An association between rs7635818 polymorphism located on chromosome 3p12.3 and the presence of abdominal aortic aneurysm.

The association between gene variant rs7635818 located on chromosome 3p12.3 and abdominal aortic aneurysm (AAA) was not unambiguously determined by the results of genome-wide association studies. The aim of our study was to examine this possible association in the Slovak population, with respect to the presence and severity of AAA.A cross-sectional study was conducted between August 2016 and March 2020. The study included 329 participans, 166 AAA patients and a control group of 163 subjects without confirmed AAA with comparable distribution of genders. The anteroposterior diameter of the abdominal aorta was determined by duplex ultrasonography. AAA was defined as subrenal aortic diameter ≥ 30 mm. DNA samples were genotyped using real-time polymerase chain reaction and subsequent high-resolution melting analysis in presence of unlabelled probe. Genetic models studying the possible association were adjusted to age, sex, smoking, arterial hypertension, diabetes mellitus, creatinine and body mass index (BMI) in multivariate analysis. In the additive model, presence of each C-allele of rs7635818 polymorphism was associated with an almost 50 % increase in probability of developing AAA (OR 1.49; 95 % CI 1.06-2.08; p=0.020). Compared to GG homozygotes, CC homozygotes had more than two times higher risk of developing AAA (OR 2.23; 95 % CI 1.14-4.39; p=0.020). The risk of AAA was also in the recessive model higher for CC homozygotes compared to G-allele carriers (GC/GG) (OR 1.79; 95 % CI 1.01-3.19; p=0.047).The abdominal aortic diameter in CC homozygotes of the rs7635818 polymorphism was 7.66 mm greater compared to GG homozygotes (42.5±22.0 mm vs 34.8±21.3 mm; p=0.022) and 5.88 mm greater compared to G-allele carriers (GC/GG) (42.5±22.0 mm vs 36.6±21.0 mm; p=0.04) in univariate analysis. C-allele variant in rs7635818 G>C polymorphism is associated with a higher probability of developing AAA in the Slovak population.

Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis.

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

A missense variant in GLP1R gene is associated with the glycaemic response to treatment with gliptins.

Gliptins act by increasing endogenous incretin levels. Glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic peptide receptor (GIPR) are their indirect drug targets. Variants of GLP1R and GIPR have previously been associated with the incretin effect. The aim of the present pilot study was to examine associations of the GLP1R and GIPR gene variants with the glycaemic response to gliptins. A total of 140 consecutive patients with type 2 diabetes were followed-up 6 months after initiation of gliptin treatment. GLP1R rs6923761 (Gly168Ser) and GIPR rs10423928 genotyping was performed using real-time PCR, with subsequent high-resolution melting analysis. The main study outcome was reduction in glycated haemoglobin (HbA1c) after treatment. GLP1R Gly168Ser variant was significantly associated with reduction in HbA1c in an additive model (ß = -0.33, p = 0.011). The mean reduction in HbA1c in Ser/Ser homozygotes was significantly lower compared with Gly-allele carriers [0.12 ± 0.23% vs. 0.80 ± 0.09% (1.3 ± 2.5 mmol/mol vs. 8.7 ± 1.0 mmol/mol); p = 0.008]. In conclusion, GLP1R missense variant was associated with a reduced response to gliptin treatment. The genotype-related effect size of ∼0.7% (8 mmol/mol) is equal to an average effect of gliptin treatment and makes this variant a candidate for use in precision medicine.

Effects of hypoxia on adipose tissue expression of NFκB, IκBα, IKKγ and IKAP in patients with chronic obstructive pulmonary disease.

