Myonuclear alterations associated with exercise are independent of age in humans.

Age-related decline in skeletal muscle structure and function can be mitigated by regular exercise. However, the precise mechanisms that govern this are not fully understood. The nucleus plays an active role in translating forces into biochemical signals (mechanotransduction), with the nuclear lamina protein lamin A regulating nuclear shape, nuclear mechanics and ultimately gene expression. Defective lamin A expression causes muscle pathologies and premature ageing syndromes, but the roles of nuclear structure and function in physiological ageing and in exercise adaptations remain obscure. Here, we isolated single muscle fibres and carried out detailed morphological and functional analyses on myonuclei from young and older exercise-trained individuals. Strikingly, myonuclei from trained individuals were more spherical, less deformable, and contained a thicker nuclear lamina than those from untrained individuals. Complementary to this, exercise resulted in increased levels of lamin A and increased myonuclear stiffness in mice. We conclude that exercise is associated with myonuclear remodelling, independently of age, which may contribute to the preservative effects of exercise on muscle function throughout the lifespan. KEY POINTS: The nucleus plays an active role in translating forces into biochemical signals. Myonuclear aberrations in a group of muscular dystrophies called laminopathies suggest that the shape and mechanical properties of myonuclei are important for maintaining muscle function. Here, striking differences are presented in myonuclear shape and mechanics associated with exercise, in both young and old humans. Myonuclei from trained individuals were more spherical, less deformable and contained a thicker nuclear lamina than untrained individuals. It is concluded that exercise is associated with age-independent myonuclear remodelling, which may help to maintain muscle function throughout the lifespan.

International Exercise Recommendations in Older Adults (ICFSR): Expert Consensus Guidelines.

The human ageing process is universal, ubiquitous and inevitable. Every physiological function is being continuously diminished. There is a range between two distinct phenotypes of ageing, shaped by patterns of living - experiences and behaviours, and in particular by the presence or absence of physical activity (PA) and structured exercise (i.e., a sedentary lifestyle). Ageing and a sedentary lifestyle are associated with declines in muscle function and cardiorespiratory fitness, resulting in an impaired capacity to perform daily activities and maintain independent functioning. However, in the presence of adequate exercise/PA these changes in muscular and aerobic capacity with age are substantially attenuated. Additionally, both structured exercise and overall PA play important roles as preventive strategies for many chronic diseases, including cardiovascular disease, stroke, diabetes, osteoporosis, and obesity; improvement of mobility, mental health, and quality of life; and reduction in mortality, among other benefits. Notably, exercise intervention programmes improve the hallmarks of frailty (low body mass, strength, mobility, PA level, energy) and cognition, thus optimising functional capacity during ageing. In these pathological conditions exercise is used as a therapeutic agent and follows the precepts of identifying the cause of a disease and then using an agent in an evidence-based dose to eliminate or moderate the disease. Prescription of PA/structured exercise should therefore be based on the intended outcome (e.g., primary prevention, improvement in fitness or functional status or disease treatment), and individualised, adjusted and controlled like any other medical treatment. In addition, in line with other therapeutic agents, exercise shows a dose-response effect and can be individualised using different modalities, volumes and/or intensities as appropriate to the health state or medical condition. Importantly, exercise therapy is often directed at several physiological systems simultaneously, rather than targeted to a single outcome as is generally the case with pharmacological approaches to disease management. There are diseases for which exercise is an alternative to pharmacological treatment (such as depression), thus contributing to the goal of deprescribing of potentially inappropriate medications (PIMS). There are other conditions where no effective drug therapy is currently available (such as sarcopenia or dementia), where it may serve a primary role in prevention and treatment. Therefore, this consensus statement provides an evidence-based rationale for using exercise and PA for health promotion and disease prevention and treatment in older adults. Exercise prescription is discussed in terms of the specific modalities and doses that have been studied in randomised controlled trials for their effectiveness in attenuating physiological changes of ageing, disease prevention, and/or improvement of older adults with chronic disease and disability. Recommendations are proposed to bridge gaps in the current literature and to optimise the use of exercise/PA both as a preventative medicine and as a therapeutic agent.

In vitro study of enhanced photodynamic cancer cell killing effect by nanometer-thick gold nanosheets.

