A gerophysiology perspective on healthy ageing.

Improvements in public health and health care have resulted in significant increases in lifespan globally, but also in a significant increase in chronic disease prevalence. This has led to a focus on healthy ageing bringing a shift from a pathology-centered to an intrinsic capacity and function-centered view. In parallel, the emerging field of geroscience has promoted the exploration of the biomolecular drivers of ageing towards a transverse vision by proposing an integrated set of molecular hallmarks. In this review, we propose to take a step further in this direction, highlighting a gerophysiological perspective that considers the notion of homeostasis/allostasis relating to robustness/fragility respectively. While robustness is associated with homeostasis achieved by an optimal structure/function relationship in all organs, successive repair processes occurring after daily injuries and infections result in accumulation of scar healing leading to progressive tissue degeneration, allostasis and frailty. Considering biological ageing as the accumulation of scarring at the level of the whole organism emphasizes three transverse and shared elements in the body - mesenchymal stroma cells/immunity/metabolism (SIM). This SIM tryptich drives tissue and organ fate to regulate the age-related evolution of body functions. It provides the basis of a gerophysiology perspective, possibly representing a better way to decipher healthy ageing, not only by defining a composite biomarker(s) but also by developing new preventive/curative strategies.

Towards a Large-Scale Assessment of the Relationship between Biological and Chronological Aging: The INSPIRE Mouse Cohort.

Aging is the major risk factor for the development of chronic diseases. After decades of research focused on extending lifespan, current efforts seek primarily to promote healthy aging. Recent advances suggest that biological processes linked to aging are more reliable than chronological age to account for an individual's functional status, i.e. frail or robust. It is becoming increasingly apparent that biological aging may be detectable as a progressive loss of resilience much earlier than the appearance of clinical signs of frailty. In this context, the INSPIRE program was built to identify the mechanisms of accelerated aging and the early biological signs predicting frailty and pathological aging. To address this issue, we designed a cohort of outbred Swiss mice (1576 male and female mice) in which we will continuously monitor spontaneous and voluntary physical activity from 6 to 24 months of age under either normal or high fat/high sucrose diet. At different age points (6, 12, 18, 24 months), multiorgan functional phenotyping will be carried out to identify early signs of organ dysfunction and generate a large biological fluids/feces/organs biobank (100,000 samples). A comprehensive correlation between functional and biological phenotypes will be assessed to determine: 1) the early signs of biological aging and their relationship with chronological age; 2) the role of dietary and exercise interventions on accelerating or decelerating the rate of biological aging; and 3) novel targets for the promotion of healthy aging. All the functional and omics data, as well as the biobank generated in the framework of the INSPIRE cohort will be available to the aging scientific community. The present article describes the scientific background and the strategies employed for the design of the INSPIRE Mouse cohort.

Does childhood experience of attention-deficit hyperactivity disorder symptoms increase sleep/wake cycle disturbances as measured with actigraphy in adult patients with bipolar disorder?

Childhood attention-deficit hyperactivity disorder (ADHD) is a common precursor of adult bipolar disorders (BD). Furthermore, actigraphy studies demonstrate that each disorder may be associated with abnormalities in sleep and activity patterns. This study investigates whether the presence or absence of self-reported childhood experiences of ADHD symptoms is associated with different sleep and activity patterns in adults with BD. A sample of 115 euthymic adult patients with BD was assessed for childhood ADHD symptoms using the Wender Utah Rating Scale (WURS) and then completed 21 days of actigraphy monitoring. Actigraphic measures of sleep quantity and variability and daytime activity were compared between BD groups classified as ADHD+ (n = 24) or ADHD- (n = 91), defined according to established cutoff scores for the WURS; then we examined any associations between sleep-wake cycle parameters and ADHD dimensions (using the continuous score on the WURS). Neither approach revealed any statistically significant associations between actigraphy parameters and childhood ADHD categories or dimensions. We conclude that the sleep and activity patterns of adult patients with BD do not differ according to their self-reported history of ADHD symptoms. We discuss the implications of these findings and suggest how future studies might confirm or refute our findings.

Which actigraphic variables optimally characterize the sleep-wake cycle of individuals with bipolar disorders?

