Reply to Comment: Evaluation of the Association of Omentin 1 rs2274907 A > T and rs2274908 G > A Gene Polymorphisms with Coronary Artery Disease in Indian Population: A Case-Control Study.

Coronary artery disease (CAD) is a major cause of death all over the world. CAD is caused by atherosclerosis which is induced by the interaction of genetic factors and environmental factors. Genome-wide association studies have revealed the association of certain gene polymorphisms with susceptibility to CAD. Omentin 1 is an adipokine secreted by the visceral adipose tissues and has been reported to have anti-inflammatory, cardioprotective, and enhances insulin sensitivity. In this study, we examined the role of omentin-1 common single nucleotide polymorphisms (SNPs) (rs2274907 A > T and rs2274908 G > A) in CAD. We conclude that the AT genotype and the T allele of the rs2274907 A > T is associated with Cad in the south Indian population. Our results indicated that the rs2274907 SNP may be associated with CAD in this population. This finding needs further validation in well-designed and large-sample size studies before being introduced in clinical settings.

LDLR Gene Polymorphisms (rs5925 and rs1529729) Are Associated with Susceptibility to Coronary Artery Disease in a South Indian Population.

Cardiovascular diseases (CVD) are a major cause of death in India and worldwide. Atherosclerosis is caused by the interaction of environmental and genetic factors. Hypercholesterolemia is an example of a classical risk factor for CVD. The low-density lipoprotein receptor (LDLR) is one of the regulating mechanisms the liver uses for cholesterol homeostasis. Gene variations in the LDLR have been reported to cause hypercholesterolemia and consequently CVD. We investigated the association of polymorphisms in the LDLR (rs5925 and rs1529729) with coronary artery disease (CAD) in 200 coronary artery disease patients and 200 matched healthy controls using allele-specific PCR (AS-PCR). The results indicated that the CT genotype of the rs1529729 polymorphism was associated a decreased susceptibility to CAD with an odds ratio (OR) = 0.42 (95% confidence interval (CI), 0.23-0.77), risk ratio (RR) = 0.59 (0.39-0.89), P = 0.0047. The TT genotype of the rs1529729 polymorphism was also associated with decreased susceptibility to CAD with an OR = 0.19 (95% CI, 0.076-0.47), RR = 0.57 (0.47-0.69), P = 0.0003. The GA genotype of the rs5925 polymorphism was associated with decreased susceptibility to CAD with an OR = 0.45 (95% CI, 0.27-0.75), RR = 0.65 (0.47-0.88), P = 0.002. We concluded that the CT and TT genotypes of the rs1529729 polymorphism and the GA genotype of the rs5925 polymorphism are probably associated with decreased susceptibility to CAD. The simplicity of AS-PCR makes it particularly suitable for the rapid, large-scale screening of gene variabilities in the LDLR. AS-PCR could provide significant benefits in clinical applications with its ability to amplify a lower quantity of samples in a cost-saving manner. Nevertheless, these findings need to be validated in well-designed studies with larger sample sizes and in different populations.

Evaluation of the Association of Omentin 1 rs2274907 A>T and rs2274908 G>A Gene Polymorphisms with Coronary Artery Disease in Indian Population: A Case Control Study.

Coronary artery disease (CAD) is a major cause of death all over the world. CAD is caused by atherosclerosis which is induced by the interaction of genetic factors and environmental factors. Traditional environmental risk factors include hyperlipidemia, diabetes mellitus, lack of exercise, obesity, poor diet and others. Genome-wide association studies have revealed the association of certain gene polymorphisms with susceptibility to CAD. Omentin 1 is an adipokine secreted by the visceral adipose tissues and has been reported to have anti-inflammatory, cardioprotective, and enhances insulin sensitivity. In this study, we examined the role of omentin-1 common single nucleotide polymorphisms (SNPs) (rs2274907 A>T and rs2274908 G>A) in CAD. We genotyped 100 CAD patients and 100 matched healthy controls from the south Indian population using an amplification refractory mutation system (ARMS-PCR) and allele-specific PCR (AS-PCR). Our result indicated the rs2274908 G>A is not associated with CAD. Results showed that there was a significant difference in rs2274907 A>T genotype distribution between controls and CAD cases (P-value < 0.05). Results indicated that the AT genotype of the rs2274907 is associated with CAD with OR = 3.0 (95% confidence interval (CI), 1.64 to 5.49), 1.65 (1.27 to 2.163), P = 0.002. The T allele of the rs2274907 was also associated with CAD with OR = 1.82 (95% CI, 1.193 to 2.80), 1.37 (1.08 to 1.74), P = 0.005. Rs2274907 genotype distribution was also correlated with serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), hypertension and diabetes. We conclude that the AT genotype and the T allele of the rs2274907 A>T is associated with Cad in the south Indian population. Further studies on the effect of the rs2274907 A>T on omentin-1 function are recommended, and future well-designed studies with larger sample sizes and in different populations are required to validate our findings.

