Time-Reversal Measurement of the p-Wave Cross Sections of the

The cross sections of the ^{7}Be(n,α)^{4}He reaction for p-wave neutrons were experimentally determined at E_{c.m.}=0.20-0.81 MeV slightly above the big bang nucleosynthesis (BBN) energy window for the first time on the basis of the detailed balance principle by measuring the time-reverse reaction. The obtained cross sections are much larger than the cross sections for s-wave neutrons inferred from the recent measurement at the n_TOF facility in CERN, but significantly smaller than the theoretical estimation widely used in the BBN calculations. The present results suggest the ^{7}Be(n,α)^{4}He reaction rate is not large enough to solve the cosmological lithium problem, and this conclusion agrees with the recent result from the direct measurement of the s-wave cross sections using a low-energy neutron beam and the evaluated nuclear data library ENDF/B-VII.1.

Candidate Resonant Tetraneutron State Populated by the

A candidate resonant tetraneutron state is found in the missing-mass spectrum obtained in the double-charge-exchange reaction ^{4}He(^{8}He,^{8}Be) at 186 MeV/u. The energy of the state is 0.83±0.65(stat)±1.25(syst) MeV above the threshold of four-neutron decay with a significance level of 4.9σ. Utilizing the large positive Q value of the (^{8}He,^{8}Be) reaction, an almost recoilless condition of the four-neutron system was achieved so as to obtain a weakly interacting four-neutron system efficiently.

Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene.

OBJECTIVE: Severe congenital neutropenia (SCN), also known as Kostmann syndrome (SCN3, OMIM 610738), includes a variety of haematological disorders caused by different genetic abnormalities. Mutations in ELA2 are most often the cause in autosomal dominant or sporadic forms. Recently, mutations in HAX1 have been identified as the cause of some autosomal recessive forms of SCN, including those present in the original pedigree first reported by Kostmann. We sought to determine the relationship between HAX1 gene mutations and the clinical characteristics of Japanese cases of SCN. METHODS: The genes implicated in SCN (ELA2, HAX1, Gfi-1, WAS, and P14) were analysed in 18 Japanese patients with SCN. The clinical features of these patients were obtained from medical records. Immunoblotting of HAX1 was performed on cell extracts from peripheral blood leucocytes from patients and/or their parents. RESULTS: We found five patients with HAX1 deficiency and 11 patients with mutations in the ELA2 gene. In HAX1 deficiency, a homozygous single base pair substitution (256C>T), which causes the nonsense change R86X, was identified in three affected individuals. Two sibling patients showed a compound heterozygous mutation consisting of a single base pair substitution (256C>T) and a 59 bp deletion at nucleotides 376-434. There was no detectable phenotype in any heterozygous carrier. All patients with HAX1 deficiency had experienced developmental delay. Three patients carrying R86X also suffered from epileptic seizures. In contrast, no SCN patient with heterozygous mutations in the ELA2 gene suffered from any neurodevelopmental abnormality. CONCLUSIONS: These findings suggest that the R86X mutation in the HAX1 gene is an abnormality in Japanese SCN patients with HAX1 deficiency and may lead to neurodevelopmental abnormalities and severe myelopoietic defects.

Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency.

HAX1 deficiency has recently been identified as a cause of severe congenital neutropenia (SCN), but little is known about the phenotype. We described an SCN patient with a homozygous 256C-to-T transition causing an R86X mutation in the HAX1 gene. Notably, the patient has been complicated by epilepsy and severe delay of motor, cognitive, and intellectual development; each developmental quotient was 21-26 at 7 years old. Growth failure and dental development delay were also noted. Neurodevelopmental delay in this patient expands the clinical phenotype of HAX1 deficiency and suggests an important role of HAX1 on neural development as well as myelopoiesis.

Serum lipid metabolism abnormalities and change in lipoprotein contents in patients with advanced-stage renal disease.

