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Background and Aims: The impact of hepatitis C virus (HCV) eradication via direct-acting antiviral (DAA) therapy on overall mortality, particularly non-liver-related mortality, is understudied., Methods: We recruited 4180 patients with chronic HCV infection who achieved sustained virological response (SVR) (HCV eradication) through DAA therapy (n = 2501, SVR group) or who did not receive antiviral therapy (n = 1679, non-SVR group); 1236 from each group were chosen using propensity score matching. Causes of death and all-cause mortality, including non-liver-related diseases, were investigated., Results: Of the 4180 patients, 592 died during the follow-up period. In the SVR group, the mortality rates from liver-related and non-liver-related diseases were 16.5% and 83.5%, respectively. Compared to the non-SVR group, mortality rates from liver-related and non-liver-related diseases were 50.1% and 49.9%, respectively (p < .001). In non-cirrhotic patients, multivariable analysis revealed that SVR was an independent factor associated with both liver-related (hazard ratio [HR], .251; 95% confidence interval [CI], .092-.686) and non-liver-related (HR, .641; 95% CI, .415-.990) mortalities. In cirrhotic patients, multivariable analysis revealed that SVR remained an independent factor significantly associated with liver-related mortality (HR, .151; 95% CI, .081-.279). In propensity score-matched patients, the eradication of HCV (SVR group) decreased both liver-related (p < .001) and non-liver-related mortality (p = .008) rates compared to persistent HCV infection (non-SVR group)., Conclusions: The elimination of HCV via DAA therapy reduced not only liver-related mortality but also non-liver-related mortality in patients with chronic HCV., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Tracheostomy procedures inhibit swallowing, although details of subsequent recovery of oral intake remain unknown. This retrospective cohort study aimed to investigate factors influencing dysphagia improvement in patients with subacute stroke after tracheostomy., Methods and Results: The study included 117 patients who underwent tracheostomy after subacute stroke, cerebral hemorrhage, or endogenous subarachnoid hemorrhage and received care at 2 convalescent rehabilitation wards in urban and suburban Japan between 2015 and 2022. The primary outcome measure was the achievement of complete oral intake. Patient demographics, Functional Independence Measure scores, body mass index, food intake level scale scores, and the presence of severe white matter hyperintensities on imaging were retrospectively collected from medical records. Statistical analysis involved univariate logistic regression to identify potential predictors and multivariate logistic regression to refine the model while accounting for multicollinearity. In total, 47% of patients achieved complete oral intake on discharge. Sex, days from onset to admission, Functional Independence Measure motor and cognitive scores, body mass index, food intake level scale scores, and severe white matter hyperintensities were identified as potential predictors in the univariate analysis. However, multivariate logistic regression identified only food intake level scale scores (odds ratio [OR], 3.687 [95% CI, 1.519-8.949]; P =0.004) and severe white matter hyperintensities (OR, 0.302 [95% CI, 0.096-0.956]; P =0.042) as significant predictors of complete oral intake., Conclusions: In patients with subacute stroke undergoing tracheostomy, the level of oral intake on admission and severe white matter hyperintensities on imaging may be better predictors of complete oral intake. However, prospective studies with larger sample sizes and more comprehensive data are warranted to confirm these findings.

A case of cytoplasmic anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) initially involving the skin in a 44-year-old Japanese female is reported. The patient had a hemorrhagic erythematous tumor on the right thigh without any systemic symptoms. Pathology showed diffuse infiltration of CD30-positive anaplastic large cells positive for epithelial membrane antigen and cytoplasmic ALK. The right inguinal lymph node showed infiltration of tumor cells in the marginal sinus. Only 2 weeks after radiation therapy, the patient developed multiple subcutaneous nodules and lung involvement. Even after subsequent multichemotherapy sessions, cutaneous recurrence occurred. Literature review of cytoplasmic ALK-positive ALCL initially involving in the skin revealed that skin lesions were mostly seen in the extremities and that half of the cases developed extracutaneous lesions. Radiation and chemotherapy were effective for most cases. Inverse RT-PCR identified a tumor necrosis factor receptor-associated factor (TRAF)1-ALK fusion in our case. Most reported cases with this translocation experienced repeated changes in chemotherapy, suggesting poorer prognosis. Although ALK-positive ALCL generally responds well to chemotherapy, the presence of a TRAF1-ALK fusion may suggest resistance to treatment. Detection of fusion partners of ALK is important for predicting clinical courses and deciding treatment options., (© 2023 Japanese Dermatological Association.)

The helicase-primase inhibitor amenamevir (AMNV) was approved for herpes zoster in Japan in 2017. The authors conducted a 1-month postmarketing observational study to evaluate the real-world safety and efficacy (cutaneous improvement and pain resolution) of AMNV in patients with herpes zoster. Of the 3453 patients registered between March 2018 and December 2020, 3110 were included in the safety analyses. The mean age (±standard deviation) was 63.7 ± 17.5 years, with 57.9% of patients aged ≥65 years. Most patients had mild (53.3%) or moderate (41.0%) cutaneous lesions. Regarding pain, 43.9%, 25.6%, and 12.5% of patients had pain at the levels of 1-3, 4-6, and 7-10 on the numerical rating scale. In total, 30.0%, 27.2%, and 16.1% of patients were concomitantly treated with analgesics: acetaminophen, nonsteroidal anti-inflammatory drugs, and Ca 2+ channel α 2δ ligands, respectively, and 10.6% were treated with topical antiherpetic drugs. Adverse drug reactions occurred in 0.77% of patients, including four serious adverse drug reactions in four patients (hyponatremia, thrombocytopenia, rash, and rhabdomyolysis). Regarding important potential risks, renal disorder, cardiovascular events, and decreased platelets were observed in one, one, and two patients, respectively. Concerning efficacy, the cutaneous improvement rate (significantly improved or improved) was 95.5%, with significantly higher improvement rates in patients treated with AMNV for 7 days and in patients with less severe cutaneous lesions or less pain. Factors affecting the time to pain resolution were the severity of cutaneous lesions and pain at the start of AMNV treatment and older age. This study demonstrated that the AMNV is safe and effective in patients with herpes zoster in a real-world clinical setting., (© 2023 Japanese Dermatological Association.)

