SEARCH · PubMed Health

Results for “Integrated functions”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 937 records · Page 52Linked to original sources

PubMed1999

Functional and genetic integrity of the CD8 T-cell repertoire in advanced HIV infection.

BACKGROUND: HIV-specific cytotoxic T lymphocytes (CTL) can restrict HIV replication in acute and chronic infection, but disease progression occurs in parallel with declining CTL activity. An understanding of why CTL fail to control HIV replication might reveal important mechanisms of disease progression and enhance prospects for developing effective CTL-based immunotherapies. OBJECTIVES: To investigate the functional integrity, T-cell repertoire diversity, and HIV reactivity of CD8 T lymphocytes in individuals with advanced HIV infection. METHODS: Individuals were considered to have progressed to advanced HIV infection if their total T-cell count was < 500 x 10(6) cells/(l) on at least two successive clinic visits. CD8 T cells from these individuals were analyzed for CTL function, HIV reactivity and T-cell receptor (TCR) diversity by chromium release assays and reverse transcriptase polymerase chain reaction. RESULTS: CD8 T cells from all individuals with advanced HIV infection proliferated and differentiated into functional CTL in vitro. Despite extremely low T-cell counts and previous AIDS-defining illnesses, six individuals had inducible anti-HIV CTL responses. In two additional cases, HIV-specific CTL activity became detectable following significant treatment-associated remission of T-cell lymphopenia. Assessment of TCRbetaV gene family representation and betaV gene intrafamily diversity indicated CD8 T-cell repertoire diversity is maintained through advanced HIV infection. CONCLUSIONS: These data suggest that HIV-specific CTL activity can be selectively compromised while the functional and genetic integrity of the CD8 population as a whole remains intact. A substantial fraction of individuals retain inducible anti-HIV CTL activity through advanced HIV infection and, in at least some cases, effective treatment can restore HIV-specific CTL responses even at this late stage of disease.

Animals↗

PubMed2000

Surface chimeric receptors as tools in study of lymphocyte activation.

In this chapter we have described a powerful technology that has allowed the functional dissection of individual subunits from oligomeric receptors. We have focused primarily on chimeras derived from antigen receptors or their downstream signaling components to illustrate the wide utility of the approach; however, the technology has been applied to numerous multimeric receptors of the immune system including cytokine receptors, Fc receptors, and natural killer (NK) cell inhibitory receptors. Although the significance of the structural complexity of oligomeric receptors is by no means understood, it is certain that valuable benefits must be derived from the integrated function of their subunits. In the case of antigen receptors, the multiplicity of ITAMs likely allows the cell to distinguish subtle variations in ligand affinities with exquisite sensitivity. Clearly, an isolated subunit that is ligated with antibodies cannot confer such complex function. For instance, it cannot reveal the subtle changes in signal transduction that likely occur on stimulation with altered antigenic peptide ligands or during a complex cell-cell interaction. However, before the intricacies of integrated receptor function can be appreciated, the potential or unique functional properties contributed by each individual receptor component must first be understood. Providing a tool to acquire this kind of understanding has been the greatest asset of this technology. Acknowledging its limitations, the use of surface chimeric receptors remains an invaluable approach toward our understanding the complex function of oligomeric receptors.

Biochemistry↗

PubMed2007

Functional neural circuits for mental timekeeping.

Theories of mental timekeeping suggest frontostriatal networks may mediate performance of tasks requiring precise timing. We assessed whether frontostriatal networks are functionally integrated during the performance of timing tasks. Functional magnetic resonance imaging (fMRI) data from 31 healthy adults were collected during performance of several different types of discrete interval timing tasks. Independent component analysis (ICA) was used to examine functional connectivity within frontostriatal circuits. ICA identifies groups of spatially discrete brain regions sharing similar patterns of hemodynamic signal change over time. The results confirm the existence of a frontostriatal neural timing circuit that includes anterior cingulate gyrus, supplementary motor area, bilateral anterior insula, bilateral putamen/globus pallidus, bilateral thalamus, and right superior temporal gyrus and supramarginal gyrus. Several other distinct neural circuits were identified that may represent the neurobiological substrates of different information processing stages of mental timekeeping. Small areas of right cerebellum were engaged in several of these circuits, suggesting that cerebellar function may be important in, but not the primary substrate of, the mental timing tasks used in this experiment. These findings are discussed within the context of current biological and information processing models of neural timekeeping.

