Synthesis of methyl dihydrohardwickiate and its C-4 epimer. Structural amendment of natural crolechinic acid.

Reduction of the alpha, beta-unsaturated ester moiety of (+)-methyl hardwickiate with magnesium in methanol afforded methyl (4aS,6S,8aS,1R,5R)-5, 6,8a-trimethyl-5-[2'-(3"-oxoyl)-ethyl-perhydro-1-naphthalenyl]- carboxaylate, while reduction with sodium in n-propanol, followed by esterification with diazomethane, furnished its C-4 epimer. After comparison of the 1H- and 13C-NMR data of these compounds with those reported for crolechinic acid isolated from Croton lechleri, a stereochemical revision for the natural product is suggested.

Clinical study on localization-related epilepsy in infancy without underlying disorders.

A clinical study of 15 patients without underlying disorders whose first seizures occurred before 1 year of age was performed to determine the characteristics of localization-related epilepsies in infancy. The patients were retrospectively divided into two groups: the seizure-controlled group (10 patients) and the refractory group (five patients). The seizure-controlled group included patients whose seizures were controlled completely within 1 year after onset; the refractory group included all other patients. The characteristics of the refractory group were as follows: (1) interictal electroencephalography showed focal abnormalities, particularly on the left side, and (2) all of the patients exhibited developmental retardation. Even in the seizure-controlled group, 40% of the patients exhibited developmental retardation, and all of them were indistinguishable from patients with benign complex partial epilepsies in infancy at the onset of the seizures. Aggressive treatment should be re-evaluated for early-onset localization-related epilepsies.

Endovascular and surgical treatment of a metameric spinal arteriovenous malformation.

Metameric spinal arteriovenous malformations (AVMs) refer to the lesions completely outside of the spinal cord and the surrounding dura. This paper presents an unusual metameric spinal AVM that was fed by multiple radiculomeningeal arteries and was located totally within the extradural space and the vertebral bodies. The metameric spinal AVM has an exclusive epidural venous drainage and presents as a distinct mass from the dural and the intradural spinal AVMs. Total removal of metameric spinal AVMs are sometimes difficult because of wide extension, profound bleeding, and spinal instability after resection. Therefore, the basic management strategy for these lesions is preoperative arterial or venous embolization and resection.

[A case of adult moyamoya disease showing fulminant clinical course associated with progression from unilateral to bilateral involvement].

We reported a case of adult moyamoya disease showing acute deterioration in which a unilateral occlusive lesion progressed to bilateral involvement during a period of 49 months. A 54-year-old male suffered from progressive weakness in his right extremities and disturbance of speech. On admission, neurological examination demonstrated mild right hemiparesis with global aphasia. A computed tomography (CT) scan showed a strange low density area in the territory of the left ACA and frontal branches of the left MCA. Left carotid angiography showed stenosis of the ICA at the terminal portion, occlusion of the ACA and MCA at each origin, and basal moyamoya vessels. Right carotid angiography demonstrated no occlusive lesions except for the general narrowing of the right ACA, without moyamoya vessels. This case was classified as adult-onset "probable" moyamoya disease according to the diagnostic criteria of the Japan Cooperative Research Committee. Left superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis was performed. The patient showed gradual amelioration of neurological symptoms, and was discharged on foot with mild motor aphasia. However, 4 years later he complained of weakness in his left lower extremity. A second cerebral angiography, performed 49 months after the initial angiography demonstrated severe stenosis of the left ICA at the terminal portion progressing in the proximal direction with decreasing basal moyamoya vessels, while severe stenosis extended from the terminal portion of the right ICA to the M1 portion with newly developed moyamoya vessels in the right basal area. At this time, we considered that this case was a definite case of moyamoya disease. The second cerebral angiography was completed uneventfully. However, the patient then suddenly showed acute deterioration 5 hours after the angiography. Emergent cerebral angiography disclosed an occlusion of the right ICA at the terminal portion. Thereafter he showed acute deterioration in consciousness. A CT scan at the time revealed a huge low density area in the territory of the right ACA and MCA. We performed emergent external decompression, but he did not recover from the sequelae of cerebral infarction and died 3 days later. This rare case suggested the possibility of progression to bilateral involvement although it was a case of adult-onset "probable" moyamoya disease. We consider that acute ischemic deterioration should be kept in mind especially in aged cases of adult-onset moyamoya disease. Careful observation should be performed by the serial MR angiography in adults with "probable" moyamoya disease even though they are clinically asymptomatic.

