Makiko Naka Mieno

Semen quality of 1559 young men from four cities in Japan: a cross-sectional population-based study

Objectives To provide information of semen quality among normal young Japanese men and indicate the frequency of reduced semen quality. Design Cross-sectional, coordinated studies of Japanese young men included from university areas. The men had to be 18–24 years, and both the man and his mother had to be born in Japan. Background information was obtained from questionnaires. Standardised and quality-controlled semen analyses were performed, reproductive hormones analysed centrally and results adjusted for confounding factors. Setting Four study centres in Japan (Kawasaki, Osaka, Kanazawa and Nagasaki). Participants 1559 men, median age 21.1 years, included during 1999–2003. Outcome measures Semen volume, sperm concentration, total sperm count, sperm motility, sperm morphology and reproductive hormone levels. Results Median sperm concentration was 59 (95% CI 52 to 68) million/ml, and 9% and 31.9% had less than 15 and 40 million/ml, respectively. Median percentage of morphologically normal spermatozoa was 9.6 (8.8 to 10.3)%. Small, but statistically significant, differences were detected for both semen and reproductive hormone variables between men from the four cities. Overall, the semen values were lower than those of a reference population of 792 fertile Japanese men. Conclusions Assuming that the investigated men were representative for young Japanese men, a significant proportion of the population had suboptimal semen quality with reduced fertility potential, and as a group they had lower semen quality than fertile men. However, the definitive role—if any—of low semen quality for subfertility and low fertility rates remain to be investigated.

Involvement of surfactant protein D in emphysema revealed by genetic association study

Surfactant protein D (SFTPD) induces emphysema in knockout mice, but the association of SFTPD with chronic obstructive pulmonary disease (COPD) and emphysema in humans is unclear. Therefore, we aimed to determine the association between genetic variations in SFTPD and susceptibility to COPD and emphysema.Two populations were studied: population A comprised 270 smokers, including 188 COPD and 82 at-risk subjects, and population B comprised 1131 autopsy cases including 160 cases with emphysema. Six single-nucleotide polymorphisms (SNPs) that tagged the linkage disequilibrium blocks on the entire SFTPD gene were genotyped; the associations of the genotypes with COPD, pulmonary function, percentage of the low-attenuation area (LAA%), and percentage of the airway wall area (WA%) were determined in population A. In population B, the associations of the genotypes with emphysema were assessed.A C allele at SNP rs721917 that results in the replacement of Met with Thr at position 11 in SFTPD was positively correlated with the LAA% in the upper lung (P=1.1 × 10−5) and overall LAA% (P=1.0 × 10−4), and negatively correlated with the serum concentration of SFTPD (P=7 × 10−11) in the population A. The C/C (rs721917/rs10887199) haplotype was associated with emphysema in both the populations.Subjects with a C allele at rs721917 have a lower serum SFTPD concentration and are more susceptible to emphysema. This suggests a protective effect of SFTPD against COPD and emphysema.

Semen quality of fertile Japanese men: a cross-sectional population-based study of 792 men

Objectives To establish a base line for future studies on temporal trends, to describe potential geographical differences in semen quality and reference values for studies of men from the general population. Design Cross-sectional study of fertile men from four areas in Japan. Inclusion criteria were: age 20–45 years at the time of invitation, and both the man and his mother had to be born in Japan. Additionally, the current pregnancy of the female partner had to be achieved by normal sexual relations without any fertility treatment. Setting Four Japanese study centres at urban areas located in Sapporo, Osaka, Kanazawa and Fukuoka. Participants 792 men, median age 31.4 years, included from 1999 to 2002. Outcome measures Semen volume, sperm concentration, total sperm count, sperm motility and sperm morphology. Results Semen volumes, percentages of motile spermatozoa and morphologically normal spermatozoa differed slightly between the four groups, whereas no differences in sperm concentrations or total sperm counts were found. In total, 1.2% of men had a sperm concentration below 5 million/ml, 2.1% below 10 million/ml, 3.5% below 15 million/ml and 16.3% below 40 million/ml. For morphology, 14.7% had less than 5% normal spermatozoa. Reproductive hormone levels varied significantly, however, only little from a biological point of view. Conclusions This is the first cross-sectional study on semen quality covering fertile men from the major regions of Japan. It showed that semen quality of fertile Japanese men is comparable to that of the best in European regions. The results may serve as reference values for studies of men from the general population.

Quantitative diagnosis of diffuse alveolar damage using extravascular lung water.

