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PubMed2004

A dominantly inherited progressive deafness affecting distal auditory nerve and hair cells.

We have studied 72 members belonging to a large kindred with a hearing disorder inherited in an autosomal dominant pattern. We used audiological, physiological, and psychoacoustic measures to characterize the hearing disorders. The initial phenotypic features of the hearing loss are of an auditory neuropathy (AN) with abnormal auditory nerve and brainstem responses (ABRs) and normal outer hair cell functions [otoacoustic emissions (OAEs) and cochlear microphonics (CMs)]. Psychoacoustic studies revealed profound abnormalities of auditory temporal processes (gap detection, amplitude modulation detection, speech discrimination) and frequency processes (difference limens) beyond that seen in hearing impairment accompanying cochlear sensory disorders. The hearing loss progresses over 10-20 years to also involve outer hair cells, producing a profound sensorineural hearing loss with absent ABRs and OAEs. Affected family members do not have evidence of other cranial or peripheral neuropathies. There was a marked improvement of auditory functions in three affected family members studied after cochlear implantation with return of electrically evoked auditory brainstem responses (EABRs), auditory temporal processes, and speech recognition. These findings are compatible with a distal auditory nerve disorder affecting one or all of the components in the auditory periphery including terminal auditory nerve dendrites, inner hair cells, and the synapses between inner hair cells and auditory nerve. There is relative sparing of auditory ganglion cells and their axons.

Acoustic Impedance Tests↗

PubMed1998

Oxidative stress response and characterization of the oxyR-ahpC and furA-katG loci in Mycobacterium marinum.

Oxidative stress response in pathogenic mycobacteria is believed to be of significance for host-pathogen interactions at various stages of infection. It also plays a role in determining the intrinsic susceptibility to isoniazid in mycobacterial species. In this work, we characterized the oxyR-ahpC and furA-katG loci in the nontuberculous pathogen Mycobacterium marinum. In contrast to Mycobacterium smegmatis and like Mycobacterium tuberculosis and Mycobacterium leprae, M. marinum was shown to possess a closely linked and divergently oriented equivalents of the regulator of peroxide stress response oxyR and its subordinate gene ahpC, encoding a homolog of alkyl hydroperoxide reductase. Purified mycobacterial OxyR was found to bind to the oxyR-ahpC promoter region from M. marinum and additional mycobacterial species. Mobility shift DNA binding analyses using OxyR binding sites from several mycobacteria and a panel of in vitro-generated mutants validated the proposed consensus mycobacterial recognition sequence. M. marinum AhpC levels detected by immunoblotting, were increased upon treatment with H2O2, in keeping with the presence of a functional OxyR and its binding site within the promoter region of ahpC. In contrast, OxyR did not bind to the sequences upstream of the katG structural gene, and katG expression did not follow the pattern seen with ahpC. Instead, a new open reading frame encoding a homolog of the ferric uptake regulator Fur was identified immediately upstream of katG in M. marinum. The furA-katG linkage and arrangement are ubiquitous in mycobacteria, suggesting the presence of additional regulators of oxidative stress response and potentially explaining the observed differences in ahpC and katG expression. Collectively, these findings broaden our understanding of oxidative stress response in mycobacteria. They also suggest that M. marinum will be useful as a model system for studying the role of oxidative stress response in mycobacterial physiology, intracellular survival, and other host-pathogen interactions associated with mycobacterial diseases.

Amino Acid Sequence↗

PubMed1992

Automated recognition of corrupted arterial waveforms using neural network techniques.

A data acquisition system that automatically discards corrupted or undesirable signals would save untold hours of drudgery for researchers. Continuous recording of variables to provide detailed behavior patterns generates huge amounts of raw data. Unfortunately waveforms usually require visual inspection for isolating desired behavior or validating signal integrity. This tedious and time-consuming step can potentially be eliminated using a novel computer science technique. We have trained a simulated neural network to recognize corrupted arterial pressure waveforms. Our system can now evaluate the validity of the arterial waveform without human intervention with an average false positive error rate of 2.2% and an average false negative error rate of 12.6%.