[Transient inhibitors developed in two cases of hemophilia A].

This report describes the transient development of inhibitors in two cases of hemophilia A. Case 1 was an 8-month-old boy who suffered from subcutaneous hematoma with extremely low level (1.5%) of plasma factor VIII activity (F VIII:C). He showed an inhibitor titer of 2.5 Bethesda units (BU)/ml when he suffered from measles at age 24 months with poor clinical response to factor VIII. This inhibitor elevated to 11.6 BU/ml at 29 months, but completely disappeared at 32 months. Case 2 was a 5-month-old boy who suffered from subcutaneous hematoma with extremely low level (< 1%) of plasma F VIII:C. At 8 months his inhibitor titer peaked at 19 BU/ml but subsequently declined to 11.5 BU/ml at 12 months and completely disappeared at 14 months. A review of the literature revealed that the median (range) titer of transient inhibitor initially developed at 2 (0.5-19) BU/ml on 225 (79-448) days, immediately peaked at 3.6 (0.5-60) BU/ml and disappeared by 665 (282-1140) days, suggesting that careful monitoring of F VIII inhibitors is required in the treatment of hemophilia A.

Adrenoleukodystrophy indicated by abnormal electro-encephalography.

An 8 year old boy with adrenoleukodystrophy and his asymptomatic brother, both with abnormal electro-encephalography as the initial sign of adrenoleukodystrophy, are reported. After suffering from aseptic meningitis caused by Echo virus 30, the first case was suspected of having a complication of meningitis because of persistent abnormal electro-encephalography (i.e. slow wave bursts in the occipital region). This patient was finally diagnosed as having adrenoleukodystrophy because of the increased level of very long chain saturated fatty acids, and typical occipital lesions demonstrated by magnetic resonance imaging and computed tomography. Dietary therapy was tried, but the course was progressive. The brother's electro-encephalography was also abnormal and so was diagnosed as having asymptomatic adrenoleukodystrophy because of an increased level of very long chain saturated fatty acids, although brain magnetic resonance imaging was normal. Abnormal electro-encephalography can therefore be an initial sign of adrenoleukodystrophy even if magnetic resonance imaging shows no abnormality in the brain.

Hyper-interleukin (IL)-6-naemia in haemophagocytic lymphohistiocytosis.

Clinical features in patients with haemophagocytic lymphohistiocytosis (HLH) have been demonstrated to be characterized by hypercytokinaemia. Previously, we reported the impact of high serum levels of interferon (IFN)-gamma and soluble IL-2 receptor (sIL-2R) on patient outcome; however, it was not known if serum levels of interleukin (IL)-6 also could be a prognostic factor. In a study during the active phase of disease in 25 cases of HLH in children and young adults (median age 3 years, range 0.1-23 years), we noted 12 cases which showed serum IL-6 > 100 (normal < 4.0) pg/ml. Five of these cases showed hyper-IL-6-naemia alone without hyper-IFN-gamma-naemia (group A) whereas seven cases showed both hyper-IL-6- and IFN-gamma-naemia (group B). Patient outcome did not differ between the patients with IL-6 > 100 pg/ml and those with IL-6 < 100 pg/ml, suggesting that high serum concentrations of IL-6 alone do not necessarily indicate poor prognosis in patients with HLH. Among the cases with hyper-IL-6-naemia ( > 100 pg/ml), underlying disorders causing haemophagocytosis were found to be different between groups A and B.

