Changes in peroxidation under conditions of 3,4-benzypyrene-induced carcinogenesis

The activities of enzymatic systems generating and destroying peroxides and the lipid peroxide content in neoplastic rat liver and 3,4-benzpyrene-induced sarcoma were studied. The tumour was characterized by high activity of glutathione peroxidase and low activity of catalase. No urate- and glycolate oxidases or ascorbat dependent peroxidation of lipids and lipid peroxides were found in the tumour. In the liver of neoplastic animals the activities of glutathione peroxidase and NADPH-dependent system of microsomal phospholipid peroxidation and the lipd peroxides content were increased, whereas the activities of catalase and urate oxidase were decreased.     

Hatching asynchrony and brood reduction influence immune response in Common Kestrel Falco tinnunculus nestlings

The onset of incubation before the end of laying imposes asynchrony at hatching and, therefore, a size hierarchy in the brood. It has been argued that hatching asynchrony might be a strategy to improve reproductive output in terms of quality or quantity of offspring. However, little is known about the mediating effect of hatching asynchrony on offspring quality when brood reduction occurs. Here, we investigate the relationship between phenotypic quality and hatching asynchrony in Common Kestrel Falco tinnunculus nestlings in Spain. Hatching asynchrony did not increase breeding success or nestling quality. Furthermore, hatching asynchrony and brood reduction had different effects on nestlings’ phytohaematogglutinin (PHA)‐mediated immune response and nestling growth. In asynchronous and reduced broods (in which at least one nestling died), nestlings showed a stronger PHA‐mediated immune response and tended to have a smaller body size compared with nestlings raised in synchronous and reduced broods. When brood reduction occurred in broods hatched synchronously, there was no effect on nestling size, but nestlings had a relatively poor PHA‐mediated immune response compared with nestlings raised in asynchronous and reduced broods. We suggest that resources for growth can be directed to immune function only in asynchronously hatched broods, resulting in improved nestling quality, as suggested by their immune response. We also found that males produced a greater PHA‐mediated immune response than females only in brood‐reduced nests without any effect on nestling size or condition, suggesting that females may trade off immune activities and body condition, size or weight. Overall, our results suggest that hatching pattern and brood reduction may mediate resource allocation to different fitness traits. They also highlight that the resolution of immune‐related trade‐offs when brood reduction occurs may differ between male and female nestlings.     

Risk Factors for Death in 632 Patients with Sickle Cell Disease in the United States and United Kingdom

Background

The role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial.

Methods and Results

We evaluated the relationship between an elevated estimated pulmonary artery systolic pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)≥3.0 m/s cuttof, which has a 67–75% positive predictive value for mean pulmonary artery pressure ≥25 mm Hg was used. Among 572 subjects, 11.2% had TRV≥3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values ≥160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV≥3.0 m/sec. At 24 months the cumulative survival was 83% with TRV≥3.0 m/sec and 98% with TRV<3.0 m/sec (p<0.0001). The hazard ratios for death were 11.1 (95% CI 4.1–30.1; p<0.0001) for TRV≥3.0 m/sec, 4.6 (1.8–11.3; p = 0.001) for NT-proBNP≥160 pg/mL, and 14.9 (5.5–39.9; p<0.0001) for both TRV≥3.0 m/sec and NT-proBNP≥160 pg/mL. Age >47 years, male gender, chronic transfusions, WHO class III–IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death.

Conclusions

A TRV≥3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable.

The study is registered in ClinicalTrials.gov with identifier

{"type":"clinical-trial","attrs":{"text":"NCT00492531","term_id":"NCT00492531"}}NCT00492531     

Stages in the improvement of drug therapy at a polyclinic]

