Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter.

In an attempt to identify transcription factors which activate sterol-regulatory element-binding protein 1c (SREBP-1c) transcription, we screened an expression cDNA library from adipose tissue of SREBP-1 knockout mice using a reporter gene containing the 2.6-kb mouse SREBP-1 gene promoter. We cloned and identified the oxysterol receptors liver X receptor (LXRalpha) and LXRbeta as strong activators of the mouse SREBP-1c promoter. In the transfection studies, expression of either LXRalpha or -beta activated the SREBP-1c promoter-luciferase gene in a dose-dependent manner. Deletion and mutation studies, as well as gel mobility shift assays, located an LXR response element complex consisting of two new LXR-binding motifs which showed high similarity to an LXR response element recently found in the ABC1 gene promoter, a reverse cholesterol transporter. Addition of an LXR ligand, 22(R)-hydroxycholesterol, increased the promoter activity. Coexpression of retinoid X receptor (RXR), a heterodimeric partner, and its ligand 9-cis-retinoic acid also synergistically activated the SREBP-1c promoter. In HepG2 cells, SREBP-1c mRNA and precursor protein levels were induced by treatment with 22(R)-hydroxycholesterol and 9-cis-retinoic acid, confirming that endogenous LXR-RXR activation can induce endogenous SREBP-1c expression. The activation of SREBP-1c by LXR is associated with a slight increase in nuclear SREBP-1c, resulting in activation of the gene for fatty acid synthase, one of its downstream genes, as measured by the luciferase assay. These data demonstrate that LXR-RXR can modify the expression of genes for lipogenic enzymes by regulating SREBP-1c expression, providing a novel link between fatty acid and cholesterol metabolism.

A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling.

Here, by combining lipidomics with transcriptome analysis, we demonstrate that Rb depletion in mouse embryonic fibroblastss induces significant alterations in their lipid composition. We discovered that Rb depletion induced increase in lysophosphatidylserine, diacylglycerol (DAG), fatty acid (FA), acylcarnitine, phosphatidylcholine (PC), arachidonoyl ethanolamine, and decrease in phosphatidylglycerol, monoacylglycerol, without change in total lipid per protein levels. Analysis of the acyl chain composition of DAG, PC and phosphatidylserine revealed increase of saturated and mono-unsaturated acyl chains with specific carbon chain length. Consistently, we observed that Rb depletion increased the levels of fatty acids with the corresponding carbon chain length and number of carbon-carbon double bondssuch as myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0) and all forms of FA 18:1. Microarray analysis revealed that Rb depletion induced significant upregulation of enzymes involved in elongation and desaturation of fatty acids. Among these, we found that elongation of long chain fatty acid family member 6 (Elovl6) and stearoyl-CoA desaturase 1 (Scd1) are the most robustly controlled by Rb possibly through E2F and sterol regulatory element-binding protein transcription factors. Depletion of Elovl6 or Scd1 significantly suppressed colony formation, sphere formation and xenograft tumor growth of Rb-deficient tumor cells. Suppression of self-renewal by the SCD1 inhibitor was rescued upon supplementation of the mono-unsaturated fatty acids generated by this enzyme. This study suggests a novel role for Rb in suppressing the malignant progression of tumors by controlling the lipid composition.

Walker-Warburg syndrome is genetically distinct from Fukuyama type congenital muscular dystrophy.

A female patient who fulfilled the diagnostic criteria of Walker-Warburg syndrome had muscle biopsy finding of muscular dystrophy. There was normal expression of merosin (laminin alpha2 chain) and dystrophin and only slightly reduced dystrophin-associated glycoprotein expression. On genetic analysis, she had no specific haplotype, the common mutation of 3kb insertion, or point mutations in the Fukuyama-type congenital muscular dystrophy gene, suggesting that the two diseases are not genetically identical.

Facioscapulohumeral dystrophy associated with mental retardation, hearing loss, and tortuosity of retinal arterioles.

A rare case of facioscapulohumeral muscular dystrophy with an early onset and progression is described. The patient had mental retardation, sensorineural hearing loss, and marked tortuosity of the retinal arterioles. On reviewing previous reports of related cases, our case and those of Small shared similar clinical manifestations, although the retinal findings in our patient were different from the typical Coats' disease of Small's patients. However, we postulate that these cases represent a specific nosological entity, although genetic transmission has yet to be proven.