Recently we observed increased adipose tissue (AT) expression of CD40-related signaling proteins but no activation of tumor necrosis factor-α or CD68 in patients with chronic sustained hypoxia resulting from chronic obstructive pulmonary disease (COPD). Transcription factor nuclear factor-κB (NFκB) is involved in cellular responses to hypoxia and activates the proinflammatory gene expression with concomitant upregulation of its own repressors--inhibitors of κB (IκB) in an auto feedback loop. Inhibitor of kappaB kinase (IKK)-γ and inhibitor of kappaB kinase complex-associated protein (IKAP) are further regulatory proteins involved in NFκB signaling. In this study, we hypothesized that chronic sustained hypoxia significantly relates to IκBα, IKKγ and IKAP within the AT in COPD patients. In 20 patients with stable disease, samples of subcutaneous AT were analyzed using real-time PCR. Although no significant differences were observed between two groups categorized by median PaO2 in NFκB (p = 0.065), gene expressions of IκBα, IKKγ and IKAP were all higher in hypoxemic patients (p = 0.033; p = 0.050; p = 0.010, respectively). In multivariate analyses, PaO2 independently predicted AT IκBα, IKKγ and IKAP (R (2) = 0.490, p = 0.012; R (2) = 0.586, p = 0.002; R (2) = 0.504, p = 0.009, respectively). In conclusion, our data suggest significant AT upregulation of IκBα, IKKγ and IKAP by chronic sustained hypoxia in COPD patients.

Pharmacogenomic association between a variant in SLC47A1 gene and therapeutic response to metformin in type 2 diabetes.

Pharmacogenetic studies revealed that variants in genes related to the pharmacokinetics of metformin were associated with glucose-lowering effect of metformin. The aim of this study was to investigate possible associations of the variants in genes encoding organic cationic transporters-solute carrier family 22, members A1, A2 (SLC22A1, SLC22A2) and solute carrier family 47, member A1 (SLC47A1) with response to metformin in type 2 diabetes. One hundred forty-eight drug-naive patients with type 2 diabetes were included in the study. Genotyping for SLC22A1 rs622342, SLC22A2 rs316019 and SLC47A1 rs2289669 variants was performed using real-time PCR with subsequent melting-curve analysis. SLC47A1 rs2289669 genotype was significantly associated with the reduction in haemoglobin A1c (HbA1c) after 6 months. Twenty percentage of patients with diabetes that are homozygous for A-allele of SLC47A1 had twofold reduction in HbA1c in comparison with the patients carrying G-allele (GG + GA: 0.55 ± 0.09% vs. AA: 1.10 ± 0.18%, p = 0.018). In conclusion, the results of this study might have in future practical implication in personalised treatment of patients with type 2 diabetes.

Circulatory and adipose tissue leptin and adiponectin in relationship to resting energy expenditure in patients with chronic obstructive pulmonary disease.

Increases in resting energy expenditure (REE) likely contribute to weight loss in various chronic diseases. In chronic obstructive pulmonary disease (COPD), relationships between the ventilatory impairment and increased REE, and between disturbances in adipokines and weight loss were previously described. Therefore, we investigated serum levels and adipose tissue expression of leptin and adiponectin, and their relationships to REE in patients with COPD. In 44 patients with stable COPD (38 male; age 62.3+/-7.2 years), REE was assessed using indirect calorimetry. Subcutaneous adipose tissue samples were analyzed using real-time PCR. From underweight [n=9; body mass index (BMI) <20.0 kg.m(-2)], to normal weight-overweight (n=24, BMI=20.0-29.9 kg.m(-2)) and obese patients (n=11; BMI>/=30 kg.m(-2)), REE adjusted for body weight decreased (32.9+/-6.1 vs. 26.2+/-5.8 vs. 23.9+/-6.6 kcal.kg(-1).24 h(-1), p=0.006), serum levels and adipose tissue expression of leptin increased (p<0.001 for both), and serum and adipose tissue adiponectin decreased (p<0.001; p=0.004, respectively). REE was inversely related to serum and adipose tissue leptin (R=-0.547, p<0.001; R=-0.458, p=0.002), and directly to serum adiponectin (R=0.316, p=0.039). Underweight patients had increased REE compared to normal weight-overweight patients, in association with reductions in serum and adipose tissue leptin, and increased serum adiponectin, suggesting a role of adipokines in energy imbalance in COPD-related cachexia.

Variation in CDKAL1 gene is associated with therapeutic response to sulphonylureas.