Artifacts↗

PubMed2004

Selective recognition of fibroblast growth factor-2 by the long pentraxin PTX3 inhibits angiogenesis.

The long pentraxin PTX3 is a soluble pattern recognition receptor produced by monocytes and endothelial cells that plays a nonredundant role in inflammation. Several pathologic conditions are characterized by local production of both PTX3 and the angiogenic fibroblast growth factor-2 (FGF2). Here, solid-phase binding assays demonstrated that PTX3 binds with high affinity to FGF2 but not to a panel of cytokines and growth factors, including FGF1, FGF4, and FGF8. Accordingly, PTX3 prevented (125)I-FGF2 binding to endothelial cell receptors, leading to specific inhibition of FGF2-induced proliferation. PTX3 hampered also the motogenic activity exerted by endogenous FGF2 on a wounded endothelial cell monolayer. Moreover, PTX3 cDNA transduction in FGF2-transformed endothelial cells inhibited their autocrine FGF2-dependent proliferation and morphogenesis in vitro and their capacity to generate vascular lesions when injected in nude mice. Finally, PTX3 suppressed neovascularization triggered by FGF2 in the chick embryo chorioallantoic membrane with no effect on physiologic angiogenesis. In contrast, the short pentraxin C-reactive protein was a poor FGF2 ligand/antagonist. These results establish the selective binding of a member of the pentraxin superfamily to a growth factor. PTX3/FGF2 interaction may modulate angiogenesis in various physiopathologic conditions driven by inflammation, innate immunity, and/or neoplastic transformation.

Angiogenesis Inhibitors↗

PubMed1984

Intensified rates of venous sampling unmask the presence of spontaneous, high-frequency pulsations of luteinizing hormone in man.

To test the validity of venous sampling rates that are generally used to characterize pulsatile LH release in man (e.g. sampling every 15-20 min), we characterized apparent LH pulse frequency in blood withdrawn variously at 20- or 4-min intervals in 19 men, at 2-min intervals in 14 men, and at 1-min intervals in 6 men. In an effort to minimize detection bias, significant LH pulses were evaluated objectively using a computerized pulse-detection algorithm, which tended to maximize recognition of true-positive LH pulses, and minimize false-positive and false-negative pulses. Under these conditions, intensified rates of venous sampling at 4-, 2-, and 1-min intervals exposed approximately 3.6, 4.9, and 13.7-fold more LH pulses, respectively, than could be discerned at a 20-min sampling frequency. In addition, more rapid rates of venous sampling disclosed a previously unobserved pattern of LH pulses, in which higher frequency, lower amplitude LH pulsations were interposed among low frequency, high amplitude LH peaks. Quantitatively, LH pulses unmasked by intensified rates of venous sampling exhibited significantly lower pulse amplitudes, expressed either as a fractional (%) or absolute (mIU/ml) increment, than pulses identified at 20-min intervals. In conclusion, we demonstrated that intensified rates of venous sampling unmask a significant number of otherwise unrecognized LH pulses in the circulation of normal men. Moreover, because generally employed sampling rates overlooked these more rapid physiological fluctuations in LH concentrations, patterns of both high and low frequency LH pulsations must now be characterized in various states of health and disease using more rapid sampling paradigms.

Adult↗

PubMed1997

Temporal correlations between functional and molecular changes in NMDA receptors and GABA neurotransmission in the superior colliculus.

Activation of the NMDA subtype of glutamate receptor is required for activity-dependent structural plasticity in many areas of the young brain. Previous work has shown that NMDA receptor currents decline approximately at the time that developmental synaptic plasticity ends, and in situ hybridization studies have suggested that receptor subunit changes may be occurring during the same developmental interval. To establish a system in which the relationship between these properties of developing synapses can be explored, we have combined patch-clamp recordings with mRNA- and protein-level biochemical analyses to study the developmental regulation of NMDA receptors in the superficial layers of the rat superior colliculus. These experiments document an abrupt decrease in the NMDA receptor contribution to synaptic currents that occurs before eye opening and is closely associated with changes in NR1 protein, rapidly rising levels of the NMDA receptor subunit NR2A, and decreasing levels of NR2B. The functional and molecular changes also are correlated with the developmental decline in structural plasticity in these layers. In addition, both physiological and biochemical methods show evidence of GABA-mediated inhibition in the superficial collicular layers beginning after eye opening. This may provide an additional heterosynaptic mechanism for controlling excitation and plasticity in this neuropil by pattern vision. Thus our findings lend support to the idea that high levels of NMDA receptor function are associated with the potential for structural rearrangement in CNS neuropil and that the functional downregulation of this molecule results, at least partially, from changes in its subunit composition.

