Apoptotic stress causes mtDNA release during senescence and drives the SASP.

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.

Remote dried blood spot collection for inflammatory markers in older adults is feasible, reliable, and valid.

Dried blood spots (DBS) provide a minimally invasive method to assess inflammatory markers and can be collected remotely at-home or in-person in the lab. However, there is a lack of methodological information comparing these different collection methods and in older adults. We investigated the feasibility (including adherence, yield, quality, and participant preferences) and measurement properties (reliability, validity) of remotely collected DBS inflammatory markers in older adults. Participants (N = 167, mean age = 72, range: 60-96 years) collected their own DBS (finger prick on filter paper) during three remote interviews over âˆ¼ 6 months. Within 4-5 days on average of their last remote interview, a subset of 41 participants also attended an in-person lab visit that included a researcher-collected DBS sample, venous blood draw, and survey to assess participant preferences of DBS collection. DBS and venous blood were assayed for CRP, IL-6, and TNF-α. Adherence: 98% of expected DBS samples (493 out of 501) were completed and mailed back to the lab. Yield: 97% of DBS samples were sufficient for all assays. Quality: On average, 0.80 fewer optimal spots (60uL of blood that filled the entire circle) were obtained remotely vs. in-person (p = 0.013), but the number of useable or better spots (at least 30-40uL of blood) did not differ (p = 0.89). Preference: A slight majority of participants (54%) preferred in-person DBS collection. Reliability: DBS test-retest reliabilities were good: CRP (ICC = 0.74), IL-6 (ICC = 0.76), and TNF-α (ICC = 0.70). Validity: Inflammatory levels from DBS correlated strongly with levels from venous blood (r = 0.60-0.99) and correlated as expected with sociodemographic and physical health and function variables. Older adults can remotely collect their own DBS to acquire reliable and valid inflammatory data. Remote DBS collection is highly feasible and may allow for inflammatory markers to be assessed in larger, more representative samples than are possible with lab- or clinic-based research designs.

Composite outcome measures in high-impact critical care randomised controlled trials: a systematic review.

BACKGROUND: The use of composite outcome measures (COM) in clinical trials is increasing. Whilst their use is associated with benefits, several limitations have been highlighted and there is limited literature exploring their use within critical care. The primary aim of this study was to evaluate the use of COM in high-impact critical care trials, and compare study parameters (including sample size, statistical significance, and consistency of effect estimates) in trials using composite versus non-composite outcomes. METHODS: A systematic review of 16 high-impact journals was conducted. Randomised controlled trials published between 2012 and 2022 reporting a patient important outcome and involving critical care patients, were included. RESULTS: 8271 trials were screened, and 194 included. 39.1% of all trials used a COM and this increased over time. Of those using a COM, only 52.6% explicitly described the outcome as composite. The median number of components was 2 (IQR 2-3). Trials using a COM recruited fewer participants (409 (198.8-851.5) vs 584 (300-1566, p = 0.004), and their use was not associated with increased rates of statistical significance (19.7% vs 17.8%, p = 0.380). Predicted effect sizes were overestimated in all but 6 trials. For studies using a COM the effect estimates were consistent across all components in 43.4% of trials. 93% of COM included components that were not patient important. CONCLUSIONS: COM are increasingly used in critical care trials; however effect estimates are frequently inconsistent across COM components confounding outcome interpretations. The use of COM was associated with smaller sample sizes, and no increased likelihood of statistically significant results. Many of the limitations inherent to the use of COM are relevant to critical care research.

Cellular Senescence and Ageing.

Cellular senescence has become a subject of great interest within the ageing research field over the last 60 years, from the first observation in vitro by Leonard Hayflick and Paul Moorhead in 1961, to novel findings of phenotypic sub-types and senescence-like phenotype in post-mitotic cells. It has essential roles in wound healing, tumour suppression and the very first stages of human development, while causing widespread damage and dysfunction with age leading to a raft of age-related diseases. This chapter discusses these roles and their interlinking pathways, and how the observed accumulation of senescent cells with age has initiated a whole new field of ageing research, covering pathologies in the heart, liver, kidneys, muscles, brain and bone. This chapter will also examine how senescent cell accumulation presents in these different tissues, along with their roles in disease development. Finally, there is much focus on developing treatments for senescent cell accumulation in advanced age as a method of alleviating age-related disease. We will discuss here the various senolytic and senostatic treatment approaches and their successes and limitations, and the innovative new strategies being developed to address the differing effects of cellular senescence in ageing and disease.

