Genetic predisposition to development of toxic liver cirrhosis caused by alcohol]

Comprehensive analysis of the contribution of genetic factors into predisposition to alcoholic toxic cirrhosis (TC) was performed. The ABO, RH, HP, TF, GC, PI, ACP1, PGM1, ESD, GLO1, and GST1 genetic polymorphisms were compared in 34- to 59-year-old male TC patients and control donors of the same sex and age. The phenotypic frequencies in the TC group deviated from the theoretically expected values; the main difference was the excess of rare homozygotes for the loci GC, ACP1, ESD, and GLO1. In the TC patients, the observed heterozygosity (Ho) was considerably lower than the theoretically expected value (H(e)). Wright's fixation index (F) in the TC patients was 30 times higher than in the control group (0.0888 and 0.0027, respectively). The frequencies of PI*Z and PI*S, the PI alleles that are responsible for lower concentrations of proteinase inhibitor, were 12 and 6 times higher in the TC than in the control group. The TC patients exhibited a significantly higher frequency of the liver glutathione-S-transferase GST1*0 allele, whereas the GST1*2 frequency was two times higher in the control subjects than in the TC patients (0.2522 and 0.0953, respectively). The TC and control groups showed statistically significant differences in the frequencies of the following alleles of six independent loci: ABO*0, TF*C1, TF*C2, PI*M1, PI*Z, ACP1*C, PGM1*1+, PGM1*1-, PGM1*2-, GST1*0, and GST1*2. The haptoglobin level was significantly higher and the serum transferrin level was drastically lower in all phenotypic groups of TC patients than in control subjects. The concentrations of IgM and IgG depended on the HP, GC, and PI phenotypes. The total and direct reacting bilirubin concentrations depended on the erythrocytic-enzyme phenotypes (ACP1, PGM1, and GLO1) in both TC and control groups.     

Genetic serum protein markers (HP,GC, TF,PI) in four Turkish population samples

Four population samples from different regions of Turkey (Thracia, Karadeniz Bölgesi, West Anatolia and East Anatolia) with a total of 338 individuals have been typed for haptoglobin (HP) and for group specific component (GC), transferrin (TF) and alpha₁-antitrypsin (PI) subtype polymorphisms. The allele frequencies show some regional differences, which, however, are statistically insignificant. In general the Turkish HP, GC, TF and PI allele frequencies do not differ obviously from those observed in other populations of Caucasoid origin.     

Genetic serum protein markers (HP,TF, GC,PI) in three population samples from Thuringia (Germany); Jena,Erfurt and Suhl

Haptoglobin (HP), transferrin (TF), group specific component (GC) and protease inhibitor (PI) polymorphisms were studied in three population samples from Thuringia: Jena, n=204; Erfurt, n=213; Suhl, n=180. GC and in particular TF allele frequencies show some statistically significant distribution heterogeneity, whereas HP and PI allele frequencies do not show any remarkable distribution differences. The results are discussed and compared with those obtained previously on other population samples from the eastern parts of Germany.     

The use of discrete characters in discriminant analysis for diagnosis of pulmonary tuberculosis and for classification of patients differing in treatment efficiency based on polymorphisms at nine codominant loci-HP,GC, TF,PI, PGM1, GLO1, C3, ACP1 and ESD

Discriminant analysis was used to differentiate patients with pulmonary tuberculosis (N = 106) from healthy individuals (N = 328) and patients whose treatment was efficient (N = 71) from those whose treatment was inefficient (N = 35). The analysis involved the data on nine polymorphic codominant loci: HP, GC, TF, PI, PGM1, GLO1, C3, ACP1, and ESD. The loci were selected by significance of differences in genotype frequencies between tuberculosis patients and healthy controls (GC, TF, PI, C3, ACP1) or between the two groups of patients differing in treatment efficiency (HP, GC, PI, PGM1, C3, ESD). Discrimination was based on a graphic method of Bayes classification procedure with a single-variate nomograph allowing easy estimation of the a posteriori probabilities for an individual to be classified. The two groups of patients proved to be discriminated sufficiently well (probability of misclassification Perr = 0.24), whereas discrimination between tuberculosis patients and healthy individuals was less efficient (Perr = 0.33). The method was proposed as a means of predicting the efficiency of treatment in pulmonary tuberculosis. Along with clinical, roentgenological, and laboratory examination, discriminant analysis may be employed as an accessory test in diagnostics of pulmonary tuberculosis, especially when the diagnosis is questionable.     