Objectives:Acute respiratory distress syndrome is characterized by diffuse alveolar damage and increased extravascular lung water levels. However, there is no threshold extravascular lung water level that can indicate diffuse alveolar damage in lungs. We aimed to determine the threshold extravascular lung water level that discriminates between normal lungs and lungs affected with diffuse alveolar damage. Design:A retrospective analysis of normal lungs and lungs affected with diffuse alveolar damage was performed. Setting:Normal lung cases were taken from published data. Lung cases with diffuse alveolar damage were taken from a nationwide autopsy database. All cases of autopsy followed hospital deaths in Japan from more than 800 hospitals between 2004 and 2009; complete autopsies with histopathologic examinations were performed by board-certified pathologists authorized by the Japanese Society of Pathology. Patients:Normal lungs: 534; lungs with diffuse alveolar damage: 1,688. Interventions:We compared the postmortem weights of both lungs between the two groups. These lung weights were converted to extravascular lung water values using a validated equation. Finally, the extravascular lung water value that indicated diffuse alveolar damage was estimated using receiver operating characteristic analysis. Measurements and Main Results:The extravascular lung water values of the lungs showing diffuse alveolar damage were approximately two-fold higher than those of normal lungs (normal group, 7.3 ± 2.8 mL/kg vs diffuse alveolar damage group 13.7 ± 4.5 mL/kg; p < 0.001). An extravascular lung water level of 9.8 mL/kg allowed the diagnosis of diffuse alveolar damage to be established with a sensitivity of 81.3% and a specificity of 81.2% (area under the curve, 0.90; 95% CI, 0.88–0.91). An extravascular lung water level of 14.6 mL/kg represented a 99% positive predictive value. Conclusions:This study may provide the first validated quantitative bedside diagnostic tool for diffuse alveolar damage. Extravascular lung water may allow the detection of diffuse alveolar damage and may support the clinical diagnosis of acute respiratory distress syndrome. The best extravascular lung water cut-off value to discriminate between normal lungs and lungs with diffuse alveolar damage is around 10 mL/kg. (Crit Care Med 2013; 41:2144–2150)

Association Between Genetic Variations In Surfactant Protein D and Emphysema, Interstitial Pneumonia, and Lung Cancer in a Japanese Population

Abstract Surfactant protein D (SFTPD) is a lung-specific anti-inflammatory factor that antagonizes inflammation by inhibiting oxidative stress and stimulating innate immunity. Variations in SFTPA2 and SFTPB, genes for other surfactant proteins, have been associated with lung cancer. We therefore investigated associations between SFTPD variations and lung cancer as well as emphysema and interstitial pneumonia, which are characterized by chronic inflammation from which lung cancer often arises. DNA from 1342 autopsy samples, including those from 140 subjects with lung cancer, was investigated. The single nucleotide polymorphism (SNP) rs721917, which results in methionine being exchanged for threonine at amino acid 11 (the Met11Thr variation), tended to be associated with emphysema and was associated with interstitial pneumonia and lung cancer. A haplotype analysis revealed that the haplotypes associated with emphysema and lung cancer differed from that associated with interstitial pneumonia, suggesting a differential role for SFTPD in the development of these diseases. A mediating analysis did not reveal a mediating effect exerted by emphysema or interstitial pneumonia on lung cancer. Our results suggested that SFTPD plays a role in the development of lung cancer and that the role for lung cancer may differ from that for interstitial pneumonia.

Pyrethroid insecticide exposure and semen quality of young Japanese men.

The present study aimed at assessing the relationship between exposure to pyrethroid insecticides and semen quality in 323 university students recruited in a population-based manner in Metropolitan Tokyo. Urinary concentrations of pyrethroid insecticide metabolite, 3-phenoxybenzoic acid (3-PBA), were measured by LC/MS/MS and semen parameters were measured by following internationally harmonized protocols. Median urinary 3-PBA concentration was 0.641 ng/mL (specific gravity-adjusted, n=322). Median values of semen volume, sperm concentration, motility, total number of sperm, and total number of motile sperm were 2.5 mL, 56×10(6)/mL, 61%, 141×10(6), and 82×10(6), respectively. Urinary concentration of 3-PBA was not selected as significant in multiple regression models indicating, in contrast to previous findings, that environmental exposure to pyrethroid insecticides did not affect semen quality. This inconsistency may be related to exposure to different pyrethroid insecticides and/or levels of exposure as well as to survey design (hospital- vs population-based subject recruitment).

