HOXA10 controls osteoblastogenesis by directly activating bone regulatory and phenotypic genes

HOXA10 is necessary for embryonic patterning of skeletal elements, but its function in bone formation beyond this early developmental stage is unknown. Here we show that HOXA10 contributes to osteogenic lineage determination through activation of Runx2 and directly regulates osteoblastic phenotypic genes. In response to bone morphogenic protein BMP2, Hoxa10 is rapidly induced and functions to activate the Runx2 transcription factor essential for bone formation. A functional element with the Hox core motif was characterized for the bone-related Runx2 P1 promoter. HOXA10 also activates other osteogenic genes, including the alkaline phosphatase, osteocalcin, and bone sialoprotein genes, and temporally associates with these target gene promoters during stages of osteoblast differentiation prior to the recruitment of RUNX2. Exogenous expression and small interfering RNA knockdown studies establish that HOXA10 mediates chromatin hyperacetylation and trimethyl histone K4 (H3K4) methylation of these genes, correlating to active transcription. HOXA10 therefore contributes to early expression of osteogenic genes through chromatin remodeling. Importantly, HOXA10 can induce osteoblast genes in Runx2 null cells, providing evidence for a direct role in mediating osteoblast differentiation independent of RUNX2. We propose that HOXA10 activates RUNX2 in mesenchymal cells, contributing to the onset of osteogenesis, and that HOXA10 subsequently supports bone formation by direct regulation of osteoblast phenotypic genes. <br/

Predicting referral practices of traditional healers of their patients with a mental illness: An application of the Theory of Planned Behaviour

Objective: Although many studies indicate that traditional healers are willing to collaborate with Western practitioners in South Africa, none focus specifically on mental health care, and none use a theory of health behaviour to explain their findings. The present study applies the Theory of Planned Behaviour (TPB) to predict traditional healer referral practices of patients with a mental illness.Method: One hundred traditional healers were first interviewed to assess the TPB variables and were contacted again 5 months later to measure self-reported behaviour.Results: Herbalists were less likely than other types of healers to referpatients with a mental illness to Western health professionals. From the TPB application, the following cognitive variables were found to predict intentions: attitudes (ß = 0.612, p&lt; 0.01); perceived behavioural control (ß = 0.355, p&lt; 0.01); and past behaviour (ß = 0.704, p&lt; 0.01). Subjective norms and knowledge of mental illness did not predict intentions. Finally, past behaviour (ß = 0.297, p = 0.040) and intentions to refer patients (ß = 0.758, p&lt; 0.01) predicted greater self-reported behaviour.Conclusion: The TPB may be a useful theoretical model for predicting the referral practices of traditional healers. The empirical data here may be useful for future work designing interventions to provide traditional healers with the information and skills they require to appropriately refer patients with mental illness.Keywords: Medicine, African traditional; Referral and Consultation; Decision Analyses; South Afric

A comparison of two-coloured filter systems for treating visual reading difficulties

Copyright @ 2013 Informa UK Ltd.Purpose: Visual disturbances that make it difficult to read text are often termed “visual stress”. Coloured filters in spectacles may help some children overcome reading problems that are often caused by visual stress. It has been suggested that for optimal effect each child requires an individually prescribed colour for each eye, as determined in systems such as the “Harris Foundation” coloured filters. Alternatively, it has been argued that only blue or yellow filters, as used in the “Dyslexia Research Trust” (DRT) filter system, are necessary to affect the underlying physiology. Method: A randomised, double blind trial with 73 delayed readers, was undertaken to compare changes in reading and spelling as well as irregular and non-word reading skills after 3 months of wearing either the Harris or the DRT filters. Results: Reading improved significantly after wearing either type of filter (t = −8.4, p < 0.01), with 40% of the children improving their reading age by 6 months or more during the 3 month trial. However, spelling ability (t = 2.1, p = 0.05) and non-word reading (f = 4.7, p < 0.05) improved significantly more with the DRT than with the Harris filters. Conclusion: Education and rehabilitation professionals should therefore, consider coloured filters as an effective intervention for delayed readers experiencing visual stress