Lifespan socioeconomic context is associated with cytomegalovirus and late-differentiated CD8+ T and NK cells: Initial results in older adults.

OBJECTIVE: Lower socioeconomic status (SES) can accelerate immune aging; however, it is unknown whether and how lifespan socioeconomic context (SEC) -the relative wealth and quality of the communities an individual lives in across their lifespan- impacts immune aging. We examined the effects of childhood and adulthood SEC on late-differentiated immune cells and investigated the mediating and moderating role of cytomegalovirus (CMV), a key driver of immune aging. METHODS: Adults 60 years and older (N = 109) reported their addresses from birth to age 60, which were coded for county-level employment, education, and income to construct a latent SEC variable, averaged across ages 0-18 (childhood SEC) and 19-60 (adulthood SEC). Blood was drawn semiannually over 5 years for CMV serostatus and flow cytometry estimates of late-differentiated CD8+ T and natural killer (NK) cells. Models were adjusted for chronological age, time, gender, and individual SES (current income and education). RESULTS: Lower childhood SEC was associated with higher percentages of late-differentiated CD8+ T and NK cells via CMV seropositivity (indirect effects ps .015-.028). Additionally, an interaction between CMV serostatus and SEC on CD8+ T cell aging (p = .049) demonstrated that adulthood SEC was negatively associated with immune aging among CMV- but not CMV+ adults. CONCLUSIONS: Beyond current SES, socioeconomic context related to immune aging in distinct patterns by lifespan phase. Lower childhood SEC importantly may influence who acquires CMV, which in turn, predicts higher levels of immune aging, whereas higher adulthood SEC was protective against immune aging among CMV- older adults. These initial results need to be explored in larger samples.

Life stressors and immune aging: Protective effects of cognitive reappraisal.

Stressful life events may accelerate aspects of immune aging, but habitual use of an adaptive emotion regulation strategy, cognitive reappraisal, may attenuate these effects. This study examined whether cognitive reappraisal moderates the associations between life stressor frequency and stressor desirability on aspects of immune aging, including late-differentiated CD8+ T and natural killer (NK) cells and inflammatory markers (IL-6, TNF-α, and CRP), both between and within people in a longitudinal sample of 149 older adults (mean age = 77.8, range: 64-92 years). Participants reported stressful life events, use of cognitive reappraisal, and provided blood semiannually for up to 5 years to assess aspects of immune aging. Multilevel models, adjusted for demographic and health covariates, tested the between-person (stable, trait-like differences) and within-person associations (dynamic fluctuations) among life stressors and reappraisal on immune aging. Experiencing more frequent life stressors than usual was associated with higher levels of late-differentiated NK cells within person, but this effect was accounted for by experiencing health-related stressors. Unexpectedly, experiencing more frequent and less desirable stressors were associated with lower average levels of TNF-α. As expected, reappraisal moderated the associations between life stressors and late-differentiated NK cells between people and IL-6 within people. Specifically, older adults who experienced less desirable stressors but also used more reappraisal had significantly lower proportions of late-differentiated NK cells on average and lower levels of IL-6 within-person. These results suggest cognitive reappraisal may play a protective role in attenuating the effects of stressful life events on aspects of innate immune aging in older adults.

The presence of circulating genetically abnormal cells in blood predicts risk of lung cancer in individuals with indeterminate pulmonary nodules.

PURPOSE: Computed tomography is the standard method by which pulmonary nodules are detected. Greater than 40% of pulmonary biopsies are not lung cancer and therefore not necessary, suggesting that improved diagnostic tools are needed. The LungLB™ blood test was developed to aid the clinical assessment of indeterminate nodules suspicious for lung cancer. LungLB™ identifies circulating genetically abnormal cells (CGACs) that are present early in lung cancer pathogenesis. METHODS: LungLB™ is a 4-color fluorescence in-situ hybridization assay for detecting CGACs from peripheral blood. A prospective correlational study was performed on 151 participants scheduled for a pulmonary nodule biopsy. Mann-Whitney, Fisher's Exact and Chi-Square tests were used to assess participant demographics and correlation of LungLB™ with biopsy results, and sensitivity and specificity were also evaluated. RESULTS: Participants from Mount Sinai Hospital (n = 83) and MD Anderson (n = 68), scheduled for a pulmonary biopsy were enrolled to have a LungLB™ test. Additional clinical variables including smoking history, previous cancer, lesion size, and nodule appearance were also collected. LungLB™ achieved 77% sensitivity and 72% specificity with an AUC of 0.78 for predicting lung cancer in the associated needle biopsy. Multivariate analysis found that clinical and radiological factors commonly used in malignancy prediction models did not impact the test performance. High test performance was observed across all participant characteristics, including clinical categories where other tests perform poorly (Mayo Clinic Model, AUC = 0.52). CONCLUSION: Early clinical performance of the LungLB™ test supports a role in the discrimination of benign from malignant pulmonary nodules. Extended studies are underway.

