[Evaluation of the diaphragm in patients with COPD (emphysema dominant type) by abdominal ultrasonography].

UNLABELLED: The aim of this study was to clarify whether the diaphragm in patients with COPD (emphysema dominant type) can be evaluated by abdominal ultrasonography. We therefore established a method for diaphragm scanning: The dome of the right hemidiaphragm was detected by epigastric right oblique scan passing through the right edge of the inferior vena cava and the zone of apposition. Diaphragmatic flattening, correlation between the flattening and %FEV1.0, diaphragmatic motion, and the inspiratory time cycle were also measured. We studied 14 patients with COPD (emphysema dominant type) and 12 healthy control subjects. RESULTS: (i) Diaphragmatic flattening was recognized in patients with COPD and the radius of the right hemidiaphragmatic curvature (index of diaphragmatic flattening) correlated with %FEV1.0. (ii) Motion of the anterior diaphragm was poor in patients with COPD. (iii) Expiration time was prolonged in patients with COPD. CONCLUSION: Flattening and motion of the diaphragm, as well as the prolonged expiratory time were possible to evaluate by abdominal ultrasonography. Diaphragmatic flattening reflects %FEV1.0. Based on these observations we believe that abdominal ultrasonography may be useful to avoid underdiagnosis of COPD.

[Immunity tests for respiratory diseases--SP-A, SP-D, KL-6].

We present the measurement methods, physiological means and clinical utilities of surfactant protein-A (SP-A), surfactant protein-D and KL-6 of current immunity tests for pulmonary diseases in Japan. The measurement methods of SP-A and SP-D are Enzyme Immunoassays(EIA), and SP-D cannot be measured automatically. KL-6 can be measured directly by the Sandwich method, developed in 1985 by our co-researcher Professor Kohno. SP-A and SP-D, proteins in pulmonary surfactants (phosphoric lipids), can kill many causative bacteria of respiratory infectious diseases by the activation of natural immune defective functions of macrophages. KL-6 is MUC-1, which responded to sixth antibodies extracted from lung cancer cells by Professor Kohno's monoclonal antibody method. SP-A, SP D and KL-6 are very used in the clinical field as injury markers of the lungs, because they have been proved to increase abnormity in difficult pulmonary fibrotic diseases such as idiopathic interstitial pulmonitis (IIP), etc. In particular, we could prove that KL-6 increased the movement and volume of pulmonary fibroblastic cells and decreased the apoptosis of pulmonary fibroblastic cells. In the near future, we are planning to develop new therapeutic drugs for pulmonary fibrotic diseases, as the target the fibrotic mechanism of the lungs by KL-6.

[The expectations for the third generation clinical laboratories in Japan].

The author expressed his hopes and expectations for third generation clinical laboratory schemes or systems in Japan. The history of development of the clinical laboratory in Japan can be classified three generations after the Second World War, the first generation (1945-1975), the second generation (1970-2005) and the third generation (2001-). The third generation clinical laboratory can be called "the clinical laboratory for the 21st century". The author advised some suggestions for the clinical laboratory for the 21st century. The main advice of the author is as follows: 1) The necessity of professional physicians of clinical laboratory medicine in hospitals. 2) The necessity of standardization and holding nationwide common reference values of main clinical laboratory tests. 3) The realization of a network of high-grade laboratory tests between all clinical laboratory divisions of the national university hospitals.

[My hope for the future of the medical scientist--to the medical doctor of clinical laboratory medicine from internal medicine].

This is the essence of my last lecture to the medical students of Hiroshima University. My 38-year career as a medical school teacher can be sectioned three parts. My main four studies are shown at the third part. 1) We advocated respiratory physiologic-chemistry based on the relationships between pulmonary function and the constitutive chemical components of lungs. 2) We proved the mechanisms of hypertension at the molecular level by renin-angiotensin-adrenaline theory. 3) We showed the difference of mitochondria DNA in Diabetes Mellitus patients between Japanese and Chinese. 4) We suggested the necessity of standardization and holding common national reference values of main clinical laboratory tests by reporting our data. I am delighted that the very good studies of my colleagues achieved 500 IFs and express my gratitude for my colleagues' cooperation.