Age Factors↗

PubMed1999

Regulation of microtubule organization during interphase and M phase.

Microtubule (MT) dynamics and organization change markedly during interphase-M phase transition of the cell cycle. This mini review focuses first on p220, a ubiquitous MT-associated protein of Xenopus. p220 is phosphorylated by p34cdc2 kinase and MAP kinase in M phase, and concomitantly loses its MT-binding and MT-stabilizing activities. A cDNA encoding p220 was cloned, which identified p220 as a Xenopus homolog of MAP4, and p220 was therefore termed XMAP4. To examine the physiological relevance of XMAP4 phosphorylation during mitosis, Xenopus A6 cells were transfected with cDNA encoding wild-type or various XMAP4 mutants fused with a green fluorescent protein (GFP). Mutations of serine and threonine within potential phosphorylation sites for p34cdc2 kinase to nonphosphorylatable alanine interfered with mitosis-associated reduction in MT-affinity of XMAP4 and their overexpression affected chromosome movement during anaphase A. These results indicated that phosphorylation of XMAP4 by p34cdc2 kinase is responsible for the decrease in its MT-binding and MT-stabilizing activities during mitosis which are important for chromosome movement during anaphase A. The second focus is on a novel monoclonal antibody W8C3, which recognizes alpha-tubulin. W8C3 stained spindle MTs but not interphase MTs of Xenopus A6 cells, although tubulin dimers in M phase and interphase were equally recognized by this antibody. The difference in MT staining pattern may be because the W8C3-recognition site on alpha-tubulin is sterically hidden in interphase MTs but not in spindle MTs.

Anaphase↗

PubMed1988

Computer-assisted Doppler monitoring to enhance detection of air emboli.

Currently, two of the most sensitive clinical approaches commonly used to monitor for venous air embolism, i.e., precordial Doppler audio and capnography, require the attention of the anesthesiologist's eye or ear, which is a distraction from other aspects of care. To assess the feasibility of allowing the computer to relieve the necessity for continuous human monitoring, we developed a computer algorithm for monitoring the precordial Doppler audio. This algorithm extracted (1) the amplitude of certain higher-frequency components of the Doppler audio, (2) a measure of the average value of the envelope of Doppler audio, and (3) the ratio between the average value of the Doppler envelope and the amount of envelope signal variation at heart rate frequency and its multiples. These three features were monitored by an adaptive pattern recognition algorithm that compared each new value for each feature with the previously developed mean and standard deviation for that feature. If the changes in the three features exceeded a detection threshold, an alarm (indicating suspected air embolism) was activated. Implemented as a prototype system, the algorithm was given preliminary testing in 2 dogs and activated alarms at levels of air well below those reported to cause clinically significant hemodynamic changes in dogs. While decreasing the distraction for the anesthesiologist, this early prototype alarm system alerts its user to the need for analysis of the Doppler signals when it senses an air embolus.

Algorithms↗

PubMed2002

Pattern-motion responses in human visual cortex.

Physiological models of visual motion processing posit that 'pattern-motion cells' represent the direction of moving objects independent of their particular spatial pattern. We performed fMRI experiments to identify neuronal activity in the human brain selective for pattern motion. A protocol using adaptation to moving 'plaid' stimuli allowed us to separate pattern-motion responses from other types of motion-related activity within the same brain structures, and revealed strong pattern-motion selectivity in human visual area MT+. Reducing the perceptual coherence of the plaids yielded a corresponding decrease in pattern-motion responsivity, providing evidence that percepts of coherent motion are closely linked to the activity of pattern-motion cells in human MT+.