Acoustic Stimulation↗

PubMed2006

An update on biomarkers of bone turnover and their utility in biomedical research and clinical practice.

BACKGROUND: Maintenance of the structural and functional integrity of the skeleton is a critical function of a continuous remodeling driven by highly associated processes of bone resorption and synthetic activities driven by osteoclasts and osteoblasts, respectively. Acceleration of bone turnover, accompanied with a disruption of the coupling between these cellular activities, plays an established role in the pathogenesis of metabolic bone diseases, such as osteoporosis. During the past decades, major efforts have been dedicated to the development and clinical assessment of biochemical markers that can reflect the rate of bone turnover. Numerous studies have provided evidence that serum levels or urinary excretion of these biomarkers correlate with the rate of bone loss and fracture risk, proving them as useful tools for improving identification of high-risk patients. OBJECTIVE: The aim of the present review is to give an update on biomarkers of bone turnover and give an overview of their applications in epidemiological and clinical research. DISCUSSION: Special attention is given to their utility in clinical trials testing the efficacy of drugs for the treatment of osteoporosis and how they supplement bone mass measurements. Recent evidence suggests that biochemical markers may provide information on bone age that may have indirectly relates to bone quality; the latter is receiving increasing attention. A more targeted use of biomarkers could further optimize identification of high-risk patients, the process of drug discovery, and monitoring of the efficacy of osteoporosis treatment in clinical settings.

Biomarkers↗

PubMed1992

Integration of radiology and hospital information systems (RIS, HIS) with PACS: requirements of the radiologist.

PACS development has now reached a stage where it can clearly be stated that the technology for storage, networking and display in a fully digital environment is available. This is reflected by an already large and rapidly increasing number of PACS installations in USA, Western Europe and Japan. Such installations consist of a great variety of information systems, more or less interconnected, like PACS, HIS, RIS and other departmental systems, differing in both hardware and software. Various data - even if they only concern one person - are stored in different systems distributed in the hospital. The integration of all digital systems into a functional unit is determined by the radiologist's need of quick access to all relevant information regardless where it is stored. The interconnection and functional integration of all digital systems in the hospital determine the clinical benefits of PACS. This paper (1) describes the radiologist's requirements concerning this integration, and (2) presents some realistic solutions such as the Siemens ISI (Information System Interface), and a mobile viewing station for the wards (visitBox).

Austria↗

PubMed2006

They are not too excited: the possible role of adult-born neurons in epilepsy.

In a new study in this issue of Neuron, Jakubs and colleagues report that adult-generated hippocampal granule cells develop particular functional properties when their birth is induced by epileptic seizures. The new neurons showed reduced excitatory synaptic input and decreased excitability. Their functional integration was thus adjusted to the prevailing functional state in the network. By this means, adult neurogenesis might contribute to network homeostasis in the epileptic temporal lobe.

Animals↗

PubMed2005

Banishing the homunculus: making working memory work.

The prefrontal cortex has long been thought to subserve both working memory and "executive" function, but the mechanistic basis of their integrated function has remained poorly understood, often amounting to a homunculus. This paper reviews the progress in our laboratory and others pursuing a long-term research agenda to deconstruct this homunculus by elucidating the precise computational and neural mechanisms underlying these phenomena. We outline six key functional demands underlying working memory, and then describe the current state of our computational model of the prefrontal cortex and associated systems in the basal ganglia (BG). The model, called PBWM (prefrontal cortex, basal ganglia working memory model), relies on actively maintained representations in the prefrontal cortex, which are dynamically updated/gated by the basal ganglia. It is capable of developing human-like performance largely on its own by taking advantage of powerful reinforcement learning mechanisms, based on the midbrain dopaminergic system and its activation via the basal ganglia and amygdala. These learning mechanisms enable the model to learn to control both itself and other brain areas in a strategic, task-appropriate manner. The model can learn challenging working memory tasks, and has been corroborated by several important empirical studies.

Amygdala↗

PubMed1977

Significant structure theory applied to liquid helium-3.

