A phase III clinical trial of a mixture agent of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors.

INTRODUCTION: MC710, a 1:10 protein weight ratio mixture of plasma-derived activated factor VII (FVIIa) and factor X (FX), is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. We evaluated the haemostatic efficacy and safety of one to two administrations of MC710 in 21 joint, muscle, and subcutaneous bleeding episodes in 14 male patients, in a multi-centre, open-label, non-randomized clinical trial. METHODS: Subjects were intravenously administered one or two doses of 60 or 120 µg kg-1 MC710 (as FVIIa) once or twice (to a maximum of 180 µg kg-1 ) over up to five bleeding episodes per subject. The haemostatic efficacy of MC710 was determined for each episode by investigator evaluation, using changes in visual analogue scale (VAS) for pain relief, and/or knee joint or muscle circumference for swelling reduction, and range of motion (ROM) for improvement of joint mobility. RESULTS: In 21 treatments for bleeding episodes, 19 were rated "excellent" or "effective" 8 h after the last treatment. VAS significantly decreased over time, and ROM significantly improved over time compared with the values before treatment. One mild adverse reaction, decreased blood potassium, and two serious adverse events, both knee joint bleeding, were observed within 1 week after first administration, with no significant effect on safety. Furthermore, diagnostic markers did not show any signs of disseminated intravascular coagulation (DIC). CONCLUSION: These results show that MC710 has sufficient haemostatic efficacy and safety, and can be used as a potential bypassing agent to control bleeding in haemophilia patients with inhibitors.

Molecular genetic analysis of 30 families with Joubert syndrome.

Joubert syndrome (JS) is rare recessive disorders characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles, and a deep interpeduncular fossa which is defined by neuroimaging and is termed the 'molar tooth sign'. JS is genetically highly heterogeneous, with at least 29 disease genes being involved. To further understand the genetic causes of JS, we performed whole-exome sequencing in 24 newly recruited JS families. Together with six previously reported families, we identified causative mutations in 25 out of 30 (24 + 6) families (83.3%). We identified eight mutated genes in 27 (21 + 6) Japanese families, TMEM67 (7/27, 25.9%) and CEP290 (6/27, 22.2%) were the most commonly mutated. Interestingly, 9 of 12 CEP290 disease alleles were c.6012-12T>A (75.0%), an allele that has not been reported in non-Japanese populations. Therefore c.6012-12T>A is a common allele in the Japanese population. Importantly, one Japanese and one Omani families carried compound biallelic mutations in two distinct genes (TMEM67/RPGRIP1L and TMEM138/BBS1, respectively). BBS1 is the causative gene in Bardet-Biedl syndrome. These concomitant mutations led to severe and/or complex clinical features in the patients, suggesting combined effects of different mutant genes.

Unified asymptotic theory for all partial directed coherence forms.

This paper presents a unified mathematical derivation of the asymptotic behaviour of the three main forms of partial directed coherence (PDC). Numerical examples are used to contrast PDC, gPDC (generalized PDC) and iPDC (information PDC) as to meaning and applicability and, more importantly, to show their essential statistical equivalence insofar as connectivity inference is concerned.

Thalamic bursting in rats during different awake behavioral states.

Thalamic neurons have two firing modes: tonic and bursting. It was originally suggested that bursting occurs only during states such as slow-wave sleep, when little or no information is relayed by the thalamus. However, bursting occurs during wakefulness in the visual and somatosensory thalamus, and could theoretically influence sensory processing. Here we used chronically implanted electrodes to record from the ventroposterior medial thalamic nucleus (VPM) and primary somatosensory cortex (SI) of awake, freely moving rats during different behaviors. These behaviors included quiet immobility, exploratory whisking (large-amplitude whisker movements), and whisker twitching (small-amplitude, 7- to 12-Hz whisker movements). We demonstrated that thalamic bursting appeared during the oscillatory activity occurring before whisker twitching movements, and continued throughout the whisker twitching. Further, thalamic bursting occurred during whisker twitching substantially more often than during the other behaviors, and a neuron was most likely to respond to a stimulus if a burst occurred approximately 120 ms before the stimulation. In addition, the amount of cortical area activated was similar to that during whisking. However, when SI was inactivated by muscimol infusion, whisker twitching was never observed. Finally, we used a statistical technique called partial directed coherence to identify the direction of influence of neural activity between VPM and SI, and observed that there was more directional coherence from SI to VPM during whisker twitching than during the other behaviors. Based on these findings, we propose that during whisker twitching, a descending signal from SI triggers thalamic bursting that primes the thalamocortical loop for enhanced signal detection during the whisker twitching behavior.

