IL-18 inhibits growth of murine orthotopic prostate carcinomas via both adaptive and innate immune mechanisms

Interleukin(IL)-18 is a pleiotrophic cytokine with functions in immune modulation, angiogenesis and bone metabolism. In this study, the potential of IL-18 as an immunotherapy for prostate cancer (PCa) was examined using the murine model of prostate carcinoma, RM1 and a bone metastatic variant RM1(BM)/B4H7-luc. RM1 and RM1(BM)/B4H7-luc cells were stably transfected to express bioactive IL-18. These cells were implanted into syngeneic immunocompetent mice, with or without an IL-18-neutralising antibody (αIL-18, SK113AE4). IL-18 significantly inhibited the growth of both subcutaneous and orthotopic RM1 tumors and the IL-18 neutralizing antibody abrogated the tumor growth-inhibition. In vivo neutralization of interferon-gamma (IFN-γ) completely eliminated the anti-tumor effects of IL-18 confirming an essential role of IFN-γ as a down-stream mediator of the anti-tumor activity of IL-18. Tumors from mice in which IL-18 and/or IFN-γ was neutralized contained significantly fewer CD4+ and CD8+ T cells than those with functional IL-18. The essential role of adaptive immunity was demonstrated as tumors grew more rapidly in RAG1−/− mice or in mice depleted of CD4+ and/or CD8+ cells than in normal mice. The tumors in RAG1−/− mice were also significantly smaller when IL-18 was present, indicating that innate immune mechanisms are involved. IL-18 also induced an increase in tumor infiltration of macrophages and neutrophils but not NK cells. In other experiments, direct injection of recombinant IL-18 into established tumors also inhibited tumor growth, which was associated with an increase in intratumoral macrophages, but not T cells. These results suggest that local IL-18 in the tumor environment can significantly potentiate anti-tumor immunity in the prostate and clearly demonstrate that this effect is mediated by innate and adaptive immune mechanisms.

Inhibitors of human immunodeficiency virus type 1 reverse transcriptase target distinct phases of early reverse transcription

Early HIV-1 reverse transcription can be separated into initiation and elongation phases. Here we show, using PCR analysis of negative-strand strong-stop DNA [(−)ssDNA] synthesis in intact virus, that different reverse transcriptase (RT) inhibitors affect distinct phases of early natural endogenous reverse transcription (NERT). The effects of nevirapine on NERT were consistent with a mechanism of action including both specific and nonspecific binding events. The nonspecific component of this inhibition targeted the elongation reaction, whereas the specific effect seemed principally to be directed at very early events (initiation or the initiation-elongation switch). In contrast, foscarnet and the nucleoside analog ddATP inhibited both early and late (−)ssDNA synthesis in a similar manner. We also examined compounds that targeted other viral proteins and found that Ro24-7429 (a Tat antagonist) and rosmarinic acid (an integrase inhibitor) also directly inhibited RT. Our results indicate that NERT can be used to identify and evaluate compounds that directly target the reverse transcription complex.

Secondary curve behavior in Lenke Type 1C adolescent idiopathic scoliosis after thoracoscopic selective anterior thoracic fusion

Study Design. Analysis of a case series of 24 Lenke 1C adolescent idiopathic scoliosis (AIS) patients receiving selective thoracoscopic anterior scoliosis correction. Objective. To report the behaviour of the compensatory lumbar curve in a group of Lenke IC AIS patients following thoracoscopic anterior scoliosis correction, and to compare the results of this study with previously published data. Summary of Background Data. Several prior studies have reported spontaneous lumbar curve correction for both anterior and posterior selective fusion in Lenke 1C/King-Moe II patients; however to our knowledge no previous studies have reported outcomes of thoracoscopic anterior correction for this curve type. Methods. All AIS patients with a curve classification of Lenke 1C and a minimum of 24 months follow-up were retrieved from a consecutive series of 190 AIS patients who underwent thoracoscopic anterior instrumented fusion. Cobb angles of the major curve, instrumented levels, compensatory lumbar curve, and T5-T12 kyphosis were recorded, as well as coronal spinal balance, T1 tilt angle and shoulder balance. All radiographic parameters were measured before surgery and at 2, 6, 12 and 24 months after surgery. Results. Twenty-four female patients with right thoracic curves had a mean thoracic Cobb angle of 53.0° before surgery, decreasing to 24.9° two years after surgery. The mean lumbar compensatory Cobb angle was 43.5° before surgery, spontaneously correcting to 25.4° two years after surgery, indicating balance between the thoracic and lumbar scoliotic curves. The lumbar correction achieved (41.8%) compares favourably to previous studies. Conclusions. Selective thoracoscopic anterior fusion allows spontaneous lumbar curve correction and achieves coronal balance of main thoracic and compensatory lumbar curves, good cosmesis and patient satisfaction. Correction and balance are maintained 24 months after surgery.

