Prediction of major osteoporotic and hip fractures in Australian men using FRAX scores adjusted with trabecular bone score.

There was no significant difference between the areas under receiver operating characteristics (AUROCs) and diagnostic indexes (sensitivity, specificity, positive predictive value, negative predictive value) for either major osteoporotic or hip fracture FRAX scores when comparing the unadjusted and trabecular bone score (TBS)-adjusted scores. INTRODUCTION: FRAX 10-year probability of fracture can be calculated with adjustment for the TBS. Studies have shown that TBS can improve FRAX assessments in some populations. This study aimed to determine if TBS-adjusted FRAX score is better than the unadjusted score for predicting major osteoporotic fracture (MOF) and hip fracture in Australian men. METHODS: This study involved 591 men aged 40-90 years, enrolled in the Geelong Osteoporosis Study. Incident MOF (n = 50) and hip fractures (n = 14) were ascertained using radiological reports. Median follow-up time was 9.5 years (IQR7.5-11.4). Diagnostic indexes were calculated using cut points of ≥20% for MOF and ≥3% for the hip. AUROC curves were also determined for adjusted and unadjusted scores as continuous variables. RESULTS: Sensitivity was higher in the TBS-adjusted scores (MOF 4%, hip 78.6%) than the unadjusted scores (MOF 2%, hip 57.1%), with a decrease in specificity (MOF 98.9 vs 99.3%; hip 79.9 vs 83.9%). When considering TBS-adjusted and unadjusted FRAX as continuous scores, AUROCs were 0.738 and 0.740, respectively, for MOF and 0.849 and 0.848 for the hip. CONCLUSIONS: Prediction of fractures by MOF or hip FRAX was not substantially improved by TBS adjustment. There was no difference in AUROCs or diagnostic indexes for cut-off points of ≥20 for MOF and ≥3% for hip FRAX.

Maternal vitamin D and offspring trabecular bone score.

No studies have explored the relationship with maternal vitamin D (25(OH)D) in pregnancy and offspring trabecular bone score (TBS). Our data suggest that maternal 25(OH)D in early pregnancy, but not late, may be associated with offspring TBS in boys. These data act as hypothesis-generating findings for confirmation in larger, longer-term studies. INTRODUCTION: Trabecular bone score (TBS), a novel tool derived from dual-energy X-ray absorptiometry (DXA), reflects the microarchitecture of the vertebrae. It has been shown to predict fracture independent of standard DXA parameters in adult populations. Previously, we demonstrated that maternal serum 25-hydroxyvitamin D (25(OH)D) during pregnancy is associated with offspring bone mineral content at age 11 years. However, associations with TBS have not been explored, thus we aimed to determine associations between maternal 25(OH)D and offspring TBS. METHODS: Data were collected from the Vitamin D in Pregnancy (VIP) study. Venous blood samples were taken at recruitment and at 28-32 weeks' gestation. Maternal 25(OH)D was measured by radioimmunoassay. Offspring (n = 195, n = 181 with complete measures) underwent spine DXA (GE Lunar), at age 11 years (median = 10.9 (IQR 10.9-11.4)). TBS was calculated using TBS iNsight software. RESULTS: Offspring of mothers with sufficient 25(OH)D levels (≥50 nmol/L) at recruitment had a higher TBS (1.363 vs. 1.340, p = 0.04). In multivariable linear regression models, after adjustment for child relative lean mass, sex and pubertal stage, a 10 nmol/L increase in maternal 25(OH)D was associated with a 0.005 (95% CI 0.000, 0.010, p = 0.04) increase in TBS. However when stratified by sex (p for interaction = 0.16), the association was significant in boys, but not girls. There were no associations with TBS and maternal 25(OH)D at 28-32 weeks. CONCLUSIONS: We speculate that maternal 25(OH)D in early pregnancy may be associated with TBS in offspring at age 11 in boys. These hypothesis-generating findings warrant confirmation with larger interventional and long-term follow-up studies.

Non-hip and non-vertebral fractures: the neglected fracture sites.

