Calcaneal quantitative ultrasound is associated with all-cause and cardiovascular disease mortality independent of hip bone mineral density.

Osteoporosis has been linked with increased risk of cardiovascular disease previously. However, few studies have detailed bone and vascular information. In a prospective study of older women, we demonstrated heel quantitative ultrasound measures were associated with increased cardiovascular and all-cause mortality, independent of established cardiovascular risk factors. INTRODUCTION: Osteoporosis and low bone mineral density (BMD) have been previously linked to cardiovascular disease (CVD) and mortality. Calcaneal quantitative ultrasound (QUS) is used to evaluate bone material properties, especially in older women. However, it is uncertain whether it is related to risk of mortality. This study was aimed to investigate the association between calcaneal QUS measurements and 15-year all-cause and CVD mortality in 1404 older women (mean age 75.2 ± 2.7 years). METHODS: One thousand four hundred four older women, participants of Calcium Intake Fracture Outcome study (CAIFOS), had calcaneal bone measured at baseline (1998) and followed for 15 years. The primary outcomes, any deaths, and deaths attributable to cardiovascular causes ascertained by using linked data were obtained from Western Australia data linkage system. RESULTS: Over the 15 years of follow-up (17,955 person years), 584 of the women died, and 223 from CVD. For every standard deviation (SD), reduction in broadband ultrasound attenuation (BUA) in minimally and multivariable-adjusted model including cardiovascular risk factors increased relative hazards for all-cause (multivariable-adjusted HR 1.15; 95%CI: 1.06-1.26, p = 0.001) and CVD mortality (multivariable-adjusted HR 1.20; 95%CI: 1.04-1.38, p = 0.010). Such relationships also persisted when hip BMD was included in the model (all-cause mortality HR 1.19; 95%CI: 1.07-1.33, p = 0.002; CVD mortality HR 1.28; 95%CI: 1.07-1.53, p = 0.008). CONCLUSION: BUA is associated with all-cause and CVD mortality in older women independent of BMD and established CVD risk factors. Understanding why and how these are related may provide further insights about the bone-vascular nexus as well as therapeutic targets benefiting both systems.

Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation.

An intergenic region of human chromosome 2 (2p25.3) harbors genetic variants which are among those most strongly and reproducibly associated with obesity. The gene closest to these variants is TMEM18, although the molecular mechanisms mediating these effects remain entirely unknown. Tmem18 expression in the murine hypothalamic paraventricular nucleus (PVN) was altered by changes in nutritional state. Germline loss of Tmem18 in mice resulted in increased body weight, which was exacerbated by high fat diet and driven by increased food intake. Selective overexpression of Tmem18 in the PVN of wild-type mice reduced food intake and also increased energy expenditure. We provide evidence that TMEM18 has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex. Our data support the hypothesis that TMEM18 itself, acting within the central nervous system, is a plausible mediator of the impact of adjacent genetic variation on human adiposity.

Utility of four sarcopenia criteria for the prediction of falls-related hospitalization in older Australian women.

