stimulated a human microglial cell line (CHME3) with conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb). MMP-1 and MMP-3 secretion was detected using ELISAs confirmed with casein zymography or western blotting. Key results of a phospho-array profile that detects a wide range of kinase activity were confirmed with phospho-Western blotting. Chemical inhibition (SB203580) of microglial cells allowed investigation of expression and secretion of MMP-1 and MMP-3. Finally we used promoter reporter assays employing full length and MMP-3 promoter deletion constructs. Student's t-test was used for comparison of continuous variables and multiple intervention experiments were compared by one-way ANOVA with Tukey's correction for multiple pairwise comparisons. RESULTS: CoMTb up-regulated microglial MMP-1 and MMP-3 secretion in a dose- and time-dependent manner. The phospho-array profiling showed that the major increase in kinase activity due to CoMTb stimulation was in p38 mitogen activated protein kinase (MAPK), principally the α and γ subunits. p38 phosphorylation was detected at 15 minutes, with a second peak of activity at 120 minutes. High basal extracellular signal-regulated kinase activity was further increased by CoMTb. Secretion and expression of MMP-1 and MMP-3 were both p38 dependent. CoMTb stimulation of full length and MMP-3 promoter deletion constructs demonstrated up-regulation of activity in the wild type but a suppression site between -2183 and -1612 bp. CONCLUSIONS: Monocyte-microglial network-dependent MMP-1 and MMP-3 gene expression and secretion are dependent upon p38 MAPK in tuberculosis. p38 is therefore a potential target for adjuvant therapy in CNS TB

Nor-hopanes from Zanha africana root bark with toxicity to bruchid beetles

Zanha africana (Radlk.) Exell (Sapindaceae) root bark is used by farmers throughout sub-Saharan Africa to protect stored grain from bruchid beetles, such as Callosobruchus maculatus. Chloroform, methanol and water extracts of Z. africana root bark inhibited oviposition and caused significantly higher mortality of C. maculatus at a rate of application equivalent to that applied by farmers compared to control insects. The chloroform extract contained nor-hopanes rarely found in plants of which seven were isolated, one of which was previously known. Two of the most abundant nor-hopanes 3β,6β-dihydroxy-7β-[(4-hydroxybenzoyl)oxy]-21αH-24-norhopa-4(23),22(29)-diene and 3β,6β-dihydroxy-7β-[(4-hydroxybenzoyl)oxy]-24-norhopa-4(23),17(21)-diene were toxic to and reduced oviposition of C. maculatus in a dose dependent manner. Z. africana root bark is rich in insecticidal compounds that account for its effective use by smallholder farmers as an alternative to conventional insecticides

Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit

Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an <i>in vitro</i> model of CNS tuberculosis

Central nervous system tuberculosis (CNS TB) has a high mortality and morbidity associated with severe inflammation. The blood-brain barrier (BBB) protects the brain from inflammation but the mechanisms causing BBB damage in CNS TB are uncharacterized. We demonstrate that Mycobacterium tuberculosis (Mtb) causes breakdown of type IV collagen and decreases tight junction protein (TJP) expression in a co-culture model of the BBB. This increases permeability, surface expression of endothelial adhesion molecules and leukocyte transmigration. TJP breakdown was driven by Mtb-dependent secretion of matrix metalloproteinase (MMP)-9. TJP expression is regulated by Sonic hedgehog (Shh) through transcription factor Gli-1. In our model, the hedgehog pathway was downregulated by Mtb-stimulation, but Shh levels in astrocytes were unchanged. However, Scube2, a glycoprotein regulating astrocyte Shh release was decreased, inhibiting Shh delivery to brain endothelial cells. Activation of the hedgehog pathway by addition of a Smoothened agonist or by addition of exogenous Shh, or neutralizing MMP-9 activity, decreased permeability and increased TJP expression in the Mtb-stimulated BBB co-cultures. In summary, the BBB is disrupted by downregulation of the Shh pathway and breakdown of TJPs, secondary to increased MMP-9 activity which suggests that these pathways are potential novel targets for host directed therapy in CNS TB