Photodynamic therapy (PDT) by near-infrared (NIR) irradiation is a promising technique for treating various cancers. Here, we reported the development of free-standing wafer-scale Au nanosheets (NSs) that exhibited an impressive PDT effect. The Au NSs were synthesized by ionic layer epitaxy at the air-water interface with a uniform thickness in the range from 2 to 8.5 nm. These Au NSs were found very effective in generating singlet oxygen under NIR irradiation. In vitro cellular study showed that the Au NSs had very low cytotoxicity and high PDT efficiency due to their uniform 2D morphology. Au NSs could kill cancer cells after 5 min NIR irradiation with little heat generation. This performance is comparable to using 10 times mass loading of Au nanoparticles (NPs). This work suggests that two-dimensional (2D) Au NSs could be a new type of biocompatible nanomaterial for PDT of cancer with an extraordinary photon conversion and cancer cell killing efficiency.

Enhanced Ferromagnetism from Organic-Cerium Oxide Hybrid Ultrathin Nanosheets.

Room-temperature ferromagnetism in two-dimensional (2D) oxide materials is an intriguing phenomenon for spintronic applications. Here, we report significantly enhanced room-temperature ferromagnetism observed from ultrathin cerium oxide nanosheets hybridized with organic surfactant molecules. The hybrid nanosheets were synthesized by ionic layer epitaxy over a large area at the water-air interface. The nanosheets exhibited a saturation magnetization of 0.149 emu/g as their thickness reduced to 0.67 nm. This value was 5 times higher than that for CeO2 thin films and more than 20 times higher than that for CeO2 nanoparticles. The magnetization was attributed to the high concentration (15.5%) of oxygen vacancies stabilized by surfactant hybridization as well as electron transfer between organic and oxide layers. This work brings an effective strategy of introducing strong ferromagnetism to functional oxide materials, which leads to a promising route toward exploring new physical properties in 2D hybrid nanomaterials.

Cardiorespiratory fitness not sedentary time or physical activity is associated with cardiometabolic risk in active older adults.

Sedentary time (ST) and moderate-to-vigorous physical activity (MVPA) are associated with cardiometabolic health. Cardiorespiratory fitness (CRF) is also implicated but often overlooked in health recommendations. This study assessed the relationships between ST, MVPA, CRF, and cardiometabolic health in highly active older individuals. 125 healthy amateur cyclists aged 55 to 79 years had their ST and MVPA levels assessed by actigraphy over a 7-day period. CRF was assessed using a maximal effort cycle ergometry test to determine VO2max with results normalized to both body mass and fat-free mass measured by DXA. Markers of cardiometabolic risk (blood glucose, triglycerides, cholesterol, HDL, LDL, Insulin, HOMA IR, blood pressure, and body fat) were assessed and used to determine cumulative cardiometabolic risk. Multiple linear regression was used to assess ST, MVPA, and CRF associations with cardiometabolic health with the relationship between activity levels and CRF determined. CRF was associated with training volume (P = .003), but not ST or MVPA. A high CRF was associated with lower cumulative cardiometabolic risk, body fat percentage, triglyceride, and HDL levels (P < .05 in all cases). MVPA was negatively associated with body fat percentage, while ST was not associated with any marker of cardiometabolic risk when adjusting for activity levels. An association between CRF and cardiometabolic risk even in a group of older individuals with high fitness levels highlights the importance that CRF may have in maintaining health.

Active GSK3ß and an intact ß-catenin TCF complex are essential for the differentiation of human myogenic progenitor cells.

Wnt-ß-catenin signalling is essential for skeletal muscle myogenesis during development, but its role in adult human skeletal muscle remains unknown. Here we have used human primary CD56Pos satellite cell-derived myogenic progenitors obtained from healthy individuals to study the role of Wnt-ß-catenin signalling in myogenic differentiation. We show that dephosphorylated ß-catenin (active-ß-catenin), the central effector of the canonical Wnt cascade, is strongly upregulated at the onset of differentiation and undergoes nuclear translocation as differentiation progresses. To establish the role of Wnt signalling in regulating the differentiation process we manipulated key nodes of this pathway through a series of ß-catenin gain-of-function (GSK3 inhibition and ß-catenin overexpression) or loss-of-function experiments (dominant negative TCF4). Our data showed that manipulation of these critical pathway components led to varying degrees of disruption to the normal differentiation phenotype indicating the importance of Wnt signalling in regulating this process. We reveal an independent necessity for active-ß-catenin in the fusion and differentiation of human myogenic progenitors and that dominant negative inhibition of TCF4 prevents differentiation completely. Together these data add new mechanistic insights into both Wnt signalling and adult human myogenic progenitor differentiation.