[Chemotherapy for B lymphoid malignancy in childhood--results in BLK88 protocol].

Ten cases of newly diagnosed pediatric B cell non-Hodgkin's lymphoma or acute lymphoblastic leukemia (B-NHL, stage I & II 6 cases, stage III & IV 2 cases/ALL 2 cases) experienced during the last 7 years (1987-1994) were treated by BLK88 protocol, which consisted of HD-CPM (1,200 mg/m2), and HD-MTX (1,000 mg/m2) with VCR, ADR, and/or AraC combination, and CNS prophylaxis by triple intrathecal injection. The therapy duration was 24 weeks for B-NHL (36 weeks for B-ALL). The results showed that while one of the six cases in stage I & II relapsed, and other 4 cases of stage III & IV B-NHL/ALL remained in complete remission. On the other hand, all of the four cases in stage III & IV in historical controls had relapsed. Neutropenia and liver dysfunction were observed during therapy, but they were tolerable. We conclude that BLK88 is a very useful protocol for B-NHL/ALL in childhood.

Intradural spinal lipomas not associated with spinal dysraphism: a report of four cases.

Intradural spinal lipomas that are not associated with spinal dysraphism are rare. We report four cases of adult patients with intradural spinal lipomas. All of the patients were young adults, three women and one man, who ranged in age from 22 to 37 years (mean, 30.3 yr). The clinical presentation of these lesions varied, depending upon the size and location of each lipoma. It is interesting that the symptoms in the women gradually deteriorated during pregnancy or after delivery. Magnetic resonance imaging was very useful in determining the exact location of lipoma. In three of four patients, neurological improvement was obtained after decompressive laminectomy and partial removal of the lipoma.

Serum and urine beta-2-microglobulin in hemophagocytic syndrome.

BACKGROUND: Previous reports suggesting a correlation between lymphoproliferative disease and serum levels of beta-2-microglobulin (beta-2M) and in vitro data indicating a role of cytokines in the production of beta-2M prompted a study of serum and urine beta-2M concentration in patients with hemophagocytic syndrome (HPS), because no data were previously available for HPS, a pathologic state associated with excessive cytokines secreted from activated reactive/malignant lymphocytes and histiocytes. METHODS: Serum and urine beta-2M levels were measured in six children with HPS during active and convalescent phase and in other diseases. RESULTS: Serum and urine beta-2M levels during active phase HPS were significantly high not only in serum (median, 7.5 mg/l; range, 2.3-16.0 mg/l; P < 0.01), but also in urine (median, > 31,650 micrograms/gram Creatinine (gCr); range, 8179-236,333 micrograms/gCr; P < 0.01), compared with levels during convalescent phase HPS (median, 2.0 mg/l; range, 0.9-2.5 mg/l in serum and median, 338 micrograms/gCr; range, 223-585 micrograms/gCr in urine) and in control subjects with diseases such as acute lymphocytic leukemia (median, 2.3 mg/l; range, 1.0-2.8 mg/l in serum and median, 327 micrograms/gCr; range, 48-2684 micrograms/gCr in urine), infectious mononucleosis (median, 2.9 mg/l; range, 2.5-5.5 mg/l in serum and median, 348 micrograms/gCr; range, 80-1325 micrograms/gCr in urine), and Kawasaki disease (median, 2.8 mg/l; range, 1.5-3.3 mg/l in serum and median, 1016 micrograms/gCr; range, 214-4500 micrograms/gCr in urine). Noteworthy was the observation that urine beta-2M levels correlated closely with HPS disease activity. CONCLUSIONS: Urine beta-2M appears to be a useful marker for assessing disease activity in patients with HPS.

Adenosine enhances neuronal damage during deprivation of oxygen and glucose in guinea pig superior collicular slices.