Cytomegalovirus and Toxoplasma Gondii Serostatus Prospectively Correlated With Problems in Self-Regulation but not Executive Function Among Older Adults.

OBJECTIVE: Cytomegalovirus (CMV) and Toxoplasma gondii are organisms that may infect the brain and have cognitive and behavioral consequences. We hypothesized that these latent infections would be prospectively associated with poorer cognition and more problems in self-regulation among older adults. METHODS: Older adults (n = 138, mean age = 75.5 years, 59% women) had CMV and T. gondii serostatus tested, crystallized intelligence estimated (North American Adult Reading Test), and executive function (EF; e.g., Trail Making Test) and self-regulation (Behavior Regulation Inventory of Executive Function-Adult) assessed in visits occurring every 6 months (mean visits = 16). RESULTS: CMV+ people (79%) had significantly poorer self-regulation versus CMV- people (21%; behavioral regulation: γ = 0.108, 95% confidence interval [CI] = 0.009-0.206; metacognition: γ = 0.117, 95% CI = 0.005-0.229), but not intelligence or EF. T. gondii+ people (24%) were not significantly different from T. gondii- people (76%) on any outcome. However, T. gondii+ men had better self-regulation versus T. gondii- men, and the opposite was true of women (behavioral regulation interaction: γ = 0.267, 95% CI = 0.093-0.441). CONCLUSIONS: CMV latent infection was associated with more problems in self-regulation, and the magnitude of this difference was clinically significant. T. gondii latent infection was associated with more problems, but only for women. Latent infection might associate with self-regulation but not EF because of factors influencing self-regulation but not neuropsychological test performance, such as values and emotion. Efforts to link latent infection with EFs might, in the future, include the application of those functions to self-regulation in daily life.

Daily Stressors, Emotion Dynamics, and Inflammation in the MIDUS Cohort.

BACKGROUND: The current study (1) examined links between daily stressors and inflammation and (2) tested whether negative emotion dynamics (emotional variability) is one pathway through which stressors are linked to inflammation. METHOD: A cross-sectional sample of 986 adults (aged 35-86 years, 57% female) from MIDUS reported daily stressor frequency and severity and negative emotions on 8 consecutive nights. Negative emotion variability (intraindividual standard deviation), controlling for overall mean level (intraindividual mean), was the focus of the current study. Interleukin-6 (IL-6) and C-reactive protein (CRP) were assayed from blood drawn at a clinic visit. Regression models adjusted for demographics, health factors, and the time between assessments. RESULTS: More severe daily stressors were associated with higher CRP, but this effect was accounted for by covariates. More frequent daily stressors were associated with lower IL-6 and CRP. In follow-up analyses, significant interactions between stressor severity and frequency suggested that participants with lower stressor severity and higher stressor frequency had the lowest levels of IL-6 and CRP, whereas those with higher stressor severity had the highest levels of IL-6 and CRP, regardless of frequency. Daily stressor frequency and severity were positively associated with negative emotion variability, but variability was not linearly associated with inflammation and did not operate as a mediator. CONCLUSION: Among midlife and older adults, daily stressor frequency and severity may interact and synergistically associate with inflammatory markers, potentially due to these adults being advantaged in other ways related to lower inflammation, or in a pattern aligning with hormetic stress, where frequent but manageable stressors may yield physiological benefits, or both. Negative emotion variability does not operate as a mediator. Additional work is needed to reliably measure and test other emotion dynamic metrics that may contribute to inflammation.

Perceived stress, cytomegalovirus titers, and late-differentiated T and NK cells: Between-, within-person associations in a longitudinal study of older adults.

