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Evolution in functional complexity of heart rate dynamics: a measure of cardiac allograft adaptability.

The capacity of self-organized systems to adapt is embodied in the functional organization of intrinsic control mechanisms. Evolution in functional complexity of heart rate variability (HRV) was used as measure of the capacity of the transplanted heart to express newly emergent regulatory order. In a cross-sectional study of 100 patients after (0-10 yr) heart transplantation (HTX), heart rate dynamics were assessed using pointwise correlation dimension (PD2) analysis. A new observation is that, commencing with the acute event of allograft transplantation, the dynamics of rhythm formation proceed through complex phase transitions. At implantation, the donor heart manifested metronome-like chronotropic behavior (PD2 approximately 1.0). At 11-100 days, dimensional complexity of HRV reached a peak (PD2 approximately 2.0) associated with resurgence in the high-frequency component (0.15-0.5 Hz) of the power spectral density. Subsequent dimensional loss to PD2 approximately 1.0 at 20-30 mo after HTX was followed by a progressive near-linear gain in system complexity, reaching PD2 approximately 3.0 7-10 yr after HTX. The "dynamic reorganization" in the allograft rhythm-generating system, seen in the first 100 days, is a manifestation of the adaptive capacity of intrinsic control mechanisms. The loss of HRV 2 yr after HTX implies a withdrawal of intrinsic autonomic control and/or development of an entrained dynamic pattern characteristic of extrinsic sympathetic input. The subsequent long-term progressive rise in dimensional complexity of HRV can be attributed to the restoration of a functional order patterning parasympathetic control. The recognition that the decentralized heart can restitute the multidimensional state space of HR generator dynamics independent of external autonomic signaling may provide a new perspective on principles that constitute homeodynamic regulation.

Adaptation, Physiological↗

[Psychological versus physical stress conditions as determinants of psychophysical regulatory processes].

In a psychophysiological experimental study, two methods of standardization to induce failure-type stress situations were tested. "Psychological standardization" uses a computerized adaptive procedure to obtain a similar and stable amount of failure (about 60% incorrect solutions) both for each individual and over time; the number of tasks, however could change. The conventional "physical standardization" uses a constant number of identical tasks, both for each person and over time. The results show a better standardization of failure-type situations by using the psychological standardization method. It was further shown that heart rate and skin conductance reactions depend mainly on coping motivation and coping success rather than on the stressor intensity (objective number of tasks). Results also revealed that dispositional action control (Kuhl, 1983) was a better predictor of physiological regulation under psychological standardization than under physical standardization of failure-type stress situations.

Adult↗

Cortical anatomy, size invariance, and spatial frequency analysis.

In a recent application of an algorithm developed in computer and optical pattern recognition, Cavanagh has suggested that a composite of spatial frequency mapping and complex logarithmic mapping would provide translationally, rotationally, and size-invariant mechanism for human vision. In this work, Cavanagh has not made explicit the fact that this transformation is composite, that is, that the first step (global Fourier analysis) perceptually, anatomically, and physiologically inconsistent with primate vision, but that the second step (complex logarithmic mapping) is actually embodied in the anatomy of the primate retinostriate projection. Moreover, it is the complex logarithmic remapping step which is entirely responsible for the computational simplification of the symmetries of size and rotation invariance. These facts, which have been extensively discussed in a recent series of papers, are briefly reviewed and illustrated. Furthermore, it is shown that the architecture of the retinostriate map may provide an example of computational anatomy in vision, such that the spatial representation of a stimulus in the brain may be of direct functional significance to perception, and to the nature of certain visual illusions.

Afterimage↗

Tremor.

Tremor is a rhythmic, involuntary muscular contraction with consistency of rate, amplitude and pattern. It is the most common of all involuntary movements. Several systems for classifying tremor exist with the most frequent system classed according to behavioral context, ie, resting, postural and action. Clinical recognition of tremor type is extremely important as type determines prognosis, treatment and need for genetic counseling. The most common forms are parkinsonian, physiological, cerebellar intention and essential tremor. Essential or hereditary tremor is the most common of all neurologic conditions with 3-4 million Americans affected. Nursing implications of caring for essential tremor patients are presented.

Adrenergic beta-Antagonists↗

Evaluation of abdominal pain.

