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Background & aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Long-term azacitidine (AZA) treatment is necessary for its maximal therapeutic effect. This study examined the continuity and efficacy of AZA treatment in real-world use. We conducted a retrospective study in 38 patients who had completed AZA treatment at the Ogaki Municipal Hospital between April 2011 and August 2019. The median number of AZA received cycles was 4. The number of AZA treatment cycles received was 1-3 cycles in 15 (39.5%), 4-6 cycles in 15 (39.5%), and ≥ 7 cycles in 8 (21.1%). The most common reason for discontinued AZA treatment was infection. Overall response rate was 33.3% in patients with discontinued AZA use (4 cycles) and 56.5% in patients with continued AZA (≥ 4). Median overall survival (OS) was 124 (15-529) days and 391 (132-2,825) days in the respective groups (p0.01). The presence of peripheral blood blasts (PBs) was a prognostic factor for continuation of treatment (

Ten patients had intrasynovial tendon grafting harvested from the toes for secondary flexor tendon reconstruction in nine fingers and one thumb in our institutes from 2009 to 2014. These patients were followed for a mean of 15 (range: 8–36) months. The ranges of total active motion of the proximal and distal interphalangeal joints of these nine fingers were 143° (range: 108–175°) and of the metacarpophalangeal and interphalangeal joints of one thumb were 110°. In conclusion, this technique is feasible and gives a good result when successful but with a high complication rate.Level of Evidence IV

Contains fulltext : 79933.pdf (Publisher’s version ) (Closed access) BACKGROUND: Intestinal mucosal barrier injury (MBI), resulting from myeloablative conditioning for haematopoietic stem-cell transplantation (HSCT), is an important cause of morbidity. Despite its frequency, recognition presents a challenge, while the aetiology needs still to be unravelled. The relationship between enterocyte mass and enterocyte loss was explored by examining citrulline serum levels and by assessing circulating intestinal fatty acid-binding protein (I-FABP) and ileal bile acid-binding protein (I-BABP), proteins released by dying mature enterocytes. PATIENTS AND METHODS: Thirty-four adult patients with haematological malignancy received allogeneic HSCT (HSCT day 0) 12 days after being given idarubicin, cyclophosphamide and total body irradiation as myeloablative conditioning, a regimen known to induce oral and intestinal MBI. Serum levels of citrulline, I-FABP and I-BABP were measured on HSCT days -12, -6, 0, +7, +14 and +21. RESULTS: Myeloablative conditioning resulted in a significant decrease in serum citrulline with the nadir on HSCT day +7; thereafter, levels rose gradually. Simultaneously, a significant decrease in I-FABP and I-BABP levels occurred from the day of transplant until day +14. CONCLUSIONS: Simultaneous reduction and subsequent increase of citrulline and I-FABP and I-BABP levels following cytotoxic treatment show that enterocyte mass corresponds to lower rate of dying enterocytes, indicating reduced turnover of enterocytes. Assessment of enterocyte turnover and mass offers opportunities for evaluation of new MBI therapies.

Previous research has shown the inhibitory effects of hop bract polyphenols (HBP) on cariogenic streptococci in vitro, but their effects in humans have not been investigated. This double-blind, crossover clinical study tested the hypothesis that HBP delivered in a mouthrinse suppresses plaque regrowth in humans. Twenty-nine healthy male volunteers had all plaque removed, and refrained from all oral hygiene for 3 days, except for rinsing with a mouthrinse containing 0.1% HBP or a placebo. The results showed that the mean amount of plaque assessed by the Patient Hygiene Performance score after the volunteers used the HBP mouthrinse was significantly less than that after they used the placebo (p < 0.001). The number of mutans streptococci in the plaque samples after volunteers used the HBP mouthrinse was significantly lower than that after they used the placebo (p < 0.05). These findings suggested that HBP, delivered in a mouthrinse, successfully reduced dental plaque regrowth in humans.

Research and development of the adenosine A 2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson’s disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A 2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A 2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A 2A receptors in the “dual” modulation of GABAergic synaptic transmission. Experiments with dopamine D 2 receptor knockout mice showed that A 2A receptors can function and anti-PD activities of A 2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with l-dopa–related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A 2A biologic research has been applied successfully to “proof of concept” clinical studies. The selective A 2A antagonist should provide a novel nondopaminergic approach to PD therapy.

We measured leptin concentrations in patients with acute myocardial infarction (AMI, n = 21) and in 15 age-matched controls, and compared leptin concentrations with levels of other myocardial enzymes and indicators of AMI. Blood was sampled immediately after hospital admission and at 1 h, 2 h, 3 h, 6 h and 9 h, then every 12 h until 5 days post-admission. Patients were stratified into three groups according to peak leptin concentrations: hypoleptinaemia (< 3 ng/ml); normoleptinaemia (≥ 3 – < 15 ng/ml) and hyperleptinaemia (≥ 15 ng/ml). Hypoleptinaemic AMI patients had significantly increased concentrations of plasma lactate dehydrogenase compared with normoleptinaemic patients. No significant differences in other serum markers were noted between hyperleptinaemic and normoleptinaemic AMI patients. A significant negative correlation was found between the peak concentrations of leptin and interleukin 6. Leptin may play a role in the regulation of the development of cardiac damage in patients with AMI.