Cytomegalovirus (CMV) and psychological stress are implicated as drivers of immunological aging. It is unknown, however, whether associations among CMV titers, stress, and immune aging are more stable or dynamic over time. The present investigation tested the between-person (stable differences) and within-person (dynamic fluctuations) associations of CMV titers and perceived stress on late-differentiated T and natural killer (NK) peripheral blood cells in a longitudinal study of older adults aged 64-92 years (N = 149). Participants reported stress levels and provided blood biannually for 2.5 years (up to 5 waves per person) to assess CMV IgG titers and composites of late-differentiated CD8 T cells (CD28- and CD57 + subsets) and CD56dim NK cells (CD57+, NKG2C+, and FcεRIγ- subsets). In multilevel models that controlled for demographic variables, higher CMV titers were associated with higher proportions and counts of aged T and NK cells between people and lower counts of aged T cells within people. Perceived stress was associated with higher counts of aged T cells between people, but was not associated with aged NK cells. A significant interaction between stress and CMV titers on T cells between people indicated that older adults with lower stress levels and lower CMV titers had the lowest proportions of late-differentiated T cells, whereas those with higher stress levels had high proportions, regardless of CMV control. Our results provide evidence for longer-term, between-person associations among CMV titers, stress, and immunological aging, rather than dynamic within-person associations. We propose that targeting factors that promote low, stable perceived stress in older adults may retard T cell differentiation and ultimately support healthy aging.

Intelligence and Interleukin-6 in Older Adults: The Role of Repetitive Thought.

OBJECTIVE: Higher intelligence quotient (IQ) correlates with lower systemic inflammation, consistent with an association between lower IQ and disease risk. The present study examined the role of repetitive thought (RT) in the relationship between IQ and interleukin (IL)-6. RT is thinking attentively, repeatedly, and frequently about oneself and one's world and is characterized by valence (positive-negative), purpose (searching-solving), and total quantity (much-little). METHODS: Estimated IQ and RT dimension scores were assessed at baseline in a sample of older adults (N = 120, mean age = 74 years), who thereafter had blood drawn up to 10 times semiannually (n = 799). Models were adjusted for body mass index, chronological age, and statin medication. RESULTS: Higher IQ was associated with lower IL-6 (γ = -0.225, SE = 0.111, p = .045). Of the RT dimensions, only more total RT predicted lower IL-6 (γ = -0.037, SE = 0.011, p = .001), an effect that was not moderated by valence or purpose. More total RT accounted for part of the effect of IQ on IL-6 (indirect effect = -0.06 [confidence interval = -0.14 to -0.002]). There was also a significant interaction between IQ and total RT (F(1,119) = 6.97, p = .009), in which more total RT was more strongly associated with lower IL-6 for people with lower IQ. CONCLUSIONS: Although some forms of RT such as worry may have negative health correlates for older adults, engaging in RT per se can be healthy insofar as it also encompasses planning, processing, and coping. Older adults with higher IQ were more likely to engage in RT, but those with average IQ benefitted the most with regard to a marker of systemic inflammation.

Cytomegalovirus serostatus, inflammation, and antibody response to influenza vaccination in older adults: The moderating effect of beta blockade.

Cytomegalovirus (CMV) has been implicated as a factor in immunosenescence, including poor antibody response to vaccination and higher immune activation and inflammation. Some people may be more or less vulnerable to the negative effects of CMV. The present investigation tested the effects of beta-blocker use and chronological age on the associations between CMV and immunity in adults aged 60-91 (N=98; 69% CMV seropositive) who were administered the trivalent influenza vaccine for up to 5years. Peak antibody response, corrected for baseline, and spring (persistent) antibody response, corrected for peak, were assessed, as well as beta-2 microglobulin (ß2µ) and interleukin-6 (IL-6). In multi-level models with years at Level 1 and people at Level 2, CMV serostatus did not predict peak antibody response, but there was a 3-way interaction between CMV serostatus, age, and beta-blockers. Age was negatively associated with peak antibody, but only among adults who were CMV seropositive and taking beta-blockers. CMV seronegative adults who were not taking beta-blockers had the highest antibody persistence. CMV serostatus was not associated with ß2µ or IL-6. Results suggest that CMV+ serostatus may negatively compromise antibody response to a greater degree than inflammatory markers in older adults. Furthermore, older adults who take beta-blockers may be more vulnerable to negative effects of age and CMV on peak antibody response, perhaps by virtue of their underlying health condition.

Emotional acceptance, inflammation, and sickness symptoms across the first two years following breast cancer diagnosis.

