Sputum-to-serum hydrogen sulphide ratio as a novel biomarker of predicting future risks of asthma exacerbation.

BACKGROUND: Increased level of hydrogen sulphide (H2 S) in sputum is reported to be a new biomarker of neutrophilic airway inflammation in chronic airway disorders. However, the relationship between H2 S and disease activity remains unclear. OBJECTIVE: We investigated whether H2 S levels could vary during different conditions in asthma. METHOD: H2 S levels in sputum and serum were measured using a sulphide-sensitive electrode in 47 stable asthmatic subjects (S-BA), 21 uncontrolled asthmatic subjects (UC-BA), 26 asthmatic subjects with acute exacerbation (AE-BA) and 15 healthy subjects. Of these, H2 S levels during stable, as well as exacerbation states, were obtained in 13 asthmatic subjects. RESULTS: Sputum H2 S levels were significantly higher in the AE-BA subjects compared to the UC-BA and healthy subjects (P < .05). However, serum H2 S levels in the AE-BA subjects were lower than in the S-BA subjects (P < .001) and similar to those in healthy subjects. Thus, the sputum-to-serum ratio of H2 S (H2 S ratio) in the AE-BA subjects was significantly higher than in the S-BA, UC-BA and healthy subjects (P < .05). Among all subjects, sputum H2 S levels showed a trend to decrease with FEV1 %predicted and significantly positive correlations with sputum neutrophils (%), sputum IL-8 and serum IL-8. A multiple linear regression analysis showed that sputum H2 S was independently associated with increased sputum neutrophils (%) and decreased FEV1 %predicted (P < .05). The cut-off level of H2 S ratio to indicate an exacerbation was ≥0.34 (area under the curve; 0.88, with a sensitivity of 81.8% and specificity of 72.7%, P < .001). Furthermore, half of the asthmatic subjects with H2 S ratios higher than the cut-off level experienced asthma exacerbations over the following 3 months after enrolment. CONCLUSIONS: The H2 S ratio may provide useful information on predicting future risks of asthma exacerbation, as well as on obstructive neutrophilic airway inflammation as one of the non-Th2 biomarkers, in asthma.

Randomised phase II trial of irinotecan plus S-1 in patients with gemcitabine-refractory pancreatic cancer.

BACKGROUND: We aimed to compare the efficacy and safety of irinotecan/S-1 (IRIS) therapy with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer. METHODS: Patients were treated with oral S-1 (80-120 mg for 14 days every 4 weeks) plus intravenous irinotecan (100 mg m-2 on days 1 and 15 every 4 weeks; IRIS group) or oral S-1 group (80-120 mg daily for 28 days every 6 weeks). The primary endpoint was progression-free survival (PFS). RESULTS: Of 137 patients enrolled, 127 were eligible for efficacy. The median PFS in the IRIS group and S-1 monotherapy group were 3.5 and 1.9 months, respectively (hazard ratio (HR)=0.77; 95% confidence interval (CI), 0.53-1.11; P=0.18), while the median overall survival (OS) were 6.8 and 5.8 months, respectively (HR=0.75; 95% CI, 0.51-1.09; P=0.13). Response rate was significantly higher in the IRIS group than in the S-1 monotherapy group (18.3% vs 6.0%, P=0.03). Grade 3 or higher neutropenia and anorexia occurred more frequently in the IRIS group. CONCLUSIONS: There was a trend for better PFS and OS in the IRIS group that could be a treatment arm in the clinical trials for gemcitabine-refractory pancreatic cancer.

Polymorphism in promoter region of growth hormone receptor is associated with potential production capacity of insulin-like growth factor-1 in pre-pubertal Holstein heifers.

