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Biomedical subjects

A Niimi

Publications and source records attributed to A Niimi.

At least 19 recordsLinked to original sources
PubMed2006

Evidence that errors made by DNA polymerase alpha are corrected by DNA polymerase delta.

Eukaryotic replication begins at origins and on the lagging strand with RNA-primed DNA synthesis of a few nucleotides by polymerase alpha, which lacks proofreading activity. A polymerase switch then allows chain elongation by proofreading-proficient pol delta and pol epsilon. Pol delta and pol epsilon are essential, but their roles in replication are not yet completely defined . Here, we investigate their roles by using yeast pol alpha with a Leu868Met substitution . L868M pol alpha copies DNA in vitro with normal activity and processivity but with reduced fidelity. In vivo, the pol1-L868M allele confers a mutator phenotype. This mutator phenotype is strongly increased upon inactivation of the 3' exonuclease of pol delta but not that of pol epsilon. Several nonexclusive explanations are considered, including the hypothesis that the 3' exonuclease of pol delta proofreads errors generated by pol alpha during initiation of Okazaki fragments. Given that eukaryotes encode specialized, proofreading-deficient polymerases with even lower fidelity than pol alpha, such intermolecular proofreading could be relevant to several DNA transactions that control genome stability.

Catalysis↗
PubMed2005

Relationship of airway wall thickening to an imbalance between matrix metalloproteinase-9 and its inhibitor in asthma.

BACKGROUND: The balance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be critical in extracellular matrix remodelling, a characteristic of asthmatic airways. An excess of TIMP-1 over MMP-9 has been associated with chronic airflow obstruction but the mechanisms underlying this association remain unknown. Recent computed tomographic (CT) studies indicate that airway wall thickening is associated with chronic airflow obstruction. METHODS: Sputum levels of MMP-9, TIMP-1, and their molar ratio were examined in 26 patients with stable asthma and their relationship with pulmonary function and airway wall thickness, assessed by a validated CT technique which measured wall area corrected by body surface area (WA/BSA), the ratio of WA to outer wall area (WA%), and the absolute wall thickness corrected by radicalBSA of a segmental bronchus (T/ radicalBSA), was examined. RESULTS: Sputum MMP-9 levels were inversely correlated with WA% and TIMP-1 levels were positively correlated with WA/BSA and T/ radicalBSA. The MMP-9/TIMP-1 molar ratio was inversely correlated with WA% and T/ radicalBSA and positively correlated with post-bronchodilator values of mid-forced expiratory flow and maximum expiratory flow at the quartile of lung volume. CONCLUSION: Excess TIMP-1 may have a pathogenetic role in airway wall thickening in asthmatic patients which may result in chronic airflow obstruction.

Asthma↗
PubMed2004

An immunoglobulin agent (IVIG) inhibits NF-kappaB activation in cultured endothelial cells of coronary arteries in vitro.

OBJECTIVE: Kawasaki disease (KD) is an acute febrile vasculitis of unknown etiology that may lead to cardiovascular disorders. High-dose intravenous immunoglobulin (IVIG) therapy is well established as a standard therapy for KD. Tumor necrosis factor-alpha (TNF-alpha) is responsible for the pathogenesis of acute KD. We examined whether or not IVIG inhibits TNF-alpha-induced activation of transcription factor NF-kappaB, a factor that is essential for the expression of proinflammatory cytokines, in human coronary artery endothelial cells (CAEC). METHODS: The inhibitory effect of IVIG on NF-kappaB activation induced by TNF-alpha was evaluated by Western blot analysis and ELISA. Moreover, the inhibitory effects of IVIG on IkappaBalpha degradation, interleukin-6 (IL-6) production, and E-selectin expression induced by TNF-alpha were evaluated by Western blot analysis, ELISA, and flow cytometry, respectively. RESULTS: Western blot analysis and ELISA demonstrated that IVIG inhibits NF-kappaB activation induced by TNF-alpha in CAEC. Moreover, IVIG inhibited IkappaBalpha degradation, IL-6 production, and E-selectin expression induced by TNF-alpha in CAEC. CONCLUSION: The data suggest that IVIG inhibits NF-kappaB activation induced by TNF-alpha in CAEC, thereby possibly modulating IL-6 production and E-selectin expression.

Arteries↗
PubMed2004

Reduced pH and chloride levels in exhaled breath condensate of patients with chronic cough.