Don's Party and the AV Jennings type 15 home

Australian housing underwent a watershed when 1960s mass-produced houses slowly started subscribing to a new aesthetic of continuous living spaces, known as the ‘open plan’ home. This created a new landscape for Australian playwrights to observe and explore in their work when representing domesticity on the stage. Instead of representing a single room of the house on the stage, plays such as ‘Don’s Party’, started to work with a number of openly connected spaces bound by doorways to private sections of the house or to specific outdoor areas. In representing this dialectic between interior and the exterior, private and public spaces in the home, the continuous spaces of the AV Jennings house in ‘Don’s Party’ acted to blur these conditions creating an outer interior. These connected spaces became the place for an outward performance on the family’s interiority, while simultaneously presenting a boundary to an inner interior in the offstage spaces of the home. This paper focuses on the play 'Don's Party' by David Williamson and how the spatial arrangements of the AV Jennings home, in which it was set, influenced the playwright. The research includes a textual analysis of the play, biographical research and interviews with the playwright alongside an analysis of the spatial arrangements of AV Jennings houses.

The relationship between Bayesian motor unit number estimation and histological measurements of motor neurons in wild-type and SOD1 G93A mice

Objective: To assess the relationship between Bayesian MUNE and histological motor neuron counts in wild-type mice and in an animal model of ALS. Methods: We performed Bayesian MUNE paired with histological counts of motor neurons in the lumbar spinal cord of wild-type mice and transgenic SOD1 G93A mice that show progressive weakness over time. We evaluated the number of acetylcholine endplates that were innervated by a presynaptic nerve. Results: In wild-type mice, the motor unit number in the gastrocnemius muscle estimated by Bayesian MUNE was approximately half the number of motor neurons in the region of the spinal cord that contains the cell bodies of the motor neurons supplying the hindlimb crural flexor muscles. In SOD1 G93A mice, motor neuron numbers declined over time. This was associated with motor endplate denervation at the end-stage of disease. Conclusion: The number of motor neurons in the spinal cord of wild-type mice is proportional to the number of motor units estimated by Bayesian MUNE. In SOD1 G93A mice, there is a lower number of estimated motor units compared to the number of spinal cord motor neurons at the end-stage of disease, and this is associated with disruption of the neuromuscular junction. Significance: Our finding that the Bayesian MUNE method gives estimates of motor unit numbers that are proportional to the numbers of motor neurons in the spinal cord supports the clinical use of Bayesian MUNE in monitoring motor unit loss in ALS patients. © 2012 International Federation of Clinical Neurophysiology.

Lifestyle risk factor modification in midlife women with type 2 diabetes : theoretical modelling of perceived barriers

Objective: The aim of this paper is to propose a ‘Perceived barriers and lifestyle risk factor modification model’ that could be incorporated into existing frameworks for diabetes education to enhance lifestyle risk factor education in women. Setting: Diabetes education, community health. Primary argument: ‘Perceived barriers’ is a health promotion concept that has been found to be a significant predictor of health promotion behaviour. There is evidence that women face a range of perceived barriers that prevent them from engaging in healthy lifestyle activities. Despite this, current evidence based models of diabetes education do not explicitly incorporate the concept of perceived barriers. A model of risk factor reduction that incorporates ‘perceived barriers’ is proposed. Conclusion: Although further research is required, current approaches to risk factor reduction in type 2 diabetes could be enhanced by identification and goal setting to reduce an individual’s perceived barriers.