Genetic ablation of the transcription repressor Bach1 leads to myocardial protection against ischemia/reperfusion in mice.

Bach1 is a transcriptional repressor of heme oxygenase-1 gene (Hmox-1) and beta-globin gene. Heme oxygenase (HO)-1 is an inducible cytoprotective enzyme that degrades pro-oxidant heme to carbon monoxide (CO) and biliverdin/bilirubin, which are thought to mediate anti-inflammatory and anti-oxidant actions of HO-1. In the present study, we investigated the role of Bach1 in tissue protection against myocardial ischemia/reperfusion (I/R) injury in vivo using mice lacking the Bach1 gene (Bach1(-/-)) and wild-type (Bach1(+/+)) mice. In Bach1(-/-) mice, myocardial expression of HO-1 protein was constitutively up-regulated by 3.4-fold compared to that in Bach1(+/+) mice. While myocardial I/R induced HO-1 protein in ischemic myocytes in both strains of mice, the extent of induction was significantly greater in Bach1(-/-) mice than in Bach1(+/+) mice. Myocardial infarction was markedly reduced in size by 48.4% in Bach1(-/-) mice. Pretreatment of Bach1(-/-) mice with zinc-protoporphyrin, an inhibitor of HO activity, abolished the infarction-reducing effect of Bach1 disruption, indicating that reduction in the infarct size was mediated, at least in part, by HO-1 activity. Thus, Bach1 plays a pivotal role in setting the levels of both constitutive and inducible expression of HO-1 in the myocardium. Bach1 inactivation during I/R appears to be a key mechanism controlling the activation level of cytoprotective program involving HO-1.

Differential impact of family history on age-associated increase in the prevalence of hypertension and diabetes in male Japanese workers.

Family history and aging are independent risk factors for the development of hypertension as well as for the development of diabetes. However, it is unclear how the family histories influence the rate of age-associated increase in these diseases. Moreover, despite the fact that hypertension and diabetes often occur concomitantly, it is not known whether family history of hypertension increases the risk of diabetes or vice versa. To gain an insight into these questions, we investigated the cross-sectional prevalence and family history of hypertension and diabetes in 1,123 male subjects (mean age, 42.1 +/- 12 years; range, 20-60 years) who participated in annual medical check-ups. The data were analyzed by 10-year age groups (20s, 30s, 40s and 50s). The prevalence of hypertension increased with age group either in the absence (12% in the 20s and 39% in the 50s) or in the presence (21% in the 20s and 59% in the 50s) of family history of hypertension, and thus the increasing rate of prevalence with age was not affected by family history. The prevalence of diabetes in the absence of family history of diabetes was low until the 40s (< 1.2%) but it jumped in the 50s (4.3%). On the other hand, in the presence of family history, the prevalence was 4% in the 20s and progressively increased to 20% in the 50s. The impact of family history on the risk of diabetes was strong and appeared to increase with age. Family history of hypertension did not increase the risk of diabetes, and family history of diabetes did not increase the risk of hypertension. These results suggest that family history of hypertension has an additive impact on the age-associated increase in the risk of hypertension, whereas family history of diabetes has an exponential impact on aging-associated increase in the risk of diabetes.

A semi-parametric method for describing the age-specific distribution of clinical measurements in cross-sectional study.

Age-specific distribution of clinical measurements in cross-sectional study is described in this paper. Since the distribution of measurements usually varies with age, a model with an age-dependent structure is needed. We propose here a statistical method for describing the age-specific distribution using an extension of the power-normal-model. The age-dependent parameters are to be estimated through a nonparametric smoothing technique based on the local likelihood method. As a consequence, we can compute a smoothed percentile curve of measurements with reference to age. Several kinds of clinical measurements are analyzed to determine the proposed method.

Association of Helicobacter pylori infection with systemic inflammation and endothelial dysfunction in healthy male subjects.