The significant structure theory of liquids is successfully applied to the quantum liquid (3)He. The partition function uses the Debye partition function for the solid-like molecules and the Fermi-Dirac partition function for the gas-like degrees of freedom. To evaluate the gas-like partition function, numerical calculations are performed and some integral functions appearing in the equation of state of the ideal Fermi-Dirac gas are tabulated. In the solid-like molecules, the molar volume V(s) depends on the temperature, and a linear dependence is used.The thermodynamic properties, such as molar volume, vapor pressure, entropy, heat capacity, and the critical constants as well as the surface tension of liquid (3)He are calculated. The agreement between theory and experiment is satisfactory.

Journal Article↗

PubMed2026

Modelling time-varying genetic effects on binary disease risk via functional Mendelian randomization.

MOTIVATION: Genome-wide association studies have identified thousands of genetic variants associated with complex traits, establishing Mendelian randomization (MR) as a powerful framework for causal inference using variants as natural experiments. However, existing MR methods treat causal effects as static, relying on cross-sectional exposure measurements and ignoring how genetic predispositions to disease operate dynamically across the life course. Recovering age-specific causal effect functions from longitudinal data requires combining functional data representations of exposure trajectories with instrumental variable estimation strategies suitable for binary disease endpoints, a methodological gap that has remained unaddressed. RESULTS: We develop a functional MR framework for binary outcomes that integrates functional principal component analysis with two-stage residual inclusion (2SRI), ensuring consistent estimation under the nonlinear logistic link function that renders standard instrumental variable estimators inconsistent. Simulations across different causal effect trajectory shapes, varying measurement densities, and varying instrument strengths demonstrate accurate recovery of time-varying genetically predicted effects with minimal bias. Applied to UK Biobank data, the framework identifies an age-specific causal effect of genetically predicted body mass index on type 2 diabetes risk concentrated in early mid-adulthood and progressively attenuating thereafter. Concordance between the proposed 2SRI estimator applied to type 2 diabetes and the established continuous-outcome functional MR estimator applied to the paired glycated haemoglobin marker in the same cohort provides indirect empirical support for the validity of the proposed approach. AVAILABILITY AND IMPLEMENTATION: The method is implemented in the R package mvfmr, with a full tutorial vignette.

Mendelian Randomization Analysis↗

PubMed2005

MLC1: a novel protein in distal astroglial processes.

Megaloencephalic leukoencephalopathy with subcortical cysts (MLC) is a progressive cerebral white matter disease in children caused by mutations in the MLC1 gene. This disease is histopathologically characterized by myelin splitting and intramyelinic vacuole formation. MLC1 encodes a novel protein, MLC1, which is mainly expressed in the brain and leukocytes. The function is unknown, although a transport function has been suggested. In this article, we provide experimental data addressing the membrane topology and cellular localization of MLC1. We show that MLC1 contains an even number of transmembrane domains, supporting the possible transport function of MLC1. We demonstrate that MLC1 is specifically expressed in distal astroglial processes in perivascular, subependymal, and subpial regions. This localization suggests a role for MLC1 in a transport process across the blood-brain and brain-cerebrospinal fluid barriers. Astrocyte functions have long been debated. It is becoming increasingly clear that these cells are of fundamental importance in maintaining the structural and functional integrity of neural tissue. Elucidation of the function of MLC1 will contribute to a better understanding of not only the pathophysiology of the disease, but also the role of astrocytes in normal neural tissue.

Amino Acid Sequence↗

PubMed1989

Marked blood pressure fluctuations during narcoleptic attacks alternating with abnormal wakefulness: effects of treatment with clonidine.

A middle-aged man was admitted to our department because of sleep-wake cycle disorders (alternating hypersomnia and sleeplessness), bipolar behavioural disturbances and marked fluctuations in blood pressure and heart rate. Neither evident precipitating stimuli nor an obvious cause for his illness were found. When tests that normally activate intrinsic autonomic responses were performed, two distinct circulatory patterns were recognized. During hypersomnia (phase A), cardiovascular reflex activity was blunted or abolished and orthostasis could not be maintained. The clinical, biochemical, behavioural pictures and the observed decrease in sympathetic outflow resembled the effects of clonidine administration. On the contrary, during sleeplessness (phase B) the autonomic pathways were functionally integral and orthostatic hypotension was not detected. The clinical, biochemical, behavioural features and cardiovascular overactivity closely mimicked the abrupt withdrawal syndrome encountered with clonidine. Three hypothetical mechanisms are advanced to explain this intriguing case as well as the acute and chronic relief of our patient's clinical problem following institution of clonidine therapy (phase C). The role played by central alpha adrenoceptors in integrating sleep-wake, cardiovascular and behavioural functions is also suggested.