Numerous sarcopenia definitions are not associated with increased falls-related hospitalization risk over 5 years to 9.5 years in older community-dwelling Australian women. Measures of muscle strength and physical function, but not appendicular lean mass (measured by dual-energy X-ray absorptiometry) may help discriminate the risk of falls-related hospitalization. INTRODUCTION: The aim of this prospective, population-based cohort study of 903 Caucasian-Australian women (mean age 79.9 ± 2.6 years) was to compare the clinical utility of four sarcopenia definitions for the prediction of falls-related hospitalization over 9.5 years. METHODS: The four definitions were the United States Foundation for the National Institutes of Health (FNIH), the European Working Group on Sarcopenia in Older People (EWGSOP), and modified FNIH (AUS-POPF) and EWGSOP (AUS-POPE) definitions using Australian population-specific cut points (< 2 SD below the mean of young healthy Australian women). Components of sarcopenia including muscle strength, physical function, and appendicular lean mass (ALM) were quantified using hand grip strength, timed-up-and-go (TUG), and dual-energy X-ray absorptiometry (DXA), respectively. Incident 9.5-year falls-related hospitalization were captured by linked data. RESULTS: Baseline prevalence of sarcopenia according to FNIH (9.4%), EWGSOP (24.1%), AUS-POPF (12.0%), and AUS-POPE (10.7%) differed substantially. Sarcopenia did not increase the relative hazard ratio (HR) for falls-related hospitalization before or after adjustment for age (aHR): FNIH aHR 1.00 95%CI (0.69-1.47), EWGSOP aHR 1.20 95%CI (0.93-1.54), AUS-POPF aHR 0.96 95%CI (0.68-1.35), and AUS-POPE aHR 1.33 95%CI (0.94-1.88). When examining individual components of sarcopenia, only muscle strength and physical function but not ALM (adjusted for height2 or BMI) were associated with falls-related hospitalization. CONCLUSION: Current definitions of sarcopenia were not associated with falls-related hospitalization risk in this cohort of community-dwelling older Australian women. Finally, measures of muscle strength and physical function, but not ALM (measured by DXA) may help discriminate the risk of falls-related hospitalization.

Effects of calcium supplementation on circulating osteocalcin and glycated haemoglobin in older women.

One year of calcium supplementation in older women led to modest reductions in total osteocalcin and undercarboxylated osteocalcin (ucOC), with no changes in muscle or fat mass, or glycated haemoglobin. Future studies should explore whether treatments with more profound effects of suppressing ucOC may lead to impaired glycaemic control. INTRODUCTION: Total osteocalcin (TOC) is a marker of bone turnover, while its undercarboxylated form has beneficial effects on glucose metabolism in mice. This post hoc analysis of a randomised double-blind, placebo-controlled trial examined whether 1 year of calcium supplementation affected circulating TOC, undercarboxylated osteocalcin (ucOC) or glycated haemoglobin (HbA1c) in 1368 older community-dwelling women (mean age 75.2 ± 2.7 years). METHODS: Women enrolled in the Calcium Intake Fracture Outcome Study trial (1998-2003) were supplemented with 1.2 g/d of elemental calcium (in the form of calcium carbonate) or placebo. Circulating TOC, ucOC and HbA1c was measured at 1 year (1999). RESULTS: After 1 year of calcium supplementation, TOC and ucOC levels were 17% and 22% lower compared with placebo (mean 22.7 ± 9.1 vs. 27.3 ± 10.9 µg/L and 11.1 ± 4.9 vs. 13.0 ± 5.7 µg/L, both P < 0.001). Carboxylated osteocalcin/ucOC was 6% lower after calcium supplementation (P < 0.05). Despite this, no differences in HbA1c were observed (calcium, 5.2 ± 0.6 vs. placebo, 5.3 ± 0.8%; P = 0.08). Calcium supplementation did not affect BMI, whole body lean or fat mass. In exploratory analyses, total calcium (dietary and supplemental) was inversely related to TOC and ucOC, indicating calcium intake is an important dietary determinant of osteocalcin levels. CONCLUSION: One year of calcium supplementation in older women led to modest reductions in TOC and ucOC, with no changes in muscle or fat mass, or HbA1c. Future studies should explore whether treatments with more profound effects of suppressing ucOC may lead to impaired glycaemic control.

Successful Resuscitation with Extracorporeal Membrane Oxygenation in a Case with Prolonged Cardiac Arrest.

This case study describes a 25-year-old patient who had a witnessed cardiac arrest in the medical intensive care unit. The patient received 107 minutes of cardiopulmonary resuscitation before the veno-arterial extracorporeal membrane oxygenation was initiated. During extracorporeal life support, the patient's cardiac function improved. The patient was weaned from extracorporeal membrane oxygenation on day 6 and was discharged without physical and neurological complications on day 28. The successful resuscitation in this case attributed to high-quality CCPR and timely ECMO support.

Mortality and cancer incidence in a cohort of male paid Australian firefighters.