Seventeen strains of Streptococcus pyogenes were isolated from 17 patients in the Dermatological Ward of Gunma University Hospital in Japan between June 1994 and March 1995. Of these 17 strains, 14 were isolated from the pus of skin infections, two from blood, and one from ascitic fluid. The strains showed the same minimum inhibitory concentrations; 4 mg/L of minomycin, 4 mg/L of ofloxacin and 16 mg/L of fosfomycin. T-antigen typing of the strains indicated they were T11 type. The restriction endonuclease digestion patterns of chromosomal DNA from the 17 strains were all identical. The vinyl sheet covering the bed on which the patients were treated was found to be contaminated with S. pyogenes. This strain showed identical characteristics to the strains derived from the patients. These results suggest that S. pyogenes was transmitted to patients in the Dermatological Ward from the surface of the vinyl sheet covering the bed.

Objective: To investigate the safety and usefulness of salvage-type autologous blood transfusion for abdominal simple total hysterectomy for uterine myoma. Methods: Forty patients with uterine myoma diagnosed histologically were treated by abdominal simple total hysterectomy using an intraoperative blood salvage apparatus. Bacterial contamination in the processed blood was studied. Results: Homologous blood transfusion was unnecessary. There was a positive relationship between bleeding volume and the hemoglobin (g) level in the processed blood. All vaginal swabs were positive for bacteria. Bacterial cultures of all processed blood samples without an antibiotic were positive whereas results were negative in 11 (50%) of the processed blood samples with an antibiotic. There were no significant side effects after reinfusion. Conclusion: Salvage-type autologous blood transfusion in abdominal simple total hysterectomy for uterine myoma was safe and its future use is promising.

Background: An impaired right ventricular function is associated with a poor survival rate in patients with heart failure. Few investigations have analyzed the prognostic value of right ventricular function on the outcomes of mitral valve (MV) surgery. The objectives of this study were to define the effect of right ventricular function on postoperative outcomes after MV repair (MVP) or replacement (MVR).Methods: From September 2007 to February 2012, 335 consecutive patients underwent MVP or MVR at our institution. Preoperative transthoracic and transesophageal echocardiography (TEE) and postoperative TEE were used to define right ventricular function and MV performance. Preoperative right ventricular function was graded as normal to mild (grade 1-2) or as moderate to severe (grade 3-4). MV or tricuspid valve regurgitation was graded as non-trivial to mild (grade 0-2) or as moderate to severe (grade 3-4) preoperatively and postoperatively. Survival rate was evaluated at 1 year after surgery.Results: Of the 334 patients in the study, 280 patients showed a normal to a mildly impaired right ventricular function preoperatively (group 1). Fifty-four patients presented with moderate to severe right ventricular dysfunction (group 2). Patients with a compromised right ventricular function were more likely to undergo MVR (28.6% versus 53.7%, P P P P P P = .005). The rate of postoperative MV regurgitation was significantly higher in group 2 (1.8 versus 14.8%, P P = .59).Conclusions: This study has shown that a dysfunctional preoperative right ventricular function uses more resources and is associated with postoperative MV regurgitation, but it is not associated short- and mid-term mortality after MV surgery.

In vitro mRNA synthesis by Sendai virus is almost entirely dependent on the addition of cellular proteins (positive host factors), one of which could be tubulin. In this study, we investigated the distribution of host factors in various rat organs. Extracts from the brain, thymus, heart, lung, testis, ovary, and uterus all supported in vitro Sendai virus transcription, among which the highest activity was obtained with the brain extract. On the other hand, little or no activity was detected in the liver, spleen, and kidney extracts. An inverse correlation between the apparent host factor activity to stimulate mRNA synthesis and RNase activity that hydrolyzes Sendai virus mRNAs was found, except in the liver extract. However, when a transcription initiation complex was isolated and subjected to RNA chain elongation reaction, all of the extracts including those from liver, spleen and kidney, were active. Immunoblotting showed that tubulin molecules were integrated in these initiation complexes, supporting the notion that tubulin is involved in the initiation complex formation. We also identified a transcription inhibitory activity without any detectable RNase activity in the liver extract. This negative host factor seemed to act on RNA chain elongation. It is likely that Sendai virus transcription is regulated by both positive and negative regulatory factors.

Until HCV NS3/4A protease inhibitors become available at the end of 2011, the combination pegylated-interferon (PEG-IFN)-alfa and ribavirin (RBV) will remain the standard treatment for chronic hepatitis C patients. In some hepatitis C virus-infected patients, PEG-IFN plus RBV treatment against HCV should continue to be used because of side effects of new drugs such as anemia. Our Japanese experiences should provide new information for the treatment of chronic hepatitis C.

Quantitative serology for hepatitis B surface antigen (HBsAg) is a new candidate marker for prediction of clinical outcome. The aim of this study was to investigate the clinical significance of quantifying HBsAg in patients with hepatitis B virus (HBV) infection. A total of 424 patients who tested positive for HBsAg and were referred to Chiba University Hospital between January 1985 and April 2008 were included in the study, and the following characteristics were analyzed: age, gender, status of hepatitis B e antigen (HBeAg), alanine aminotransferase level (ALT), HBV DNA level, number of platelets and development of hepatocellular carcinoma. Measurement of HBsAg was performed using the chemiluminescent enzyme immunoassay method. The study group consisted of 239 men and 185 women, and their average age was 40.6 ± 14.0 years. HBsAg showed a positive correlation with HBV DNA level (Pearson's product moment correlation, r = 0.586, P0.001) and a weak inverse correlation with age (r = 0.3325, P0.001). A control study, matched with age and sex, was performed between two groups with and without HBeAg seroconversion during follow-up period. Compared with the age and sex-matched controls, the change in HBsAg levels per year showed a significant decrease 2 years before seroconversion (paired t-test, P0.05). The serial measurement of quantitative HBsAg level has the possibility of predicting the occurrence of HBeAg seroconversion.