Genetic serum protein markers (HP,TF, GC and PI) in eight Slovakian population samples

1194 individuals from eight different regions of Slovakia have been typed for haptoglobin (HP) types and for transferrin (TF), group specific component (GC) and alpha-1-antitrypsin (PI) subtypes. Whereas the HP allele frequencies do not show a remarkable regional variability within Slovakia, this could be demonstrated concerning the TF, GC and PI allele frequencies. The reason for these distribution heterogeneities seems to be due to the incomplete panmixia of the Slovakian population by which local variations in the distribution of genetic markers could be maintained.     

The Use of Discrete Characters in Discriminant Analysis for Diagnosis of Pulmonary Tuberculosis and for Classification of Patients Differing in Treatment Efficiency Based on Polymorphisms at Nine Codominant Loci: HP,GC, TF,PI, PGM1, GLO1, C3, ACP1, and ESD

Discriminant analysis was used to differentiate patients with pulmonary tuberculosis (N = 106) from healthy individuals (N = 328) and patients whose treatment was efficient (N = 71) from those whose treatment was inefficient (N = 35). The analysis involved the data on nine polymorphic codominant loci: HP, GC, TF, PI, PGM1, GLO1, C3, ACP1, and ESD. The loci were selected by significance of differences in genotype frequencies between tuberculosis patients and healthy controls (GC, TF, PI, C3, ACP1) or between the two groups of patients differing in treatment efficiency (HP, GC, PI, PGM1, C3, ESD). Discrimination was based on a graphic method of Bayes classification procedure with a single-variate nomograph allowing easy estimation of the a posteriori probabilities for an individual to be classified. The two groups of patients proved to be discriminated sufficiently well (probability of misclassification P _err = 0.24), whereas discrimination between tuberculosis patients and healthy individuals was less efficient (P _err = 0.33). The method was proposed as a means of predicting the efficiency of treatment in pulmonary tuberculosis. Along with clinical, roentgenological, and laboratory examination, discriminant analysis may be employed as an accessory test in diagnostics of pulmonary tuberculosis, especially when the diagnosis is questionable.     

Distribution of the ABO blood groups and the HP,TF, GC,PI and C3 serum proteins in Yakuts

In Yakut populations examined, polymorphisms of immunological and serum protein markers, including AB0 and Rhesus blood groups, HP, TF, GC, PI and C3, were revealed. Gene frequencies for the systems studied fell into the following ranges: AB0 system: r, 0.514 to 0.663; p, 0.136 to 0.306; q, 0.110 to 0.337; haptoglobin HP*1: 0.214 to 0.431; transferrin TF*C: 0.700 to 1.0; group specific component GC*1: 0.821 to 0.978; PI*M1 proteinase inhibitor (or alpha 1-antitrypsin) PIM1: 0.860 to 0.946; and third component of the complement C3*F: 0.031 to 0.143.     

The Russian gene pool. Genogeography of serum genetic markers (HP, GC, PI, TF)

The study continues the series of works on the Russian gene pool. Gene geographic analysis of four serum gene markers best studied in the Russian population (HP, GC, PI, and TF) has been performed. Gene-geographic electronic maps have been constructed for 14 alleles of these loci and their correlations with geographic latitude and longitude. For all maps, statistical characteristics are presented, including the variation range and mean gene frequencies, partial and multiple correlations with latitude and longitude, and parameters of heterozygosity and interpopulation diversity. The maps of five alleles (HP*1, GC*2, GC*1S, PI*M2, and TF*C2) are shown and analyzed in detail. The genetic relief and structural elements of the maps are compared with the ecumenical trends, main variation patterns of these genes in northern Eurasia, and genetic characteristics of the indigenous populations of the Urals and Europe.     

Electrophoretic and isoelectric focusing studies in Brazilian Indians: data on four systems

Three-hundred ninety-nine individuals living in seven populations of two Brazilian Indian tribes (Macushi and I?ana River Indians) were tested for the phosphoglucomutase 1 (PGM1), properdin factor B (BF), haptoglobin (HP), and alpha-1-antitrypsin (PI) systems. We observed significant internal heterogeneity in the two tribes for the PGM1 alleles and in the Macushi for the HP markers. Frequencies in three of the four systems (the exception being BF) also show clear differences in the Macushi and I?ana River Indians. Compared with other ethnic groups, South American Indians generally present high frequencies of PGM1*1B, BF*S, HP*1S, and PI*M3. On the other hand, PGM1*1A, PI*M1, and PI*M2 are reduced, and HP*1F is absent or rare. This is the first report about HP subtypes among American Indians.     

