Prevalence of non-alcoholic steatohepatitis (NASH) among biopsied cases of a urban hospital in Japan: significance of measurement of serum ferritin in the detection of NASH]

From April 1989 to December 2004, we performed liver biopsy on 475 patients and obtained biopsy proven 35 cases of non-alcoholic fatty liver. Among them, 18 cases were diagnosed as non-alcoholic steatohepatitis (NASH). During the last three years, we have tried to detect NASH using ultrasonography and elevated value of serum ferritin (> 300 ng/ml). All of the eligible 7 cases biopsied during the course were diagnosed as NASH. In these 7 cases, ALT levels improved after the body weight loss accompanied by the parallel decrease of serum ferritin levels. Measurement of serum ferritin is useful in the detection of NASH but the normal value of ferritin cannot rule out the possibility of NASH.     

Molecular basis of severe myoclonic epilepsy in infancy

Severe myoclonic epilepsy (SMEI) or Dravet syndrome is caused by mutations of the SCN1A gene that encodes voltage-gated sodium channel alpha-1 subunit. Recently, we generated and characterized a knock-in (KI) mice with an SCN1A nonsense mutation that appeared in three independent SMEI patients. The SCN1A-KI mice well reproduced the SMEI disease phenotypes. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. In heterozygous knock-in mice, trains of evoked action potentials in inhibitory neurons exhibited pronounced spike amplitude decrement late in the burst but not in pyramidal neurons. We further showed that in wild-type mice the Nav1.1 protein is expressed dominantly in axons and moderately in somata of parbalbumin (PV) – positive inhibitory interneurons. Our immunohistochemical observations of the Nav1.1 are clearly distinct to the previous studies, and our findings has corrected the view of the Nav1.1 protein distribution. The data indicate that Nav1.1 plays critical roles in the spike output from PV interneurons and further, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice. These information should contribute to the understanding of molecular pathomechanism of SMEI and to develop its effective therapies.     

Pathological and biochemical studies on a case of Pick disease with severe white matter atrophy

We report on a male patient with Pick disease who had shown severe white matter atrophy and dilatation of the lateral ventricle in the frontal lobe from an early stage. Upon admission to our hospital 2 years after disease onset, the patient showed apathy, and MRI revealed severe atrophy of the cortex and white matter of the frontal lobe. He died at age 74, 11 years after disease onset. Autopsy revealed severe atrophy of the frontal and temporal lobes, severe loss of white matter in the frontal lobe, dilatation of the lateral ventricles, and cortical thinning. Histopathological examination showed severe loss of myelinated fibers in the frontal white matter and severe neuronal loss with gliosis in the frontal and temporal cortices. Many Pick bodies were seen. Our patient had a rare case of Pick disease predominantly affecting the frontal lobe with severe involvement of the white matter from an early stage. This case suggests that myelinated fibers in the white matter as well as cerebral neurons are primarily affected in Pick disease.     

Activation of Ca2+/calmodulin-dependent protein kinase II by stimulation with bradykinin in neuroblastoma x glioma hybrid NG108-15 cells.

To elucidate the mechanisms of the intracellular signal transduction elicited with bradykinin in NG108-15 neuroblastoma x glioma hybrid cells, we examined the activation of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) by bradykinin stimulation. When the extract of NG108-15 cells was immunoprecipitated with the affinity-purified antibody to brain CaM kinase II, a 50-kDa protein in the immunoprecipitate mainly became autophosphorylated in a Ca2+/calmodulin-dependent manner. The results suggest that the 50-kDa protein is the subunit of CaM kinase II in NG108-15 cells. The Ca2+/calmodulin-independent activity (autonomous activity) of the enzyme increased twice within 10 s by stimulation with 1 microM bradykinin in the cells. The increase in the autonomous activity of the enzyme had two phases: the transient early-peak phase and the long late-plateau phase. The former was abolished by the pretreatment of the cells with 10 mM caffeine or 20 microM BAPTA-AM, and the latter was abolished by the removal of the extracellular Ca2+ with 1 mM EGTA or by the pretreatment with 1 microM nifedipine. Stimulation of 32P-labeled NG108-15 cells with 1 microM bradykinin increased the autophosphorylation of CaM kinase II and this increase was abolished by pretreatment with caffeine or BAPTA-AM. These results suggest that CaM kinase II is activated via the inositol phospholipid signaling pathway induced with bradykinin in NG108-15 cells.     

Progressive supranuclear palsy with asymmetric lesions in the thalamus and cerebellum,with special reference to the unilateral predominance of many torpedoes

This report concerns a notable case of progressive supranuclear palsy exhibiting asymmetric dentate nucleus and thalamic degeneration with numerous torpedoes. The neuronal loss in the ventral lateral nucleus of the thalamus was predominant on the right side, while in the cerebellum, a quantitative study revealed the contralateral predominance of the neuronal loss in the dentate nuclei and torpedo formation, with preserved Purkinje cells. The abnormal tau-protein-related profiles in the two nuclei did not show any laterality in their distribution, indicating that the dentatothalamic tract may have been affected in a non-specific way in this case. In addition, the fact that the prominent sites of torpedo formation and loss of dentate nucleus neurons are identical supports the hypothesis that the torpedoes may be formed in association with neuronal loss in the dentate nucleus because of a plausible metabolic change in Purkinje cells through synaptic detachment of their axon terminals. Received: 4 January 1996 / Revised: 27 March 1996 / Accepted: 5 April 1996     

Some chemical and serological properties of perchloric acid-soluble glycoproteins separated from ascitic fluid of a patient with metastatic omentum tumor from ovarian cancer

One mol perchloric acid-soluble fraction (PASF) obtained from ascitic fluid of a patient (blood group B) with metastatic omentum tumor from ovarian cancer was a glycoprotein fraction containing 35.4% carbohydrate and exhibited A, B and Thomsen-Friedenreich (T) activities. This fraction was separated into three fractions, Frs. 1-3, by a gel filtration with Bio-Gel A-1.5 m column. Among these fractions, Fr. 1 which was obtained in a 5.5% yield to PASF, was a glycoprotein fraction with a high molecular weight, 23.3% carbohydrate and A, B and T activities. Other minor fraction, Fr. 2, and the major fraction, Fr. 3, contained 43.2% and 43.9% carbohydrate, but did not show A, B and T activities, respectively.     

Cell surface phenotype of in vitro proliferating lymphocytes in HTLV-I-associated myelopathy (HAM/TSP)

The in vitro proliferation of peripheral blood lymphocytes (PBLs) without any mitogenic stimulation is one of the hallmarks of human T lymphotropic virus type I (HTLV-I) infection. Recent evidence suggests a difference in the degree of the phenomenon between HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and asymptomatic HTLV-I carriers (AC). In this article, we demonstrated several alterations in the features of the in vitro transformed lymphocytes between patients with HAM/TSP (n = 16) and AC (n = 8). The percentages of total CD8+ and CD8+CD28+ cells were significantly increased in the in vitro proliferating T lymphocytes derived from the patients with HAM/TSP when compared to those from AC. HAM/TSP was segregated from AC by the high degree of the proliferation of CD8+CD28+ cells. The expression of HTLV-I-specific antigens on the cultured PBLs was detected only in the subjects which showed low CD8+CD28+/CD4+ ratio of the in vitro proliferating lymphocytes. These findings suggest that this phenomenon distinguishes HAM/TSP from AC, not only in quantity but also in quality.