Braggballard8781

To assess the effect of age on mechanisms of exercise tolerance.

Prospective observational study recruited 71 healthy individuals divided into two groups according to their age i.e. younger (≤40years of age, N=43); and older (≥55years of age, N=28). All participants underwent maximal graded cardiopulmonary exercise stress testing using cycle ergometer with simultaneous non-invasive gas-exchange and central haemodynamic measurements. Using the Fick equation, arteriovenous O

difference was calculated as the ratio between measured O

consumption and cardiac output.

The mean age of younger and older participants was 26.0±5.7years, and 65.1±6.6years respectively. Peak O

consumption was significantly lower in older compared to the younger age group (18.8±5.2 vs 34.4±9.8mL/kg/min, p<0.01). Peak exercise cardiac output and cardiac index were not significantly different between the younger and older age groups (22.7±5.0 vs 22.1±3.9L/min, p=0.59; and 12.4±2.9 vs 11.8±1.9L/min/m

, p=0.29). Despite demonstrating significantly lower peak heart rate by 33 beats/min (129±18.3 vs 162±19.9, p<0.01), older participants demonstrated significantly higher stroke volume and stroke volume index compared to the younger age group (173±41.5 vs 142±34.9mL/min, p<0.01; and 92.1±18.1 vs 78.3±19.5mL/m

, p<0.01). Arteriovenous O

difference was significantly lower in older compared to younger age group participants (9.01±3.0 vs 15.8±4.3 mlO

/100mL blood, p<0.01).

Ability of skeletal muscles to extract delivered oxygen represented by reduced arteriovenous O

difference at peak exercise appears to be the key determinant of exercise tolerance in healthy older individuals.

Ability of skeletal muscles to extract delivered oxygen represented by reduced arteriovenous O2 difference at peak exercise appears to be the key determinant of exercise tolerance in healthy older individuals.The concept of physical resilience may help geriatric medicine objectively assess patients' ability to 'bounce back' from future health challenges. Indicators putatively forecasting resilience have been developed under two paradigms with different perspectives Critical Slowing Down and Loss of Complexity. This study explored whether these indicators validly reflect the construct of resilience in geriatric inpatients. Geriatric patients (n = 121, 60% female) had their heart rate and physical activity continuously monitored using a chest-worn sensor. Indicators from both paradigms were extracted from both physiological signals. Measures of health functioning, concomitant with low resilience, were obtained by questionnaire at admission. The relationships among indicators and their associations with health functioning were assessed by correlation and linear regression analyses, respectively. Greater complexity and higher variance in physical activity were associated with lower frailty (β = -0.28, p = .004 and β = -0.37, p less then .001, respectively) and better ADL function (β = 0.23, p = .022 and β = 0.38, p less then .001). The associations of physical activity variance with health functioning were not in the expected direction based on Critical Slowing Down. In retrospect, these observations stress the importance of matching the resilience paradigm's assumptions to the homeostatic role of the variable monitored. We present several lessons learned.Ageing is associated with a progressive reduction in physical capacity reducing quality of life. One key physiological limitation of physical capacity that deteriorates in a progressive age-dependent manner is cardiac reserve. Peak cardiac output falls progressively with advancing age such that in extreme old age there is limited ability to enhance cardiac output beyond basal function as is required to support the increased metabolic needs of physical activity. This loss of dynamic range in cardiac output associates with a progressive reduction in the heart's response to adrenergic stimulation. A combination of decreases in the expression and functioning of beta1 adrenergic receptors partially underlies this change. Changes in end effector proteins also have a role to play in this decline. Alterations in the efficiency of excitation-contraction coupling contribute to the reduced chronotropic, inotropic and lusitropic responses of the aged heart. Moderate to vigorous endurance exercise training however has some potential to counter elements of these changes. Further studies are required to fully elucidate the key pivotal mechanisms involved in the age-related loss of response to adrenergic signalling to allow targeted therapeutic strategies to be developed with the aim of preserving physical capacity in advanced old age.

Everyday walking often involves simultaneous performance of a cognitive task in environments with competing auditory and visual stimuli. Previous research has not evaluated task performance in these situations, where older adults are known to fall, limiting our understanding of how older adults adjust their gait, visual scanning (gaze), and cognitive processing to avoid falls (or not). The purpose of this study was to examine the effect of dual-task walking in a high-distraction real-world environment on cognitive performance, gait performance, and gaze behavior in older adult fallers relative to non-fallers.

Fourteen community-dwelling, older adult fallers (76.6±9.1years, 11 females) and 15 community-dwelling, older adult non-fallers (77.4±7.6years, 11 females) participated. Participants performed single-task walking, single-task cognitive (seated category naming), and dual-task walking (category naming + walking) trials for 1min each in a real-world environment (busy hospital lobby). Gait speed, stride importance, non-fallers appear to have had more freedom to divert their gaze to less relevant environmental stimuli while walking, and two measures of fall risk impacted patterns of gaze behavior differently. Thus, overt visual attention during walking in real-world environments should be further explored in relation to fall risk.