OBJECTIVES: To investigate mortality and cancer incidence of paid male Australian firefighters and of subgroups of firefighters by era of first employment, duration of employment and number and type of incidents attended. METHODS: Participating fire agencies supplied records of individual firefighters including their job histories and incidents attended. The cohort was linked to the Australian National Death Index and Australian Cancer Database. SMRs and SIRs were calculated. Firefighters were grouped into tertiles by duration of employment and by number of incidents attended and relative mortality ratios and relative incidence ratios calculated. Analyses were carried out separately for full-time and part-time male firefighters. RESULTS: Compared to the Australian population, there were significant increases in overall risk of cancer, for all paid firefighters SIR 1.09 (95% CI 1.03 to 1.14), in prostate cancer, full-time firefighters 1.23 (95% CI 1.10 to 1.37), part-time 1.51 (1.28 to 1.77), and melanoma full-time 1.45 (95% CI 1.26 to 1.66), part-time firefighters 1.43 (95% CI 1.15 to 1.76). Kidney cancer was associated with longer service in internal analyses for paid firefighters. Prostate cancer was associated with longer service and increased attendance at fires, particularly structural fires for full-time firefighters.The overall risk of mortality was significantly decreased and almost all major causes of death were significantly reduced for paid firefighters. CONCLUSIONS: Male paid firefighters have an increased risk of cancer. They have reduced mortality compared with the general population, which is likely to be a result of a strong healthy worker effect and likely lower smoking rates among firefighters compared with the Australian population.

Stability of symptom patterns in Australian Gulf War veterans: 10-year longitudinal study.

OBJECTIVES: Previously we established that symptoms reported by 1990-1991 Gulf War veterans were correlated and exhibited a pattern with 3 factors (psychophysiological distress, somatic distress and arthroneuromuscular distress), and this pattern was similar to that observed in a military comparison group. In this follow-up study, we examined whether the patterns of symptomatology have changed over time. METHODS: Using data on 56 symptoms that was collected in 2000-2003 (wave 1) and 2011-2012 (wave 2) from an Australian cohort of Gulf War veterans (veterans) and a military comparison group, exploratory factor analysis was conducted and Tucker's Congruence Coefficient (TCC) was used to determine factor structure similarity across study groups and waves. RESULTS: The results showed that the 3 factors observed at wave 1 were still present at wave 2, and factor structures across study groups and study waves were fairly similar, with TCC ranging 0.86-0.92. Veterans consistently reported more symptoms across all 3 factors. Veterans' symptomatology specific to psychophysiological distress increased between waves 1 and 2 (ratio of means 1.15; 95% CI 1.07 to 1.25) but psychophysiological distress symptomatology was constant in the comparison group (ratio of means 0.97; 95% CI 0.89 to 1.06). Somatic and arthroneuromuscular distress symptomatology significantly increased over time for both study groups, although at a similar rate. CONCLUSIONS: While the symptom groupings (measured by the 3 factors) remained unchanged at 10 years of follow-up, and remained comparable between Gulf War and comparison group, symptomatology continued to be elevated in Gulf War veterans than in the comparison group, and was most evident for psychophysiological distress.

Mortality and cancer incidence at a fire training college.

BACKGROUND: An investigation into concerns about possible health effects of fire training practices at an Australian training facility recommended a study to investigate the risk of cancer and mortality of those with risk of chronic occupational exposure to several chemicals. AIMS: To investigate mortality and cancer incidence in firefighters at the Country Fire Authority (CFA) Fiskville training facility, Victoria, Australia, between 1971 and 1999. METHODS: CFA supplied human resources records, supplemented by self-reported information for a retrospective cohort, and allocated firefighters to low, medium or high groups based on probability of exposure. We linked the cohort to state and national cancer and mortality data. We calculated standardized mortality ratios and standardized cancer incidence ratios (SIRs). RESULTS: The high group (n = 95) had a clearly increased risk of overall cancers SIR = 1.85 (95% CI 1.20-2.73), testicular cancer SIR = 11.9 (1.44-42.9) and melanoma SIR = 4.59 (1.68-9.99) relative to the population of Victoria. Brain cancer was significantly increased for the medium group (n = 256): SIR = 5.74 (1.56-14.7). Mortality was significantly reduced for all groups. CONCLUSIONS: Dealing with supplied records can be problematic but despite the small numbers, we identified an increased risk of cancer for the high group. The mortality data suggested that there was under-ascertainment for the medium and low groups which underestimated risk and a possible reporting bias for brain cancer. Small cohorts can still provide statistically significant findings when investigating locations for cancer risk.