This article discusses the approach to evaluation of abdominal pain in the Emergency Department setting. The physiologic differences among visceral, somatic, and referred pain are reviewed, as is the clinical significance of anorexia, nausea, and vomiting. The correlation of historical facts, interrelationships of symptoms, and pain patterns with specific intra-abdominal processes is reviewed. Recommendations for high-yield expedient laboratory studies to facilitate diagnosis are provided. Proficiency in the recognition and interpretation of these clinical symptoms, physical signs, laboratory data, ECGs, and radiographic findings is important when evaluating acutely ill, uncooperative, or unresponsive patients.

Abdomen↗

Coupling of signal transduction to alternative pre-mRNA splicing by a composite splice regulator.

Alternative splicing of pre-mRNA is a fundamental mechanism of differential gene expression in that it can give rise to functionally distinct proteins from a single gene, according to the developmental or physiological state of cells in multicellular organisms. In the pre-mRNA of the cell surface molecule CD44, the inclusion of up to 10 variant exons (v1-v10) is regulated during development, upon activation of lymphocytes and dendritic cells, and during tumour progression. Using minigene constructs containing CD44 exon v5, we have discovered exonic RNA elements that couple signal transduction to alternative splicing. They form a composite splice regulator encompassing an exon recognition element and splice silencer elements. Both type of elements are necessary to govern cell type-specific inclusion of the exon as well as inducible inclusion in T cells after stimulation by concanavalin A, by Ras signalling or after activation of protein kinase C by phorbol ester. Inducible splicing does not depend on de novo protein synthesis. The coupling of signal transduction to alternative splicing by such elements probably represents the mechanism whereby splice patterns of genes are established during development and can be changed under physiological and pathological conditions.

Alternative Splicing↗

View-dependent object recognition by monkeys.

BACKGROUND: How do we recognize visually perceived three-dimensional objects, particularly when they are seen from novel view-points? Recent psychophysical studies have suggested that the human visual system may store a relatively small number of two-dimensional views of a three-dimensional object, recognizing novel views of the object by interpolation between the stored sample views. In order to investigate the neural mechanisms underlying this process, physiological experiments are required and, as a prelude to such experiments, we have been interested to know whether the observations made with human observers extend to monkeys. RESULTS: We trained monkeys to recognize computer-generated images of objects presented from an arbitrarily chosen training view and containing sufficient three-dimensional information to specify the object's structure. We subsequently tested the trained monkeys' ability to generalize recognition of the object to views generated by rotation of the target object around any arbitrary axis. The monkeys recognized as the target only those two-dimensional views that were close to the familiar, training view. Recognition became increasingly difficult for the monkeys as the stimulus was rotated away from the experienced viewpoint, and failed for views farther than about 40 degrees from the training view. This suggests that, in the early stages of learning to recognize a previously unfamiliar object, the monkeys build two-dimensional, viewer-centered object representations, rather than a three-dimensional model of the object. When the animals were trained with as few as three views of the object, 120 degrees apart, they could often recognize all the views of the object resulting from rotations around the same axis. CONCLUSION: Our experiments show that recognition of three-dimensional novel objects is a function of the object's retinal projection. This suggests that non-human primates, like humans, may accomplish view-invariant recognition of familiar objects by a viewer-centered system that interpolates between a small number of stored views. The measures of recognition performance can be simulated by a regularization network that stores a few familiar views, and is endowed with the ability to interpolate between these views. Our results provide the basis for physiological studies of object-recognition by monkeys and suggest that the insights gained from such studies should apply also to humans.

Animals↗

Electrical brain responses evoked by human faces in acute psychosis.

Patients with schizophrenia are known to have behavioral deficits in recognizing faces and facial expressions. However, the ability to process simple visual stimuli appears to be intact in first-episode psychosis. The aim of this study was to examine complex visual processing, especially the event-related potentials (ERPs) elicited by human faces, in early psychosis. Never-medicated patients in acute psychosis (n=18) were compared with healthy controls (n=19). Photographs of human faces were presented in a classic oddball paradigm requiring a motor response to a smiling face. Cerebral sources of ERPs were analyzed of the averaged responses, using minimum norm estimates, and dipole models. Face-sensitive response at 145 ms after the face stimuli was of significantly higher amplitude in our never-medicated patients, and the activity distribution between the groups was clearly different. At the early phase of a psychotic illness, these alterations in face-related neuronal network processes represent perceptual disturbance in psychosis, possibly including state and trait, as well as potential physiological compensatory features.

