Low Ps

Association of factor VII genotype with plasma factor VII activity and antigen levels in healthy Indian adults and interaction with triglycerides.

Plasma factor VII activity (factor VIIc) is one of the independent risk factors for coronary artery disease and is controlled by both genetic and environmental factors. Several studies in healthy Caucasian subjects have revealed an association of a common genetic polymorphism at residue 353 (Arg-->Gln) of the factor VII gene with plasma factor VIIc. We have investigated the influence of this polymorphism (factor VII Arg/Gln353) on fasting plasma factor VIIc and antigen (factor VIIag) levels and its interaction with triglyceride levels in 185 healthy Dravidian Indians of both sexes (128 men, 57 women). The frequency of Gln353 has been found to be significantly higher in Dravidian Indians (0.29; confidence interval, 0.27 to 0.30) than in Caucasians (0.10). The distribution of factor VII Arg/Gln353 genotypes was at Hardy-Weinberg equilibrium. The carriers of the Gln353 allele had significantly lower plasma factor VIIc and factor VIIag in men (P < .05). The factor VII Arg/Gln353 polymorphism explained 13% and 11% of the total variance of plasma factor VIIc and factor VIIag, respectively, in men (P < .001) and 6% and 9% in women (P > .1). The genotype-specific correlation of factor VIIc and factor VIIag with triglyceride levels was stronger in carriers of the Gln353 allele (r = .38 and .41; P < .001) than in Arg353 homozygotes (r = .09 and .27; P = .19 and .005, respectively).

Racial Variation of Cord Plasma Lipoprotein(a) Levels in Relation to Coronary Risk Level: A Study in Three Ethnic Groups in Singapore

Lipoprotein(a) [Lp(a)] is recognized as an independent risk factor for atherosclerosis. Studies have also shown that there are racial differences in the Lp(a) profile. The multiracial population of Singapore has demonstrated a differential prevalence of coronary artery disease, which is concordant with the plasma Lp(a) profile in the adult populations of Singapore. The level of Lp(a) is under strict genetic control, and its plasma concentration is determined significantly by inheritance. Expression of the racial profile of Lp(a) at birth was studied in the cord blood of 542 male and 468 female newborns from three ethnic groups of Singapore using the sandwich-ELISA. The Lp(a) levels were then related to the coronary risk levels of their respective adult populations. Lp(a) levels in Singapore newborns were found to be independent of the infants birth weight and sex but were significantly influenced by race. Indian newborns had significantly higher plasma levels of Lp(a). Chinese newborns had the lowest Lp(a) levels at birth. The ranking of Lp(a) levels at birth was concordant with the relative coronary mortality rates for the respective adult populations of Singapore. Racial differences in plasma Lp(a) levels are present and expressed at birth.

Variations in the Promoter Region of the Apolipoprotein A-1 Gene Influence Plasma Lipoprotein(a) Levels in Asian Indian Neonates from Singapore

We studied the influence of two DNA polymorphisms (−75 bp G/A and +83 bp C/T) in the promoter region of the apolipoprotein A-1 (apoA1) gene on cord plasma level of lipoprotein(a) [Lp(a)] in 1076 newborns of both genders from the three major ethnic groups in Singapore—Chinese, Malays, and Asian Indians. The frequency of the A allele at −75 bp in the Indians was significantly lower than the Chinese and Malays. There was no linkage disequilibrium between the two sites studied. Both polymorphic sites were not significantly associated with any lipid factors except for Lp(a) levels in the Asian Indians. The AA and CC homozygotes were significantly associated with lower Lp(a) levels. These associations were specific only to the male Indian neonates. The genetic variations at the −75 and +83 bp explained 6.9% and 7.2%, respectively, of the total variability of plasma Lp(a) levels at birth in the Asian Indians. The Lp(a) levels were also significantly different between composite genotypes in the order GG/TT >GA/CT >GG/CT >GA/CC >GG/CC >AA/CC. The effects of the two polymorphisms seem to be additive as the composite genotypes were able to explain 14% of the Lp(a) variance, equivalent to the sum of the two constituent sites. Our results showed that there is significant ethnic- and gender-specific influence of the apoA1 gene on plasma Lp(a) levels at birth that is inherent and independent of known gene-environment interactions.