Ethnogenetics of Yakuts from Three Regions of Republic' of Sakha (Yakutia) Inferred from the Frequencies of Biochemical Gene Markers

Comparative data on the distribution of immunological markers (AB0 and RH), serum proteins (HP, TF, GC, PI, and C3), and red cell enzymes (PGM1, ACP1, ESD, and GLO1) polymorphisms in Yakut populations from three regions of the Republic are presented. Close genetic affinities of Yakuts to Altaians, Mongols, and Buryats along with their notable difference from Evenks, Evens, and Chukchi were demonstrated.     

Ethnogenetics of yakuts from three regions of Republic of Sakha (Yakutia) inferred from the frequencies of biochemical gene markers

Comparative data on the distribution of immunological markers (AB0 and RH), serum proteins (HP, TF, GC, PI, and C3), and red cell enzymes (PGM1, ACP1, ESD, and GLO1) polymorphisms in Yakut populations from three regions of the Republic are presented. Close genetic affinities of Yakuts to Altaians, Mongols, and Buryats along with their notable difference from Evenks, Evens, and Chukchi were demonstrated.     

An ecogenetic approach to studying the adaptation and human health]

Genetic markers--blood groups ABO, RH, MN; serum proteins HP, PI, TF, C3; erythrocyte enzymes ACP1, ESD, AK1, PGM1, GLO1, PGD, PGP; and the other: PTC-tasting, ear wax types and color vision, were studied in two aboriginal Buryatian populations of Baikal Lake region: in Chitinskaya and Irkutskaya Provinces. Two samples were further divided into subgroups, according to their health status: "healthy", "indefinite" and "sick" by means of special regression procedure. The "healthy" subgroup of the Chitinskaya Province population is characterized by higher frequencies of PTC-tasters: 0.871 vs. 0.757 in the "sick" part (chi 2 = 5.36, p less than 0.05); higher frequency of the phenotype PI M1M1: 0.734 in "healthy" vs. 0.547 in "sick" (chi 2 = 8.89, p less than 0.01); also, lower frequency of the PI M1M2 phenotype: 0.148 and 0.299, respectively (chi 2 = 7.49, p less than 0.01); the frequencies of the phenotype TF C2C2 are: 0.015 and 0.076 (chi 2 = 5.48, p less than 0.05). In Irkutskaya Province population differences between "healthy" and "sick" subgroups were discovered for blood group AB: "healthy" 0.046 and "sick"--0.175 (chi 2 = 11.28, p less than 0.010); for GC (1F-2)--0.214 and 0.116 (chi 2 = 4.45, p less than 0.05). Some other differences between "healthy" and "sick" in both populations are not significant. Some trends concerning heterozygosity in loci--GC, PGM, TF were discovered. The results are considered from the viewpoint of higher fitness of some genetic traits in the populations studied.     

To the research of the gene pool of the Gagauz population of Moldavia

Population genetic data on Gagauzes from Moldavia are reported here for the first time. AB0 and Rhesus blood groups, serum protein group (HP, TF, GC) and the red cell enzyme polymorphism PGM1 were determined in 190 Gagauzes. In addition to this the ability to taste PTC was tested. The following allele frequencies were found: AB0*0 = 0.5241, AB0*A = 0.3279, AB0*B = 0.1480; RH*D = 0.6083, RH*d = 0.3917; HP*1 = 0.3544, HP*2 = 0.6456; TF*C1 = 0.7472, TF*C2 = 0.1770, TF*C3 = 0.0730, TF*B = 0.0028; GC*1F = 0.1025, GC*1S = 0.5932, GC*2 = 0.3043; PGM*1+ = 0.5932; PGM*1- = 0.1000, PGM*2+ = 0.2607, PGM*2- = 0.1107. The frequency of the PTC*T allele was found to be 0.5298. These frequencies and genetic distance analyses show that the gene pool of the Gagauzes is similar to that of neighbouring southeastern European populations.     