Incidence of MicroR-4513C/T Gene Variability in Coronary Artery Disease - A Case-Control Study.

BACKGROUND: Genetic variants in pre-microRNA genes or the 3'UTR of miRNA target genes could influence miRNA-mediated regulation of gene expression and thus contribute to the susceptibility and prognosis of human diseases. Several studies have investigated the association of genetic variants in the seed region of miRNAs with cardiometabolic phenotypes .Therefore the aim of study was to investigate the potential association of miR-4513 rs2168518 C>T gene variability with the risk of developing CAD and its association with different cardiometabolic phenotypes in an Indian cohort to stratify CAD burden in the general population. METHODS: The study was conducted on 100 clinically confirmed CAD patients and 100 healthy individuals. Genotyping of MicroR-4513 rs2168518C>T gene variability was performed using Amplification refractory mutation system PCR method. RESULTS: A significant difference was observed in the genotype distribution among CAD cases and healthy controls. The frequencies of three genotypes CC, CT, TT in CAD patient and healthy controls were 5%, 77%, 18%, and 28%, 45% and 27% respectively. A multivariate analysis showed that miR- 4513 rs2168518 polymorphism is associated with an increased susceptibility to CAD in codominant inheritance model for variant CC vs. CT OR 9.58 CI (3.45-26.57), RR 2.3(1.75-3.02), P=0.001. Results also indicate a potential dominant effect of miR-4513 rs2168518 C/T polymorphism on susceptibility of CAD in dominant inheritance model for variant CC vs. (CT+TT) OR 7.38 (2.71-20.07), RR 1.96 (1.56-2.46), P=0.001. In allelic comparison, T allele weakly increased risk of CAD compared to C allele (OR=1.50, 95% CI (1.09-2.26) RR 1.15 (0.94-1.39) P=0.044. CONCLUSION: It is concluded that CT genotype and T allele of microR-4513 rs2168518 is strongly associated with increased susceptibility to CAD. Furthers studies with larger sample sizes are necessary to confirm this result.

Glycomacropeptide: long-term use and impact on blood phenylalanine, growth and nutritional status in children with PKU.

In phenylketonuria, casein glycomacropeptide (CGMP) requires modification with the addition of some essential and semi essential amino acids to ensure suitability as a protein substitute. The optimal amount and ratio of additional amino acids is undefined. AIM: A longitudinal, parallel, controlled study over 12 months evaluating a CGMP (CGMP-AA2) formulation compared with phenylalanine-free L-amino acid supplements (L-AA) on blood Phe, Tyr, Phe:Tyr ratio, biochemical nutritional status and growth in children with PKU. The CGMP-AA2 contained 36 mg Phe per 20 g protein equivalent. METHODS: Children with PKU, with a median age of 9.2 y (5-16y) were divided into 2 groups: 29 were given CGMP-AA2, 19 remained on Phe-free L-AA. The CGMP-AA2 formula gradually replaced L-AA, providing blood Phe concentrations were maintained within target range. Median blood Phe, Tyr, Phe:Tyr ratio and anthropometry, were compared within and between the two groups at baseline, 26 and 52 weeks. Nutritional biochemistry was studied at baseline and 26 weeks only. RESULTS: At the end of 52 weeks only 48% of subjects were able to completely use CGMP-AA2 as their single source of protein substitute. At 52 weeks CGMP-AA2 provided a median of 75% (30-100) of the total protein substitute with the remainder being given as L-AA. Within the CGMP-AA2 group, blood Phe increased significantly between baseline and 52 weeks: [baseline to 26 weeks; baseline Phe 270 µmol/L (170-430); 26 weeks, Phe 300 µmol/L (125-485) p = 0.06; baseline to 52 weeks: baseline, Phe 270 µmol/L (170-430), 52 weeks Phe 300 µmol/L (200-490), p < 0.001)]. However, there were no differences between the CGMP-AA2 and L-AA group for Phe, Tyr, Phe:Tyr ratio or anthropometry at any of the three measured time points. Within the CGMP-AA2 group only weight (p = 0.0001) and BMI z scores (p = 0.0001) increased significantly between baseline to 52 weeks. Whole blood and plasma selenium were significantly higher (whole blood selenium [p = 0.0002]; plasma selenium [p = 0.0007]) at 26 weeks in the CGMP-AA2 group compared L-AA. No differences were observed within the L-AA group for any of the nutritional markers. CONCLUSIONS: CGMP-AA increases blood Phe concentrations and so it can only be used partly to contribute to protein substitute in some children with PKU. CGMP-AA should be carefully introduced in children with PKU and close monitoring of blood Phe control is essential.

