Adaptive Compensatory Responses Research Articles

PB1. Functional network alterations in multisystem atrophy (MSA)

Background In multisystem atrophy (MSA), the functional brain connectivity within cortical and subcortical networks and its clinical correlates is a challenging topic of research. Objective Assessment of functional brain connectivity alterations in MSA. Methods Whole-brain based ‘intrinsic functional connectivity’ MRI data were obtained from 22 MSA patients and 22 matched healthy controls, together with standardized clinical assessment and video-oculographic recordings (EyeLink®). Results MSA patients vs. controls showed significantly increased ponto-cerebellar functional connectivity and decreased default mode network connectivity ( p 0.05 , corrected). No differences were observed in the motor network. Saccadized smooth pursuit significantly correlated with increased functional ponto-cerebellar connectivity ( p 0.05 , corrected). Conclusion This intrinsic functional connectivity analysis supports a network-dependent combination of hyper- and hypoconnectivity states in MSA, in agreement with adaptive compensatory responses (hyperconnectivity) and a function disconnection syndrome (hypoconnectivity) ( Gorges et al., 2017 ) that may occur in a consecutive sequence.

From genetics to response to injury: vascular smooth muscle cells in aneurysms and dissections of the ascending aorta.

Vascular smooth muscle cells (vSMCs) play a crucial role in both the pathogenesis of Aneurysms and Dissections of the ascending thoracic aorta (TAAD) in humans and in the associated adaptive compensatory responses, since thrombosis and inflammatory processes are absent in the majority of cases. Aneurysms and dissections share numerous characteristics, including aetiologies and histopathological alterations: vSMC disappearance, medial areas of mucoid degeneration, and extracellular matrix (ECM) breakdown. Three aetiologies predominate in TAAD in humans: (i) genetic causes in heritable familial forms, (ii) an association with bicuspid aortic valves, and (iii) a sporadic degenerative form linked to the aortic aging process. Genetic forms include mutations in vSMC genes encoding for molecules of the ECM or the TGF-β pathways, or participating in vSMC tone. On the other hand, aneurysms and dissections, whatever their aetiologies, are characterized by an increase in wall permeability leading to transmural advection of plasma proteins which could interact with vSMCs and ECM components. In this context, blood-borne plasminogen appears to play an important role, because its outward convection through the wall is increased in TAAD, and it could be converted to active plasmin at the vSMC membrane. Active plasmin can induce vSMC disappearance, proteolysis of adhesive proteins, activation of MMPs and release of TGF-β from its ECM storage sites. Conversely, vSMCs could respond to aneurysmal biomechanical and proteolytic injury by an epigenetic phenotypic switch, including constitutional overexpression and nuclear translocation of Smad2 and an increase in antiprotease and ECM protein synthesis. In contrast, such an epigenetic phenomenon is not observed in dissections. In this context, dysfunction of proteins involved in vSMC tone are interesting to study, particularly in interaction with plasma protein transport through the wall and TGF-β activation, to establish the relationship between these dysfunctions and ECM proteolysis.

