Association between K469E allele of intercellular adhesion molecule 1 gene and inflammatory bowel disease in a Japanese population.

BACKGROUND AND AIMS: The genetic contribution to inflammatory bowel disease (IBD) is under investigation. Recent evidence indicates a significant linkage between a locus on chromosome 19p13 and IBD. We investigated the association between an intercellular adhesion molecule 1 gene (ICAM-1) polymorphism located on chromosome 19p13 and IBD in a Japanese population. METHODS: We compared 207 Japanese patients who had IBD (79 with Crohn's disease (CD); 128 with ulcerative colitis (UC)) with 103 unrelated Japanese controls. We determined R241G and K469E polymorphisms of the ICAM-1 gene using polymerase chain reaction (PCR) techniques. RESULTS: Both frequency and carriage rate of the K469 allele were significantly higher in IBD patients than in controls (allelic frequency, p(c)=0.0026; carriage rate, p(c)=0.0034; odds ratio 2.59; 95% confidence interval 1.42-4.68). Furthermore, the frequency of the K469 allele was significantly increased in both CD and UC. Subgroup analysis demonstrated that both K469 allelic frequency and K469 carriage rate were significantly higher in patients with the small bowel and colon type of CD and entire colitis compared with healthy controls. CONCLUSIONS: We identified an overall association between IBD and ICAM-1 K469 in a Japanese population. Further studies of this chromosome region are required to elucidate the gene responsible for IBD.

[Two siblings with eyelid myoclonia with absences].

We report two siblings with eyelid myoclonia with absences. Patient 1, a 7-year-old boy, visited us because of eyelid blinking resembling a tic. He had experienced the movements since 2 years old. The diagnosis of a simple motor tic was initially made, however, the episodes worsened gradually. Patient 2, a younger brother of patient 1, was a 5-year-old boy. His eyelid blinking also began at age of 2 years. Additionally, the mother's aunt and her cousin had a history of grand mal on awakening, and the patient's cousin has febrile seizures. Their clinical features were as follows; (i) eyelid myoclonia, described as rapid, rhythmic eyelid fluttering with upward jerking of the eyes and head, lasting for 1-2 seconds; (ii) it occurred frequently each day; (iii) when it lasted for more than 2-3 seconds, it was associated with absences; (iv) both hyperventilation and photic stimulation on 18 f/c induced clinical seizures; and (v) ictal EEG revealed 3-4 c/s generalized irregular spike-waves with a duration of 1-3 seconds. Based on these characteristics, a diagnosis of eyelid myoclonia with absences was made. The present cases are the first sibling cases reported in Japan and, according to their family history, a genetic predisposition should be considered.

Stratification analysis of MICA triplet repeat polymorphisms and HLA antigens associated with ulcerative colitis in Japanese.

We previously reported a conserved haplotype of HLA B52-DR2 and a significantly high frequency of the major histocompatibility complex (MHC) class I chain-related gene A (MICA) transmembrane-short tandem repeat (TM-STR) 6 allele in Japanese patients with ulcerative colitis (UC). To examine the predominance of the MICA TM-STR 6 allele as a marker of the susceptibility to UC within the susceptible haplotype, the association of each allele with UC was estimated following stratification of the patients to control for any possible confounding effects of other alleles positively associated with UC. Sixty-four patients with UC and 236 unrelated healthy controls were included in this study. All subjects were Japanese. HLA-A, -B, -C, and -DR antigens were determined serologically. A triplet repeat polymorphism of the MICA was determined by direct sequencing. To control for the effect of linkage disequilibrium, Mantel-Haenszel weighed odds ratios were calculated. Significantly higher phenotype frequencies of B52, MICA TM-STR 6, and DR2 were observed in patients with UC. Linkage disequilibria among alleles associated with UC revealed that a B52 - MICA TM-STR 6 - DR2 haplotype was conserved in patients with UC, as in controls. When the association of HLA-B52 was estimated after patient stratification for the possible confounding effect of MICA TM-STR 6 or DR2, a strong significant association of B52 with UC was still observed. In contrast, no association with UC was observed for MICA TM-STR 6 or DR2, after stratification of the possible confounding effect of HLA-B52. These results imply that the significant increase in MICA TM-STR 6 in Japanese patients with UC is attributable to linkage disequilibrium with HLA-B52.

[Factors related to satisfaction level in daily life for older people].