BACKGROUND: Increased hydrogen and reduced chloride ionic environments of the airways are conducive to the stimulation of cough. However, the constituents of the local milieu of the airways of patients with chronic cough are unknown. METHODS: The pH and chloride levels in exhaled breath condensate and capsaicin cough threshold (C5) were measured in 50 patients with chronic cough and in 16 healthy controls. pH and chloride measurements were repeated after capsaicin challenge in those with cough. The cause of cough was asthma (n = 13), postnasal drip/rhinitis (n = 7), gastro-oesophageal reflux (n = 5), bronchiectasis (n = 5), but remained unidentified in 20. RESULTS: Compared with controls, patients with chronic cough had lower pH (mean 7.9 v 8.3, 95% CI of difference -0.5 to -0.2, p<0.0001), chloride levels (median 4 v 6 mmol/l, 95% CI -3.1 to -0.2, p = 0.007), and C5 (median 3.9 v 125 micro M, 95% CI -270.0 to -17.6, p = 0.002). The pH levels were different in the six subgroups including controls, and were reduced in all diagnostic subgroups of patients with cough compared with controls but did not differ between them. Chloride levels were significantly different in the six subgroups but were lower than controls in only the gastro-oesophageal reflux subgroup. There was a weak but significant correlation between chloride levels and C5 when all participants were analysed together, but not between pH and C5 or chloride levels. pH and chloride levels did not change after capsaicin challenge. CONCLUSIONS: The epithelial lining fluid of patients with chronic cough has a reduced pH and reduced chloride levels which could contribute to the enhanced cough reflex.

Adult↗
PubMed2003

Impaired cough reflex in patients with recurrent pneumonia.

BACKGROUND: A substantial proportion of patients with recurrent pneumonia do not have an apparent underlying condition, but they may have unknown defects in host defence mechanisms such as cough reflex. METHODS: Capsaicin cough sensitivity was measured in seven patients with recurrent pneumonia but no underlying condition. Recurrent pneumonia was defined as at least two episodes of pneumonia in 1 year, or three or more episodes at any time. After remission of pneumonia, 10 doubling concentrations of capsaicin (1.22-625 microM) were inhaled until five or more coughs were induced (cough threshold). Mucociliary clearance was assessed on the basis of nasal ciliary beat frequency and nasal clearance time. Twenty one age and sex matched healthy subjects were studied as controls. RESULTS: Each patient had 2-6 episodes of pneumonia. Most episodes developed in dependent lung segments, suggesting the involvement of silent aspiration. Log transformed cough threshold was significantly higher in patients than in controls (mean 2.37 M (95% CI 1.84 to 2.90) v 1.29 microM (95% CI 1.11 to 1.47); p<0.0001). The effect of pneumonia per se on cough reflex seemed unlikely since the cough threshold showed little change when re-examined after 3 months. The patients and controls did not differ with respect to the indices of mucociliary clearance. CONCLUSIONS: Impaired cough reflex may be involved in the pathogenesis of recurrent pneumonia.

Adult↗
PubMed2002

Eosinophilic bronchitis: clinical manifestations and implications for treatment.

Airway inflammation with eosinophils is now reported to occur not only in asthma but in other airway diseases such as cough variant asthma, chronic cough, atopic cough, episodic symptoms without asthma, allergic rhinitis, and COPD. Although the prevalence of eosinophilic bronchitis (EB) is less than in asthma, the causes, mechanisms and treatment of EB in these conditions appears to be similar to asthma where allergen induced IL-5 secretion and symptoms are readily responsive to inhaled corticosteroids. The prognosis of EB without asthma is not known but it may be a precursor for asthma and, if so, recognition of this syndrome may permit effective treatment and reduction in the rising prevalence of asthma. Induced sputum analysis allows recognition of EB in clinical practice. The place of the asthma treatment paradigm with early and sustained corticosteroid treatment needs to be defined in EB without asthma. Airway wall remodelling can occur in rhinitis, COPD, and cough variant asthma with EB. The mechanisms and long term implications of this complication in EB without asthma need to be clarified.

Asthma↗
PubMed2002

Plasma leptin levels and cardiac sympathetic function in patients with obstructive sleep apnoea-hypopnoea syndrome.