Explanatory models of mental disorders and treatment practices among traditional healers in Mpumulanga, South Africa

Objective:  Key Words: Explanatory models; Traditional healers; Mental illness; South AfricaIn many traditional belief systems in Africa, including South Africa, mental health problems may be attributed to the influence of ancestors or to bewitchment. Traditional healers are viewed as having the expertise to address these causes. However, there is limited information on their explanatory models and consequent treatment practices. The present study examines traditional healers’ explanatory models (EMs) and treatment practices for psychotic and non-psychotic mental illnesses. Method: 4 focus group discussions (8 healers in each group) and 18 in-depth interviews were conducted. Four vignettes were presented (schizophrenia, depression, panic and somatization) and traditional healers’ views on the nature of the problem, cause, consequence, treatment and patient expectations were elicited. Results: Traditional healers held multiple explanatory models for psychotic and non-psychotic disorders. Psychotic illnesses appear to be the main exemplar of mental illness and were treated with traditional medicine, while nonpsychotic illnesses were not viewed as a mental illness at all. Additionally, traditional healers do not only use herbs and substances solely from “traditional” sources but rather have incorporated into their treatment practices modern ingredients that are potentially toxic. Conclusion: Interventions aimed at increasing the mental health literacy of traditional healers are essential. In addition, investigations of the effectiveness of traditional healer treatment for psychiatric disorders should be conducted

The neurobiology of HIV dementia: implications for practice in South Africa

In this review, the neuropathogenesis of HIV dementia (HIV-D) is discussed in the context of the local epidemic. HIV-D continues to be prevalent in the era of highly active anti-retroviral therapy. HIV neuro-invasion into the central nervous system may result in the development of separate HIV genotypes in an individual through compartmentalisation. The blood brain barrier continues to limit penetration of anti-retroviral drugs into the cerebrospinal fluid. Individuals with active neuro-inflammation appear to respond well to HAART. In some cases low grade neuro-degeneration persists with consequent clinical deterioration. In South Africa, the emergence of a sub-epidemic of HIV-D is being driven by various factors, including the incomplete coverage of HAART to all who need it, the late stage presentation of people living with HIV/AIDS (PLWHA) and a co-occurring methamphetamine epidemic. Differences in viral subtype do not appear to confer protection against HIV-D. Implications for PLWHA who are at risk for HIV-D in South Africa are explored, with a view to providing suggestions for improving practice and research into this area.Key words: Dementia; HIV; HAART; South Afric

Using coloured filters to reduce the symptoms of visual stress in children with reading delay

Background: Meares Irlen Syndrome (MIS), otherwise known as “visual stress”, is one condition that can cause difficulties with reading. Aim: This study aimed to compare the effect of two coloured-filter systems on the symptoms of visual stress in children with reading delay. Methods: The study design was a pre-test, post-test, randomized head-to-head comparison of two filter systems on the symptoms of visual stress in school children. A total of 68 UK mainstream schoolchildren with significant impairment in reading ability completed the study. Results: The filter systems appeared to have a large effect on the reported symptoms between pre and post three-month time points (d = 2.5, r = 0.78). Both filter types appeared to have large effects (Harris d = 1.79, r = 0.69 and DRT d = 3.22, r = 0.85). Importantly, 35% of participants’ reported that their symptoms had resolved completely; 72% of the 68 children appeared to gain improvements in three or more visual stress symptoms. Conclusion and significance: The reduction in symptoms, which appeared to be brought about by the use of coloured filters, eased the visual discomfort experienced by these children when reading. This type of intervention therefore has the potential to facilitate occupational engagement

The re-emergence of natural products for drug discovery in the genomics era

Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein-protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery

Estimating the cost-effectiveness of detecting cases of chronic hepatitis C infection on reception into prison

