Polymorphisms rs2167444 and rs508384 in the SCD1 Gene Are Linked with High ApoB-48 Levels and Adverse Profile of Cardiometabolic Risk Factors.

Elevated plasma concentration of apolipoprotein B-48 (apoB-48) is an independent risk factor of cardiovascular disease. Stearoyl-CoA desaturase-1 (SCD1) is a rate-limiting lipogenic enzyme and a key regulator of fuel metabolism. The aim of this study was to analyse associations between clinical, biochemical, and genetic factors and different apoB-48 levels in subjects at increased cardiometabolic risk. We examined 220 subjects exhibiting at least one metabolic syndrome (MetS) component. In conjunction with basic clinical, anthropometric and laboratory measurements, we analysed various polymorphisms of stearoyl-CoA desaturase-1 (SCD1). Subjects were divided into two groups according to the median apoB-48 level: (1) high apoB-48 (≥ 7.9 mg/l, N = 112) and (2) low apoB-48 (< 7.9 mg/l, N = 108). Neither group differed significantly in anthropometric measures. High plasma apoB-48 levels were associated with increased systolic blood pressure (+3 %; P < 0.05), MetS prevalence (59.8 vs. 32.4 %; P < 0.001), small-dense LDL frequency (46.4 vs. 20.4 %; P < 0.001), triglycerides (+97 %; P < 0.001), non-HDLcholesterol (+27 %; P < 0.001), and lower concentrations of HDL-cholesterol (-11 %; P < 0.01). This group was further characterized by a higher HOMA-IR index (+54 %; P < 0.001) and increased concentrations of conjugated dienes (+11 %; P < 0.001) and oxidatively modified LDL (+ 38 %; P < 0.05). Lower frequencies of SCD1 minor genotypes (rs2167444, rs508384, P < 0.05) were observed in subjects with elevated plasma concentrations of apoB-48. Elevated plasma concentrations of apoB-48 are associated with an adverse lipid profile, higher systolic blood pressure, insulin resistance, and oxidative stress. Lower proportions of minor SCD1 genotypes (rs2167444, rs508384) implicate the role of genetic factors in the pathogenesis of elevated levels of apoB-48.

Paraoxonase-1 (PON1) status in pancreatic cancer: relation to clinical parameters.

Human paraoxonase 1 (PON1) has been shown to decrease the level of systemic oxidative stress, which is thought to contribute to cancer development. The aim of this study was to examine the interrelationships between PON1 status and some clinical characteristics in patients with pancreatic cancer (PC). A group of 73 consecutive patients with PC (stage II-IV) and 73 control subjects were examined. Laboratory studies included five polymorphisms of the PON1 gene (L55M, Q192R, -108C/T, -126C/T, and -162A/G), PON1 arylesterase (PON1-A) and lactonase (PON1-L) activities, as well as some markers of protein metabolism, insulin resistance, and oxidative stress. In comparison with the control group, no difference in the distribution of the PON1 polymorphisms was found in cancer patients, both arylesterase and lactonase activities being significantly lower (-33, -47 %, respectively, both P < 0.001). There was neither statistically significant association of PON1 polymorphisms with tumour stages nor with diabetes mellitus connected with PC. The genotype distribution of L55M and ­108C/T differed only in a subgroup of patients presenting clinically relevant malnutrition (χ² = 6.50, 6.25, respectively, both P < 0.05). In the PC group, PON1-A and PON1-L activities correlated with Nutritional Risk Index (r = 0.351, 0.409, respectively, both P < 0.01), PON1-L with mid-arm muscle circumference (r = 0.328, P < 0.05), and PON1-A and PON1-L with serum albumin (r = 0.352, 0.391 respectively, both < 0.01). Our results suggest that PON1 plays an important role in PC, especially in cancer-associated malnutrition.

[On the concept of the metabolic syndrome]. / Ke koncepci metabolického syndromu.

During the last twenty years, a cluster of risk factors called metabolic syndrome (MetS) attracts interest in preventive medicine. According to the prevailing notion, which evolved from clinical observations, the core of the MetS consists of visceral obesity, impaired metabolism of glucose, atherogenic dyslipidemia, and arterial hypertension. These risk factors tend to cluster and are believed to be causally associated with insulin resistance. Components of the MetS are to a various degree involved in chronic inflammation, prothrombotic state, endothelial dysfunction, and oxidative stress. Supporters of the concept of MetS as a physiological and clinical entity believe that systems approach can help in understanding pathogenesis, improve prediction of cardiovascular risk, and increase motivation for prevention and treatment. On the other hand, serious criticisms emerged, which concern insufficient experimental evidence, imprecise diagnostic criteria, and questionable justification in general practice. To clarify unresolved problems which evolved in the ongoing debate, further research is needed.