PURPOSE: Breast cancer diagnosis and treatment are associated with increased inflammatory activity, which can induce sickness symptoms. We examined whether emotional acceptance moderates the association between proinflammatory cytokines and self-reported sickness symptoms in women recently diagnosed with breast cancer. METHODS: Women (N=136) diagnosed with stage 0-III breast cancer within the previous 6months provided plasma samples and completed the FACT: Physical Well-Being Scale, as well as the Acceptance of Emotion Scale every 3months for 2years. At each time point, we quantified interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α using a high sensitivity multiplex assay. RESULTS: Higher within-subject mean TNF-α across all time-points predicted higher mean sickness symptoms. At individual time-points, higher IL-6 and IL-8 levels were associated with higher sickness symptoms. Mean emotional acceptance across all time-points moderated the relationship between mean IL-8 and sickness symptoms, with sickness symptoms remaining persistently high in women with low emotional acceptance even when IL-8 levels were low. At individual time-points, emotional acceptance positively moderated the correlations of IL-8 and TNF-α with sickness symptoms, such that the associations between higher levels of these proinflammatory cytokines and higher sickness symptoms were attenuated when emotional acceptance was high. CONCLUSION: Emotional acceptance was shown for the first time to moderate the associations of cytokines with sickness symptoms in breast cancer patients over time following diagnosis and treatment. The association between emotional acceptance and sickness symptoms was significantly different from zero but relatively small in comparison to the range of sickness symptoms. Results suggest that targeting emotion regulation may help to break the cycle between inflammation and sickness symptoms in women with breast cancer.

Head Start Oral Health Assessment.

PURPOSE: A Head Start program located in Paterson, New Jersey considered establishing a school-based dental clinic to address unmet oral health needs such as access to care and the need for restorative treatment. The purpose of this study was to establish the oral health status of Head Start children, their treatment needs, and parents' interest and willingness to utilize a school-based dental clinic. DESCRIPTION: School-based dental care has been used to address access to care issues, particularly among children who live in underserved areas. A 21 item survey was used to correlate the results of an oral exam performed on the Head Start children and the parents' preferences, beliefs and access patterns. Fisher's exact test and Chi squared test were used to study the association among variable with significance levels set at 0.05. Assessment The oral exam revealed a high caries rate amongst all of the children. Parental responses indicated strong support for the establishment of a school-based clinic and identified the need for further parental education. Having a regular source of care was found to be unrelated to treatment needs. CONCLUSION: Further education of the parents regarding the child's oral health is critical to the success and viability of this school-based clinic.

The molecular chaperone Hsp70 activates protein phosphatase 5 (PP5) by binding the tetratricopeptide repeat (TPR) domain.

Protein phosphatase 5 (PP5) is auto-inhibited by intramolecular interactions with its tetratricopeptide repeat (TPR) domain. Hsp90 has been shown to bind PP5 to activate its phosphatase activity. However, the functional implications of binding Hsp70 to PP5 are not yet clear. In this study, we find that both Hsp90 and Hsp70 bind to PP5 using a luciferase fragment complementation assay. A fluorescence polarization assay shows that Hsp90 (MEEVD motif) binds to the TPR domain of PP5 almost 3-fold higher affinity than Hsp70 (IEEVD motif). However, Hsp70 binding to PP5 stimulates higher phosphatase activity of PP5 than the binding of Hsp90. We find that PP5 forms a stable 1:1 complex with Hsp70, but the interaction appears asymmetric with Hsp90, with one PP5 binding the dimer. Solution NMR studies reveal that Hsc70 and PP5 proteins are dynamically independent in complex, tethered by a disordered region that connects the Hsc70 core and the IEEVD-TPR contact area. This tethered binding is expected to allow PP5 to carry out multi-site dephosphorylation of Hsp70-bound clients with a range of sizes and shapes. Together, these results demonstrate that Hsp70 recruits PP5 and activates its phosphatase activity which suggests dual roles for PP5 that might link chaperone systems with signaling pathways in cancer and development.

Psychological stress and the longitudinal progression of subclinical atherosclerosis.