To characterize the prodromal phase of adult T-cell leukemia (ATL), a prospective follow-up study was conducted on 50 carriers in a putative pre-ATL state. This state was defined by the presence of molecularly- detectable monoclonal proliferation of human T-lymphotropic virus type I (HTLV-I)-infected T lymphocytes, and the absence of clinical symptoms of leukemia. The median observation time was 50 months. The pre-ATL subjects were divided into two groups according to initial white blood cell (WBC) counts: group A, those with a normal WBC count (9,000/microL) (n = 30), and group B, those with an increased WBC count (9,000 to 15,000) (n = 20). Comparisons were made between the two groups and with a group of 25 patients with chronic ATL (group C) who had WBC counts of more than 15,000. Significant differences in survival rate were found between groups A and B (10-year survival 65.7%) and group C (32.8%) (P < .01), and between group A (10-year survival 90.0%) and group B (52.1%) (P < .05). The incidence of transformation to overt ATL was 10% (3 of 30) in group A and 50% (10 of 20) in group B (P < .01). In six transformed cases (one in A and five in B) we found exactly the same integration sites in pre-ATL and overt ATL phases, confirming the multistep leukemogenesis hypothesized for this disease. However, the pre-ATL subjects could be divided into two distinct prognostic groups based on the initial WBC count; those with good and those with poor prognosis. Although the 10% transformation rate (2.5% annually) in group A seemed to be extremely high compared with that in the general population of HTLV-I carriers (around 0.06% to 0.4% annually), the majority of group A subjects and some in group B showed stable clinical courses without transformation. Further, development of ATL was not observed in four group A subjects with HTLV-I-associated myelopathy (HAM), which is rarely associated with ATL. We propose to call this group of rather benign HTLV-I carriers “HTLV-I carriers with monoclonal proliferation of T lymphocytes (HCMPT).” Thus far we have been unable to identify reliable parameters other than WBC counts that prospectively distinguish HCMPT from the true pre-ATL state, in which there is a high probability of developing ATL. Further clinical and biologic approaches should elucidate the natural history of the HTLV-I carrier state and early events in ATL leukemogenesis.

To assess determinants of muscle strength in-patients with hemiplegia, steps were counted using a pedometer. Isokinetic muscle strength and muscle thickness in the lower extremity was compared between 66 hemiplegic patients and 34 healthy male controls. A significant correlation was observed between the number of steps and muscle strength as well as muscle thickness in the lower extremity of the unaffected side. No significant correlation was observed between the number of steps and muscle strength or muscle thickness on the dominant side in healthy subjects. Hemiplegic patients with a low grade of palsy revealed greater muscle strength and muscle thickness in the lower extremity. Walking steps were more numerous than those with source paralysis.

We often encounter persistent allergic rhinitis due to house dust mites in the practice of otolaryngology, and its prevalence in Japan is high (18.7%). Persistent allergic rhinitis is usually treated with antihistamines and local steroids, but they often cause adverse effects such as sedation and drowsiness. Polyphenols derived from apples have been reported to suppress histamine release from rat cells, reduce auricular swelling in allergic mice, and alleviate skin inflammation in atopic patients. These effects suggest that apple polyphenols are effective for the treatment of various allergic disorders, but the results of their clinical use have not been reported.To assess the effect of drinks containing apple polyphenols on clinical symptoms of persistent allergic rhinitis.Thirty-three patients aged 15 to 65 years with moderate or severe persistent allergic rhinitis in whom the symptoms persisted for 3 years or longer were treated without apple polyphenols (control group), with a low dose of apple polyphenols, or with a high dose of apple polyphenols, and changes in the clinical symptoms were examined.Significant improvements were observed in sneezing attacks (P.05) and nasal discharge (P.01) in the high-dose group and in sneezing attacks (P.05) in the low-dose group. Compared with the control group, an improvement was observed in sneezing attacks and nasal discharge in many patients of the polyphenol-treated groups. In terms of intranasal findings, a significant improvement was observed in swelling of the nasal turbinate in the low-dose group (P.05). The percentage of patients who showed an improvement in swelling of the nasal turbinate was higher in the polyphenol-treated groups.We conclude that apple polyphenols are effective in alleviating symptoms of persistent allergic rhinitis.