[Atherogenic dyslipidemia and the metabolic syndrome: pathophysiological mechanisms]. / Aterogenní dyslipidémie a metabolický syndrom: patofyziologické mechanismy.

Atherogenic dyslipidemia (ADL), a frequent metabolic derangement found in patients with manifest atherosclerosis, is characterized by hypertriglyceridemia, low plasma HDL cholesterol and prevalence of small dense LDL particles. The key pathogenetic mechanisms of ADL are closely linked to insulin resistance, the lack of appropriate responses to insulin in peripheral cells, especially in adipose tissue, skeletal muscles and liver. Impaired insulin signalling leads to a decreased suppression of lipolysis, defective fat storage in adipocytes, and increased flux of free fatty acids to the liver, which together with posttranslational stabilization of apolipoprotein B enhances the assembly and secretion of VLDL particles. Decreased activity of lipoprotein lipase contributes to slow clearance of triglyceride-rich particles, with negative consequences in LDL metabolism. Impaired HDL synthesis, intravascular remodelling, and catabolism decreases reverse cholesterol transport from peripheral tissues, hepatocytes and macrophages. Small dense LDL particles are considered to be highly atherogenic, due to increased penetration of arterial intima, and decreased antioxidant capacity. Better understanding of pathophysiological mechanisms involved in ADL could promote new therapeutic methods, as well as increase the compliance with essential lifestyle interventions.

[Factors modulating parameters of cholesterol homeostasis in the metabolic syndrome]. / Faktory ovlivnující ukazatele homeostázy cholesterolu u metabolického syndromu.

BACKGROUND: Newly described component of the metabolic syndrome is the elevated synthesis of cholesterol accompanied with its decreased intestinal absorption. The aim of our study was to ascertain the incidence of genotypes and alleles of several candidate genes, which modulate insulin resistance and metabolism of lipids and to find their role in lipid, lipoprotein and cholesterol homeostasis. The concentrations of cholesterol precursors (lathosterol, desmosterol, respectively their rations to cholesterol) are related to the synthesis of cholesterol; concentrations of fytosterols (kampesterol, sitosterol, respectively their rations to cholesterol) are related to the intestinal absorption of cholesterol. METHODS AND RESULTS: 95 patients with metabolic syndrome (56 M/39 F) and 195 healthy persons (99 M/96 F) were included into the study. Beside the basic clinical and anthropometric data, parameters of glucose homeostasis, plasma concentration of lipids, ultracentrifugation separated lipoproteins, and conjugated diens in LDL were determined. Non-cholesterol sterols were estimated by capillary gas chromatography. Polymorphisms of apolipoprotein E, intestinal isoforms of fatty acids binding protein (Ala54Thr), microsomal transfer protein (-493G/T), and gamma-2 isoforms of peroxisomal proliferator activated receptor (Ala12Pro) were analysed by combination of methods of polymerase chain reaction and by determination of polymorphism of the length of restriction fragments. After adjustation to the age, patients with metabolic syndrome had higher BMI, body fat and lean body weight (all P < 0.001), waist circumference, systolic and diastolic blood pressure (all P < 0.01). At the same time they had higher levels of glucose, insulin (P < 0.001), C-peptide, CRP (P < 0.05), uric acid, conjugated diens in LDL and HOMA insulin resistance index (P < 0.001). After adjustation to the age, higher concentration of triglycerides (P < 0.001), apo B (P < 0.01), cholesterol and triglycerides in VLDL (both P < 0.001), triglycerides in LDL (P < 0.01) were found. Incidence of alleles and genotypes of studied polymorphisms did not differ in both groups. Cholesterol synthesis is modulated by the presence of metabolic syndrome and by sex; cholesterol resorption is modulated only by the presence of metabolic syndrome. CONCLUSIONS: In patients with metabolic syndrome we found higher synthesis and lower intestinal absorption of cholesterol. We did not confirm relation between alleles of studied polymorphisms and clinical and anthropometric parameters, neither relation of these alleles to lipid or lipoprotein levels, oxidation stress, inflammation, or parameters of synthesis and absorption of cholesterol.

[Gene-diet interactions in atherogenic dyslipidemias (part 1)]. / Interakce nekterých genetických a nutricních faktoru v patogenezi aterogenních dyslipidémií--1. cást.