Simultaneous Enhancement of Charge Separation and Hole Transportation in a TiO2 -SrTiO3 Core-Shell Nanowire Photoelectrochemical System.

Efficient charge separation and transportation are key factors that determine the photoelectrochemical (PEC) water-splitting efficiency. Here, a simultaneous enhancement of charge separation and hole transportation on the basis of ferroelectric polarization in TiO2 -SrTiO3 core-shell nanowires (NWs) is reported. The SrTiO3 shell with controllable thicknesses generates a considerable spontaneous polarization, which effectively tunes the electrical band bending of TiO2 . Combined with its intrinsically high charge mobility, the ferroelectric SrTiO3 thin shell significantly improves the charge-separation efficiency (ηseparation ) with minimized influence on the hole-migration property of TiO2 photoelectrodes, leading to a drastically increased photocurrent density ( Jph ). Specifically, the 10 nm-thick SrTiO3 shell yields the highest Jph and ηseparation of 1.43 mA cm-2 and 87.7% at 1.23 V versus reversible hydrogen electrode, respectively, corresponding to 83% and 79% improvements compared with those of pristine TiO2 NWs. The PEC performance can be further manipulated by thermal treatment, and the control of SrTiO3 film thicknesses and electric poling directions. This work suggests a material with combined ferroelectric and semiconducting features could be a promising solution for advancing PEC systems by concurrently promoting the charge-separation and hole-transportation properties.

The role of preoperative biopsy in pancreatic cancer.

BACKGROUND: Cyto-histological diagnosis of pancreatic pathology in the management of suspected pancreatic malignancy is re-evaluated in the light of evolving trends in management and tissue sampling. METHODS: The literature on cyto-histological diagnosis of pancreatic pathology was reviewed over the period 1977-2003. RESULTS AND CONCLUSION: Endoluminal techniques of tissue sampling carry less risk of tumour seeding and are the sampling methods of choice for potentially resectable lesions if a tissue diagnosis will alter therapy. Endosonar-guided biopsy in expert hands appears to be the most reliable tissue sampling technique. Transcoelomic sampling methods should be reserved for those with un-resectable disease. All methods of cyto-histological diagnosis have high specificity but have a low negative predictive value. Therefore, potentially resectable lesions that are highly suspicious for malignancy should be explored even if pre-operative histology or cytology is negative.

A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues.

Mucosae-associated epithelial chemokine (MEC) is a novel chemokine whose mRNA is most abundant in salivary gland, with strong expression in other mucosal sites, including colon, trachea, and mammary gland. MEC is constitutively expressed by epithelial cells; MEC mRNA is detected in cultured bronchial and mammary gland epithelial cell lines and in epithelia isolated from salivary gland and colon using laser capture microdissection, but not in the endothelial, hemolymphoid, or fibroblastic cell lines tested. Although MEC is poorly expressed in skin, its closest homologue is the keratinocyte-expressed cutaneous T cell-attracting chemokine (CTACK; CCL27), and MEC supports chemotaxis of transfected lymphoid cells expressing CCR10, a known CTACK receptor. In contrast to CTACK, however, MEC also supports migration through CCR3. Consistent with this, MEC attracts eosinophils in addition to memory lymphocyte subsets. These results suggest an important role for MEC in the physiology of extracutaneous epithelial tissues, including diverse mucosal organs.

Expression of proinflammatory genes during estrogen-induced inflammation of the rat prostate.

BACKGROUND: Exposure of male Wistar rats to estradiol-17beta (E(2)) in the presence or absence of dihydrotestosterone propionate (DHT) was previously shown to result in prostate inflammation. The present study examines, for the first time, changes in the expression level of several proinflammatory genes during the course of this experimentally induced prostatitis. METHODS: Adult male Wistar rats were given chronic exposure to E(2) + DHT by capsule implantation or were injected with E(2) for short-term exposure. Semiquantitative RT-PCR was employed to measure changes in proinflammatory transcript levels in the separated lobes of the prostate after various times of exposure to estrogen with or without DHT. RESULTS: We observed an upregulation of IL-1beta, IL-6, MIP-2, and inducible nitric oxide synthase (iNOS) after only 4 days treatment with E(2). After 4 weeks of treatment with E(2) + DHT, a significant increase in transcript levels of IL-4, IL-5, IL-6, MIP-2, eotaxin, and iNOS was detected, while IL-1beta and TNF-alpha transcript levels only increased slightly. No increase in transcript levels for cyclooxygenase-2 (cox-2), IFN-gamma, IL-2, or IL-12 was observed. CONCLUSIONS: Upregulation of proinflammatory transcripts occurred shortly after exposure to E(2) and well before any inflammatory cells were observed in the prostate. The pattern of gene expression resembled a T(H)2-type helper-cell response.