OBJECTIVE: To examine which combination of objectively measured actigraphy parameters best characterizes the sleep-wake cycle of euthymic individuals with bipolar disorder (BD) compared with healthy controls (HC). METHODS: Sixty-one BD cases and 61 matched HC undertook 21 consecutive days of actigraphy. Groups were compared using discriminant function analyses (DFA) that explored dimensions derived from mean values of sleep parameters (Model 1); variability of sleep parameters (2); daytime activity (3); and combined sleep and activity parameters (4). Exploratory within-group analyses examined characteristics associated with misclassification. RESULTS: After controlling for depressive symptoms, the combined model (4) correctly classified 75% cases, while the sleep models (1 and 2) correctly classified 87% controls. The area under the curve favored the combined model (0.86). Age was significantly associated with misclassification among HC, while a diagnosis of BD-II was associated with an increased risk of misclassifications of cases. CONCLUSION: Including sleep variability and activity parameters alongside measures of sleep quantity improves the characterization of cases of euthymic BD and helps distinguish them from HC. If replicated, the findings indicate that traditional approaches to actigraphy (examining mean values for the standard set of sleep parameters) may represent a suboptimal approach to understanding sleep-wake cycles in BD.

Sleep and circadian rhythms as possible trait markers of suicide attempt in bipolar disorders: An actigraphy study.

BACKGROUND: The poor prognostic of Bipolar disorders (BD) is closely linked to deaths by suicide. Sleep and circadian abnormalities are observed during all phases of BD and are also associated with suicide attempt (SA). In this context, this study sought to identify specific sleep and circadian rhythms markers associated with suicidal attempt in euthymic patients with BD. METHODS: The sample (N = 236) comprised 3 groups: 147 patients with BD including 57 with a history of SA and 90 without (NoSA), and 89 healthy controls (HC). All participants were recorded during 21 days with actigraphy. RESULTS: SA was associated with women gender (p = 0.03), familial history of SA (p = 0.03), mixed episodes (p = 0.001), and benzodiazepines (p = 0.019). SA, compared to noSA, had a morning phase preference (p = 0.04), and were more vigorous on the circadian type inventory (p = 0.04), and tended to suffer more from insomnia (45% versus 25% respectively, p = 0.10). SA was also associated with an earlier onset of daily activity assessed with actigraphy (M10 onset: p = 0.01). Backward stepwise linear regression indicated that a combination of four variables (Gender, vigour, insomnia, M10onset) significantly differentiated patients with SA from NoSA (p = 0.03). LIMITATIONS: Cross-sectional design, and no examination of suicidal behaviors' subgroups such as first attempters or repeaters, or violent suicide attempt. CONCLUSIONS: Woman gender, vigorous circadian type, insomnia and an earlier daily activity appeared independently associated with SA in BD. If these biomarkers are confirmed in prospective studies, they should be screened and used to prevent suicide, with the development of personal and targeted chronobiological treatments.

[Impacts of a brief contact intervention in suicide prevention on medical care consumptions]. / Impacts d'un système de veille en prévention du suicide sur les consommations de soins.

INTRODUCTION: Suicide prevention is a major objective in public health. The development of alternative approaches to the prevention of suicide, such as monitoring systems, is growing quickly. The results are encouraging, but the analysis of the effectiveness remains complex. The objective of this study is to evaluate the medico-economic impact of the ALGOS brief contact intervention (BCI) on the consumption of medical care. METHOD: ALGOS is a prospective, comparative, multicentre, single-blind, randomized, controlled trial, which compared two groups after a suicide attempt (SA). The ALGOS algorithm assigned each BCI to the subgroup of participants. The medico-economic impact of each intervention was evaluated at 6 and 13 months after inclusion. RESULTS: In all, 987 patients were included. There was no significant difference between the two groups at 6 months and at 13 months after SA in the total number of patients who had been hospitalized in psychiatry or other care services. However, the average number of rheumatology visits was significantly higher in the control group (P=0.01) at 13 months. The total number of rheumatologist and physiotherapist visits was significantly higher in the control group at 6 and 13 months. CONCLUSION: Our results suggest that the use of a BCI after SA does not lead to increased consumption of medical care.

Metabolic syndrome and actigraphy measures of sleep and circadian rhythms in bipolar disorders during remission.