Chronic abdominal pain, defined as long-lasting intermittent or constant abdominal pain, is a common pediatric problem encountered by primary care physicians, medical subspecialists and surgical specialists. Chronic abdominal pain in children is usually functional-that is, without objective evidence of an underlying organic disorder. The Subcommittee on Chronic Abdominal Pain of the American Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has prepared this report based on a comprehensive, systematic review and rating of the medical literature. This report accompanies a clinical report based on the literature review and expert opinion. The subcommittee examined the diagnostic and therapeutic value of a medical and psychologic history, diagnostic tests, and pharmacological and behavioral therapy. The presence of alarm symptoms or signs (such as weight loss, gastrointestinal bleeding, persistent fever, chronic severe diarrhea and significant vomiting) is associated with a higher prevalence of organic disease. There was insufficient evidence to state that the nature of the abdominal pain or the presence of associated symptoms (such as anorexia, nausea, headache and joint pain) can discriminate between functional and organic disorders. Although children with chronic abdominal pain and their parents are more often anxious or depressed, the presence of anxiety, depression, behavior problems or recent negative life events does not distinguish between functional and organic abdominal pain. Most children who are brought to the primary care physician's office for chronic abdominal pain are unlikely to require diagnostic testing. Pediatric studies of therapeutic interventions were examined and found to be limited or inconclusive.

The CarboMedics AnnuloFlex annuloplasty system includes a flexible ring that may be implanted as a complete or partial ring to correct mitral annular dilatation by reinforcement of the entire annulus, or only the posterior portion of the annulus. The study aim was to evaluate clinical and functional results during the first year in patients receiving this flexible annuloplasty system.Between February 2001 and August 2002, 69 patients (mean age 55 years; range: 27-81 years) underwent mitral valve repair that included implant of the AnnuloFlex annuloplasty ring. Mitral regurgitation (MR) was the predominant lesion, with 98.6% of patients exhibiting grade 3/4 insufficiency. Functional classification of valve pathology was normal leaflet motion (type I) in 4% of patients, leaflet prolapse (type II) in 93%, and restricted leaflet motion (type III) in 3%. Valve disease was degenerative in 90%, ischemic in 4%, infectious in 3%, and other in 3%.There was one hospital death. Late follow up was obtained for 62 patients; cumulative follow up was 61 patient-years. One-year actuarial survival was 99%, freedom from thromboembolism was 94%, from endocarditis 98%, and from reoperation 98%. Echocardiographic evaluations performed at 3-6 months after repair (mean 4.7 months) showed MR to be grade 0/1+ in 90% of patients and grade 2+ in 8%. Mitral valve area was 3.4+/-1.7 cm2, within normal limits (mitral valve areaor =1.5 cm2) in 95% of patients. Average peak and mean pressure gradients were 5.9+/-3.0 and 2.8+/-1.7 mmHg, respectively. Left ventricular end-diastolic diameter decreased postoperatively, which may reflect successful correction of MR after mitral valve repair.These early results show that the AnnuloFlex annuloplasty system is safe and effective when used with other techniques for repair of MR, and preserves mitral annular flexibility and function at one-year follow up.

Polymerase chain reaction (PCR) amplification was used for detecting circulating tumor cells. However, PCR was so sensitive that it detected a very low level of mRNA with no relevance to tumor cells. We analyzed the degree of micro-tumor spread in esophageal cancer patients using quantitative PCR. Samples were collected from 28 patients and 35 controls. Real-time quantitative PCR (LightCycler) was employed for the detection of carcinoembryonic antigen (CEA) and cytokeratin 20 (CK-20). In the CEA and CK-20 mRNA assays, 7 and 3 out of 28 patients, respectively, showed higher mRNA levels in peripheral blood than the normal range based on values of controls (mean+/-2SD). Eleven out of 19, 4 out of 14, and 2 out of 5 patients showed higher CEA mRNA levels in the samples from tumor drainage vein, costal bone marrow, and thoracic duct lymph, respectively. One of the 7 patients who showed higher CEA mRNA levels in pretreatment peripheral blood is currently free from disease. These findings reveal that quantitative PCR can discriminate high levels of cancer-specific expression from low levels of illegitimate expression in blood. They also suggest that the identification of circulating tumor cells by the CEA mRNA assay is a reliable means of predicting early recurrence.

Blunt injury to the right subclavian artery is a rare complication of severe deceleration trauma often associated with significant morbidity and mortality. We describe an atypical presentation in a patient who sustained a traumatic avulsion of his right subclavian artery arising off the aortic arch. An interposition graft was used to restore the continuity of the artery to the ascending thoracic aorta.

In patients with acute myocardial infarction (AMI), euthyroid sick syndrome (ESS) has been reported to be linked to increase in interleukin (IL)-6 and activation of its receptors. Recent reports have shown that IL-10, an anti-inflammatory cytokine, also plays a key role in the pathogenesis of AMI. Therefore we investigated the relationship between thyroid state and IL-10 in patients with AMI. We measured thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), IL-10, and IL-6 in plasma from 20 patients with AMI and 20 healthy controls. All 20 AMI patients showed significantly lower concentrations of FT3 than in controls accompanied by normal or subnormal levels of TSH, characterized ESS. Concentrations of IL- 10 and IL-6 were higher in patients than in controls. Both IL-10 and IL-6 significantly (p0.05, respectively) correlated with thyroid hormone in patients with AMI. Time course of IL-10, IL-6, and FT3 seemed to be tightly linking. In conclusion, IL-10 and IL-6 appears to affect thyroid hormone homeostasis in patients with AMI.