Peri-orbital foreign body: a case report

<p>Abstract</p> <p>Introduction</p> <p>Foreign bodies inside the orbital cavity are rare. They can cause more or less serious complications, depending on their nature and size.</p> <p>Case presentation</p> <p>We report a case of a work-related accident involving a peri-orbital foreign body. The patient was a 50-year-old Caucasian man whose face was injured on the right side while he was working with an agricultural machine. On admission, he was fully conscious and did not have any neurological deficits. He had no loss of vision or ocular motility, but had a laceration of the lateral side of his right upper eyelid. A computed tomographic scan revealed a 6-cm-long bended metal object lodged in the lateral bulbar space of the right orbit. The patient recovered well after surgery and a course of antibiotic therapy.</p> <p>Conclusion</p> <p>The original aspects of this case are the singularity of the foreign body and its relative harmlessness in spite of its large size.</p

IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F

Isocitrate dehydrogenase (IDH) mutations are frequent in blast-phase myeloproliferative neoplasms and might therefore contribute to leukemic transformation. We examined this possibility in 301 consecutive patients with chronic-phase primary myelofibrosis (PMF). The mutant IDH was detected in 12 patients (4%): 7 IDH2 (5 R140Q, 1 R140W and 1 R172G) and 5 IDH1 (3 R132S and 2 R132C). In all, 6 (50%) of the 12 IDH-mutated patients also expressed JAK2V617F. Overall, 18 (6%) patients displayed only MPL and 164 (54.3%) only JAK2 mutations. Multivariable analysis that accounted for conventional risk factors disclosed inferior overall survival (OS; P=0.03) and leukemia-free survival (LFS; P=0.003) in IDH-mutated patients: OS hazard ratio (HR) was 0.39 (95% confidence interval (95% CI) 0.2–0.75), 0.50 (95% CI 0.27–0.95) and 0.53 (95% CI 0.23–1.2) for patients with no, JAK2 or MPL mutations, respectively. Further analysis disclosed a more pronounced effect for the mutant IDH on OS and LFS in the presence (P=0.0002 and P<0.0001, respectively) as opposed to the absence (P=0.34 and P=0.64) of concomitant JAK2V617F. Analysis of paired samples obtained during chronic- and blast-phase disease revealed the presence of both IDH and JAK2 mutations at both time points. Our observations suggest that IDH mutations in PMF are independent predictors of leukemic transformation and raise the possibility of leukemogenic collaboration with JAK2V617F

Dacron® vs. PTFE as bypass materials in peripheral vascular surgery – systematic review and meta-analysis

Roll S, Müller-Nordhorn J, Keil T, et al. Dacron® vs. PTFE as bypass materials in peripheral vascular surgery – systematic review and meta-analysis. BMC Surgery. 2008;8(1): 22.Background: In peripheral vascular bypass surgery different synthetic materials are available for bypass grafting. It is unclear which of the two commonly used materials, polytetrafluoroethylene (PTFE) or polyester (Dacron®) grafts, is to be preferred. Thus, the aim of this meta-analysis and systematic review was to compare the effectiveness of these two prosthetic bypass materials (Dacron® and PTFE). Methods: We performed a systematic literature search in MEDLINE, Cochrane-Library – CENTRAL, EMBASE and other databases for relevant publications in English and German published between 1999 and 2008. Only randomized controlled trials were considered for inclusion. We assessed the methodological quality by means of standardized checklists. Primary patency was used as the main endpoint. Random-effect meta-analysis as well as pooling data in life table format was performed to combine study results. Results: Nine randomized controlled trials (RCT) were included. Two trials showed statistically significant differences in primary patency, one favouring Dacron® and one favouring PTFE grafts, while 7 trials did not show statistically significant differences between the two materials. Meta-analysis on the comparison of PTFE vs. Dacron® grafts yielded no differences with regard to primary patency rates (hazard ratio 1.04 (95% confidence interval [0.85;1.28]), no significant heterogeneity (p = 0.32, I2 = 14%)). Similarly, there were no significant differences with regard to secondary patency rates. Conclusion: Systematic evaluation and meta-analysis of randomized controlled trials comparing Dacron® and PTFE as bypass materials for peripheral vascular surgery showed no evidence of an advantage of one synthetic material over the other