OBJECTIVES: The goal of the present study was to determine whether seropositivity to Helicobacter pylori (HP), Chlamydia pneumoniae (CP), and cytomegalovirus (CMV) is associated with systemic inflammation and endothelial dysfunction in healthy male subjects. BACKGROUND: Chronic infection with certain bacteria and viruses may play an important role in inflammation as the pathogenesis of atherosclerosis. METHODS: The serum levels of immunoglobulin G antibodies to HP, CP, CMV, high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 were determined in 81 healthy Japanese men (40 +/- 10 years of age). High-frequency ultrasonographic imaging of the brachial artery was used to study endothelium-dependent (flow-mediated vasodilation) and endothelium-independent (nitroglycerin-induced) vasodilation. RESULTS: Prevalences of seropositive antibodies to HP, CP, and CMV were 67.9%, 61.7%, and 56.8%, respectively. Infection with HP, CP, or CMV had no relationship with age, blood pressure, or level of serum glucose, lipid, or soluble vascular cell adhesion molecule-1. The levels of C-reactive protein and soluble intercellular adhesion molecule-1 were significantly higher, and flow-mediated vasodilation was significantly lower in subjects with seropositive antibodies to HP than in subjects with seronegative antibodies to HP. Endothelium-independent vasodilation was similar in both groups. CONCLUSIONS: Chronic infection with HP may be involved in the development of the atherosclerosis via endothelial dysfunction and systemic and vascular inflammation.

[New monitoring test for sleep apnea syndrome].

We introduce change in pulse transit time (change in PTT: noninvasive intrathoracic pressure monitoring) as a new monitoring test of sleep apnea syndrome, which is being developed for clinical application. In addition, we report the kinetics of cardiogenic oscillation (CGO: noninvasive upper airway obstruction monitoring), which was published in this journal in 2003, and the response of the upper airway in clinical practice (under an endoscope). We also review diaphragmatic movement by abdominal echography (respiration generator monitoring).

[Lung function testing --the Official Guideline of the Japanese Respiratory Society].

This review article introduces the official guideline for the lung function testing firstly established by the Japanese Respiratory Society in November 2004. The members of the Japanese Society of Laboratory Medicine were also included in the working group to make the guideline. A central goal of the guideline is to standardize the skill of lung function testing and thus minimize its variability. The guideline includes the chapters for spirometry, flow-volume curve, and diffusing capacity of the lung, where principles and quality controls are introduced with reference values for each testing. Furthermore, the algorithm for differential diagnosis using the lung function testing is demonstrated in the last chapter. The lung function testing can bring a strong impact on patients' lifestyle and future treatment plan. We sincerely hope that this guideline will contribute to routine laboratory practice.

[Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2004].

The antibacterial activity of meropenem (MEPM) and other parenteral antibiotics against clinical isolates of 907 strains of Gram-positive bacteria, 1790 strains of Gram-negative bacteria, and 192 strains of anaerobic bacteria obtained from 30 medical institutions during 2004 was measured. The results were as follows; 1. MIC90 of MEPM for almost all of enterobacteriaceae and Haemophilus influenzae were 4-fold to 32-fold lower than those of other carbapenems. MEPM was more active than other carbapenem antibiotics against Gram-negative bacteria, especially against enterobacteriaceae and H. influenzae. MEPM were active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus. 2. As for Pseudomonas aeruginosa, imipenem (IPM) showed high cross-resistant rate againt meropenem-resistant P. aeruginosa (87.9%). MEPM showed low cross-resistant rate both againt IPM-resistant P. aeruginosa (49.2%) and ciprofloxacin-resistant P. aeruginosa (38.0%). 3. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 3.1% (4 strains) in Escherichia coli, 8.0% (2 strains) in Citrobacter koseri, 2.5% (3 strains) in Klebsiella pneumoniae, 2.5% (2 strains) in Enterobacter cloacae, 0.9% (1 strains) in Serratia marcescens, and 2.2% (2 strains) in Proteus mirabilis. The proportion of metallo-beta-lactamase strains was 1.6% (5 strains) in P. aeruginosa. 4. Of all species tested, Peptostreptococcus spp. was the only species, which MIC90 of MEPM was more than 4-fold higher than that in our previous study using clinical isolates during 2002 (0.25 microg/ml --> 1 microg/ml). Therefore, there is almost no siginificant decrease in susceptibility of clinical isolates to meropenem. In conclusion, the results from this surveillance study suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem at present, 9 years after available for commercial use.

