Antitumor activity of N-(phosphonacetyl)-L-aspartic acid, a transition-state inhibitor of aspartate transcarbamylase.

N-(Phosphonacetyl)-L-aspartate (PALA) is an analog of the transition state for the aspartate transcarbamylase reaction and has been reported previously to be a potent and specific inhibitor of de novo pyrimidine nucleotide biosynthesis. It is now shown that PALA has considerable antitumor activity against certain transplantable tumors in mice. PALA, unlike other antimetabolites, was less effective against ascitic leukemias than against two solid tumors, B16 melanoma and Lewis lung carcinoma. Another solid tumor, Ridgway osteogenic sarcoma, which is sensitivie to many established chemotherapeutic agents, did not respond to PALA. Daily or intermittent treatment with PALA did not significantly increase the life-span of mice bearing i.p. leukemia L1210. The survival time of mice bearing i.p. P388 leukemia was prolonged by PALA treatment by up to 64%. In a number of experiments mice bearing i.p. B16 melanoma survived 77 to 86% longer than did controls when treated with PALA (490 mg/kg) on Days 1, 5, and 9. Lewis lung carcinoma, a tumor refractory to most established antineoplastic agents, was highly sensitive to PALA. Treatment on Days 1, 5, and 9 following s.c. implantation of Lewis lung carcinoma was curative to 50% of the mice. If treatment was delayed until s.c. Lewis lung tumors had reached about 500 mg, PALA neither cured the mice nor produced significant tumor regression. However, extensive delay of tumor growth and prolongation of survival were still observed.

A new segmentation method of electroencephalograms by use of Akaike's information criterion.

Non-stationary EEGs, whose statistical properties change with time, were segmented into stationary segments to closely track the behavior of EEG characteristics. We have developed a new segmentation method of optimizing segmentation parameters by using AIC (Akaike's information criterion) as an objective criterion. We applied the segmentation method to EEGs. The instantaneous power spectra of EEGs estimated with wavelet transform were compared with the segmented EEGs. EEGs were recorded from F3, F4, C3, C4, P3, P4, 01 and 02 in 13 normal subjects. Artifact-free 15-s epochs were taken at each electrode location. Each epoch was divided into stationary segments, consisting of several fixed intervals, by optimizing 2 segmentation parameters (interval length and starting point) so that the sum of AICs for several sequences of segments could be the smallest. The EEG segmentation could represent differences in the power spectra between segments. The average length of segments during relaxed wakefulness was 6.0 +/- 3.8 s. The EEG segmentation during mental arithmetic could detect the start of mental arithmetic.

Moving potential field of frontal midline theta activity during a mental task.

The movement of potential field (potential flow) of frontal midline theta activity (Fm theta) was examined by using optical flow detection techniques in image processing in 6 normal subjects. Electroencephalograms (EEGs) over the fronto-central region were recorded from 13 electrodes around Fz. The potential flow of Fm theta was estimated on a frame which consisted of a square grid of 19 x 19 points in which each of the 13 electrodes was positioned with Fz at the center of grid. The peak-to-trough amplitude distribution was rounded or oval with a maximum just anterior to Fz. In each hemisphere, potential field moved medially in a region anterior to Fz, posteriorly near or at the midline and laterally in a region posterior to Fz. In the temporal sequence of potential field, at each point velocity directions tended to change progressively clockwise or counterclockwise. In the whole frame, a rotary movement of potential flow was found with a center at the middle on each side. Our findings suggested that a potential maximum at the midline may be due to overlapping of fields of opposite direction over the frontal scalp, arising from sources of similar orientation in both hemispheres. It can be assumed that Fm theta propagates in a clockwise direction in the left hemisphere and in a counterclockwise direction in the right hemisphere.

Medial prefrontal cortex generates frontal midline theta rhythm.

Frontal midline theta rhythm (Fm theta) is a distinct theta activity of EEG in the frontal midline area that appears during concentrated performance of mental tasks in normal subjects and reflects focused attentional processing. To tomographically visualize the source current density distributions of Fm theta, we recorded Fm theta by using a 64-channel whole-head MEG system from four healthy subjects, and applied a new analysis method, synthetic aperture magnetometry (SAM), an adaptive beam forming method. Fm theta was observed in the MEG signals over the bilateral frontal regions. SAM analysis showed bilateral medial prefrontal cortices, including anterior cingulate cortex, as the source of Fm theta. This result suggests that focused attention is mainly related to medial prefrontal cortex.