The aim of the present pilot pharmacogenetic study was to analyse quantitative effects of sulphonylurea treatment in addition to metformin on parameters of glycemic control with respect to CDKAL1 genotypes in patients with type 2 diabetes. Effect of 6-month sulphonylurea therapy on glycemic control according to CDKAL1 genotypes was evaluated in 101 patients with type 2 diabetes who failed to achieve glycemic control on metformin monotherapy. CDKAL1 rs7756992 polymorphism was determined by melting curve analysis of small amplicon following real-time PCR. After sulphonylurea treatment fasting plasma glucose (FPG) levels were significantly different (p=0.045) among three CDKAL1 genotype groups (AA: n=49; AG: n=36; GG: n=16). In a dominant genetic model, carriers of the G-allele (AG+GG, n=52) achieved significantly lower FPG levels in comparison with patients with the AA genotype (6.90±1.08 vs. 7.48±1.12 mmol/l, p=0.013). Consequently, adjusted ΔFPG was significantly higher in the AG+GG compared to the AA group (1.48±1.51 vs. 1.02±1.33 mmol/l, p=0.022). Similar trend was observed for HbA(1c) levels, but the difference between the genotype groups did not reach the level of statistical significance. Relatively small number of included patients is a limitation of the present study. In conclusion, our results suggest that the magnitude of FPG reduction after 6-month sulphonylurea treatment in patients with type 2 diabetes is related to the variation in CDKAL1.

Pharmacogenetics of oral antidiabetic treatment.

In the majority of patients with type 2 diabetes (T2D), oral antidiabetic drug (OAD) treatment is the first line treatment after lifestyle measures fail. Two major groups of OAD are used in clinical practice--insulin secretagogues and insulin sensitisers. Sulphonyluea (SU) derivatives are insulin secretagogues and stimulate insulin secretion by inhibiting ATP-sensitive potassium channels. Genes KCNJ11 and ABCC8 encode potassium channel proteins. KCNJ11 gene Glu23Lys polymorphism was associated with an increased risk of SU secondary failure, while Ser1369Ala polymorphism of ABCC8 gene had influence antidiabetic efficacy of SU drug gliclazide. In addition, the polymorphism of TCF7L2 gene, which has the strongest association with T2D, also influenced secondary SU drug failure. Insulin sensitisers include both metformin and glitazones. Some drug-genotype associations were observed for metformin in patients with T2D. Several genes influenced the effect of glitazone treatment. Rosiglitazone was more effective in diabetes control in carriers of Prol2Ala polymorphism of PPARG gene encoding the PPARg-receptor--the target of this drug. Rosiglitazone treatment had less effect on glycemic control and adiponectin increase in T2D patients with GG-genotypes of adiponectin (APM1) polymorphism. Pioglitazone treatment had smaller effect on glycemic control in patients with LPL Ser447X polymorphism. Identification of drug-genotype interactions in pharmacogenetic studies of the OAD treatment might have clinical implications in the near future resulting in selection of more specific "patient-tailored therapy" in T2D (Tab. 1, Ref. 58).

Carotid intima-media thickness in patients with chronic obstructive pulmonary disease.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is associated with increased cardiovascular morbidity and mortality. Several large population-based cohort studies identified an association between reduced lung function and increased intima-media thickness (IMT). Nevertheless, a vast majority of subjects in these studies did not suffer from COPD and thus it remains unclear whether IMT differs among various stages of COPD severity. The aim of the present pilot study was to evaluate IMT in central European patients with moderate, severe and very severe COPD. METHODS: In forty-nine patients (34 men, 15 women; mean age 66.1 +/- 10.9 years) with COPD, the combined thickness of intima and media layers of the common carotid arteries was measured using B-mode ultrasound imaging. RESULTS: Increased cardiovascular disease risk as evidenced by carotid IMT values greater or equal to 75th percentile were present in 14 (28.6%), whereas IMT hypertrophy (IMT values greater or equal 0.80 mm) was present in 24 (49.0%) of patients. Average IMT in the entire cohort was 0.85 +/- 0.21 mm, with no significant differences from stage II to stages III and IV of COPD. CONCLUSION: Present results indicate a high prevalence of IMT hypertrophy and increased cardiovascular disease risk as assessed by carotid ultrasonography in COPD patients with a broad spectrum of airway obstruction severity. The lack of differences in carotid IMT between various stages of lung impairment severity suggests that atherosclerosis starts early in the course of COPD. Therefore, the need to screen patients for the presence of concomitant atherosclerosis in early stages of COPD severity may be warranted (Tab. 2, Ref. 33).