Within 1968-1997 the authors studied the steps of introduction of the achievements of the medical science, technology and pharmacology to therapy of exacerbations and complications of peptic ulcer (PU). The scientific and practical value of endoscopic, histological, biochemical and bacteriological examinations in the improvement of the methods of pharmacotherapy of exacerbations and complications of PU was shown. Three phases of the PU development were indicated by the clinical signs and results of esophagogastroduodenoscopy, target biopsy and histological examinations. These data and available scientific achievements were assumed as a basis for the design of optimal drug combinations and their introduction to the medical practice. The use of such combinations made it possible to prevent relapses and life-threatening complications of the disease in the overwhelming majority of the patients. The best results of the pharmacotherapy were recorded in the years (1988-1997) when the drug combinations began to be used. The combinations provided eradication of Helicobacter pylori in the gastroduodenal mucosa and it was proved that in all the patients with PU and the relapsing lesions in the duodenum and in the overwhelming majority of the patients with gastric ulcer the disease developed at the background of chronic active gastroduodenitis associated with H.pylori. The success of the pharmacotherapy in the patients with PU was due to the use of the rational combinations of antibacterial and antisecretory agents.     

Identification and mapping on human chromosome 19 of chromosome-specific repeated element preferentially binding with nuclear matrix]

From a library of sequences binding preferentially to nuclear matrix (matrix attachment regions, MARs), a fragment of about 300 bp in length (CEA (carcinoembryonic antigen)-MAR) was isolated and characterized. The CEA-MAR sequence was found in more than ten loci of chromosome 19 containing elements similar to genes of the CEA family. No sequences of this group were found on other human chromosomes. Two CEA-MAR-containing loci were sequenced, and sequences for another seven loci were found in GenBank. A comparative analysis of CEA-MARs and the flanking sequences is reported. Based on the sequence of the CEA-containing chromosome 19 loci, a hypothetical model of the domain structure of a 2-Mb chromosome region was constructed and the mutual arrangement of CEA-MARs and genes of CEA family was elucidated. The CEA-MARs were located 5-20 kb downstream of the CEA genes. These results suggest that the duplication unit of the CEA family may coincide with chromatin domains containing these genes.     

RPE65, Visual Cycle Retinol Isomerase, Is Not Inherently 11-cis-specific: SUPPORT FOR A CARBOCATION MECHANISM OF RETINOL ISOMERIZATION*

The mechanism of retinol isomerization in the vertebrate retina visual cycle remains controversial. Does the isomerase enzyme RPE65 operate via nucleophilic addition at C₁₁ of the all-trans substrate, or via a carbocation mechanism? To determine this, we modeled the RPE65 substrate cleft to identify residues interacting with substrate and/or intermediate. We find that wild-type RPE65 in vitro produces 13-cis and 11-cis isomers equally robustly. All Tyr-239 mutations abolish activity. Trp-331 mutations reduce activity (W331Y to ∼75% of wild type, W331F to ∼50%, and W331L and W331Q to 0%) establishing a requirement for aromaticity, consistent with cation-π carbocation stabilization. Two cleft residues modulate isomerization specificity: Thr-147 is important, because replacement by Ser increases 11-cis relative to 13-cis by 40% compared with wild type. Phe-103 mutations are opposite in action: F103L and F103I dramatically reduce 11-cis synthesis relative to 13-cis synthesis compared with wild type. Thr-147 and Phe-103 thus may be pivotal in controlling RPE65 specificity. Also, mutations affecting RPE65 activity coordinately depress 11-cis and 13-cis isomer production but diverge as 11-cis decreases to zero, whereas 13-cis reaches a plateau consistent with thermal isomerization. Lastly, experiments using labeled retinol showed exchange at 13-cis-retinol C₁₅ oxygen, thus confirming enzymatic isomerization for both isomers. Thus, RPE65 is not inherently 11-cis-specific and can produce both 11- and 13-cis isomers, supporting a carbocation (or radical cation) mechanism for isomerization. Specific visual cycle selectivity for 11-cis isomers instead resides downstream, attributable to mass action by CRALBP, retinol dehydrogenase 5, and high affinity of opsin apoproteins for 11-cis-retinal.     

Prenatal DNA-diagnosis of Duchenne muscular dystrophy]

Two prenatal diagnoses were carried out by the technique of intragenic polymorphous marker detecting heterozygosity in pregnant women in the families with cases of Duchenne muscular dystrophy. In both cases the DNA fragment from pERT87-15 region was amplified. This fragment includes a polymorphous site in BamHI region of recognition. DNA analyses of the families members have been made and the genetical risk has been calculated by the Bayes method. The prognoses for both fetuses are good.