Adult↗

PubMed2006

scyllo-inositol pentakisphosphate as an analogue of myo-inositol 1,3,4,5,6-pentakisphosphate: chemical synthesis, physicochemistry and biological applications.

myo-Inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P(5)), an inositol polyphosphate of emerging significance in cellular signalling, and its C-2 epimer scyllo-inositol pentakisphosphate (scyllo-InsP(5)) were synthesised from the same myo-inositol-based precursor. Potentiometric and NMR titrations show that both pentakisphosphates undergo a conformational ring-flip at higher pH, beginning at pH 8 for scyllo-InsP(5) and pH 9 for Ins(1,3,4,5,6)P(5). Over the physiological pH range, however, the conformation of the inositol rings and the microprotonation patterns of the phosphate groups in Ins(1,3,4,5,6)P(5) and scyllo-InsP(5) are similar. Thus, scyllo-InsP(5) should be a useful tool for identifying biologically relevant actions of Ins(1,3,4,5,6)P(5), mediated by specific binding sites, and distinguishing them from nonspecific electrostatic effects. We also demonstrate that, although scyllo-InsP(5) and Ins(1,3,4,5,6)P(5) are both hydrolysed by multiple inositol polyphosphate phosphatase (MINPP), scyllo-InsP(5) is not dephosphorylated by PTEN or phosphorylated by Ins(1,3,4,5,6)P(5) 2-kinases. This finding both reinforces the value of scyllo-InsP(5) as a biological control and shows that the axial 2-OH group of Ins(1,3,4,5,6)P(5) plays a part in substrate recognition by PTEN and the Ins(1,3,4,5,6)P(5) 2-kinases.

Inositol Phosphates↗

PubMedDate not supplied

Achromatic parvocellular contrast gain in normal and color defective observers: Implications for the evolution of color vision.

The PC pathway conveys both chromatic and achromatic information, with PC neurons being more responsive to chromatic (L-M) than to achromatic (L+M) stimuli. In considering the evolution of color vision, it has been suggested that the dynamic range of chromatic PC-pathway processing is tuned to the chromatic content of the natural environment. Anomalous trichromats, with reduced separation of their L- and M-cone spectral sensitivities, have diminished chromatic input to PC-pathway cells. Dichromats, with absent L or M cones, should have no chromatic input to PC-pathway cells. Therefore, the PC-pathway dynamic range of color defectives should be released from any constraint imposed by the chromatic environment. Here we ask whether this results in compensatory enhancement of achromatic PC-pathway processing in color defectives. This study employed a psychophysical method designed to isolate PC-pathway processing using achromatic stimuli. In a pulsed-pedestal condition, a four-square stimulus array appeared within a uniform surround. During a trial, one of the test squares differed from the other three, and the observer's task was to choose the square that was different. A four-alternative, forced-choice method was used to determine thresholds as a function of the contrast of the four-square array to the surround. Seven color defective and four normal observers participated. Results showed no systematic differences between normals and color defectives. There was no enhancement of achromatic processing as compensation for reduced chromatic processing in the PC-pathway system in color defectives. From physiological recordings, PC-pathway achromatic contrast gains of dichromatic and trichromatic New World primates and trichromatic Old World macaques have also been shown to be similar to each other. Our study and the animal studies imply that PC-pathway contrast gain parameters were regulated by factors other than the environmental chromaticity gamut, and may have arisen in a nontrichromatic common ancestor to both Old and New World primates.

Animals↗

PubMed1996

Elucidation of the molecular actions of NCAM and structurally related cell adhesion molecules.