BACKGROUND: The control of body weight and cardiac sympathetic function in patients with obstructive sleep apnoea-hypopnoea syndrome (OSAHS) are important because both factors have significant effects on the mortality of these patients. It has recently been reported that OSAHS has a significant effect on the secretion of leptin, a hormone involved in the control of body weight and sympathetic nerve activity. In addition to the circadian rhythm of leptin secretion, the effects of one night of treatment with nasal continuous positive airway pressure (nCPAP) and the mechanism of the effects of nCPAP on nocturnal leptin secretion in patients with OSAHS has not yet been elucidated. METHODS: Blood samples were obtained at 21.00 hours, 00.00 hours, 03.00 hours, and 06.30 hours from 21 subjects with OSAHS (mean apnoea and hypopnoea index 52.4/h), with and without nCPAP treatment. Iodine-123 (I(123))-meta-iodobenzylguanidine (MIBG) imaging was used to evaluate myocardial sympathetic function before nCPAP treatment. RESULTS: Plasma leptin reached a peak level at 00:00 hours (p<0.01) in patients with OSAHS, both with and without nCPAP treatment. The first night of nCPAP treatment significantly decreased the plasma leptin levels at 03.00 hours (without nCPAP: mean (SE) 21.6 (4.7) ng/ml; with nCPAP: 19.3 (4.1) ng/ml, p<0.02) and at 06.30 hours (without nCPAP: 17.6 (3.8) ng/ml; with nCPAP: 15.2 (3.2) ng/ml, p<0.01). The magnitude of the decrease in leptin levels after nCPAP treatment was significantly correlated with cardiac sympathetic function measured before nCPAP treatment (p<0.03). CONCLUSIONS: Patients with OSAHS undergo nocturnal increases in leptin levels in spite of interruption of sleep due to apnoea and hypopnoea, a trend seen in normal subjects. Plasma leptin levels in patients with OSAHS decreased significantly after the first night of nCPAP treatment. Enhanced cardiac sympathetic function in these patients may contribute to the leptin levels before nCPAP treatment and vice versa.

3-Iodobenzylguanidine↗
PubMed2001

Co-localization of chicken DNA topoisomerase IIalpha, but not beta, with sites of DNA replication and possible involvement of a C-terminal region of alpha through its binding to PCNA.

Clones for DNA topoisomerase IIalpha and beta (topo-IIalpha and beta) were isolated from a cDNA expression library of chicken MSB-1 cells by immunoscreening. The deduced sequences of chicken topo-IIalpha and beta were about 80% identical for the N-terminal ATPase domain and the central core domain but only 37% for the C-terminal domain. Polyclonal antibodies were raised against C-terminal polypeptides specific to topo-IIalpha and beta. Indirect immunofluorescence with these antibodies to chicken embryonic fibroblasts demonstrated that topo-IIalpha was distributed in discrete intranuclear spots, which coincided with sites of DNA replication as indicated by incorporation of 5-bromo-2'-deoxyuridine, whereas topo-IIbeta was distributed rather uniformly within a nucleus. Examination of intranuclear distribution patterns of chimeric constructs between topo-IIalpha and beta suggested that a sequence region (residues 1280-1294) in the C-terminal domain of topo-IIalpha was effective in co-localization with sites of DNA replication. This region consists of a QTxhxF motif (x, any residue; h, hydrophobic residue) followed by a KR-rich sequence, which resembles those found in several proteins known to associate with proliferating cell nuclear antigen (PCNA) or targeted to the replication factory. An in vitro pull-down assay with glutathione-S-transferase-PCNA and (His)6-tagged truncated forms of topo-IIalpha demonstrated that polypeptides containing the above region (residues 1158-1553 or 1158-1294) bound to PCNA in vitro.

Amino Acid Sequence↗
PubMed2001

Serum eosinophil cationic protein levels measured during exacerbation of asthma: characteristics of patients with low titres.

BACKGROUND: Serum eosinophil cationic protein (ECP) levels reflect ongoing eosinophilic airway inflammation and are used as a marker for asthma activity. ECP levels, however, may not be elevated in some asthmatic patients, even when they are symptomatic. OBJECTIVE: To clarify the characteristics of patients with 'low' ECP titres despite asthma exacerbation. METHODS: Serum ECP levels were measured in 113 asthmatic patients during exacerbation. Patients were divided into two groups according to ECP titre: a high ECP group (H; ECP > or = 16.0 microg/L) and a low ECP group (L; ECP <16.0 microg/L). Twenty-two patients who had recently received systemic steroids were excluded and the clinical features of the remaining patients in H (n = 54) and L (n = 37 were compared. RESULTS: Gender, atopic or smoking status, disease severity, inhaled steroid or theophylline usage, peak expiratory flow (% personal best) and forced expiratory volume in 1 s (FEV1) (% predicted) did not significantly differ between the two groups. Patients in L were significantly older and had longer disease duration and lower serum IgE levels than those in H. Multivariate analysis combining age, disease duration and IgE levels showed that age and disease duration were independently associated with ECP level. Airway wall thickness, assessed in a subset of patients using computed tomography, was significantly larger in L. CONCLUSION: Serum ECP levels in asthmatic patients may not be elevated during exacerbation and thus may not be a useful marker in patients who are older, have longer disease duration or possibly have thicker airway walls. Mechanisms other than eosinophilic inflammation, such as airway remodelling, may be involved in asthma exacerbation in these patients.