[Relationship of the CDKAL1 and KCNQ1 gene polymorphisms to the age at diagnosis of type 2 diabetes in the Slovakian population]. / Vzt'ah polymorfizmov génov CDKAL1 a KCNQ1 k veku diagnózy diabetu 2. typu v populácii slovenska.

BACKGROUND/AIMS: The association of CDKAL1 and KCNQ1 genes with type 2 diabetes mellitus (DM2T) was confirmed by several genome-wide association studies in both Caucasian and Asian populations. For both genes, it is supposed that the risk of DM2T development is related to impaired insulin secretion. Based on assumption that the presence of risk allele might predispose to an earlier onset of DM2T, the aim of the present study was to assess the frequency of risk alleles of CDKAL1 rs7756992 and KCNQ1 rs163184 polymorphisms and to analyze their association with the age at DM2T diagnosis in the Slovakian population. METHODS: CDKAL1 rs7756992 A/G and KCNQ1 rs163184 G/T polymorphisms were genotyped using asymmetric PCR with subsequent melting curve analysis in a group of 538 patients with DM2T. Anthropometric and laboratory parameters were determined by using standard methods. Since two genes were analysed, the required level for statistical significance was defined as p < 0.025. RESULTS: Risk homozygotes (CG) for KCNQ1 polymorphism had higher mean age of DM2T diagnosis by 2 years when compared to T-allele carriers (GT + TT) in a recessive model, but the difference did not reach the predefined level of statistical significance. No relationship of CDKAL1 polymorphism to the age at onset of DM2T diagnosis was observed. CONCLUSIONS: In the present study, no relationship of CDKAL1 and KCNQ1 polymorphisms to the earlier onset of type 2 diabetes was observed.

Effect of sulphonylurea treatment on glycaemic control is related to TCF7L2 genotype in patients with type 2 diabetes.

The aim of the present study was to analyse effects of sulphonylurea treatment on parameters of glycaemic control in relation to transcription factor 7-like 2 (TCF7L2) genotypes. In 87 patients with type 2 diabetes who failed to achieve glycaemic control on metformin monotherapy, effects of 6-month sulphonylurea in addition to metformin on reductions in haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) levels were evaluated. Reduction in HbA1c and FPG in response to 6-month sulphonylurea treatment was significantly higher in patients with CC genotype compared to those with the CT+TT genotype (1.16 ± 0.07 vs. 0.86 ± 0.07%, p = 0.003; 1.57 ± 0.12 vs. 1.14 ± 0.14 mmol/l, p = 0.031, respectively). In the multivariate analysis, baseline HbA1c and the TCF7L2 genotype were the only significant predictors of HbA1c reduction. In conclusion, the magnitude of HbA1c and FPG reductions after 6-month sulphonylurea treatment in addition to metformin is related to the TCF7L2 gene polymorphism.

Relationship of five type 2 diabetes candidate gene polymorphisms to the age at diagnosis of diabetes in the Slovakian population.

OBJECTIVES: To examine the relationship between polymorphisms of five candidate genes for type 2 diabetes mellitus (T2DM) and the age at diagnosis of T2DM. METHODS: 538 Slovakian patients with T2DM were included and their age at diagnosis of T2DM retrieved from their medical records. Polymorphisms of genes encoding peroxisome proliferator activated receptor gamma (PPARG), PPARG-coactivator-1 (PGC1), insulin-receptor substrate 1 (IRS1), the subunit Kir 6.2 of the ATP-dependent potassium-channel (KCNJ11) and transcription factor 7-like 2 (TCF7L2) were detected by PCR-RFLP methods. RESULTS: No significant relationship between the risk alleles of the examined gene polymorphisms to the lower mean age at diagnosis of T2DM was observed. The carriers of the TT-genotype of TCF7L2 rs7903146 polymorphism had significantly increased odds ratio for diagnosis of diabetes before the age of 40 years [OR 3.02 (1.34, 6.81), p = 0.008], in comparison with the CC/CT genotype carriers. CONCLUSION: No significant association of PPARG, PGC1, IRS1, KCNJ11 and TCF7L2 gene polymorphisms and the age at diagnosis of T2DM was observed in the present study. Homozygotes for the risk allele of TCF7L2 had more frequently early onset of T2DM, before age of 40 years (Tab. 4, Ref. 15).