Prediction of endocrine disruptors based on a new structure-activity relationship for sex and environmental hormones using chemical hardness concept.

Classification of the relationship between electronic structures and biological activities of endocrine disruptors (so-called environmental hormones) was attempted using the parameters of absolute hardness (eta), absolute electronegativity (chi), and global softness (S), approximately defined as eta=1/2(epsilonLUMO-epsilonHOMO), chi=-1/2(epsilonHOMO+ epsilonLUMO), and S=1/eta, respectively, based on the hardness concept. The strength of binding affinity and toxicity of the chemicals were approximately proportional to the absolute hardness, and laterally toxic chlorinated PCDDs, PCBs, and DDTs are classified as chemically soft. Here we found that the electronic structures of environmental hormones can be classified into four main groups: 17beta-estradiol type (group I), testosterone type (group II), thyroxine type (group III), and HCH (hexachlorocyclohexane) type (group IV). Therefore, if we can predict the coordinate (chi, eta) of the electronic structure of one chemical on the eta-chi activity diagram, we would be able to predict the receptor with which the chemicals (environmental hormones) interact. For instance, 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) is classified in group II, therefore, it would bind with the thyroid receptor more than the estrogen receptor (group I). It appears that dibutyl phthalate would not interact with estrogen receptor because it does not belong to group I. In addition, the coordinates of these four groups do not complementarily overlap with the electronic structures of 20 natural amino acid residues. The eta-chi activity diagram is a new tool for the prediction of the toxicity and biological activity of environmental hormones.

Partial directed coherence: a new concept in neural structure determination.

This paper introduces a new frequency-domain approach to describe the relationships (direction of information flow) between multivariate time series based on the decomposition of multivariate partial coherences computed from multivariate autoregressive models. We discuss its application and compare its performance to other approaches to the problem of determining neural structure relations from the simultaneous measurement of neural electrophysiological signals. The new concept is shown to reflect a frequency-domain representation of the concept of Granger causality.

Non-linear analysis of the rhythmic activity in rodent brains.

This paper discusses the employment of non-parametric non-linear prediction algorithms to investigate non-linear dynamics in the rhythmic brain activity of rats. Three algorithms (Sugihara-May Simplex, K-neighbour and Casdagli's) were tested yielding similar prediction results which--when subject to a suitable bootstrap based t-tests--revealed that the theta waves recorded in rat brains cannot have their intrinsic non-linearity dismissed at a significance of 0.05.

Using partial directed coherence to describe neuronal ensemble interactions.

This paper illustrates the use of the recently introduced method of partial directed coherence in approaching how interactions among neural structures change over short time spans that characterize well defined behavioral states. Central to the method is its use of multivariate time series modelling in conjunction with the concept of Granger causality. Simulated neural network models were used to illustrate the technique's power and limitations when dealing with neural spiking data. This was followed by the analysis of multi-unit activity data illustrating dynamical change in the interaction of thalamo-cortical structures in a behaving rat.

Transient low T cell response to streptococcal pyrogenic exotoxin-C in patients with Kawasaki disease.

Superantigens (SAs) are known to induce transient anergy followed by T cell activation. Recent reports have suggested that SAs are involved in the pathogenesis of Kawasaki disease (KD). In the present study, we investigated the peripheral T cell response to SAs by measuring proliferation and IL-2 production to determine whether the T cell anergy is induced by SAs in patients with KD. T cells were obtained from 45 Japanese patients with KD in different stages of the disease and were stimulated by streptococcal pyrogenic exotoxin (SPE)-A, SPE-C, and toxic shock syndrome toxin-1 (TSST-1). T cells from patients with KD in the acute or convalescent stage up to 2 mo showed significantly lower proliferation and IL-2 production than did T cells from healthy control subjects stimulated by SPE-C, but not SPE-A or TSST-1. The T cell response to SPE-C normalized within 1 y. The low T cell response to SPE-C in the acute stage correlated with a peak platelet count and the C-reactive protein-positive period. These findings suggest that the transient low T cell response to SPE-C in patients with KD may have been related to SA-induced anergy or disappearance of SPE-C-responding cells from the circulation. The present results suggested that SPE-C may be involved in the pathogenesis of KD.