SUMMARY: Non-hip, non-vertebral fractures (NHNVF) were compared with hip, vertebral and controls. NHNVF were younger and heavier than controls and hip/vertebral fractures in both men and women, respectively. Falls and prior fractures were less common in NHNVF than hip fractures. Glucocorticoid use was lower in NHNVF compared to vertebral fracture (VF) in men. INTRODUCTION: Although hip fracture (HF) and vertebral fractures (VF) receive the most attention in the literature and are the targeted sites for fracture prevention, non-hip, non-vertebral fracture (NHNVF) sites account for a greater proportion of fractures than the hip or vertebrae. This study aimed to assess risk factors for NHNVF and compare them with those for HF, VF and controls. METHODS: Incident fractures during 2005-2007 for men and 1994-1996 for women were identified using computerised keyword searches of radiological reports, and controls were selected at random from electoral rolls for participation in the Geelong Osteoporosis Study. Participants aged 60+ years were included in this study. RESULTS: Compared to controls, men and women with NHNVF were younger (ORs, 0.90, 95% CI 0.86-0.94; and 0.96, 0.93-0.98, respectively) and had a lower femoral neck bone mineral density (BMD) T-score (age-adjusted; difference [men] 0.383, P = 0.002; [women] 0.287, P = 0.001). Compared to HF, men and women with NHNVF were heavier (difference [men] 9.0 kg, P = 0.01; [women] 7.6 kg, P < 0.001). Heavier weight was also a risk factor for women with NHNVF compared to VF (1.03, 1.01-1.06). In men with NHNVF, falls (0.37, 0.14-0.97) and prior fractures (0.38, 0.15-0.98) were less common compared to HF; and glucocorticoid use was less common for NHNVF (0.30, 0.11-0.85) compared to VF. CONCLUSIONS: Given the high numbers of NHNVF sustained by men and women in this study, fracture prevention strategies should focus on individuals with high risk of sustaining these types of fractures, as well as on individuals who are more likely to sustain a HF or VF.

Prior fracture as a risk factor for future fracture in an Australian cohort.

SUMMARY: This study investigated the influence of prior fracture on the risk of subsequent fracture. There was a higher risk of subsequent fracture in both young and older adult age groups when Australian males or females had already sustained a prior fracture. Fracture prevention is important throughout life for both sexes. INTRODUCTION: The purpose of this study was to determine the impact of prior fracture on the risk of subsequent fracture across the adult age range in Australian males and females. METHODS: All-cause fractures were grouped into age categories for males and females enrolled in the Geelong Osteoporosis Study (Australia) using retrospective self-report data and prospective radiology-confirmed data. For all age categories, the relative risk (RR and 95% confidence interval (CI)) of subsequent fracture in a later age category was compared between those with prior fracture and those without. RESULTS: For both sexes, childhood fracture increased the risk of subsequent fracture in adolescence (males: RR 21.7; 95% CI 16.0, 27.4; females: RR 8.1; 3.5, 12.8). Males with adolescent fracture had increased risk of subsequent fracture in early adulthood (RR 11.5; 5.7, 17.3) and mid-adulthood (RR 13.0; 6.3, 19.7). Additionally, males with young adulthood or mid-adulthood fracture had increased risk of subsequent fracture in the following age group (RR 11.2; 4.4, 17.9, and RR 6.2; 0.8, 11.7, respectively). Mid-adult fractures increased the risk of subsequent fracture in older adulthood (RR 6.2; 0.8, 11.7). Females with childhood or adolescent fracture had an increased risk of fracture in young adulthood (RR 4.3; 0.7, 7.9, and RR 10.5; 4.4, 16.6), and prior fracture in older adult life increased the risk of subsequent fracture in old age (RR 14.9; 6.4. 23.3). CONCLUSIONS: Fracture prevention strategies may be more effective if attention is directed towards individuals with prior fracture at any age as they have a higher likelihood of sustaining a subsequent fracture later in life.

The social gradient of fractures at any skeletal site in men and women: data from the Geelong Osteoporosis Study Fracture Grid.