Nitric oxide synthase type-II is synthesized by human gingival tissue and cultured human gingival fibroblasts

Nitric oxide is known to be an important inflammatory mediator, and is implicated in the pathophysiology of a range of inflammatory disorders. The aim of this study was to determine the localization and distribution of endothelial NOS (NOS-II) in human gingival tissue, and to ascertain if human gingival fibroblasts express NOS-II when stimulated with interferon gamma (IFN-gamma) and bacterial lipopolysaccharide (LPS). The distribution of NOS-II in inflamed and non-inflamed specimens of human gingivae was studied using a monoclonal antibody against nitric oxide synthase II. Cultures of fibroblasts derived from healthy human gingivae were used for the cell culture experiments. The results from immunohistochemical staining of the tissues indicated an upregulation of NOS-II expression in inflamed compared to non-inflamed gingival tissue. Fibroblasts and inflammatory cells within the inflamed connective tissue were positively stained for NOS-II. In addition, basal keratinocytes also stained strongly for NOS-II, in both healthy and inflamed tissue sections. When cultured human gingival fibroblasts were stimulated by INF-gamma and Porphyromonas gingivalis LPS, NOS-II was more strongly expressed than when the cells were exposed to LPS or IFN-gamma alone. These data suggest that, as for other inflammatory diseases, NO plays a role in the pathophysiology of periodontitis.

Depression: an emotional obstacle to seeking medical advice for infertility

Objective: To investigate the mental and general health of infertile women who had not sought medical advice for their recognized infertility and were therefore not represented in clinical populations. Design: Longitudinal cohort study.Setting Population based.Patient(s) Participants in the Australian Longitudinal Study on Women's Health aged 28-33 years in 2006 who had ever tried to conceive or had been pregnant (n = 5,936).Intervention(s) None.Main Outcome Measure(s) Infertility, not seeking medical advice. Result(s): Compared with fertile women (n = 4,905), infertile women (n = 1,031) had higher odds of self-reported depression (odds ratio [OR] 1.20, 95% confidence interval [CI] 1.01-1.43), endometriosis (5.43, 4.01-7.36), polycystic ovary syndrome (9.52, 7.30-12.41), irregular periods (1.99, 1.68-2.36), type II diabetes (4.70, 1.79-12.37), or gestational diabetes (1.66, 1.12-2.46). Compared with infertile women who sought medical advice (n = 728), those who had not sought medical advice (n = 303) had higher odds of self-reported depression (1.67, 1.18-2.37), other mental health problems (3.14, 1.14-8.64), urinary tract infections (1.67, 1.12-2.49), heavy periods (1.63, 1.16-2.29), or a cancer diagnosis (11.33, 2.57-49.89). Infertile women who had or had not sought medical advice had similar odds of reporting an anxiety disorder or anxiety-related symptoms. Conclusion(s): Women with self-reported depression were unlikely to have sought medical advice for infertility. Depression and depressive symptoms may be barriers to seeking medical advice for infertility.

Inflammatory cytokine responses to progressive resistance training and supplementation with fortified milk in men aged 50+ years : an 18-month randomized controlled trial

We examined the effects of progressive resistance training (PRT) and supplementation with calcium-vitamin D(3) fortified milk on markers of systemic inflammation, and the relationship between inflammation and changes in muscle mass, size and strength. Healthy men aged 50-79 years (n = 180) participated in this 18-month randomized controlled trial that comprised a factorial 2 x 2 design. Participants were randomized to (1) PRT + fortified milk supplement, (2) PRT, (3) fortified milk supplement, or (4) a control group. Participants assigned to PRT trained 3 days per week, while those in the supplement groups consumed 400 ml day(-1) of milk containing 1,000 mg calcium plus 800 IU vitamin D(3). We collected venous blood samples at baseline, 12 and 18 months to measure the serum concentrations of IL-6, TNF-alpha and hs-CRP. There were no exercise x supplement interactions, but serum IL-6 was 29% lower (95% CI, -62, 0) in the PRT group compared with the control group after 12 months. Conversely, IL-6 was 31% higher (95% CI, -2, 65) in the supplement group compared with the non-supplemented groups after 12 and 18 months. These between-group differences did not persist after adjusting for changes in fat mass. In the PRT group, mid-tibia muscle cross-sectional area increased less in men with higher pre-training inflammation compared with those men with lower inflammation (net difference similar to 2.5%, p < 0.05). In conclusion, serum IL-6 concentration decreased following PRT, whereas it increased after supplementation with fortified milk concomitant with changes in fat mass. Furthermore, low-grade inflammation at baseline restricted muscle hypertrophy following PRT.