Insulin-like growth factor-1 (IGF-1) is one of the important factors for growth, milk production and reproductive functions and mainly released from the liver in response to growth hormone (GH) via GH receptor (GHR) in cattle. Recently, some single nucleotide polymorphisms (SNPs) were identified in the bovine GHR gene. Some GHR-SNPs were shown to be related to plasma IGF-1 concentration in cattle. Hence, the capacity to IGF-1 production in the liver might be affected by GHR-SNP and associated with performance in the future. This study examined whether GHR-SNP is associated with IGF-1 production in the liver of pre-pubertal heifers. In 71 Holstein calves, blood samples for genomic DNA extraction were obtained immediately after birth. To genotype the GHR-SNPs in the promoter region, polymerase chain reaction (PCR) products were digested with restriction enzyme NsiI (cutting sites: AA, AG and GG). All heifers at 4 months of age were intramuscularly injected with 0.4 mg oestradiol benzoate. Blood samples were obtained from the jugular vein just before (0 h) and 24 h after injection. The number of AA, AG and GG at the NsiI site was 0, 17 and 54 respectively. In AG and GG, plasma GH concentrations were higher pre-injection than 24 h post-injection (p < 0.01). Moreover, plasma GH concentrations in AG post-injection were higher than in GG (p < 0.05). In contrast, the GG genotype exhibited higher plasma IGF-1 concentrations in pre-injection than post-injection (p < 0.01), although oestradiol did not change IGF-1 concentration in the AG genotype. We conclude that the GG polymorphism in the promoter region of GHR is associated with a higher potential capacity of IGF-1 production in the liver of cattle.

Influence of menopause on mandibular bone quantity and quality in Japanese women receiving dental implants.

SUMMARY: The purpose of this study was to evaluate the effect of menopause on bone mineral density and bone width of the mandible. Results indicate that menopause affects the bone quality and quantity of the partially edentulous molar region of the mandible, which should be considered in dental implant treatment for postmenopausal women. INTRODUCTION: The recovery of oral function with dental implant is clinically effective and highly predictable. Bone quantity and quality at the implant installation site affect its prognosis; however, the effects of menopause on jaw bone have not been well documented. The purpose of this study was to evaluate the effect of menopause on bone mineral density (BMD) and bone width of the mandible. METHODS: The subjects were 72 female patients with a partially edentulous molar region of the mandible: 30 premenopausal and 42 postmenopausal women aged 30 to 70 years. Trabecular BMD was measured with quantitative computed tomography. Trabecular region width (TW) and cortical width (CW) were measured with CT. The BMD, TW, and CW of the two groups were compared. RESULTS: The trabecular BMD of postmenopausal women was lower than that of the premenopausal women. The TW of postmenopausal women was greater than that of premenopausal women, whereas the CW of postmenopausal women was significantly smaller than that of premenopausal women. In all these women, BMD correlated negatively with TW and positively with CW. In the premenopausal women, BMD negatively correlated with TW, but it did not correlate with CW. In the postmenopausal women, there was no correlation between BMD and bone width. CONCLUSION: These results indicate that menopause affects the bone quality and quantity of the partially edentulous molar region of the mandible, which should be considered in dental implant treatment for postmenopausal women.

Progressive atrophy of the cerebrum in 2 Japanese sisters with microcephaly with simplified gyri and enlarged extraaxial space.

This is a case report that describes 2 sisters with microcephaly, simplified gyri, and enlarged extraaxial space. Clinical features of the cases include dysmorphic features, congenital microcephaly, failure of postnatal brain growth, neonatal onset of seizures, quadriplegia, and severe psychomotor delay. Neuroradiological imaging demonstrated hypoplasia of bilateral cerebral hemispheres with enlarged extraaxial spaces, simplified gyral patterns without a thickened cortex, hypoplastic corpus callosum, and enlarged lateral ventricles, with a reduction in gray and white matter volume during the prenatal and neonatal periods. Repeat MRI revealed progressive atrophy of the cerebral gray and white matter, with enlarged lateral ventricles, although the sizes of the bilateral basal ganglia, thalamus, and infratentorial structures were relatively preserved. These neuroradiological findings imply that this disease is caused by the gene involved in neuronal and glial proliferation in the ventricular zone and in tangential neuronal migration from the ganglionic eminence. The nature of the progressive degeneration of the hemispheric structures should be clarified.

Hepatic arterial infusion of mitomycin C with degradable starch microspheres for unresectable intrahepatic cholangiocarcinoma.