BACKGROUND: Arteriosclerosis is the major cause of death in patients with chronic renal failure. There is much interest in the lipid metabolism of patients treated with hemodialysis. METHODS: We analyzed low-density lipoproteins (LDL) and high-density lipoproteins (HDL) in chronic renal failure (CRF) patients according to patients on hemodialysis (HD), patients with diabetic nephropathy before initiation of dialysis (DN), and patients with chronic glomerulonephritis in the conservative stage (CGN); and compared the lipid metabolic abnormalities in patients on hemodialysis and those not yet on hemodialysis. We also analyzed the qualitative abnormalities of LDL and HDL and their relationship with the pathological stages. RESULTS: Electrophoretic patterns identified small LDL particles and small HDL particles in the three groups, and the degree of denaturation was more enhanced in CRF patients in the conservative stage than in HD patients. For LDL susceptibility to oxidation LDL (oxLDL) by addition of Cu(2+), the lag time was approximately 57 min in healthy controls and CGN patients, but was prolonged to approximately 75 min in HD and DN patients. For HDL susceptibility to oxidation HDL (oxHDL), HD, DN and CGN patients showed lag times shorter than those found in healthy control subjects. These results showed that LDL and HDL in the serum of CRF patients were in a state of enhanced susceptibility to oxidative modification. In Western blot analysis using anti-human-denatured LDL and anti-human-oxidized HDL monoclonal antibodies, bands of low molecular oxLDL at 150-197 kDa were detected in all CRF patients, with marked tailing in CGN patients. Similarly, bands of small oxHDL particles at 110 and 120 kDa were found in HD, DN and CGN patients. CONCLUSIONS: Oxidative modification of both LDL and HDL occurs in patients with advanced CRF resulting in small lipoproteins. Increased production of oxLDL and oxHDL is the main cause of lipid metabolic abnormality in CRF patients.

Atypical alkaline phosphatase isozymes in serum and urine of patients with renal failure.

BACKGROUND: Alkaline phosphatases (ALPs) originating from different organs are frequently detected in the serum and urine of patients with renal failure. METHODS: We investigated the characteristics of ALPs in the serum and urine of 108 patients with chronic renal failure (CRF) and of 106 healthy control subjects. RESULTS: In polyacrylamide gel electrophoresis, three atypical ALP bands in serum of patients were designated as atypical-s1, -s2 and -s3, respectively. In contrast, five atypical bands (u1, u2, u3, u4 and u5) were detected in the urine of patients. The atypical ALPs were electrophoretically isolated and assayed to determine their biochemical properties, i.e., neuraminidase sensitivity, heat stability, reactivity to anti-intestinal or anti-tissue nonspecific ALP antibodies, molecular sizes and sugar chain heterogeneities. From these results, we found that atypical-s1 and -s2 were the intestinal-type ALP, while s3 was the tissue-unspecific type ALP. Atypical-u1, -u2 and -u3 were high-molecular type ALPs, which we suggested as the ones that originated from the intestine. Atypical-u4, a tissue-unspecific type ALP, was detected with considerable frequency in the urine of patients. In patients with CRF, the appearance of these atypical ALPs was accompanied by a deterioration of the creatinine clearance. CONCLUSIONS: The appearance of atypical ALPs in the serum and urine of patients with CRF may be a useful marker for renal disease.

[Subependymoma of the lateral ventricle: a case report].

We report a case of subependymoma of the right lateral ventricle in a 59-year-old man. CT revealed a mass lesion in the right lateral ventricle. No calcification was seen in the tumor, and the right lateral ventricle was dilated dominantly by the tumor. The tumor showed intermediate intensity on T1-weighted MR images and high intensity on T2-weighted MR images. On contrast study, the tumor showed heterogeneous enhancement. We suspected this to be a case of central neurocytoma, and surgical resection was performed. The histological diagnosis was subependymoma, but we considered it difficult to differentiate from astrocytoma, central neurocytoma, and ependymoma.

Increased expression of insulin-like growth factor I in skin in amyotrophic lateral sclerosis.

OBJECTIVES: Insulin-like growth factor I (IGF-I) has potent effects on motor neuron survival and is being studied as a possible therapeutic agent for ALS. However, little is known concerning IGF-I in the skin of patients with amyotrophic lateral sclerosis (ALS). The aim was to evaluate IGF-I immunoreactivity of skin in patients with ALS. METHODS: IGF-I immunoreactivity of skin from 18 patients with ALS and 16 controls was examined. RESULTS: IGF-I immunoreactivity was markedly positive in the epidermis and dermal blood vessels and glands and was moderately positive in the reticular dermis in all patients with ALS. On the other hand, the epidermis and dermal blood vessels and glands and the reticular dermis showed a weak IGF-I immunoreactivity in controls. The optical density for IGF-I immunoreactivity of the epidermis and dermal blood vessels and glands, and the reticular dermis in patients with ALS was significantly higher than in diseased controls, and was significantly increased with duration of illness. CONCLUSIONS: These data suggest that a metabolic alteration of IGF-I may take place in the skin of patients with ALS.

