Decreased repair activities of 1,N(6)-ethenoadenine and 3,N(4)-ethenocytosine in lung adenocarcinoma patients

To assess the role of oxidative stress and lipid peroxidation (LPO) in the pathogenesis of lung cancer, we measured the levels of 1,N(6)-ethenoadenine (epsilonA) and 3,N(4)-ethenocytosine (epsilonC) in the DNA by immunoaffinity/(32)P postlabeling (33 cases). We also measured the capacity for epsilonA and epsilonC repair (by the nicking assay) in normal and tumor lung tissues, as well as in blood leukocytes of lung cancer patients (56 cases). Repair activities for epsilonA and epsilonC were also assayed in leukocytes of healthy volunteers, matched with cancer patients for age, sex, and smoking habit (25 individuals). Up to 10-fold variations among individuals were observed both in adducts level and repair activities. No differences in epsilonA and epsilonC levels between tumor and nonaffected lung tissues were recorded. However, leukocytes accumulated a significantly higher number of DNA adducts than the lung tissues. Repair activities for both epsilonA and epsilonC were significantly higher in tumor than in normal lung tissue. No significant differences in epsilonA and epsilonC repair activities were associated with age, sex, or smoking habit. However, a significant difference in repair capacity was observed between two histological types of lung cancer, squamous cell carcinoma (SQ) and adenocarcinoma (AD). In individuals suffering from lung AD, epsilonA- and epsilonC-repair activities in normal lung and blood leukocytes were significantly lower than in SQ patients. Moreover, in nonaffected lung tissue of AD patients, the ratio epsilonA/epsilonC adducts was lower than in SQ patients. Differences have also been found between epsilonA and epsilonC repair activities of cancer patients and healthy volunteers. Repair capacity for epsilonA was significantly lower in blood leukocytes of lung cancer patients than in leukocytes of healthy volunteers (P = 0.012). This difference was even larger between healthy volunteers and patients developing inflammation-related AD (P = 0.00033). Repair activities for epsilonC were the same in leukocytes of healthy controls, all lung cancer patients, and SQ patients. However, individuals with ADs revealed significantly lower epsilonC-repair activity (P = 0.013). These results suggest that oxidative stress-mediated lipid peroxidation might contribute to induction and/or progression of lung cancer. Decreased activity of base excision repair pathway for epsilonA and epsilonC is associated particularly with inflammation-related lung AD.     

Modification of the structure of 4, 6-disubstituted 2-(4-alkyl-1-piperazinyl)pyridines: synthesis and their 5-HT2A receptor activity

Structure-activity relationship studies of a series of novel 4, 6-disubstituted 2-(1-piperazinyl)pyridines were conducted to revise our model of serotonin 5-HT(2A) receptor antagonist. Target compounds were synthesized using the benzotriazole-assisted Katritzky method. The majority of those compounds were found to be selective 5-HT(2A)/5-HT(1A) receptor ligands, though less potent than their previously described pyrimidine counterparts. In particular, the three compounds 6-8 showed the highest 5-HT(2A) receptor affinity (K(i) = 34-78 nM) and were classified as 5-HT(2A) antagonists in in vivo experiments. The influence of the structural modifications on the in vitro results was discussed; however, the elucidation of the role of the central core system requires further studies.     

Cancers of the kidney and urinary tract in patients on dialysis for end-stage renal disease: analysis of data from the United States,Europe, and Australia and New Zealand