Theta rhythm increases in left superior temporal cortex during auditory hallucinations in schizophrenia: a case report.

Auditory hallucinations (AH), the perception of sounds and voices in the absence of external stimuli, remain a serious problem for a large subgroup of patients with schizophrenia. Functional imaging of brain activity associated with AH is difficult, since the target event is involuntary and its timing cannot be predicted. Prior efforts to image the patterns of cortical activity during AH have yielded conflicting results. In this study, MEG was used to directly image the brain electrophysiological events associated with AH in schizophrenia. We observed an increase in theta rhythm, as sporadic bursts, in the left superior temporal area during the AH states, whereas there was steady theta band activity in the resting state. The present finding suggests strong association of the left superior temporal cortex with the experience of AH in this patient. This is consistent with the hypothesis that AH arises from areas of auditory cortex subserving receptive language processing.

Colonial variation and fimbriation of Actinobacillus actinomycetemcomitans.

Three colonial variants of Actinobacillus actinomycetemcomitans, which formed transparent rough (TR)-, transparent smooth (TS)-, and opaque smooth (OS)-surfaced colonies, were described in relation to their fimbriation. TR- and TS-cells were adhesive to agar and glass surfaces but not the OS-cells. The examination by electron microscopy revealed that TR-cells were highly fimbriated but not TS- and OS-cells. Thus, TS-cells seemed to be an intermediate type. The fimbriae were isolated from TR-cells by suspending in 0.15 M ethanolamine-HCl buffer (pH 10.5) and purified by dissolving non-fimbrial components in 0.5% deoxycholate and 0.7% n-octyl-beta-D-glucopyranoside. The relative molecular mass of the fimbrial subunit protein was 54,000.

NMR second moment imaging using Jeener-Broekaert dipolar signals.

It is demonstrated that imaging of the 1H NMR second moment can be achieved by using the Jeener-Broekaert (JB) dipolar signal instead of the Zeeman FID signal commonly employed. The JB dipolar signal can be induced by applying a JB pulse sequence, 90 degrees (x)-tau-45 degrees (y)-tau(')-45 degrees (y), which is followed by the time-suspension magic echo sequence, TREV-16TS, for imaging detection. Scanning the imaging detection to cover the whole evolution of the JB dipolar signal finally results in producing spatially resolved JB dipolar signals. The local value of the quantity called the "JB second moment," M(2(JB)), is then estimated from the initial slope of each resolved JB dipolar signal. The M(2(JB)) can be regarded as the "weighted" powder average of the usual second moment. The "weighting" effect due to the JB sequence leads to the tau dependent M(2(JB)) value. The tau dependence is potentially useful for characterizing the second moment distribution resulting from the crystal orientation dependence: For example, in addition to the usual powder average, an approximate distribution range can be deduced by a simple analysis of the tau dependence, serving as a new contrast for materials imaging. This is illustrated by preliminary experiments performed on test samples.

Potential flow of alpha activity in the human electroencephalogram.

The movement of potential field of alpha activity was investigated with a potential flow technique, alpha activity was divided into slow, medium and fast subbands. The peak-to-peak amplitude and source density distribution of each subband was also constructed. The potential flow of medium alpha was from medial to lateral in the anterior region, and from lateral to medial in the posterior region. The flow patterns of slow and fast alpha were more complicated. Similar flow directions formed a group. Different groups met or diverged at discontinuous grid points around the local maxima of potential distribution. The discontinuous points of medium alpha were centered in the parieto-occipital region, and those of slow and fast alpha were more equally distributed over the scalp. Against potential gradients, several groups of similar flow directions participated in the formation of potential field. The generation of potential field was assumed to be controlled widely for medium alpha and locally for slow and fast alpha.

Increases in the power spectral slope of background electroencephalogram just prior to asymmetric spike and wave complexes in epileptic patients.

Moment-to-moment electroencephalogram (EEG) changes just before spike and wave complexes (SWCs) were investigated by using a non-stationary power spectral analysis in 10 epileptic patients with asymmetric SWCs. The instantaneous power spectra of background EEG were estimated for a 10-s period just before SWCs in 10 locations. The spectral shape, showing a l/f amplitude characteristic, was assessed by the negative slope (spectral slope) of a straight line on a plot of log power versus frequency. Spectral slope significantly increased toward SWCs at locations with greater SWCs. This finding suggested structural changes in EEG frequency composition just before SWCs because of an epileptogenic process.

Potential flow of frontal midline theta activity during a mental task in the human electroencephalogram.