OBJECTIVE: In a midlife sample of adults, the present study tested the extent to which changes in psychological stress relate to the progression of subclinical cardiovascular disease over multiple years and explored the potential moderating role of cardiometabolic risk. METHOD: Participants were screened to exclude those with clinical cardiovascular, respiratory, metabolic, and other chronic illnesses, as well as those taking psychotropic, cardiovascular, lipid, and glucose control medications. At baseline (N = 331) and then again at follow-up an average of 3 years later (N = 260), participants completed the 10-item Perceived Stress Scale, underwent assessments of their cardiometabolic risk, and underwent ultrasonography to measure carotid artery intima-media thickness (IMT), which is a surrogate indicator of subclinical atherosclerosis. RESULTS: Regression models showed that the change in psychological stress from baseline to follow-up was positively associated with the corresponding change in IMT, with covariate control for age at baseline, sex at birth, and variability in length of follow-up across participants. Cardiometabolic risk factors did not statistically moderate this longitudinal association. In exploratory analyses, cardiometabolic risk factors also did not statistically mediate this association. CONCLUSION: These longitudinal findings suggest that increases in psychological stress in midlife relate to corresponding increases in subclinical atherosclerosis. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Childhood trauma and hair cortisol response over the year following onset of a chronic life event stressor.

OBJECTIVE: Childhood trauma may contribute to poor lifelong health in part through programming of the HPA-axis response to future life stressors. To date, empirical evidence shows an association of childhood trauma with dysregulation of the HPA-axis and blunted cortisol reactivity to acute stressors. Here, we conduct an initial examination of childhood trauma as a moderator of changes over time in perceived stress levels and HPA-axis response to a major chronic stressor in adulthood. METHODS: Participants were 83 maternal caregivers of children newly diagnosed with cancer who completed the Childhood Trauma Questionnaire (CTQ), and who, over the year following their child's cancer diagnosis, had hair samples collected up to 7 times for the assessment of cortisol and completed monthly measures of perceived stress. RESULTS: CTQ scores were in the expected range for a community sample and associated with changes in perceived stress and cortisol concentration over time (γ =.003, p =.002; γ = -.0004, p =.008, respectively) independently of age, education, treatment intensity and randomization to stress management intervention. Maternal caregivers who endorsed lower childhood trauma showed a steeper decline in perceived stress and a larger increase in cortisol levels across the year than caregivers who recalled more childhood trauma. CONCLUSIONS: Findings extend animal models and studies that examine cortisol reactivity to acute stressors and suggest that childhood trauma may program a phenotype that is more psychologically reactive but shows a blunted HPA-axis response to chronic stress. While adaptive in the short-term, this early life programming may incur long-term costs for health. Further work is warranted to examine this possibility.

Investigation of the role of linker moieties in bifunctional tacrine hybrids.

Alzheimer's disease (AD) is a complex neurological disorder with multiple inter-connected factors playing roles in the onset and progression of the disease. One strategy currently being explored for the development of new therapeutics for AD involves linking tacrine, a known acetylcholinesterase (AChE) inhibitor, to another drug to create bifunctional hybrids. The role and influence on activity of the linker moiety in these hybrids remains ill-defined. In this study, three series of 6-chlorotacrine with linkers varying in terminal functional group and length were synthesized, evaluated for AChE inhibition, and compared to tacrine and 6-chlorotacrine-mefenamic acid hybrids. Out of the compounds with terminal amine, methyl, and hydroxyl moieties tested, several highly potent molecules (low nanomolar IC50 values) comprised of linkers with terminal amines were identified. These 6-chlorotacrine with linkers were significantly more potent than tacrine alone and were often more potent than similar 6-chlorotacrine-mefenamic acid hybrids.

Global positioning system watches for estimating energy expenditure.

Global positioning system (GPS) watches have been introduced commercially, converting frequent measurements of time, location, speed (pace), and elevation into energy expenditure (EE) estimates. The purpose of this study was to compare EE estimates of 4 different GPS watches (Forerunner, Suunto, Polar, Adeo), at various walking speeds, with EE estimate from a triaxial accelerometer (RT3), which was used as a reference measure in this study. Sixteen healthy young adults completed the study. Participants wore 4 different GPS watches and an RT3 accelerometer and walked at 6-minute intervals on an outdoor track at 3 speeds (3, 5, and 7 km/hr). The statistical significance of differences in EE between the 3 watches was assessed using linear contrasts of the coefficients from the overall model. Reliability across trials for a given device was assessed using intraclass correlation coefficients as estimated in the mixed model. The GPS watches demonstrated lower reliability (intraclass correlation coefficient) across trials when compared with the RT3, particularly at the higher speed, 7 km/hr. Three GPS watches (Forerunner, Polar, and Suunto) significantly and consistently underestimated EE compared with the reference EE given by the RT3 accelerometer (average mean difference: Garmin, -50.5%; Polar, -41.7%; and Suunto, -41.7%; all p < 0.001). Results suggested that caution should be exercised when using commercial GPS watches to estimate EE in athletes during field-based testing and training.