Kiyotaro Kondo

A Case-Control Study of Alzheimer's Disease in Japan – Significance of Life-Styles

A case-control study of Alzheimers disease was conducted in Japan; it involved 60 cases matched for sex and age with two resident controls each. Life-style was particularly highlighted in this study. Among many factors, 5 were accepted as significant risk factors: psychosocial inactivity, physical inactivity, head injury, loss of teeth and low education. A multiple logistic model was applied in order to evaluate synergism of major factors. Compared with those who have none of the factors, those who have all were 934.5 times more liable to develop Alzheimers disease. Risk factors are not only useful for etiological studies but they give clues to identify high-risk individuals, and by eliminating these factors, the studies may also be applicable in the primary and the secondary prevention of this tragic disease.

Risk factors for Creutzfeldt-Jakob disease : A reanalysis of case-control studies

To review the evidence for risk factors of Creutzfeldt-Jakob disease (CJD), we pooled and reanalyzed the raw data of three case-control studies. The pooled data set comprised 178 patients and 333 control subjects. The strength of association between CJD and putative risk factors was assessed by computing the odds ratio as estimate of the relative risk. The risk of CJD was statistically significantly increased for subjects with a family history of CJD (odds ratio = 19.1; 95% CI 1.1 to 348.0). Further, there was a significant association between the risk of CJD and a history of psychotic disease (odds ratio = 9.9; 95% CI 1.1 to 86.1). Although not significantly increased, there was an elevated risk of CJD for subjects with a family history of dementia, a history of poliomyelitis, subjects employed as health professionals, and subjects ever exposed to cows and sheep. No association could be shown with organ meat consumption, including brain. The negative results of this reanalysis reassures the absence of a common risk factor in all CJD patients. However, the ongoing epidemiologic surveillance of CJD in several European countries may provide more evidence to exclude any environmental exposure early in childhood.

Angiotensin converting enzyme as a genetic risk factor for coronary artery spasm. Implication in the pathogenesis of myocardial infarction.

It has been reported that individuals with the D allele of an insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene are at greater risk for myocardial infarction (MI), especially among subjects normally considered to be at low risk. However, little is known about the mechanism by which the ACE polymorphism affects the risk of MI. Coronary artery spasm (CAS) is considered to be one possible mechanism for developing MI. We therefore examined the ACE polymorphism relation to CAS to determine if this was the mechanism by which the DD genotype influences MI. We studied 150 angiographically assessed Japanese males, all more than 60 yr old. CASs were detected using intracoronary injection of ergonovine maleate. Subjects were divided into three groups: those with CAS (group 1), those without CAS, but with fixed organic stenosis (group 2); and those without CAS and no organic stenosis (group 3). DD subjects were significantly represented in group 1 when compared with groups 2 (P = 0.002) and 3 (P = 0.026). These results suggest that the DD genotype relates to the greater risk for MI in the patients with CAS.

Angiotensinogen gene polymorphism in Japanese patients with hypertrophic cardiomyopathy

To examine the contribution of the renin-angiotensin system to hypertrophic cardiomyopathy (HCM), we studied 96 patients with HCM (mean age 50 years, 55% male), 105 of their unaffected siblings and offspring, and 160 healthy subjects without known hypertension and left ventricular hypertrophy (LVH) who were frequency matched to cases by age and sex. Patients were divided into familial or sporadic HCM (FHCM or SHCM) groups with or without affected members of their family. The region of interest in the angiotensinogen (AGT) gene, the missense mutation with methione-to-threonine amino acid substitution at codon 235 in angiotensinogen (M235T), was amplified by polymerase chain reaction with the use of allele-specific oligonucleotide primers flanking the polymorphic region of the AGT gene to amplify template deoxyribonucleic acid prepared from peripheral leukocytes. The T allele frequency was higher in the SHCM group than in unaffected siblings and offspring (88% vs 78%, X2 = 4.6, p < 0.05). The M allele frequency was higher in unaffected siblings and offspring than in patients with SHCM (23% vs 12%, X2 = 4.6, p < 0.05). The T allele frequency among unaffected siblings and offspring was similar to that observed in healthy subjects (78% vs 78%). We conclude that HCM, especially in sporadic cases, is partially determined by genetic disposition. The molecular variant of angiotensinogen T235 seems to be a predisposing factor for cardiac hypertrophy in HCM and carries an approximately twofold increased risk.

Life spans of Duchenne muscular dystrophy patients in the hospital care program in Japan

Analysis of 176 autopsy cases of Duchenne muscular dystrophy (DMD) demonstrated that (1) hospitalized patients showed longer life spans than their non-hospitalized affected maternal uncles, (2) patients hospitalized recently lived longer than those hospitalized in the past, and (3) pulmonary infection has become a less frequent cause of death in recent years, whereas dystrophic changes of the cardiac and respiratory muscles are more closely related with recent fatal cases. These results indicate the changing life span expectancy of patients with DMD and the changes in cause of death over the last decade, probably owing to the benefits of a hospital care program.

Absence of association between a common mutation in the methylenetetrahydrofolate reductase gene and preeclampsia in Japanese women

An association between preeclampsia (PE) and a common missense mutation of the methylenetetrahydrofolate reductase gene (MTHFR), a C to T substitution at nucleotide 677 (C677T), which converts an alanine to a valine residue, has been reported in Italian and Japanese populations. We examined 101 cases of hypertension in pregnancy (HP), including 73 cases of PE, and 215 normal pregnancy controls to confirm the association in Japanese women. No significant differences of the frequency of the T677 allele frequency or percentage of T677 homozygotes were detected among the various types of cases: HP (0.38, 12%, respectively), severe HP (0. 40, 12%), PE (0.38, 11%), severe PE (0.41, 11%), primiparous HP (0. 40, 12%), primiparous PE (0.44, 18%), nonelderly HP (0.39, 13%), nonelderly PE (0.40, 14%), nonobese HP (0.38, 12%), nonobese PE (0. 39, 10%), HP without homozygous T235 of the angiotensinogen gene (TT of AGT) (0.38, 15%), PE without TT of AGT (0.38, 15%), and controls (0.38, 15%). The results indicate that T677 of MTHFR may not be a risk factor for PE in Japanese population.