The movement of potential field (potential flow) of frontal midline theta activity (Fm theta) as well as its potential distribution was examined in 7 subjects by using optical flow detection techniques in image processing. Electroencephalograms (EEGs) over the fronto-central region were recorded from 13 electrodes near the frontal midline (Fz) while the subjects were performing a mental task. The potential flow of Fm theta was estimated on a frame consisting of a square grid with Fz at its center. In regions anterior to Fz, the direction of potential flow was from lateral to medial, whereas it was from medial to lateral in regions posterior to Fz. The peak-to-trough amplitude distribution was round or oval with a maximum just anterior to Fz. The source density distribution showed the greatest potential along the midline in the frontal region and bilaterally symmetric smaller maximum areas mostly in the prefrontal regions. Our findings suggested the presence of 2 different source areas of opposite direction in each hemisphere in spite of a round or oval amplitude distribution.

Changes in the fractal dimension of alpha envelope from wakefulness to drowsiness in the human electroencephalogram.

Changes in the fractal dimension of the waxing and waning of alpha activity from wakefulness to drowsiness were investigated in 10 normal subjects. The envelope of filtered alpha activity was estimated with the Hilbert transform. A subset time series was constructed from the alpha envelope data taken at an interval (k). The points of the logarithm of interval k vs. the logarithm of the curve length of the subset time series (log L(k)) were fitted by a two-segment curve, consisting of small and long line segments (segments 1 and 2). The fractal dimension was estimated from the slope of straight line for each segment by using Higuchi's method. The mean fractal dimension was 1.16 for segment 1 and 1.95 for segment 2 during wakefulness and 1.15 for segment 1 and 1.89 for segment 2 during drowsiness. The fractal dimension significantly decreased in both segments during drowsiness, thus, indicating decreases in the complexity of alpha envelope.

Image reconstruction algorithm for single-photon-emission computed tomography with uniform attenuation.

A new method is presented for obtaining an analytical solution to the image-reconstruction problem in single-photon-emission computed tomography. The rigorous solution is introduced by applying an analytical continuation process to the two-dimensional Fourier transform of the image, which is derived from the one-dimensional Fourier transforms of projection functions. The calculations can be carried out in a short computation time without involving unstable procedures. Numerical simulations were made to demonstrate the effectiveness of the proposed method.

Suppression of mitomycin C-induced micronuclei in mouse bone marrow cells by post-treatment with vanillin.

Induction of micronuclei by mitomycin C (MMC) in mouse bone marrow cells was suppressed by post-treatment with vanillin, a component of vanilla essence flavour. Vanillin was given orally to mice 7.5 h after intraperitoneal injection of 2 mg/kg MMC. Post-treatment with vanillin at 500 mg/kg caused about 50% decrease in the frequency of micronucleated polychromatic erythrocytes (MN-PCEs). The effect of vanillin administration on the time-course of formation of MN-PCEs was also investigated. The suppressing effect was not due to a delay in the formation of MN-PCEs by the cytotoxic action of vanillin. Vanillin acts as an anticlastogenic factor in vivo.

Structure-dependent variation in the mutagenic, prophage-inducing and antibacterial activities of 5-nitro-2-furamide derivatives.

A comparative survey of the mutagenic, prophage-inducing and antibacterial activities of 3 structure-related series of 5-nitro-furan derivatives including 5-nitro-2-furohydrazide imide, 5-nitro-2-furamide oxime and 5-nitro-2-furohydrazide has been undertaken. Among the compounds assayed, the 5-nitro-2-furohydrazide imide series was found to be most active with regard to mutagenic and antibacterial activities against Salmonella typhimurium TA100 and prophage-inducing activity in Escherichia coli GY5027. A clear correlation was observed between the chemical structure and the mutagenic and prophage-inducing activities which were approximately correlated to the antibacterial activity.

Micronucleus test with procarbazine hydrochloride administered by intraperitoneal injection and oral gavage.

The difference in effect of route of administration of procarbazine hydrochloride (PCZ) in the mouse was investigated in the micronucleus test. PCZ was administered by intraperitoneal injection (i.p.) and oral administration (p.o.) to 2 strains of male mice (MS/Ae and CD-1). On the basis of a small-scale acute toxicity test and a pilot micronucleus test, bone marrow preparations were prepared 24 h after the administration by the i.p. and p.o. routes of 50-400 mg/kg and 200-1600 mg/kg, respectively. The maximum incidence of polychromatic erythrocytes with micronuclei (MNPCEs) was somewhat higher after p.o. treatment in MS/Ae mice and the same with both routes in CD-1 mice. Thus, the clastogenicity of PCZ in mouse bone marrow was revealed by both routes.