Biological and Mechanical Evaluation of Novel Prototype Dental Composites.

The breakdown of the polymeric component of contemporary composite dental restorative materials compromises their longevity, while leachable compounds from these materials have cellular consequences. Thus, a new generation of composite materials needed to be designed to have a longer service life and ensure that any leachable compounds are not harmful to appropriate cell lines. To accomplish this, we have developed concurrent thiol-ene-based polymerization and allyl sulfide-based addition-fragmentation chain transfer chemistries to afford cross-linked polymeric resins that demonstrate low shrinkage and low shrinkage stress. In the past, the filler used in dental composites mainly consisted of glass, which is biologically inert. In several of our prototype composites, we introduced fluorapatite (FA) crystals, which resemble enamel crystals and are bioactive. These novel prototype composites were benchmarked against similarly filled methacrylate-based bisphenol A diglycidyl ether dimethacrylate / triethylene glycol dimethacrylate (bisGMA/TEGDMA) composite for their cytotoxicity, mechanical properties, biofilm formation, and fluoride release. The leachables at pH 7 from all the composites were nontoxic to dental pulp stem cells. There was a trend toward an increase in total toughness of the glass-only-filled prototype composites as compared with the similarly filled bisGMA/TEGDMA composite. Other mechanical properties of the glass-only-filled prototype composites were comparable to the similarly filled bisGMA/TEGDMA composite. Incorporation of the FA reduced the mechanical properties of the prototype and bisGMA/TEGDMA composite. Biofilm mass and colony-forming units per milliliter were reduced on the glass-only-filled prototype composites as compared with the glass-only-filled bisGMA/TEGDMA composite and were significantly reduced by the addition of FA to all composites. Fluoride release at pH 7 was greatest after 24 h for the bisGMA/TEGDMA glass + FA composite as compared with the similarly filled prototypes, but overall the F- release was marginal and not at a concentration to affect bacterial metabolism.

LDLR rs688 TT Genotype and T Allele Are Associated with Increased Susceptibility to Coronary Artery Disease-A Case-Control Study.

PURPOSE: The low-density lipoprotein receptor is responsible for the binding and uptake of plasma LDL particles and plays a critical role in maintaining cellular cholesterol homeostasis. LDLR gene SNP rs688 has been reported to be associated with increased plasma total and LDL cholesterol in several populations and can lead to elevated plasma LDL levels, resulting in an increased risk for atherosclerosis and coronary artery disease. This study aimed to explore genetic LDLR variant rs688 for its potential roles in coronary artery disease. METHODOLOGY: This study recruited 200 coronary artery disease patients and 200 healthy individuals. Genotyping of LDLR-rs688C > T gene variations was performed using the allele specific PCR method. Correlation of LDLR-rs688C > T gene variants with different clinicopathological features of coronary artery disease patients was performed. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the correlation of this microRNA polymorphism with coronary artery disease risk. RESULTS: A significant difference was observed in genotype distribution among the coronary artery disease and matched healthy controls (p = 0.003). The frequencies of all three genotypes CC, CT, TT reported in the patient samples were 14%, 65% and 21% and in the healthy controls samples were 18%, 73% and 9%, respectively. The increased risk of developing CAD in Indian patients was found to be associated with LDLR rs688 TT genotype (OR = 3.0, 95% CI, 1.43 × 6.2; p = 0.003) RR 1.87 (1.20⁻2.91) p = 0.0037) and also the increased risk of developing CAD was reported to be associated with LDLR rs688 T allele (OR = 0.74, 95% CI, 1.57⁻0.97; p = 0.03) RR 0.85 (0.73⁻0.99) p = 0.03) compared to the C allele. Therefore, it was observed that more than a 3.0- and 0.74-fold increase risk of developing CAD was associated with TT genotype and T allele in Indian coronary artery disease patients. CONCLUSION: The findings indicated that LDLR rs688 TT genotype and T allele are associated with an increased susceptibility to coronary artery disease patients. LDLR-rs688C > T gene variation can be used as a predisposing genetic marker for coronary artery disease. Further studies with larger sample sizes are necessary to confirm our findings.

