Hearing evaluation in patients suffering from hypercholesterolemia

The negative influence of hypercholesterolemia on the blood vessels condition and following degeneration lesions of the organs is well known. The aim of our study was to estimate the lipid balance disorders influence on the small blood vessels of the brain and inner ear in the patients with hypercholesterolemia and hypertriglyceridemia on the base of the audiometric, ABR and TEOAE evaluations. In our study we observed no statistical significant differences between the mean auditory thresholds in the study and control groups as well as statistical negative correlation between cholesterol serum level and amplitudes of TEOAE. In the ABR evaluation we stated the prolonged latency of the wave III and V as well as I-III and III-V interpeaklatencies in the patients with hyperlipidemia in comparison with the control group.     

Constraint, pathology, and adaptation: how can we tell them apart?

Adaptation is a central concept of modern evolutionary biology, but remains a difficult one nevertheless. Definitions of adaptation are often confounded with definitions of natural selection, rendering them somewhat circular and difficult to operationalize. Williams introduced a definition that avoids such tautology and a strategy for testing adaptive claims against chance as an alternative explanation for design complexity. Gould and Lewontin ([1979]: Proc R Soc Lond B Biol Sci 205:581-598) challenged this strategy for pitting adaptation against a straw alternative, and argued that constraint is often the cause of design complexity. The field of Darwinian medicine has underscored the fact that adaptation can also be difficult to discriminate from pathology, which can also produce design complexity. We suggest that an updated version of Williams' strategy is to consider any claim of adaptation against constraint and pathology as alternatives. We use an example drawn from the intersection of human reproductive ecology and developmental biology to illustrate how this updated strategy can be applied. Where we can generate distinct predictions for the three alternative hypotheses, constraint, pathology, and adaptation, we have a better situation in which to evaluate adaptive claims with a real possibility of falsification. We view this strategy as an improvement over Williams' original suggestion, but not as a definitive strategy. Further advances, however, will likely also be based on a sound understanding of the concept of adaptation and the identification of the strongest competing alternatives to it.     

Epidemiology of type 1 diabetes among Silesian children aged 0–14 years, 1989–2005

The aim of this study was to estimate the present Polish incidence rate of diabetes mellitus type 1 in children aged 0–14. The research was conducted between 1989 and 2005 among the children of Upper Silesia region (Poland), being the part of the EURODIAB program, according to all criteria of this project. During this period, 1,385 new cases (720 boys) of diabetes mellitus type 1 were recognized. The analysis of the standardized incidence rates performed after dividing into shorter periods (1989–1994, 1995–1999, 2000–2005) showed a sharp increase from 5.80/10⁵/year through 9.54/10⁵/year to 15.26/10⁵/year, respectively, in the periods. Analysis of age subgroups showed the greatest increase in the incidence rate among the younger children: 3.59 times for children aged 0–4, 3.40 times for children aged 5–9 and 2.08 times for children aged 10–14. No significant difference of incidence rate between boys and girls was established. Such high increase of incidence rate of diabetes mellitus type 1 (above 260%) noted since 1989 shows a secular trend of an epidemic of diabetes mellitus type 1 in Poland and a conversion from countries with the lower incidence rates in Europe to the countries with the highest incidence rates.     

Differential oxidation of two thiophene-containing regioisomers to reactive metabolites by cytochrome P450 2C9

The uricosuric diuretic agent tienilic acid (TA) is a thiophene-containing compound that is metabolized by P450 2C9 to 5-OH-TA. A reactive metabolite of TA also forms a covalent adduct to P450 2C9 that inactivates the enzyme and initiates immune-mediated hepatic injury in humans, purportedly through a thiophene-S-oxide intermediate. The 3-thenoyl regioisomer of TA, tienilic acid isomer (TAI), is chemically very similar and is reported to be oxidized by P450 2C9 to a thiophene-S-oxide, yet it is not a mechanism-based inactivator (MBI) of P450 2C9 and is reported to be an intrinsic hepatotoxin in rats. The goal of the work presented in this article was to identify the reactive metabolites of TA and TAI by the characterization of products derived from P450 2C9-mediated oxidation. In addition, in silico approaches were used to better understand both the mechanisms of oxidation of TA and TAI and/or the structural rearrangements of oxidized thiophene compounds. Incubation of TA with P450 2C9 and NADPH yielded the well-characterized 5-OH-TA metabolite as the major product. However, contrary to previous reports, it was found that TAI was oxidized to two different types of reactive intermediates that ultimately lead to two types of products, a pair of hydroxythiophene/thiolactone tautomers and an S-oxide dimer. Both TA and TAI incorporated 1?O from 1?O? into their respective hydroxythiophene/thiolactone metabolites indicating that these products are derived from an arene oxide pathway. Intrinsic reaction coordinate calculations of the rearrangement reactions of the model compound 2-acetylthiophene-S-oxide showed that a 1,5-oxygen migration mechanism is energetically unfavorable and does not yield the 5-OH product but instead yields a six-membered oxathiine ring. Therefore, arene oxide formation and subsequent NIH-shift rearrangement remains the favored mechanism for formation of 5-OH-TA. This also implicates the arene oxide as the initiating factor in TA induced liver injury via covalent modification of P450 2C9. Finally, in silico modeling of P450 2C9 active site ligand interactions with TA using the catalytically active iron-oxo species revealed significant differences in the orientations of TA and TAI in the active site, which correlated well with experimental results showing that TA was oxidized only to a ring carbon hydroxylated product, whereas TAI formed both ring carbon hydroxylated products and an S-oxide.     