Objectives: The effectiveness of the use of carbonation in preventing penetration/aspiration or enhancing swallowing function in adults remains unclear. This systematic review aimed to evaluate the effectiveness of carbonation on improving swallowing function in adult subjects., Methods: Literature published before March 2021 was inspected using MEDLINE, CINAHL, Web of Science Core Collection, The Cochrane Library, Cochrane Central Register of Controlled Trials, and Ichushi-web databases. We searched for intervention studies or randomized control trials considering the effects of carbonated liquids on swallowing function. The risk of bias was assessed using the Cochrane tool for assessing the risk of bias for randomized controlled trials and the Risk of Bias Assessment Tool for Nonrandomized Studies., Results: The systematic review identified 19 studies with a total of 586 participants. The effects of carbonation on swallowing function are diverse. Overall, most studies showed that carbonation promotes swallowing function compared to other liquids. Five studies were included in the quantitative synthesis. Meta-analysis showed that carbonated liquids prevent aspiration (risk difference [RD] -0.27%, 95% confidence interval [CI] -0.44 to -0.10; I 2  = 0%; number needed to treat 3.8, 95% CI 2.2 to 15.0; moderate quality of evidence) when compared to noncarbonated thin liquids. Carbonated liquids also increased the duration of swallowing apnea than did noncarbonated liquids (standardized mean difference 0.25 (mean difference 0.36 seconds), 95% CI 0.03 to 0.47; I 2  = 0%; low quality of evidence)., Conclusions: Carbonation had favorable effects on swallowing function. Further in-depth studies are needed to clarify the benefits of carbonation., Level of Evidence: NA Laryngoscope, 132:1924-1933, 2022., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Left ventricular (LV) twist can be evaluated using two-dimensional speckle tracking echocardiography (2DSTE) by analyzing difference between apical and basal rotation. However, it is unable to evaluate global rotational dyssynchrony because it cannot assess mid-wall rotation. Recently developed three-dimensional STE (3DSTE) can investigate LV global rotational dyssynchrony. In this study, we investigated the role of torsion on the long-term effects of cardiac resynchronization therapy (CRT) using 3DSTE. We evaluated 43 patients by 3DSTE: 12 CRT responders, 14 CRT nonresponders, and 17 healthy normal controls. Regional torsion and rotation were assessed using 3DSTE across 16 segments during CRT-off (native conduction) and CRT-on. The following parameters were calculated: global peak twist, Δ global peak twist (difference between CRT-on and CRT-off), and torsion delay index. The torsion delay index was considered to be the rotational energy lost by rotational dyssynchrony. Global peak twist did not show significant differences between the responders and nonresponders during CRT-off (4.0 ± 3.4° vs. 2.8 ± 2.3°, P = 0.295), but it significantly improved in responders compared to nonresponders after CRT-on (5.4 ± 3.5° vs. 2.6 ± 2.6°, P = 0.029). The torsion delay index during CRT-off was significantly higher in responders compared to nonresponders and normal controls (18.5 ± 11.3 vs. 8.6 ± 3.8 and 7.8 ± 5.5, P = 0.010 and P = 0.004, respectively). The torsion delay index during CRT-off significantly correlated with the Δ global peak twist (r = 0.503, P = 0.009). Improvement in LV global peak twist, which is one of the mechanisms for the long-term effects of CRT correlated with the torsion delay index during native conduction that can only be calculated by 3DSTE., (© 2013, Wiley Periodicals, Inc.)

There is an interaction between heart and kidney diseases, which is a condition termed cardiorenal syndrome. Exercise training has cardioprotective effects, involving upregulation of endothelial (e) nitric oxide synthase (NOS) in the cardiovascular system. However, the effects of exercise training on NOS in the kidney with heart disease are unknown. The aim of the present study was to investigate whether exercise training upregulates NOS in the kidney, left ventricle and aorta of rats with chronic heart failure (CHF). Male Sprague-Dawley rats underwent left coronary artery ligation (LCAL) to induce CHF and were randomly assigned to sedentary or treadmill exercise groups 4 weeks after LCAL. Three days after exercising for 4 weeks, urine samples were collected for 24 h and blood samples were collected following decapitation. Nitric oxide synthase activity and protein expression were examined. Significant interactions between CHF and exercise training were observed on parameters of cardiac and renal function. Exercise training improved cardiac function, decreased plasma B-type natriuretic peptide levels, decreased urinary albumin excretion and increased creatinine clearance in CHF rats. Nitric oxide synthase activity, eNOS expression and neuronal (n) NOS expression were significantly decreased in the left ventricle and kidney of CHF rats. Exercise training significantly increased NOS activity and eNOS and nNOS expression. Upregulation of NOS in the kidney and left ventricle may contribute, in part, to the renal and cardiac protective effects of exercise training in cardiorenal syndrome in CHF rats., (© 2013 Wiley Publishing Asia Pty Ltd.)

Exercise training is known to have antihypertensive effects in humans and animals with hypertension, as well as to exhibit renal protective effects in animal models of hypertension and chronic renal failure. However, the mechanisms regulating these effects of exercise training remain unclear. The present study examined the effects of exercise training on nitric oxide synthase (NOS) in the kidneys of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Male SHR and WKY rats were randomly divided into a sedentary group and a treadmill exercise group for 8 weeks. Systolic blood pressure (SBP) was measured every 2 weeks by the tail-cuff method and urine and blood samples were collected after the exercise protocol. Nitric oxide synthase activity and protein expression and endothelial (e) NOS phosphorylation in the kidney were examined. Exercise training significantly lowered SBP, decreased urinary albumin excretion, thiobarbituric acid-reactive substances levels and renal NADPH oxidase activity, and increased creatinine clearance in SHR. Exercise training significantly increased plasma and urinary nitrate/nitrite, NOS activity and eNOS and neuronal NOS expression, but decreased eNOS phosphorylation at Ser(1177) and Thr(495) in kidneys of SHR and WKY rats. Renal NOS may be involved in the antihypertensive and renal protective effects of exercise training in SHR., (© 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.)

Objectives/hypothesis: Pott's puffy tumor (PPT) is defined as one or more subperiosteal abscesses of the frontal bone based on osteomyelitis. PPT is observed predominantly in the adolescent age group and rarely in adults. Some parameters affecting prognosis and an appropriate surgical approach for antecedent frontal sinusitis have not been elucidated due to the rarity of patients with adult PPT., Study Design: Retrospective patient record and literature study., Methods: Five patients from our cohort and 27 patients identified in a literature search formed the study group., Results: The incidence rate of intracranial complications was lower than in previous reports at 29.0%. There was no correlation between the incidence rate of intracranial complications and each patient's parameters. It was indicated that the department first consulted by the patients was possibly related to the initial diagnosis and the incidence rate of intracranial complications., Conclusions: Although the incidence rate of major complications is lower than in children and later than in earlier published adult cases, patients are still at high risk of serious intracranial complications. Early diagnosis and adequate treatment may contribute to reducing the incidence rate., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Results of genome-wide association studies (GWASs) for bipolar disorder (BD) have indicated ANK3 as one of the most promising candidates for a susceptibility gene. In this study, we performed genetic association analysis of two single-nucleotide polymorphisms (SNPs) in ANK3 (rs1938526 and rs10994336), whose genome-wide significant associations were reported in a previous meta-analysis of GWASs, using genotyping data of Korean and Japanese case-control samples and a part of data from a GWAS in Han-Chinese from Taiwan. The total number of participants was 2,212 cases (352 from Korea, 860 from Japan, and 1,000 from Taiwan) and 2,244 controls (349 from Korea, 895 from Japan, and 1,000 from Taiwan). We could not detect any significant difference of allele frequency in individual analyses using each of the three populations. However, when we combined the three data sets and performed a meta-analysis, rs1938526 showed nominally significant association (P = 0.048, odds ratio = 1.09). The over-represented allele in BD was same as that reported in Caucasian GWASs. On the other hand, any significant association was not detected in rs10994336. This discrepancy between two SNPs may be explained by the different degree of linkage disequilibrium between Asian and Caucasian. These findings further supported the association between ANK3 and BD, and also suggested the genomic region around rs1938526 as a common risk locus across ethnicities., (Copyright © 2011 Wiley-Liss, Inc.)