Rett's syndrome: progression of symptoms from infancy to childhood.

The results of studies of seven girls with Rett's syndrome and two additional cases suggestive of Rett's syndrome are presented. After normal neurological development up to the age of 7 to 20 months, there was a rapid regression of higher cortical function. Rett's syndrome was initially manifested by a delay of further motor development and the appearance of autistic traits. As the disease progressed, there was a loss of ability to crawl, loss of purposeful hand movements, abnormal respirations, truncal ataxia, seizures, and spastic increase in muscle tone. Blood chemistries, including ammonia levels, were normal. Metabolic interference, a recently hypothesized form of inheritance, may occur in this syndrome.

Cerebro-oculo-hepato-renal syndrome (Arima' syndrome): a distinct clinicopathological entity.

Three children with Leber's congenital amaurosis, agenesis of the cerebellar vermis, and infantile polycystic kidneys are described. The common clinical findings of three unrelated patients (two boys and one girl) included severe visual impairment from early infancy, profound psychomotor retardation, hypotonia, nystagmus, characteristic facial appearance with blepharoptosis, and progressive chronic renal insufficiency. The two boys died of uremia at ages 13 and 12 years. The common pathological findings in these two patients consisted of minor disproportions of cerebral lobes, almost total aplasia of the cerebellar vermis, micropolygyria of the dentate nuclei, malformations of the brain stem (including pachygyria of the inferior olivary nuclei and partial absence and anomalous position of the pyramidal tracts), and infantile polycystic kidneys; there was fatty liver in one case and hepatic fibrosis in the other. The clinicopathological findings of our two patients were entirely compatible with those of patients previously reported by Arima and other Japanese authors. Therefore, these patients seem to comprise a distinct clinicopathological entity, cerebro-oculo-hepato-renal syndrome (Arima's syndrome), different from other syndromes with retinal, cerebellar, and renal abnormalities.

Prophylaxis of intracranial hemorrhage due to vitamin K deficiency in infants.

To determine the most effective way of preventing intracranial hemorrhage due to vitamin K deficiency in infants, we first performed a comparative study using Normotest on the effects of several regimens for the oral administration of vitamin K2. Based on the results, we gave vitamin K2 orally, 2 mg, at birth, and then, 4 mg, at 1 week of age (on discharge from the newborn nursery) to all infants except premature and low-birth-weight infants born in Nagasaki Prefecture, Japan. Since then, as the number of infants with vitamin K2 prophylaxis increased, patients with intracranial hemorrhage due to vitamin K deficiency decreased in number, and no patient was found in 1984. The incidence of this disease in infants with vitamin K prophylaxis was 1/68,500, which was one-twentieth of that (1/3,500 live births) before the period when most neonates received vitamin K prophylaxis. From the results, we concluded that the oral administration of vitamin K2 at birth and 1 week of age prevents this disease.

Incidence and causes of intracranial hemorrhage in infancy: a prospective surveillance study after vitamin K prophylaxis.

In order to evaluate the effect of vitamin K prophylaxis on the incidence of intracranial hemorrhage (ICH) in infants aged from 1 week to 12 months, a prospective surveillance study, from 1974 to 1988, was performed on the well-defined population of Nagasaki Prefecture, Japan. The incidence of ICH in infancy markedly decreased, from 34.3/100,000 to 10.1/100,000 live births, with the oral administration of vitamin K2 at both birth and 1 week, or with additional supplementation at 1 month of age. The diminished incidence was attributed to the decreased occurrence of acute ICH due to late hemorrhagic disease (LHD), a late onset form of vitamin K deficiency, and chronic subdural hematoma. On comparing the possible etiological factors, and clinical and laboratory findings between these 2 groups, it became apparent that chronic subdural hematoma shared some etiological factors (such as breast-feeding, liver dysfunction and no supplementation of vitamin K) with LHD. Furthermore, chronic subdural hematoma developed in some patients who had previously had acute ICH due to LHD. These findings suggest that coagulopathy due to vitamin K deficiency, including LHD, is causally related in the majority of, if not all, cases of chronic subdural hematoma without any history of trauma or central nervous system infections.

Epidemiological and clinical studies of West syndrome in Nagasaki Prefecture, Japan.