Beneficial effect of T-type calcium channel blockers on endothelial function in patients with essential hypertension.

Endothelial function is impaired in essential hypertension. T-type but not L-type voltage-gated Ca2+ channels were detected in the vascular endothelium. The purpose of the present study was to clarify the role of T-type Ca2+ channels in endothelial function. We studied flow-mediated vasodilation (FMD) and sublingual nitroglycerin (NTG)-induced vasodilation in the brachial artery. Forty patients with essential hypertension were randomly assigned to treatment with efonidipine, a T- and L-type Ca2+ channel blocker, or with nifedipine, an L-type Ca2+ channel blocker. Twenty healthy normotensive individuals were included as a control group. In patients with essential hypertension, FMD was attenuated and NTG was similar that of compared to healthy controls. After 12 weeks, the decrease in mean blood pressure in the efonidipine and nifedipine groups were similar. The endothelial function index, a ratio of FMD/NTG, was significantly increased by efonidipine (73 +/- 24 to 94 +/- 20%) but unchanged by nifedipine. Urinary excretion 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malondialdehyde-modified low-density lipoprotein (LDL) were decreased by efonidipine but unchanged by nifedipine. These results suggest that a T-type Ca2+ channel blocker, but not an L-type Ca2+ channel blocker, may improve vascular endothelial dysfunction in patients with essential hypertension via a reduction in oxidative stress.

[Cardiogenic oscillation--utility of classifying types of sleep apnea].

Cardiogenic pulse waves that travel along the airway wall are captured as airflow variations synchronized with the electrocardiogram at the airway exit. We have used airflow variations caused by cardiogenic pulse waves (hereinafter referred to as cardiogenic oscillation) to classify types of sleep apnea. Pulse waves do not travel downstream if there is an airway obstruction or choke point (wave speed theory). Thus, cardiogenic oscillation was detectable in central apnea or hypopnea, but not in obstructive apnea. In mixed-type sleep apnea, cardiogenic oscillation disappeared, and thus airway obstruction was judged to have occurred, during central sleep apnea. It was thought that obstructive sleep apnea followed central sleep apnea because there was an airway obstruction, although respiratory effort resumed after the end of central sleep apnea. The pattern of mixed-type sleep apnea was understood from the observation of cardiogenic oscillation. Cardiogenic oscillation is useful for not only classifying types of sleep apnea but also for detecting an airway obstruction.

Telomere attrition in white blood cell correlating with cardiovascular damage.

Aging is a major risk factor for cardiovascular disease. Chronological aging does not always parallel biological aging, but there is no reliable biomarker for the latter. In the present study, we tested the hypothesis that telomere attrition in white blood cells is related to endothelial dysfunction and the extent of atherosclerosis, and thus may serve as a useful marker for biological aging. We evaluated telomere lengths in white blood cells by measuring the mean telomere restriction fragment length (mTRFL), as well as endothelial function by flow mediated dilatation (FMD) in the brachial artery, in patients with various degrees of cardiovascular damage and in normal subjects. Cardiovascular damage was assessed by a cardiovascular damage (CVD) score, with 1 point being given for the presence of each cardiovascular risk factor (hypertension, hyperlipidemia and diabetes) and for each event (angina, myocardial infarction, cerebrovascular event and peripheral vascular disease). Subset analysis of CVD score groups revealed that mTRFL and FMD decreased in the rank order of CVD score. Although mTRFL was inversely correlated with age, telomere index, defined as the ratio of TRFL to TRFL predicted by age, also decreased with increase in CVD score. These results indicate that telomere attrition in white blood cells is more closely associated with endothelial damage and atherosclerosis than is chronological aging, supporting the hypothesis that mTRFL in white blood cells is a useful marker for biological aging of the cardiovascular system.

[Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2002].

The antibacterial activity of meropenem (MEPM) and other parenteral antibiotics against clinical isolates of 899 strains of Gram-positive bacteria, 1500 strains of Gram-negative bacteria, and 158 strains of anaerobic bacteria obtained from 28 medical institutions during 2002 was measured. The results were as follows; 1. MEPM was more active than other carbapenem antibiotics against Gram-negative bacteria, especially against enterobacteriaceae and Haemophilus influenzae. MIC90 of MEPM against Pseudomonas aeruginosa was the lowest of the drugs tested. MEPM showed low cross-resistant rate against both imipenem-resistant P. aeruginosa and ciprofloxacin-resistant P. aeruginosa. MEPM was active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE). 2. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 3.1% (4 strains) in Escherichia coli and 1.9% (2 strains) in Klebsiella pneumoniae. Carbapenems including MEPM were active against these ESBL strains. In conclusion, the results from this surveillance study suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem; at present, 7 years after available for commercial use.

Significance of human neutrophil antigen-2a (NB1) expression and neutrophil number in pregnancy.

BACKGROUND: Expression of human neutrophil antigen-2a (HNA-2a) is greater in women than in men. The size of the HNA-2a-positive neutrophil population increases with pregnancy. STUDY DESIGN AND METHODS: T he relationship between HNA-2a expression on neutrophils and monocytes, and their relative numbers, was investigated. HNA-2a expression shown as the size of the HNA-2a-positive cell population and the fluorescence intensity on the cells was analyzed using flow cytometry. This investigation was done among 165 pregnant women during pregnancy and postpartum. RESULTS: In normal pregnancy, numbers of neutrophils and monocytes changed in relation to HNA-2a expression. HNA-2a was also expressed intensively on monocytes from some pregnant women in the first and second trimesters. HNA-2a expression and the number of cells markedly decreased postpartum. In threatened premature labor, the number of neutrophils decreased earlier than in normal pregnancy. CONCLUSION: HNA-2a expression may increase soon after fertilization. In this study, the results indicate that the change in the number of neutrophils and monocytes is related to HNA-2a expression.

[Fascinated by pulmonary function].

I would like to tell you about my 35 years of research, starting when I became a medical doctor, titled "Fascinated by Pulmonary Function". For the first 10 years, I studied the automation of pulmonary function tests and developed some automatic pulmonary function test apparatuses such as the spiro-computer, panspiro-computer, automatic respiratory resistant test apparatus and automatic respiratory central function test apparatus. For the next 15 years, I studied the relationships between some important pulmonary diseases and respiratory pulmonary functions. In particular, I studied respiratory efficiency and respiratory center functions. For the most recent 10 years, I have been studying the relationships between non-respiratory pulmonary functions and chronic respiratory diseases. I am studying the relationships between ATP(Adenosine Tri Phosphate) in the blood for the parameters of mitochondria function and pneumoconiosis and other chronic pulmonary diseases. I had very interesting results regarding DNA types of arteriosclerosis in chronic pulmonary emphysema. I thank all my research fellows during these 35 years from the bottom of my heart.

[Establishment of a clinical method for evaluating flow-mediated vasodilation(FMD) in brachial artery].

We have established a clinical routine method for evaluating the endothelial function in forearm circulation in humans. Flow-mediated vasodilation(FMD) was used as the endothelium-dependent and the response to nitroglycerin(NTG) as the endothelium-independent vasodilation. Diameter of the brachial artery was measured by high-frequency ultrasonographic imaging before and after hyperemia following artery occlusion. Because vasodilation reached the maximal level when the artery was occluded for 5 min, this time was selected as the occlusion time. FMD was greater (12 vs 9%) after upper-arm occlusion than after forearm occlusion. The peak time to maximal vasodilation was 50 sec after forearm occlusion and 70 sec after upper-arm occlusion. During NO synthesis inhibitor infusion, vasodilation after forearm occlusion was abolished, whereas that after upper-arm occlusion was attenuated by half. Therefore, the mechanisms for FMD may differ by occlusion position. The response to NTG was attenuated by aging. FMD was significantly decreased by coronary artery disease and coronary risk factors such as hypertension, hyperlipidemia and diabetes, but the response to NTG was not changed by these diseases. These measurements may offer useful tools for assessment of endothelial function.