Acute Disease↗

The prevalence of recordings of the signs of critical conditions and emergency responses in hospital wards--the SOCCER study.

OBJECTIVE: To estimate the prevalence of recordings in case notes of disturbed physiological variables in adult admissions in general hospital wards. DESIGN AND SETTING: Retrospective cross-sectional survey of 3160 admissions in general wards in five hospitals in a 14-day period. MAIN OUTCOME MEASURES: Recordings of 26 potential early signs (ES) and 21 potential late signs (LS) of critical conditions. Eight late signs were classified as Liverpool Hospital Equivalent Calling Signs (LES). RESULTS: 54.7% admissions had at least one recording of early signs, 16.0% late signs and 6.4% LES. When ranked in order of recordings per 100 admissions, the top five ES were SpO(2) 90-95% (193.7), systolic blood pressure (SBP) 80-100 mmHg (85.2), pulse rate 40-49 or 121-140 b/min (32.0), SBP 181-240 mmHg (23.0) and "Other" (22.1) (mainly breathlessness or temperature > 38 degrees C). The top five LS were SpO2 < 90% (31.5), pulse rate < 40 or > 140 /min (6.6), SBP < 80 mmHg (4.2), GCS < or = 8 (3.8) and unresponsiveness to verbal commands (2.4). There were average signs per admission of ES 4.4, LS 0.6 and LES 0.19. Although there were differences in rates of recordings of signs across the five hospitals, the patterns of top 10 most frequent were similar. CONCLUSIONS: There was a high incidence of recordings of disturbed physiological variables in general ward patients. Changes to hospital emergency response systems to include rapidly responding teams to patients with the signs of developing critical conditions should be supported by training programmes for ward staff on the early recognition and management of patients with the warning signs.

Adult↗

Acute toxicity screening of novel AChE inhibitors using neuronal networks on microelectrode arrays.

Spontaneously active neuronal networks grown from embryonic murine frontal cortex on substrate integrated electrode arrays with 64 recording sites were used to assess acute neurobiological and toxic effects of a series of seven symmetrical, bifunctional alkylene-linked bis-thiocarbonate compounds designed to possess anticholinesterase activity. Acute functional neurotoxicity in the absence of cytotoxicity was defined as total collapse of spontaneous activity. All of the compounds were characterized as mixed inhibitors of AChE, with K(i)'s in the 10(-7)-10(-6) M range. The neuronal network assays revealed high repeatability for each compound, but surprisingly diverse effects among these closely related compounds. Six of the seven compounds produced changes in network activity at concentrations of 10-350 microM. Three of the compounds were excitatory, two were biphasic (excitatory at lower concentrations, inhibitory at higher), and one was solely inhibitory. Two of the inhibitory compounds produced irreversible inhibition of activity. Responses of cortical cultures to eserine were compared to the effects produced by the test compounds, with only one of seven providing a close match to the eserine profile. Matching of response patterns allows the classification of new drugs according to their response similarity to well-characterized agents. Spontaneously active neuronal networks reflect the interactions of multiple neurotransmitter and receptor systems, and can reveal unexpected side effects due to secondary binding. Utilizing such networks holds the promise of greater research efficiency through a more rapid recognition of physiological tissue responses.

Animals↗

Mapping of factor XIII solvent accessibility as a function of activation state using chemical modification methods.