The purpose of this study was to examine relations between satisfaction levels and life-style in daily life for older people. A questionnaire, based on 7 factors of life satisfaction level and 13 factors of life-style chosen after considering theoretical validity, was administered to 1,320 healthy people aged 60 or more in the community (665 males and 655 females). Remarkable gender and grade differences were confirmed in the "physical health" satisfaction level. Satisfaction level for "personal relations" related to the number of friends for both sexes and to volunteer activities for males. The influence of the life-style factor on satisfaction level was highest in physical health. The influence of the number of friends was high for each satisfaction level. It was inferred that there are many aspects of life-style backgrounds contributing to the satisfaction level of older people in the community, and individual satisfaction with daily life is affected by different life-style factors.

[A case of successful management of nonresectable pancreas cancer with liver metastasis by intra-arterial infusion chemotherapy with angiotensin-II and administration of tegafur/uracil].

Nontypical chemotherapy regimens exist for advanced pancreatic cancer. We herein report a 62-year-old man whose nonresectable pancreatic cancer was treated effectively with a new method of intra-arterial regional chemotherapy with angiotensin-II (AT-II). The patient was admitted to our hospital with obstructive jaundice and anorexia. He was diagnosed as having inoperable advanced pancreatic cancer with liver metastasis. Enteric-coated tegafur/uracil (400 mg) was administered for 3 weeks. Simultaneously, intraarterial infusion with 5-fluorouracil (500 mg) and infusion of methotrexate (100 mg) with 50 micrograms of AT-II was given every week. A catheter connected to a subcutaneously implanted port system was placed into the common hepatic artery. As a result of this treatment, the maximum diameter of the pancreatic tumor decreased from 3 cm to 2 cm on the CT-scan. Serum carbohydrate antigen 19-9 (CA19-9) decreased from 24,000 U/ml to 186 U/ml. Moreover, the performance status of patient also improved, and he was discharged from our hospital despite his terminal cancer. This regimen could well be effective in cases of advanced pancreatic cancer.

Age-related volumetric changes of brain gray and white matter in healthy infants and children.

To date there is little information about brain development during infancy and childhood, although several quantitative studies have shown volume changes in adult brains. We performed three-dimensional magnetic resonance imaging (3D-MRI) in 28 healthy children aged 1 month to 10 years. We examined the volumes of whole brain and frontal and temporal lobes with an advanced method for segmenting images into gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) compartments. Growth spurts of whole brain and frontal and temporal lobes could be seen during the first 2 years after birth. During this period the frontal lobes grew more rapidly than the temporal lobes, the right--left asymmetry was more noticeable in the temporal lobes than in the frontal lobes and the increase in GM was larger than that in WM in the temporal lobes. Subsequently, WM volume increased at a higher rate than GM volume throughout childhood. Quantitative information on normal brain development may play a pivotal role in clarifying brain neurodevelopmental abnormalities.

Influence of interleukin-10 on the interleukin-1 receptor antagonist/interleukin-1 beta ratio in the colonic mucosa of ulcerative colitis.

A decrease in the ratio of IL-1ra/IL-1 beta produced regionally by the colonic mucosa of patients with ulcerative colitis (UC) is believed to play a role in the pathogenesis of UC. To investigate factors influencing intramucosal IL-1ra/IL-1 beta ratios, we evaluated polymorphism of the IL-1ra gene and the production of mucosal cytokines in Japanese patients with UC. Colonic biopsy specimens of mucosal tissue were placed in organ cultures for 24 h. Then, the supernatant concentrations of IL-1 beta, IL-1ra, IL-8, IL-4, IL-10, and TGF-beta were assayed by ELISA. Genomic DNA was extracted from patient peripheral blood samples, then IL-1ra gene polymorphism was determined using PCR amplification. The mucosa from patients with active stage UC showed a tendency toward a decreased IL-1ra/IL-1 beta ratio. In the resolving stage, IL-1ra/IL-1 beta ratios increased with increasing IL-10 and TGF-beta concentrations. The addition of human recombinant IL-10 to the culture supernatants produced concentration-dependent inhibition of IL-1 beta. In Japanese patients with UC, the IL-1ra allele gene 2 phenotype had no effect on the IL-1ra/IL-1 beta ratio. Our findings suggest that a relative deficiency of IL-10 in patients with UC may contribute to persistent inflammatory changes.

A close relationship of triplet repeat polymorphism in MHC class I chain-related gene A (MICA) to the disease susceptibility and behavior in ulcerative colitis.