Comparative study on deletions of the dystrophin gene in three Asian populations

AbstractThe frequency and distribution of deletions of 19 deletion-prone exons clustered in two hot spots in the proximal and central regions of the dystrophin gene were compared in three populations from Singaporean, Japan, and Vietnam. DNA samples obtained from 105 Singaporean, 86 Japanese, and 34 Vietnamese Duchenne muscular dystrophy patients were examined by polymerase chain reaction amplification. Deletions of the examined exons were found in 51.2% of Japanese patients but in 40.0% or less of the Singaporeans and Vietnamese. About two thirds of the deletions were localized in the central region and the remaining deletions were clustered at the proximal region. The most commonly deleted exons at the central deletion hot spot were exon 50 in the Singaporean, exons 49 and 50 in the Japanese, and exon 51 in the Vietnamese population. At the proximal deletion hot spot, the most commonly deleted exons were exons 6 and 8 in the Singaporeans, exons 12 and 17 in the Japanese, and exons 8 and 12 in the Vietnamese. Two cases each from Singapore and Japan had large-scale gross mutations spanning both deletion hot spots. Our results suggest that, although the presence and frequency of the two deletion hot spots may be similar in the three Asian populations analyzed, the distribution and frequency of deletions among the different exons can vary as a result of population-specific intronic sequences that predispose individuals to preferential deletion breakpoints.

Evolution of the apolipoprotein B gene and coronary artery disease: a study in low and high risk Asians

This study traces the evolutionary pathways of the apolipoprotein B gene in the low risk Chinese and high risk Asian Indians in relation to coronary artery disease (CAD). Haplotypes were constructed from six apoB polymorphisms sp24/27, Ag(c/g), Ag(a1/d), XbaI, Ag(h/i) and, Ag(t/z). These were genotyped from 474 Chinese (253 healthy, 221 CAD patients) and 248 Asian Indians (164 healthy, 84 CAD patients). The maximum parsimony method was used to construct a cladogram for each ethnic group. Three haplotypes in the Chinese and one in the Indians were found exclusively in CAD patients. These haplotypes were sp27ca1X‐ht, sp24ga1X‐iz and sp24ca1X+it in Chinese, and sp24cdX‐it in Indians. Those in the Chinese all occurred as terminal haplotypes and represented the most recent mutations. Evolutionary pathways for both ethnic groups were similar for majority of the haplotypes except for the presence of an additional third branch in the Indians arising from the ancestral haplotype. However, this third branch does not appear to contribute to the susceptibility of the Indians to CAD.

Racial variation of factor VII activity and antigen levels and their correlates in healthy Chinese and Indians at low and high risk for coronary artery disease

Plasma factor VII activity (FVIIc) is one of the independent risk factors of coronary artery disease (CAD) and is controlled by both genetic and environmental factors. South Asians including Indians have one of the highest prevalence and mortality rates from CAD while the Chinese have a much lower risk. Generally accepted risk factors cannot explain the high mortality from CAD in Indians. We examined two hundred and seventy seven Chinese (124 m, 153 f); and 216 healthy Indian (150 m, 66 f) adults for serum lipids; plasma FVIIc and FVIIag levels in order to examine racial variations of these and their correlates in these two populations. Both Indian men and women had significantly higher FVIIc levels (12% and 11%, respectively) than the Chinese even after adjustments of age, BMI and lipids (P < 0.01). In contrast, Indians had significantly lower plasma FVIIag levels than Chinese (8% and 9%, respectively in men and women; P < 0.01). Multiple linear regression analysis shows a strong correlation of FVIIc with serum triglycerides accounting for 4-8% of the total variability of FVIIc in different groups. Further, there was a stronger correlation between FVIIc and FVIIag in Indians than that in the Chinese (0.43 vs. 25) suggesting a greater activation resulting in higher FVIIc in Indians inspite of lower FVIIag levels. The higher FVIIc and stronger activation by triglycerides observed in this study partly explain the higher risk of CAD in Indians.

Inflammatory response in bacterial meningitis: cytokine levels in the cerebrospinal fluid.