The FXYD domain-containing ion transport regulator 6 (FXYD6) gene encodes phosphohippolin that regulates cellular ion transport by altering the kinetic properties of Na,K-ATPase. Phosphohippolin is highly expressed in brain regions that are relevant to schizophrenia. The FXYD6 gene is located at chromosome 11q22-24, one of the most established linkage regions for schizophrenia. Therefore, it may be possible that genetic variants in FXYD6, including the regulatory genomic elements could cause abnormal function or expression of phosphohippolin and increase the genetic risk for schizophrenia. A previous study suggested that polymorphisms in FXYD6 are associated with schizophrenia in UK samples. However, conflicting results have been reported in the Japanese population. In this study, we aimed to test the prior genetic association findings using different samples from the ethnically homogeneous Japanese population (1,060 schizophrenic patients and 1,060 age- and sex-matched controls). From the FXYD6 gene, we examined six single nucleotide polymorphisms (rs11216573, rs555577, rs1815774, rs4938445, rs4938446, and rs497768), all of which were previously analyzed for association. We did not detect any significant allelic, genotypic or haplotypic association in our Japanese samples. Meta-analysis incorporating previous and the present studies also showed that the FXYD6 gene is not associated with schizophrenia. We conclude that the FXYD6 gene does not have a major influence on susceptibility to schizophrenia across populations., ((c) 2010 Wiley-Liss, Inc.)

The FoxO transcription factors may be involved in the antiaging effect of calorie restriction (CR) in mammals. To test the hypothesis, we used FoxO1 knockout heterozygotic (HT) mice, in which the FoxO1 mRNA level was reduced by 50%, or less, of that in wild-type (WT) mouse tissues. The WT and HT mice were fed ad libitum (AL) or 30% CR diets from 12 weeks of age. Aging- and CR-related changes in body weight, food intake, blood glucose, and insulin concentrations were similar between the WT and HT mice in the lifespan study. The response to oxidative stress, induced by intraperitoneal injection of 3-nitropropionic acid (3-NPA), was evaluated in the liver and hippocampus at 6 months of age. Several of the selected FoxO1-target genes for cell cycle arrest, DNA repair, apoptosis, and stress resistance were up-regulated in the WT-CR tissues after 3-NPA injection, while the effect was mostly diminished in the HT-CR tissues. Of these gene products, we focused on the nuclear p21 protein level in the liver and confirmed its up-regulation only in the WT-CR mice in response to oxidative stress. The lifespan did not differ significantly between the WT and HT mice in AL or CR conditions. However, the antineoplastic effect of CR, as indicated by reduced incidence of tumors at death in the WT-CR mice, was mostly abrogated in the HT-CR mice. The present results suggest a role for FoxO1 in the antineoplastic effect of CR through the induction of genes responsible for protection against oxidative and genotoxic stress.

Recent progress in genotyping technology and the development of public databases has enabled large-scale genome-wide association tests with diseases. We performed a two-stage genome-wide association study (GWAS) of bipolar disorder (BD) in Japanese cohorts. First we used Affymetrix 100K GeneChip arrays in the analysis of 107 cases with bipolar I disorder and 107 controls, and selected markers that were nominally significant (P < 0.01) in at least one of the three models (1,577 markers in total). In the follow-up stage, we analyzed these markers using an Illumina platform (1,526 markers; 51 markers were not designable for the platform) and an independent sample set, which consisted of 395 cases (bipolar I + II) and 409 controls. We also assessed the population stratification of current samples using principal components analysis. After the two-stage analysis, 89 markers remained nominally significant (allelic P < 0.05) with the same allele being consistently over-represented in both the first and the follow-up stages. However, none of these were significant after correction for multiple-testing by false discovery rates. Sample stratification was virtually negligible. Collectively, this is the first GWAS of BD in the Japanese population. But given the small sample size and the limited genomic coverage, these results should be taken as preliminary., (2009 Wiley-Liss, Inc.)

Disrupted-in-Schizophrenia 1 (DISC1) and its molecular cascade have been implicated in the pathophysiology of major psychoses. Previously, we identified pericentrin 2 (PCNT2) and DISC1-binding zinc finger protein (DBZ) as binding partners of DISC1; further, we observed elevated expression of PCNT2 in the postmortem brains and in the lymphocytes of bipolar disorder patients, compared to controls. Here, we examined the association of PCNT2 with schizophrenia in a case-control study of Japanese cohorts. We also examined the association of DBZ with schizophrenia and with bipolar disorder, and compared the mRNA levels of DBZ in the postmortem brains of schizophrenia, bipolar and control samples. DNA from 180 schizophrenia patients 201 controls were used for the association study of PCNT2 and DBZ with schizophrenia. Association of DBZ with bipolar disorder was examined in DNA from 238 bipolar patients and 240 age- and gender-matched controls. We observed significant allelic and genotypic associations of the PCNT2 SNPs, rs2249057, rs2268524, and rs2073380 (Ser/Arg) with schizophrenia; the association of rs2249057 (P = 0.002) withstand multiple testing correction. Several two SNP- and three SNP-haplotypes showed significant associations; the associations of haplotypes involving rs2249057 withstand multiple testing correction. No associations were observed for DBZ with schizophrenia or with bipolar disorder; further, there was no significant difference between the DBZ mRNA levels of control, schizophrenia and bipolar postmortem brains. We suggest a possible role of PCNT2 in the pathogenesis of schizophrenia. Abnormalities of PCNT2, the centrosomal protein essential for microtubule organization, may be suggested to lead to neurodevelopmental abnormalities., ((c) 2009 Wiley-Liss, Inc.)

