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.

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.

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.

Stationarity and normality of distribution of rat cortical brain waves.

Establishing the stationarity and statistical distribution of potentials recorded from the nervous system is crucial for the application of frequency analysis. Both parameters were determined in the electrocorticograms of six adult Wistar rats during wakefulness and desynchronized sleep, during both of which desynchronization prevails. Stationarity of the signals was found to occur during at least 20 s in both states of the wakefulness-sleep cycle. A normal distribution was also found for at least 6.7 s. These findings provide strong support for the use of frequency analysis of brain waves as a reliable method to quantify neural electro-oscillograms.

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.

Electrical activity of the posterior thalamic nucleus and the hippocampus during wakefulness and desynchronized sleep in the rat: a spectral analysis.

The electrical activity of the posterior thalamic nuclear complex was studied in rats and related to the simultaneous hippocampal electro-oscillogram. Electrocorticographic tracings and spectral analysis showed that during attentive wakefulness the electro-oscillogram peaked at 8 Hz and in desynchronized sleep it oscillated at regular frequencies between 8 and 9 Hz. In quiet wakefulness, frequency was lower (around 6 Hz) and during synchronized sleep rhythmicity disappeared. The electrophysiological patterns during wakefulness and desynchronized sleep are proposed to be linked to the retrieval and combination of information for the generation of attention and dream content.

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.

[Reproductive and developmental toxicity study of mofezolac (N-22) (3)--Teratogenicity study in rabbits by oral administration].

Mofezolac (N-22) is a new developed analgesic and anti-inflammatory agent. A teratogenicity study of N-22 was carried out in New Zealand White rabbits to examine the effect on the dams and the teratogenic potentiality. N-22 was administered orally at the dose levels of 12.5, 50 and 200 mg/kg during the organogenesis from day 6 to day 18 of gestation. All pregnant females were sacrificed on day 28 of gestation and their fetuses were examined. There were no growth retardation and teratogenic effects on fetuses from the dams administered N-22, although the administration of 200 mg/kg produced a decrease in food consumption of the dams concomitant with the embryocidal effects as shown by an increase in the early resorption rate. Thus, non-toxic dose level of N-22 on the dams and fetuses was considered to be 50 mg/kg.

Cleft hand in Silver-Russell syndrome.

A case of Silver-Russell Syndrome with a typical cleft hand is presented. The association of cleft hand with this syndrome has never been reported before.

[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.

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.

[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.

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.

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.

9p deletion and distal 9q duplication due to a paternal pericentric inversion 9(p22q32).

A female infant with 46,XX,rec(9), dup q,inv(9)(p22q32)pat is presented. She had a duplication from 9q32 to qter and a deletion from 9p22 to 9pter. Phenotypical abnormalities observed corresponded with features noted in cases with distal dup (9q), while pathognomonic features of del(9p) syndrome were not observed.

16q21 is critical for 16q deletion syndrome.

A 1-year-old girl with an interstitial deletion of the long arm of chromosome 16 is reported. She was characterized by a distinct craniofacial dysmorphism, meningoencephalocele, mild hydrocephalus, short neck, broad great toes and abnormally positioned toes. High resolution GTG and RBG banding analyses revealed a karyotype: 46,XX,del(16) (q13q22) de novo. An analysis of the smallest region of overlap revealed that the critical band region for 16q deletion syndrome is 16q21.

[Two cases of amylase-producing lung cancer].

In 1951, Weiss et al. first reported a case of an amylase-producing lung cancer. Since then, reports on immunohistochemical, ultrastructural, and biochemical studies have been published. We recently have experienced two autopsy cases of lung cancer that manifested high amylase activity in the serum, urine, and pleural effusions. Histologically, both lung cancers were classified as being well differentiated adenocarcinomas, and immunohistochemically, the tumor cells showed positive immunoreactivity for amylase. This paper discusses the histogenesis of amylase-producing lung cancers and cases found in the literature.

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.