Inflammatory response plays an important role in the pathogenesis of cerebral injury in bacterial meningitis. In this study, we evaluated the cytokine levels of interleukin 1-beta (IL1 beta), tumour necrosis factor alpha (TNF alpha) and interleukin 6 (IL6) in the cerebrospinal fluid (CSF), and determined their correlation with acute clinical complications and with changes in CSF biochemistry. Interleukin 6, TNF alpha and IL1 beta were present in 9/9, 3/9 and 4/9 patients, respectively. The CSFs with detectable TNF alpha or IL1 beta had higher levels of IL6 (p < 0.02), protein (NS) and lower glucose levels (p < 0.02), compared with those in which TNF alpha and IL1 beta were absent. Tumour necrosis factor alpha and IL1 beta levels also correlated with the presence of prolonged fever, fits, spasticity and death (logTNF alpha: r = 0.70, p < 0.05; logIL1 beta: r = 0.62, p = 0.08). The cytokine levels reflect the degree of inflammatory response and are positively correlated with the severity of acute clinical complications. Modulation of this inflammatory response in bacterial meningitis may improve its morbidity and mortality.

The Effects of Three Factor VII Polymorphisms on Factor VII Coagulant Levels in Healthy Singaporean Chinese, Malay and Indian Newborns

Factor VII (FVII) is an independent risk factor for coronary artery disease. Three polymorphisms of the factor VII gene (F7) were studied in a group of healthy newborns comprising 561 Chinese, 398 Malays and 226 Asian Indians from Singapore. The allele frequencies of 3 polymorphisms (R353Q, Promoter 0/10bp Del/Ins and Intron 7) in the FVII gene were ascertained through genotyping by polymerase chain reaction and restriction digestion of amplified fragments. In Chinese the minor allele frequencies are Q: 0.04, Ins: 0.03, R7: 0.44; Malays, Q: 0.06, Ins: 0.10, R7: 0.41; and Indians, Q: 0.25, Ins: 0.23, R7: 0.43. Strong linkage disequilibrium (Δ > 0.7) is observed between the 0/10bp and the R353Q sites in all ethnic groups. We conclude that: (i) the prevalence of the minor Q and Ins alleles of the R353Q and 0/10 bp polymorphisms are significantly higher in the Indian newborns than the Chinese and Malays; (ii) the Q allele is significantly associated (p = 0.01) with a lower plasma FVII coagulant level in the Indian and Malay neonates; and this polymorphism explains up to 3.8% of the variance in FVII coagulant levels; (iii) there is no significant difference in allele frequencies of the three polymorphisms between neonates with and without family histories of CAD.

Pathogenesis of Duchenne muscular dystrophy: the calcium hypothesis revisited.

Abstract Rapid advances in the molecular genetics of Duchenne muscular dystrophy (DMD) and the discovery and localization of the gene product dystrophin has brought new hope that successful treatment for this disease may not be too far away. Dystrophin has been postulated to have a mechanical function, helping to resist stress associated with muscle contraction. The presence of dystrophin in low concentrations in muscle cells, its expression in nervous tissue and the observation that hypercontraction of the sarcomeres precedes membrane rupture make the hypothesis unlikely. On the basis of an analogy with a cytoskeletal protein ankyrin, which is associated with the sodium/potassium adenosine triphosphatase (ATPase) in the kidney, it is possible that dystrophin deficiency leads initially to an increased but inefficient calcium‐ATPase activity, which pumps calcium out of the cell. Partial failure of the pump would result in intracellular accumulation of calcium, hypercontractions of the sarcomeres, rupture of the cell membrane, massive influx of calcium and cell necrosis.

Simple instructions for partial sleep deprivation prior to pediatric EEG reduces the need for sedation

OBJECTIVE To study the effects of providing simple instructions for partial sleep deprivation on the necessity for sedation in children and adolescents undergoing electroencephalography (EEG). METHODS Children and adolescents below 18 years undergoing non-urgent routine EEG were studied for the need for sedation during the EEG test. Two consecutive 3-year periods were reviewed. During the first 3 years no instructions for sleep deprivation were given, and during the second 3-year period, simple instructions were given to the patient or parents of young children to have less sleep prior to the EEG test. This was achieved by using the same sleep deprivation schedule irrespective of the age of the patient. RESULTS In the first 3-year period between January 1996 and December 1998, 785 non-urgent routine EEG recordings were performed in which only 146 (19%) pediatric patients managed to fall asleep without the need for any sedation within 30 min of being ready for the sleep recording. When partial sleep deprivation was implemented in the 3-year period between January 2000 and December 2002, 449 (55%) out of 821 patients undergoing the test fell asleep in the laboratory without sedation, an overall increase of 36%. Analyzing the different age-specific groups, the maximal increase in the success for natural sleep following partial sleep deprivation was 44% for pediatric patients aged above 10 years. CONCLUSIONS Simple instructions for partial sleep deprivation prior to the EEG reduced the need for sedation in children and adolescents undergoing the test.