Refining low protein modular feeds for children on low protein tube feeds with organic acidaemias.

Children with inherited metabolic disorders (IMD) who are dependent on tube feeding and require a protein restriction are commonly fed by 'modular tube feeds' consisting of several ingredients. A longitudinal, prospective two-phase study, conducted over 18 months assessed the long-term efficacy of a pre-measured protein-free composite feed. This was specifically designed to meet the non-protein nutritional requirements of children (aged over 1 year) with organic acidaemias on low protein enteral feeds and to be used as a supplement with an enteral feeding protein source. METHODOLOGY: All non-protein individual feed ingredients were replaced with one protein-free composite feed supplying fat, carbohydrate, and micronutrients. Thirteen subjects, median age 7.4y (3-15.5y), all nutritionally tube dependent (supplying nutritional intake: ≥ 90%, n = 12; 75%, n = 1), and diagnosed with organic acidaemias (Propionic acidaemia, n = 6; Vitamin B12 non-responsive methyl malonic acidaemia, n = 4; Isovaleric acidaemia, n = 2; Glutaric aciduria type1, n = 1); were studied. Nutritional intake, biochemistry and anthropometry were monitored at week - 8, 0, 12, 26 and 79. RESULTS: Energy intake remained unchanged, providing 76% of estimated energy requirements. Dietary intakes of vitamins, minerals and essential fatty acids significantly increased from week 0 to week 79, but sodium, potassium, magnesium, decosahexanoic acid and fibre did not meet suggested requirements. Plasma zinc, selenium, haemoglobin and MCV significantly improved, and growth remained satisfactory. Natural protein intake met WHO/FAO/UNU 2007 recommendations. CONCLUSIONS: A protein-free composite feed formulated to meet the non-protein nutritional requirements of children aged over 1 year improved nutritional intake, biochemical nutritional status, and simplified enteral tube feeding regimens in children with organic acidaemias.

The challenge of nutritional profiling of a protein-free feed module for children on low protein tube feeds with organic acidaemias.

BACKGROUND: Enteral tube feeding for children with organic acidaemias (OA) is recommended. Protein restriction, providing minimum safe levels of protein intake, is advocated. Standard paediatric tube feeding formulae provide more than the minimum safe protein requirements and are unsuitable in OA without modification. Modified paediatric enteral feeds consist of several modular ingredients. The aim of this prospective longitudinal interventional study was to assess the efficacy of a premeasured novel protein-free module developed for children aged over 12 months compared to conventional practice. METHODS: In total, 15 children with OA (11.6-31 kg) needing enteral feeding were recruited. The protein-free module, from either a protein-free infant feed or modular ingredients, was replaced by the study feed. To ensure metabolic stability, energy and protein intake were unchanged. Dietary intake, anthropometry and nutritional biochemistry were recorded at baseline and week 26. RESULTS: Dietary intakes of magnesium (P = 0.02), sodium (P = 0.005), vitamin D (P = 0.04), docosahexaenoic acid (P = 0.01) and arachidonic acid (P = 0.001) significantly improved; plasma selenium (P = 0.002) and whole blood glutathione peroxidase (P = 0.02) significantly increased. Feed preparation accuracy as measured by composition analysis showed consistent errors both in pre- and study feeds. CONCLUSIONS: A protein-free module improved nutritional intake and biochemistry, although feed preparation errors remained a common finding.