Patients on maintenance dialysis have increased risk for cancer, especially in the kidney and urinary tract. In a retrospective cohort of 831,804 patients starting dialysis during 1980 to 1994 in the United States, Europe, or Australia and New Zealand, standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated for kidney and bladder cancers. Risks for cancers of the kidney (SIR 3.6; CI 3.5 to 3.8) and bladder (SIR 1.5; CI 1.4 to 1.6) were increased, relatively more in younger than older patients and more in female patients (kidney: SIR 4.6, CI 4.3 to 4.9; bladder: SIR 2.7, CI 2.4 to 2.9) than male patients (kidney: SIR 3.2, CI 3.0 to 3.4; bladder: SIR 1.3, CI 1.2 to 1.3). SIR for kidney cancer were raised in all categories of primary renal disease, and for bladder cancer in all but diabetes and familial, hereditary diseases. Notably high SIR occurred in toxic nephropathies (chiefly analgesic nephropathy) and miscellaneous conditions (a category that includes Balkan nephropathy), the excess of kidney cancer in these conditions being urothelial in origin. SIR for kidney cancer rose significantly, and those for bladder cancer fell (not reaching significance) with time on dialysis. There was no association with type of dialysis. The pattern of increased risk for renal parenchymal cancer in dialysis patients is consistent with causation through acquired renal cystic disease and of urothelial cancers of the kidney and bladder with the carcinogenic effects of certain primary renal diseases.     

Ontogenetic quinpirole treatments fail to prime for D<Subscript>2</Subscript> agonist-enhancement of locomotor activity in 6-hydroxydopamine-lesioned rats

Repeated treatments with a dopamine (DA) D₂ receptor agonist result in the induction of DA D₂ receptor supersensitivity, as evidenced by enhanced behavioral responses to subsequent D₂ agonist treatments—a phenomenon known aspriming of receptors. Priming of D₂ receptors has been well-studied in otherwise intact (non-lesioned) rats. In contrast to D₂ priming, repeated treatments with a DA D₁ agonist are unable to prime D₁ receptors unless nigrostriatal DA fibers are largely destroyed in early postnatal ontogeny. In order to determine if D₂ receptors could be primed in rats in which nigrostriatal DA fibers were largely destroyed in early postnatal ontogeny, rats were (a) lesioned at 3 days after birth with 6-hydroxydopamine (67 μg in each lateral ventricle; desipramine, 20 mg/kg IP, 1 h; 6-OHDA), (b) treated daily for the first 28 days after birth with the D₂ agonist quinpirole HCl (3.0 mg/kg IP), and (c) observed in adulthood for both quinpirole-induced and SKF 38393- (D₁ agonist-) induced locomotor activity and stereotyped activities. In 6-OHDA-lesioned rats in which endogenous striatal DA was reduced by 99%, quinpirole did not produce enhanced locomotor or stereotyped activities. However, SKF 38393 produced increased locomotor and stereotyped activities even after the first dose of SKF 38393. These findings demonstrate that D₂ receptors are not primed by ontogenetic quinpirole treatments of neonatally 6-OHDA-lesioned rats, although D₂ agonist treatments do at least partially prime D₁ receptors in 6-OHDA-lesioned rats.     

Dopamine receptor supersensitivity: an outcome and index of neurotoxicity

The characteristic feature of neurotoxicity is a definable lesion which can account for observed deficits, corresponding to loss of nuclei or axonal fibers normally comprising a specific pathway or tract. However, with ontogenetic lesions, the operative definition fails. In rats lesioned as neonates with 6-hydroxydopamine (6-OHDA), near-total destruction of dopamine- (DA-) containing nerves is produced, and this itself is definable. However, the most prominent feature of rats so-lesioned is the DA receptor supersensitivity (DARSS) that develops and then persists throughout the lifespan. DA D(1) receptors show overt supersensitivity to agonists producing vacuous chewing movements (VCMs), while D(1) receptors associated with locomotor activity have a latent supersensitivity that must be unmasked by repeated D(1) or D(2) agonist treatments - a 'priming' phenomenon. This D(1) DARSS is not usually associated in either a change in D(1) receptor number (B(max)) or affinity (K(d)). In contrast to D(1) DARSS, D(2) receptors are not so predictably supersensitized by a lesion of DA neurons. In reality, the permanently exaggerated response to an agonist by supersensitized receptors is per se a manifestation of neurotoxicity. Despite dramatic behavioral responses mediated by supersensitized receptors, DARSS has not been easy to correlate with enhanced production of second messengers or early response genes. Altered signaling (i.e., neuronal cross-talk) in defined pathways may represent the mechanism that produces so-called receptor supersensitization. Long-lived agonist-induced behavioral abnormality, with or without anatomic evidence of a neuronal lesion, is one of the products of DA D(1) receptor supersensitization -- itself an index of neurotoxicity.     