AIMS: With no effective chemotherapy, the prognosis of unresectable intrahepatic cholangiocarcinoma is extremely poor. Hepatic arterial infusion of mitomycin C with degradable starch microspheres has been reported to be an effective treatment for unresectable liver metastasis. We retrospectively evaluated the efficacy and safety of this chemotherapy for treating unresectable intrahepatic cholangiocarcinoma. MATERIALS AND METHODS: Hepatic arterial infusion chemotherapy through an implanted port system was carried out in 20 patients with unresectable intrahepatic cholangiocarcinoma. Degradable starch microspheres mixed with mitomycin C and contrast media were injected until either embolisation of the hepatic artery or influx to the gastroduodenal system was confirmed. This treatment was repeated weekly. RESULTS: Hepatic arterial infusion chemotherapy was carried out 204 times. The response rate was 50.0%. Twelve patients experienced transient epigastralgia and four experienced gastroduodenal ulcer. The time to progression was 8.3 months and the median survival time was 14.1 months. CONCLUSIONS: This chemotherapy was effective and feasible for patients with unresectable intrahepatic cholangiocarcinoma. Further study with a larger number of patients is warranted.

Mannose binding lectin gene polymorphisms and asthma.

BACKGROUND: Bronchial asthma is a chronic inflammatory disorder of the airways. Recently, it has been suggested that complement plays significant roles in asthma. Mannose-binding lectin (MBL) is one of the key molecules in complement activation pathways that are associated with several infectious and immune disorders. SUBJECTS AND METHOD: To investigate whether MBL plays roles in asthma, we analysed MBL2 polymorphisms (allele B, H/L and Y/X) and plasma MBL levels in a Japanese adult population including 232 healthy controls and 579 asthmatics. RESULTS: Although there was linkage disequilibrium among the three polymorphisms, each polymorphism significantly affects serum MBL levels independently. However, there were no significant differences between asthmatics and controls in MBL2 genotype distribution and in MBL concentrations [1.47+/-0.07(SE) mg/L for asthmatics and 1.66+/-0.14 mg/L for controls, P=0.2]. MBL levels and genotype have no significant relationship with serum IgE, pulmonary functions, and the severity of asthma. CONCLUSION: Although plasma MBL levels depend on the MBL2 polymorphisms, these polymorphisms and plasma MBL levels are not associated with the asthma phenotype.

[Successful treatment for descending necrotizing mediastinitis; report of a case].

A case of a 55-year-old man with descending necrotizing mediastinitis (DNM) after a tooth removal was reported. Chest computed tomography (CT) showed a fluid collection in the right thorax, in the cervical region and in the mediastinum. The patient underwent cervical drainage and thoracoscopic pleural dissective drainage. The cervical and right anterior thoracic drain was removed on the 6th day and posterior drain was removed on the 8th day after the operation. The patient was discharged on the postoperative day 13, and showed no recurrence.

Genetic linkage analysis of pulmonary fibrotic response to silica in mice.

Inter-individual variations in the development of silicosis, even within the same environments, have been reported, which suggest the contribution of genetic factors in silicosis aetiology. The aim of the present study was to determine whether there is any significant genetic influence on the development of silicosis. Furthermore, which genetic loci are responsible for the pulmonary response to silica exposure? Eight strains of inbred mice were used to examine the genetic influence on the lung fibrotic response to silica exposure. After intercross-breeding between the most susceptible and most resistant strains, a genome-wide linkage analysis of quantitative trait loci (QTL) was performed. Hydroxyproline was applied as an index, and genotypes of 167 marker genes were analysed by fragment analysis using a capillary-type sequencer. There was significant inter-strain difference in the mean concentration of hydroxyproline contents among the eight strains of mice. Breeding studies were conducted between the most susceptible, C57BL/6J, and the most resistant strain, CBA/J. A genome-wide linkage analysis of silica-exposed intercrossed cohorts identified significant QTL on chromosome 4 and suggestive QTL on chromosomes 3 and 18. The present study demonstrates that genetic factors may play a significant role in fibrotic-lung responses to silica; one significant and two suggestive quantitative trait loci were identified.