UNLABELLED: Age-specific and age-standardized associations between socioeconomic status (SES) and fractures in adults showed a social gradient of fracture, irrespective of fracture site. Compared to the highest SES, males in the lowest SES group had a sixfold increased odds for any fracture, whilst females had a twofold increased odds. INTRODUCTION: The effective identification of predisposing risk factors for fracture requires understanding any association with SES. These investigations should consider both sexes, span the adult age range and include any fractures. We investigated age- and sex-specific and age-standardized associations between SES and fractures at any skeletal site in Australians aged ≥ 50 years. METHODS: Incident fractures that occurred 2006-2007 for adults aged ≥ 50 years were identified from radiological reports extracted for the Barwon Statistical Division, in south-eastern Australia. SES was determined by cross-referencing residential addresses with Australian Bureau of Statistics census data and then categorized in quintiles. We compared frequencies of observed vs. expected fractures for SES quintiles using χ (2) comparison, calculated age-specific fracture incidence across SES and compared age-standardized fracture rates in SES quintile 1 to quintile 5. RESULTS: We identified 3943 incident fractures (69.4 % female); 47.4 % had occurred at major osteoporotic fracture (MOF) sites (hip, humerus, spine and forearm/wrist). Differences existed in observed vs. expected fractures across SES quintiles (p ≤ 0.001, sexes combined); all fractures showed an inverse association with SES (p ≤ 0.001, sexes combined). Compared to the highest SES quintile, individuals from the lowest SES quintile had between two to six times greater standardized fracture rates. CONCLUSIONS: Disadvantaged men and women have an increased fracture incidence compared to their less disadvantaged counterparts. The large differences in fracture rates between SES groups warrant further research into designing appropriate, targeted interventions for those demographics at most risk.

Is there an interaction between socioeconomic status and FRAX 10-year fracture probability determined with and without bone density measures? Data from the Geelong Osteoporosis Study of female cohort.

FRAX(©) evaluates 10-year fracture probabilities and can be calculated with and without bone mineral density (BMD). Low socioeconomic status (SES) may affect BMD, and is associated with increased fracture risk. Clinical risk factors differ by SES; however, it is unknown whether aninteraction exists between SES and FRAX determined with and without the BMD. From the Geelong Osteoporosis Study, we drew 819 females aged ≥50 years. Clinical data were collected during 1993-1997. SES was determined by cross-referencing residential addresses with Australian Bureau of Statistics census data and categorized in quintiles. BMD was measured by dual energy X-ray absorptiometry at the same time as other clinical data were collected. Ten-year fracture probabilities were calculated using FRAX (Australia). Using multivariable regression analyses, we examined whether interactions existed between SES and 10-year probability for hip and any major osteoporotic fracture (MOF) defined by use of FRAX with and without BMD. We observed a trend for a SES * FRAX(no-BMD) interaction term for 10-year hip fracture probability (p = 0.09); however, not for MOF (p = 0.42). In women without prior fracture (n = 518), we observed a significant SES * FRAX(no-BMD) interaction term for hip fracture (p = 0.03) and MOF (p = 0.04). SES does not appear to have an interaction with 10-year fracture probabilities determined by FRAX with and without BMD in women with previous fracture; however, it does appear to exist for those without previous fracture.

Lessons from history of socioeconomic improvements: a new approach to treating multi-drug-resistant tuberculosis.

This study investigated the trends in tuberculosis mortality through time in Switzerland. Information on the decline in mortality before chemotherapies were introduced may be useful in developing countries where drug-resistant tuberculosis is now becoming a major problem. Swiss data were collected from historical records and comparative data were obtained from the literature for England and Wales, New York, Japan, Brazil and Sierra Leone. Logistic curves were fitted to examine the rate of decline before introduction of pharmacotherapies and these show that the decline would have continued without the introduction of chemical therapies, including antibiotics. In Switzerland, England and Wales and New York, the decline had occurred long before the introduction of specific anti-tuberculosis agents. In Brazil and Japan, chemical therapy was co-incident with the decline in tuberculosis mortality rates. Overall, it is suggested that the effective control of tuberculosis can be achieved through a combination of chemical interventions, conservative therapy (rest, good nutrition, ventilation, etc.) as well as public health interventions addressing hygiene, nutrition, reducing exposure to infections and educating the population about tuberculosis.

Have we improved use of medicines in developing and transitional countries and do we know how to? Two decades of evidence.