Depression in Gulf War veterans: a systematic review and meta-analysis.

BACKGROUND: Although post-traumatic stress disorder (PTSD) has been a focus of attention in 1990/1991 Gulf War veterans, the excess risk of depression has not been clearly identified. We investigated this through a systematic review and meta-analysis of studies comparing depression in Gulf War veterans to depression in a comparison group of non-deployed military personnel. METHOD: Multiple electronic databases and grey literature were searched from 1990 to 2012. Studies were assessed for eligibility and risk of bias according to established criteria. RESULTS: Of 14 098 titles and abstracts assessed, 14 studies met the inclusion criteria. Gulf War veterans had over twice the odds of experiencing depression [odds ratio (OR) 2.28, 95% confidence interval (CI) 1.88-2.76] and dysthymia or chronic dysphoria (OR 2.39, 95% CI 2.0-2.86) compared to non-deployed military personnel. This finding was robust in sensitivity analyses, and to differences in overall risk of bias and psychological measures used. CONCLUSIONS: Despite divergent methodologies between studies, depression and dysthymia were twice as common in Gulf War veterans and are important medical conditions for clinicians and policymakers to be aware of in managing Gulf War veterans' health.

Is there a relationship between occupational activities and low back pain in obese, middle-aged women?

BACKGROUND: Although low back pain and obesity are major health issues for women, our understanding of the relationship between these conditions is limited. This study aimed to investigate the relationship between occupational activities and low back pain and disability in obese and non-obese, middle-aged females. METHODS: Eighty-nine obese and 56 non-obese participants were recruited for a community-based study of musculoskeletal health. Low back pain intensity and disability were examined using the Chronic Pain Grade Questionnaire and participants were asked about their involvement in occupational activities. RESULTS: More manual activity and heavy lifting, bending or squatting were found to be associated with low back pain intensity in obese females (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.14-2.94; OR 3.02, 95% CI 1.24-7.37, respectively), but not in non-obese females (OR 0.83, 95% CI 0.42-1.63; OR 0.81, 95% CI 0.25-2.6, respectively), after adjusting for age and recreational activity. Similarly, there were also relationships between performance of more manual activity and heavy lifting, bending or squatting and low back disability in the obese (OR 1.68, 95% CI 1.07-2.63; OR 2.79, 95% CI 1.21-6.46, respectively), but not in the non-obese (OR 0.88, 95% CI 0.36-2.13; OR 1.78, 95% CI 0.39-8.22, respectively). CONCLUSIONS: Obese females who perform predominately manual activity or heavy lifting, bending or squatting at work have high levels of low back pain and disability, independent of their recreational activity. This was not the case for non-obese, female workers. Although longitudinal investigation is needed, these findings highlight the role of obesity in low back pain and disability for middle-aged females in occupational settings.

Analysis of naturally occurring mutations in the human lipodystrophy protein seipin reveals multiple potential pathogenic mechanisms.