Gene polymorphisms of renin angiotensin system and serotonin transporter gene in patients with vasovagal syncope.

UNLABELLED: Objective of this study was to compare the distribution frequencies of gene polymorphisms of renin-angiotensin and serotonin system in patients with positive and negative head- up tilt test (HUT). METHODS: DNA from 191 patients (mean age 44+ 18 years, 61 men) was collected. HUT was positive in 117 and negative in 74 patients. Following gene polymorphisms were determined by the PCR method: ACE insertion/deletion (I/D ACE), angiotensinogen (AGT) (M 235), angiotensin II receptor (ATR1) (A 1166C) and serotonin transporter (SERT) polymorphism (5HTTLPR). RESULTS: No significant differences in the distribution of gene polymorphisms between syncopal patients with positive and negative HUT were dectected. Distribution of polymorphisms included: I/D ACE: II 19 vs 20%, ID 55 vs 52%, DD 26 vs 28%. Angiotensinogen gene polymorphism MM 27% vs 30%, MT 48% vs 46%, TT 25% vs 24%. ATR1 polymorphism AA 44 vs 32%, AC50 vs 60%, CC 6 vs 8%, 5HTTLPR serotonin transporter gene polymorphism LL 42 vs 43%, SL 41 vs 39%, SS 17 vs 18%. CONCLUSIONS: An association between polymorphisms of ACE, AGT, ATR1 and SERT gene, and predisposition to VVS was not proven by the present study (Tab. 2, Ref. 22). Full Text (Free, PDF) www.bmj.sk.

Monitoring antioxidant enzymes in red cells during allergen immunotherapy.

The aim of this report was to answer the question how specific immunotherapy influences the antioxidant enzyme system in patients with respiratory allergy and in longer perspective to find markers suitable to assess the efficacy of treatment. In open prospective randomised study 28 patients (18 females and 10 males, age 14-48 years) with seasonal respiratory allergy were treated with allergen immunotherapy. Subjects received subcutaneous therapy with allergens absorbed on calcium phoshate or aluminium hydroxide and were analyzed by the established protocol at the beginning, after three and 12 month of the treatment. In all treatment group red cell superoxide dismutase and glutathione peroxidase activities were in the normal range in allergic patients both before and during the treatment. Catalase activity in the allergic patients was lower as compared with controls and a significant increase of the enzyme activity occurred during and at the end of the treatment. In patients treated with calcium phosphate adsorbed allergen there was a continous increase of catalase activity from beginning up to the end of observation. In the case of the aluminium hydroxide treatment there was an increase from the baseline values up in the third month of the treatment and a decrease on the 12th month. In summary, the present results open the question that allergen immunotherapy may cause imbalance of oxidants and antioxidants. To support our findings larger controlled field studies are needed.

Monitoring antioxidant enzymes in red cells during allergen immunotherapy

The aim of this report was to answer the question how specific immunotherapyinfluences the antioxidant enzyme system in patients with respiratory allergy and inlonger perspective to find markers suitable to assess the efficacy of treatment. In openprospective randomised study 28 patients (18 females and 10 males, age 14 – 48 years)with seasonal respiratory allergy were treated with allergen immunotherapy. Subjectsreceived subcutaneous therapy with allergens absorbed on calcium phoshate or aluminiumhydroxide and were analyzed by the established protocol at the beginning,after three and 12 month of the treatment. In all treatment group red cell superoxidedismutase and glutathione peroxidase activities were in the normal range in allergicpatients both before and during the treatment. Catalase activity in the allergicpatients was lower as compared with controls and a significant increase of theenzyme activity occurred during and at the end of the treatment. In patients treatedwith calcium phosphate adsorbed allergen there was a continous increase of catalaseactivity from beginning up to the end of observation. In the case of the aluminiumhydroxide treatment there was an increase from the baseline values up in the thirdmonth of the treatment and a decrease on the 12th month. In summary, the presentresults open the question that allergen immunotherapy may cause imbalance of oxidantsand antioxidants. To support our findings larger controlled field studies areneeded (AU)

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An intravenous immunoglobulin therapy of serious autoimmune rheumatic diseases.