Serum markers of type I collagen synthesis and degradation in amyotrophic lateral sclerosis.

Collagen abnormalities in the skin and spinal cord have been reported in amyotrophic lateral sclerosis (ALS) patients. Serum carboxyterminal propeptide of type I procollagen (PICP) and the carboxyterminal cross-linked telopeptide of type I collagen (ICTP) reflect type I collagen synthesis and degradation, respectively. However, there has been no study concerning PICP or ICTP in ALS. We studied collagen contents of the skin and measured serum levels of PICP and ICTP in patients with ALS and control subjects. Serum PICP levels were significantly lower in ALS patients than in controls. Serum ICTP levels were significantly higher in ALS patients than in controls, and there was an appreciable positive correlation between serum ICTP levels and the duration of illness in ALS patients. In ALS patients, the collagen content of the skin was significantly smaller than in controls and indicated a progressive decrease in relation to illness. In addition, there was a significant negative correlation between serum ICTP concentrations and the collagen content of the skin in ALS patients. These data suggest that increased ICTP levels and decreased serum PICP levels may reflect unique changes in the skin, with a predominance of degradation compared to the synthesis of type I collagen in ALS.

Decreased plasma levels of fibronectin in amyotrophic lateral sclerosis.

OBJECTIVES: Fibronectin (FN) possesses a wide range of biological functions. However, the role of plasma FN in vivo has not yet been established and there have been no published studies of plasma FN in ALS. The aim of this study was to measure plasma FN in ALS patients. MATERIAL AND METHODS: We measured plasma FN levels in 28 ALS patients, 18 control subjects with other neurologic or muscular diseases (control group A) and 21 healthy adults (control group B). The age and sex distributions among the 3 groups were comparable. RESULTS: Plasma FN levels were significantly lower in ALS patients than in control groups A and B. There was also a significant negative correlation between plasma FN levels and duration of illness in ALS patients. CONCLUSION: These data suggest that a metabolic alteration of FN may take place in ALS and that the measurement of plasma FN may serve as an indicator of clinical progression of this disorder.

Granulocyte-colony stimulating factor enhances anti-tumour effect of hyperthermia.

The combined effect of granulocyte-colony stimulating factor (GCSF) and hyperthermia in the treatment of experimental tumours was studied to examine the possible involvement of activated granulocytes in the antitumour effect of hyperthermia. Two weeks after transplantation of SCC VII cells (1 x 10(5)) into the instep of the left leg of C3H/HeJ male mice, the mice were given subcutaneous injections of GCSF (0.2 mg/kg) for 4 days. On day 4, hyperthermia was applied locally at 43 degrees C for 40 min. Hyperthermia inhibited the tumour growth, and this effect was enhanced by pre-treating the animals with GCSF. The numbers of circulating neutrophils in control and GCSF-treated mice were 2728 +/- 517/microl and 3124 +/- 194/microl, respectively (p = 0.53). Hyperthermia increased the number of neutrophils to 4409 +/- 700/microl (p < 0.05). Hyperthermia combined with GCSF significantly increased the number of netrophils to 5479 +/- 691/microl (p < 0.01). Chemiluminescence analysis using L-012 revealed that GCSF enhanced the generation of reactive oxygen species by about 10-fold. Glutathione contents in tumours 24 h after hyperthermia decreased by about 50% in both the hyperthermia groups with or without GCSF, as compared to those in the control. The GCSF-enhanced anti-tumour activity of hyperthermia was markedly inhibited by administration of a long-acting superoxide dismutase derivative (SM-SOD). These results suggest that GCSF activates the ability to generate active oxygen species by neutrophils and, thereby, enhances the anti-tumour effect of hyperthermia.

Novel potassium channel opener prodrugs with a slow onset and prolonged duration of action.

(-)-(3S,4R,1'R,6'S)-4-(4-Benzyl-5-oxo-3,4-diazabicyclo[4.1.0]hept-2-en-2 -yloxy)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbo nitrile and its derivatives with a modified benzyl group were synthesized with the objective of discovering novel ATP-sensitive potassium channel openers (PCOs) with a slow onset of action and a reduced tendency to induce tachycardia. Among the compounds synthesized, 4-(2-chlorobenzyl) derivative 5bB had potent hypotensive activity in spontaneously hypertensive rats (SHRs). In addition, compound 5bB showed the desired pharmacological profile with a slow onset and long duration of action and induction of only mild tachycardia. Compound 5bB was found to be quantitatively metabolized in rats to give active des-2-chlorobenzyl derivative 6B. These results suggest that the incorporation of an N-benzyl group is a useful method for the preparation of prodrugs, the function of which is to delay the onset and prolong the duration of action of the active substance.