Glycomacropeptide in children with phenylketonuria: does its phenylalanine content affect blood phenylalanine control?

BACKGROUND: In phenylketonuria (PKU), there are no data available for children with respect to evaluating casein glycomacropeptide (CGMP) as an alternative to phenylalanine-free protein substitutes [Phe-free L-amino acid (AA)]. CGMP contains a residual amount of phenylalanine, which may alter blood phenylalanine control. METHODS: In a prospective 6-month pilot study, we investigated the effect on blood phenylalanine control of CGMP-amino acid (CGMP-AA) protein substitute in 22 PKU subjects (13 boys, nine girls), median age (range) 11 years (6-16 years). Twelve received CGMP-AA and nine received Phe-free L-AA, (1 CGMP-AA withdrawal). Subjects partially or wholly replaced Phe-free L-AA with CGMP-AA. If blood phenylalanine exceeded the target range, the CGMP-AA dose was reduced and replaced with Phe-free L-amino acids. The control group remained on Phe-free L-AAs. Phenylalanine, tyrosine and Phe : Tyr ratio concentrations were compared with the results for the previous year. RESULTS: In the CGMP-AA group, there was a significant increase in blood phenylalanine concentrations (pre-study, 275 µmol L-1 ; CGMP-AA, 317 µmol L-1 ; P = 0.02), a decrease in tyrosine concentrations (pre-study, 50 µmol L-1 ; CGMP-AA, 40 µmol L-1 ; P = 0.03) and an increase in Phe : Tyr ratios (pre-study, Phe : Tyr 4.9:1; CGMP-AA, Phe : Tyr 8:1; P = 0.02). In the control group there was a non-significant fall in phenylalanine concentrations (pre-study 325µmol/L: study 280µmol/L [p = 0.9], and no significant changes for tyrosine or phe/tyr ratios [p = 0.9]. Children taking the CGMP-AA found it more acceptable to L-AA. CONCLUSIONS: Blood phenylalanine control declined with CGMP-AA but, by titrating the dose of CGMP-AA, blood phenylalanine control remained within target range. The additional intake of phenylalanine may have contributed to the change in blood phenylalanine concentration. CGMP-AA use requires careful monitoring in children.

The challenges of vitamin and mineral supplementation in children with inherited metabolic disorders: a prospective trial.

BACKGROUND: In order to achieve metabolic stability, dietary treatment of inborn errors of metabolism may require restriction of protein, fat or carbohydrate. Manipulation of dietary intake potentially reduces micronutrient status, and provision of a comprehensive vitamin and mineral supplement becomes an essential adjunct to dietary treatment. AIM: To review the efficacy of a new complete vitamin and mineral supplement [Fruitivits, Vitaflo Ltd] in 14 subjects in an open prospective 26-week study. METHOD: All subjects had dietary restrictions: low protein diets (57%, n = 8), regular daytime cornstarch and overnight glucose polymer tube feeds (29%, n = 4), low fat diet (7%, n = 1) and modified Atkins diet (7%, n = 1). Plasma nutritional biochemistry, anthropometry and food frequency questionnaires were collected at week 0, 12 and 26 weeks respectively. RESULTS: Five nutritional parameters showed a significant improvement from baseline (week 0) to study end (week 26): folate (P = 0.01), vitamin E (P = 0.04), plasma selenium (P = 0.002), whole blood selenium (P = 0.04) and total vitamin D (P = 0.008). All the other nutritional markers did not significantly change. Even with regular monitoring, 37% of the product remained unused. CONCLUSIONS: Despite improvements in some nutritional markers, overall use of the vitamin and mineral supplement was less than prescribed. New methods are needed to guarantee delivery of micronutrients in children at risk of deficiencies as a result of an essential manipulation of diet in inborn disorders of metabolism.

Food acceptance and neophobia in children with phenylketonuria: a prospective controlled study.