The Neural Cell Adhesion Molecule (NCAM) is a founder member of a large family of cell surface glycoproteins that share structural motifs related to immunoglobulin and fibronectin type III (FN III) domains [Walsh and Doherty (1991) (Fig. 1). These glycoproteins have been grouped based on the respective number of each type of domain. In vertebrates members of this family of glycoproteins include L1/NILE, NgCAM, axonin-1/TAG-1, and Thy-1 as well as NCAM. In addition structural homologs of NCAM and L1 have been identified in Drosophila and Grasshoppers [Walsh and Doherty (1991)]. These insect homologs are called fasciclins and a series of mutants corresponding to these aspects of synaptic plasticity [Mayford et al. (1992) Science 256:638-644]. In vertebrates all of these glycoproteins are expressed in the developing nervous system where they have been identified as candidate molecules for mediating axon outgrowth, fasciculation, regeneration, and target recognition. In addition, NCAM is expressed in a number of different tissues and cell types. For example, NCAM is expressed in a dynamic pattern in developing and regenerating adult muscle. In this review we aim to describe important aspects of the role of these CAMS in development of the nervous system, including the neuromuscular junction. Furthermore, we will explore the prospective use of molecular biology, cell biology, and molecular genetic techniques, such as transgenic mice, to understand the role and molecular action of this family of cell adhesion molecules in vivo.

Amino Acid Sequence↗

PubMed1991

Electrotactile and vibrotactile displays for sensory substitution systems.

Sensory substitution systems provide their users with environmental information through a human sensory channel (eye, ear, or skin) different from that normally used, or with the information processed in some useful way. We review the methods used to present visual, auditory, and modified tactile information to the skin. First, we discuss present and potential future applications of sensory substitution, including tactile vision substitution (TVS), tactile auditory substitution, and remote tactile sensing or feedback (teletouch). Next, we review the relevant sensory physiology of the skin, including both the mechanisms of normal touch and the mechanisms and sensations associated with electrical stimulation of the skin using surface electrodes (electrotactile (also called electrocutaneous) stimulation). We briefly summarize the information-processing ability of the tactile sense and its relevance to sensory substitution. Finally, we discuss the limitations of current tactile display technologies and suggest areas requiring further research for sensory substitution systems to become more practical.

Artificial Intelligence↗

PubMed2004

A general automatic method for the analysis of NREM sleep microstructure.

OBJECTIVE: To define a unified method for the automatic recognition and quantitative description of EEG phasic events of sleep microstructure occurring during NREM sleep, particularly arousals, phase A subtypes of cyclic alternating pattern and spindles. METHODS: The NREM sleep EEG of 10 normal young subjects was examined in order to recognize formal phasic events of sleep microstructure. The following 'formal' events (i.e. events defined exclusively on the basis of automatic analysis criteria) were classified: arousals, A1-phases (A-phases not including arousals) and A2- and A3-phases (A-phases including arousals). Spindle bursts, corresponding to visually recognized spindles, were also formally defined. The identification of these events was carried out following a three-step procedure: (1) computation of band-related descriptors derived from the EEG signal, (2) introduction of suitable thresholds and (3) application of simple logical principles, i.e. an exclusion principle and an overlapping principle. RESULTS: Formal A-phases, arousals and spindle bursts showed spectral characteristics which were consistent with visual inspection. The value of the parameter Correctness for the recognition of the A-phases was 83.5%. In particular, the different physiological distribution of the A-phases in Stage 2 preceding slow wave sleep with respect to Stage 2 preceding REM sleep was confirmed. CONCLUSIONS: The proposed method provides a unified quantitative approach to the study of sleep microstructure. Visually defined events can be reliably identified by means of automatic recognition.

Adult↗

PubMed2006

Compressed EEG pattern analysis for critically ill neurological-neurosurgical patients.

Recent advances in continuous electroencephalogram (EEG) monitoring with digital EEG acquisition, storage, and quantitative analysis allow uninterrupted assessment of cerebral cortical activity in critically ill neurological-neurosurgical patients. Early recognition of worsening brain function can prove of vital importance as one can initiate measures aimed to prevent further brain damage. Although continuous EEG monitoring provides adequate spatial and temporal resolution and is able to continuously assess brain function in these critically ill patients, it requires a trained electroencephalographer to interpret the massive amounts of data generated. This limitation impedes the widespread use of EEG in assessing real-time brain function in critically ill patients. Here, we demonstrate the utility of a novel method of automated EEG analysis that segments and extracts EEG features, classifies and groups them according to various patterns, and then presents them in a compressed fashion. This permits real-time viewing of several hours of EEG on a single page. Examples are presented from three patients, two with recurrent seizures and one with diagnosis of subarachnoid hemorrhage. These patients illustrate the ability of this novel method to detect important real-time physiological changes in brain function that could enable early interventions aimed to prevent irreversible brain damage.