With advances in molecular genetics, functional polymorphisms of various lipid-related genes have been investigated, to discern their metabolic effects and role in gene-diet interactions. New interdisciplinary concepts have emerged; while nutrigenetics examines genetic variation and associated responses to nutrients, in order to generate individual dietary recommendations, nutrigenomics focuses on the effects of nutrients on regulatory functions of genes and their products. This review summarizes recent knowledge concerning common polymorphisms of candidate genes for some apolipoproteins, transfer proteins, cell receptors, and enzymes, which presumably modulate cardiovascular risk. Most studies investigate isolated single nucleotide polymorphisms and nutrients, while only few try to elucidate complex interrelationships between coexistent multiple gene variants.

[Gene-diet interactions in atherogenic dyslipidemias (part 2)]. / Interakce nekterých genetických a nutricních faktoru v patogenezi aterogenních dyslipidémií--2. cást.

In the second part of the review, functional polymorphisms of some other lipid-related genes are considered, with a special emphasis on genetic variability of the fatty acid binding protein, lipoprotein lipase, hepatic lipase, and PPARs. Gene polymorphisms can profoundly influence metabolic responses to various dietary factors, e.g. effects of a special diet; on the other hand, dietary habits have modulatory effects on the expression of specific genotypes. Atherosclerosis and cardiovascular disease develop as a result of negative nutritional factors and individual genetic predisposition. A better comprehension of complex gene-gene and gene-environment interactions involved in cardiovascular risk could contribute to new preventive and therapeutic methods.

Sexualization of the female foot as a response to sexually transmitted epidemics: a preliminary study.

The authors reviewed historical literature and hypothesized a relationship between epidemics of sexually transmitted diseases and foot fetishism. They tested this hypothesis by quantifying foot-fetish depictions in the mass-circulation pornographic literature during a 30-yr. interval. An exponential increase was noted during the period of the current AIDS epidemic. The authors offer reasons for this possible relationship.

Crystal structures of two self-hydroxylating ribonucleotide reductase protein R2 mutants: structural basis for the oxygen-insertion step of hydroxylation reactions catalyzed by diiron proteins.

The R2 protein of ribonucleotide reductase catalyzes the dioxygen-dependent one-electron oxidation of Tyr122 at a diiron-carboxylate site. Methane monooxygenase and related hydroxylases catalyze hydrocarbon hydroxylation at diiron sites structurally related to the one in R2. In protein R2, the likely reaction site for dioxygen is close to Phe208. The crystal structure of an iron ligand mutant R2, Y122F/E238A, reveals the hydroxylation of Phe208 at the meta, or epsilon-, ring position and the subsequent coordination of this residue to the diiron site. In another mutant, F208Y, the "foreign" residue Tyr208 is hydroxylated to Dopa. The structures of apo and diferrous F208Y presented here suggest that Tyr208 is coordinated to the iron site of F208Y throughout the Dopa generation cycle. Together, the structural data on these two mutants suggest two possible reaction geometries for the hydroxylation reaction catalyzed by these modified R2 diiron sites, geometries which might be relevant for the hydroxylation reaction catalyzed by other diiron sites such as methane monooxygenase. A critical role for residue Glu238 in directing the oxidative power of the reactive intermediate toward oxidation of Tyr122 is proposed.

Bioethical concepts of health in medicine.

As a fundamental human need, and consequently one of the principal ethical values, health has to be examined both from the experiential and normative aspects. The following concepts of health have successively developed and found their place in internal medicine: a) absence of manifest disorders, b) state of complete well-being, c) active process aimed at achieving consistency of functions in a dynamic equilibrium with the environment, in order to secure optimum satisfaction of biological and cultural needs. The essential unity of the somatic, psychic, social and spiritual dimensions of the human person should be considered, when assessing health of individual subjects as well as of the whole community.

Tryptophan radicals formed by iron/oxygen reaction with Escherichia coli ribonucleotide reductase protein R2 mutant Y122F.

The active state of the small subunit, protein R2, of ribonucleotide reductase is formed by the reaction of apoprotein with Fe2+ and O2, whereby the diferric site and a stable phenoxy free radical on a tyrosyl residue (Tyr122) is formed. The corresponding reaction was studied in the mutant Y122F R2. It leads to a normal iron site, but the reduction equivalent from Tyr122 now has to be supplied from elsewhere. EPR spectroscopy shows formation of several paramagnetic species on different time scales. Using apoprotein with deuterium-labeled tryptophan residues, at least two species could be assigned to tryptophan free radicals. This is the first EPR observation of relatively stable protein-linked tryptophan radicals at room temperature and at 77 K. These tryptophan radicals may be involved as redox intermediates in long range electron transfer within the protein structure.