BACKGROUND: In phenylketonuria (PKU), little is known about the effect of bitter-tasting phenylalanine-free l-amino acid exposure on taste preference development. The present prospective study aimed to determine the flavour preferences of children with PKU versus healthy control children. METHODS: Thirty-five children with PKU and 35 age/gender-matched controls, aged 4-13 years, tasted 10 blinded puree foods in random order. They were rated using a seven-point pictorial hedonic scale (super yummy to super yucky) and ranked in preferential order. Caregivers completed a neophobia and food frequency questionnaire on behalf of their children. RESULTS: Both PKU and control groups rated sweet foods higher than savoury, bitter and sour foods. However, control children ranked fruits as a group higher than PKU children (mean 3.7 versus 4.6; P = 0.03), whereas PKU children ranked vegetables as a group higher than controls (mean 5.6 versus 6.3; P = 0.05). Children with PKU had more neophobia and were untrusting/fearful of new foods. CONCLUSIONS: Although there was some evidence to suggest that children with PKU aged ≥4 years prefer savoury foods (vegetables) more than control children, they did not prefer bitter-tasting foods, and so early and persistent administration of bitter-tasting l-amino acids was not associated with apparent taste imprinting. Neophobia appears to play significant part in food refusal in PKU, perhaps more so than taste preferences.

Errors in emergency feeds in inherited metabolic disorders: a randomised controlled trial of three preparation methods.

OBJECTIVE: Glucose polymer-based emergency feeds (EF), used during illness to prevent metabolic decompensation and encephalopathy in inherited metabolic disorders, should be produced accurately and safely. DESIGN: In a randomised, prospective, controlled study, the aim was to investigate if when preparing age-appropriate EF, a pre-measured sachet of glucose polymer, compared with scoops and weighing (using digital scales), decreased carer errors. SUBJECTS: 47 carers (3 men, 44 women) of 52 inherited metabolic disorders patients were recruited. SETTING AND INTERVENTION: The carers made EF using all three techniques (weighing, scoops and pre-measured sachets) under supervision in controlled and home conditions. A 100-ml aliquot of each EF was analysed for carbohydrate concentration. RESULTS: Under controlled preparation conditions, with 1 litre EFs, the % median glucose polymer concentration closest to target amounts was (1) pre-measured sachets (105%), (2) weighing (107%) and (3) scoops (118%; p<0.001). Similarly, under home conditions, the closest method was (1) pre-measured sachets (111%), (2) weighing (112%) and (3) scoops (118%; p<0.05). Under home preparation conditions, with 200 ml EFs, the pre-measured sachets were more likely to be within 20% of target weight than weighing (p<0.05), but there was no difference with scoops. Common errors observed were inaccurate water measurements (40% controlled and home conditions), incorrect scoop measurements and difficulty using digital scales. CONCLUSIONS; Overall, using pre-measured sachets was more accurate in EF production. Pre-measured sachets are likely to decrease preparation error and, therefore, reduce the risk of feed intolerance, particularly osmotic diarrhoea and consequential metabolic decompensation and encephalopathy.

Genetic variation and structure of the people of Uttarakhand, central Himalayas, India.

The Indian Himalayas, being semi-isolated geographically, provide ideal conditions for population genetics investigations. The main aim of this study is to genetically characterize and analyze the genetic structure of the people of Uttarakhand, a newly created North Indian hill state in the Central Himalayas, using original phenotype and allele-frequency data on a battery of seven red cell enzyme polymorphisms. For this analysis, blood samples were collected from 3,222 unrelated subjects belonging to various endogamous caste populations (Brahmin, Rajput, and Shilpkar) and tribal Bhotia inhabiting seven different districts in the Garhwal (northern) and Kumaon (southern) regions of Uttarakhand. Hemolysates were typed for isozymes of ESD, PGM1, ADA, AK1, GLO1, ACP1, and GPI using standard electrophoretic techniques. The genetic structure of these regional caste and tribal population groups was investigated with the help of different statistical measures. The present biochemical marker results show that the overall genetic constitution of the different populations of Uttarakhand is rather heterogeneous but similar to that of various caste and tribal populations of the neighboring hill state of Himachal Pradesh, situated on Uttarakhand's western border. The extent of genic differentiation observed in different contemporary populations of Garhwal was twice as high as that of Kumaon. Interestingly, in genetic distance dendrograms of both the regions and of all of Uttarakhand, all the Shilpkar groups are differentiated from the remaining groups of Brahmin, Rajput, and Bhotia. The genetic constitution of the Shilpkar (a scheduled caste population of Uttarakhand) and to a lesser extent that of the Bhotia (a scheduled tribe population of Uttarakhand) are rather different from both the Brahmin and Rajput high-caste populations, which tend to show genetic similarities between them. These observations are corroborated by the known ethnohistory of different populations of Uttarakhand.

