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.

Adipose mesenchymal stromal cells: Definition, immunomodulatory properties, mechanical isolation and interest for plastic surgery.

Ever since their discovery in 2001, adipose mesenchymal stromal cells (ASC) have profoundly modified clinical indications and our practice of plastic surgery, thereby placing our discipline at the forefront of regenerative medicine. These cells act through paracrine signaling by synthesizing immunosuppressive and pro-angiogenic factors. They are of key importance with regard to the regenerative properties of autologously grafted adipose tissue (AT). Taken together, they make up the stromal vascular fraction (SVF) comprising all AT cells except for adipocytes. As our knowledge evolves, we are moving from fat grafting towards SVF grafting, of which the essential sought-after effect is tissue regeneration. The objective of the present review is to synthesize present-day information on ASCs and their immunomodulatory properties and, from a practical standpoint, to indicate present-day and future steps towards establishment of clinical routine, particularly through application of techniques favoring mechanical digestion of adipose tissue.

Cell-assisted lipotransfer: Friend or foe in fat grafting? Systematic review and meta-analysis.

Autologous fat grafting is a common procedure for soft-tissue reconstruction but is associated with a graft resorption rate ranging from 20% to 80%. To improve the fat graft survival rate, a new technique, called cell-assisted lipotransfer (CAL), was developed. With CAL, fat is injected along with adipose-derived stromal cells that are assumed to improve fat survival rate. We conducted an evidence-based meta-analysis to evaluate the efficacy and safety of CAL as compared with conventional autologous fat grafting (non-CAL). The databases MEDLINE (via PubMed), Cochrane Library, EBSCO, Web of Science, and EMBASE were searched for reports of clinical trials, case series, and cohorts available from 2008 to 2016. We conducted a meta-analysis of the efficacy of CAL with data analysis concerning fat survival rate. The incidence of complications and the need for multiple procedures were evaluated to determine the safety of CAL. We identified 25 studies (696 patients) that were included in the systematic review; 16 studies were included in the meta-analysis to evaluate the efficacy of CAL. The fat survival rate was significantly higher with CAL than non-CAL (64% vs. 44%, p < .0001) independent of injection site (breast and face). This benefit of CAL was significant for only injection volumes <100 ml (p = .03). The two groups did not differ in frequency of multiple procedures after fat grafting, but the incidence of complications was greater with CAL than non-CAL (8.4% vs. 1.5%, p = .0019). The CAL method is associated with better fat survival rate than with conventional fat grafting but only for small volumes of fat grafting (<100 ml). Nonetheless, the new technique is associated with more complications and did not reduce the number of surgical procedures needed after the first fat grafting. More prospective studies are required to draw clinical conclusions and to demonstrate the real benefit of CAL as compared with common autologous fat grafting.

Cell-assisted lipotransfer: Current concepts.

Autologous fat transfer, or lipofilling, is a common technique used for soft tissue reconstruction. It has been used for many years, but the technique is associated with a significant graft resorption rate (20% to 80%). To improve the fat graft survival rate, several methods have been tested, and one has appeared more promising: cell-assisted lipotransfer (CAL). In the CAL method, fat is enriched with adipose-derived stromal cells (ASC), contained in the stromal vascular fraction (SVF) obtained after enzymatic digestion of fat or after cell culture to improve the fat survival rate. In this concise review, we present the clinical indications, and the technical principles of CAL, as well as a presentation of ASC. To conclude, we present the main results (efficacy, complications and safety) obtained from different studies of this technique.

A cardiac mitochondrial cAMP signaling pathway regulates calcium accumulation, permeability transition and cell death.

Although cardiac cytosolic cyclic 3',5'-adenosine monophosphate (cAMP) regulates multiple processes, such as beating, contractility, metabolism and apoptosis, little is known yet on the role of this second messenger within cardiac mitochondria. Using cellular and subcellular approaches, we demonstrate here the local expression of several actors of cAMP signaling within cardiac mitochondria, namely a truncated form of soluble AC (sACt) and the exchange protein directly activated by cAMP 1 (Epac1), and show a protective role for sACt against cell death, apoptosis as well as necrosis in primary cardiomyocytes. Upon stimulation with bicarbonate (HCO3(-)) and Ca(2+), sACt produces cAMP, which in turn stimulates oxygen consumption, increases the mitochondrial membrane potential (ΔΨm) and ATP production. cAMP is rate limiting for matrix Ca(2+) entry via Epac1 and the mitochondrial calcium uniporter and, as a consequence, prevents mitochondrial permeability transition (MPT). The mitochondrial cAMP effects involve neither protein kinase A, Epac2 nor the mitochondrial Na(+)/Ca(2+) exchanger. In addition, in mitochondria isolated from failing rat hearts, stimulation of the mitochondrial cAMP pathway by HCO3(-) rescued the sensitization of mitochondria to Ca(2+)-induced MPT. Thus, our study identifies a link between mitochondrial cAMP, mitochondrial metabolism and cell death in the heart, which is independent of cytosolic cAMP signaling. Our results might have implications for therapeutic prevention of cell death in cardiac pathologies.