КЛІНІЧНА ЕФЕКТИВНІСТЬ ЗАСТОСУВАННЯ ФІТОПРЕПАРАТУ «РЕСВЕРАЗИН» В КОМПЛЕКСНОМУ ЛІКУВАННІ ГЕНЕРАЛІЗОВАНОГО ПАРОДОНТИТУ

Захворювання пародонта – сьогодні одне із найпоширеніших уражень організму людини. За даними ВООЗ (1990), від 55 до 98 % дорослого населення планети має патологію пародонта, найвищий рівень захворюваності зареєстровано в осіб 15–19 років (55–89 %) та 35–44 років (65–98 %) [1, 3, 6]. Висока поширеність, несприятливий вплив вогнищ пародонтальної інфекції на стан порожнини рота та організм у цілому, високий рівень ускладнень, пов’язаних із функціональними та морфологічними порушеннями внаслідок втрати зубів, – все це визначає актуальність даної проблеми.Мета дослідження – оцінити клінічну ефективність препарату “Ресверазин” у складі комплексного лікування генералізованого пародонтиту.Матеріали і методи. У дослідженні взяли участь 43 пацієнти, хворі на хронічний генералізований пародонтит. Оцінку стану пародонта проводили за клінічними ознаками. Для оцінки гігієнічного стану порожнини рота використовували індекси Green–Wermillion, ОНІ-S, Silness–Loe, Stallard, пародонтологічні індекси: РМА, ПІ, індекс кровоточивості за Мuhlleman. Визначення і підрахунок індексів проводили за загальноприйнятими методиками. Пацієнтам основної групи в комплексній терапії призначали препарат “Ресверазин” по 1 капсулі 2 рази на добу. Курс лікування становив 2 місяці.Результати дослідження та їх обговорення. Дані клінічних досліджень, які ми отримали, послугували обґрунтуванням для впровадження в медичну стоматологічну практику лікування генералізованого пародонтиту (ГП) фітопрепаратом “Ресверазин”. Включення до комплексної терапії хворих на пародонтит препарату “Ресверазин” сприяло підвищенню ефективності проведеного етіотропного, патогенетичного та симптоматичного лікування хворих, що забезпечило клінічно виражені ознаки стабілізації пародонтиту та швидший перехід ГП у стадію ремісії. Позитивний клінічний результат отриманий за основними критеріями ефективності, які заключались у зменшенні симптомів запалення – гіперемії, набряку та кровоточивості міжзубних сосочків і маргінальної частини ясен. Тенденція до зменшення ознак запалення за клінічними, суб’єктивними даними, підтвердилась позитивною динамікою показника поширеності запаленнятканин пародонта (РМА). Зниження значення інтегративного пародонтального індексу відбувається переважно за рахунок зменшення тяжкості симптоматичного гінгівіту та глибини пародонтальних кишень. У результаті проведеного лікування настає нормалізація функціональних адаптаційно-компенсаторних реакцій, що підтверджується нормалізацією показників – гігієнічними індексами Green–Wermillion, ОНІ-S, Silness–Loe, Stallard та пародонтальними індексами: папілярно-маргінально-альвеолярним (РМА), індексом кровоточивості за Muhlleman, пародонтальним індексом (ПІ).Висновки. Результати клінічного дослідження свідчать про необхідність застосування фітопрепаратів, зокрема фітопрепарату “Ресвератрол”, із протизапальною, антиангіогенною, імунотропною, антиоксидантною дією в комплексному лікуванні хворих на генералізований пародонтит.

Hyperconnective and hypoconnective cortical and subcortical functional networks in multiple system atrophy

IntroductionIn multiple system atrophy (MSA), the organization of the functional brain connectivity within cortical and subcortical networks and its clinical correlates remains to be investigated. MethodsWhole-brain based ‘resting-state’ fMRI data were obtained from 22 MSA patients (11 MSA-C, 11 MSA-P) and 22 matched healthy controls, together with standardized clinical assessment and video-oculographic recordings (EyeLink®). ResultsMSA patients vs. controls showed significantly higher ponto-cerebellar functional connectivity and lower default mode network connectivity (p < .05, corrected). No differences were observed in the motor network and in the control network. The higher the ponto-cerebellar network functional connectivity was, the more pronounced was smooth pursuit impairment. ConclusionThis functional connectivity analysis supports a network-dependent combination of hyper- and hypoconnectivity states in MSA, in agreement with adaptive compensatory responses (hyperconnectivity) and a function disconnection syndrome (hypoconnectivity) that may occur in a consecutive sequence.

Evidence for Auditory-Motor Impairment in Individuals With Hyperfunctional Voice Disorders.

