Metabolic changes in summer active and anuric hibernating free-ranging brown bears (ursus arctos)

The brown bear (Ursus arctos) hibernates for 5 to 6 months each winter and during this time ingests no food or water and remains anuric and inactive. Despite these extreme conditions, bears do not develop azotemia and preserve their muscle and bone strength. To date most renal studies have been limited to small numbers of bears, often in captive environments. Sixteen free-ranging bears were darted and had blood drawn both during hibernation in winter and summer. Samples were collected for measurement of creatinine and urea, markers of inflammation, the calcium-phosphate axis, and nutritional parameters including amino acids. In winter the bear serum creatinine increased 2.5 fold despite a 2-fold decrease in urea, indicating a remarkable ability to recycle urea nitrogen during hibernation. During hibernation serum calcium remained constant despite a decrease in serum phosphate and a rise in FGF23 levels. Despite prolonged inactivity and reduced renal function, inflammation does not ensue and bears seem to have enhanced antioxidant defense mechanisms during hibernation. Nutrition parameters showed high fat stores, preserved amino acids and mild hyperglycemia during hibernation. While total, essential, non-essential and branched chain amino acids concentrations do not change during hibernation anorexia, changes in individual amino acids ornithine, citrulline and arginine indicate an active, although reduced urea cycle and nitrogen recycling to proteins. Serum uric acid and serum fructose levels were elevated in summer and changes between seasons were positively correlated. Further studies to understand how bears can prevent the development of uremia despite minimal renal function during hibernation could provide new therapeutic avenues for the treatment of human kidney disease

The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histological progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution towards an IDHwt-like phenotype

The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype.</p

Glioma Through the Looking GLASS: Molecular Evolution of Diffuse Gliomas and the Glioma Longitudinal AnalySiS Consortium

Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas (TCGA) and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal AnalySiS Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities, and ultimately, improved outcomes for a patient population in need

142. Occupational exposure to chemicals and hearing impairment.

Research conducted over the last two decades has brought attention to the ototoxicity of chemicals in the workplace and their interaction with noise. Chemicals that have been specifically studied for their ototoxicity include solvents, metals, asphyxiants, PCBs and pesticides. Noise exposure is particularly damaging to the cochlea, a part of the peripheral auditory system, whereas chemicals tend to affect both the cochlear structures and the central auditory system. Reduced blood flow and free radical formation are important ototoxic mechanisms shared by noise and chemical exposures. Solvents and asphyxiants may also disrupt intrinsic anti-oxidant defences and make the ear more vulnerable to the effects of e.g. noise exposure. The chemicals reviewed in the present document have all been associated with auditory effects in animals. Some of the solvents and the asphyxiants interact synergistically with noise or potentiate noise effects on the auditory system. Combinations of chemical exposure with noise and other stressors such as physical activity during exposure may lower the concentration of the chemical exposure necessary for induction of an auditory effect. Auditory effects have also been indicated in humans for all agents covered in this document for which there are data. Noise is often present in the occupational arena, which makes prediction of the outcome challenging. As combined exposure (e.g. chemical and noise) is currently not taken care of in the regular occupational exposure limit (OEL) setting procedure, a noise notation can be used to indicate an increased risk of hearing loss after exposure to the chemical at a level close to the OEL with concurrent noise exposure. The strength of evidence for ototoxicity differs between the agents but falls basically into three categories, i.e. agents for which: 1) human data indicate auditory effects under or near existing OELs and robust animal data support an effect on hearing from exposure (styrene, toluene, carbon disulphide, lead, mercury and carbon monoxide), 2) human data are lacking whereas animal data indicate auditory effects under or near existing OELs (p-xylene, ethylbenzene and hydrogen cyanide), 3) human data are poor or lacking and animal data indicate an auditory effect well above the existing OELs (chlorobenzene, trichloroethylene, n-hexane, n-heptane, some solvent mixtures, trimethyltin, acrylonitrile, 3,3'-iminodipropionitrile, pesticides and PCBs)

Subjective and Clinically Assessed Hearing Loss; A Cross-Sectional Register-Based Study on a Swedish Population Aged 18 through 50 Years

Objectives Questionnaire studies suggest that hearing is declining among young adults. However, few studies have examined the reliability of hearing questionnaires among young adult subjects. This study examined the associations between pure tone audiometrically assessed (PTA) hearing loss and questionnaire responses in young to middle aged adults. Materials and Methods A cross-sectional study using questionnaire and screening PTA (500 through 6000 Hz) data from 15322 Swedish subjects (62% women) aged 18 through 50 years. PTA hearing loss was defined as a hearing threshold above 20 dB in both ears at one or more frequencies. Data were analysed with chi-square tests, nonlinear regression, binary logistic regression, and the generalized estimating equation (GEE) approach. Results The prevalence of PTA hearing loss was 6.0% in men and 2.9% in women (p &lt; 0.001). Slight hearing impairment was reported by 18.5% of the men and 14.8% of the women (p &lt; 0.001), whereas 0.5% of men and women reported very impaired hearing. Using multivariate GEE modelling, the odds ratio of PTA hearing loss was 30.4 (95% CI, 12.7-72.9) in men and 36.5 (17.2-77.3) in women reporting very impaired hearing. The corresponding figures in those reporting slightly impaired hearing were 7.06 (5.25-9.49) in men and 8.99 (6.38-12.7) in women. These values depended on the sound stimulus frequency (p = 0.001). The area under the ROC curve was 0.904 (0.892-0.915) in men and 0.886 (0.872-0.900) in women. Conclusions Subjective hearing impairment predicted clinically assessed hearing loss, suggesting that there is cause for concern as regards the future development of hearing in young to middle-aged people