Background: Helicobacter pylori secretes vacuolating cytotoxin (VacA) that damages the gastric epithelium by erosion and loosening of tight junctions. VacA has also immunosuppressive effects, inhibiting interleukin (IL)-2 secretion by interference with the T cell receptor/IL-2 signaling pathway. This study investigated the effect of VacA on gene expression of T cells., Materials and Methods: Gene expression profile of a T cell line, Jurkat, was analyzed by the cDNA microarray technique after VacA challenge. The expression of specific mRNAs was assessed by reverse transcription-polymerase chain reaction. Interleukin (IL)-8 concentrations in culture supernatants and cell surface expression of CD69 were measured by enzyme-linked immunosorbent assay and flow cytometry, respectively. We evaluated nuclear factor-kappaB (NF-kappaB) activation in Jurkat cells challenged with VacA by luciferase assay, electrophoretic mobility shift assay, and Western blot analysis., Results: VacA produced two or greater fold up-regulation of expression of 60 genes. Most of these genes were associated with signal transduction, regulation of gene expression, apoptosis, and inflammation. Up-regulation of four genes (IL8, IL2RA, ICAM1, and CD69) was confirmed. The supernatants of cells incubated with VacA showed significantly higher secretion levels of IL-8 than those incubated without VacA. VacA also induced the cell surface expression of CD69. Since microarray analysis indicated NF-kappaB was involved in the transcriptional activation of the above genes, we examined NF-kappaB signaling pathway. VacA activated NF-kappaB via classical but not alternative pathway., Conclusions: VacA has two paradoxical effects on T cells, immunosuppression, and proinflammatory effects. The latter is mediated by NF-kappaB activation.

A technique is described for fabricating an interim obturator for a partial maxillectomy patient. This technique enables the immediate and easy chairside fabrication of a lightweight hollow-type interim obturator when a preoperative cast is not available. After a master cast is formed, two duplicate casts are made from the master cast. One portion of the obturator is fabricated on a duplicate cast with a corrected defect, and the other portion of the prosthetic base is made on the second duplicate cast with a corrected alveolar ridge. These two portions are connected and adjusted in the patient's oral cavity. This technique is beneficial because it helps patients maintain good esthetics and their ability to speak, swallow, and chew just after surgery.

Several lines of evidence support mitochondrial dysfunction in bipolar disorder. Elevated calcium level in platelets is reported in this disease. To verify mitochondrial DNA (mtDNA) haplogroups characteristic to bipolar disorder, we sequenced mtDNA of seven regions and performed haplogroup analysis in 195 patients with bipolar disorder and 255 controls. They belonged to 16 major mtDNA haplogroups, A, B4, B5, C, D4, D5, F, G, M7, M8, M9, M10-12, N9a, N9b, Y, and Z. The logistic regression analysis revealed that the haplogroup N9a was over-represented in bipolar disorder. We also performed a case-control study for two functional mtDNA polymorphisms, mtDNA5460G > A and 12358A > G, that altered intracellular calcium dynamics. While the mtDNA5460G > A polymorphism was not associated with bipolar disorder, the mtDNA12358A > G polymorphism was associated with bipolar disorder in 199 patients with bipolar disorder and 260 controls. However, this association was not replicated in an independent sample set. Possible significances of these findings are discussed., (2008 Wiley-Liss, Inc.)

Objective: Burning mouth syndrome (BMS) is an orofacial pain disorder characterized by a chronic, idiopathic burning sensation of the oral mucosa that mostly affects middle-aged women. Although both psychological and neuropathological factors have been postulated to underlie BMS, the pathogenic mechanism of the condition remains controversial, as do the treatment strategies., Method: A single case was reported., Results: Ms A, a 66-year-old woman with BMS type 1, which is characterized by daily burning pain associated with circadian variation, underwent electroconvulsive therapy (ECT). After the completion of 12 ECTs, the pain markedly diminished and the pronounced ECT effect persisted over the subsequent 24-week period of observation., Conclusion: To our knowledge, this is the first clinical report on the efficacy of ECT for treating pain associated with BMS. ECT can be considered to be an option for treating individuals with enduring and intractable intraoral burning pain.

Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (SERT) modulates serotonin levels, and is a major therapeutic target in autism. Factors that regulate SERT expression might be implicated in the pathophysiology of autism. One candidate SERT regulatory protein is the roundabout axon guidance molecule, ROBO. SerT expression in Drosophila is regulated by robo; it plays a vital role in mammalian neurodevelopment also. Here, we examined the associations of ROBO3 and ROBO4 with autism, in a trio association study using DNA from 252 families recruited to AGRE. Four SNPs of ROBO3 (rs3923890, P = 0.023; rs7925879, P = 0.017; rs4606490, P = 0.033; and rs3802905, P = 0.049) and a single SNP of ROBO4 (rs6590109, P = 0.009) showed associations with autism; the A/A genotype of rs3923890 showed lower ADI-R&#95;A scores, which reflect social interaction. Significant haplotype associations were also observed for ROBO3 and ROBO4. We further compared the mRNA expressions of ROBO1, ROBO2, ROBO3, and ROBO4 in the lymphocytes of 19 drug-naïve autistic patients and 20 age- and sex-matched controls. Expressions of ROBO1 (P = 0.018) and ROBO2 (P = 0.023) were significantly reduced in the autistic group; the possibility of using the altered expressions of ROBO as peripheral markers for autism, may be explored. In conclusion, we suggest a possible role of ROBO in the pathogenesis of autism. Abnormalities of ROBO may lead to autism either by interfering with serotonergic system, or by disrupting neurodevelopment. To the best of our knowledge, this is the first report relating ROBO with autism.

The identification of galectin-9 as a ligand for T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3), expressed on T-helper type-1 (Th1) cells, has established the Tim-3-galectin-9 pathway as a regulator of Th1 immunity. Whereas there is compelling evidence for the effects of galectin-9 on T-cell fate, limited information is available on the impact of galectin-9 on B lymphocytes. We found that protease-resistant galectin-9, hG9NC(null), but not galectin-1 or -8, prevented cell growth of malignant B cells, such as Burkitt lymphoma (BL) and Hodgkin lymphoma (HL). beta-galactoside binding was essential for galectin-9-induced cell growth suppression. hG9NC(null) induced cell cycle arrest by reducing the expression of cyclin D1, D2, B1, Cdk4, Cdc25C and c-Myc, and apoptosis by reducing the expression of XIAP, c-IAP2 and survivin. Most of the genes that encode these proteins are regulated by nuclear factor-kappaB (NF-kappaB), and constitutive activation of NF-kappaBeta is a common characteristic of both types of malignancies. hG9NC(null) inhibited IkappaBalpha phosphorylation, resulting in suppression of NF-kappaB. AP-1 has also been implicated in the control of cell survival. hG9NC(null) inhibited the expression of JunD, resulting in the suppression of AP-1. Our results suggest that hG9NC(null) is a potentially suitable agent for the management of BL and HL.