Background In England and Wales where less than 1% of the population are Injecting drug users (IDUs), 97% of HCV reports are attributed to injecting drug use. As over 60% of the IDU population will have been imprisoned by the age of 30 years, prison may provide a good location in which to offer HCV screening and treatment. The aim of this work is to examine the cost effectiveness of a number of alternative HCV case-finding strategies on prison reception Methods A decision analysis model embedded in a model of the flow of IDUs through prison was used to estimate the cost effectiveness of a number of alternative case-finding strategies. The model estimates the average cost of identifying a new case of HCV from the perspective of the health care provider and how these estimates may evolve over time. Results The results suggest that administering verbal screening for a past positive HCV test and for ever having engaged in illicit drug use prior to the administering of ELISA and PCR tests can have a significant impact on the cost effectiveness of HCV case-finding strategies on prison reception; the discounted cost in 2017 being £2,102 per new HCV case detected compared to £3,107 when no verbal screening is employed. Conclusion The work here demonstrates the importance of targeting those individuals that have ever engaged in illicit drug use for HCV testing in prisons, these individuals can then be targeted for future intervention measures such as treatment or monitored to prevent future transmission

Predicting suicides after outpatient mental health visits in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS).

The 2013 US Veterans Administration/Department of Defense Clinical Practice Guidelines (VA/DoD CPG) require comprehensive suicide risk assessments for VA/DoD patients with mental disorders but provide minimal guidance on how to carry out these assessments. Given that clinician-based assessments are not known to be strong predictors of suicide, we investigated whether a precision medicine model using administrative data after outpatient mental health specialty visits could be developed to predict suicides among outpatients. We focused on male nondeployed Regular US Army soldiers because they account for the vast majority of such suicides. Four machine learning classifiers (naive Bayes, random forests, support vector regression and elastic net penalized regression) were explored. Of the Army suicides in 2004-2009, 41.5% occurred among 12.0% of soldiers seen as outpatient by mental health specialists, with risk especially high within 26 weeks of visits. An elastic net classifier with 10-14 predictors optimized sensitivity (45.6% of suicide deaths occurring after the 15% of visits with highest predicted risk). Good model stability was found for a model using 2004-2007 data to predict 2008-2009 suicides, although stability decreased in a model using 2008-2009 data to predict 2010-2012 suicides. The 5% of visits with highest risk included only 0.1% of soldiers (1047.1 suicides/100 000 person-years in the 5 weeks after the visit). This is a high enough concentration of risk to have implications for targeting preventive interventions. An even better model might be developed in the future by including the enriched information on clinician-evaluated suicide risk mandated by the VA/DoD CPG to be recorded

Mechanical strain-mediated reduction in RANKL expression is associated with RUNX2 and BRD2

Mechanical loading-related strains trigger bone formation by osteoblasts while suppressing resorption by osteoclasts, uncoupling the processes of formation and resorption. Osteocytes may orchestrate this process in part by secreting sclerostin (SOST), which inhibits osteoblasts, and expressing receptor activator of nuclear factor-κB ligand (RANKL/TNFSF11) which recruits osteoclasts. Both SOST and RANKL are targets of the master osteoblastic transcription factor RUNX2. Subjecting human osteoblastic Saos-2 cells to strain by four point bending down-regulates their expression of SOST and RANKL without altering RUNX2 expression. RUNX2 knockdown increases basal SOST expression, but does not alter SOST down-regulation following strain. Conversely, RUNX2 knockdown does not alter basal RANKL expression, but prevents its down-regulation by strain. Chromatin immunoprecipitation revealed RUNX2 occupies a region of the RANKL promoter containing a consensus RUNX2 binding site and its occupancy of this site decreases following strain. The expression of epigenetic acetyl and methyl writers and readers was quantified by RT-qPCR to investigate potential epigenetic bases for this change. Strain and RUNX2 knockdown both down-regulate expression of the bromodomain acetyl reader BRD2. BRD2 and RUNX2 co-immunoprecipitate, suggesting interaction within regulatory complexes, and BRD2 was confirmed to interact with the RUNX2 promoter. BRD2 also occupies the RANKL promoter and its occupancy was reduced following exposure to strain. Thus, RUNX2 may contribute to bone remodeling by suppressing basal SOST expression, while facilitating the acute strain-induced down-regulation of RANKL through a mechanosensitive epigenetic loop involving BRD2