Blood Pressure↗

PubMed2006

Lattice-gas model of DNA charge inversion by a positively charged polyelectrolyte.

The model of DNA charge inversion by Nguyen and Shklovskii [T. T. Nguyen and B. I. Shklovskii, Phys. Rev. Lett. 89, 018101 (2002)] is extended. A single double-helix strand of DNA is represented by a lattice of negative charges at the positions of the protruding oxygens of the phosphates along the DNA backbone, and the adsorbed polyelectrolyte molecules are represented by charged dimers. A lattice-gas model is used in which dimers adsorbing either parallel or perpendicular to the lattice are treated as separate species, and the model allows for vacancies between adsorbed species. The mean field theory used is formulated as a saddle-point approximation of the exact functional integral representation of the grand canonical partition function, opening the way for the inclusion of the effects of charge fluctuation corrections.

Computer Simulation↗

PubMed1990

Clinical physiology: an accepted branch of physiology.

Clinical physiology is a branch of physiology particularly dealing with functional disturbances in disease (pathophysiology) and the integrated function of the human body in disease against the background of normal function in healthy subjects, suitable physiological methods for the study of patients--particularly for diagnostic purposes--as well as for research, and the education of medical students and laboratory assistants in these fields. Departments of clinical physiology in university hospitals form a bridge between basic physiology and many clinical specialties. Independent departments of clinical physiology developed early in Sweden due to the work of Professor Torgny Sjöstrand at the Karolinska Hospital in Stockholm, and have been models of research, teaching and hospital organization which have been followed in several other countries. The International Union of Physiological Sciences (IUPS) has recognized clinical physiology as a separate branch of physiology by approving a Commission of Clinical Physiology which has contributed to the programme of this and, we hope, future congresses, as well as promote the development of clinical physiology internationally.

Humans↗

PubMed2005

Minireview: the neuroendocrine regulation of puberty: is the time ripe for a systems biology approach?

The initiation of mammalian puberty requires an increase in pulsatile release of GnRH from the hypothalamus. This increase is brought about by coordinated changes in transsynaptic and glial-neuronal communication. As the neuronal and glial excitatory inputs to the GnRH neuronal network increase, the transsynaptic inhibitory tone decreases, leading to the pubertal activation of GnRH secretion. The excitatory neuronal systems most prevalently involved in this process use glutamate and the peptide kisspeptin for neurotransmission/neuromodulation, whereas the most important inhibitory inputs are provided by gamma-aminobutyric acid (GABA)ergic and opiatergic neurons. Glial cells, on the other hand, facilitate GnRH secretion via growth factor-dependent cell-cell signaling. Coordination of this regulatory neuronal-glial network may require a hierarchical arrangement. One level of coordination appears to be provided by a host of unrelated genes encoding proteins required for cell-cell communication. A second, but overlapping, level might be provided by a second tier of genes engaged in specific cell functions required for productive cell-cell interaction. A third and higher level of control involves the transcriptional regulation of these subordinate genes by a handful of upper echelon genes that, operating within the different neuronal and glial subsets required for the initiation of the pubertal process, sustain the functional integration of the network. The existence of functionally connected genes controlling the pubertal process is consistent with the concept that puberty is under genetic control and that the genetic underpinnings of both normal and deranged puberty are polygenic rather than specified by a single gene. The availability of improved high-throughput techniques and computational methods for global analysis of mRNAs and proteins will allow us to not only initiate the systematic identification of the different components of this neuroendocrine network but also to define their functional interactions.

Animals↗

PubMed1999

A novel pancreatic model: the snip method of pancreatic isolation for in vitro study.