The purpose of the present study was to clarify whether adenosine has a neuroprotective effect against neuronal damage during deprivation of oxygen and glucose in superior collicular slices. After deprivation of oxygen and glucose for 7 min, the concentration of ATP in slices incubated with adenosine (100 microM) for 60 min was significantly higher (6.43 +/- 0.16 nmol/mg protein, mean +/- S.E.M.) than that in slices incubated without adenosine (4.77 +/- 0.61). The postsynaptic field potential (PSP) recorded in the superficial gray layer of the SC slice completely disappeared within 7 min after deprivation of oxygen and glucose and it recovered to approximately 80% of the original amplitude in the medium without adenosine. But, in the presence of adenosine (100 microM) during and after oxygen and glucose removal, the PSP showed only approximately 40% recovery. These results indicate that in the superior colliculus adenosine has no protective effect on functional derangement caused by anoxia although it may facilitate the resynthesis of tissue ATP during recovery.

Haemophagocytic lymphohistiocytosis, interferon-gamma-naemia and Epstein-Barr virus involvement.

To clarify the correlation between Epstein-Barr virus (EBV) involvement and hypercytokinaemia in haemophagocytic lymphohistiocytosis (HLH), we analysed serum interferon-gamma levels and EBV-DNA in biological specimens obtained from 25 HLH cases (23 children and two adults). We found that HLH patients showed a wide range of serum IFN-gamma levels from 0.2 to 1300 U/ml, with a median 126 U/ml for EBV-DNA-positive (n = 9) and 4.5 U/ml for EBV-DNA-negative (n = 16) groups. The latter group could be classified further into a group with hyper-IFN-gamma-naemia (> 4.5 U/ml) (n = 8) and a group without hyper-IFN-gamma-naemia (n = 8). The survival of the hyper-IFN-gamma-naemic cases was significantly poorer than non-hyper-IFN-gamma-naemic cases. We conclude that EBV is probably involved in one third of the HLH cases, all of whom show hyper-IFN-gamma-naemia, and in the half of the HLH cases with hyper-IFN-gamma-naemia who have a rapidly fatal outcome.

A case of bacterial meningitis complicated by post-traumatic cerebrospinal fluid rhinorrhea.

This paper reports an 11 year old boy with bacterial meningitis accompanied by post-traumatic cerebrospinal fluid (CSF) rhinorrhea. Streptococcus pneumoniae was cultured from CSF. The clinical course was very rapid before admission and his age relatively high for usual bacterial meningitis. Consequently, we examined the cause in detail. Immunological findings were within normal limits. Although routine graphic examinations, such as cranial X-ray photography, horizontal cranial computed tomography (CT) and magnetic resonance imaging, could not demonstrate a bone defect, both coronal thin-section cranial CT scanning and radioactive isotope counting by means of cotton packed into the nasal cavity were useful for detecting CSF rhinorrhea. In a case of atypical meningitis, the past history should be examined with caution and coronal thin-section CT should be performed.

Hypercytokinemia in hemophagocytic syndrome.

PURPOSE: The study was performed to clarify in the hemophagocytic syndrome (HPS) how cytokinemia plays a role in its pathogenesis and if cytokinemia is of prognostic value. PATIENTS AND METHODS: Serum concentrations of ferritin, interferon (IFN)-gamma, soluble interleukin-2 (IL-2) receptor, IL-6, and other cytokines were determined during the acute phase of the HPS in 29 children and three adults. Data comparing malignancy-associated (MAHS; n = 17) and infection-associated hemophagocytic syndrome (IAHS; n = 15) and those comparing surviving and fatal cases were assessed. RESULTS: Hyperferritinemia and hypercytokinemia were present in all patients with HPS. Eleven of the 17 MAHS and three of the 15 IAHS cases were fatal (p < 0.05). No significant difference in cytokine concentrations was observed between MAHS and IAHS. CONCLUSIONS: In terms of cytokine effect on patient outcome, serum concentrations of IL-6 > 300 ng/L and IFN-gamma concentrations > 30 U/ml or soluble IL-2 receptor (sIL-2R) concentrations > 10,000 U/ml were considered to reflect a poor prognosis in HPS patients.