OBJECTIVE: To assess progress in improving use of medicines in developing and transitional countries by reviewing empirical evidence, 1990-2009, concerning patterns of primary care medicine use and intervention effects. METHODS: We extracted data on medicines use, study setting, methodology and interventions from published and unpublished studies on primary care medicine use. We calculated the medians of six medicines use indicators by study year, country income level, geographic region, facility ownership and prescriber type. To estimate intervention impacts, we calculated greatest positive (GES) and median effect sizes (MES) from studies meeting accepted design criteria. RESULTS: Our review comprises 900 studies conducted in 104 countries, reporting data on 1033 study groups from public (62%), and private (mostly for profit) facilities (26%), and households. The proportion of treatment according to standard treatment guidelines was 40% in public and <30% in private-for-profit sector facilities. Most indicators showed suboptimal use and little progress over time: Average number of medicines prescribed per patient increased from 2.1 to 2.8 and the percentage of patients receiving antibiotics from 45% to 54%. Of 405 (39%) studies reporting on interventions, 110 (27%) used adequate study design and were further analysed. Multicomponent interventions had larger effects than single component ones. Median GES was 40% for provider and consumer education with supervision, 17% for provider education alone and 8% for distribution of printed education materials alone. Median MES showed more modest improvements. CONCLUSIONS: Inappropriate medicine use remains a serious global problem.

Irrational use of antibiotics and role of the pharmacist: an insight from a qualitative study in New Delhi, India.

WHAT IS KNOWN AND OBJECTIVE: The overall volume of antibiotic consumption in the community is one of the foremost causes of antimicrobial resistance. In developing countries like India, pharmacists often dispense 'prescription-only' drugs, like antibiotics, to patients who do not have a prescription. Not much data is available regarding detailed information on behaviour of antibiotic use by community pharmacists which is of particular significance to develop a suitable and sustainable intervention programme to promote rational use of antibiotics. A qualitative study was conducted to understand the dispensing practices and behaviour of community pharmacists to develop policy interventions that would improve the use of antibiotics at the community level. METHODS: Focus group discussions (FGDs) were held for five municipal wards of Delhi with retail pharmacists, public sector pharmacists and the office bearers of pharmacists' associations. Data on antibiotic use and resistance were collected earlier from these five wards. FGDs (n = 3 with 40 pharmacists) were analysed through grounded theory. RESULTS AND DISCUSSION: Four broad themes identified were as follows: prescribing and dispensing behaviour; commercial interests; advisory role; and intervention strategies for rational use of antibiotics. FGDs with pharmacists working in the public sector revealed that, besides the factors listed above, overstock and near-expiry, and under-supply of antibiotics promoted antibiotic misuse. Suggestions for interventions from pharmacists were the following: (i) education to increase awareness of rational use and resistance to antibiotics; (ii) involving pharmacists as partners for creating awareness among communities for rational use and resistance to antibiotics; (iii) developing an easy return policy for near-expiry antibiotics in public sector facilities; and (iv) motivating and showing appreciation for community pharmacists who participate in intervention programmes. WHAT IS NEW AND CONCLUSIONS: Inappropriate antibiotic dispensing and use owing to commercial interests and lack of knowledge about the rational use of antibiotics and antibiotic resistance were the main findings of this in-depth qualitative study. Community pharmacists were willing to participate in educational programme aimed at improving use of antibiotics. Such programmes should be initiated within a multidisciplinary framework including doctors, pharmacists, social scientists, government agencies and non-profit organizations.

Amyloid-beta-induced occludin down-regulation and increased permeability in human brain endothelial cells is mediated by MAPK activation.

