Family-based association study of Epsin 4 and Schizophrenia.

Recently, Pimm et al. identified Epsin 4 on chromosome 5q33 as a susceptibility gene for schizophrenia in the British population, based on linkage and association evidence. In Pimm's case-control study, both the single polymorphisms and the individual haplotypes at the 5' end of the gene showed genetic association with schizophrenia. Here, we report the first study evaluating the relevance of Epsin 4 and schizophrenia outside the British population. Markers showing positive results in the original work as well as two additional polymorphisms were genotyped in 308 Han Chinese family trios. Transmission disequilibrium analysis was used to test for association of single-locus markers and multi-locus haplotypes with schizophrenia. Although no individual marker was significant at the P=0.05 level, the haplotypes detected in our samples, different from those previously reported, showed strong evidence of association (most significant global P=0.0021). Our results indicate the presence of a locus near the 5' end of Epsin 4 conferring susceptibility to the disease and provide further support for Epsin 4 as an important potential contributor to genetic risk in schizophrenia.

Models describing nonlinear interactions in graded neuron synapses.

An intracellular recording made from the retinal luminosity horizontal cell (LHC) demonstrated that repetitive red flashes enhanced the cell's responsiveness to red stimulus and depressed its responsiveness to green stimulus and that repetitive green flashes suppressed the cell's red response but produced little change in its green response. Based on the idea that the spectral plasticity of LHCs may reflect some synaptic efficacy changes between the LHC and various cones, a self-organizing system is proposed to investigate the possible manner of information processing and storage within the synapses. The results of model analysis suggest that the stimulus-pattern-related spectral plasticity is attributable to the excitatory interaction within the same kinds of synapses and the inhibitory interaction between different kinds of synapses. This system is able to encode and store the history of signal transmission in a graded and cumulative fashion.

Stimulus pattern related plasticity of synapses between cones and horizontal cells in carp retina.

Stimulus pattern related synaptic plasticity in the luminosity-type horizontal cell (LHC) of isolated carp retina was investigated. The major findings were: (1) repetitive red flashes progressively strengthened the synaptic connection between red-cone and LHC, whereas weakened that between green-cone and LHC; (2) repetitive green flashes remarkably depressed the LHC's red response, but caused little changes in the cell's green response. A competitive depression between different cone signals is suggested.

The feedforward component in depolarizing red responses of R/G horizontal cells in carp retina.

Light responses of R/G chromaticity-type horizontal cells (R/G HCs) and luminosity-type horizontal cells (LHCs) were intracellularly recorded in isolated superfused carp retina, and the response dynamics analyzed. The results revealed that (1) No significant difference in delay was detected between R/G HC red and green responses; (2) The rising speed was quicker for R/G HC depolarizing red responses compared to that of its hyperpolarizing green responses; and (3) Dynamic characteristics of R/G HC red responses and its changes caused by green background illumination did not follow that of LHC red response. All these results suggest that the depolarizing response of the R/G HCs cannot be entirely mediated by the negative feedback pathway from LHCs onto cones. A direct inhibitory input from red cones to R/G HCs may exist.

Interaction of cone signals on L-type horizontal cell in carp retina: experiments and modeling.

Intracellular recordings were made from the luminosity type cone driven horizontal cells (LHCs) in the isolated carp retina and model analysis was performed to investigate possible mechanisms underlying the interaction of different cone signals converging onto these cells. It was observed that a green background light enhanced the LHC's red response, and such enhancement was closely related to the activation of green cones. Model analysis showed that the activity of both glutamate- and GABA-related pathways were potentiated during green background illumination. GABA application did not abolish the response enhancement. It is speculated that the extent of the LHC's response enhancement may be determined by the balance of the increased activity between the feedforward and feedback pathways.

Fast and slow components of cerebral blood flow response to step decreases in end-tidal PCO2 in humans.