Opioid sensitivity of analgesia induced by microinjections of nonsteroidal anti-inflammatory drugs into the <Emphasis Type="Italic">nucleus raphe magnus</Emphasis>

Our recent investigations demonstrated that microinjections of three nonsteroidal anti-inflammatory drugs (NSAIDs), Analgin, ketorolac, or xefocam, into the central nucleus of the amygdala produce tolerance to these drugs and cross-tolerance to morphine. We observed the same phenomenon in the midbrain periaqueductal gray matter. In this report, we show that microinjections of NSAIDs into the nucleus raphe magnus (NRM) produces antinociception, as indicated by latency increases in both tail-flick (TF) and hot-plate (HP) reflexes compared to controls with saline microinjected into the same nucleus. Furthermore, microinjection of the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs characterized by the TF and HP latencies on the 1st experimental day. On the 2nd day, naloxone also provided some trend effects in both TF and HP tests. These results strongly support the suggestion that the endogenous opioid system is significantly involved in NSAID-induced antinociception and tolerance.     

Circadian Rhythm of Acute Phase Proteins under the Influence of Bright/Dim Light during the Daytime

We investigated the influence of two different light intensities, dim (100 lx) and bright (5,000 lx), during the daytime on the circadian rhythms of selected acute phase proteins of C‐reactive protein (CRP), α1‐acid glycoprotein (AGP), α1‐antichymotrypsin (ACT), transfferin (TF), α2‐macroglobulin (α2‐m), haptoglobin (HP), and ceruloplasmin (CP). Serum samples were collected from 7 healthy volunteers at 4 h intervals during two separate single 24 h spans during which they were exposed to the respective light intensity conditions. A circadian rhythm was detected only in ACT concentration in the bright light condition. The concentration of ACT, a positive acute phase protein (APP), increased (significantly significant differences in the ACT concentration were detected at 14:00 and 22:00 h) and AGP showed a tendency to be higher under the daytime bright compared to dim light conditions. There were no significant differences between the time point means under daytime dim and bright light conditions for α2‐M, AGP, Tf, Cp, or Hp. The findings suggest that some, but not all, APP may be influenced by the environmental light intensity.     

Circadian rhythm of acute phase proteins under the influence of bright/dim light during the daytime

We investigated the influence of two different light intensities, dim (100 lx) and bright (5000 lx), during the daytime on the circadian rhythms of selected acute phase proteins of C-reactive protein (CRP), alpha1-acid glycoprotein (AGP), alpha1-antichymotrypsin (ACT), transfferin (TF), alpha2-macroglobulin (alpha2-m), haptoglobin (HP), and ceruloplasmin (CP). Serum samples were collected from 7 healthy volunteers at 4 h intervals during two separate single 24 h spans during which they were exposed to the respective light intensity conditions. A circadian rhythm was detected only in ACT concentration in the bright light condition. The concentration of ACT, a positive acute phase protein (APP), increased (significantly significant differences in the ACT concentration were detected at 14:00 and 22:00 h) and AGP showed a tendency to be higher under the daytime bright compared to dim light conditions. There were no significant differences between the time point means under daytime dim and bright light conditions for alpha2-M, AGP, Tf, Cp, or Hp. The findings suggest that some, but not all, APP may be influenced by the environmental light intensity.     

Characteristics of the gene pool of the Gagauz population of Moldova]

Population genetic data on Gagauzes from Moldova are reported for the first time. Blood groups AB0 and Rh and biochemical markers of genes HP, TF, GC, and PGM1 were determined in 190 Gagauzes. The following allelic frequencies were determined: AB0*0, 0.5241; AB0*A, 0.3279; RH*d, 0.4571; HP*1, 0.3544; TF*C1, 0.7472; TF*C2, 0.1770; TFC3, 0.0730; TF*B, 0.0028; GC*1F, 0.1025; GC*1S, 0.5932; GC*2, 0.3043; PGM1*1+, 0.5286; PGM*1-, 0.1000; PGM1*2+, 0.2607; and PGM1*2-, 0.1107. The data obtained indicate that the gene pool of Gagauzes is similar to those of neighboring southeastern European populations.     

Antibiotic activity and synergistic effect of antimicrobial peptide against pathogens from a patient with gallstones