AIMS/HYPOTHESIS: In humans, disruption of the gene BSCL2, encoding the protein seipin, causes congenital generalised lipodystrophy (CGL) with severe insulin resistance and dyslipidaemia. While the causative gene has been known for over a decade, the molecular functions of seipin are only now being uncovered. Most pathogenic mutations in BSCL2 represent substantial disruptions including significant deletions and frameshifts. However, several more subtle mutations have been reported that cause premature stop codons or single amino acid substitutions. Here we have examined these mutant forms of seipin to gain insight into how they may cause CGL. METHODS: We generated constructs expressing mutant seipin proteins and determined their expression and localisation. We also assessed their capacity to recruit the key adipogenic phosphatidic acid phosphatase lipin 1, a recently identified molecular role of seipin in developing adipocytes. Finally, we used atomic force microscopy to define the oligomeric structure of seipin and to determine whether this is affected by the mutations. RESULTS: We show that the R275X mutant of seipin is not expressed in pre-adipocytes. While the other premature stop mutant forms fail to bind lipin 1 appropriately, the point mutants T78A, L91P and A212P all retain this capacity. We demonstrate that wild-type human seipin forms oligomers of 12 subunits in a circular configuration but that the L91P and A212P mutants of seipin do not. CONCLUSIONS/INTERPRETATION: Our study represents the most comprehensive analysis so far of mutants of seipin causing lipodystrophy and reveals several different molecular mechanisms by which these mutations may cause disease.

Higher Dietary Vitamin K Intake is Associated with Better Physical Function and Lower Long-Term Injurious Falls Risk in Community-Dwelling Older Women.

BACKGROUND: In recent years, a potential beneficial role of Vitamin K in neuromuscular function has been recognised. However, the optimal dietary intake of Vitamin K to support muscle function in the context of falls prevention remains unknown. OBJECTIVE: To examine the relationship of dietary Vitamin K1 and K2 with muscle function and long-term injurious fall-related hospitalisations in older women. DESIGN: Cohort study. PARTICIPANTS: 1347 community-dwelling older Australian women ≥70 years. MEASUREMENTS: A new Australian Vitamin K nutrient database, supplemented with published data, was used to calculate Vitamin K1 and K2 intake from a validated food frequency questionnaire at baseline (1998). Muscle function (grip strength and timed-up-and-go; TUG) as well plasma Vitamin D status (25OHD) were also assessed at baseline. Fall-related hospitalisations over 14.5 years were obtained from linked health records. Multivariable-adjusted logistic regression and Cox-proportional hazard models were used to analyse the data. RESULTS: Over 14.5 years of follow-up (14,774 person-years), 535 (39.7%) women experienced a fall-related hospitalisation. Compared to women with the lowest Vitamin K1 intake (Quartile 1, median 49 µg/d), those with the highest intake (Quartile 4, median 120 µg/d) had 29% lower odds (OR 0.71 95%CI 0.52-0.97) for slow TUG performance (>10.2 s), and 26% lower relative hazards of a fall-related hospitalisation (HR 0.74 95%CI 0.59-0.93) after multivariable adjustment. These associations were non-linear and plateaued at moderate intakes of ~70-100 µg/d. There was no relation to grip strength. Vitamin K2 intakes were not associated with muscle function or falls. CONCLUSION: A higher habitual Vitamin K1 intake was associated with better physical function and lower long-term injurious falls risk in community-dwelling older women. In the context of musculoskeletal health, Vitamin K1 found abundantly in green leafy vegetables should be promoted.

Aberrant hypermethylation in primary tumours and sentinel lymph node metastases in paediatric patients with cutaneous melanoma.