To clarify whether reelin signaling is involved in dopaminergic neurotransmission in the adult mouse brain, we investigated dopamine function in mice lacking reelin (reeler). We found that methamphetamine-induced locomotor activity is significantly attenuated in reeler mice. To elucidate the mechanism of this phenomenon, we first investigated presynaptic dopamine release; however, there were no significant differences in wildtype, heterozygous reeler and homozygous reeler mice. Next, we examined the locomotor response to intra-accumbens injection of dopamine D1 and D2 receptor agonists, and found that lack of reelin signaling results in decreases in both D1 and D2 receptor-mediated dopaminergic functions. In addition, we measured dopamine receptor binding in the striatum, and found that both D1 and D2 classes of dopamine receptors are reduced in reeler mice. Furthermore, we found that the phosphorylation levels of DARPP-32 are also changed by lack of reelin signaling. Finally, to distinguish between a developmental role of reelin or an acute role of reelin in adult mouse, we intraventricularly infused CR-50, a monoclonal antibody against reelin. Interestingly, infusion of CR-50 also significantly reduced methamphetamine-induced hyperlocomotion in wildtype mice, showing that reelin has an acute role in the dopaminergic system. These results indicate that reelin signaling plays a pivotal role in the dopaminergic system in adult mice, especially in postsynaptic levels.

Objective: We used multichannel near-infrared spectroscopy (MNIRS) to monitor the activity of the frontal cortex as mirrored by hemodynamic responses subjected to olfactory stimulation. The aim of this study was to clarify the functional brain imaging of olfactory activity., Study Design: Prospective study., Methods: This study was conducted on eight healthy subjects aged from 22 to 39 years (4 men and 4 women; mean age, 28.8 yr). We used a 22-channel near-infrared spectroscopy device with eight light-incident fibers and seven detector fibers, each with an interoptode distance of 2.5 cm on the frontal region. Olfactory stimulation consisted of five repetitions, each lasting 5 seconds and followed by a 55 seconds rest period. Isovaleric acid was used as odor stimulation, and saline was used as a control. We measured the changes in concentrations of oxyhemoglobin [oxyHb], deoxyhemoglobin [deoxyHb], and total hemoglobin [totalHb] from prebaseline values. Furthermore, we divided the frontal cortex into four areas (right upper, left upper, right lower, left lower) and investigated the activity in each area., Results: Isovaleric acid caused changes, especially in the lower area, but saline caused no changes. [oxyHb] and [totalHb] increased after odor stimulation, but [deoxyHb] did not change. These active areas may be related to the orbitofrontal cortex, corresponding to olfactory cortices., Conclusion: This study has shown that MNIRS enables evaluation of changes in hemodynamics related to brain activity by olfactory stimulation.

Anti-resorptive bisphosphonates are used for the treatment of hypercalcaemia and bone complications associated with malignancies and osteoporosis, but also have been shown to have anti-tumour effects in various cancers. Adult T-cell leukaemia (ATL) is a fatal T-cell malignancy caused by infection with human T-cell leukaemia virus type I (HTLV-I), and remains incurable. ATL is associated with osteolytic bone lesions and hypercalcaemia, both of which are major factors in the morbidity of ATL. Thus, the search for anti-ATL agents that have both anti-tumour and anti-resorptive activity is warranted. The bisphosphonate agent, incadronate, prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells, but not of non-infected T-cell lines or normal peripheral blood mononuclear cells. Incadronate induced S-phase cell cycle arrest and apoptosis in HTLV-I-infected T-cell lines, and treatment of these cells with substrates of the mevalonate pathway blocked the incadronate-mediated growth suppression. Incadronate also prevented the prenylation of Rap1A protein. These results demonstrated that incadronate-induced growth suppression occurs by interfering with the mevalonate pathway. Importantly, treatment with incadronate reduced tumour formation from an HTLV-I-infected T-cell line when these cells were inoculated subcutaneously into severe combined immunodeficient mice. These findings suggest that incadronate could be potentially useful for the treatment of ATL.

Legionella pneumophila is the etiologic agent of Legionnaires' disease. This bacterium contains a single monopolar flagellum, of which the FlaA subunit is a major protein constituent. The murine macrophage resistance against this bacterium is controlled by the Birc1e/Naip5 gene, which belongs to the NOD family. We evaluated the intracellular growth of the flaA mutant bacteria as well as another aflagellated fliA mutant, within bone marrow-derived macrophages from mice with an intact (C57BL/6, BALB/c) or mutated (A/J) Birc1e/Naip5 gene. The flaA mutant L. pneumophila multiplied within C57BL/6 and BALB/c macrophages while the wild-type strain did not. Cell viability was not impaired until 3 days after infection when the flaA mutant bacteria replicated 10(2-3)-fold in macrophages, implying that L. pneumophila inhibited host cell death during the early phase of intracellular replication. The addition of recombinant interferon-gamma (IFN-gamma) to the infected macrophages restricted replication of the flaA mutant within macrophages; these treated cells also showed enhanced nitric oxide production, although inhibition of nitric oxide production did not affect the IFN-gamma induced inhibition of Legionella replication. These findings suggested that IFN-gamma activated macrophages to restrict the intracellular growth of the L. pneumophila flaA mutant by a NO independent pathway.

Here, we analysed quantitative trait loci (QTL) for fatty acid composition, one of the factors affecting fat quality, in a Japanese wild boar x Large White cross. We found 25 significant effects for 17 traits at 13 positions at the 5% genome-wise level, of which 16 effects for 12 traits at 10 positions were significant at the 1% level. QTL for saturated fatty acids (SFA) in back fat were mapped to swine (Sus scrofa) chromosomes (SSC) 1p, 9 and 15. QTL for unsaturated fatty acids in back fat were mapped to SSC1p, 1q, 4, 5, 9, 15 and 17. Using a regression model that fits back fat thickness as a covariate, two of the QTL for linoleic acid content on SSC4 and SSC17 were not significant, but one QTL for total SFA composition was detected on SSC5 with correction for back fat thickness. Wild boar alleles at six of seven QTL tended to increase SFAs and to decrease unsaturated fatty acids. QTL for fatty acid composition in perirenal fat were mapped on SSC2, 3, 4, 5, 6, 14, 16 and X. QTL for melting point (in back fat samples) were mapped on SSC1, 2 and 15. Wild boar alleles in QTL on SSC1 and SSC15 were associated with elevated melting points whereas those on SSC2 were associated with lower melting point measurements.