The vocal auditory-motor control of individuals with hyperfunctional voice disorders was examined using a sensorimotor adaptation paradigm. Nine individuals with hyperfunctional voice disorders and 9 individuals with typical voices produced sustained vowels over 160 trials in 2 separate conditions: (a) while experiencing gradual upward perturbations in the fundamental frequency (fo) of their auditory feedback (shift-up) and (b) under no auditory perturbation (control). The shift-up condition consisted of 4 ordered (fixed) phases: baseline (no perturbation), ramp (gradual increases in heard fo), hold (a consistently higher heard fo), and after-effect (no perturbation). Adaptive responses were defined as the difference in produced fo during control and shift-up conditions. Adaptive responses were significantly different between groups. Individuals with typical voices generally showed compensatory adaptive responses, with decreased fo during the ramp and hold phases. Conversely, many individuals with hyperfunctional voice disorders instead displayed the opposite effect by following the direction of the perturbation. When fo was experimentally increased, speakers further increased their fo. Results indicate that some individuals diagnosed with hyperfunctional voice disorders have disrupted auditory-motor control, suggesting atypical neurological function. These findings may eventually allow for the development of new interventions for hyperfunctional voice disorders.

MICROECOLOGICAL STATUS OF UPPER RESPIRATORY WAYS MUCOSA IN TEENAGERS LIVING IN TOWNS WITH CHEMICAL INDUSTRY

The complex studies on assessing the microecological status of the upper respiratory ways (URW) have been performed in schoolchildren of senior classes living in centers of chemical industry. Some features of adaptive-compensatory responses of the immune system have been determined. The result analysis of the microecological and immunological studies of the respiratory tract allowed to detect inhibition of the respiratory ways colonizational resistance, changes in the qualitative properties of the microorganisms, decreased local immunity of URW and common organism resistance. Disorders of the microecological status of the teenagers' respiratory ways mucosa in body disadaptation can result in development of clinically pronounced pathologies and aggravation of the respiratory organs' diseases.

Aberrant spontaneous low-frequency brain activity in male patients with severe obstructive sleep apnea revealed by resting-state functional MRI.

BackgroundThe majority of previous neuroimaging studies have demonstrated both structural and functional abnormalities in obstructive sleep apnea (OSA). However, few studies have focused on the regional intensity of spontaneous fluctuations during the resting state and the relationship between the abnormal properties and the behavioral performances. In the present study, we employed the amplitude of low-frequency fluctuation (ALFF) method to explore the local features of spontaneous brain activity in OSA patients (OSAs).MethodsTwenty-five untreated male severe OSAs and 25 age-matched and years-of-education-matched male good sleepers (GSs) were included in this study. The ALFF method was used to assess the local features of spontaneous brain activity. The mean signal values of the altered ALFF areas were analyzed with receiver operating characteristic curve. Partial correlation analysis was used to explore the relationship between the observed mean ALFF values of the different areas and the behavioral performances.ResultsCompared with GSs, OSAs had significantly higher scores for body mass index, apnea–hypopnea index, arterial oxygen saturation <90%, arousal index, and Epworth Sleepiness Scale (ESS) score; furthermore, OSAs had significantly lower scores for rapid eye movement sleep and in the Montreal Cognitive Assessment (MoCA). Compared with GSs, OSAs showed significant lower-ALFF areas in the cluster of the right precuneus and bilateral posterior cingulate gyrus, as well as a higher-ALFF area in the left inferior frontal gyrus. The area under the curve values of the lower- and higher-ALFF areas were 0.90 and 0.93, respectively. Further diagnostic analysis exhibited that the sensibility and specificity of the two clusters were 80% and 92%, respectively. The mean signal value of the lower-ALFF cluster displayed significant positive correlations with lowest oxygen saturation (r=0.447, P=0.025) and MoCA score (r =0.405, P=0.045).ConclusionOSAs may involve in a dysfunction in the default mode network and an adaptive compensatory response in the frontal lobe, which reflect the underlying pathophysiology of cognitive impairment.