To investigate the host genetic factors affecting the clinical course of falciparum malaria, polymorphism of the tumor necrosis factor-alpha (TNF-alpha) promoter region was analyzed in patients with cerebral malaria. Two hundred and forty-three Myanmar patients with falciparum malaria at Mae Sot Malaria clinic and Mae Sot General Hospital located at the border between Thailand and Myanmar, were included in this study. Among the patients (128 from Karen, 115 from Burma), 200 were uncomplicated and 43 had cerebral malaria. The TNF-alpha 5'- flanking region showed biallelic polymorphic sites at -238, -308, -857, -863, -1031, and there were 7 alleles (TNFP-A, B, C, D, M1, M4, M7) found in the patients from Myanmar. We found that the TNFP-D allele was significantly associated with cerebral malaria in the populations from Karen (Pc0.0001, OR=124.86) and Burma (Pc0.0001, OR=34.50). TNFP-D showed no significant linkage disequilibrium with any alleles of HLA-B or HLA-DRB1, suggesting that TNFP-D was primarily associated with cerebral malaria in Myanmar.

Activated inflammatory responses appear to play a role in the development of congestive heart failure (CHF). We investigated interleukin-18 (IL-18), which is a cytokine synthesized by activated macrophage, changes in patients with CHF. We evaluated 11 Japanese patients with angina pectoris (n=4) or CHF (n=7). Blood was sampled immediately after admission and at 1, 2, 3, 6, and 9 hours after admission and then every 12 hours until 5 days after admission. Plasma IL-18 concentrations were measured by an enzyme-linked immunosorbent assay. Expression of atrial natriuretic peptide (ANP) mRNA and protein synthesis was examined in cardiac myocyte by stimulation of IL-18. Plasma IL-18 concentration was significantly higher in patients with CHF than in 15 healthy volunteers (51+/-21 pg/mL, and 28+11 pg/mL, respectively, P0.05). Increased expression of ANP mRNA was demonstrated in IL-18 treated myocytes. Protein synthesis in myocytes was increased by IL-18 in a dose-dependent manner. Increased secretion of IL-18 is induced in patients with CHF and correlates with the severity of myocardial damage and dysfunction.

Intracortical efferent zones in the primary motor cortex for thumb movements, namely thumb flexion, extension, adduction, and abduction, have been described in Macaca mulatta monkeys but not in humans. Even recent cortical mapping based on intraoperative monitoring does not provide information about intracortical efferent zones as it is not ethically possible to search the human motor cortex extensively by punctate electrodes. A 78-year-old man with discrete cortical embolism over the left central sulcus is described. Only a mild weakness of his right thumb was observed. Thumb flexion was affected to a greater degree than thumb extension, adduction, and abduction. The lesion ran along the bottom of the central sulcus and affected part of the precentral and postcentral gyri on both sides of it. Animal studies in Macaca mulatta monkeys have shown that the intracortical efferent zones for thumb movement, especially for thumb flexion, are located in the part of the motor cortex just adjoining the central sulcus that folds down from the "bank" to the depth of the central sulcus. It was possible to explain the prominent weakness of thumb flexion if we applied the results of the animal studies. Our case suggests that the same arrangement of intracortical efferent zones found in monkeys may also exist in human beings.

To explore the possible histogenesis of superficially spreading carcinoma of the esophagus, the clinicopathological features of these tumors (n = 44) were compared with those of ordinary superficial carcinoma (n = 163). Tumors of a heterogeneous histological type and having in situ carcinoma components were significantly more common (P.05), and the number of residual squamous islands was significantly greater (P0.05) in the former group than the latter. Furthermore, the tumor size was not different among in situ, intramucosal, and submucosal carcinomas of the former, whereas the tumors became larger according to the depth of invasion in the latter group. These results indicate that the collision of multiple simultaneously developing superficial tumors is a plausible histogenesis of superficially spreading carcinoma of the esophagus.

In order to establish the age-adjusted standard values of lipids in both sexes in Japan, we examined the plasma levels of total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglyceride levels in 1262 healthy Japanese subjects (male 616, female 646). LDL-cholesterol levels in women increased significantly in relation to menopause as it rises from 112 mg/dL in 40 year olds to 131.2 mg/dL in 50 year olds. Menopause seems to affect the triglyceride levels as well. These age- and sex-dependent changes should be considered in evaluation of patients' lipid profiles.

Beneficial effects of hormone replacement therapy are reported on plasma concentrations of lipids and lipoproteins. Plasma leptin levels are reported to reflect lipid metabolism. We treated 40 healthy postmenopausal women with continuous combined HRT (0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate orally) daily for 6 months and then investigated total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol, which are considered to be factors inducing cardiovascular disease (CVD). We measured the plasma levels of lipids and leptin, which are considered to be altered with HRT. Plasma leptin and lipid levels were measured at baseline and after 3 and 6 months of HRT. The plasma levels of leptin in PMW were not significantly reduced by HRT. Although the plasma levels of total cholesterol and LDL-cholesterol did not change by HRT, the administration of HRT significantly increased plasma levels of triglycerides and HDL-cholesterol in PMW. The correlation between leptin and total cholesterol or triglycerides was positive after HRT while these relations were not correlated at baseline. The correlation between lipid levels and leptin may explain the new role of leptin in plasma lipid levels in HRT.