HP (2-20) is a peptide derived from the N-terminus of Helicobacter pylori ribosomal protein L1 that has been shown to have antimicrobial activity against various species of bacteria. When we tested the effects of HP (2-20), we found that this peptide displayed strong activity against pathogens from a patient with gallstones, but it did not have hemolytic activity against human erythrocytes. We also found that HP (2-20) had potent activity against cefazolin sodium-resistant bacterial cell lines, and that HP (2-20) and cefazolin sodium had synergistic effects against cell lines resistant to the latter. To investigate the mechanism of action of HP (2-20), we performed fluorescence activated flow cytometry using pathogens from the patient with gallstones. As determined by propidium iodide (PI) staining, pathogenic bacteria treated with HP (2-20) showed higher fluorescence intensity than untreated cells, similar to melittin-treated cells, and that HP (2-20) acted in an energy- and salt-dependent manner. Scanning electron microscopy showed that HP (2-20) caused significant morphological alterations in the cell surface of pathogens from the patient with gallstones. By determining their 16S rDNA sequences, we found that both the pathogens from the patient with gallstones and the cefazolin sodium-resistant cell lines showed 100% homology with sequences from Pseudomonas aeruginosa. Taken together, these results suggest that HP (2-20) has antibiotic activity and that it may be used as a lead drug for the treatment of acquired pathogens from patients with gallstones and antibiotic-resistant cell lines.     

Verotoxin-1 stimulation of macrophage-like THP-1 cells up-regulates tissue factor expression through activation of c-Yes tyrosine kinase: Possible signal transduction in tissue factor up-regulation

Verotoxin (VT)-producing Escherichia coli (E. coli) O157:H7 infections are frequently complicated by thrombotic angiopathy, hemolytic uremic syndrome (HUS) and neurological symptoms. The present data demonstrate that VT-1 (Shiga toxin) stimulation of macrophage-like THP-1 cells up-regulates the activity, antigen and mRNA levels of tissue factor (TF), a key cofactor of the coagulation-inflammation-thrombosis circuit. This up-regulation is accompanied by phosphorylation of phosphatidylinositol 3-kinase (PI3-kinase), IkappaB kinase beta (IKKbeta) and extracellular signal-regulated kinase 2 (ERK2). Changes in TF mRNA levels were in parallel with the activation of NF-kappaB/Rel and Egr-1 activation, but not with AP-1. Inhibition of PI3-kinase attenuated VT-1-induced phosphorylation of IKKbeta and ERK2, and the up-regulation of TF mRNA levels. VT-1 stimulation rapidly activated c-Yes tyrosine kinase, a member of the Src family. Treatment of the cells with c-Yes antisense oligos attenuated the VT-1-induced phosphorylation of PI3-kinase, IKKbeta and ERK2, activations of NF-kappaB/Rel and Egr-1, and up-regulation of TF mRNA levels. These results suggest that VT-1-induced macrophage stimulation activates c-Yes, which then up-regulates TF expression through activation of the IKKbeta/proteasome/NF-kappaB/Rel and MEK/ERK2/Egr-1 pathways via activation of PI3-kinase. Induction of macrophage TF expression by VT-1 may play an important role in the acceleration of the coagulation-inflammation-thrombosis circuit during infections by VT-producing E. coli.     

Analysis of heterozygosity levels at P1,TF, PGM1, ACP1, HP, GC, GLO, C3, and ESD loci in pulmonary tuberculosis patients with different treatment outcomes]

Heterozygosity at nine genetic loci (PI, TF, PGM1, ACP1, HP, GC, GLO1, C3, and ESD) was analyzed in pulmonary tuberculosis patients with good (group 1, N = 71) and poor (group 2, N = 35) response to treatment. The observed heterozygosities were compared with the expected values, which were calculated from allele frequencies in a control sample of healthy individuals (N = 328 with all but one locus and 78 with ESD) according to Hardy-Weinberg expectations. The analysis showed that the observed heterozygosities gl of patients significantly differed from the expected values hl in the case of four loci (GC, PI, C3, and ACP1). The observed heterozygosity was higher than expected in three cases (PI, C3, and ACP1) and lower then expected (GC) in one case. When data on each individual locus were compared using Fisher's exact test, both groups of patients proved to significantly differ (PF < 0.05) from the control group in the same four loci. No difference in observed heterozygosity was detected between the two groups of patients. The mean expected heterozygosity was h = 0.386 +/- 0.00674; the mean observed heterozygosity was g = 0.415 +/- 0.02 in group 1, g = 0.402 +/- 0.026 in group 2, and g = 0.371 +/- 0.00955 in the control group. The t test did not reveal a significant difference between the mean values of expected observed heterozygosities. Heterozygosity at individual loci, rather than mean heterozygosity, was proposed as an integral nonspecific indicator of the genetic control of a disease, because the former directly implicates individual marker loci in the development of a disorder, whereas effects of individual loci may eliminate each other when mean heterozygosity is computed. Based on the results obtained, a genetic control was assumed for the development of the tuberculosis process in the lungs.