Panic disorder (PD) is the repeated sudden occurrence of panic attacks, episodes characterized by psychological symptoms. Peripheral benzodiazepine receptor (PBR) is closely associated with personality traits for anxiety tolerance, and that it holds promise as a biological marker of stressful conditions. We have performed association analyses using the polymorphism to determine the PBR in PD. We screened the subjects for sequence variations within the 5' region, the coding region (exons 2-4), and the 3' noncoding region. One novel missense variant in exon 4, derived from the nucleotide transition in codon 162 (CGT --> CAT:485G > A) resulting in an arginine-to-histidine (Arg --> His) change, was detected in these subjects. The 485G > polymorphism of the PBR gene was analyzed in 91 PD patients and 178 controls. The genotypic and allelic analyses of the 485G > A revealed significant differences between the panic patients and the comparison subjects (P = 0.021 and 0.014, respectively). The present study provides new and important evidence that variation in the PBR gene influences susceptibility to PD., (Copyright 2006 Wiley-Liss, Inc.)

CCL20 is expected to play a crucial role in the initiation of immune responses and tumour growth. However, expression of CCL20 in Epstein-Barr virus (EBV)-associated diseases has not been studied. We examined the contribution of EBV infection and EBV-encoded latent membrane protein (LMP)-1 to CCL20 expression. EBV infection and LMP-1 induced CCL20 mRNA expression in the EBV-negative Burkitt lymphoma (BL) cell lines and the embryonic kidney cell line. Histone deacetylase inhibitor-stimulated endogenous LMP-1 also induced CCL20 expression in an EBV-positive BL cell line. Analysis of the CCL20 promoter showed that it was activated by LMP-1 C-terminal activation region (CTAR)-1 and CTAR-2. Co-expression of IkappaB alpha, IkappaB beta, IkappaB kinase (IKK)alpha, IKKbeta, IKKgamma, nuclear factor (NF)-kappaB-inducing kinase and tumour necrosis factor receptor-associated factor 2 dominant-negative constructs with LMP-1 inhibited the activation of the CCL20 promoter by LMP-1, suggesting that LMP-1 induces CCL20 via NF-kappaB signalling. The requirement for the NF-kappaB-binding site in the CCL20 promoter in LMP-1 responsiveness was established. Our results indicate that activation of the NF-kappaB pathway by LMP-1 is required for the activation of CCL20 expression.

Neuronal growth-associated proteins, including superior cervical ganglia clone 10 (SCG10) family molecules, play roles in neurite outgrowth and network formation as well as structural and functional plasticity. The present ontogenetic study revealed that the expression of neuronal growth-associated proteins in the visual cortex (VC) exhibited a sharp peak in the early postnatal period when growing lateral geniculate nucleus (LGN) axon terminals segregate into the ocular dominance columns depending on retinal activity. We then hypothesized that SCG10 family molecules, known for catastrophic factors of microtubules, play important roles in the formation of ocular dominance columns. To test this hypothesis, we studied whether: (i) monocular blockade of retinal activity changed the SCG10 expression in LGN and VC and (ii) brain-derived neurotrophic factor (BDNF) cortical infusion modified the expression of SCG10 family molecules and the number of excitatory/inhibitory cortical synapses. Using northern blot and in situ hybridization, we revealed that: (i) silencing retinal activity with tetrodotoxin eye injections dynamically reduced the expression of SCG10 mRNA and (ii) it was enhanced by BDNF in VC and LGN of kittens but not adult cats. These findings suggest that cortical infusion of BDNF and retinal activity up-regulate the expression of SCG10 in the LGN and VC and that up-regulated SCG10 in turn initiates marked reorganization of the microtuble network, eventually resulting in increase in synapse formation in the VC.

Loss of nonshivering thermogenesis in mice by inactivation of the mitochondrial uncoupling protein gene (Ucp1-/- mice) causes increased sensitivity to cold and unexpected resistance to diet-induced obesity at a young age. To clarify the role of UCP1 in body weight regulation throughout life and influence of UCP1 deficiency on longevity, we longitudinally analyzed the phenotypes of Ucp1-/- mice maintained in a room at 23 degrees C. There was no difference in body weight and lifespan between genotypes under the standard chow diet condition, whereas the mutant mice developed obesity with age under the high-fat (HF) diet condition. Compared with Ucp1+/+ mice, Ucp1-/- mice showed increased expression of genes related to thermogenesis and fatty acid metabolism, such as beta3-adrenergic receptor, in adipose tissues of the 3-month-old mutants; however, the augmented expression was reduced in Ucp1+/+ mice in 11-month-old Ucp1-/- mice fed the HF diet. Likewise, the increased levels of UCP3 and cAMP-dependent protein kinase in the brown adipose tissue of Ucp1-/- mice given the standard diet were decreased significantly in that of Ucp1-/- mice fed the HF diet, which animals showed impaired norepinephrine-induced lipolysis in their adipose tissues. These results suggest profound attenuation of beta-adrenergic responsiveness and fatty acid utilization in Ucp1-/- mice fed the HF diet, bringing them to late-onset obesity. Our findings provide evidence that UCP1 is neither essential for body weight regulation nor for longevity under conditions of standard diet and normal housing temperature, but deficiency increases susceptibility to obesity with age in combination with HF diet.

Objective: To discuss the relationship between obsessive-compulsive symptoms and a right orbitofrontal lesion., Method: Single case report., Results: A 59-year-old man developed obsessive-compulsive disorder (OCD) symptoms after his head injury. Magnetic resonance imaging brain scans showed a small contusion in the right orbitofrontal region, and single-photon emission computed tomography revealed hypoperfusion in blood flow at the same region., Conclusion: The OCD symptoms that developed in the present case may be attributable primarily to hypofunction in the lesion localized to the right orbitofrontal area. Although caution is needed for interpretation of the observation because of our experience of only a single case, it suggests that the right orbitofrontal region may be important in forming OCD symptoms., (Blackwell Munksgaard 2004)

Objective: We investigated whether antenatal factors in mothers would increase the risk of schizophrenia in the offspring, and also examined any relationship between these factors and histories of obstetric complications (OCs)., Method: Using the Mother and Child Health Handbooks of 52 patients with schizophrenia and 284 healthy subjects, we evaluated the risk-increasing effects of the frequency of antenatal care visits and mothers' body mass index (BMI) at both early and late pregnancy., Results: In logistic regression analysis, there was a significant association between the number of antenatal care visits and the risk of the disorder; an increase in a unit of visits corresponds to a reduction of the risk by 12%. We also found a 24% increase in the risk with a one-unit increase of BMI at the early pregnancy, and a 19% increase at the late pregnancy. These antenatal factors were found to contribute, in part, to an excess of OCs in individuals with schizophrenia., Conclusion: Poor maternal care during pregnancy and comparatively high maternal BMI especially at early pregnancy may cause a predisposition to schizophrenia in the offspring.