Abstract 695: p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling

Abstract Targeted cancer therapies often induce compensatory adaptive responses that blunt drug effectiveness, resulting in therapeutic resistance - intrinsic or acquired. Adaptive responses are characteristic of the complex nature of the cancer cell signaling network. Within this network, nodes of convergence between signaling modules are critical mediators of adaptive responses to targeted drugs. The critical nodes in an oncogenically-activated signaling network represent potential therapeutic vulnerabilities because their inhibition could result in collapse of the network and hence enhanced cytotoxicity. We have previously used high-throughput combinatorial drug screening to empirically identify adaptive survival responses to targeted therapies. We found that HER-family and PI3K represented compensatory signaling pathways, and combination therapy caused synergistic cytotoxicity in cases where inhibition of neither target was effective as a monotherapy. RPPA analysis identified ribosomal protein S6 as being synergistically down-regulated upon HER-family and PI3K co-inhibition. Expression of a constitutively active construct of the upstream activator of S6, p70S6K, was protective against apoptosis induced by combined HER-family and PI3K inhibition. Direct inhibition of p70S6K using small molecule inhibitors phenocopied the growth inhibition and apoptosis caused by HER-family and PI3K inhibition. These data implicate p70S6K as a critical node and druggable target in the HER-family / PI3K signaling network. The ability of direct inhibitors of p70S6K to phenocopy the co-inhibition of upstream signaling indicates that identification and targeting of critical nodes may be a way to overcome adaptive resistance to targeted therapies. Citation Format: Mark J. Axelrod, Rolando E. Mendez, Daniel G. Gioeli, Mark J. Jameson, Michael J. Weber. p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 695. doi:10.1158/1538-7445.AM2014-695

P70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling networks

Therapies targeting oncogenic drivers rapidly induce compensatory adaptive responses that blunt drug effectiveness, contributing to therapeutic resistance. Adaptive responses are characteristic of robust cell signaling networks, and thus there is increasing interest in drug combinations that co-target the driver and the adaptive response. An alternative approach to co-inhibiting oncogenic and adaptive targets is to identify a critical node where the activities of these targets converge. Nodes of convergence between signaling modules represent potential therapeutic vulnerabilities because their inhibition could result in the collapse of the network, leading to enhanced cytotoxicity. In this report we demonstrate that p70S6 kinase (p70S6K) can function as a critical node linking HER-family and phosphoinositide-3-kinase (PI3K) pathway signaling. We used high-throughput combinatorial drug screening to identify adaptive survival responses to targeted therapies, and found that HER-family and PI3K represented compensatory signaling pathways. Co-targeting these pathways with drug combinations caused synergistic cytotoxicity in cases where inhibition of neither target was effective as a monotherapy. We utilized Reverse Phase Protein Arrays and determined that phosphorylation of ribosomal protein S6 was synergistically down-regulated upon HER-family and PI3K/mammalian target of rapamycin (mTOR) co-inhibition. Expression of constitutively active p70S6K protected against apoptosis induced by combined HER-family and PI3K/mTOR inhibition. Direct inhibition of p70S6K with small molecule inhibitors phenocopied HER-family and PI3K/mTOR co-inhibition. These data implicate p70S6K as a critical node in the HER-family/PI3K signaling network. The ability of direct inhibitors of p70S6K to phenocopy co-inhibition of two upstream signaling targets indicates that identification and targeting of critical nodes can overcome adaptive resistance to targeted therapies.

Adaptive-compensatory responses in the adolescents belonging to indigenous northern ethnic groups in Irkutsk oblast

The pro- and antioxidant statuses of apparently healthy adolescent Tofalar and Evenks of both sexes has been estimated and compared to those of the newcomer Caucasian people. Both girls and boys display an activation of adaptive-compensatory response relative to Caucasian newcomers, which manifests itself as a statistically significant increase in nonenzymatic components of the antioxidant defense system.