Intravenous immunoglobulins (IVIg) have been widely used in clinical practice for more than 35 years. Their efficacy has been established in many clinical trials for the treatment of autoimmune rheumatic diseases including systemic lupus erythematosus, ANCA positive vasculitis and dermatomyositis, but these indications are classified as the "off label" treatment. For the diseases mentioned above there are no generally accepted therapeutic guidelines. The case reports (one patient with lupus erythematosus chorea, two patients with dermatomyositis and one with the Wegener's granulomatosis) present a treatment of systemic connective tissue diseases with IVIg following the failure of standard therapeutic regimens. A successful therapy has been realized using different doses of IVIg, which raises a question on an appropriate dose. Based on our experience, we conclude that intravenous immunoglobulins are effective in the treatment of many "off label" indications in rheumatology, particularly in cases when standard immunosuppressive therapy could be harmful. Despite the evidence of efficacy, the dosage and timing of IVIg therapy, and questions of costs/benefits ratio still remain insufficiently documented and multicentric controlled clinical trials with consecutive development of guidelines are necessary (Ref. 27).

Relationship among urinary albumin excretion rate, lipoprotein lipase PvuII polymorphism and plasma fibrinogen in type 2 diabetic patients.

Plasma fibrinogen level represents a strong cardiovascular risk factor and is regulated by an interplay of genetic and environmental factors. Hyperfibrinogenemia frequently occurs in cluster with dyslipidemia within the frame of insulin resistance syndrome (IRS) and type 2 diabetes mellitus. Genetic variants with a pleiotropic effect have been proposed to cause IRS features including hyperfibrinogenemia. We studied the influence of polymorphisms in lipoprotein lipase (LPL) gene, beta-fibrinogen gene (FIBB) and environmental factors on plasma fibrinogen levels in type 2 diabetes patients. 131 type 2 diabetes patients (mean age 62+/-10 years, 33% male) were genotyped for polymorphisms in LPL gene (intron 6 PvuII, intron 8 HindIII) and FIBB gene (-148C/T, -455G/A) by PCR-RFLP method. Fibrinogen was measured by thrombin coagulation method, albuminuria by immunoturbidimetric assay. Polymorphism LPL PvuII showed a gene-dose effect on fibrinogen levels, with the highest fibrinogen in P-P- homozygotes (p = 0.05, analysis of variance). P-carriers (P-P- and P+P- combined) had significantly higher fibrinogen levels compared with P+P+ homozygotes (3.74+/-1.40 g/l vs 3.06+/-1.20 g/l, p=0.03). Other studied polymorphisms were not significantly related to fibrinogen levels. Age- and sex-adjusted fibrinogenemia correlated significantly with albuminuria (r = 0.48, p=0.001), serum uric acid (r = 0.42, p=0.006) and serum creatinine (r = 0.32, p=0.04). Multiple stepwise linear regression identified interaction term of LPL PvuII and albuminuria as an independent predictor of fibrinogen level, explaining 18% of fibrinogen variance. Albuminuria thus appears to be the best predictor of fibrinogen plasma levels in type 2 diabetic patients. Relationship between albuminuria and fibrinogenemia may be modified by the genotype LPL PvuII, which also shows a weak association with plasma fibrinogen level in type 2 diabetes patients.

Effect of gene polymorphisms on lipoprotein levels in patients with dyslipidemia of metabolic syndrome.