BACKGROUND: Debate on how to manage paediatric patients with cutaneous melanoma continues, particularly in those with sentinel lymph node (SLN) metastases who are at higher risk of poor outcomes. Management is often based on adult algorithms, although differences in clinical outcomes between paediatric and adult patients suggest that melanoma in paediatric patients differs biologically. Yet, there are no molecular prognostic studies identifying these differences. OBJECTIVES: We investigated the epigenetic (methylation) regulation of several tumour-related genes (TRGs) known to be significant in adult melanoma progression in histopathology(+) SLN metastases (n = 17) and primary tumours (n = 20) of paediatric patients with melanoma to determine their clinical relevance. METHODS: Paediatric patients (n = 37; ≤ 21 years at diagnosis) with American Joint Committee on Cancer stage I-III cutaneous melanoma were analysed. Gene promoter methylation of the TRGs RASSF1A, RARß2, WIF1 and APC was evaluated. RESULTS: Hypermethylation of RASSF1A, RARß2, WIF1 and APC was found in 29% (5/17), 25% (4/16), 25% (4/16) and 19% (3/16) of histopathology(+) SLNs, respectively. When matched to adult cutaneous melanomas by Breslow thickness and ulceration, hypermethylation of all four TRGs in SLN(+) paediatric patients with melanoma was equivalent to or less than in adults. With a median follow-up of 55 months, SLN(+) paediatric patients with melanoma with hypermethylation of > 1 TRG vs. ≤ 1 TRG had worse disease-free (P = 0·02) and overall survival (P = 0·02). CONCLUSIONS: Differences in the methylation status of these TRGs in SLN(+) paediatric and adult patients with melanoma may account for why SLN(+) paediatric patients have different clinical outcomes. SLN biopsy should continue to be performed; within SLN(+) paediatric patients with melanoma, hypermethylation of TRGs can be used to identify a subpopulation at highest risk for poor outcomes who warrant vigilant clinical follow-up.

Doxycycline treatment attenuates acute lung injury in mice infected with virulent influenza H3N2 virus: involvement of matrix metalloproteinases.

Acute respiratory distress syndrome, a severe form of acute lung injury (ALI), is a major cause of death during influenza pneumonia. We have provided evidence for the involvement of recruited neutrophils, their toxic enzymes such as myeloperoxidase and matrix metalloproteinases (MMPs), and neutrophil extracellular traps in aggravating alveolar-capillary damage. In this study, we investigated the effects of doxycycline (DOX), an inhibitor of MMPs, on influenza-induced ALI. BALB/c mice were infected with a sublethal dose of mouse-adapted virulent influenza A/Aichi/2/68 (H3N2) virus, and administered daily with 20mg/kg or 60 mg/kg DOX orally. The effects of DOX on ALI were determined by measuring inflammation, capillary leakage, and MMP activities. Furthermore, levels of T1-α (a membrane protein of alveolar type I epithelium) and thrombomodulin (an endothelial protein) in the bronchoalveolar lavage fluid were evaluated by Western blot analysis. Our results demonstrate significantly decreased inflammation and protein leakage in the lungs after DOX treatment. Levels of MMP-2 and MMP-9 activity, T1-α and thrombomodulin were also diminished in the DOX-treated group. These findings were corroborated by histopathologic analyses, which demonstrated significant reduction in lung damage. Although DOX treatment reduced ALI, there were no effects on virus titers and body weights. Taken together, these results demonstrate that DOX may be useful in ameliorating ALI during influenza pneumonia. Further studies are warranted to determine whether DOX can be used in combination with anti-viral agents to alleviate severe influenza pneumonia.

[Perforative gastroduodenal ulcers].

Treatment results of 986 patients with perforative gastroduodenal ulcers were analyzed. The sequence of surgeon's acts was diagnostically effective in 99.5%. 776 (78.7%) of patients presented with duodenal ulcer; 210 (21.3%) had gastric ulcer. Ulcer closure was performed in 934 (94.7%) cases; gastric resection was made in 52 (5.3%) cases. Postoperative lethality rate was 4.3%. Tissue destruction proved to be partly connected with the level of the connective tissue metabolites in blood. The balance of factors of aggression and defense (Helicobacter invasion, level of mucus formation, mucosal leucocytal infiltration, acid level in stomach and level of necrosis factor in blood) was registered in long-term follow-up in dependence of the operation performed. Ulcer perforation recurrence was registered in 18.8% of simple closure cases and in 3.8% of patients after gastric resection.

Disparity in female and Asian representation amongst cardiology journal editorial boards members: a call for empowerment.