CRP (C-reactive protein) is an acute-phase reactant, the levels of which increase dramatically in response to severe bacterial infection, physical trauma, and other inflammatory conditions. CRP is found in human atherosclerotic lesions. Atherosclerosis is clearly multifactorial in origin, and chronic inflammation is an important component in its pathogenesis. Focus on inflammation is critical in research on atherosclerosis. Elevated levels of CRP have been associated with increased risk of future coronary artery disease (CAD) events. I have summarized the recent literature on CRP studies in CAD. Both coronary heart disease and dilated cardiomyopathy(DCM) result in congestive heart failure due to myocardial damage. The inflammatory state produced by myocarditis of viral or other origin may induce advanced myocardial damage, resulting in heart failure with a poor prognosis. Routine CRP measurement proved to be valuable for identifying high-risk patients with DCM and lymphocytic myocarditis. I suggest that measurement of circulating CRP would be useful for the diagnosis of and for selecting therapeutic strategies for cardiovascular disorders.

Autonomous replicons, such as viral episomes and oncogene containing double minute chromosomes (DMs), lack centromeres and consequently should be lost rapidly when the nuclear membrane breaks down at mitosis. Surprisingly, they are not. This raises the important question of the mechanisms that enable their efficient transmission to daughter cells. We review recent developments in GFP-based chromosome labeling strategies that enable real time analyses using high resolution light microscopy to provide insights into this issue. The results reveal that episomes and DMs both adhere to host chromosomes, a process referred to as "chromosome tethering". Such association enables acentric molecules to use the chromosomal centromere in trans, thereby achieving efficient transmission to daughter cells. This unique mechanism of mitotic segregation also raises the possibility of developing a new class of anti-cancer drugs that work by selectively eliminating growth enhancing genes from cancer cells. J. Cell. Biochem. Suppl. 35:107-114, 2000.

A 52-year-old female came to this institution complaining of a right leg mass lesion. Ultrasonography showed a 16 x 12 x 20mm hypoechoic solid mass lesion in the right leg. The patient underwent surgery during the diagnosis of Schwannoma. Preoperative diagnosis of Schwannoma is difficult by examination. Computerized tomography and magnetic resonance imaging, showed the origin of Schwannoma. However, the lesion was noted to be in a direct continuity with the cord-like echogenic structure consistent with a nerve by echography. We prefer to conduct preoperative examination by ultrasonography in patients with Schwannoma. In conclusion, we have reported a case of Schwannoma diagnosed by non-invasive ultrasonography.

We propose that carcinoembryonic antigen (CEA) may be a tumor marker for prostatic cancer in addition to prostate specific antigen (PSA), gamma-seminoprotein and prostate acid phosphatase (PAP). The tests were done on 15 sera and autopsy specimens of prostatic cancer. Eight of them were clinical cancers and the remaining seven were incidental ones. We measured serum PAP, PSA, CEA and CA 19-9 and immunohistochemically evaluated these specimens. In clinical cancers, serum PAP, PSA, CEA and CA 19-9 were 1272.9 +/- 3094.4, 146.7 +/- 233.6, 36.3 +/- 36.0 and 80.4 +/- 92.0. Immunohistochemically, all were positive for PAP, PSA, CEA and CA 19-9. In incidental cancers, serum PAP, PSA, CEA and CA 19-9 were 2.4 +/- 1.5, 7.9 +/- 16.9, 128.1 +/- 182.7 and 201.8 +/- 416.1. We conclude that the patients with higher levels of plasma PAP or PSA should go through CEA and CA 19-9 measurement in order to diagnose clinical prostatic cancer.

A 38-year-old Japanese male without any significant respiratory risk factors was admitted to our hospital because of an acute onset of fulminant pneumonia refractory to intravenous antibiotics administration and an unexplained creatine kinase elevation. He was intubated and under ventilator support on the second hospital day, but responded dramatically to i.v. pulse methylprednisone treatment. After exclusion of secondary etiologies including collagen diseases, we concluded this case as a probable acute (idiopathic) interstitial pneumonia, or Hamman-Rich syndrome, responding dramatically to the corticosteroid pulse administration.

To evaluate the effects of left ventricular (LV) dysfunction upon the sympathetic nervous and renin-aldosterone-angiotensin systems, neurohormonal factors were measured in patients with ischemic heart disease. Eleven patients were divided into two groups by their LV ejection fraction based on previous catheterization; preserved (EFor = 60%) and impaired (EF60%) LV systolic function groups. They performed supine ergometer exercise and blood samples were drawn at rest and at peak exercise. After dynamic exercise, plasma norepinephrine was significantly (p0.05) increased in patients with preserved LV function, whereas it was not altered in patients with impaired LV function (norepinephrine 20.8 +/- 20.5 vs 45.8 +/- 41.9, respectively). We observed no differences in basal or peak levels of neurohormonal factors, including plasma renin activity, aldosterone, and brain natriuretic peptide (BNP), between the groups. Although the plasma levels of angiotensin I and II were not different in the two groups at rest or at peak exercise, their increasing ratios from rest to peak exercise were significantly higher in patients with impaired LV function compared to those with preserved LV function (angiotensin I; -18.6 +/- 31.0% vs 64.8 +/- 66.5%, p0.05, angiotensin II; -5.9 +/- 41.2% vs 60.7 +/- 40.4% , p0.05). These results suggest that the increasing ratios of angiotensin I and II are superior to BNP as predictors of LV dysfunction, and that the sympathetic nervous system has already been activated even at rest and did not respond to dynamic exercise in patients with LV dysfunction in ischemic heart disease.