Phase I/II study of docetaxel and S-1 in patients with advanced gastric cancer.

The aims of this phase I/II study of docetaxel and S-1 were to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and recommended dose (RD) in the phase I part and to explore the tumour response, survival and safety in the phase II part. Patients with histologically- or cytologically confirmed unresectable or recurrent gastric cancer were eligible. Treatment consisted of intravenous docetaxel on day 1 (starting dose 50 mg m(-2)) and oral S-1 at a fixed dose of 40 mg m(-2) twice daily on days 1-14, every 4 weeks up to six cycles. Nine patients took part in the phase I portion of the study. The MTD of docetaxel was determined to be 50 mg m(-2), with the DLTs of grade 3 infection associated with grade 3 neutropenia and grade 4 neutropenia during S-1 administration. The RD of docetaxel was 40 mg m(-2) in combination with S-1 40 mg m(-2) b.i.d. The efficacy and safety of this regimen was therefore assessed in 46 patients with at least one measurable lesion. The overall response rate and estimated median overall survival were 46% (95% CI, 31-61%) and 14.0 months (8.3-17.3 months), respectively. The most common grade 3/4 toxicity was neutropenia (67% of patients), which was predictable and manageable. This regimen showed promising activity with moderate toxicities in advanced gastric cancer.

[Modified bentall operation using composite graft without resection of aortic valve].

A 27-year-old male whose diagnoses were aortic dissection (Stanford A), aortic regurgitation, annulo-aortic ectasia, and Marfan syndrome underwent modified Bentall operation using composite graft and total arch replacement. Modification of proximal suture without resection of aortic valve like intravalvular implantation might have resulted in good recovery without blood transfusion. Another 63-year-old male who suffered from spontaneous aortic rupture with aortic regurgitation also underwent modified Bentall operation in the similar manner as the first case with good result. Spontaneous aortic rupture reported here is a rare case, and operation is thought to be prerequisite for the patient who suffers from this disease to survive.

[A report of three surgical cases in a family of Marfan syndrome].

A family of 3 patients with Marfan syndrome was reported. All of them had surgical interventions in cardiovascular disorders such as DeBakey type I, III aortic dissection and thoracoabdominal aortic aneurysm. In 2 patients, multiple surgical treatments were performed for aneurysmal dilatation of the distal false lumen or another lesions of the treated aorta. Since cardiovascular lesions of Marfan syndrome are systemic and progressive, the postoperative long term follow-up, including systemic evaluation of the arterial system, is essential to detect the latent cardiovascular complications. Careful examining the family with Marfan syndrome is necessary to discover any cardiovascular abnormalities in these people early.

Dissociation between airway responsiveness to methacholine and responsiveness to antigen.

Repeated aerosolized antigen challenges to brown Norway (BN) rats generate nonspecific airway hyperresponsiveness (AHR). On the other hand, some studies have demonstrated that repeated antigen challenge could attenuate antigen-specific AHR in BN rats. The authors questioned whether such dissociation in airway responses actually occurs when assessed in a single study in the same animals. The authors simultaneously measured AHR to methacholine and antigen-specific AHR in rats that were repeatedly exposed to aerosolized ovalbumin (OA) for 1 or 3 months after sensitization. Four days after the last challenge, airway responses to methacholine and OA, morphometry of the airways, the cell profile in bronchoalveolar lavage fluid, and cytokine messenger ribonucleic acid (mRNA) expression in the lungs were evaluated. The two types of AHR were modulated in opposite directions by repeated antigen challenges. The AHR to methacholine was significantly increased in the rats receiving antigen challenges compared with the control rats receiving saline challenges after sensitization; whereas, the antigen-specific AHR was significantly decreased. The number of alveolar macrophages in lavaged fluid and the expression of transforming growth factor-beta1 mRNA in lung tissue was significantly different between the antigen-challenged rats and the control rats. In conclusion, dissociation between nonspecific airway hyperresponsiveness and antigen-specific airway hyperresponsiveness in brown Norway rats after repeated antigen challenges was demonstrated. Sustained airway inflammation with macrophages and/or upregulation of transforming growth factor-beta1 messenger ribonucleic acid in the lung tissue may be responsible for this dissociation.