Effects of water deficiency on mitochondrion functions and polymorphism of respiratory enzymes in plants

In plants, adaptive-compensatory responses to stress always entail additional energy expenditure. A suggestion was brought forward that in plants growing under conditions of water stress there is a relationship between genetic variability of respiratory enzymes and their functional significance. With Kochia prostrate (L.) Schrad. as a case study, intraspecies genetic polymorphism under the conditions of drought has been analyzed using typical protein markers which, considering their functional importance, can be viewed as respiratory enzymes. Out of eight protein markers examined, four enzymes were singled out for which dominating combination of genotypes Dia B (a), G6pd (a), Gdh (c), and Mdh A (a) was incidental. In all populations from arid and semiarid zone, these genotypes frequency of occurrence was in the range of 0.53-1.0, i.e., it comprised more than 50% of the whole variety of combinations. Thus, it seems plausible that this combination of genotypes can be an "adaptive collection" for K. prostrata populations growing in arid habitats. A characteristic feature of the picked out enzymes is their belonging to NAD(P)(+)-depending oxidoreductases that play a key role in functioning and redox-regulation of respiratory metabolism in course of adapting to water deficiency. It is suggested that the presence of such well-balanced co-adaptive genotype combinations, that provide enzymes important in terms of energetics, determine the formation of energetic and redox-balances during the process of adaptation to water stress.

Attenuation of Monocyte Chemotaxis—A Novel Anti-inflammatory Mechanism of Action for the Cardio-protective Hormone B-Type Natriuretic Peptide

B-type natriuretic peptide (BNP) is a prognostic and diagnostic marker for heart failure (HF). An anti-inflammatory, cardio-protective role for BNP was proposed. In cardiovascular diseases including pressure overload-induced HF, perivascular inflammation and cardiac fibrosis are, in part, mediated by monocyte chemoattractant protein (MCP)1-driven monocyte migration. We aimed to determine the role of BNP in monocyte motility to MCP1. A functional BNP receptor, natriuretic peptide receptor-A (NPRA) was identified in human monocytes. BNP treatment inhibited MCP1-induced THP1 (monocytic leukemia cells) and primary monocyte chemotaxis (70 and 50 %, respectively). BNP did not interfere with MCP1 receptor expression or with calcium. BNP inhibited activation of the cytoskeletal protein RhoA in MCP1-stimulated THP1 (70 %). Finally, BNP failed to inhibit MCP1-directed motility of monocytes from patients with hypertension (n = 10) and HF (n = 6) suggesting attenuation of this anti-inflammatory mechanism in chronic heart disease. We provide novel evidence for a direct role of BNP/NPRA in opposing human monocyte migration and support a role for BNP as a cardio-protective hormone up-regulated as part of an adaptive compensatory response to combat excess inflammation.

Running on Empty: Cardiovascular Reserve Capacity and Late Effects of Therapy in Cancer Survivorship

Seminal investigations by Frank 1 and Starling 2 provided thefirst evidence that the heart possesses inherent reserve capacity—a key principle that is a pillar of modern cardiology research and practice. After 150 years of research, we now understand that cardiovascular reserve capacity (CVRC) is determined by the integrative ability of cross-system mechanisms (eg, neurohormonal, central, and peripheral oxygen delivery 3 ), which collectively possess remarkable adaptive capacity. Sequential as well as concurrent pathologic perturbations to either one or more of these mechanisms are offset by initial compensatory adaptive responses in other component systems to maintain whole-body homeostatic regulation—a process termed coordinated adaptation. 4 Unfortunately, CVRC is finite, and continued insults ultimately lead to overt dysfunction (eg, acute coronary syndromes, left ventricular dysfunction). Pathologic impairments in CVRC are etiologicinmanychronicdiseaseconditionsandarethusanintegralconsiderationindailypractice.Thepurposeofthiscommentaryistoprovidean overviewoftheguidingprinciplesandapplicationofCVRCintheoncology setting using early breast cancer as an illustrative model. Measurement of CVRC

Quantitative Assessment of Regulatory Proteins in Blood as Markers of Radiation Effects in the Late Period After Occupational Exposure