Increased serum hyaluronic acid in amyotrophic lateral sclerosis: relation to its skin content.

BACKGROUND: Abnormalities of hyaluronic acid (HA) of skin have been reported in patients with amyotrophic lateral sclerosis (ALS). However, little is known concerning the changes of serum HA in ALS. The purpose of this study was to investigate skin HA content and serum HA levels in ALS patients. METHODS: We measured skin HA content and serum HA levels in patients with ALS, and compared the results with those of control subjects. RESULTS: Skin HA content in ALS patients was significantly higher than in diseased control subjects and control subjects without neurological disorders, and increased significantly, the longer the duration of illness. Serum HA concentrations in patients with ALS were significantly higher than in diseased control subjects and in healthy control subjects, and were positively and significantly associated with duration of illness. There was an appreciable positive correlation between serum HA concentrations and skin HA content in ALS patients. CONCLUSION: These data suggest that a metabolic alteration of HA may take place in ALS and increased levels of serum HA may reflect an increased content of skin HA in ALS.

[Inter-examiner reliability of nerve conduction measurements].

A total of 122 patients were performed motor and sensory nerve conduction studies of the upper limb by two examiners (1. doctor, 2. medical technician) to know the inter-examiner reliability of nerve conduction measurements. Subjects contained normal individuals and various types of neuropathy patients. Motor nerve conduction studies were carried out in the median nerve, and antidromic sensory nerve conduction studies were performed in the median and ulnar nerves. F-wave latency of the median nerve and sensory conduction velocity between finger and wrist of the median and ulnar nerves presented the equal mean value between two examiners. A relatively good correlation between two examiners was pointed out in the distal motor latency and F-wave latency. Inappropriate measurements were caused by the differences in the site of placement of stimulating or recording electrodes and effects of submaximum stimuli or stimulus spread to other nerves. In sensory nerve conduction studies, especially in the ulnar nerve, careful attention should be paid to avoid the influence of motor artifact in giving supramaximum stimuli. Amplitude measurements showed larger inter-examiner difference than latency or velocity measurements. We reported the present condition of measurement reliability. We should do our best to minimize the error.

Effect of lactic acid in tumours on antitumour activity of hyperthermia.

The change of lactic acid concentration in the tumour after intraperitoneal administration of 5 g/kg glucose, and the effect of the lactic acid concentration on antitumour activity of hyperthermia were studied in an experimental murine tumour. The lactic acid concentration in SCC VII tumours transplanted into the legs of C3H/HeJ male mice was measured by gas chromatography. Local hyperthermic treatment to the tumour was performed with a water bath at 43 degrees C for 40 min. Antitumour effects were evaluated by measuring tumour volume doubling time (DT) as an index. The mean concentration of lactic acid in the tumour was 10.4 mumol/g in the no-treatment group. The lactic acid concentration gradually increased after glucose administration, reaching a significantly high concentration of 20.0 mumol/g at 90 min later. The DTs in the no-treatment group and hyperthermia alone group were 2.4 and 3.7 days respectively. The DTs in the glucose administration groups shortly before, 30 and 60 min before the hyperthermia were 3.6, 3.6 and 5.6 days respectively. The DT in the 60 min group was significantly extended (p < 0.0001). Hyperthermia during the period of increased lactic acid concentration significantly prolonged the DT of the tumour. These results clearly showed that an increase of lactic acid concentration in the tumour improved the effect of local hyperthermia.

Pharmacokinetics and radiosensitizing effect of PR-350.

PURPOSE: The in vivo pharmacokinetics and sensitizing effects of PR-350, a newly developed, highly water-soluble radiosensitizer were examined. MATERIALS AND METHODS: C3H/HeJ mice bearing SCC-VII tumor cells were used in the experiments. Results were compared with those of PR-28 and SR-2508. RESULTS: The intratumoral concentration of PR-350 reached the maximum value of 77.7 mg/kg 20 min after intravenous injection. The concentration in the brain was below the detection limit. The enhancement ratios of PR-350 calculated using the growth delay method were 0.9 for PR-350 at 50 mg/kg and 1.4 for PR-350 at 100 mg/kg, compared with 1.4 for SR-2508 at 100 mg/kg and 1.0 for PR-28 at 100 mg/kg. CONCLUSION: PR-350 and SR-2508 revealed similar sensitizing effects. The side effects of PR-350 are expected to be equal to or less than those of SR-2508. PR-350 seems to be a promising radiosensitizer.