Psychosocial correlates of dietary fat intake in African-American adults: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Current dietary guidelines recommend that dietary fat should comprise 20–35% percent of total energy intake, with less than 10% of energy from saturated fat. However, many Americans exceed these goals and data suggest that African Americans tend to consume a higher percentage of energy from dietary fat than Whites. Because diets low in dietary fat, particularly saturated fat, are associated with lower risk for many chronic illnesses, it is important to identify strategies to reduce high fat intakes. This study examined associations of psychosocial factors with dietary fat intake in African American adults 18 to 70 years.</p> <p>Methods</p> <p>Data are self-reported from a cross-sectional survey of African Americans (n = 658) using an 11-page questionnaire, collected from June to October 2003. Associations of psychosocial (predisposing, reinforcing, and enabling) factors based on the PRECEDE framework, dietary fat-related behaviors, and participant characteristics (e.g., age, sex, education, BMI) with total and saturated fat consumption are described using linear regression and analysis of variance.</p> <p>Results</p> <p>The mean age of participants was 43.9 years, 57% were female, 37% were college graduates, and 76% were overweight/obese. Respondents with lower fat intakes were female, older, had high education and very good/excellent perceived health. Among the psychosocial factors, the strongest (inverse) associations with fat intake were with two predisposing factors: <it>belief in the importance of a low-fat diet </it>(both genders) and <it>high self-efficacy </it>(women only). Fat intake was also significantly lower among participants who could <it>count on those close for encouragement to eat healthy foods </it>(a reinforcing factor) and among men who <it>needed more information about preparing healthy foods </it>(an enabling factor).</p> <p>Conclusion</p> <p>Dietary interventions to decrease fat intake in African American adults may benefit from incorporating predisposing factors, such as personal beliefs and self-efficacy, in their design and implementation.</p

Use of conventional and alternative treatment strategies for a case of low back pain in a F/A-18 aviator

BACKGROUND: Low back pain can diminish jet pilot concentration and function during flight and be severe enough to ground pilots or cause decreased flying time. The objective of this case report is to present an example of the integration of chiropractic care with conventional treatments for the management of low back pain in a F/A-18 aviator. CASE PRESENTATION: The patient had insidious severe low back pain without radiation or neurological deficit, resulting in 24 hours of hospitalization. Spinal degeneration was discovered upon imaging. Four months later, it still took up to 10 minutes for him to get out of bed and several minutes to exit the jet due to stiffness and pain. He had discontinued his regular Marine Corps fitness training due to pain avoidance. Pain severity ranged from 1.5–7.1 cm on a visual analog scale. His Roland Morris Disability Questionnaire score was 5 out of 24. The pilot's pain was managed with the coordinated efforts of the flight surgeon, physiatrist, physical therapist, and doctor of chiropractic. Following this regimen he had no pain and no functional disability; he was able to fly multiple training missions per week and exercise to Marine Corps standards. CONCLUSION: A course of care integrating flight medicine, chiropractic, physical therapy, and physiatry appeared to alleviate pain and restore function to this F/A-18 aviator with low back pain

Optimising reproductive and child health outcomes by building evidence-based research and practice in South East Asia (SEA-ORCHID): study protocol

Background Disorders related to pregnancy and childbirth are a major health issue in South East Asia. They represent one of the biggest health risk differentials between the developed and developing world. Our broad research question is: Can the health of mothers and babies in Thailand, Indonesia, the Philippines and Malaysia be improved by increasing the local capacity for the synthesis of research, implementation of effective interventions, and identification of gaps in knowledge needing further research? Methods/Design The project is a before-after study which planned to benefit from and extend existing regional and international networks. Over five years the project was designed to comprise five phases; pre-study, pre-intervention, intervention, outcome assessment and reporting/dissemination. The study was proposed to be conducted across seven project nodes: four in South East Asia and three in Australia. Each South East Asian study node was planned to be established within an existing department of obstetrics and gynaecology or neonatology and was intended to form the project coordinating centre and focus for evidence-based practice activities within that region. Nine hospitals in South East Asia planned to participate, representing a range of clinical settings. The three project nodes in Australia were intended to provide project support. The intervention was planned to consist of capacity-strengthening activities targeted at three groups: generators of evidence, users of evidence and teachers of evidence. The primary outcome was established as changes in adherence to recommended clinical practices from baseline to completion of the project and impact on health outcomes. Discussion The SEA-ORCHID project was intended to improve care during pregnancy and the perinatal period of mothers and their babies in South East Asia. The possible benefits extend beyond this however, as at the end of this project there is hoped to be an existing network of South East Asian researchers and health care providers with the capacity to generalise this model to other health priority areas. It is anticipated that this project facilitate ongoing development of evidence-based practice and policy in South East Asia through attracting long-term funding, expansion into other hospitals and community-based care and the establishment of nodes in other countries.David J Henderson-Smart, Pisake Lumbiganon, Mario R Festin, Jacqueline J Ho, Hakimi Mohammad, Steve J McDonald, Sally Green and Caroline A Crowther for the SEA-ORCHID Study Grou