Mnk1 is required for angiotensin II-induced protein synthesis in vascular smooth muscle cells.

Angiotensin II (Ang II) stimulates protein synthesis in vascular smooth muscle cells (VSMCs), possibly secondary to regulatory changes at the initiation of mRNA translation. Mitogen-activated protein (MAP) kinase signal-integrating kinase-1 (Mnk1), a substrate of ERK and p38 MAP kinase, phosphorylates eukaryotic initiation factor 4E (eIF4E), an important factor in translation. The goal of the present study was to investigate the role of Mnk1 in Ang II-induced protein synthesis and to characterize the molecular mechanisms by which Mnk1 and eIF4E is activated in rat VSMCs. Ang II treatment resulted in increased Mnk1 activity and eIF4E phosphorylation. Expression of a dominant-negative Mnk1 mutant abolished Ang II-induced eIF4E phosphorylation. PD98059 or introduction of kinase-inactive MEK1/MKK1, but not SB202190 or kinase-inactive p38 MAP kinase, inhibited Ang II-induced Mnk1 activation and eIF4E phosphorylation, suggesting that ERK, but not p38 MAP kinase, is required for Ang II-induced Mnk1-eIF4E activation. Further, dominant-negative constructs for Ras, but not for Rho, Rac, or Cdc42, abolished Ang II-induced Mnk1 activation. Finally, treatment of VSMCs with CGP57380, a novel specific kinase inhibitor of Mnk1, resulted in dose-dependent decreases in Ang II-stimulated phosphorylation of eIF4E, protein synthesis, and VSMC hypertrophy. In summary, these data demonstrated that (1) Ang II-induced Mnk1 activation is mediated by the Ras-ERK cascade in VSMCs, and (2) Mnk1 is involved in Ang II-mediated protein synthesis and hypertrophy, presumably through the activation of translation-initiation. The Mnk1-eIF4E pathway may provide new insights into molecular mechanisms involved in vascular hypertrophy and other Ang II-mediated pathological states.

Disruption of the type 2 dopamine receptor gene causes a sodium-dependent increase in blood pressure in mice.

BACKGROUND: Dopamine D(2) receptors (D(2)Rs) are expressed in the kidney. It has not been determined whether D(2)Rs are involved in the mechanism of sodium handling and blood pressure (BP) control. METHODS: The function of D(2)Rs was investigated in mice disrupted with D(2)R gene (D(2)KO mice). Six-week-old male D(2)KO mice and wild-type (WT) mice were fed high-salt (4% NaCl) or low-salt (0.01% NaCl) diets for 8 weeks. RESULTS: Before starting the metabolic diet, there were no significant differences in body weight, food consumption, and 24-h urine excretions of creatinine, sodium and potassium. The high-salt diet caused a significant elevation in systolic BP in D(2)KO mice but not in WT mice. Calculation of sodium and potassium balances revealed a significantly high level of sodium retention in D(2)KO mice placed on the high-salt diet. Twenty-four-hour urine norepinephrine excretions and heart rates, indicators of sympathetic activity, were not different in D(2)KO and WT mice on the high-salt diet. Administration of nemonapride, a specific D(2)-like receptor antagonist, to WT mice given 0.9% NaCl in drinking water caused suppression of urinary sodium excretion but had no effect in mice without salt loading. CONCLUSIONS: These results suggest that D(2) receptors promote sodium excretion during a period of high salt intake. A defect in this mechanism may result in sodium-dependent BP elevation.