This study examined the dynamics of the middle cerebral artery (MCA) blood flow response to hypocapnia in humans (n = 6) by using transcranial Doppler ultrasound. In a control protocol, end-tidal PCO2 (PETCO2) was held near eucapnia (1.5 Torr above resting) for 40 min. In a hypocapnic protocol, PETCO2 was held near eucapnia for 10 min, then at 15 Torr below eucapnia for 20 min, and then near eucapnia for 10 min. During both protocols, subjects hyperventilated throughout and PETCO2 and end-tidal PO2 were controlled by using the dynamic end-tidal forcing technique. Beat-by-beat values were calculated for the intensity-weighted mean velocity (VIWM), signal power (P), and their instantaneous product (P.VIWM). A simple model consisting of a delay, gain terms, time constants (tauf,on, tauf, off) and baseline levels of flow for the on- and off-transients, and a gain term (gs) and time constant (taus) for a second slower component was fitted to the hypocapnic protocol. The cerebral blood flow response to hypocapnia was characterized by a significant (P < 0.001) slow progressive adaptation in P.VIWM, with gs = 1.26 %/Torr and taus = 427 s, that persisted throughout the hypocapnic period. Finally, the responses at the onset and relief of hypocapnia were asymmetric (P < 0.001), with tauf,on (6.8 s) faster than tauf,off (14.3 s).

Extended models of the ventilatory response to sustained isocapnic hypoxia in humans.

The purpose of this study was to examine extensions of a model of hypoxic ventilatory decline (HVD) in humans. In the original model (model I) devised by R. Painter, S. Khamnei, and P. Robbins (J. Appl. Physiol. 74: 2007-2015, 1993), HVD is modeled entirely by a modulation of peripheral chemoreflex sensitivity. In the first extension (model II), a more complicated dynamic is used for the change in peripheral chemoreflex sensitivity. In the second extension (model III), HVD is modeled as a combination of both the mechanisms of Painter et al. and a component that is independent of peripheral chemoreflex sensitivity. In all cases, a parallel noise structure was incorporated to describe the stochastic properties of the ventilatory behavior to remove the correlation of the residuals. Data came from six subjects from a study by D.A. Bascom, J.J Pandit, I.D. Clement, and P.A. Robbins (Respir. Physiol. 88: 299-312, 1992). For model II, there was a significant improvement in fit for two out of six subjects. The reasons for this were not entirely clear. For model III, the fit was again significantly improved in two subjects, but in this case the subjects were those who had the most marked undershoot and recovery of ventilation at the relief of hypoxia. In these two subjects, the chemoreflex-independent component contributed approximately 50% to total HVD. In the other four subjects, the chemoreflex-independent component contributed approximately 10% to total HVD. It is concluded that in some subjects, but not in others, there may be a component of HVD that is independent of peripheral chemoreflex sensitivity.

Statistical properties of breath-to-breath variations in ventilation at constant PETCO2 and PETO2 in humans.

The purpose of this study was to provide a statistical description of the breath-to-breath variations in ventilation during steady breathing in both rest and during light exercise, with the end-tidal gases controlled by using an end-tidal forcing system. Sixty data sets were studied, only one of which was white (i.e., did not show autocorrelation). Three simple autoregressive moving average (ARMA) models, i.e., AR1, AR2, and AR1MA1, and one simple state-space model were fitted to the data and resulted in white residuals in 15, 31, 46, and 48 out of 60 occasions, respectively. Evolutionary spectral analysis revealed that only 13 data sets had a constant power spectrum, although 50 were uniformly modulated. An autoregressive estimate of variance could be used to "demodulate" the data in most cases, but the results were not significantly affected by fitting the model to the demodulated data. The results indicate that 1) both simple ARMA models and a simple state-space model can describe the autocorrelation present; 2) variations in spectral power were present in the data that cannot be described by these models; and 3) these variations were often due to a uniform modulation and did not significantly affect the coefficients for the models. For these kinds of data, a heteroscedastic form of state-space model provides an attractive theoretical structure for the noise processes.

Breath-to-breath relationships between respiratory cycle variables in humans at fixed end-tidal PCO2 and PO2.