Effects of thermochemotherapy [1-hexylcarbamoyl-5-fluorouracil (HCFU) combined with hyperthermia]: a basic study on the most effective timing and sequence in vivo.

1-Hexylcarbamoyl-5-fluorouracil (HCFU) is known to be hydrolyzed to 5-fluorouracil (5-FU) by heating. We have previously reported the enhancement of the antitumor effects of HCFU when combined with hyperthermia (1). This study aimed at determining the most effective timing schedule for HCFU combined with hyperthermia for clinical application. On the third, 6th, 9th, 12th and 15th day after transplantation, HCFU (80 mg/kg) was administered and hyperthermia induced. The antitumor effect was evaluated by the measurement of tumor volume. 5-FU concentration in the tumor tissue was analyzed on the 12th day after transplantation after administering 150 mg/kg HCFU, with or without hyperthermia (43.5 degrees C, 45 min). 5-FU concentration in serum and other tissues (kidney, liver and submandibular gland) were also analyzed. The concentration was measured by a high performance liquid chromatograph (HPLC) following Mori et al 's method (2). An enhanced antitumor effect and a significant increase in 5-FU concentration in tumor tissue were observed in post-heated groups of mice as compared with pre-heated groups and groups given HCFU alone. The results showed that HCFU given 1 to 2 hours prior to hyperthermia was the most effective treatment.

Identification of major biliary and urinary metabolites of ecabapide in rats.

1. The structures of major biliary and urinary metabolites of ecabapide in rat were identified by comparison with authentic standards using lc-ms and 1H-nmr spectrometry. 2. A major metabolite was found in the bile obtained from rat after an oral dose of 14C-ecabapide and identified as the amidaldehyde derivative. In the urine, two polar metabolites were characterized as the phenolic sulphates. Further, two lipophilic metabolites were identified as alcohol derivatives, and two others as oxamic acids. 3. From these results, it was estimated that the first step in the metabolism of ecabapide in rat was oxidative N-dealkylation to produce the amidaldehyde. This amidaldehyde was further metabolized by two routes, one by reduction of the amidaldehyde into the corresponding alcohol followed by mono-demethylation and subsequent aromatic O-sulphation, the second by oxidation of the amidaldehyde into the oxamic acid followed by mono-demethylation and subsequent aromatic O-sulphation.

[Expression of CD44 variant 6 and its metastatic potential in squamous cell carcinoma of the oral cavity].

Using antihuman CD44 variant 6 monoclonal antibody (2F10), immunohistochemical screenings were performed for 38 oral squamous cell carcinoma cases and 10 oral mucosa in healthy cases as normal counterpart. Normal epithelium in the oral surface was stained intensely by the antibody. The reactivity was particularly strong in the spinous layers of stratified squamous epithelium. Cells in the basal layers exhibited moderate staining. In contrast, expression of CD44v6 tended to be downregulated in 38 oral squamous cell carcinoma materials. Interestingly, more faint or no staining by the anti-CD44v6 monoclonal antibody was found in the primary squamous cell carcinomas involving regional lymphnode metastasis. Downregulation of CD44v6 isoform was suggested to occur during regional lymphnode metastasis on oral squamous, cell carcinomas.

Enhancement of antitumor effects of new analogue of platinum, cis-diammine (glycolato) platinum (254-S) combined with hyperthermia in vivo.

Cis-diammine (glycolato) platinum (254-S) is a second generation platinum complex with reduced nephrotoxicity. In this study the antitumor effect of 254-S combined with hyperthermia in vivo in mice was studied. On the 6th day after inoculation of the Ehrlich ascites tumour cells, 254-S (15mg/kg) was administered intraperitoneally (i.p.) and hyperthermia was induced by using a circulating water bath at 42.5 degrees C for 45 min. The antitumour effect was evaluated by relative tumour volume. Furthermore, platinum concentration in tumour tissue was determined by using atomic absorption spectrophotometry. The most effective condition was found to be the combination of 254-S with hyperthermia. A significantly higher concentration of platinum in the tumour tissue was observed when treatment with 254-S was combined with hyperthermia, than with treatment using 254-S alone. Our study suggested that the accumulation of 254-S in the tumour tissue, and its retention at a high concentration within the tumour tissue long term was one of the reasons for the enhancement of antitumour effect of 254-S treatment when combined with hyperthermia.