The effect of a high fat meal on postprandial arterial stiffness in men with obesity and type 2 diabetes

Context: Postprandial dysmetabolism is emerging as an important cardiovascular risk factor. Augmentation index (AIx) is a measure of systemic arterial stiffness and independently predicts cardiovascular outcome. Objective: The objective of this study was to assess the effect of a standardized high-fat meal on metabolic parameters and AIx in 1) lean, 2) obese nondiabetic, and 3) subjects with type 2 diabetes mellitus (T2DM). Design and Setting: Male subjects (lean, n = 8; obese, n = 10; and T2DM, n = 10) were studied for 6 h after a high-fat meal and water control. Glucose, insulin, triglycerides, and AIx (radial applanation tonometry) were measured serially to determine the incremental area under the curve (iAUC). Results: AIx decreased in all three groups after a high-fat meal. A greater overall postprandial reduction in AIx was seen in lean and T2DM compared with obese subjects (iAUC, 2251 +/- 1204, 2764 +/- 1102, and 1187 +/- 429% . min, respectively; P < 0.05). The time to return to baseline AIx was significantly delayed in subjects with T2DM (297 +/- 68 min) compared with lean subjects (161 +/- 88 min; P < 0.05). There was a significant correlation between iAUC AIx and iAUC triglycerides (r = 0.50; P < 0.05). Conclusions: Obesity is associated with an attenuated overall postprandial decrease in AIx. Subjects with T2DM have a preserved, but significantly prolonged, reduction in AIx after a high-fat meal. The correlation between AIx and triglycerides suggests that postprandial dysmetabolism may impact on vascular dynamics. The markedly different response observed in the obese subjects compared with those with T2DM was unexpected and warrants additional evaluation.

Bariatric surgery or medicine for type 2 diabetes?

Diet and medical treatment are the standard treatment for type 2 diabetes. In obese subjects with type 2 diabetes, bariatric surgery is effective in resolving diabetes. Two clinical trials comparing bariatric surgery to medical treatment were evaluated. Both the Surgical Treatment And Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial (laparoscopic Roux-En Y gastric bypass and sleeve gastrectomy) and the DIet and medical therapy versus BAriatric SurgerY in type 2 diabetes (DIBASY) trial (laparoscopic gastric bypass and biliopancreatic-diversion) showed that surgery was more effective than medical care in resolving or managing type 2 diabetes. Larger studies, or a compilation of studies, are needed to determine whether one of these procedures is better, or if they are all similarly effective, and this should also be weighed against the risk of the operations.

What are the key conditions associated with lower limb amputations in a major Australian teaching hospital?

Background Lower extremity amputation results in significant global morbidity and mortality. Australia appears to have a paucity of studies investigating lower extremity amputation. The primary aim of this retrospective study was to investigate key conditions associated with lower extremity amputations in an Australian population. Secondary objectives were to determine the influence of age and sex on lower extremity amputations, and the reliability of hospital coded amputations. Methods: Lower extremity amputation cases performed at the Princess Alexandra Hospital (Brisbane, Australia) between July 2006 and June 2007 were identified through the relevant hospital discharge dataset (n = 197). All eligible clinical records were interrogated for age, sex, key condition associated with amputation, amputation site, first ever amputation status and the accuracy of the original hospital coding. Exclusion criteria included records unavailable for audit and cases where the key condition was unable to be determined. Chi-squared, t-tests, ANOVA and post hoc tests were used to determine differences between groups. Kappa statistics were used to measure reliability between coded and audited amputations. A minimum significance level of p < 0.05 was used throughout. Results: One hundred and eighty-six cases were eligible and audited. Overall 69% were male, 56% were first amputations, 54% were major amputations, and mean age was 62 ± 16 years. Key conditions associated included type 2 diabetes (53%), peripheral arterial disease (non-diabetes) (18%), trauma (8%), type 1 diabetes (7%) and malignant tumours (5%). Differences in ages at amputation were associated with trauma 36 ± 10 years, type 1 diabetes 52 ± 12 years and type 2 diabetes 67 ± 10 years (p < 0.01). Reliability of original hospital coding was high with Kappa values over 0.8 for all variables. Conclusions: This study, the first in over 20 years to report on all levels of lower extremity amputations in Australia, found that people undergoing amputation are more likely to be older, male and have diabetes. It is recommended that large prospective studies are implemented and national lower extremity amputation rates are established to address the large preventable burden of lower extremity amputation in Australia.