Increased burden of respiratory disease in the first six months of life due to prenatal environmental tobacco smoke: Krakow birth cohort study

The main purpose of our study was to assess the effects of prenatal tobacco smoke on respiratory symptoms and on doctor consultations in a birth cohort of 445 infants who had no smoking mothers and who had no postnatal exposure to environmental tobacco smoke (ETS). Before and after delivery, questionnaires and interviews with mothers were administered to solicit information on prenatal and postnatal ETS exposure. Newborns were followed-up over six months of life, and respiratory outcomes such as runny or stuffed nose, cough with or without cold, difficult (puffed) breathing, wheezing or whistling in the chest irrespective of respiratory infection were considered. In addition, medical visits related to the occurrence of respiratory symptoms were recorded for each child over a six-month study period. In the multivariate Poisson regression analysis, a set of potential confounders has been taken into account such as gender of child, season of birth, gestational age, maternal education, maternal atopy, presence of moulds in households and prenatal level of personal exposure to fine particles. The adjusted rate ratio (RR) estimated for the occurrence of episodes of running nose was significantly higher in infants exposed to prenatal ETS (1.40; 95% confidence interval [CI]: 1.11-1.68) and the corresponding RR estimates for cough, difficult breathing and wheezing were 1.49 (95% CI: 1.15-1.93), 1.96 (95% CI: 1.22-3.16) and 5.12 (95% CI: 2.86-9.16). The rate ratios of doctor consultations attributable to prenatal ETS because of cough was 1.94 (95% CI: 1.49-2.54). The risk estimate for consultations due to difficult breathing was 2.77 (95% CI: 1.76-4.36), and that for wheezing was 5.86 (95% CI: 3.56-9.64). The data strongly support the view about the impact of the in-utero effect of passive smoking on children's respiratory health. Higher utilization rates of doctor consultations in infants attributable to prenatal ETS exposure demand the revision of public health policy, which should be focused also on cessation of smoking practices by all household members during and after the pregnancy period.     

Enhanced Recovery after Surgery (ERAS) Protocol Is a Safe and Effective Approach in Patients with Gastrointestinal Fistulas Undergoing Reconstruction: Results from a Prospective Study

Background and Aims: An enterocutaneous fistula (ECF) poses a major surgical problem. The definitive surgical repair of persistent fistulas remains a surgical challenge with a high rate of re-fistulation and mortality, and the reasons for that is not the surgical technique alone. Enhanced Recovery after Surgery (ERAS^®) is an evidence-based multimodal perioperative protocol proven to reduce postoperative complications. The aim of the study was to assess the clinical value of the ERAS protocol in surgical patients with ECF. Methods: ERAS protocol was used in all patients scheduled for surgery for ECF at the Stanley Dudrick’s Memorial Hospital in Skawina between 2011 and 2020. A multidisciplinary team (MDT) was in charge of the program and performed annual audits. A consecutive series of 100 ECF patients (44 females, 56 males, mean age 54.1 years) were evaluated. Postoperative complications rate, readmission rate, length of hospital stay, prevalence of postoperative nausea and vomiting were assessed. Registered under ClinicalTrials.gov Identifier no. {"type":"clinical-trial","attrs":{"text":"NCT04771832","term_id":"NCT04771832"}}NCT04771832. Results: ERAS protocol was successfully introduced for ECF surgeries; however, eight modifications to the ERAS program was performed in 2015. They led to improvement of surgical outcomes: reduction of postoperative nausea and vomiting (15 vs. 17% patients, p = 0.025), overall complication rate (11 vs. 10, p = 0.021), median length of hospital stay (overall and after surgery, p = 0.022 and 0.002, respectively). Conclusions: ERAS protocol can be successfully used for ECF patients. Prescheduled audits can contribute to the improvement of care.