Combined mutagenicity of cobalt(II) salt and heteroaromatic compounds in Salmonella typhimurium.

Mutagenic activities of 4-aminopyridine (4AP), 4-aminoquinoline (4AQ), 9-aminoacridine (9AA) and harman (HM) were examined by the Salmonella test system in the presence of cobalt(II) chloride (CoCl2), which itself is non-mutagenic in this system. Mutagenic activity of the mixture of 9AA and CoCl2 was found to be much higher than that of 9AA alone in strains TA1537 and TA2637. A similar enhancing phenomenon was observed in 4AQ-CoCl2 and HM-CoCl2 mixtures but not in that of 4AP-CoCl2. Judging from visible and nuclear magnetic resonance spectral data, this increased mutagenicity may be attributable to the formation of moderate to weak complexes between these chemicals and the Co(II) cation. A survey of the mutagenicity of several Co(II) complexes supported this interpretation.

Excitability of evoked sharp wave: a case study.

In a 16-year-old boy, a sharp wave occurred spontaneously and was evoked by each individual light flash at rates of less than 4 f/sec. The excitability of the sharp wave was studied by use of double flashes at different intervals as well as IPS at different rates. With double flashes at intervals of 25 msec to 1 sec, the absolute refractory period was estimated to be less than 75 msec, and the subnormal excitability period in the range of 75 msec to less than 1 sec. With increased rates of flash trains from 3 to 24 f/sec, the sharp waves disappeared at the average rate of 10.4 f/sec. The disappearance of sharp waves at higher rates may be due to both the absolute refractoriness and the subnormal excitability. The sharp waves tended to vary in a waxing and waning manner. With long-lasting stimulation at a rate of 1 f/sec, sharp waves disappeared 30 sec after the stimulus onset. In our case, therefore, various factors influenced the excitability of the sharp wave response over a short to long period of time.

Spindle activity in the waking EEG in older adults.

Sleep spindles are an EEG sign of light sleep under physiological conditions. We reported the simultaneous occurrence of sleep spindles and alpha activity in the waking EEG in 12 patients with a mean age of 59.0 years. Most of the patients were diagnosed as cerebrovascular disorders such as cerebral arteriosclerosis, transient ischemic attack and vascular dementia. The mean alpha frequency in the presence of WSA significantly decreased by 1.5 Hz. The frequency and spatial distribution of waking spindle activity were similar to those of sleep spindles. In our cases, at least the two factors of cerebrovascular involvement and older adults were considered to be primarily responsible for the intrusion of sleep spindles into wakefulness (presumably a state close to very light drowsiness) due possibly to the instability of sleep-waking cycle regulation.

Primary squamous cell carcinoma of the middle ear invading the cochlea. A histopathological case report.

This report describes the histopathological changes in the temporal bone of a 71-year-old man who died of meningitis and epidural abscess complicated by primary squamous cell carcinoma of the middle ear. The present case is unusual and differs somewhat from previously reported cases of the primary squamous cell carcinoma of the middle ear in three respects: 1) an extensive invasion of the cancer into the membranous labyrinth, 2) cholesterol deposits in the cochlear spiral canal, and 3) presence of ossifying labyrinthitis. Among these findings, extensive involvement of the inner ear by cancer destroying the lower part of the otic capsule is particularly unusual. It is assumed that squamous cell carcinoma overcame the biological resistance to neoplastic infiltration which probably exists in the otic capsule and the membranous labyrinth.

Effects of head rotation on pharyngeal function during normal swallow.

This study quantified the effects of head rotation on pharyngeal swallowing in healthy subjects. Videofluoroscopic and oropharyngeal manometric examinations of pharyngeal swallowing were performed on seven volunteers with the head in neutral and rotated positions. Videofluoroscopic study revealed that head rotation swallow causes the bolus to lateralize away from the direction of head rotation. Pharyngeal manometric study indicated that the pharyngeal peak pressures toward the side of head rotation were significantly increased, whereas the pharyngeal pressures opposite the side of head rotation were not affected. Head rotation swallow produced a significant fall in upper esophageal sphincter (UES) resting pressure and a delay in UES closing. We concluded that the head rotation swallow in normal subjects not only alters the bolus pathway, but also has a useful effect on both pharyngeal clearance and UES dynamics.