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.

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.

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.

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.

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).

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.

Metabolic changes in rat brain after prolonged ethanol consumption measured by 1H and 31P MRS experiments.

1. In vivo 1H and 31P magnetic resonance spectroscopy techniques were applied to reveal biochemical changes in the rat brain caused by prolonged ethanol consumption. 2. Three models of ethanol intoxication were used. 3. 1H MRS showed a significant decrease in the concentration of myo-inositol in the brain of rats fed with 20% ethanol for 8 weeks. This change is consistent with perturbances in astrocytes. On the other hand, N-acetyl aspartate and choline content did not differ from controls. 4. 31P MRS did not reveal any significant changes in the high-energy phosphates or intracellular free Mg2+ content in the brain of rats after 14 weeks of 20% ethanol drinking. The intracellular pH was diminished. 5. By means of a 31P saturation transfer technique, a significant decrease was observed for the pseudo first-order rate constant k(for) of the creatine kinase reaction in the brain of rats administered 30% ethanol for 3 weeks using a gastric tube. 6. The 1H MRS results may indicate that myo-inositol loss, reflecting a disorder in astrocytes, might be one of the first changes associated with alcoholism, which could be detected in the brain by means of in vivo 1H MRS. 7. The results from 31p MRS experiments suggest that alcoholism is associated with decreased brain energy metabolism. 8. 31P saturation transfer, which provides insight into the turnover of high-energy phosphates, could be a more suitable technique for studying the brain energetics in chronic pathological states than conventional 31P MRS.

Serum creatinine level is an independent risk factor for the angiographic severity of internal carotid artery stenosis in subjects who have previously had transient ischaemic attacks.

BACKGROUND: Serum creatinine level has been reported to be related to the incidence of strokes. OBJECTIVE: To examine the relationship between serum creatinine level and the severity of extracranial carotid artery atherosclerosis. DESIGN AND METHODS: This is a secondary analysis of data from 88 patients (59 men and 29 women) who had previously had transient ischaemic attacks or minor strokes and had been included in intervention trials of symptomatic carotid disease. Narrowing of internal carotid artery was estimated by angiography. Both internal carotid arteries were measured and the severity was expressed as the sum of percentage stenoses on both sides. The risk profiles of patients with moderate and severe internal carotid artery stenosis were compared. RESULTS: The sex-adjusted mean serum creatinine concentration in those with severe carotid disease was significantly higher than that in those with moderate disease (106.3 +/- 3.3 versus 91.3 +/- 3.7 mumol/l, P = 0.003), but still within the normal range. The risk of having severe disease was compared with risk of having moderate disease for people ranked by their serum creatinine levels. Univariate logistic regression showed that the odds ratio (OR) for having severe involvement of internal carotid artery was greater for patients in mid-tertile of creatinine values than it was for those in the lowest tertile (OR 6.3, 95% confidence interval 2.0-20.4, P = 0.002). The creatinine levels of patients in these two tertiles were within the normal range. The OR was no greater for patients in the highest tertile of creatinine values, which were slightly elevated above the normal range. These OR did not change after adjustment for age, sex, hypertension or systolic blood pressure, diabetes, smoking and lipid levels. CONCLUSION: Results of this study demonstrate for the first time that serum creatinine level, even within the range of upper normal or mildly elevated levels, is related to the angiographic severity of internal carotid artery disease in patients who have previously had transient ischaemic attacks and that this relationship is independent of classic cardiovascular risk factors.

Application of NMR spectroscopy in biochemical studies of tumor cells sensitive and resistant to anticancer drugs.

Drug resistance is a prominent problem of cancer therapy. Differences in quantity and quality of many metabolites in normal and malignant cells and their changes after treatment by anticancer drugs can be detected by nuclear magnetic resonance (NMR) both in vivo and in vitro. The results of in vivo and in vitro 1H, 13C, 19F and 31P NMR spectroscopy and their correlation with the degree of resistance to anticancer drugs are discussed. Monitoring of treatment and development of drug resistance by this non-invasive method could be useful not only in cancer research related to drug resistance but also in clinical medical oncology.

[Characteristics of diabetic macroangiopathy of the lower extremities]. / Niektoré zvlástnosti diabetickej makroangiopatie dolných koncatín.

Macroangiopathy of the lower extremities is one of the most frequent complications of diabetes and has a very adverse impact on the quality of life of the patients. It affects approximately as much as half the diabetics with the duration of the disease for more than 15 years. It is encountered in two forms. The first type of affection--obliterating atherosclerosis--reminds of affections of the arteries of the lower extremities in the non-diabetic population, although some differences in the site of affection, morphology of sclerotic changes as well as the spectrum of risk factors were found, when compared with obliterating atherosclerosis in non-diabetics. Risk factors of this form of macroangiopathy include cholesterol, triacylglycerols, reduced values of HDL-cholesterol, hypertension, fibrinogen, smoking and apparently also albuminuria. The second form of macroangiopathy--mediocalcinosis--is not associated with the mentioned risk factors of atherosclerosis but is probably the consequence of diabetic neuropathy. Contrary to atherosclerosis, it does not lead to the development of obliteration but has also an adverse effect on the function of blood vessels. Its incidence correlates with the duration and compensation of diabetes as well as deteriorated perception of vibrations. With regard to the high incidence of gangrenes requiring amputation, it seems rational to influence in diabetics all known risk factors of macroangiopathy although convincing results of long-term intervention studies are still lacking.