Genetic affinities of the Siddis of South India: an emigrant population of East Africa.

Historical records indicate that the Portuguese brought the African Siddis to Goa, India, as slaves about 500 years ago. Subsequently, the Siddis moved into the interior regions of the state of Karnataka, India, and have remained there ever since. Over time the Siddis have experienced considerable cultural changes because of their proximity to neighboring population groups. To understand the biological consequences of these changes, we studied the Siddis to determine the extent of genetic variation and the contributions from the African, European, and Indian ancestral populations. In the present study we typed the Siddis for 20 polymorphic serological, red cell, and Alu insertion-deletion loci. The overall pattern of phenotype (and genotype) distribution is in accordance with Hardy-Weinberg expectations. Considering the ethnohistorical records and the availability of secondary-source genetic data, we used two data sets in the analysis: one comprising eight serological and red cell enzyme markers with eight population groups and another comprising six Alu insertion-deletion markers with seven tribal groups of South India. The dendrograms generated from these two data sets on the basis of genetic distance analysis between the selected populations of African, European, and Indian descent reveals that the Siddis are closer to the Africans than they are to the South Indian populations. Genetic admixture analysis using a dihybrid model (19 loci) and a trihybrid model (10 loci and 8 loci) shows that the predominant influence comes from the Africans, a lesser contribution from the South Indians, and a slight contribution from the Portuguese. Thus the original composition of the African genes among the Siddis has been diluted to some extent by the contribution from southern Indian population groups. There is no nonrandom association of alleles among a set of 10 genetic marker systems considered in the present study. The demonstration of genetic homogeneity of the Siddis, despite their admixed origin, suggests the utility of this population for genetic and epidemiological studies.

Hematological neoplasms with first presentation as spinal cord compression syndromes: a 10-year retrospective series and review of the literature.

CONTEXT: The epidural space is a well-known, albeit uncommon, location for lymphomatous involvement, estimated to occur in less than 3% of all systemic lymphomas. Initial presentation of the patient with disease in this site (i.e. primary spinal epidural lymphoma) has been considered to be "rare". When it has been reported, many studies have emphasized the occurrence of aggressive lymphomas with a poor prognosis. DESIGN: A 10-year retrospective search of our files generated 7 patients who presented initially with back pain, incontinence and/or lower extremity weakness, and by neuroimaging studies were found to have masses causing spinal cord compression syndromes necessitating neurosurgical intervention. RESULTS: The 7 patients included 4 males and 3 females with thoracic and lumbar epidural masses. Tumor types included high-grade non-Hodgkin lymphoma, B cell type (n = 4), indolent B cell lymphoma (n = 1), nodular sclerosing Hodgkin lymphoma (n = 1) and plasmacytoma (n = 1). Advanced disease (stage 4) was subsequently identified in all 7 patients. Despite this, survival varied greatly with therapy, from 3 weeks to almost 6 years, underscoring the need for correct classification of the lymphoma in order to optimize chemotherapeutic choices. The epidural space was the site of presentation of disease in 4% of all lymphomas diagnosed at our institution. CONCLUSIONS: Combining all reports in the literature, epidural presentation of lymphoma is not rare. Epidural lymphomas are distinct from both primary central nervous system lymphomas and from primary dural lymphomas. A broad range of systemic hematological tumor types can present as epidural masses. A full work-up for lymphoma classification may only be possible from the tissues received at the time of the neurosurgical decompression or biopsy procedure.

Fulminant ascending paralysis as a delayed sequela of diethylene glycol (Sterno) ingestion.

The authors report a 57-year-old man who survived 18 days after swallowing an 8-oz. can of Sterno in a suicide attempt. Two days after ingestion, he developed confusion and acute renal failure requiring hemodialysis, followed on day 8 by a delayed but rapidly evolving ascending paralysis. Pathologic examination showed severe demyelination, with lesser axonal damage, of virtually all cranial and peripheral nerves sampled and sparing of central myelin. The diethylene glycol in the Sterno was considered responsible for this intoxication.