Addiction: the treatment of dual diagnosis.

Dual diagnosis is used when two disorders occur simultaneously in one person. The two disorders can refer to two medical illnesses, a psychiatric illness and a medical or surgical illness, or two psychiatric illnesses. The cost of misdiagnosis of dual disorders is high.

[Ethical decision-making on limitations and needs in terminal care]. / Etické rozhodováni o hranicich a náplni terminální péce.

Many physicians are refusing euthanasia as a possible solution of a patient's excessive distress, being aware of their responsibility for decision-making in the terminal care. A sharp dividing line has to be drawn between accepting inevitable death and unjustifiable manipulations with human life based on arbitrary qualitative criteria. Ethical decision-making should proceed from the particular clinical situation, which influences the definition of ordinary and extraordinary therapeutic means. Contemporary medicine has progressed towards authentic terminal care, respecting the fundamental needs of the terminally ill patient, in all dimensions of human person.

Differential diagnosis and management of suicidal behavior.

Suicidal behavior, like fever and headache, has a differential diagnosis. The physician, confronted with a patient who is suicidal, must identify the etiology of the self-destructive behavior and provide diagnostic-specific treatment. Suicide, in most instances, is a preventable cause of death.

Does sequential automated measurement improve the estimate of resting blood pressure?

Repeated blood pressure measurements made in sequence over short time intervals have been recommended in some studies of antihypertensive drugs, with the aim of improving the estimate of 'true' resting BP values. In order to examine this claim, the variance of four sequential automatic recordings of BP and heart rate was evaluated in 66 subjects. The oscillometric Nippon Colin BP-103N sphygmomanometer has been previously shown by our group to give accurate and consistent measurements of BP. The means and medians of three sequential readings, by significantly decreasing the variability, were found to be superior to single measurements. The recorded mean arterial pressures were significantly higher than those calculated according to the current formula, on average by 3.6 mmHg, being situated between one third and one half of the distance between the systolic and diastolic pressures. The Page's rank test revealed that the first measurements were not uniformly the highest ones. Since the variability of the first to third BP values did not differ, medians of the three sequential recordings made at one minute intervals can be recommended as a standard BP characteristic.

Creativity, depression and suicide.

The relationship between suicide and creativity has long been a subject of considerable concern. The author presents evidence indicating that in fact depression, suicide, and creativity are related. Several hypotheses for the relationship are posited. It is suggested that the same changes in the serotonergic system that are associated with depression in general and with impulsive suicides and homicides in the extreme may also be responsible for an element of risk taking that characterizes creativity and innovation in a person psychodynamically predisposed to being creative.

Acute treatment of alcohol and cocaine emergencies.

This chapter addresses the acute treatment of alcohol and cocaine. Because of the widespread use of both these drugs, health professionals must recognize the medical complications of alcohol and cocaine abuse and addiction. The biochemistry will be briefly reviewed as an avenue to understand the different treatment targets and modalities.

De Clérambault's syndrome in sexually experienced women.

De Clérambault's syndrome is said to usually occur in heterosexual women with little overt sexual experience. The authors present five cases of women with considerable sexual experience including, in some instances, homosexual activity and discuss their diagnosis of De Clérambault's syndrome in the context of what has been reported in the literature.

[Contribution of automatic sphygmomanometers for one-time measurement of blood pressure]. / Prínos automatických sfygmomanometru pro jednorázové merení krevního tlaku.

Due to high intra-individual variability of arterial blood pressure, single measurements provide only estimates of true actual values. Two or three recordings made in sequence in one or a few minutes' intervals are recommended in some clinical studies of antihypertensive therapy, with the aim of decreasing the variability. In order to examine the value of repeated measurements made on one occasion, four sequential resting recordings of blood pressure and heart rate made in one minute intervals with the automatic oscillometric Nippon Colin BP-103N sphygmomanometer were evaluated in 66 subjects, using the analysis of variance methods. Means of three recordings showed a significantly lower variability than single measurements (almost by one half), while the difference between three and four readings was not significant. The Page's rank test revealed that the first measurements are not uniformly the highest ones, and therefore the medians of three readings made in sequence are recommended as characteristics of resting blood pressure. An advantage of the oscillometric method is the possibility of measuring mean arterial pressure. The recorded values were significantly higher than those calculated from the systolic and diastolic pressures according to the current formula, being situated between one third and one half of the pulse pressure. The intra-individual coefficient of variation of the recorded mean arterial pressure was comparable with that of systolic and significantly lower than that of diastolic pressure.