Major histocompatibility complex (MHC) class I chain-related gene A (MICA) has been found near the HLA-B gene. The MICA molecule is exclusively expressed on gastrointestinal epithelium and recognized by intestinal epithelial gamma delta T cells, where it exhibits a triplet repeat polymorphism in the transmembrane region. We investigated the possible correlation between MICA genetic polymorphism and ulcerative colitis (UC). Eighty-three patients with UC and 132 unrelated controls were included in this study. All subjects were Japanese. A triplet repeat polymorphism in the transmembrane region of the MICA was determined by direct sequencing procedures after amplification by a polymerase chain reaction. A significantly higher allele and phenotype frequencies of MICA A6 allele were observed in patients with UC than controls (allele frequency: P(c)=0.000011, phenotype frequency: P(c)=0.0049 odds ratio=2.62). A6 homozygous patients with UC showed significantly earlier onset of UC than patients without the A6 allele ((P)c=0.0042). Phenotypes of MICA A6 allele in Japanese are closely related to the disease susceptibility and behavior in UC. Examinations of MICA polymorphism in other ethnic groups may provide important information about the locus of primary responsible gene for UC.

Ability to coordinate exertion of force by the dominant hand: comparisons among university students and 65- to 78-year-old men and women.

The purposes of this study were to examine the characteristics of ability to coordinate exertion of force in 60 healthy older people (30 men, 30 women) from the viewpoint of sex differences and to compare their performance with those of 60 healthy university students (30 men, 30 women). The test of ability to coordinate exertion of force was conducted by having the subject fit the exertion value of grip strength to a changing demand value appearing on the display of a personal computer (using a bar chart-description form). The changes in the demand value were tracked. The variable estimating ability to coordinate exertion of force was the total sum of the differences between demand and the produced grip strength induced by time lapses. The ability to coordinate exertion of force in the older subjects was inferior to that of the younger subjects, and large individual differences were observed. Unlike the younger subjects, the means of the ability to coordinate exertion of force of the older subjects significantly decreased between trials. The ability to coordinate exertion of force of the older women was significantly inferior to that of the older men, but the means of the measurements among three trials shows a similar tendency to decrease in both sexes.

[Relapse of seizure after withdrawal of antiepileptic drug treatment in childhood epilepsy: age-dependent factors].

In 556 epileptic children, clinical and encephalographic factors concerning the discontinuation of antiepileptic drugs (AED) were studied, with emphasis on age-related factors. Seizures relapsed in 80 patients (14.4%), the incidence being high in idiopathic generalized epilepsy with onsets in adolescence or adulthood (juvenile absence epilepsy, juvenile myoclonic epilepsy, grand mal on awakening), symptomatic partial epilepsy and symptomatic generalized epilepsy. The age distribution at the relapse showed two peaks; 9 to 11 and 17 to 19 years. The first peak represented patients with school-age onset epilepsies, and the second those with the adolescent or adult onset epilepsies. The age at discontinuation of AED depended on each epileptic syndrome, and the relapse rate was significantly higher when the AED was discontinued after adolescence. In 56 patients, seizure relapsed during the withdrawal phase or less than 1 year after the discontinuation. The type of the relapsing seizure was the same as the previous ones. On the other hand, in 16 out of 24 patients whose relapse occurred 1 year or more after the discontinuation, the seizure type was different from the previous ones. These results suggest the relevance of age-dependent factors to the discontinuation of therapy.

The striking effect of hyperbaric oxygenation therapy in the management of chronic idiopathic intestinal pseudo-obstruction.

Chronic idiopathic intestinal pseudo-obstruction is one of the disorders that is most refractory to medical and surgical treatment. Even when patients are given nutritional support, including total parenteral nutrition, obstructive symptoms seldom disappear. We report a case of chronic idiopathic intestinal pseudo-obstruction, due to myopathy, in which hyperbaric oxygenation therapy was strikingly effective. The presence of myopathy was histologically confirmed on the surgically resected jejunal specimen. Hyperbaric oxygenation resulted not only in relief of the patient's obstructive symptoms but also in a rapid decrease of abnormally accumulated intestinal gas. At last, he could resume oral intake without any critical adverse effects. These observations strongly suggest that hyperbaric oxygenation can be an effective therapy in the management of chronic idiopathic intestinal pseudo-obstruction.

[Partial seizures during the course in patients with absence epilepsy].

We studied the incidence and clinicoelectrographic features of partial seizures in 46 patients with absence epilepsy. Ten patients (21.7%) showed obvious partial seizure symptoms during the course. Five patients had absence attacks with partial seizure symptoms, the ictal EEGs being a generalized 3 Hz spike-wave burst complex preceded by focal discharges. These absence attacks may be partial seizures with secondary bilateral synchronization, which originated from the frontal lobe. Three patients initially had partial seizures related to the frontal lobe, followed by absence attacks 8 months to 2.6 years after the start of CBZ therapy. The appearance of absence attacks may have been triggered by CBZ administration. Two patients had partial seizures at the relapse of epilepsy after the discontinuation of AED therapy for childhood absence epilepsy. This change of seizure types may be associated with the CNS maturation, or with localized cortical hyperexcitability subsequent to the foregoing generalized seizures. The prognosis of absence attacks in the all patients were excellent, and comparable to that of typical absence attacks. Our results suggest that localized cortical areas, especially the frontal lobe, are commonly involved in absence epilepsy. More detailed clinical observation is necessary to understand the pathogenesis of absence epilepsy.

p16(INK4) is inactivated by extensive CpG methylation in human hepatocellular carcinoma.