Effects of maternal antenatal glucocorticoid treatment on apoptosis in the ovine fetal cerebral cortex

We examined the effects of single and multiple maternal glucocorticoid courses on apoptosis in the cerebral cortices of ovine fetuses (CC). Ewes received single dexamethasone or placebo courses at 104-106 or 133-135 days or multiple courses between 76-78 and 104-106 days gestation. In the single-course groups, ewes received four 6 mg dexamethasone or placebo injections every 12 hr for 48 hr. Multiple-course groups received the same treatment once per week for 5 weeks. Neuronal and nonneuronal apoptotic cell numbers per square millimeter were determined with TUNEL and NeuN staining and with caspase-3 enzyme activity on CC tissues harvested at 106-108 (70%) or 135-137 (90%) days of gestation. Apoptotic cell numbers and caspase-3 activity were 50% lower (P < 0.02) after single placebo courses at 90% than 70% gestation; 90% of apoptotic cells were (P < 0.01) nonneuronal at both ages. Nonneuronal apoptotic cells and caspase-3 activity were 40% and 20% lower (P < 0.02) after single dexamethasone than placebo courses at 70%, but not 90%, gestation. Caspase-3 activity was 20% lower (P < 0.01) after multiple dexamethasone than placebo courses, but apoptotic cell number did not differ. We conclude that nonneuronal apoptosis represents the major form of apoptosis in the CC at both 70% and 90% of gestation. Apoptosis in nonneuronal cells decreases with maturity and after a single course of dexamethasone at 70%, but not at 90%, gestation and not after multiple courses at 70% gestation. We speculate that a single course of glucocorticoids exerts maturational changes on the rate of apoptosis in the cerebral cortex of preterm ovine fetuses.     

Regulation of renal ouabain-resistant Na+-ATPase by leptin, nitric oxide, reactive oxygen species, and cyclic nucleotides: implications for obesity-associated hypertension

This study examined the effect of leptin on renal ouabain-resistant Na(+)-ATPase, which drives the reabsorption of about 10% of sodium transported in the proximal tubule. Chronic leptin administration (0.25 mg/kg s.c. twice daily for seven days) increased Na(+)-ATPase activity by 62.9%. This effect was prevented by the coadministration of superoxide dismutase mimetic, tempol, or the NADPH oxidase inhibitor, apocynin (2 mM in the drinking water). Acutely administered NO donors decreased Na(+)-ATPase activity. This effect was abolished by soluble guanylate cyclase inhibitor, ODQ, but not by protein kinase G inhibitors. Exogenous cGMP reduced Na(+)-ATPase activity, but its synthetic analogues, 8-bromo-cGMP and 8-pCPT-cGMP, were ineffective. The inhibitory effect of NO donors and cGMP was abolished by EHNA, an inhibitor of cGMP-stimulated phosphodiesterase (PDE2). Exogenous cAMP analogue and dibutyryl-cAMP increased Na(+)-ATPase activity and abolished the inhibitory effect of cGMP. Finally, the administration of superoxide-generating mixture (xanthine oxidase+hypoxanthine) increased Na(+)-ATPase activity. The results suggest that nitric oxide decreases renal Na(+)-ATPase activity by stimulating cGMP, which in turn activates PDE2 and decreases cAMP concentration. Increased production of reactive oxygen species may lead to the elevation of Na(+)-ATPase activity by scavenging NO and limiting its inhibitory effect. Chronic hyperleptinemia is associated with increased Na(+)-ATPase activity due to excessive oxidative stress.     

DQA1*03011 allele: protective or an adverse effect on the development of sarcoidosis; preliminary study

BACKGROUND: Sarcoidosis (SA) is a multisystem granulomatous disorder of unknown etiology. It seems likely that in genetically different predisposed hosts, the same antigen(s) may cause the development of sarcoid Th1 response. The interaction of the T-cell receptor with the human leukocyte antigen-DQA1*03011 peptide-complex can affect T lymphocytes activation in a dose-response manner. OBJECTIVES/METHODS: To test occurrence of DQA1*03011 allele in SA, we compared the distribution of DQA1 alleles in 32 SA patients, 37 TB patients and in 58 healthy volunteers, using a PCR-SSP "high-resolution" method. RESULTS: Our results revealed that after Bonferroni correction DQA1*03011 were less common in SA patients than in the controls (OR 0.16, 95%CI 0.03-0.75). In TB, DQA1*0303 were significantly more frequent and DQA1*0505 less present as compared to the controls (OR 11.03, 95% CI 1.20-95.80, OR 0.29, 95% CI 0.01-0.88). Comparing DQA1 alleles in both patient groups, DQA1*0501, DQA1*0505 alleles were more common and DQA1*03011, DQA1*0302, DQA1*0303 were less common after Bonferroni correction in SA than in TB. CONCLUSION: We revealed that DQA1*03011 allele was less common in SA than in the controls and TB. It seems possible that a low frequency of DQA1*03011 occurrence may be also involved in the etiopathogenesis of SA.