Myocardial protection of the pressure overload hypertrophied heart in human cardiac surgery by acceleration of anaerobic glycolysis.

BACKGROUND: Because of the decreased tolerance to ischemia and increased reperfusion injury in hypertrophied myocardium, myocardial hypertrophy is a well known risk factor for cardiac surgery. We have previously demonstrated in a left ventricular hypertrophy (LVH) model that a highly buffered cardioplegic solution (HBS) that provided glucose as a substrate and promoted anaerobic glycolysis during ischemia afforded superior myocardial protection when compared to standard formulations. And we reported the superiority of this cardioplegia in human cardiac surgery. METHODS: In this study, 16 patients with aortic stenosis (AS) and LVH receiving HBS were reviewed and compared to another patient group with AS and LVH who received either cold blood cardioplegia (CBC; n=5) or glucose insulin potassium (GIK; n=6). RESULTS: Postoperative cardiac index was better in the HBS group than the other two groups with similar or lower catecholamine. CK-MB was lower in HBS group than GIK group, but this was not significant. Only one DC cardioversion was required in the HBS group, whereas 2 DC in the CBC group and total 7 DC in the GIK group. CONCLUSIONS: We found that histidine buffered cardioplegic solution provided comparable or better pump performance after surgery with relatively lower inotropic requirement, less DC cardioversion and homologous blood requirements for left ventricular hypertrophied heart associated with aortic stenosis.

Mechanism of tonic spasms in West syndrome viewed from ictal SPECT findings.

To clarify the pathophysiology of tonic spasms, 21 patients with West syndrome were analyzed using ictal and interictal single photon emission computed tomography (SPECT). We focused on whether ictal perfusion changes were observed in the focal cortical region. Eight of the patients studied showed definite focal cortical ictal hyperperfusion, indicating that there is a unique subset of West syndrome that can be classified as infantile localization-related epilepsy. Of those eight patients, only two showed asymmetric spasms, suggesting that seizure symptomatology in infants gives only limited information on the localization-related nature of epilepsy. Furthermore, the activation of subcortical structures by focal cortical regions might be attributable to the symmetric seizure phenomena. Thirteen patients showed a diffuse pattern in their ictal SPECTs; this probably included patients with diffuse hyperperfusion and those with no changes. The following have yet to be determined: (1) whether West syndrome is divided into subgroups based on the origin of spasms, in that some patients have the origin in the cortical hemisphere and some have the origin in structures other than the cortical hemisphere, such as the brain stem; (2) whether differences in ictal SPECT patterns reflect a unique nature of tonic spasms in West syndrome, where tonic spasms appear in clusters and the interval of each spasm is different among each patient.

A novel mutation in glial fibrillary acidic protein gene in a patient with Alexander disease.

Alexander disease is a rare, progressive, leukoencephalopathy whose hallmark is the widespread accumulation of Rosenthal fibers. The most common form affects infants and young children, and is characterized by progressive failure of central myelination, usually leading to death before adulthood. Definitive diagnosis of Alexander disease has required biopsy or autopsy to demonstrate the presence of Rosenthal fibers. However, missense mutations in the coding region of the glial fibrillary acidic protein (GFAP) gene have recently been associated with a high percentage of pathologically proven cases. Here we report that a 10-year-old Japanese patient who showed clinical signs of Alexander disease is heterozygous for a C to T transition in which predicts a novel A244V amino acid substitution in the conserved 2A alpha-helix domain of GFAP. The nucleotide change was not found in 65 normal individuals (130 alleles). These results provide further support for a causative role for GFAP mutations in Alexander disease, and suggest DNA sequencing as an alternative diagnostic to biopsy.