Adolescent↗
PubMed2001

Effects of inhaled corticosteroid and short courses of oral corticosteroids on bone mineral density in asthmatic patients : a 4-year longitudinal study.

BACKGROUND: It is not certain whether inhaled corticosteroid (ICS) therapy reduces bone mineral density (BMD) in asthmatic patients. In addition, the potential risk of osteoporosis associated with the rescue use of short courses of oral corticosteroids (SC-OCS) is unclear. OBJECTIVE: To evaluate the effect of inhaled beclomethasone dipropionate (BDP) and SC-OCS on BMD in asthmatic patients. DESIGN: A 4-year longitudinal study. METHOD: Lumbar BMD was measured twice by dual-energy x-ray absorptiometry at a mean (+/- SD) interval of 4.2 +/- 0.1 years in 35 asthmatic adults (15 men and 20 postmenopausal women; mean age at the second evaluation, 60.6 +/- 11.5 years) who had been treated with BDP and SC-OCS. RESULTS: The average period of BDP treatment was 7.7 +/- 2.2 years (range, 4.8 to 13.0 years) at the second evaluation. During the study period, the daily dose of BDP was 765 +/- 389 microg (range, 100 to 1,730 microg), and the frequency of SC-OCS was 1.9 +/- 2.7 courses per year (range, 0.0 to 8.9 courses per year). As a whole, lumbar BMD was unchanged during the course of the study, whereas the Z score (ie, the percentage of normal value predicted from age and sex) increased significantly. Changes in BMD and Z scores in patients receiving high doses of BDP (ie, > 1,000 microg/d; n = 9) were not significantly different from those of patients receiving lower doses (ie, 2.5 courses per year; n = 9) showed a significantly greater loss in BMD and Z score compared with those receiving sporadic courses (ie, <or= 2.5 courses per year; n = 26) (p = 0.002 and p = 0.035, respectively). CONCLUSIONS: ICS therapy per se does not affect BMD, whereas frequent SC-OCS may do so.

Absorptiometry, Photon↗
PubMed2001

Maxillary sinus floor augmentation in rabbits: a comparative histologic-histomorphometric study between rhBMP-2 and autogenous bone.

The present study was designed to compare recombinant human bone morphogenetic protein-2 (rhBMP-2) impregnated on an absorbable collagen sponge (ACS) with particulate cancellous bone and marrow (PCBM) harvested from the iliac crest in an animal model of maxillary sinus floor augmentation. Bilateral sinus floor augmentation procedures were performed in 30 adult Japanese white rabbits. rhBMP-2/ACS or PCBM was grafted to each maxillary sinus. Animals were sacrificed at 2, 4, or 8 weeks after grafting, and bone formation in response to each implant was evaluated histologically and histometrically. Histometric results compared by analysis of variance revealed no statistically significant difference in the bone volume at augmented areas between the two types of implant (P > 0.05). Histologic evaluation documented that the trabeculae with a lamellar structure were embedded in fatty marrow at 8 weeks in both implant sites. These results suggest that sinus floor augmentation with rhBMP-2/ACS or PCBM induces comparable histologic and histometric evidence of bone formation in rabbits.

Alveolar Ridge Augmentation↗
PubMed2001

Impaired blood rheology by remnant-like lipoprotein particles: studies in patients with fatty liver disease.