Vascular dysfunction is emerging as a key pathological hallmark in Alzheimer's disease (AD). A leaky blood-brain barrier (BBB) has been described in AD patient tissue and in vivo AD mouse models. Brain endothelial cells (BECs) are linked together by tight junctional (TJ) proteins, which are a key determinant in restricting the permeability of the BBB. The amyloid beta (Abeta) peptides of 1-40 and 1-42 amino acids are believed to be pivotal in AD pathogenesis. We therefore decided to investigate the effect of Abeta 1-40, the Abeta variant found at the highest concentration in human plasma, on the permeability of an immortalized human BEC line, hCMEC/D3. Abeta 1-40 induced a marked increase in hCMEC/D3 cell permeability to the paracellular tracer 70 kD FITC-dextran when compared with cells incubated with the scrambled Abeta 1-40 peptide. Increased permeability was associated with a specific decrease, both at the protein and mRNA level, in the TJ protein occludin, whereas claudin-5 and ZO-1 were unaffected. JNK and p38MAPK inhibition prevented both Abeta 1-40-mediated down-regulation of occludin and the increase in paracellular permeability in hCMEC/D3 cells. Our findings suggest that the JNK and p38MAPK pathways might represent attractive therapeutic targets for preventing BBB dysfunction in AD.

Interleukin 2 regulates the expression of Tac antigen on peripheral blood T lymphocytes.

We investigated the effect of OKT3 antibody and interleukin 2 (IL-2) on Tac antigen expression and the proliferation of human peripheral blood mononuclear leukocytes. OKT3 monoclonal antibody at low, nonmitogenic concentrations (25 pg/ml) or IL-2 alone at optimal concentrations (20 U/ml) did not induce IL-2 receptor expression, as measured by Tac antibody or by T cell proliferation. However, costimulation with these concentrations of OKT3 antibody and IL-2 led to Tac antigen expression and T cell proliferation. These data suggest that the T cells are activated in two steps: OKT3 antibody at 25 pg/ml does not induce Tac antigen expression, but preactivates T cells to become responsive to IL-2. The addition of exogenous IL-2 then leads to expression of the IL-2 receptor, as recognized by Tac antibody, and to subsequent proliferation.

The extremely low energy cost of biosynthesis in holometabolous insect larvae.

The metabolic cost of growth, which quantifies the amount of energy required to synthesize a unit of biomass, is an important component of an animal's ontogenetic energy budget. Here we investigated this quantity as well as other energy budget variables of the larvae of a holometabolous insect species, Vanessa cardui (painted lady). We found that the high growth rate of this caterpillar cannot be explained by its metabolic rate and the percentage of the metabolic energy allocated to growth; the key to understanding its fast growth is the extremely low cost of growth, 336 Joules/gram of dry mass. The metabolic cost of growth in caterpillars is 15-65 times lower than that of the endothermic and ectothermic species investigated in previous studies. Our results suggest that the low cost cannot be attributed to its body composition, diet composition, or body size. To explain the "cheap price" of growth in caterpillars, we assumed that a high metabolic cost for biosynthesis resulted in a high "quality" of cells, which have fewer errors during biosynthesis and higher resistance to stressors. Considering the life history of the caterpillars, i.e., tissue disintegration during metamorphosis and a short developmental period and lifespan, we hypothesized that an energy budget that allocates a large amount of energy to biosynthesizing high quality cells would be selected against in this species. As a preliminary test of this hypothesis, we estimated the metabolic cost of growth in larvae of Manduca sexta (tobacco hornworm) and nymphs of Blatta lateralis (Turkestan cockroach). The preliminary data supported our hypothesis.

Enhanced neural activation in brain regions mediating sexual responses following exposure to a conditioned stimulus that predicts copulation.

Stimuli associated with sexual behavior increase reproductive success if presented prior to copulation. In Japanese quail, inseminations that take place in a context that predicts the arrival of a female are more likely to result in fertilized eggs. We demonstrate here that in male Japanese quail a sexual conditioned stimulus (CS) also enhances activity in two brain regions that mediate sexual behavior, the medial preoptic area and the medial part of the bed nucleus of the stria terminalis. C-fos expression, a marker of neural activation, was higher in these areas in subjects exposed sequentially to a sexual CS and copulation than in subjects exposed to copulation or the CS alone or in subjects exposed to no sexual stimulus, either an identical, untrained CS or an empty arena. These results suggest a link between a proximate result of sexual CS presentation, male brain activation, and a known ultimate outcome, increased fertilizations.

Lower limb fracture presentations at a regional hospital.