Help for people with mental health problems in Japan has traditionally centred on inpatient medical care. In a revision of the Mental Health Welfare Law planned for 2001, responsibility for the support of people with mental health problems will be transferred from central government to local government. Furthermore, local government will, in turn, delegate administrative tasks to a ‘community life support centre‘. We believe that such a centre could be linked to a university with a telehealth network. Connection to the network could benefit people with mental health problems living at home. We also believe that occupational therapists are ideally positioned to play a significant role in community life support centres. With the expected sustained growth in Japanese occupational therapy, it could become a key profession in the rehabilitation of people with mental health problems.

The urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) was evaluated in terms of its ability to predict renal failure following open-heart surgery. Twenty-two patients were divided into three groups; 6 patients with post-operative renal failure (RF group), 9 without renal failure (non-RF group) and 7 who underwent non-cardiac surgery (non-ECC group). NAG levels during operation were significantly higher in the non-RF group than in the non-ECC group (2.28 +/- 0.50 U vs. 0.39 +/- 0.06 U, p0.01). NAG levels in the RF group were not significantly different from those in the non-ECC group (1.12 +/- 0.28 U/hr vs. 0.39 +/- 0.06 U/hr, p0.1), and in the non-RF group (1.12 +/- 0.28 U/hr vs. 2.28 +/- 0.50 U/hr, p0.1). Post-operative NAG levels were not significantly different between the RF and non-RF groups, whereas post-operative creatinine clearance values were significantly different (on 2, 6 and 7 post-operative day, p0.05). Our data suggest that the kidney is predisposed to renal failure by cardiopulmonary bypass and the chance of renal failure depends in some part on post-operative patient management.

The euthyroid sick syndrome is reported to exist in acute myocardial infarction(AMI). Previous reports showed serum levels of triiodothyronine(T3) are low and thyroid stimulating hormone(TSH) is normal or subnormal levels in patients with AMI. However, the mechanism of altered thyroid hormone metabolism is unknown. Interleukin-6(IL-6) is reported to be a key role in the pathogenesis of AMI and euthyroid sick syndrome. We measured circulating TSH, free T3(FT3), free thyroxine (FT4), IL-6, soluble IL-6 receptor, soluble transducing 130-kD glycoprotein, atrial natriuretic peptide(ANP) and brain natriuretic peptide in 25 patients and 32 healthy subjects. Circulating FT3 levels in patients with AMI became lower than in control group(p0.05). IL-6 levels were significantly(p0.05) higher than those of healthy subjects. The peak levels of IL-6 was 30.5 +/- 46.9 pg/ml at 25-27 hours(the first peak) and 64.4 +/- 24.6 pg/ml at 70-72 hours(the second peak). FT3 was negatively related to IL-6(p0.05) and hANP(p0.05) in patients with AMI. These results indicate that the lower levels of FT3 show the greater severity of AMI. We conclude that euthyroid sick syndrome occurs in patients with AMI and euthyroid sick syndrome may regulated by IL-6 through suppressed of thyroid function.

In the cutaneous nerves, unmyelinated nerve fibers outnumber the myelinated ones but are scarcely analyzed, especially at autopsy. This indifference toward the pathology of unmyelinated nerve fibers may be due to the necessity of electron microscopic analyses and, more importantly, the obscurity of pathological alteration of unmyelinated nerve fibers in aging as well as in peripheral nerve disorders. The aim of this article is to review (1) the normal appearance including postmortem changes, (2) the age-related changes, and (3) the pathological alteration in various neuropathic and non-neuropathic conditions, of unmyelinated nerve fibers in the sural nerve. For the complete analyses of sural nerve, qualitative and quantitative estimation of unmyelinated nerve fibers in all specimens should be recommended and it sometimes has an important diagnostic value.

Human papillomavirus 6 (HPV 6) causes benign condylomata. As a model for HPV vaccine development, we tested a HPV 6 DNA vaccine candidate, constructed by subcloning the major capsid protein (L1) gene into an expression plasmid having the cytomegalovirus promoter, for its immunogenicity in BALB/c mice. Three intracutaneous inoculations of the plasmid with a gene gun at 2-week intervals elicited anti-L1 serum antibodies. The antibodies were found to recognize highly type-specific, conformation-dependent epitopes, including those to neutralize pseudovirions capable of inducing beta-galactosidase in infected monkey COS-1 cells. The data support the idea that immunization with DNA capable of expressing HPV L1 can be used as an HPV vaccine strategy for humans.

Budding yeast CDC45 encodes Cdc45p, an essential protein required to trigger initiation of DNA replication in late G1 phase. We cloned four and one species of the human Cdc45p homolog cDNA, resulting from different splicing patterns, from HeLa cell and human placenta cDNA libraries, respectively. A comparison of the cDNAs and the genomic sequence showed that the longest encoding a 610-amino acid protein was comprised of 20 exons. One species, which lacks exon 7 and contains the shorter of two exons 18, was identical with the previously reported CDC45L cDNA and constituted 24 out of 28 clones from HeLa cells. Splicing was different in HeLa cells and TIG-1 cells, a human diploid cell line. Human CDC45 protein was found to bind directly in vitro to human minichromosome maintenance 7 protein (hMCM7) and to the p70 subunit of DNA polymerase alpha. The data support a thesis that human CDC45 acts as a molecular tether to mediate loading of the DNA polymerase alpha on to the DNA replication complex through binding to hMCM7.