OBJECTIVE: This study explored the correlations between sleep and circadian rhythm measures and the metabolic syndrome (MetS) components in remitted patients with bipolar disorder (BD). METHOD: Euthymic patients with BD (n = 67) were recorded by 3 weeks with actigraphy. We used nonparametric correlations to study the links between the MetS parameters, atherogenic index of plasma (AIP), sleep efficacy, sleep latency, fragmentation index, and phase and amplitude of rhythms. We performed multivariable analyses to take into account potential confounding factors such as sleep apnea risk, antipsychotics use, and smoker status. RESULTS: We found correlations between lower sleep efficiency and higher triglyceride levels (P = 0.002), lower M10 onset (beginning of the 10 most active hours during the 24-h cycle) and higher systolic blood pressure (P = 0.03), higher fragmentation index and higher systolic blood pressure (P = 0.009), lower sleep efficiency, higher fragmentation index, and higher AIP (respectively P = 0.02 and P = 0.04). These correlations mostly remained significant when adjusting for confounders, with the exception of M10 onset and systolic blood pressure. CONCLUSION: Sleep efficiency and fragmentation index might contribute to the cardiovascular risk of patients with BD independently of major confounding factors. Although these associations did not imply causality, proposing interventions on sleep quality and circadian rhythm regularity might contribute to reduce cardiovascular risk in patients with BD.

Lithium and suicide prevention in bipolar disorder.

INTRODUCTION: Bipolar disorder (BD) is a severe and recurrent psychiatric disorder. The severity of prognosis in BD is mainly linked to the high rate of suicide in this population. Indeed, patients with BD commit suicide 20 to 30 times more frequently than the general population, and half of the BD population with an early age of onset have a history of suicide attempt. International therapeutic guidelines recommend lithium (Li) as the first-line treatment in BD for its prophylactic action on depressive or manic episodes. In addition, Li is the only mood stabilizer that has demonstrated efficacy in suicide prevention. This effect of Li is unfortunately often unknown to psychiatrists. Thus, this review aims to highlight evidence about the preventive action of Li on suicide in BD populations. METHODS: We conducted a literature search between April 1968 and August 2014 in PubMed database using the following terms: "lithium" AND "suicide" OR "suicidality" OR "suicide attempt". RESULTS: As confirmed by a recent meta-analysis, many studies show that Li has a significant effect on the reduction of suicide attempts and deaths by suicide in comparison to antidepressants or other mood-stabilisers in BD populations. Studies have demonstrated that long-term treatment with Li reduces suicide attempts by about 10% and deaths by suicide by about 20%. The combination of Li and an antidepressant could reduce suicidal behaviours by reducing suicidal ideation prior to depressive symptoms. It appears crucial for Li efficacy in suicide prevention to maintain the Li blood concentrations in the efficient therapeutic zone and to instate long-term Li treatment. The "impulsive-aggressive" endophenotype is associated with suicide in BD. The specific action of Li on the 5-HT serotoninergic system could explain the specific anti-suicidal effects of Li via the modulation of impulsiveness and aggressiveness. Furthermore, genetic variants of the glycogen synthase kinase 3α/ß (GSK3α and ß; proteins inhibited by Li) seem to be associated with more impulsiveness in BD populations. CONCLUSION: The anti-suicidal effect of Li has been very well demonstrated. By its specific action on the serotoninergic system, treatment with Li significantly reduces "impulsive-aggressive" behaviour which is a vulnerability factor common to suicide and BD. Long-term appropriately modulated treatment with Li seems to have considerable impact on the reduction of suicidal behaviours, suicidal ideation and death by suicide in the BD population.

The effectiveness of targeting never or rarely screened women in a national cervical cancer screening program for underserved women.