The objective of this research was quantitative assessment of serum and membrane regulatory proteins in blood from nuclear workers as markers of radiation-induced alterations in immune homeostasis in the late period after protracted exposure of nuclear workers with different doses. The effector and regulatory lymphocytes were measured using a flow cytofluorometer in workers from the main facilities of the Mayak PA (aged ∼60 y up to 80 y) in the late period after combined exposure to external gamma-rays and internal alpha-radiation from incorporated 239Pu. The control group included non-occupationally exposed members of the Ozyorsk population matched by gender and age to the group of Mayak workers. Thirty serum proteins involved in regulation of immune homeostasis, such as growth factors, multifunctional interleukins, pro- and anti-inflammatory cytokines, and their receptors, were measured using ELISA in blood serum specimens from the Radiobiology Human Tissue Repository. The dosimetry estimates were obtained using Doses-2005. The correlation analysis revealed a statistically significant direct relationship of T-killers and plutonium body burden and a decreasing level of T-helpers with accumulated external dose in exposed individuals. There were differences in expression of membrane markers in young regulatory cells (double null T-lymphocytes, NKT-lymphocytes, regulatory T-cells, and an increase of activated forms of T-lymphocytes), which indicated an active role of regulatory cells in maintaining immune homeostasis in terms of protracted exposure. The assessment of regulatory proteins in blood indicated that growth factors (EGF, TGF-β1, PDGF), multifunctional interleukins (IL-17A, IL-18), and pro-inflammatory cytokines (IL-1β and INF-γ) could be potential markers of radiation-induced alterations in protein status. An imbalance of pro- and antiinflammatory proteins in blood and variations of protein profiles at the lower exposure levels (gamma-ray dose <1 Gy, plutonium body burden <0.74 kBq) in the late period after protracted exposure were less pronounced than at the higher exposure levels, which was probably explained by compensatory-adaptive responses in the late period among senile individuals with polypathology.

Decoding episodic memory in ageing: a Bayesian analysis of activity patterns predicting memory.

Normal ageing is associated with a decline in episodic memory, and neuroimaging studies in older adults have shown reduced activity in prefrontal cortex and other regions critical for memory function in the young. However, older adults also activate additional regions, suggesting a degree of functional reorganisation that has been attributed variously to detrimental and adaptive changes. Evaluation of these competing hypotheses depends critically upon inferences about the relative location and distribution of activity that are not well supported by current univariate or multivariate analyses. Here, we employed a recently developed model-based multivariate ‘decoding’ approach (Friston et al., 2008) to re-analyse a rich episodic encoding dataset and examine directly how the patterns of activity change in ageing. We assessed which spatial activity patterns, within lateral prefrontal cortex, best predict successful memory formation. Bayesian model comparison showed that the older adults had more distributed and bilateral (fragmented) predictive patterns of activity in anterior inferior frontal gyrus and middle frontal gyrus. With this direct multivariate test for changes in patterns of activity, we replicate and extend earlier findings of reduced prefrontal lateralisation in ageing. These findings extend conclusions based on conventional analyses, and support the notion that ageing alters the spatial deployment of neuronal activity, to render it less spatially coherent and regionally specific. This greater distribution of activity in older adults was also linked to poorer individual memory performance, suggesting that it reflects neural ageing, rather than adaptive compensatory responses.

Characteristics of adaptive compensatory responses in heifers and pregnant cows of various ages

The state of adaptive compensatory responses in heifers and cows in lactations 1 to 7 is studied on the basis of indices of heart activity and electrical activity of the skin. It is established that the maximum tension of these responses in pregnant animals occurs in pregnancy months 2, 8, and 9. In heifers and first-calf cows, adaptive compensatory responses are characterized by tension and imperfection to a greater degree than in second, sixth, and seventh lactation cows.

Free fatty acids as mediators of adaptive compensatory responses to insulin resistance in dexamethasone‐treated rats