Measurement of the ratio of lecithin to sphingomyelin in amniotic fluid by fast atom bombardment mass spectrometry.

We describe a fast atom bombardment mass spectrometric method to determine the ratio of lecithin to sphingomyelin in amniotic fluid. Between m/z 400 and 1000, amniotic fluid extracts showed clear peaks for only sphingomyelin and lecithin. The molecular species of fatty acid in the phospholipids were analyzed quantitatively and quickly in a small volume of the extracts. The dipalmitoyllecithin/palmitoylsphingomelin ratio, determined by the proposed method, showed a reasonable correlation to the lecithin/sphingomyelin ratio measured by thin-layer chromatography. This method allows rapid and sensitive measurement of these phospholipids.

Effects of polyunsaturated fatty acids on vincristine-resistance in human neuroblastoma cells.

PUFAs such as GLA (n-6) or DHA (n-3) were shown to exert antitumor activity on a human neuroblastoma cell line (NCG) and its VCR-resistant subline (NCG/VCR1, 8.6-fold resistant to VCR) in vitro. The NCG/VCR1 line had markedly decreased intracellular accumulation of [3H]-VCR and an accelerated drug efflux, compared to the NCG. The cytotoxic activity of PUFAs was correlated with the generation of MDA-like products in these cells. When VCR was added simultaneously with GLA or DHA to culture medium, the cytotoxic effect of VCR was about 2-fold enhanced, accompanied by about 1.5-2.0-fold increase of intracellular [3H]-VCR in both cell lines. Fatty acid analysis of membrane phospholipids of the NCG and the NCG/VCR1 cells treated with GLA or DHA showed an increased total PUFAs and SFAs, associated with markedly decreased total MUFAs and an inverted PUFAs/MUFAs ratio. Such phospholipid modification may have altered the membrane physical properties and enhanced the VCR cytotoxicity by increasing intracellular VCR accumulation; however, these PUFAs did not affect the drug efflux sufficiently enough to overcome completely the VCR resistance in the NCG/VCR1 cells. These results indicate that PUFAs partially alleviate the VCR-resistance in human neuroblastoma cells, not directly acting on VCR-resistance mechanism(s).

Complement function and the synthesis of lung surfactant may be a regulation which preterm infants have in common.

The levels of CH50, the complement components, C1q, C4, and C3, C3 degradation fragments, and factor B were determined in the cord blood of 128 newborn infants. The levels of C3, C4, and C3d3 (an index of chronic in vivo complement activation) were clearly lower in the 28 infants with respiratory distress syndrome (RDS) than in the infants with other lung diseases or with normal lungs. CH50 and factor B levels were also low in RDS. Levels of C1q and other serum components in RDS infants were similar to the average levels in other infants without RDS at a corresponding gestational age. Lung surfactant is synthesized in alveolar type 2 cells, in which the complement components C4, C3, and factor B, but not C1q, have been reported to be synthesized. It seems possible that common factors regulate the synthesis of some complement components and surfactant.

Comparative study of computerized trapezoid rotation test and sinusoidal harmonic acceleration test.

By using the Contraves computerized rotary chair system, trapezoid rotation (TR) test and sinusoidal harmonic acceleration (SHA) test were performed on each subject on the same day. The results in 25 normal volunteers and 145 patients with peripheral vestibular disorders were as follows: 1) As regards directional preponderance, the results of two rotation tests agreed in 75.9% of all patients, but a discrepancy was found in the rest. Abnormality was detected by TR test in 57.2% of all patients, and, less frequently, in 45.5% by SHA test. 2) In normal subjects, the maximum slow phase velocity of nystagmus provoked by TR test was greater than that of nystagmus provoked by SHA test using angular acceleration of a magnitude comparable to that in TR test. 3) As to the detection of abnormal VOR gain, the results of two rotation tests agreed in 100% of patients with bilateral vestibular disorders. However, in patients with unilateral vestibular disorders, the detection rate was higher for SHA test than that for TR test.