PURPOSE: To evaluate the effectiveness of a policy supporting early detection and prevention of cervical cancer among low-income and uninsured women by comparing women who reported never or rarely being screened (last screen >5 years) to those who reported screening in the past ≤5 years. METHODS: We analyzed data from 1,485,251 women who received their first Pap test in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) from July 2002 through June 2012. Of these, 461,893 women (31 %) reported being never or rarely screened and 1,023,358 (69 %) reported being screened in the past 5 years. Demographic (age, race/ethnicity, residence, and region) and clinic (cytologic and histologic results) characteristics were examined for the two groups. RESULTS: Women who were aged ≥50 years, Asian and Pacific Islander, American Indian or Alaska Native, multiracial, living in non-metro areas, or living in the South or a territory were more likely to report being never or rarely screened. The percentage of abnormal Pap tests and the rate of precancer and cancer (combined) was higher in the never or rarely screened group compared with the screened group (abnormal percentage: 2.9 vs 2.6 %, p value < 0.01; rate of precancer and cancer: 6.9 vs 3.7 per 1,000 women, p value < 0.01). CONCLUSIONS: The priority of reaching never or rarely screened women should continue since those women who entered the NBCCEDP not adequately screened had a greater prevalence of high-grade histological lesions and invasive cervical cancers at later stages than women screened more recently.

[Seasons, circadian rhythms, sleep and suicidal behaviors vulnerability]. / Saisons, rythmes circadiens, sommeil et vulnérabilité aux conduites suicidaires.

INTRODUCTION: Suicidal behaviors are common in the general population and are so a major public health problem. In order to improve suicide prevention and to reduce the mortality by suicide, it appears essential to better identify suicide risk factors. Seasonality, circadian rhythms and sleep abnormalities have been already associated with numerous psychiatric disorders. This review aimed to characterize the associations between seasonality, circadian rhythms, sleep and suicidal behaviors including suicide attempts and completed suicides. METHODS: We conducted a literature search between 1973 and 2015 in PubMed databases using the following terms: ("suicide" OR "suicidality" OR "suicide attempts" OR "suicidal behavior") AND ("circadian rhythms" OR "seasons" OR "sleep"). RESULTS: Many studies confirm a specific seasonality for suicide with a higher peak of suicides in spring for both sex and a lower peak in autumn especially for women. This distribution seems to correlate with depressive symptoms (especially for the autumn peak), gender and different types of suicide. Regarding gender and type of suicide differences, males more commonly commit violent suicide with a higher rate of suicides in spring. Suicide behaviors appear to be influenced by climatic and biological factors like sunshine, daylight cycles, temperature, air pollutants, viruses, parasites and aeroallergens. Circadian variations exist in suicide rates depending on age with a morning peak for elder and an evening peak for youth. In addition, completed suicide peak in early morning whereas suicide attempts peak rather in later afternoon. Several biomarkers dysregulation like melatonin, serotonin and cortisol may be implicated in suicide circadian variations. Furthermore, specific sleep disorders like insomnia, nightmares and sleep deprivation are common risk factors of suicide and possibly independently of the presence of depressive symptoms. Finally, the efficacy of chronotherapeutics (such as luminotherapy, dark therapy, sleep deprivation and melatonin drugs) has been suggested in the reduction of suicidal behaviors. CONCLUSION: The suicide seasonality is very well documented showing a main peak in spring and another one in autumn. A suicide circadian distribution also exists depending of the suicidal behavior intensity and of the age. Numerous sleep disorders are also suicide risk factors and can be treated with chronotherapeutics. A better identification of seasonality, circadian rhythms and sleep abnormalities in suicidal behaviors could allow a better prevention in suicidal attempts and a reduction in death by suicide.

Primary care provider practices and beliefs related to cervical cancer screening with the HPV test in Federally Qualified Health Centers.

OBJECTIVE: Cervical cancer screening using the human papillomavirus (HPV) test and Pap test together (co-testing) is an option for average-risk women ≥ 30 years of age. With normal co-test results, screening intervals can be extended. The study objective is to assess primary care provider practices, beliefs, facilitators and barriers to using the co-test and extending screening intervals among low-income women. METHOD: Data were collected from 98 providers in 15 Federally Qualified Health Center (FQHC) clinics in Illinois between August 2009 and March 2010 using a cross-sectional survey. RESULTS: 39% of providers reported using the co-test, and 25% would recommend a three-year screening interval for women with normal co-test results. Providers perceived greater encouragement for co-testing than for extending screening intervals with a normal co-test result. Barriers to extending screening intervals included concerns about patients not returning annually for other screening tests (77%), patient concerns about missing cancer (62%), and liability (52%). CONCLUSION: Among FQHC providers in Illinois, few administered the co-test for screening and recommended appropriate intervals, possibly due to concerns over loss to follow-up and liability. Education regarding harms of too-frequent screening and false positives may be necessary to balance barriers to extending screening intervals.