The transglutaminase Factor XIII (FXIII) catalyzes the formation of covalent cross-links between adjacent noncovalently associated fibrin chains in blood coagulation. The resulting covalently cross-linked hard clot is much more mechanically stable and resistant to proteolytic degradation. FXIII is activated by the serine protease thrombin in the presence of calcium ions. Protein modification experiments involving the labeling of cysteine and lysine side chains of the enzyme were performed before and after activation of the enzyme in an effort to gain further insight into structural changes occurring during the activation of FXIII. The experiments revealed differences in the labeling patterns of nonactivated and activated FXIII. These differences result from the exposure or sequestration of specific cysteine or lysine residues when the enzyme is activated, either physiologically with thrombin or nonproteolytically by exposure to calcium. Of note is the acetylation of Lys 73 and Lys 221 upon activation. Both of these residues lie within possible substrate recognition regions of FXIII. The active site Cys 314 is consistently alkylated in the activated enzyme, as is Cys 409, located near the dimer interface. Within the beta-barrel 2 domain of FXIII, Cys 695 becomes alkylated in activated FXIII. Within the same domain, an acetylated Lys (677 or 678), which is observed in the zymogen, cannot be found in the activated enzyme. The results provide a more extensive view of FXIII activation than has been previously available.

Acetic Anhydrides↗

Visual discrimination by cats given lesions of visual cortex in one or two stages in infancy or in one stage in adulthood.

Sparing of visual function was studied in cats with bilateral cortical damage to Areas 17 and 18 and most of Area 19. Cats with lesions made in 2 stages, on Postnatal (P) Days 3 and 6, in 1 stage on P6, or in 1 stage in adulthood were compared with sham-operated controls on 10 visual discrimination tasks. On some tasks, both groups of cats that underwent surgery as infants showed considerable sparing of function compared with cats that had surgery as adults; the latter group showed a marked impairment. However, on several of the discriminations, 2-stage lesions permitted almost total sparing of pattern vision, whereas 1-stage lesions made neonatally were almost as debilitating as those incurred in adulthood. The findings suggest that differential behavioral consequences can follow physiological or anatomical changes, or both, that occur within a 4-day neonatal interoperative period.

Aging↗

Signal processing: from mathematical theory to clinical acceptance or vice-versa?

Signal processing in physiology and medicine hasn't developed as well as one could have hoped in spite of important efforts in research. The bases for present techniques in signal processing are evaluated for the two types of signals encountered in physiology, namely, continuous signals and point processes. It seems that morphological analysis ought to be adapted to the study of continuous physiological signals and that point processes constitute an important form of signals. The principal areas where industrial development can be expected are explored.

Action Potentials↗

Targeted disruption of the M(r) 46,000 mannose 6-phosphate receptor gene in mice results in misrouting of lysosomal proteins.

Lysosomal enzymes containing mannose 6-phosphate recognition markers are sorted to lysosomes by mannose 6-phosphate receptors (MPRs). The physiological importance of this targeting mechanism is illustrated by I-cell disease, a fatal lysosomal storage disorder caused by the absence of mannose 6-phosphate residues in lysosomal enzymes. Most mammalian cells express two MPRs. Although the binding specificities, subcellular distribution and expression pattern of the two receptors can be differentiated, their coexpression is not understood. The larger of the two receptors with an M(r) of approximately 300,000 (MPR300), which also binds IGFII, appears to have a dominant role in lysosomal enzyme targeting, while the function of the smaller receptor with an M(r) of 46,000 (MPR46) is less clear. To investigate the in vivo function of the MPR46, we generated MPR46-deficient mice using gene targeting in embryonic stem cells. Reduced intracellular retention of newly synthesized lysosomal proteins in cells from MPR46 -/- mice demonstrated an essential sorting function of MPR46. The phenotype of MPR46 -/- mice was normal, indicating mechanisms that compensate the MPR46 deficiency in vivo.

Animals↗

Specificity of T cell clones for antigen and autologous major histocompatibility complex products determines specificity for foreign major histocompatibility complex products.

We have analyzed a panel of T cell clones that corecognize defined epitopes of the insulin molecule in association with Ia for their patterns of recognition of alloantigens. A striking correlation is observed between recognition of the I-Ab gene product and cow insulin alpha loop and recognition of I-Eu of the PL/J haplotype. These results are consistent with the notion that reactions to foreign major histocompatibility complex (MHC) products reflect molecular mimicry by foreign class II antigens of 'physiologic' complexes formed by autologous class II MHC molecules and antigen.

Animals↗

Enzymatic degradation of glycosaminoglycans.