This study examined the statistical properties of breath-to-breath variations in the inspiratory and expiratory volumes and times during rest and light exercise. Sixty data sets were analyzed. Initial data and residuals after fitting time-series models were examined for 1) sustained periodicities with use of spectral analysis, 2) temporal changes in signal power with use of evolutionary spectral analysis, and 3) auto- and cross correlations with use of a portmanteau test. The major findings were as follows: 1) no sustained periodic components were detected; 2) temporal changes in signal power were normally present, but these did not affect significantly the results from time-series modeling; 3) for all variables, a simple autoregressive moving average (ARMA) AR1MA1 model generally described the autocorrelation; 4) considerable cross correlation remained between residuals from the AR1MA1 model; 5) relationships between variables could be described by using a multivariate time-series model; 6) residual fluctuations in end-tidal PCO2 had little influence; and 7) responses were broadly similar between rest and exercise, although some quantitative differences were found. The multivariate model provides a description of the structure of the interrelationships between cycle variables in a quantitative and a qualitative form.

Dynamics of the cerebral blood flow response to step changes in end-tidal PCO2 and PO2 in humans.

This study examined the dynamics of the cerebral blood flow response to hypoxia and hypercapnia in humans. Middle cerebral artery blood flow (MCAF) was assessed continuously using transcranial Doppler ultrasound. MCAF was calculated on a beat-by-beat basis as the product of the intensity-weighted mean velocity and the total power of the reflected signal. End-tidal PCO2 (PETCO2) and PO2 (PETO2) were controlled using a dynamic end-tidal forcing system. Six repeats of each of four protocols were administered to six subjects. The first was a control protocol with PETO2 held at 100 Torr and PETCO2 held 1-2 Torr above eucapnia throughout. The second was a hypoxic step protocol with PETO2 lowered from control values to 50 Torr for 20 min. The third was a hypercapnic step protocol with PETCO2 elevated from control by 7.5 Torr for 20 min. The fourth was a hypoxic-and-hypercapnic step protocol lasting 20 min. The total power of the Doppler signal remained relatively constant, suggesting that the cross-sectional area of the vessel changed little. After the initial transient in MCAF at the onset of the stimulus, no adaptation or progressive increase was observed over the remaining 20 min. A simple model consisting of a single pure delay, gain terms, time constants, and offsets for the on and off transients was fitted to the hypoxic and hypercapnic protocols. For hypercapnia, all the parameters for the onset were significantly different from the relief of the stimulus. The asymmetry was characterized by a slower on transient than off transient and also by a degree of undershoot after the relief of hypercapnia. Finally, the results from this study show that the cerebral blood flow response to hypoxia and hypercapnia in humans is much faster than has previously been thought.

[Change in calcium transport as a factor in causing dysfunction of myocardial mitochondria during hypoxia].

During normoxic incubation of isolated myocardial mitochondria, there were marked increases in mitochondrial calcium when free calcium concentration in the incubation medium was enhanced. The increases were concomitant with rises increase in the rate of state 4 respiration. Moreover, there is a positive correlation between the mitochondrial calcium and the rate of state 4 respiration. During hypoxic incubation, when the calcium concentration of the incubation medium was enhanced, there was no significant increase in mitochondrial calcium and the rises in the rate of state 4 respiration were much lower than the rises during normoxia. Hypoxic incubation in medium of low calcium concentration (pCa 8.0) resulted in slight rises in rate of state 4 respiration. The above results suggest that in myocytes, the mitochondrial dysfunction under hypoxia may be caused indirectly by changes in cytoplasm rather than directly by hypoxia. It seems that the change of cellular free calcium concentration is an important factor in the mitochondrial dysfunction.

Image processing by microcomputer on ultrastructure of griseofulvin-resistant fungi in favus.

The ultrastructure of 5 griseofulvin-resistant fungi of favus was studied by image processing with microcomputer. It was found that the cell walls of the fungi consisted of 8 layers, and the inner layer containing cytoplasm was loose. It was also found that all structures within the cytoplasm possessed a 1-3 layers integral envelope with chromatins in the nucleus. These might be contributing factors in the development of resistance to griseofulvin. This multiple-layered, thick cell wall might act as a barrier responsible for the impermeability of the cell to griseofulvin.