BACKGROUND: While progress is evident in gender and ethnic representation in the workplace, this disparity remains prevalent in academic positions. OBJECTIVES: We examined gender and Asian ethnic representation in editorial boards of cardiology journals. METHODS: A cross-sectional analysis was conducted using publicly available data on Cardiology and Cardiovascular medicine journals in the first quartile of the 2020 Scimago Journal & Country Rank indicator. The proportions of female and Asian editorial board members, associate editors and editors-in-chief were assessed. Subgroup analyses were conducted based on the journal's geographical origin, subspecialty and demographic of the editor-in-chief. RESULTS: Seventy-six cardiology journals, involving 8915 editorial board members, were included. Only 19.6% of editorial board members were female, 20.8% Asians and 4.0% Asian females. There were less female representation amongst editors-in-chief (9.9%) compared to associate editors (22.3%). European (18.1%) and North American-based journals (21.1%) had higher female representation compared to Asian-based journals (8.7%). There was lower Asian representation in European (18.1%) and North American-based journals (19.9%) compared to Asian-based journals (72.3%). Females were underrepresented in interventional (14.5%) journals, while Asians were underrepresented in general cardiology (18.3%) and heart failure (18.3%) journals. Journals led by female editors-in-chief had significantly higher female representation compared to male-led ones, while journals with Asian editors-in-chief had greater Asian representation compared to non-Asian led ones. CONCLUSION: This study highlights the female and Asian ethnic underrepresentation in academic roles in cardiology journal editorial boards. Further analysis is needed for other ethnicities, while the community pushes towards gender-balanced and ethnic diversity across editorial boards.

Wireless phone use in childhood and adolescence and neuroepithelial brain tumours: Results from the international MOBI-Kids study.

In recent decades, the possibility that use of mobile communicating devices, particularly wireless (mobile and cordless) phones, may increase brain tumour risk, has been a concern, particularly given the considerable increase in their use by young people. MOBI-Kids, a 14-country (Australia, Austria, Canada, France, Germany, Greece, India, Israel, Italy, Japan, Korea, the Netherlands, New Zealand, Spain) case-control study, was conducted to evaluate whether wireless phone use (and particularly resulting exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF)) increases risk of brain tumours in young people. Between 2010 and 2015, the study recruited 899 people with brain tumours aged 10 to 24 years old and 1,910 controls (operated for appendicitis) matched to the cases on date of diagnosis, study region and age. Participation rates were 72% for cases and 54% for controls. The mean ages of cases and controls were 16.5 and 16.6 years, respectively; 57% were males. The vast majority of study participants were wireless phones users, even in the youngest age group, and the study included substantial numbers of long-term (over 10 years) users: 22% overall, 51% in the 20-24-year-olds. Most tumours were of the neuroepithelial type (NBT; n = 671), mainly glioma. The odds ratios (OR) of NBT appeared to decrease with increasing time since start of use of wireless phones, cumulative number of calls and cumulative call time, particularly in the 15-19 years old age group. A decreasing trend in ORs was also observed with increasing estimated cumulative RF specific energy and ELF induced current density at the location of the tumour. Further analyses suggest that the large number of ORs below 1 in this study is unlikely to represent an unknown causal preventive effect of mobile phone exposure: they can be at least partially explained by differential recall by proxies and prodromal symptoms affecting phone use before diagnosis of the cases. We cannot rule out, however, residual confounding from sources we did not measure. Overall, our study provides no evidence of a causal association between wireless phone use and brain tumours in young people. However, the sources of bias summarised above prevent us from ruling out a small increased risk.

Inhibition of angiogenic and non-angiogenic targets by sorafenib in renal cell carcinoma (RCC) in a RCC xenograft model.