[Adipose-derived stromal cells: history, isolation, immunomodulatory properties and clinical perspectives]. / Les cellules stromales mésenchymateuses du tissu adipeux : historique, isolement, propriétés immunomodulatrices et perspectives cliniques.

Over the last decade, the clinical use of adipose-derived stromal/stem cells (ASC) in regenerative medicine is rapidly increasing. ASC belong to the mesenchymal stromal cells initially obtained from the bone marrow. Their limited differentiation capacity in vivo into functional mature cells has led to a reassessment of their mechanisms of action. One of the major clinical interests appears related to paracrine effects through a temporary production of trophic and immunomodulatory factors. Our purpose is to provide a review on the latest knowledge in the field of ASC, mechanisms of action, mainly immunomodulatory/immunosuppressive properties, methods of obtention, with a focus on clinical perspectives particularly in the field of cellular therapy and fat grafting technique in plastic surgery.

NF-kappaB, AP-1, Zinc-deficiency and aging.

Zinc (Zn) deficiency, a frequent condition in human population especially in aged persons, induces oxidative stress and subsequently activates/inhibits oxidant-sensitive transcription factors that can affect cell function, proliferation and survival leading to disease. Zn deficiency-triggered oxidative stress could affect cell signalling, including transcription factors containing Zn finger motifs and other oxidant-sensitive transcription factors such as nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1). AP-1 can be activated in Zn deficiency that can occur secondary to an increase in cellular H(2)O(2), followed by activation of MAPKs p38 and JNK. Similarly, the cytosolic steps of the NF-kappaB cascade are activated by oxidants in Zn deficiency. However, an impaired nuclear transport of the active transcription factor leads to a low expression of NF-kappaB-dependent genes that could be involved in multiple steps of Zn deficiency associated pathology. We present here evidence that, following experimental depletion of Zn, both NF-kappaB and AP-1 signallings are altered in primary T cells isolated from young and elderly healthy individuals under CD3/CD28 costimulation. A supplementation of Zn restored both NF-kappaB and AP-1 activation in CD3/CD28 costimulated T cells from young, but not from elderly, healthy individuals, indicating that the Zn deficiency is only one component of a more complex mechanism involved in immunosenescence. In this review we summarize our present knowledge on NF-kappaB and AP-1 activation and underline the role of Zn in this process, especially in the context of Zn deficiency observed in aged persons leading to immunosenescence.

Cytokine receptor signalling and aging.

With ageing the immune system is deregulated and this leads to the development of immunosenescence mainly affecting the adaptive immune response. There is much knowledge accumulated concerning various receptor functions and signalling with ageing such as TCR, FcRs, TLRs. Cytokines are playing a major role in haematopoietic cell functions and in the harmonious and integrated coordination of the innate and adaptive immune response. There exists a large amount of data on cytokine production changes with ageing, as IL-2 production is decreasing, while IL-6 production is increasing. In contrast, there is only scarce knowledge concerning the cytokine receptors and their signalling in ageing. However, there is some evidence that the signalling of IL-2 receptors is altered in T cells and macrophages, mainly in relation to the JAK/STAT pathway. We present here evidence that the IL-6 induced signalling is also altered in T cells with ageing. An alteration in the JAKs and STATs activations in T cells and macrophages was demonstrated. The exact cause of these altered activations is not known and future studies are needed to elucidate them. In this review we summarise our present knowledge on cytokine signalling with ageing, mainly focusing on IL-2 and IL-6 receptors signalling.

[State of the art and outlook for promoting Russian-made hemodialysis equipment with regeneration of dialyzing solution]. / Sovremennoe sostoianie i perspektivy razvitiia otechestvennoi gemodializnoi apparatury s regeneratsiei dializiruiushchego rastvora.