Species differences in peroxisome proliferation; mechanisms and relevance.

Peroxisome proliferators are a class of structurally diverse chemicals, which induce liver carcinogenesis in rodents through interaction and activation of the Peroxisome Proliferator-Activated Receptor alpha (PPARalpha). PPARalpha agonists elicit a powerful pleiotropic response, which include hypolipidaemia. We have examined the response of species that are classically unresponsive to peroxisome proliferators. Whereas hamster responds to PPARalpha agonists by hepatomegaly and induction of marker genes, the guinea pig does not undergo hepatomegaly or induction of marker genes, such as CYP4A13. Both the hamster and the guinea pig have PPARalpha, and the guinea pig receptor has been characterised to be fully functional, as demonstrated in reporter gene expression assays. However, the guinea pig PPARalpha is expressed at low levels in liver, and the currently favoured hypothesis to explain species differences in hepatic peroxisome proliferation invokes the low level of PPARalpha as the principal determinant of species responsiveness. However, the demonstration that guinea pigs and humans undergo hypolipidaemia induced by PPARalpha-agonists calls into question the mode of action of PPARalpha agonists in "non-responsive" species.

Effects of prestorage white cell reduction on platelet aggregate formation and the activation state of platelets and plasma enzyme systems.

BACKGROUND: The introduction of prestorage white cell (WBC) reduction in random-donor platelet concentrates in Canada has increased the occurrence of particulate material in PCs. The effects of filtration on platelet activation state and the activation of plasma enzyme systems were assessed. STUDY DESIGN AND METHODS: Particulate material was examined by light microscopy, electron microscopy, protein electrophoresis, and biochemical analysis. Thirty PCs (10 unfiltered, 20 filtered) were examined during processing and 5-day storage for pH, platelet count and mean volume, morphology, activation marker expression, and hypotonic shock response. Complement activation, thrombin generation, and fibrinolysis were assessed by using specific enzyme immunoassays or chromogenic assays. RESULTS: By all analyses, the particulate material appeared to be platelet aggregates. Platelets exposed to WBC-reduction filters expressed a significantly higher level of activation markers CD62 and CD63, altered morphology, and increased platelet microparticles throughout the storage period than did unfiltered platelets. Complement activation at the C3 level was significantly increased in filtered units with little evidence of coagulation or fibrinolytic system activation. CONCLUSION: Exposure of platelets to filters during prestorage WBC reduction increased platelet activation and mildly increased complement activation over the levels during the storage period. These alterations can contribute to the formation of irreversible platelet aggregates during processing.

The use of radiolabelling techniques to measure substantivity to, and penetration into, hair of protein hydrolysates.

The use of 14C-labelled amino acids enables the measurement of both the total substantivity to hair and the degree of penetration into the hair shaft of amino acid mixtures derived from complete hydrolysis of proteins. The technique utilizes the fact that direct measurement of 14C radioactivity of the treated hair detects only the surface substantivity. Total substantivity can be determined following solubilization of the hair. Data obtained for wheat amino acids show significant penetration when used to treat hair from a shampoo or conditioner formulation. A similar technique has been investigated for a wheat protein partial hydrolysate using 14CNO for radiolabelling purposes and shows that significant penetration into hair can occur. L'utilisation d'amino-acides marques au 14C permet la mesure a la fois de l'absorption totale par les cheveux et du degre de penetration dans la fibre du cheveu de melanges d'amino-acides obtenus a partir d'une hydrolyse totale de proteines. La technique utilise le fait que la mesure directe de la radioactivite du 14C des cheveux traites ne detecte que l'absorption en surface. L'absorption totale peut etre determinee apres solubilisation des cheveux. Les donnees obtenues a partir d'amino-acides de ble montrent une penetration significative lors d'une utilisation pour traiter des cheveux a partir d'une formulation de shampoing ou d'apres-shampoing. Une technique similaire a ete exploree vis-a-vis d'un hydrolysat partiel d'une proteine de ble utilisant 14CNO a des fins de marquage, et montre qu'une penetration significative dans les cheveux peut avoir lieu.