Association of a variant of the angiotensinogen gene with pure type of hypertension in pregnancy in the Japanese: Implication of a racial difference and significance of an age factor

The contribution of genetic factors to hypertension in pregnancy, including pre-eclampsia, has been well documented. The association with a common molecular variant of the angiotensinogen (AGT) gene, in which methionine (M235) is substituted for threonine (T235) at residue 235, has been reported in both Caucasians and Japanese. In the present study, we examined 115 cases of pure type of hypertension in pregnancy (PHP) and 381 normal pregnant controls in order to look for subgroups in which the AGT gene is the major factor in the PHP pathogenesis. By classification of PHP cases according to the clinical diagnosis, gravidity, and maternal age, we found significantly higher frequencies of T235 in both all PHP patients and preeclampsia/eclampsia patients than in normal controls. These results are discordant with those reported for Caucasian subjects where only a group of preeclamptic primigravidae was associated with the AGT variant, possibly indicating the existence of a racial difference. We also found that the variant frequency was significantly higher in the PHP subgroup with maternal age of 20-34 years (0.93) than in a subgroup of multigravid PHP patients age 35 years or older (0.77, P < 0.05) or in normal controls of age 20-34 years (0.76, P < 0.001). The result indicates that the AGT variant plays a significant role in hypertension in the age group 20-34 years.

A1166C variant of angiotensin II type 1 receptor gene is associated with severe hypertension in pregnancy independently of T235 variant of angiotensinogen gene

AbstractHypertension in pregnancy (HP) is a multifactorial disease manifested due to a complex combination of environmental factors and several predisposing genes including factors in the renin angiotensin system. The aim of this study was to assess the association between the A1166C variant of the angiotensin II type 1 receptor (AT1) gene and severe HP. We carried out association studies and multivariate analyses including other candidate causal factors of HP such as the M235T variant of the angiotensinogen (AGT) gene, prepregnancy body mass index (BMI), and family history of hypertension in Japanese subjects. One hundred and fourteen patients with severe HP and 291 normal pregnancy controls were genotyped. Among primiparous subjects, the frequency of “AC+CC genotype of AT1” was significantly higher in severe HP than in the controls. A multivariate analysis with “AC+CC genotype of AT1” and “TT genotype of AGT” revealed that these were independently associated with primiparous severe HP. However, when “family history of hypertension” and “prepregnancy BMI ≥25” were added as factors examined in the multivariate analysis, only “TT genotype of AGT” and “family history of hypertension” were found to be independent potent factors. The present results suggest that the C1166 allele of the AT1 gene may be concerned with the predisposition to essential hypertension independently of the T235 allele of the AGT gene.

Neurological Diseases in Karachi, Pakistan – Elevated Occurrence of Subacute Sclerosing Panencephalitis

Neurological diseases, especially subacute sclerosing panencephalitis (SSPE), were surveyed in Karachi, Pakistan disclosing following major results. (1) Indirectly estimated prevalence rates of selected neurological disease entities were comparable with the rates from western countries and Japan in heredodegenerative diseases, but grossly elevated in infectious diseases. (2) Estimated mortality statistics for the Karachi community revealed highly elevated rates for infectious, parasitic and perinatal causes of death. (3) SSPE represented about 10% of inflammatory afflictions of the cerebral parenchyma, its incidence rate being about 100% times more than that observed in developed countries. A case-control study preliminarily showed that infants who later contract SSPE have unhealthy mothers, are born small, and have various occurrences of ill health from birth to the onset of SSPE. (4) Age at the onset of measles was very young in the cases as well as in controls, unlike the average young age at onset of cases only in developed countries. Measles contracted at young age is a well known risk factor to SSPE. Whereas few children in developed countries acquire measles at such an early age, many Karachi children do. Elevated occurrence of SSPE is probably conditioned by such age patterns of measles infection, together with other risk factors more common in Karachi due to poorer health standards. A proper immunization programme is urgently needed to control measles and SSPE.

Clinical Statistics in 515 Fatal Cases of Motor Neuron Disease

In 515 cases of motor neuron disease followed until death, (1) the proportion of three subtypes of motor neuron disease (MND): amyotrophic lateral sclerosis (ALS), progressive bulbar paralysis (PBP), spinal progressive muscular atrophies (SPMA) was 78.3, 1.9, 19.8; (2) sex ratios were 1.41 in ALS, nearly one in PBP and 1.59 in SPMA, the ratio being high in cases initially involving the upper limbs; (3) age at onset was smoothly unimodal and identical in three subtypes; (4) bulbar symptoms appeared either at the initial stage or towards the fatal end; (5) duration was compatible with a compound Weibull distribution; (6) survival rates showed a reverted J type distribution and was more favorable in SPMA than ALS; (7) life expectancies decreased first but increased about 46 months after onset; (8) multivariate analysis disclosed that duration is shorter in ALS when age at onset was older, and when bulbar muscles or left limbs were initially affected, and in SPMA when age at onset was older, dysphagia was present, and probably in those patients who had a history of trauma.