Chronic low-dose dexamethasone (DEX) treatment in rats is associated to insulin resistance with compensatory hyperinsulinaemia and reduction in food intake. We tested the hypothesis that the elevation in circulating free fatty acids (FFAs) induced by DEX is the common mediator of both insulin resistance and insulin hyperproduction. For this purpose, an anti-lipolytic agent was administered during DEX treatment to lower lipacidaemia for several hours prior to glucose and insulin tolerance tests. Leptin expression in adipose tissue (by Northern blot) and plasma leptin levels (by radioimmunoassay) were also investigated to verify whether a rise in circulating leptin could be responsible for the anorectic effect of DEX. Our data show that a transient pharmacological reduction of elevated plasma FFA levels abates the post-loading hyperinsulinaemia and counteracts the insulin resistance induced by DEX, supporting the hypothesis that the chronic elevation in FFAs is the common mediator of DEX-induced changes. Despite enhanced leptin expression in white adipose tissue, DEX-treated rats show no significant increase in plasma leptin levels. This suggests that the anorectic effect of DEX should be mediated, at least partially, by other factors, possibly related to the influence of concomitantly elevated plasma FFA and insulin levels on the hypothalamic centers regulating feeding. Our results sustain the idea that a prolonged increase in plasma FFA levels plays an important role in the adaptive regulation of glucose and energy homeostasis, not only by potentiating insulin secretion but also by providing a signal of 'nutrient abundance' capable of restraining food intake.

Adaptive Responses of Secretory Cardiomyocytes of the Right Atrium during Simulation of Microgravity Effects by Long-Term and Repeated Antiorthostatic Tail Suspension of Rats

Reactive changes in right atrial cardiomyocytes during antiorthostatic tail suspension of rats, which is commonly used to simulate effects of microgravity, have been studied by electron microscopy and morphometry. A 14-day tail suspension proved to increase contractile and secretory activities of cardiomyocytes. At the same time, signs of depleted activity are observed in some cells. Prolongation of the experiment to 30 days leads to development of adaptive compensatory responses and increases their secretory capacity. A 30-day rest in the normal orthostatic position does not completely restores the structure and functioning of cardiomyocytes and leads to accumulation of internal secretion in them. A repeated 14-day tail suspension to a certain extent facilitates cardiomyocyte adaptation to altered conditions as compared to a single exposure; apparently, secretion release decreases, while its production is activated.

Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis.

Axonal injury occurs even in the earliest stages of multiple sclerosis. Magnetic resonance spectroscopic imaging (MRSI) measurements of brain N:-acetylaspartate (NAA), a marker of axonal integrity, show that this axonal injury can occur even in the absence of clinically evident functional impairments. To test whether cortical adaptive responses contribute to the maintenance of normal motor function in patients with multiple sclerosis, we performed MRSI and functional MRI (fMRI) examinations of nine multiple sclerosis patients who had unimpaired hand function. We found that activation of the ipsilateral sensorimotor cortex with simple hand movements was increased by a mean of fivefold relative to normal controls (n = 8) and that the extent of this increase was strongly correlated (sigma = -0.93, P = 0.001) with decreases in brain NAA. These results suggest that compensatory cortical adaptive responses may help to account for the limited relationship between conventional MRI measures of lesion burden and clinical measures of disability, and that therapies directed towards promoting cortical reorganization in response to brain injury could enhance recovery from relapses of multiple sclerosis.

Role of neurotrophic factors in adaptational processes of the nervous system.

Neurotrophic factors (NTF) are low-molecular-weight proteins which epigenetically determine neuron survival during embryogenesis and the maintenance of their morphofunctional properties in the adult organism. NTF are located in mesenchymal tissues and reach neuron bodies by means of retrograde axoplasmic transport in nerve fibers; in cell bodies, NTF increase anabolic activity, neurotransmitter synthesis, and structural protein production. Neuron cell bodies have two types of specialized receptors for binding the most common NTF, nerve growth factor (NGF). In the brain, NGF does not affect adrenergic neurons, as it does in the periphery, but acts on cholinergic neurons in the basal part of the forebrain. The forebrain plays the major role in the processes of learning, memory, and plasticity, i.e., in the entire complex of adaptational responses of the nervous system, and these may thus depend on the biological activities of substances, including NTF, in forebrain tissues. An experimental model was developed consisting of organotypic co-cultivation of rat hippocampus fragments with chick embryo dorsal root ganglia. This model was used to demonstrate that epileptiform activity in the hippocampus is associated with increases in NTF release, which can be regarded as an adaptive compensatory response to nerve cell damage occurring during convulsive activity.