Sudden death caused by myocardial tuberculosis: case report and review of the literature.

A 25-year-old fit man died suddenly while playing social soccer. Autopsy revealed an infiltrative lesion involving the left ventricle with overlying pericarditis. No other significant pathologic changes were observed. Histologic examination showed necrotizing granulomatous inflammation. No acid-fast bacilli were demonstrated in the pericardial fluid or on histologic examination. The presence of Mycobacterium tuberculosis DNA complex was confirmed by use of the ligase chain reaction technique. The differential diagnosis of myocardial tuberculosis includes sarcoidosis, rheumatic fever, rheumatoid arthritis, giant-cell-containing tumors, idiopathic (giant-cell) myocarditis, and bacterial infections such as tularemia and brucellosis. This case illustrates the protean manifestations of tuberculosis and highlights the use of molecular biologic techniques in arriving at a definitive diagnosis in cases of suspected tuberculosis.

Human variability and noncancer risk assessment--an analysis of the default uncertainty factor.

A 10-fold uncertainty factor is used for noncancer risk assessments to allow for possible interindividual differences between humans in the fate of the chemical in the body (kinetics) and target organ sensitivity (dynamics). Analysis of a database on the variability in each of these aspects is consistent with an even subdivision of the 10-fold factor into 10(0.5) (3.16) for kinetics and 10(0.5) (3.16) for dynamics. Analysis of the number of subjects in a normally and log-normally distributed population which would not be covered by factors of 3.16 supports this subdivision and also the use of a 10-fold factor to allow for both aspects. Analysis of kinetic data for subgroups of the population indicates that the standard default value of 3.16 for kinetics will not be adequate for all routes of elimination and all groups of the population. A scheme is proposed which would allow the selection of appropriate default uncertainty factors based on knowledge of the biological fate and effects of the chemical under review.

Population heterogeneity and its impact on the risk management of food safety.

Successful risk management of possible toxicological effects of chemicals in food, including novel foods, requires diverse strategies. This paper concentrates on the advisability of introducing post marketing surveillance as a key stratagem in the risk management of selected foods and food chemicals. It is argued that this stratagem is particularly applicable to those occasions when the population at risk is relatively easily identified. A key element therefore in the successful use of post marketing surveillance in selected foods, requires those agencies responsible for risk management to introduce a more thorough analysis of population heterogeneity into their strategies.

Gastroduodenal intussusception of a stromal gastric tumour.

An elderly patient presented with intermittent vomiting. The cause was a gastric tumour causing gastroduodenal intussusception. On excision and histological examination this was found to be a stromal tumour of uncertain malignant potential ('STUMP').

Factors associated with multiple sex partners among junior high school students.

Twenty-one percent of a sample of inner-city junior high school students were found to be sexually active (n = 403). Only 31% of them reported a single lifetime sexual partner, 25% reported two partners, and 43% reported three or more partners. Logistic regression analysis evaluated the influence of demographic, psychosocial, and behavioral factors on the adolescents' lifetime number of sex partners. Respondents whose sexual debut occurred before age 13 years were nine times more likely to report three or more sex partners compared with those whose first sexual intercourse was at age 15 or 16 years, blacks were four times more likely than non-Hispanic whites to report three or more sex partners; and males were four times as likely as females to report this number of sexual partners. Factors not independently associated with the number of sex partners included: age, Asian or Hispanic ethnicity, human immunodeficiency virus (HIV) knowledge, self-efficacy (belief that one can protect oneself from the virus), condom use, and alcohol and drug use. We conclude that a significant proportion of school-based middle adolescents are sexually active and that most of these are at risk for contracting HIV because of behaviors such as having multiple sexual partners. Topics often stressed in school-based HIV education, such as factual knowledge about HIV, avoiding drugs and alcohol, and condom use are not associated with adolescents' choice about their number of sex partners. Intervention programs will have to identify and then target each specific HIV risk behavior and its motivations in order to reduce adolescents' risks of contracting and transmitting the disease.