We explored the relationship between the tryptophan hydroxylase gene polymorphism and susceptibility to childhood-onset schizophrenia in a Japanese sample. Subjects were 51 Japanese patients who met DSM-IV criteria for schizophrenia before age 16 and 148 Japanese healthy controls. DNA was extracted from whole blood and genotyping was performed by PCR-RFLP using Nhe I. The frequency of the A allele was relatively higher in patients with childhood-onset schizophrenia than in controls (odds ratio, OR = 1.47, 95% CI = 0.97-2.37, P = 0.097). There was a nearly doubling of the risk for childhood-onset schizophrenia associated with the AA genotype compared to other genotype groups; OR = 1.97, 95% CI = 0.91-4.22, P = 0.058., (Copyright 2004 Wiley-Liss, Inc.)

1. We investigated whether chronic suppression of the renin-angiotensin system, which is known to be associated with reductions in microvascular density and vasodilator responsiveness of skeletal muscle, could affect exercise capacity in normotensive rats. 2. Rats were placed on normal rat chow, normal rat chow with captopril (100 mg/kg per day) or a high-salt diet (HS; 4%) for 4 weeks. Following these interventions, rats with indwelling carotid artery catheters were submitted to stepwise increasing exercise on a motor treadmill at a speed of 10, 20 and 30 m/min for 4 min while blood lactate was measured. 3. Blood lactate after exercise at a speed of 20 m/min was significantly higher and the duration during which rats were able to run at a speed of 30 m/min was significantly shorter in captopril-treated rats and rats fed an HS diet compared with control rats. 4. We conclude that chronic treatment with captopril or HS diet could reduce the exercise capacity in inactive normotensive rats, probably through chronic inhibition of the renin-angiotensin system.

Objective: Olfactory reference syndrome (ORS) in the Western literature is characterized as preoccupation with the idea that the body emits a foul odor. Japanese patients with a feature similar to ORS have long been recognized as jiko-shu-kyofu, which is believed to be a culture-bound syndrome and specific to Japan. The aim of the study was to clarify the relationship between the two separate syndromes that had independently been recognized in culturally different settings., Method: The phenomenology and treatment of seven patients with jiko-shu-kyofu were described. A feature of jiko-shu-kyofu was then compared with that of ORS., Results: In our cases, clinical characteristics of jiko-shu-kyofu such as symptomatology, insight, and pharmacotherapy response were found identical to those of ORS except for the onset at relatively younger ages., Conclusion: Jiko-shu-kyofu and ORS may share a common clinical entity, hence the former is not a culturally distinctive disorder.

Myelodysplastic syndrome (MDS) is a common neoplasm of haematopoietic pluripotent stem cells. Although one third of MDS patients evolve to acute myeloid leukaemia (AML), little is understood about the mechanisms responsible for this progression. We have previously detected the frequent loss of heterozygosity (LOH) on the short arm of chromosome 1 in blast crisis of chronic myelocytic leukaemia. In this study, we examined the chromosomal arm 1p for allelic loss in the progression of MDS to AML, using 17 microsatellite markers spanning chromosome 1 in 20 patients who progressed from MDS to AML. DNA was extracted from slides of bone marrow smears. In each patient, DNA from MDS was analysed alongside DNA from AML. Allelic loss on 1p was observed in six of the 20 individuals (30%). Serial cytogenetic information was available in five of the six patients with LOH on 1p; no deletions in this region were detected. Three samples showed LOH at all informative loci on 1p. The other three samples showed LOH on at least one but not all loci on 1p with consensus regions of LOH located distal to D1S253 (1p36.3) and probably proximal to D1S496 (1p32-). Our results suggest that tumour suppressor genes that play an important role in the progression of MDS to AML may reside in at least two different regions on 1p.

Schizophrenic patients with an onset before age 16 years (early-onset schizophrenia, EOS) would be a rare but attractive subpopulation for genetic studies. This study explored the relationship between the polymorphism of four dopamine-regulating-enzymes (tyrosine hydroxylase, dopamine-beta-hydroxylase, catechol-O-methyltransferase, monoamine oxidase-A) genes, four dopamine-receptors (dopamine D1, D2, D3, D4 receptors) genes and susceptibility to EOS in a Japanese sample. Subjects comprised 51 Japanese patients who met DSM-IV criteria for schizophrenia with an onset before age 16 (by age 15) and 148 Japanese healthy controls. DNA was extracted from whole blood and genotyping was carried out by PCR-RELP using each restriction endonuclease. No significant difference was found in the allele frequencies or genotype distributions of any of the eight genes examined between EOS and the control groups. We did not find the relationship between the polymorphism of eight dopamine-related genes and susceptibility to EOS in a Japanese sample., (Copyright 2002 Wiley-Liss, Inc.)

Plasma from a total of 57 patients with adult T-cell leukaemia (ATL) (acute ATL, 39 patients; lymphoma ATL, one patient; chronic ATL, 15 patients; smouldering ATL, two patients) and 20 healthy controls was analysed for the presence of type IV gelatinase activity with clinical features. A significant elevation of plasma matrix metalloproteinase-9 (MMP-9) was observed in some ATL patients, particularly in the patients with malignant cell infiltration. MMP-9 was found to be secreted into the conditioned medium from all ATL cell lines examined. Moreover, the corresponding mRNA was detectable both in all ATL cell lines examined and in the majority of primary acute ATL cells, indicating that ATL cells are capable of synthesizing and secreting MMP-9. We previously demonstrated that a high incidence of ATL cell infiltration was closely related to a high plasma level of vascular endothelial growth factor (VEGF) produced by ATL cells themselves. This present study showed that the presence of increased plasma MMP-9 was closely associated with elevated plasma VEGF in ATL patients. Furthermore, we showed that both increased plasma MMP-9 and VEGF were significantly related to high ATL cell infiltration. All these findings strongly suggest that MMP-9 and VEGF act co-operatively in the process of ATL cell invasion.

Objective: There have so far been no studies that directly compared clinical features between patients with early- and late-onset anorexia nervosa (AN)., Method: We identified 64 patients with DSM-III-R AN. We defined individuals as an early-onset group, who had an age of onset before 14 years (N = 31), and the remaining as a late-onset group (N = 33). The clinical symptoms, body weight and weight index, were compared between the two groups. Subjects were dichotomized into those with extremely low weight and those remaining. We compared the proportion of the patients with extremely low weight between the two groups., Results: The rates of 'self-induced vomiting' and 'purging' were significantly lower in a group of patients with early-onset AN than in those with late-onset AN. There were significantly fewer subjects with extremely low weight in early-onset than in late-onset AN group., Conclusion: We found clear differences in clinical features between early- and late-onset AN groups.