[Beta 2-Adrenergic receptor gene polymorphisms].

beta 2-adrenergic receptor gene is an intronless single gene coding 413 amino acid and is located on chromosome 5q31-33. This area is also noted as a candidate locus for asthma susceptibility genes. Up to now, 9 polymorphisms in the coding lesion and 10 polymorphisms in the 5' promotor lesion have been reported. Some of them have functional significance. In terms of both pathophysiological and pharmacogenetic view of asthma, these polymorphisms have been attracted an attention of many researchers. In this review, I will summarize the recent knowledge about this topic and discuss some future directions.

Prediction of safe duration of hypothermic circulatory arrest by near-infrared spectroscopy.

OBJECTIVE: Hypothermic circulatory arrest is widely used for adults with aortic arch disease as well as for children with congenital heart disease. At present, no method exists for monitoring safe duration of circulatory arrest. Near-infrared spectroscopy is a new technique for noninvasive monitoring of cerebral oxygenation and energy state. In the current study, the relationship between near-infrared spectroscopy data and neurologic outcome was evaluated in a survival piglet model with hypothermic circulatory arrest. METHODS: Thirty-six piglets (9.36 +/- 0.16 kg) underwent circulatory arrest under varying conditions with continuous monitoring by near-infrared spectroscopy (temperature 15 degrees C or 25 degrees C, hematocrit value 20% or 30%, circulatory arrest time 60, 80, or 100 minutes). Each setting included 3 animals. Neurologic recovery was evaluated daily by neurologic deficit score and overall performance category. Brain was fixed in situ on postoperative day 4 and examined by histologic score. RESULTS: Oxygenated hemoglobin signal declined to a plateau (nadir) during circulatory arrest. Time to nadir was significantly shorter with lower hematocrit value (P <.001) and higher temperature (P <.01). Duration from reaching nadir until reperfusion ("oxygenated hemoglobin signal nadir time") was significantly related to histologic score (r (s) = 0.826), neurologic deficit score (r (s) = 0.717 on postoperative day 1; 0.716 on postoperative day 4), and overall performance category (r (s) = 0.642 on postoperative day 1; 0.702 on postoperative day 4) (P <.001). All animals in which oxygenated hemoglobin signal nadir time was less than 25 minutes were free of behavioral or histologic evidence of brain injury. CONCLUSION: Oxygenated hemoglobin signal nadir time determined by near-infrared spectroscopy monitoring is a useful predictor of safe duration of circulatory arrest. Safe duration of hypothermic circulatory arrest is strongly influenced by perfusate hematocrit value and temperature during circulatory arrest.

Spiral, herringbone, and triple-decker silver(I) complexes of benzopyrene derivatives assembled through eta(2)-coordination.

Three novel silver(I) complexes with benzopyrene derivatives were synthesized and characterized in this paper. Treatment of AgClO(4)*H(2)O with 7-methylbenzo[a]pyrene (L(1)) afforded [Ag(2)(L(1))(toluene)(0.5)(ClO(4))(2)](n)() (1) which exhibits a 2-D sheet structure with double-stranded helical motifs. Reaction of AgCF(3)SO(3) with dibenzo[b,def ]chrysene (L(2)) gave rise to an unprecedented cocrystallization structure, ([Ag(2)(L(2))(CF(3)SO(3))(2)][Ag(2)(toluene)(2)(CF(3)SO(3))(2)])(n)() (2), formed by a 2-D neutral lamellar polymer and a 1-D neutral rodlike one. The ligand benzo[e]pyrene (L(3)) coordinated to silver(I) ions generating a closed triple-decker tetranuclear complex [Ag(4)(L(3))(4)(p-xylene)(ClO(4))(4)] (3) which can be regarded as a stacking polymer owing to existing intermolecular pi-pi stack interactions. The structural diversity of the silver(I) coordination polymers with polycyclic aromatic hydrocarbons is not only related to the stacking patterns of free polycyclic aromatic hydrocarbons in the crystalline state, but also the geometric shapes of the molecules for these free ligands. In addition, the coordination of solvents to metal ions plays a crucial role in the formation of the unprecedented coordination polymeric architectures. The ESR spectroscopic results, conductivity, and synthesis properties are also discussed.