Recent preclinical studies suggest combining the HSP90 inhibitor AT13387 (Onalespib) with radiation (IR) against colon cancer and head and neck squamous cell carcinoma (HNSCC). These studies emphasized that AT13387 downregulates HSP90 client proteins involved in oncogenic signaling and DNA repair mechanisms as major drivers of enhanced radiosensitivity. Given the large array of client proteins HSP90 directs, we hypothesized that other key proteins or signaling pathways may be inhibited by AT13387 and contribute to enhanced radiosensitivity. Metabolomic analysis of HSP90 inhibition by AT13387 was conducted to identify metabolic biomarkers of radiosensitization and whether modulations of key proteins were involved in IR-induced tumor vasculogenesis, a process involved in tumor recurrence.

HNSCC and non-small cell lung cancer cell lines were used to evaluate the AT13387 radiosensitization effect in vitro and in vivo. Flow cytometry, immunofluorescence, and immunoblot analysis were used to evaluate cell cycle cell metabolism that was linked to DNA damage repair. AT13387 combined with IR inhibited IR-induced vasculogenesis, a process involved in tumor recurrence postradiotherapy. Combining AT13387 with IR warrants consideration of clinical trial assessment.

AT13387 treatment resulted in pharmacologic inhibition of cancer cell metabolism that was linked to DNA damage repair. AT13387 combined with IR inhibited IR-induced vasculogenesis, a process involved in tumor recurrence postradiotherapy. Combining AT13387 with IR warrants consideration of clinical trial assessment.

Tumor control probability (TCP) models based on Poisson statistics characterize the distribution of surviving clonogens. Thus enabling the calculation of TCP for individuals. In order to mathematically describe clinically observed survival data of patient cohorts it is necessary to extend the Poisson TCP model. This is typically done by either incorporating variations of model parameters, or by using an empirical logistic model. The purpose of this work is the development of an analytical population TCP model by mechanistic extension of the Possion model.

The frequency distribution of gross tumor volumes (GTVs) was used to incorporate tumor volume variations into the TCP model. Additionally the tumor cell density variation was incorporated. Both versions of the population TCP model were fitted to clinical data and compared to existing literature.

It was shown that clinically observed brain tumor volumes of dogs undergoing radiotherapy are distributed according to an exponential distribution. The averagetablished a mechanistic link between the poisson statistics based individual TCP model and the logistic TCP model. This link can be used to determine the radiobiological parameters of patient specific TCP models from published fits of logistic models to cohorts of patients.Some cardiovascular symptoms in the early stage of Parkinson's disease (PD) were related to degeneration of the rostral ventrolateral medulla (RVLM) catecholaminergic neurons. To date, little is known about the effects of hydrogen water on early stage of PD. Here, protective actions of hydrogen-saturated saline (HS) on rotenone-induced PD rats, as well as its underlying mechanisms were investigated. HS was used to treat PD rats at three general stages; early, medium and late, which were represented by rotenone induced rats for 0, 7 and 14 days. HS treatment significantly alleviated the cardiovascular and motor symptoms in rotenone-induced PD rats, improved the survival number of RVLM catecholaminergic neurons and nigral dopamine neurons only in early and medium stages of PD rats. Decreased levels of reactive oxygen species (ROS) and alpha-synuclein (α-Syn), transformation of microtubule associated protein 1 light chain 3 (LC3)-I/II and degradation of sequestosome 1 (p62) were detected, as well as increased expression level of autophagy related protein 5 (ATG5) and B-cell lymphoma-2 interacting protein 1 (Beclin-1) in the RVLM and substantia nigra (SN) after HS treatment in early and medium stages of PD rats. In addition, phosphorylation levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) and mammalian rapamycin target protein (mTOR) decreased after HS treatment in early and medium stages of PD rats. read more The results suggested that HS treatment exerted beneficial effects in early and medium stages before motor impairments emerged but not in the late stage of rotenone-induced PD rats. It exerted neuroprotection with RVLM catecholaminergic neurons and nigral dopamine neurons, mediated in part by decreasing levels of ROS and α-Syn through increasing autophagy machinery which were partly via inhibiting PI3K-Akt-mTOR pathway.Sex differences are often observed in psychiatric patients, especially major depressive disorders (MDD), schizophrenia, and developmental disorders, including autism spectrum disorders (ASDs). The prevalence rates between males and females seem variate according to the clinical condition. Although the findings are still incipient, it is suggested that these differences can involve neuroanatomical, neurochemical, and physiological sex differences. In this context, the microbiota-gut-brain axis hypothesis arises to explain some aspects of the complex pathophysiology of neuropsychiatric disorders. The microbiota composition is host-specific and can change conforming to age, sex, diet, medication, exercise, and others. The communication between the brain and the gut is bidirectional and may impact the entire system homeostasis. Many pathways appear to be involved, including neuroanatomic communication, neuroendocrine pathways, immune system, bacteria-derived metabolites, hormones, neurotransmitters, and neurotrophic factors.