We aimed to devise a method of preparing the pancreas for in vitro study that would provide tissue that is viable and functional for 24 h, with preservation of integral functional cell-membrane structures. Pancreata of NIH Swiss mice were excised, gently insufflated with media, and carefully snipped into portions of < 0.5 mm. Snips were incubated in cell culture for 0, 8, 24, and 48 h, with viability measured by 3-[4,5-dimethylthiazol-2-yl]-2,3-diphenyltetrazolium bromide (MTT) assay and amylase production quantified after stimulation with cerulein. Recombinant tumor necrosis factor-alpha (TNF-alpha) was added to cell culture, and apoptosis demonstrated by Hoechst staining at 0, 24, and 48 h. At 0, 8, and 24 h, pancreatic snips were determined to be viable by MTT assay. They also were functional with intact cell-membrane apparatuses at these same time points, as evidenced by amylase production in response to a cholecystokinin analogue. We were able to induce apoptosis with TNF-alpha ligand in these pancreatic snips in support of viability and overall cellular function. We conclude that the snip method provides an effective in vitro pancreatic model. Acinar cells are viable and functional for > or = 24 h, with evidence that their cell-surface receptors are preserved in their operational state.

Amylases↗

PubMed1999

[Polychemotherapy-induced changes in the antioxidant state of blood in patients with inoperable cancer of the stomach].

Changes in antioxidant characteristics of blood in patients with inoperable tumors of the stomach were followed before and after combination polychemotherapy which comprised intraperitoneal and endolymphatic injection of drugs. General strengthening therapy was given prior to treatment. It was found that enzymatic activity as a component of antioxidant defenses offered by lymphocytes is low in such patients which adversely affects the structural and functional integrity of lymphocyte membranes. After chemotherapy, said function improved significantly showing a tendency towards normalizing. This effect correlated with clinical improvement and better quality of life in patients with inoperable gastric tumors.

Adult↗

PubMed1991

The effects of Depo-Medrol preservative on the rabbit visual system.

Periocular injections of corticosteroids play an important role in the management of various ophthalmologic diseases. The Depo-Medrol vehicle, injected into the vitreous, was shown to be toxic to the lens and to the retina when applied at double strength. The authors examined the effects of Depo-Medrol and one of the components of its vehicle, myristyl-gamma-picolinium chloride (MGP), on the functional integrity of the rabbit visual system. Visual function was assessed objectively from the electroretinogram (ERG) and the visual evoked potential (VEP). The experimental drugs were injected into the vitreous humor of one eye while saline was injected into the fellow eye for control. Depo-Medrol did not produce any measurable effects on the ERG or the VEP. When MGP solutions were injected in concentrations at least twice as large as that in the Depo-Medrol, significant reductions in the light- and dark-adapted ERG responses were seen. The effects of the drug on the ERG responses was seen as early as 3 days postinjection and developed to its maximal level within 1-2 weeks. No ERG recovery was seen over a period of more than 2 months. The VEP, elicited by applying light stimuli to the experimental eye, was characterized by low amplitude and delayed implicit time compared with the response obtained from the control eye.

Animals↗

PubMed1989

[Role of the endothelium in adult respiratory distress syndrome (ARDS): the present and future].

Various morphological studies indicate that the microcirculation plays a vital role in the development of ARDS. The significance of the structural and functional integrity of the endothelium for normal pulmonary function is supported by cell biological data. Biochemical studies in bronchoalveolar lavage and blood from ARDS-patients, coupled with studies in animals and endothelial cell cultures support the role of a variety of mediators such as complement factors, products of the coagulation cascade and fibrinolytic system, enzymes, endotoxins and metabolites of arachidonic acid. Of particular importance is the interaction between neutrophilic granulocytes and the endothelium, although the individual components of this interaction and the relationship between cellular and humoral factors remain unclear. Furthermore, the literature shows that it is still uncertain, how the data obtained from studies in vivo and in vitro can be applied to ARDS in humans. Future research in this field must come to terms with the cell biology and pathobiology of the pulmonary endothelium, a hitherto neglected aspect. In addition, studies are essential to investigate possible additive or synergistic effects of mediators on inflammatory and endothelial cells. Finally, the role of more recently discovered inflammatory mediators and modulators in the pathogenesis of ARDS requires clarification.

Animals↗