Recent advances in diagnostic and therapeutic techniques may have changed incidence and etiologies of West syndrome (WS). We performed a retrospective epidemiological study of WS that occurred in 47 children in Nagasaki Prefecture during a recent 10-year period from 1989 to 1998. The incidence of WS was 3.1/10,000 live births. Thirty-nine patients (83%) had symptomatic WS, in which the prenatal causes were most frequent, followed by low-birth weight (LBW) infants, perinatal and postnatal. Such high frequency of LBW may have been due to a relative increase in survivors of premature babies because of recent advances in perinatal care. The brain computerized tomography/magnetic resonance imaging performed in 41 patients revealed congenital brain malformation (10 patients), destructive brain disorders (13 patients), and no structural abnormalities (18 patients). The seizure outcome was worse in the symptomatic WS than in the cryptogenic WS. The developmental outcome was very poor in both symptomatic and cryptogenic WS. The mean developmental quotient (DQ) in all patients was 25, and only four patients (11%) had a normal DQ (>70). DQ was lower in patients with developmental delay before the onset of WS, symptomatic group, relapse and/or persistence of seizure. Developmental delay seen in WS patients seems to be related to the two major factors, that is, underlying brain abnormalities and the persistent seizures as a result of the former. Therefore, every effort should be made to control seizures, including medical and early surgical treatment, as well as prevention of brain damage through perinatal care.

Infantile cytochrome c oxidase deficiency with neonatal death.

A newborn male presented with severe respiratory insufficiency, generalized muscle weakness, and lactic acidemia. Immediately after admission, he was placed on a respirator because of respiratory arrest. He deteriorated rapidly and died 75 hours after birth. There was notable variation in fiber size and an increased number of type 2C fibers in the quadriceps femoris muscle obtained at autopsy; however, no ragged-red fibers were observed with modified Gomori trichrome staining. Markedly decreased cytochrome c oxidase activity was demonstrated in skeletal muscle by biochemical and histochemical studies, while cardiac muscle demonstrated normal cytochrome c oxidase activity. Mitochondrial myopathy should be considered in the differential diagnosis of patients with neonatal respiratory distress syndrome.

[Long-term remission of a case of Burkitt's lymphoma accompanied by cardiac tamponade treated by surgical resection and intensive chemotherapy].

A 26-year-old woman was admitted to our hospital because of abdominal mass. She became ileus and an emergency operation was consequently performed. A histological examination of the abdominal tumor indicated proliferation of undifferentiated lymphoblasts with intermingled histiocytes so called "starry sky appearance". The diagnosis was Burkitt's lymphoma. On the 4th post-operative day, a cardiac tamponade became evident. The pericardial effusion contained many lymphoblasts and the diagnosis was pericarditis due to the invasion of lymphoma cells. The pericarditis was successfully treated by infusion of doxycycline into the pericardial space following drainage. The patient responded to systemic chemotherapy with complete remission. 7 courses of systemic chemotherapy along with intrathecal infusions for CNS prophylaxis were subsequently carried out. A state of complete remission has continued for more than 13 months. Cardiac tamponade accompanied by Burkitt's lymphoma is quite rare and has not ever been reported in Japan in our knowledge. The efficacy of surgical treatment before systemic chemotherapy and the series of intrathecal infusions for CNS prophylaxis was demonstrated in this case.

[Spectral analysis of heart rate variability in the dysfunction of the brainstem].

The heart rate variability, modulated by autonomic nervous system, has been reported to decrease in depression of the central nervous system, especially of the brainstem. To assess the brainstem dysfunction, we analyzed R-R interval values (the intervals between R waves of ECG) in 9 children (7 in comatose children and 2 in central apnea) by spectral analysis using an autoregressive model. The findings of spectral analysis were compared with those of auditory brainstem response (ABR). In comatose children with the brainstem dysfunction, the reduction of the total power was apparent before the appearance of ABR abnormality. In central apnea due to the dysfunction of respiratory center in brainstem, only the respiratory component decreased without the reduction of the total power or ABR abnormality. Spectral analysis of the heart rate variability is a useful means for assessment of the brainstem function.

[Epidemiological and clinical study of West syndrome in Nagasaki Prefecture, Japan].