Fatty liver disease (FLD) characterised by a high plasma levels of lipoproteins and remnant-like lipoproteins (RLP) is a risk factor for impaired microvascular blood flow, endothelial cell dysfunction and atherosclerosis. Using an immunoseparation technique with a gel mixture containing human monoclonal antibodies to apo A-I and apo B-100, we separated and measured RLP cholesterol (RLP-C) levels which reflect RLP in patients with FLD (n=20). Whole blood transit time (TT) was determined by a microchannel method (MC-FAN) which allows blood flow to be viewed via a microscope connected to an image display unit. RLP-C levels were higher (P<0.01) in FLD, 15.6 +/- 1.0 mg/dl compared with 4.8 +/- 0.5 mg/dl for controls (n=20). Similarly, TT was longer (P<0.01) in FLD, 284.5 +/- 26.1 sec/100 microl compared with 82.8 +/- 1.0 sec/100 microl for controls. Since the liver is a major site for RLP formation and degradation, it is affected to a greater extent in patients with FLD. It is likely that high levels of RLP can impair microvascular perfusion in the liver tissue and contribute to the development and progression of FLD.

2-Chloroadenosine↗
PubMed2000

Airway remodelling in cough-variant asthma.

Subepithelial-layer thickening, a pathological feature of airway remodelling, is present in cough-variant asthma. In bronchial biopsy samples we found mean subepithelial-layer thickness was 7.1 (SE 0.4) microm in patients with cough-variant asthma, 8.6 (0.4) microm in patients with classic asthma with wheezing, and 5.0 (0.2) microm in healthy controls. Thickness was significantly higher in patients with asthma than in controls, and was significantly greater in those with classic asthma than in those with cough-variant asthma. Early anti-inflammatory treatment might, therefore, be beneficial in cough-variant asthma, as recommended in classic asthma.

Adult↗
PubMed2000

Effect of proton pump inhibitor alone or in combination with clarithromycin on mycobacterial growth in human alveolar macrophages.

The effect of omeprazole, a clinically used proton pump inhibitor, alone or in combination with clarithromycin was evaluated against Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium tuberculosis, using a human alveolar macrophage model of infection. Omeprazole exhibited no significant effect on the growth of the two M. avium complex strains or on the mycobactericidal activity of clarithromycin against them. In contrast, omeprazole significantly promoted the growth of Mycobacterium tuberculosis and the anti-mycobacterial activity of clarithromycin against it in human alveolar macrophages. It was speculated that intracellular acidic milieu around M. tuberculosis might be one reason for the lower activity of clarithromycin in the treatment of human tuberculosis.

Adult↗
PubMed2000

Allergic granulomatous angiitis (Churg-Strauss syndrome) associated with allergic bronchopulmonary candidiasis.

We describe a case of Churg-Strauss syndrome (CSS) associated with allergic bronchopulmonary candidiasis (ABPC). A 61-year-old man who had been given a diagnosis of ABPC based on serologic and radiographic findings experienced pain and purpuric rash on the left leg accompanied with motor weakness. The diagnosis of CSS was made from skin, nerve and muscle biopsies. Although immunosuppressant and prednisolone were administered and resulted in transient improvement, candidal pneumonia was suspected to have developed 60 days after the administration and the patient finally died of respiratory failure. To our knowledge, this is the first case of CSS associated with ABPC.

Asthma↗
PubMed2000

Airway wall thickness in asthma assessed by computed tomography. Relation to clinical indices.

Postmortem studies have shown that airway wall thickening is present in asthmatic patients and may play a pathophysiologic role. We investigated the presence and characteristics of airway wall thickening in patients with asthma, using helical computed tomography. Eighty-one asthmatic patients and 28 healthy control subjects were studied cross-sectionally. Airway wall thickness was assessed by a validated method on the basis of wall area (WA), WA corrected by body surface area (WA/BSA), and WA%, defined as (WA/total area) x 100 at the apical bronchus of the right upper lobe. Airway luminal area (Ai) and Ai/BSA were also examined. Asthma duration and severity, pulmonary function, and serum eosinophil cationic protein levels were evaluated. Intraobserver and interobserver reproducibility of WA, WA%, and Ai measurements were good. As compared with control, WA, WA/BSA, and WA% were significantly increased in patients with mild (n = 13), moderate (39), and severe persistent (22) asthma but not in patients with intermittent asthma (7). Comparison of the four asthmatic subgroups demonstrated thicker airways in more severe disease, but no difference in Ai or Ai/BSA. When all asthmatic patients were analyzed together, WA and WA/BSA correlated with the duration, although weakly, and severity of asthma. WA and WA/BSA negatively correlated with FEV(1) (percentage of predicted), FEV(1)/FVC (%), and FEF(25-75%) (percentage of predicted), whereas WA% negatively correlated with only FEV(1). We conclude that airway wall thickening occurs in patients with asthma and is not limited to those with severe disease. The degree of airway wall thickening may relate to the duration and severity of disease and the degree of airflow obstruction.

Adult↗