Glycosaminoglycans (GAGs) play an intricate role in the extracellular matrix (ECM), not only as soluble components and polyelectrolytes, but also by specific interactions with growth factors and other transient components of the ECM. Modifications of GAG chains, such as isomerization, sulfation, and acetylation, generate the chemical specificity of GAGs. GAGs can be depolymerized enzymatically either by eliminative cleavage with lyases (EC 4.2.2.-) or by hydrolytic cleavage with hydrolases (EC 3.2.1.-). Often, these enzymes are specific for residues in the polysaccharide chain with certain modifications. As such, the enzymes can serve as tools for studying the physiological effect of residue modifications and as models at the molecular level of protein-GAG recognition. This review examines the structure of the substrates, the properties of enzymatic degradation, and the enzyme substrate-interactions at a molecular level. The primary structure of several GAGs is organized macroscopically by segregation into alternating blocks of specific sulfation patterns and microscopically by formation of oligosaccharide sequences with specific binding functions. Among GAGs, considerable dermatan sulfate, heparin and heparan sulfate show conformational flexibility in solution. They elicit sequence-specific interactions with enzymes that degrade them, as well as with other proteins, however, the effect of conformational flexibility on protein-GAG interactions is not clear. Recent findings have established empirical rules of substrate specificity and elucidated molecular mechanisms of enzyme-substrate interactions for enzymes that degrade GAGs. Here we propose that local formation of polysaccharide secondary structure is determined by the immediate sequence environment within the GAG polymer, and that this secondary structure, in turn, governs the binding and catalytic interactions between proteins and GAGs.

Animals↗

The physiologic basis for hypernasality during connected speech in cleft palate patients: a nasendoscopic study.

A characteristic pattern of velopharyngeal movement is associated with hypernasality. Nasendoscopic examination can identify the patterns of movement of the velopharynx during connected speech. The nasendoscopic observations provide a safe, objective way of assessing the anatomic dysfunction that causes hypernasality. These observations provide a clearer rationale for the design and placement of pharyngoplasty surgery. Recognition of distinct dysfunctional patterns opens the door to nonsurgical correction of hypernaslity in selected patients using the nasendoscope and video display.

Child↗

Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects.

Zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide hemitartrate] is reported to be a rapid onset, short duration hypnotic that interacts at the benzodiazepine recognition site. The present report establishes the neuropsychopharmacological profile of zolpidem and compares it with those of benzodiazepine hypnotics. Although in mice the effects of zolpidem are qualitatively similar to those of midazolam, triazolam and flunitrazepam, sedation with zolpidem occurs at doses 10 and 20 times lower than those inducing anticonvulsant and myorelaxant effects, respectively. In contrast, the benzodiazepines studied induce sedation at doses causing myorelaxation and which are 2 to 6 times superior to those antagonizing pentetrazole-induced convulsions. In the rat, zolpidem induces sleep (as indicated behaviorally and electrocorticographically) and displays anticonflict activity in a punished drinking paradigm, as do the benzodiazepines. However, whereas benzodiazepine hypnotics induce EEG sleep patterns in curarized rats at doses similar or inferior to those active in the conflict test (in freely moving animals), the hypnotic effect of zolpidem is seen at doses 10 times lower than those producing an anticonflict effect. Moreover, a qualitative difference between the effects of zolpidem and benzodiazepines is observed in electrocorticographic recordings obtained in curarized rats: electrocorticographic hypersynchronization induced by zolpidem is dominated by the energy increase within the 2 to 4 Hz band whereas the benzodiazepines increase predominantly energy levels within the 12 to 14 Hz band. Studies of the sleep-wakefulness cycle in the rat and the cat revealed that hypnotic doses of zolpidem do not alter the pattern of physiological sleep, although elevated doses of the drug decrease paradoxical sleep and increase slow wave sleep. In rats trained to discriminate chlordiazepoxide, zolpidem fails to generalize with the chlordiazepoxide-associated lever indicating that the compound and benzodiazepines do not share the same discriminative stimulus properties. Nevertheless, the anticonvulsant, hypnotic, myorelaxant and anticonflict effects of zolpidem are antagonized by benzodiazepine receptor antagonist Ro 15-1788 and CGS 8216 indicating an involvement of the benzodiazepine recognition site in the action of this drug. The highly selective sedative effect of zolpidem (as compared to myorelaxant and anticonvulsant effects) suggests that it may possess a specificity for certain subtypes of benzodiazepine receptors.

Animals↗