BACKGROUND & AIMS: The molecular status of the p16(INK4) tumor-suppressor gene has not been fully elucidated in hepatocellular carcinoma. The aim of this study was to clarify the mechanism that gives rise to inactivation of p16(INK4) in hepatocellular carcinoma. METHODS: The status of p16(INK4) was evaluated in 60 hepatocellular carcinomas by immunohistochemical staining, differential polymerase chain reaction, single-strand conformational polymorphism, methylation-specific polymerase chain reaction, and methylation-sensitive single nucleotide primer extension. RESULTS: Immunohistochemical staining showed that 29 of the 60 tumors exhibited complete loss of p16(INK4) expression. High levels of DNA methylation were detected in 24 of 29 cases of hepatocellular carcinoma with negative p16(INK4) expression, with methylation of 60%-85% of the CpG islands. In contrast, the level of methylation was <25% in tumors with faint p16(INK4) staining, and no methylation was detected in tumors with positive immunostaining. Intragenic alteration of p16(INK4) was detected in 4 cases. CONCLUSIONS: A strong correlation was found between the extent of methylation and the degree of expression of p16(INK4) in tumor tissues, indicating that epigenetic change due to extensive CpG methylation is the main cause of inactivation of p16(INK4) in hepatocellular carcinoma.

[Examination of proposed items for a fatigue questionnaire for students based on subjective symptoms].

The purposes of this study were to examine questionnaire items on subjective symptoms of fatigue (SSF) using students for cognitive appraisal, and to select effective items. Questionnaire items were selected from each domain of a hypothetical structure of fatigue considering the theoretical validity. A total of 154 items was reselected based on preliminary survey results, and the questionnaire was then administered to 731 people aged 15-26. The subjects answered whether the content was valid as an item of SSF or not, and to what degree the content of question for each item was important. First, chi-square analysis was used to examine the statistical validity of each item. As a result, 54 items were selected as effective items to measure SSF. In addition, principal factor solution and normal varimax rotation were applied to correlation matrices consisting of 54 SSF items based on the cognitive appraisal, and 6 factors were interpreted as follows: difficulty with concentrated thinking, languor, loss of vigor, drowsiness, and a feeling of impatience and physical disintegration. Significant correlations between the 54 items and each factor were found and each item showed high reliability. Therefore, 25 items were selected as effective items to measure SSF. It was inferred that the validity and reliability of each SSF item were high.

[Morphological changes of osteogenic cells on hydroxyapatite ceramics sintered at different temperatures].

In order to clarify the relation between the synthetic condition and the biocompatibility in vitro, a dynamics of the osteogenic MC3T3-E1 cells cultured on hydroxyapatite ceramics (HAC) was examined. HAC used in this study was sintered at temperatures of 1000 degrees C or 1350 degrees C to produce the dense ceramics material, and then smoothly surfaced (0.3 micron). Disk (diameter: 10mm, thickness: 1mm) of HAC were placed in plastic disk. The cells were inoculated at 3000 cells/disk on HAC, and cultured for up to 18 Days. In scanning electron microscopic observation, cell proliferation cultured on the polished HAC was more active than that on the unpolished HAC. Furthermore, cell proliferation cultured on the 1000 degrees C-HAC was more active than that on the 1350 degrees C-HAC. Width, length and concentration of microvilli (MV) on the cell surface cultured on the 1000 degrees C-HAC were more dense, and increased with cultivation. Length and concentration of MV of the cells cultured on the 1000 degrees C-HAC were more dense than that on the 1350 degrees C-HAC. Most of the cells cultured on each material were intensely positive with alkaline phosphatase or von Kossa staining. However, the cells cultured on the 1000 degrees C-HAC were more positive than those on 1350 degrees C-HAC. In conclusion, these results suggest that the synthetic condition of HAC have close connection with the biocompatibility.

Osteocompatibility of platinum-plated titanium assessed in vitro.

Suppression of dissolution is important to increase the biocompatibility of titanium implants. Therefore, the possibility of application of platinum-coated titanium as a biomaterial was explored in in vitro experiments using the MC3T3-E1 osteogenic cell line. The data obtained from long-term cultures indicated that pure platinum or titanium thickly coated with platinum inhibited calcification significantly, suggesting that the platinum ion fails to improve the osteocompatibility of titanium implants.