Dyslipidemia in the metabolic syndrome (MS) is considered to be one of the most important risk factors for atherosclerosis. It is characterized by hypertriglyceridemia, low concentration of plasma HDL-cholesterol, predominance of small dense LDL particles and an increased concentration of plasma apolipoprotein B (apoB). The pathogenesis of this type of dyslipidemia is partially explained, but its genetic background is still unknown. To evaluate the influence of cholesterol ester transfer protein (CETP) TaqIB polymorphism, lipoprotein lipase (LPL) PvuII and HindIII polymorphisms, hepatic lipase (LIPC) G-250A polymorphism and apolipoprotein C-III (APOC3) SstI gene polymorphism on lipid levels in dyslipidemia of the metabolic syndrome, 150 patients with dyslipidemia of metabolic syndrome were included. 96 % of patients had type 2 diabetes. The patients did not take any lipid lowering treatment. The exclusion criterion was the presence of any disease that could affect lipid levels, such as thyroid disorder, liver disease, proteinuria or renal failure. Gene polymorphisms were determined using the polymerase chain reaction and restriction fragment length polymorphisms. The genotype subgroups of patients divided according to examined polymorphisms did not differ in plasma lipid levels with the exception of apoB. The apoB level was significantly higher in patients with S1S1 genotype of APOC3 SstI polymorphism when compared with S1S2 group (1.10+/-0.26 vs. 0.98+/-0.21 g/l, p=0.02). Similarly, patients with H-H- genotype of LPL HindIII polymorphism had significantly higher mean apoB, compared with H+H- and H+H+ group (1.35+/-0.30 vs. 1.10+/-0.26 g/l, p=0.02). In the multiple stepwise linear regression analysis, apoB level seemed to be influenced by APOC3 SstI genotype, which explained 6 % of its variance. The present study has shown that the S1 allele of APOC3 SstI polymorphism and the H- allele of LPL HindIII polymorphism might have a small effect on apoB levels in the Central European Caucasian population with dyslipidemia of metabolic syndrome.

Assessment of adrenoleukodystrophy lesions by high field MRS in non-sedated pediatric patients.

BACKGROUND: Early detection of white matter lesions in childhood-onset cerebral adrenoleukodystrophy (ALD) is important as hematopoietic cell transplantation (HCT), currently the only effective treatment, is beneficial only if performed early in the disease course. OBJECTIVE: To establish reliable biochemical markers of cerebral disease progression in patients with ALD to aid in treatment planning. METHODS: The authors used proton magnetic resonance spectroscopy (MRS) in combination with LCModel analysis to quantify brain metabolites in small volumes (3 to 16 mL) in the occipital and frontal white matter and the splenium of the corpus callosum of 17 unsedated patients and 26 healthy volunteers (adult n = 21, age-matched n = 5) at 4 tesla. RESULTS: Absolute concentrations of 12 metabolites were reliably determined, seven of which were established as markers of lesion development. Among these, creatine and choline containing compounds were the weakest markers while N-acetylaspartate, glutamine, and lipids + lactate were the strongest. The large extent of changes in the markers enabled detection of early neurochemical changes in lesion formation prior to detection of abnormalities by conventional MRI. Concentrations of a number of metabolites were also significantly different between normal appearing white matter of patients and controls indicating biochemical alterations in the absence of cerebral disease. Neurochemical improvements following HCT were measured in six patients. CONCLUSIONS: The progression of adrenoleukodystrophy, as well as effectiveness of its treatment, can be assessed with high precision using high field 1H magnetic resonance spectroscopy in individual patients without the need for sedation.

Methodology of H NMR Spectroscopy of the Human Brain at Very High Magnetic Fields.

An ultrashort-echo-time stimulated echo-acquisition mode (STEAM) pulse sequence with interleaved outer volume suppression and VAPOR (variable power and optimized relaxation delays) water suppression was redesigned and optimized for human applications at 4 and 7 T, taking into account the specific requirements for spectroscopy at high magnetic fields and limitations of currently available hardware. In combination with automatic shimming, automated parameter adjustments and data processing, this method provided a user-friendly tool for routine (1)H nuclear magnetic resonance (NMR) spectroscopy of the human brain at very high magnetic fields. Effects of first- and second-order shimming, single-scan averaging, frequency and phase corrections, and eddy currents were described. LCModel analysis of an in vivo (1)H NMR spectrum measured from the human brain at 7 T allowed reliable quantification of more than fifteen metabolites noninvasively, illustrating the potential of high-field NMR spectroscopy. Examples of spectroscopic studies performed at 4 and 7 T demonstrated the high reproducibility of acquired spectra quality.