Accuracy of Death Certificates and Assessment of Factors for Misclassification of Underlying Cause of Death

BACKGROUND Cause of death (COD) information taken from death certificates is often inaccurate and incomplete. However, the accuracy of Underlying CODs (UCODs) recorded on death certificates has not been comprehensively described when multiple diseases are present. METHODS A total of 450 consecutive autopsies performed at a geriatric hospital in Japan between February 2000 and August 2002 were studied. We evaluated the concordance rate, sensitivity, and specificity of major UCODs (cancer, heart disease, and pneumonia) reported on death certificates compared with a reference standard of pathologist assessment based on autopsy data and clinical records. Logistic regression analysis was performed to assess the effect of sex, age, comorbidity, and UCODs on misclassification. RESULTS The concordance rate was relatively high for cancer (81%) but low for heart disease (55%) and pneumonia (9%). The overall concordance rate was 48%. Sex and comorbidity did not affect UCOD misclassification rates, which tended to increase with patient age, although the association with age was also not significant. The strongest factor for misclassification was UCODs (P < 0.0001). Sensitivity and specificity for cancer were very high (80% and 96%, respectively), but sensitivity for heart disease and pneumonia was 60% and 46%, respectively. Specificity for each UCOD was more than 85%. CONCLUSIONS Researchers should be aware of the accuracy of COD data from death certificates used as research resources, especially for cases of elderly patients with pneumonia.

Low Lipoprotein(a) Concentration Is Associated with Cancer and All-Cause Deaths: A Population-Based Cohort Study (The JMS Cohort Study)

Background Experimental studies support the anti-neoplastic effect of apo(a), but several clinical studies have reported contradictory results. The purpose of this study was to determine whether a low lipoprotein(a) [Lp(a)] concentration is related to mortality from major causes of death, especially cancer. Methods The subjects were 10,413 participants (4,005 men and 6,408 women) from a multi-center population-based cohort study in Japan (The Jichi Medical School cohort study). The average age at registration was 55.0 years, and the median observation period was 4,559 days. As the estimated hazard ratio was high for both the low and very high Lp(a) levels, we defined two Lp(a) groups: a low Lp(a) group [Lp(a)<80 mg/L] and an intermediate-to-high Lp(a) group [Lp(a)≥80]. Participants who died from malignant neoplasms (n = 316), cardiovascular disease (202), or other causes (312) during the observation period were examined. Results Cumulative incidence plots showed higher cumulative death rates for the low Lp(a) group than for the intermediate-to-high Lp(a) group for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.03, and p = 0.03, respectively). Cox proportional hazards analyses with the sex and age of the participants, body mass index, and smoking and drinking histories as covariates showed that a low Lp(a) level was a significant risk for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.003, and p = 0.01, respectively). The hazard ratio (95% CI) [1.48, 1.15–1.92] of a low Lp(a) level for cancer deaths was almost the same as that for a male sex (1.46, 1.00–2.13). Conclusions This is the first report to describe the association between a low Lp(a) level and all-cause or cancer death, supporting the anti-neoplastic effect of Lp(a). Further epidemiological studies are needed to confirm the present results.

Meta-analysis of second cancer risk after radiotherapy among childhood cancer survivors.

Cancer risks among childhood cancer survivors following radiotherapy have not yet been well characterised in terms of radiation dose. A meta-analysis of studies on the excess relative risk per gray (ERR) of second cancer was conducted previously; unfortunately, the small number of eligible studies restricted quantitative evaluations. To solve this problem, a statistical method to calculate ERR estimates from other estimates was developed, and a meta-analysis was conducted again. The PubMed database was searched and 26 relevant studies were identified. ERR estimates were available in 15 studies, and for the other 11 studies, the regression-based model was used to calculate ERR estimates from other estimates. The overall ERR estimate was 0.40, which was much lower than that of atomic bomb survivors exposed as young children. Heterogeneity of the risk among studies was suggested, and a further study is needed to explore the heterogeneity among studies.

Pyrethroid insecticide exposure and reproductive hormone levels in healthy Japanese male subjects

The associations between serum levels of reproductive hormones (follicle‐stimulating hormone, luteinizing hormone, testosterone, sex hormone‐binding globulin, inhibin B and calculated free testosterone) and urinary metabolite concentration of pyrethroid insecticides [3‐phenoxybenzoic acid (3‐PBA)] were explored in 322 male university students in suburban Tokyo. The subjects constituted part of a large cross‐sectional survey on the reference value of semen quality of Japanese men. Urinary 3‐PBA was detectable in 91% of the subjects demonstrating ubiquitous exposure among the general population. However, there were no associations between urinary 3‐PBA and serum hormone levels. This result was inconsistent with those reported in China and the USA for subjects who had similar levels of urinary 3‐PBA to the present subjects. One of the possible reasons of the inconsistency might be different composition of pyrethroid insecticides to which the subjects were exposed; 3‐PBA is a common metabolite of a number of pyrethroids and thus lacks specificity to compounds that may have different potentials of reproductive toxicity. Another reason might be related to the fact that our subjects were university students who were not aware of their own fertility, whereas the previous study subjects were infertility patients. However, the multiple regression models could explain only a limited fraction of total variance in serum levels of hormones. Identification of other contributors is warranted.