We found that lower limb fractures, which were largely the result of minimal trauma, had high levels of hospitalisation, length of stay and surgery. It is therefore important to prevent fractures at all sites to avoid the associated morbidity and mortality. PURPOSE: Hip fractures are a major cause of morbidity and mortality, particularly in older women. In comparison, less is known about the epidemiology and burden of other lower limb fractures. The study aimed to investigate the epidemiology and burden of these fractures. METHODS: Incident fractures of the hip, femur, tibia/fibula, ankle and foot in women (≥ 20 years) managed through the University Hospital Geelong, Australia, were ascertained from 1 Jan. 2014 to 31 Dec. 2014 from radiology reports. Age, cause of fracture, post-fracture hospitalisation, surgery, length of stay and discharge location were ascertained from medical records. RESULTS: We identified 585 fractures of the lower limb (209 hip, 42 femur, 41 tibia/fibula, 162 ankle, 131 foot). Most fractures were sustained by women aged ≥ 50 years. Fractures were largely a result of minimal trauma. Most women with hip or femur fractures were hospitalised; fewer were hospitalised for fractures at other sites. Surgery for fracture followed the same pattern as hospitalisations. Length of stay was the highest for hip and femur fractures and the lowest for foot fractures. Women with hip or femur fractures were discharged to rehabilitation more often than home. Fractures at other sites were most commonly discharged home. CONCLUSIONS: Fractures of the lower limb occurred frequently in older women. Hospitalisation and subsequent surgery were common in cases of hip and femur fractures. It is important for prevention strategies to target fractures at a range of skeletal sites to reduce costs, hospitalisations, loss of independence and reduced quality of life.

Blood-brain barrier-specific properties of a human adult brain endothelial cell line.

Establishment of a human model of the blood-brain barrier has proven to be a difficult goal. To accomplish this, normal human brain endothelial cells were transduced by lentiviral vectors incorporating human telomerase or SV40 T antigen. Among the many stable immortalized clones obtained by sequential limiting dilution cloning of the transduced cells, one was selected for expression of normal endothelial markers, including CD31, VE cadherin, and von Willebrand factor. This cell line, termed hCMEC/D3, showed a stable normal karyotype, maintained contact-inhibited monolayers in tissue culture, exhibited robust proliferation in response to endothelial growth factors, and formed capillary tubes in matrix but no colonies in soft agar. hCMEC/D3 cells expressed telomerase and grew indefinitely without phenotypic dedifferentiation. These cells expressed chemokine receptors, up-regulated adhesion molecules in response to inflammatory cytokines, and demonstrated blood-brain barrier characteristics, including tight junctional proteins and the capacity to actively exclude drugs. hCMEC/D3 are excellent candidates for studies of blood-brain barrier function, the responses of brain endothelium to inflammatory and infectious stimuli, and the interaction of brain endothelium with lymphocytes or tumor cells. Thus, hCMEC/D3 represents the first stable, fully characterized, well-differentiated human brain endothelial cell line and should serve as a widely usable research tool.

Anxiety disorders and falls among older adults.

BACKGROUND: Falls are common among older adults and can lead to serious injuries, including fractures. We aimed to determine associations between anxiety disorders and falls in older adults. METHODS: Participants were 487 men and 376 women aged ≥60 years enrolled in the Geelong Osteoporosis Study, Australia. Using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Non-patient edition (SCID-I/NP), lifetime history of anxiety disorders was determined. Falls were determined by self-report. In men, a falls-risk score (Elderly Falls Screening Test (EFST)) was also calculated. RESULTS: Among fallers, 24 of 299 (8.0%) had a lifetime history of anxiety disorder compared to 36 of 634 (5.7%) non-fallers (p=0.014). Examination of the association between anxiety and falls suggested differential relationships for men and women. In men, following adjustment for psychotropic medications, mobility and blood pressure, lifetime anxiety disorder was associated with falling (OR 2.96; 95%CI 1.07-8.21) and with EFST score (OR 3.46; 95%CI 1.13-10.6). In women, an association between lifetime anxiety disorder and falls was explained by psychotropic medication use, poor mobility and socioeconomic status. LIMITATIONS: Sub-group analyses involving types of anxiety and anxiety disorders over the past 12-months were not performed due to power limitations. CONCLUSION: Although anxiety disorders were independently associated with a 3-fold increase in likelihood of reported falls and high falls risk among men, an independent association was not detected among women. These results may aid in prevention of falls through specific interventions aimed at reducing anxiety, particularly in men.

Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex.

Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modification might reduce these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during inflammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-inflammatory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor alpha or fecapentaene-12. Induction of COX2 by inflammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-kappaB). Since curcumin inhibits NF-kappaB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-kappaB-sequestering protein, IkappaB. Recently components of this pathway, NF-kappaB-inducing kinase and IkappaB kinases, IKKalpha and beta, which phosphorylate IkappaB to release NF-kappaB, have been characterised. Curcumin prevents phosphorylation of IkappaB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health effects, makes curcumin an important candidate for consideration in colon cancer prevention.

Human neuronal gamma-aminobutyric acid(A) receptors: coordinated subunit mRNA expression and functional correlates in individual dentate granule cells.

gamma-Aminobutyric acid(A) receptors (GABARs) are heteromeric proteins composed of multiple subunits. Numerous subunit subtypes are expressed in individual neurons, which assemble in specific preferred GABAR configurations. Little is known, however, about the coordination of subunit expression within individual neurons or the impact this may have on GABAR function. To investigate this, it is necessary to profile quantitatively the expression of multiple subunit mRNAs within individual cells. In this study, single-cell antisense RNA amplification was used to examine the expression of 14 different GABAR subunit mRNAs simultaneously in individual human dentate granule cells (DGCs) harvested during hippocampectomy for intractable epilepsy. alpha4, beta2, and delta-mRNA levels were tightly correlated within individual DGCs, indicating that these subunits are expressed coordinately. Levels of alpha3- and beta2-mRNAs, as well as epsilon- and beta1-mRNAs, also were strongly correlated. No other subunit correlations were identified. Coordinated expression could not be explained by the chromosomal clustering of GABAR genes and was observed in control and epileptic rats as well as in humans, suggesting that it was not species-specific or secondary to epileptogenesis. Benzodiazepine augmentation of GABA-evoked currents also was examined to determine whether levels of subunit mRNA expression correlated with receptor pharmacology. This analysis delineated two distinct cell populations that differed in clonazepam modulation and patterns of alpha-subunit expression. Clonazepam augmentation correlated positively with the relative expression of alpha1- and gamma2-mRNAs and negatively with alpha4- and delta-mRNAs. These data demonstrate that specific GABAR subunit mRNAs exhibit coordinated control of expression in individual DGCs, which has significant impact on inhibitory function.

Teaching Conflict: Professionalism and Medical Education.

Resistance by physicians, medical researchers, medical educators, and medical students to pharmaceutical industry influence in medicine is often based on the notion that physicians (guided by the ethics of their profession) and the industry (guided by profit) are in conflict. This criticism has taken the form of a professional movement opposing conflict of interest (COI) in medicine and medical education and has resulted in policies and guidelines that frame COI as the problem and outline measures to address this problem. In this paper, I offer a critique of this focus on COI that is grounded in a broader critique of neo-liberalism, arguing it individualizes the relationship between physicians and industry, too neatly delineates between the two entities, and reduces the network of social, economic, and political relations to this one dilemma.

Travel-related chikungunya cases in Canada, 2014.

Since the spring of 2014, there has been a large increase in travel-related chikungunya cases diagnosed in Canada. As of December 9, 2014, 320 confirmed and 159 probable cases have been diagnosed in Canada, with the majority of provinces identifying at least one imported case. This surge in Canadian infections has been associated with the incursion of chikungunya virus into the Caribbean and the expansion of the virus in the Americas. Ongoing outbreaks in the Asia-Pacific region have also contributed to imported cases among Canadian travellers. Heightened awareness of chikungunya among clinicians is key to diagnosis. This highlights the need to ask for a travel history from anyone who presents with fever or recent onset of polyarthralgia, and to consider testing by provincial laboratories and the National Microbiology Laboratory for chikungunya virus and other diseases as indicated. Also essential is continued communication with travellers regarding the use of preventative measures to decrease the risk of exposure to mosquitoes when travelling to endemic areas.