CD30, Ki-1 antigen, an activated T-cell antigen, is a member of the nerve growth factor receptor family. This antigen is expressed on the lymphoma cells of some adult T-cell leukaemia/lymphoma (ATL/L) patients and some patients with Epstein-Barr virus infection. CD30-positive large cell cutaneous T-cell lymphomas occasionally integrate a defective HTLV-1 provirus. We describe here an HTLV-1 carrier who developed Ki-1 lymphoma with no evidence of monoclonal integration of the HTLV-1 proviral sequence.

Emergency percutaneous cardiopulmonary bypass support (PCPS) was instituted in 3 patients with acute myocardial infarction in cardiac arrest refractory to conventional resuscitation measures. All had severe double or triple vessel disease. Percutaneous transluminal coronary angioplasty (PTCA) was performed in 1 patient and PTCA and directional coronary atherectomy (DCA) were performed in the other 2 patients on combined intraaortic balloon pumping (IABP) and PCPS. Flow rates of 2 to 5 L/min were achieved, with restoration of mean arterial pressure to more than 60 mm Hg during PCPS. The status of all patients was improved hemodynamically with PCPS. One patient died of hemorrhage during PCPS. DCA was successfully performed in the other 2 patients, and PCPS and IABP was discontinued. Time on PCPS ranged from 10 h to 8 days. Time on IABP ranged from 10 days to 2 weeks. These 2 patients died of pneumonia or multiorgan failure after 1.5 months. In conclusion, emergency PCPS is a powerful resuscitative tool that may stabilize the condition of patients in cardiac arrest to allow for definitive intervention.

We describe a case of B-lineage acute lymphoblastic leukaemia (ALL) with proliferation of leukaemic cells through an interleukin-1 alpha (IL-1 alpha) autocrine mechanism. Flow cytometric analysis using the IL-1 receptor type II (IL-1Rt II) monoclonal antibody (mAb) demonstrated the expression of the IL-1Rt II on leukaemic cells: this is the first report in IL-1RtII-positive freshly isolated ALL cells from a patient. In accordance with the expression of IL-1RtII, the leukaemic cells proliferated in response to exogenous IL-1 alpha. In addition, anti-IL-1 alpha mAb markedly inhibited the spontaneous cell proliferation. Furthermore, Northern blot analysis detected IL-1 alpha mRNA without any stimulation. These observations suggest that IL-1 alpha may play an important role as an autocrine growth factor in some cases of ALL.

We describe a case of T-chronic lymphocytic leukaemia (T-CLL) with monoclonal proliferation of CD3+4+8- T cell expressing the interleukin 2 receptor (IL-2R) beta chain without expressing the alpha chain. Southern blot analysis of T-cell receptor beta chain gene revealed rearranged bands. The serum antibody was positive against human T-cell lymphotropic virus type I (HTLV-1)-associated antigens, but monoclonal integration of proviral DNA was not detected in the leukaemic cells. In accordance with the expression of IL-2R beta chain, the leukaemic cells proliferated in response to exogenous IL-2 without prior stimulation. However, culture supernatants of these cells did not show IL-2 activity. Since the role of the IL-2R beta chain in freshly isolated cells from T-CLL patients is not well understood, detailed analysis of this case would give us valuable information on the role of IL-2/IL-2R system in the proliferation of the leukaemic T cells.

Mutations of the p53 tumour suppressor gene have frequently been observed in several types of solid tumours and are believed to be implicated in the development of these tumours. To determine the relevance of p53 mutations in haematologic neoplasms, we performed polymerase chain reaction-single strand conformation polymorphism analysis on the p53 gene in 45 patients with various types of haematologic neoplasms. In exons 5-8 containing highly conserved regions, mobility shifts indicating sequence alterations were detected in four of the 45 patients, and subsequent sequencing was performed. A point mutation resulting in a novel stop codon was detected at codon 213 in one of 23 cases of chronic myelogenous leukaemia (one of five cases of blast crisis). Point mutations causing amino acid substitutions were detected in one of four cases of myelodysplastic syndrome at codon 195, one of three cases of adult T-cell leukaemia at codon 281, and one of eight cases of acute lymphoblastic leukaemia at codon 281, and these missense mutations were accompanied by loss of the wild type allele. Patients harbouring these nonsense and missense mutations were in advanced disease stages. These findings suggest that mutational inactivation of the p53 gene is infrequent but is involved in the tumorigenesis of several types of haematologic neoplasms at least in some cases.

Twelve healthy pigs were ventilated with high frequency jet ventilation via a Mallinckrodt HiLo jet tube. The expired gas was led to a conventional ventilator and CO2 analyzer which were used to measure CO2 elimination. There was no bias flow, so that the jet entrained only expired gas, i.e. rebreathing occurred. Frequency was varied between 2 and 11 Hz and the duration of inspiration, as a fraction of the ventilatory cycle (Ti/Ttot), from 5 to 20%. The minute ventilation, Vjet, delivered by the jet ventilator was adjusted to maintain a constant PaCO2. At 2 Hz and a Ti/Ttot of 5%, Vjet was of the same magnitude as ventilation during conventional intermittent positive pressure ventilation, and the total dead space fraction, VD/VT was 0.32. Both increasing frequency at a constant Ti/Ttot, and increasing Ti/Ttot at a constant frequency, increased VD/VT which was maximal (0.8) at 11 Hz and a Ti/Ttot of 20%. When entrainment was blocked, tidal jet volume had to be greatly increased. The continuous measurement of CO2 elimination was found to be useful for maintaining isocapnia when the jet ventilator setting was changed.

A case of cutaneous malignant lymphoma in a 7-month-old infant is described. The skin was the only apparent organ involved. Immunophenotypic studies revealed that the infiltrate was positive for B4 (CD19), J5 (CD10), and cytoplasmic mu chain, and lambda chain, but negative for B1 (CD20). The significance of these findings is discussed. We believed the tumor was of B-cell origin. The reported cases of cutaneous malignant lymphoma in infancy are briefly reviewed.

The expression of class II major histocompatibility complex (MHC) antigen on the membrane of mouse sperm head was clearly demonstrated by indirect immunofluorescence (IIF) test, enzyme immunoassay (EIA), and mixed lymphocyte sperm reaction (MLSR) as well as the examination of its expression at transcriptional levels by northern dot blotting. Furthermore, the roles of class II MHC antigen of sperm in fertilization were investigated with an in vitro fertilization (IVF) system. The successful ratio of IVF was significantly decreased by treatment of sperm with anticross-reactive region of class II MHC antigen monoclonal antibody (MAb) but not with antiprivate region MAb. These results were not due to disturbances of sperm mobility by these MAbs. It was strongly suggested that the monomorphic or its related region of class II MHC antigen on sperm played an important role in the recognition between sperm and egg in fertilization.