Twenty-five types of T-cell receptor Vbeta family repertoire in patients with Kawasaki syndrome.

UNLABELLED: Recently, a possible relationship between Kawasaki syndrome (KS) and superantigen has been discussed since the report of selective expansion of specific Vbeta family in the acute phase of KS. To further investigate the relationship between KS and superantigens, we examined 25 types of T-cell receptor Vbeta family repertoire in patients with KS using the reverse transcription polymerase chain reaction. This is the first attempt to examine all of 25 Vbeta families in KS. A non radioisotope method was used to quantify mRNA so that the experiment was safer, simpler, and faster. An expression index (EI) for each Vbeta was defined as: (the amount of each Vbeta mRNA)/(the sum of all Vbeta mRNA) x 100. Ten patients with KS and ten normal children were studied. The Vbeta9 and Vbeta15 of acute phase of KS showed both significantly lower mean EI and significantly higher frequency of a decreased EI value as compared with control children. Selective expansion of the Vbeta family in the patients with KS was not observed. Although highly increased EIs were observed in various Vbetas, their frequency was not statistically significant. The pattern of increased Vbetas did not show the specific pattern that indicates a particular superantigen. CONCLUSION: In Kawasaki syndrome non-radioisotope method for analysing Vbeta mRNA is useful in cases where many samples have to be handled. The depletion of Vbeta9 and Vbeta15 or highly increased expression index in the acute phase of Kawasaki syndrome might suggest a relationship to superantigens.

A study of the quality of life in elderly people using psychological testing.

To study factors which influence the quality of life (QOL) in the elderly, we investigated the relationship between scores on the modified Philadelphia Geriatric Center (JPGC) Morale Scale and various other psychological tests in 51 elderly people residing in a long-term care facility. The JPGC Morale Scale score correlated with the scores for all sections of the Japanese version of the Cornell Medical Index (JCMI), but not with those for the Mini Mental State Examination, the Kohs block design test, the Bender Gestalt test and the activities of daily living (ADL). Both somatic and psychotic symptoms on the JCMI were correlated with the dementia behaviour disturbance scale score and walking ability according to the ADL. Subjects were further divided into four groups according to Fukamachi's neurotic discriminative diagram based on the JCMI. Scores for most sections of somatic and psychotic symptoms on the JCMI were elevated in proportion to the degree of neurotic tendencies in the elderly. These results indicate that the QOL of the elderly is influenced by subjective symptoms, but not by the degree of cognitive impairment or the ADL.

Remodelling of hand representation in adult cortex determined by timing of tactile stimulation.

The primate somatosensory cortex, which processes tactile stimuli, contains a topographic representation of the signals it receives, but the way in which such maps are maintained is poorly understood. Previous studies of cortical plasticity indicated that changes in cortical representation during learning arise largely as a result of hebbian synaptic change mechanisms. Here we show, using owl monkeys trained to respond to specific stimulus sequence events, that serial application of stimuli to the fingers results in changes to the neuronal response specificity and maps of the hand surfaces in the true primary somatosensory cortical field (S1 area 3b). In this representational remodelling stimuli applied asychronously to the fingers resulted in these fingers being integrated in their representation, whereas fingers to which stimuli were applied asynchronously were segregated in their representation. Ventroposterior thalamus response maps derived in these monkeys were not equivalently reorganized. This representational plasticity appears to be cortical in origin.

Toxicity of dioxins: role of an absolute hardness-absolute electronegativity diagram (eta-chi diagram) as a new measure in risk assessment.

The differences in biological activities among polychlorinated dibenzo-p-dioxins (dioxins) are strongly dependent on the substitution pattern of chlorine at various positions on the parent dibenzo-p-dioxin molecule. The absolute hardness, eta, of dioxins shows a good correlation with the potency of biological activity and the chlorine substitution pattern. The result means that the soft dioxins have a small HOMO-LUMO gap, and are more toxic than the hard dioxins. Therefore, the values of absolute hardness, eta, of dioxins can be used to predict their toxic potency (dioxin hardness). Moreover, we show that the absolute hardness-absolute electronegativity (eta-chi) diagrams, as an activity coordinate, play an important role as a new measure in the assessment of the toxicity and potency of the biological activity of dioxins.

[Substance P-like immunoreactivity in cerebrospinal fluid in lumbar disc herniation].