We report a successful resection of an inflammatory aneurysm following treatment with steroids in a 23-year-old man. Suffering from fever and severe lumbago, he was admitted to our hospital. An ultrasound and computed tomography of the abdomen revealed an infrarenal abdominal aortic aneurysm surrounded by dense perianeurysmal fibrous tissue. We diagnosed it as an inflammatory abdominal aortic aneurysm based on a symptomatic inflammatory reaction and the findings of ultrasound and computed tomography. Since the aneurysmal wall strongly adhered to the surrounding tissues and surgery was ruled out when it proved impossible to expose the vessels sufficiently to obtain vascular control, steroid therapy was started to control fever and severe lumbago. Five months later, we undertook surgery. Our conclusion is that steroid therapy was very effective against a young patient with inflammatory abdominal aortic aneurysm.

We compared the interpretation of an electrocardiogram (ECG) made by computer with that made by physicians in training, as well as with the diagnosis made by cardiologists. ECGs were collected from 1058 Japanese adults (812 men and 246 women, mean age 49 +/- 19 years). With the computer program, the incidence of false-negative reports was 10.5% while that of false-positive reports was 16.5%, when compared with the physician's diagnosis. The incidence of a false-positive diagnosis with the computer was 18 times higher than that found by the physicians in training. The results show the advantages and the limitations in the use of computers for analysis of ECGs.

Disseminated intra-vascular coagulation (DIC) is associated with severe bleeding tendency and organ failure, the extent of which is thought to be related to the prognosis of DIC patients. Thrombomodulin (TM) is a high-affinity thrombin receptor on vascular endothelial cells. Clinical importance of soluble TM is still controversy as a diagnostic and prognostic indicator in patients with disseminated intravascular coagulation (DIC). We compared plasma levels of TM with fibrin degradation product (FDP) in patients with DIC through the clinical course. The significant elevation of circulating TM in nonsurvivors with DIC compared with survived patients with DIC(TM 3.1+/-1.52 vs 8.1+/-3.89 FU/ml), as well as FDP (12.9+/-12.12 vs 49.8+/-55.42 microg/ml) but the levels of FDP were not different between the two groups. The measurement of circulating TM was a relatively good prognostic marker of patients with DIC.

It has been clarified that hepatitis G/GB virus-C is the minor cause of acute and chronic non-A-E hepatitis. But there exist non-A-E viral hepatitis patients. Recently, one of non-A-E hepatitis associated virus was identified and the new virus was named TT virus. We highly detected TT virus in the serum of hepatitis patients. TT virus were reported to be detected 1-37% of the general population in the world. TT virus may account for only a minor part of acute non-A-E hepatitis in Japan. However, whether TT virus infection really causes severe acute hepatitis is required to be elucidated.

In the early phase after the onset of acute aortic dissection, oxygenation impairment often occurs. However, the etiology and clinical course of this phenomenon have not been established. We examined the serial changes of oxygenation, inflammatory reaction and laboratory data in patients with acute aortic dissection.Nine patients (DeBakey type I; 4, type II; 3 and type IIIb; 2), aged 46 to 82 years were included in this study. All patients were managed in the intensive care unit, and systolic arterial pressure was maintained at around 110 to 120 mm Hg. Oxygenation was impaired in all patients, three (33%) of whom required mechanical ventilatory support.Pleural effusion was observed in eight (89%) of nine patients. Respiratory index was 0.98+/-0.19 (mean +/-SEM) at the time of admission, and elevated to 1.59+/-0.35, 1.58+/-0.21, 1.60+/-0.28 respectively, at day 1, 2 and 3. Oxygenation index was 318+/-34 at the time of admission, and decreased to 271+/-34, 255+/-19, 263+/-26, respectively, at day 1, 2 and 3. These values recovered to normal after day 4. The increase of white blood cells and high fever (38 degrees C) continued until day 3. Platelet counts recovered after day 4. The serum bilirubin level was highest (2.0+/-0.5 mg/dl) at day 3, and decreased gradually after day 4. In two recent patients whose serum interleukin-8 (IL-8) was measured, IL-8 levels increased according to the impaired oxygenation or aneurysmal enlargement. Impaired oxygenation, inflammatory changes, platelet consumption and bilirubin elevation continued until day 3 and resumed normal levels after day 4.These changes may be due to hemolysis, consumption coagulopathy or inflammation associated with acute aortic dissection. IL-8 elevation may be associated with aneurysmal enlargement and these phenomena.

This CPC concerns a 47-year-old male patient with acquired immunodeficiency syndrome (AIDS). The patient became symptomatic when he developed Pneumocystis carinii pneumonia, but recovered sufficiently to be treated as an outpatient. Two years after falling ill, he developed septic shock and died within a short time. During this period, he failed to respond to HIV drugs, and there was no improvement in his immunodeficient status. The HIV retrieved from the patient's organs at autopsy was found to be type E and to have acquired resistance to Zidovudine. It was also possible to determine the route of infection. HIV treatment guidelines are continuously being revised on the basis of HIV research and the development of new treatment plans, and at the present time, when no definitive method of treatment has yet been established, it is essential for the clinician to keep abreast of the latest information. Since HIV patients are compromised hosts, it is important to diagnose and treat other infectious complications, not only complications unique to AIDS, and we have briefly described the latest HIV therapy.