Aged↗

PubMed1988

Monitoring for central apnoea in infancy--limitations of single channel recordings.

Apparent central apnoea (absent breathing movements) detected by monitoring movement of the thoracic wall was compared with simultaneous detection by abdominal wall movement. Eighteen infants provided one or more 24 hour recording of heart rate (electrocardiography), thoracic respiration (transthoracic impedance), and abdominal wall movement (pressure sensitive capsule distortion). Detection of true apnoea, recognition of artefact, and measurement of the duration of true apnoea were all improved when two channels of respiratory monitoring were used in combination. We recommend that any study purporting to observe breathing patterns by indirect recording of respiratory movement will be more reliable if more than one channel of respiratory movements is recorded simultaneously. Further, in infants no estimation of duration of central apnoea can be made on the basis of either a transthoracic impedance record alone or an abdominal wall movement sensor alone. Comparison of findings among studies using different single channel recordings are unlikely to be meaningful.

Electrocardiography↗

PubMedDate not supplied

Field test and experimental use of CYBEST model 2 for practical gynecologic mass screening.

CYBEST is an automated cytologic screening system for uterine cancer utilizing a pattern-recognition image-analysis system. The prototype was developed in 1972 following fundamental studies of feature extraction, feature evaluation using ambiguity differential functions and segmentation of cell and nuclear images. Model 2 was developed in 1974 with an improved mechanism and function. The parameters employed are nuclear size, nuclear optical density, N/C ratio and nuclear shape. The data of field tests using 220 samples containing three cases of dysplasia, 110 cases of carcinoma and 107 nonmalignant cases were as follows: two false-negative cases (1.8%), 13 false positives (12.1%) and one reject (0.9%). This system was experimentally tested for practical mass population screening with 1,829 cases including 17 atypical cases (four epidermoid carcinomas). The data were as follows: no false-negative cases and 581 false-positive cases (32.1%). Of the latter, 311 cases (17.2%) were pathologic samples, such as severe cervicitis, senile colpitis, Trichomonas infestation, etc., and the remaining 270 cases (14.9%) were within physiologic limits, corresponding to true false-positive samples.

Autoanalysis↗

PubMed1981

Within-day physiologic variation of leukocyte types in healthy subjects as assayed by two automated leukocyte differential analyzers.

The physiologic within-day (700-2200 h) variation of leukocyte-type concentrations in blood as determined for 21 healthy young adults is reported. All blood specimens were obtained in duplicate such that the within-batch analytic variation, as well as the pertinent biologic sources of variation, was able to be determined. All specimens were analyzed on each of two automated leukocyte differential systems: Hemalog-D Differential System and the Hematrak-240 Analyzer. On the basis of a comparison of the performances of the two analyzers, it was decided to report the neutrophil and the lymphocyte values as measured on both systems, the monocyte values as measured on teh Hematrak only, and the eosinophil and basophil values as measured on the Hemalog-D only. The intrasubject within-day physiologic variations for the cell on the Hemalog-D and Hematrak, respectively, in terms of coefficient of variation wee as follows: neutrophils 19.4% and 19.6%; lymphocytes, 13.8% and 17.5%. For monocytes, as measured on the Hematrak, it was 13.4%. For eosinophils and basophils, as measured on the Hemalog-D, it was 27.2% and 8.3%, respectively. There was a consistent group-specific diurnal variance that amounted to more than 40% of the total within-day variance, both for lymphocytes and for eosinophils. The within-day physiologic variation of the cell type concentrations for eight of the volunteers was compared with that of the plasma cortisol concentrations, as determined on specimens derived from the same veni-puncture sessions. The decrease in plasma cortisol values was in most instances associated with decreases in eosinophils and increases in neutrophils. For total leukocytes and neutrophils, the mean concentration for smokers was significantly higher than that for nonsmokers.

Adult↗