Determinants of condom use among junior high school students in a minority, inner-city school district.

Condoms reduce the risk of human immunodeficiency virus (HIV) transmission; however, their use among adolescents has been inconsistent. Little is known about factors which motivate consistent condom use, particularly among younger adolescents. In a study designed to identify such factors, 1899 inner-city junior high school students were surveyed. In June 1988, students completed an anonymous self-report questionnaire assessing HIV-related knowledge, attitudes, and behaviors. Among sexually active students (N = 403), logistic regression analysis evaluated the influence of demographic, psychosocial, and behavioral factors on frequency of condom use. Respondents who believe condoms are effective in preventing HIV transmission were 2.2 times more likely to report using condoms consistently during sexual intercourse; those with low perceived costs associated with condom use were 1.9 times more likely to be consistent users. Number of lifetime sexual partners was inversely related to frequency of condom use. Respondents with a history of three or more sex partners were half as likely to use condoms consistently. Factors not associated with consistent condom use include age, age at sexual debut, ethnicity, HIV knowledge, perceived efficacy to avoid HIV infection, and alcohol and drug use. School- and community-based HIV prevention programs will have to go beyond the didactic transfer of factual information and include more interactive teaching strategies to improve adolescents' attitudes toward condoms are self-efficacy to increase condom use and to counter negative peer influences and adolescents' perceptions of invulnerability. Physicians are an underutilized source of HIV prevention information. They have an important role in counseling adolescents about effective HIV-prevention methods and dispelling misperceptions which hinder consistent condom use.

Change in alcohol consumption and risk of death from all causes and from ischaemic heart disease.

OBJECTIVE: To examine the association between alcohol consumption and mortality from all causes and from ischaemic heart disease with a focus on differentiating between long term abstainers and more recent non-drinkers. DESIGN: Cohort study of changes in alcohol consumption from 1965 to 1974 and mortality from all causes and ischaemic heart disease during 1974-84. SETTING: Population based study of adult residents of Alameda County, California. SUBJECTS: 2225 women and 1845 men aged 35 and over in 1965. MAIN OUTCOME MEASURES: Alcohol consumption in 1964 and 1974 and mortality from all causes and from ischaemic heart disease during 1974-84. RESULTS: There was a significantly higher risk of death from all causes and from ischaemic heart disease in women who gave up drinking between 1965 and 1974 than in women who continued to drink (relative risk 1.72, 95% confidence interval 1.11 to 2.66, and 2.75, 1.44 to 5.23, for all causes and ischaemic heart disease respectively). A significant increase in risk was not seen in men who gave up drinking (1.32, 0.87 to 2.01, and 0.95, 0.41 to 2.20, respectively). Among men, long term abstainers compared with drinkers were at increased risk of death from all causes and from ischaemic heart disease, though the associations were not significant (1.40, 0.98 to 2.00, and 1.40, 0.76 to 2.58, for all causes and ischaemic heart disease respectively). CONCLUSION: Some of the increased risk of death from all causes and from ischaemic heart disease associated with not drinking in women seems to be accounted for by higher risks among those who gave up drinking. Men who are long term abstainers may also be at an increased risk of death. The heterogeneity of the non-drinking group should be considered when comparisons are made with drinkers.

Physical activity and depression: evidence from the Alameda County Study.

The relation between level of physical activity and risk of subsequent depression was examined using three waves of data from the Alameda County Study. Among subjects who were not depressed at baseline, those who reported a low activity level were at significantly greater risk for depression at the 1974 follow-up than were those who reported high levels of activity at baseline. Adjustments for physical health, socioeconomic status, life events, social supports, and other health habits did not affect the association appreciably. Associations between 1965-1974 changes in activity level and depression in the 1983 follow-up suggest that the risk of depression can be altered by changes in exercise habits, although these associations were not statistically significant after adjustment for covariates. These results provide somewhat stronger evidence for an activity-depression link than do previous studies, and they argue for the inclusion of exercise programs as part of community mental health programs, as well as for further studies that focus on the relation between life-style and mental health.