[Use of adipose tissue in regenerative medicine]. / Tissu adipeux et médecine régénératrice.

Adipose tissue is abundant and well known for its involvement in obesity and associated metabolic disorders. Its uses in regenerative medicine recently attracted many investigators, as large amounts of this tissue can be easily obtained using liposuction and it contains several populations of immature cells. The largest pool of such cells corresponds to immature stromal cells, called adipose-derived stromal cells (ADSCs). These cells are purified after proteolytic digestion of adipose tissue and selection by an adherent step. ADSCs display many common features with mesenchymal stem cells derived from bone marrow, including paracrine activity, but with some specific features, among which a greater angiogenic potential. This potential is now investigating at clinical level to treat critical ischemic hindlimb by autologous cells. Other potentials are also investigated and the treatment of fistula associated or not with Crohn's disease is reaching now phase III level.

Human adipose derived stroma/stem cells grow in serum-free medium as floating spheres.

With the goal of obtaining clinically safe human adipose-derived stroma/stem cells (ASC) and eliminating the use of serum, we have developed a new culture system that allows the expansion of ASC as spheres in a defined medium. These spheres can be passaged several times. They are not only aggregated cells but rather originate from single cells as clonal spheres can be obtained after seeding at very low density and reform clonal spheres after dissociation. These spheres can also revert to monolayer growth when plated in medium containing human plasma and even generate fibroblast-like colonies (CFU-f). Under several differentiation-specific media, spheres-derived ASC maintain their capacity to differentiate into osteoblasts, endothelial cells and adipocytes. These results indicate that human ASC can be maintained in a serum-free 3D culture system, which is of great interest for the expansion in bioreactors of autologous ASC and their use in clinical trials.

Follow-up for cervical abnormalities in a managed care plan, 1999-2004.

OBJECTIVE: The objective of this study was to determine the follow-up for women after receiving an abnormal Pap test before and after the updated American Society of Colposcopic and Cervical Pathology (ASCCP) guidelines for management of abnormal cytology. METHODS: In 1999 and 2004, women who had been enrolled in a US health care plan for at least 21 months and were between 18 and 70 years of age were included. We calculated differences in type of follow-up between the time periods before and after ASCCP guideline changes in 2002. RESULTS: Overall, 1.7 million women met study criteria and received at least one Pap test. Overall, 227,802 (14%) women received additional follow-up. Of these women, 73% had a repeat Pap test within 9 months as their first follow-up, 13% received colposcopy, and 7% had other events. The proportion of women receiving a repeat Pap test decreased significantly during the post-guideline time period. The odds of a woman receiving a colposcopy versus a repeat Pap test were 41% higher in the post-guideline period, after controlling for other variables. CONCLUSIONS: Our findings indicate that for the time period after the ASCCP guidelines changed, more colposcopies and fewer repeat Pap tests were performed as a follow-up of abnormal Pap test.

Plasticity of adipose tissue: a promising therapeutic avenue in the treatment of cardiovascular and blood diseases?

The adipose tissue represents a large amount of adult tissues. For long time, it was considered as a poorly active overgrown and undesirable tissue even if its usefulness was demonstrated in reconstructive surgery. It was studied for its main involvement in energy metabolism and disorders as diabetes and obesity. More recently, its endocrine functions emerged and appeared to play a key role in many physiological situations such as inflammation and immunity. The presence of preadipocytes throughout life was demonstrated using primary culture technology from cells derived from adipose tissue. These cells can display a macrophagic or endothelial potential according to their environment and could be now considered as vascular progenitors. Differentiation of various adipose derived cell subsets towards functional cardiomyocytes, osteoblasts, haematopoietic and neural cells was also obtained in vitro. Altogether, these data emphasise the need to consider with a new look preadipocyte status and adipose tissue biology. These spectacular data, together with the fact that adipose tissue is easy to obtain lead to numerous and promising perspectives in regenerative medicine. They highlight the concept that progenitor cells from adipose tissue constitute an alternative for cells-based strategies designed for the treatment of cardiovascular diseases.