What Predicts Falls, and what are the Circumstances and Consequences of Falls in Community-Dwelling Older Adults Who Need Walking Aids or Home Help Service

The objective was to analyze predictive variables for falls in older community-dwelling adults who needed walking aids or home help service, to describe the circumstances and consequences of falls and fall injuries, and to describe the activities preceding falls, n = 175, mean age 83 years. Falls were self-reported monthly in a fall calendar and were followed up by a telephone interview. A logistic regression analysis was performed to investigate predictive baseline variables for falls. Injuries were reported in 82 of the 185 fall events. Previous falls and a high level of education had a significant association with falls odds ratios 1.9 (95% CI 1.3-2.7), and 2.7 (95% CI 1.4-5.3). Activities preceding the falls were classified according to the International Classification of Functioning (ICF). Falls and fall injuries were most common while moving around within the home and rising from sitting to standing

The Otago Exercise Program With or Without Motivational Interviewing for Community-Dwelling Older Adults : A 12-Month Follow-Up of a Randomized, Controlled Trial

The aim of this randomized controlled trial was to examine the 12-month effects of the home-based Otago Exercise Program (OEP) with or without the support of motivational interviewing (MI) on community-dwelling people 75 years and older who needed walking aids and/or home help service. In total, 175 participants were randomized into three groups: OEP (n = 61), OEP with MI (n = 58), and a control group (n = 56) (M age = 83 years). Measures were physical performance, physical activity level, balance, grip strength, fall-related self-efficacy, fall rate, and fall injury rate. The OEP with and the OEP without MI, with the support of a physical therapist (six home visits and three phone calls), demonstrated no benefits in any of the measures compared with a control group. In this subgroup of pre-frail older adults, more frequent support by personnel may be required to secure efficient intensity and progression in the exercises performed on your own at home

Hearing health care in Kenya; a regional field study

Objectives: To describe a characterize patients’ hearing health and to evaluate a method for tele-audiology in a hearing clinic in Nyeri in Kenya. Study design: Field study with quantitative approach using consecutive sampling of patients visiting the hearing clinic. Methods: Questionnaires were answered by patients to identify the amount of visitors, the prevalence of hearing loss, tinnitus, ear diseases and malaria. In addition, hearing tests of patients were gathered during a four week. The results of hearing measurements with pure tone audiometry was compared to that of a new tele-audiology device, Kuduwave, as a validation testing of the tele method under field conditions. Also the tele-audiology method was tested in a pilot study by doing a hearing test at a distance. Results: Eighty patients were included in this study. Thirty-five out of 54 adult patients had tinnitus. Forty patients received malaria medication and 37 patients had hearing aids. Comparative results with eleven patients between pure tone audiometry and Kuduwave showed significant differences on frequencies 250-2000 Hz on the right ear and 250 Hz and 1000 Hz on the left ear. Conclusions: A field study is an opportunity to get close to the population to be studied. Tele-audiology offers new opportunities in hearing health care

A comparison of occupational and nonoccupational noise exposures in Sweden

This study was conducted to evaluate noise exposures and the contributions of occupational and nonoccupational activities among three groups of Swedish workers (office workers, day care workers, and military flight technicians), and to evaluate risk factors for elevated hearing threshold levels. Forty-five subjects were recruited across the three groups. Each subject completed a risk factor questionnaire along with Békésy audiometry at frequencies between 125 and 8000 Hz. Subjects also wore a noise dosimeter continuously for 1 week, and documented their occupational and nonoccupational activities using a time-activity log. Subjects in all groups completed >7400 h of dosimetry, and had weekly exposures between 76 and 81 dBA. Day care workers had the highest daily exposures, and flight technicians had the highest weekly exposures. Most daily and weekly exposures exceeded the 70 dBA exposure limit recommended for prevention of any hearing loss. Subjects′ perceptions of their exposures generally agreed well with measured noise levels. Among office workers, exposures were predominately nonoccupational, while among flight technicians nonoccupational and occupational activities contributed roughly equally, and among day care workers occupational exposures were dominant. Extreme exposures and cumulative noise exposure were associated with an increased risk of hearing threshold levels >10 dB hearing level. Effective hearing loss prevention programs may be needed in occupations not historically considered to be at high risk of noise-induced hearing loss (e.g., day care workers). Prevention efforts need to address nonoccupational exposures as well as occupational exposures, as nonoccupational activities may present the dominant risk of noise-induced hearing loss for some workers