Radical improvements in the physiological features and self-sufficiency of hemodialysis equipment, an essential reduction of the volume of dialyzate contacting with patient's body and elimination of dependence of the equipment operation on the availability of a water-supply network can be ensured by applying a regime of circulation of a relatively small volume (3-5 l) of dialyzate through the regenerating device. The regeneration unit must eliminate the organic products of dialysis from the dialyzate and stabilize the ionic composition of the purified dialyzate according to the preset parameters. Modern methods and technical means for regenerating the used dialyzate are discussed; a regeneration unit, which ensures an electrochemical oxidation (in the used dialyzate) of nitrogen-containing organic metabolites with a subsequent sorption-type additional purification of electrochemically-processed dialyzate, is offered. The regeneration unit is made up of an electrolyser, a sorption-type additional-purification device and a gas utilizer; it eliminates organic metabolites, phosphorus, calcium and potassium from the used dialyzate and stabilizes the pH solution.

[Nuclear-medical equipment in the Research Institute for Medical Instrument-making]. / Iaderno-meditsinskaia apparatura v NII Meditsinskogo priborostroeniia.

The activity of the department for emission introscopy of the Research Institute for Medical Instrument-Making ("ZAO VNIIMP-VITA") is described in the article. A list of developed and commissioned devices and instruments for the field of nuclear medicine is presented. Methods of elaboration of some sophisticated instruments and units designed for radio-biochemical and radio-immunologic examinations as well as methods of elaboration of scintillation gamma cameras, tomograph GKS-301T, medical dosimeters and of other devices are also described.

[Diagnostic errors in the treatment of patients with pleural diseases]. / Vrachebnye oshibki v vedenii bol'nykh s zabolevaniiami plevry.

As illustrated by analysis of 342 case histories, none of 280 patients admitted for two years to the Center for Diagnosis and Treatment of Pleural Diseases had the verified admission diagnosis. Missed diagnosis was possible because the physicians in charge had not prescribed pleural puncture, tomography of the lungs and mediastinum after maximal removal of the exudate. Other causes were inadequate investigation of the pleural fluid, administration of antibacterial therapy and glucocorticoids in obscure diagnosis. Poor diagnosis of pleural disease reflects the absence of clear-cut policy of management of such patients as a result of which in general practice pleural diseases are detected 2 weeks after visit to a doctor, on the average. To the specialized center the patients are sent only 47 days after the disease onset. Specialists of the center make differential diagnosis with early use of needle biopsy of the pleura which enables to reduce the time of making diagnosis to 10-12 days.

[Supplying therapeutic equipment to tuberculosis departments and hospitals]. / Osnashchenie tuberkuleznykh otdelenii i bol'nits terapevticheskim oborudovaniem.

The paper provides evidence for that the development of new treatments of tuberculosis by using up-to-date technical means and their introduction into practice. It gives the data of the researches and developments made by the VNIIMP-VITA close joint stock company, which are both aimed at providing tuberculous units and hospitals with necessary therapeutical equipment, such as devices for pneumothorax, endoscopic studies, etc.

[Medical-technological equipment of nonphysician monitoring of health status]. / Mediko-tekhnicheskoe obespechenie vnevrachebnogo monitorirovaniia sostoianiia zdorov'ia cheloveka.

Extrahospital monitoring of the body's status is an effective method for health promotion of man and the general population. The paper presents medical engineering rationale for the software of health monitoring under different conditions, identifies three base-line configurations of these complexes: for use in health institutions: for that in the institutions lacking permanent medical staff; for individual and familial use.

[Methods and means for the noninvasive assessment of the cerebral circulation]. / Metody i sredstva neinvazivnoi otsenki mozgovogo krovoobrashcheniia.

The main clinical and diagnostic tasks while studying cerebrovascular diseases have been defined and set on the basis of analysis of the biophysical and pathophysiological factors and parameters that characterize the cerebral circulation in health and disease. The currently available physioengineering methods and means for evaluating cebral hemodynamics. Proposals to design new equipment and to improve the existing one and recommendations how to use them while examining the cerebral circulation in various clinical situations are given.

[Radionuclide methods of measuring mineral contents in the bone tissue]. / Radionuklidnye metody izmereniia soderzhaniia mineralov v kostnoi tkani.

Over the recent 10-15 years, osseous densitometers intended for measuring the content of minerals in osseous tissue have become very popular abroad. To record statistically significant changes in an osseous mineral, these devices should have reproducibility (variation rate) exceeding 2%. Mono- and biphoton densitometers may be distinguished by the type of the applied radionuclide. Biphoton densitometers are advantageous since they permit examining any part of the skeletal system of the patient or the whole body. Biphoton absorptiometry is based on measuring the transition of photons of two energies via the medium that largely consists of the two materials bone and soft tissue. The authors describe the results of examining parts of the peripheral skeleton with the aid a laboratory sample of a biphoton osseous densitometer for the peripheral skeleton.