Substance P-like immunoreactivity (SP-LI) of the cerebrospinal fluid was measured by radioimmunoassay in 40 patients with lumbar disc herniation (hernia group), and in 10 patients with no low back pain and no leg symptoms (control group). The SP-LI was significantly higher in the hernia group (5.49 +/- 3.01 pg/ml) than in the control group (2.05 +/- 0.52 pg/ml) (p < 0.01). In the hernia group, the SP-LI was significantly higher in patients with severe pain in the lower extremities than in those with only mild pain. As the SP-LI was found to be correlated with the severity of pain, it was considered to be a useful index of pain. As for the correlation of SP-LI with the hernia type, the SP-LI was significantly higher in patients with transligamentous extrusion type hernia than in those with protrusion type hernia. This result suggested that the release of substance P was increased with marked compression on the dorsal root.

[Anesthetic management of cesarean section in a patient with dilated cardiomyopathy].

We report the anesthetic management of Cesarean section in a pregnant (31 weeks) woman with dilated cardiomyopathy. She had dyspnea and chest pain which were signs of congestive heart failure. The left ventricular ejection fraction was 38%. Anesthesia was induced and maintained with fentanyl, midazolam and vecuronium. There was no significant cardiovascular changes in the mother during the operation. The baby was apneic and showed no movement at birth, but he was immediately intubated and his condition became almost normal on the following day. In the anesthesiological management of Cesarean sections with cardiac disease, general anesthesia with fentanyl can be used to minimize cardiovascular changes in the mother as long as the baby is immediately resuscitated after delivery.

What are parents of obese children concerned about in their children?

We retrospectively examined the issues that concern parents of obese children to determine the most effective means of motivating them to seek treatment for obesity in their children. Children with an obesity index > or = 40%, aged six to 12 years, were screened in Kagoshima City in 1992. Parents were notified if their children needed an evaluation that included a family history and measurements of the blood pressure, total cholesterol, high density lipoprotein (HDL)-cholesterol, atherogenic index (ASI), triglycerides, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Parents were informed of the results of the evaluation and invited to attend a lecture on the treatment of obesity in children. A total of 378 obese children were evaluated. However, the parents of only 39 children attended the lecture. Children whose parents attended had higher mean total levels of cholesterol (190 +/- 25 vs 175 +/- 28, P < 0.01) and ASI values (3.2 +/- 0.9 vs 2.7 +/- 0.9, P < 0.02) than those whose parents did not attend. There were no significant differences in other factors. Only 4.2% of parents whose children showed no abnormal values, except for obesity, attended the lecture, compared with 20.3% (P < 0.01) or 16.9% (P < 0.05) of parents whose children had abnormal levels of cholesterol or abnormal ASI. Parents may be more concerned about hypercholesterolemia or arteriosclerosis than obesity per se. We should perhaps use the total cholesterol or ASI values, not just the severity of obesity, to motivate parents to enter their children into treatment programs for obesity.

Cortical plasticity and memory.

The roles of extrinsically modulated, plastic Hebb-like synapses and dynamic cortical cell assemblies underlying cortical plasticity in learning and memory operations are described. From our understanding of the distributed form of representation of learned behaviors in somatosensory and auditory cortical fields, and given new findings about the nature and distribution of responses representing learned and remembered stimuli in the inferior temporal cortex, a hypothetical picture of the cortical engram representing learned behaviors and memories is posited.

Theta waves and behavioral manifestations of alertness and dreaming activity in the rat.

Electro-oscillographic recordings show that when rats wake up, behavioral manifestations such as head dorsal extension and snout and eye movements (which occur in this sequence), occasionally followed by brief ear and limb twitches, are preceded by and are simultaneous with theta waves (around 6.5 Hz in frequency) in neocortical areas 3 and 17 and in the hippocampus. Heart rate increases when the animal passes from synchronized sleep to relaxed wakefulness to exploratory behavior. During desynchronized sleep theta waves, similar to those found during alertness, usually precede and are simultaneous with rostrum and eye movements and brief ear and limb twitches. Heart rate also increases during dreaming activity. A high degree of coherence (near 1.0) was found among theta bursts in different hippocampal areas in both highly attentive alertness and dreaming. It is suggested that theta waves are related to attention as part of some kinds of behavior and of the process of dream shaping and expression, both characterized by consciousness.