[Adipose tissue, plastic and reconstructive surgery: come back to sources]. / Tissus adipeux, chirurgie plastique et reconstructrice: le retour aux sources.

The adipose tissue represents a large amount of adult tissue. For long time, it was considered as a filling tissue and used in plastic and reconstructive surgery. It was always studied for its main involvement in energy metabolism and energy disorders as diabetes and obesity. More recently, its endocrine functions emerged and thus play a key role in many physiological functions as inflammation and immunity. The presence of preadipocytes throughout life was demonstrated using primary culture technology from cells derived from adipose tissue. In recent papers, cells derived from adipose tissue were used for haematopoiesis, vascularisation or skeletal muscle recovery. Differentiation into functional cardiomyocytes, osteoblasts and neural cells was obtained in vitro. These spectacular data, the fact that adipose tissue is easy to sample and the possibility to create cell or tissue banks open numerous and promising perspectives in regenerative medicine.

Spontaneous cardiomyocyte differentiation from adipose tissue stroma cells.

Cardiomyocyte regeneration is limited in adult life. Thus, the identification of a putative source of cardiomyocyte progenitors is of great interest to provide a usable model in vitro and new perspective in regenerative therapy. As adipose tissues were recently demonstrated to contain pluripotent stem cells, the emergence of cardiomyocyte phenotype from adipose-derived cells was investigated. We demonstrated that rare beating cells with cardiomyocyte features could be identified after culture of adipose stroma cells without addition of 5-azacytidine. The cardiomyocyte phenotype was first identified by morphological observation, confirmed with expression of specific cardiac markers, immunocytochemistry staining, and ultrastructural analysis, revealing the presence of ventricle- and atrial-like cells. Electrophysiological studies performed on early culture revealed a pacemaker activity of the cells. Finally, functional studies showed that adrenergic agonist stimulated the beating rate whereas cholinergic agonist decreased it. Taken together, this study demonstrated that functional cardiomyocyte-like cells could be directly obtained from adipose tissue. According to the large amount of this tissue in adult mammal, it could represent a useful source of cardiomyocyte progenitors.

Characterisation of Rac activation in thrombin- and collagen-stimulated human blood platelets.

In this study, we characterised the mechanisms of Rac GTPase activation in human platelets stimulated by two physiological agonists, either thrombin, acting through membrane receptors coupled to heterotrimeric G-proteins, or collagen which is known to mobilise a tyrosine kinase-dependent pathway. Both agonists induced a rapid activation of Rac that was not significantly affected by the inhibition of integrin alpha(IIb)beta(3) engagement. Using pharmacological inhibitors, we found that phospholipase C activation and calcium mobilisation were essential for platelet Rac activation by either thrombin or collagen whereas protein kinase C inhibition was without effect. In contrast to Rac, Cdc42 activation was independent of phospholipase C activation, indicating that the two GTPases are differently regulated. We also found that phosphoinositide 3-kinase was not required for Rac activation in response to thrombin but was involved in its activation by collagen.

Race-specific results of Papanicolaou testing and the rate of cervical neoplasia in the National Breast and Cervical Cancer Early Detection Program, 1991-1998 (United States).

OBJECTIVE: To describe differences in cervical screening and biopsy results by race or ethnicity from women in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). METHODS: We examined the percentage of abnormalities detected by Papanicolaou (Pap) tests and the rate of biopsy-diagnosed high-grade precancerous or cancerous lesions by racial or ethnic group. RESULTS: Almost half the 628,085 women screened were members of racial or ethnic minority groups. American Indian or Alaska Native women were more likely than others to report never having had a prior Pap test. American Indian or Alaska Native women had the highest proportion of abnormal Pap tests for first program screens (4.4%), followed by blacks (3.2%), whites (3.0%), Hispanics (2.7%), and Asians or Pacific Islanders (1.9%). Whites had the highest biopsy detection rate of high-grade lesions for first program screens (9.9 per 1000 Pap tests), followed by Hispanics (7.6), blacks (7.1), American Indians or Alaska Natives (6.7), and Asians or Pacific Islanders (5.4). CONCLUSIONS: This program provides important data on the prevalence of cervical neoplasia among diverse populations. Our findings that black women with a high-grade Pap test were less likely to get a work-up are disconcerting and merit further study and ultimate correction.