To determine the occurrence, outcome, and prognostic factors of West syndrome (WS), we performed a retrospective epidemiological study of WS occurred in 47 children (26 boys and 21 girls) in Nagasaki prefecture during a recent 10-year period from 1989 to 1998. The incidence of WS was 3.1/10,000 live births. The mean age at onset of spasm is 6.3 months (range: 2 to 12 months). Thirty-nine patients (83%) had symptomatic WS, in which the prenatal causes (patients) were most frequent, followed by low-birth weight infants (patients), perinatal (patients) and postnatal (patients). The brain CT was performed in 37 patients, and revealed congenital brain malformations (9 patients), destructive brain disorders (12 patients), and no structural abnormalities (16 patients). The seizure outcome was worse in the symptomatic WS than in the cryptogenic WS; seizure/disappeared in 39% of the former and in 75% of the latter/developmental delay before the onset of WS, relapse of WS and persistence of seizures were associated with poor seizure outcomes. Among the remaining seizures at the time of this surveillance, a tonic seizure was most frequently observed, followed by the partial seizures. Lennox-Gastaut syndrome was observed in 2 patients only. Epileptic discharge in the latest interictal EEG were diffuse in 4.3%, focal or multifocal in 60.7%, and absent in 35%, suggesting that many patients with WS had cortical epileptogenic foci. The developmental outcome was very poor in both the symptomatic and cryptogenic WS. The mean DQ in all the patients was 25, and only 4 patients (11%) had a normal DQ (> 75). DQ was lower in patients with congenital brain malformations than in those with destructive brain disorders.

[Efficacy of FEM (5-fluorouracil, epirubicin, mitomycin C) therapy for resected advanced gastric cancer. Ehime Gastric Cancer Study Meeting].

Between April 1990 and March 1991, postoperative adjuvant chemotherapy for resected gastric cancer employing 5-fluorouracil, epirubicin and mitomycin C (FEM) was performed. Forty-two patients subjected to the therapy were considered to have positive serosal invasion and underwent curative operation. FEM therapy consisted of intraoperative intraperitoneal administration of mitomycin C (0.3-0.4 mg/kg) combined with 8 cycles of intravenous bolus injection of epirubicin (20 mg/body) every 2-3 weeks which was started 2 weeks after the operation. Daily oral administration of 5-fluorouracil (150-200 mg/body) was started 2 weeks after the operation and continued for more than 6 months. Thirty-four of the 42 cases were assessable. Major adverse effects were nausea, vomiting, and general fatigue. There were no cardiovascular symptoms. The cumulative two-year survival rate was 74.2%, and follow-up was still under way at this writing.

[A case of giant advanced breast cancer responding remarkably to CEFT therapy].

A fifty-two-year-old female was admitted with unresectable advanced giant breast cancer, which was attached to the chest wall and had a bone metastasis to the thoracic vertebrae. At first, depression and fixation were performed for the bone metastasis, and 2 courses of CEFT therapy were administered. One course was intra-arterial chemotherapy. After 2 courses of treatment, the tumor size was not changed, but tumor marker, CT and physical findings showed a remarkable improvement, and mastectomy could be performed. It was suggested that this regimen is very effective for advanced giant breast cancer.

[Catheter-induced thrombosis of the inferior vena cava--case report].

A 47-year-old woman was admitted for bleeding from gastric ulcer for which a central venous catheter was placed through the right femoral vein. Seven days later, abdominal echograms unexpectedly revealed a large thrombus along the catheter in the inferior vena cava. Because the echograms also disclosed the thrombus immobile even in postural change, the catheter was pulled out. Within two weeks following the catheter removal, the thrombus spontaneously disappeared with no evidence of pulmonary embolism. Although thrombolysis therapy may be the treatment of choice for catheter-induced thrombosis, simple removal of the catheter is effective in case that the thrombus is immobile.

[Neurological outcome associated with influenza viral infection].

Several neurological complications associated with Influenza virus infection are known as a febrile convulsion, polyneuritis, meningitis, encephalomyelitis and encephalopathy. Influenza encephalopathy is the most severe complication associated with Influenza. It may be classified into several subtypes according to the clinical symptoms and laboratory data. In this review, Reye's syndrome, acute necrotizing encephalopathy and hemorrhagic shock and encephalopathy syndrome (HSE) are described in detail. The 1995 influenza pandemia in Nagasaki prefecture was markedly neurovirulent and lethal. Twelve cases developed influenza encephalopathy, and the mortality rate between them was 50%. Almost all of them had never be inoculated of influenza vaccine before.