BACKGROUND: It is widely recognised that sorafenib inhibits a range of molecular targets in renal cell carcinoma (RCC). In this study, we aim to use patient-derived RCC xenografts to delineate the angiogenic and non-angiogenic molecular targets of sorafenib therapy for advanced RCC (aRCC). METHODS: We successfully generated three patient RCC-derived xenografts in severe combined immunodeficient mice, consisting of three different RCC histological subtypes: conventional clear cell, poorly differentiated clear cell RCC with sarcomatoid changes, and papillary RCC. This study also used clear cell RCC cells (786-0/EV) harbouring mutant VHL to investigate the clonogenic survival of cells transfected with survivin sense and antisense oligonucleotides. RESULTS: All three xenografts retain their original histological characteristics. We reported that sorafenib inhibited all three RCC xenograft lines regardless of histological subtypes in a dose-dependant manner. Sorafenib-induced growth suppression was associated with not only inhibition of angiogenic targets p-PDGFR-ß, p-VEGFR-2, and their downstream signalling pathways p-Akt and p-ERK, cell cycle, and anti-apoptotic proteins that include cyclin D1, cyclin B1, and survivin but also upregulation of proapoptotic Bim. Survivin knockdown by survivin-specific antisense-oligonucleotides inhibited colony formation and induced cell death in clear cell RCC cells. CONCLUSION: This study has shed light on the molecular mechanisms of sorafenib in RCC. Inhibition of non-angiogenic molecules by sorafenib could contribute in part to its anti-tumour activities observed in vivo, in addition to its anti-angiogenic effects.

Suicide in Australian pesticide-exposed workers.

BACKGROUND: Epidemiological research has observed that workers with exposure to anticholinesterase pesticides, and particularly those with a history of acute overexposure, may be at increased risk of depression. However, there is little published research about the risk of suicide in relation to pesticide exposure. AIMS: To investigate risk of suicide in relation to metrics of pesticide exposure and type of work. METHODS: A nested case-control study was performed within a retrospective cohort study of pesticide-exposed workers from various industries. Ninety male suicide deaths and 270 male controls were matched by age bands, state of residence and live status. Cholinesterase inhibition was determined using subject-specific biomonitoring records collected at the time of exposure. RESULTS: Suicide risk was not significantly elevated in relation to exposure to any particular pesticide classes nor in relation to pesticide overexposure, confirmed by blood test. While the risk of suicide associated with a history of cholinesterase inhibition was raised, this was not significant (odds ratio = 1.90, 95% confidence interval = 0.73-4.93). CONCLUSIONS: This study did not find an elevated suicide risk associated with use of any major class of pesticide and there was little evidence that overexposure was associated with increased risk of suicide. A non-significant association between overexposure to anticholinesterase pesticides may be consistent with previous research showing increased depression in workers with a history of cholinesterase inhibition and warrants further investigation.

Serum angiotensin converting enzyme elevation in association with artificial stone silicosis.

BACKGROUND: Silicosis is a rapidly emerging major health concern for workers in the artificial stone benchtop industry. The association between serum angiotensin converting enzyme (sACE) levels and artificial stone silicosis is unknown. METHODS: We investigated 179 male workers (median age 40 years, interquartile range (IQR) 33-48 years) from the stone benchtop industry in Victoria, Australia. All had worked in an environment where dry processing of artificial stone had occurred and were registered with the Victorian Silica-associated Disease Registry between June 2019 and August 2020. Workers had undergone protocolised assessments including respiratory function testing, high resolution CT chest and blood tests panel, including sACE. FINDINGS: Sixty workers with artificial stone silicosis were identified and they had a higher median sACE level (64.1 U/L, IQR 51.5, 87.5), compared to 119 without silicosis (35.0 U/L, IQR 25.0, 47.0). Compared to those with a normal assessment, regression modelling noted significantly higher average differences in sACE levels for workers with lymphadenopathy alone (12.1 U/L, 95% confidence interval (CI): 1.3, 22.9), simple silicosis (28.7 U/L, 95% CI: 21.3, 36.0) and complicated silicosis (36.0 U/L, 95% CI 25.2, 46.9). There was a small negative association with gas transfer, but no associations with exposure duration or spirometry. CONCLUSION: sACE levels were noted to be higher in artificial stone workers with silicosis compared to those without disease and was highest in those with complicated silicosis. Longitudinal follow up is required to evaluate sACE as a prognostic biomarker for workers with this rapidly emerging occupational lung disease.