A processive versus a distributive mechanism of action correlates with differences in ability of normal and xeroderma pigmentosum group A endonucleases to incise damaged nucleosomal DNA

A DNA endonuclease, isolated from the nuclei of normal human and xeroderma pigmentosum complementation group A (XPA) cells, which recognizes predominately pyrimidine dimers, was examined for the mechanism by which it locates sites of damage on UVC-irradiated DNA. In reaction mixtures with low ionic strengths (i.e. lacking KCl), the normal and XPA endonuclease locate sites of UV damage on both naked and reconstituted nucleosomal DNA by different mechanisms. On both of these substrates, the normal endonuclease acts by a processive mechanism, meaning that it binds non-specifically to DNA and scans the DNA for sites of damage, whereas the XPA endonuclease acts by a distributive one, meaning that it randomly locates sites of damage on DNA. However, while both the normal and XPA endonucleases can incise UVC irradiated naked DNA, they differ in ability to incise damaged nucleosomal DNA. The normal endonuclease showed increased activity on UVC treated nucleosomal DNA compared with naked DNA, whereas the XPA endonuclease showed decreased activity on the damaged nucleosomal substrate. Since a processive mechanism of action is sensitive to the ionic strength of the micro-environment, the KCl concentration of the reaction was increased. At 70 mM KCI, the normal endonuclease switched to a distributive mechanism of action and its ability to incise damaged nucleosomal DNA also decreased. These studies show that there is a correlation between the ability of these endonucleases to act by a processive mechanism and their ability to incise damaged nucleosomal DNA; the normal endonuclease, which acts processively, can incise damaged nucleosomal DNA, whereas the XPA endonuclease, which acts distributively, is defective in ability to incise this substrate.      

Plasma antioxidant vitamins, chronic hepatitis B virus infection and urinary aflatoxin B1-DNA adducts in healthy males

Epidemiological evidence indicates that aflatoxin B1 (AFB1) intake is associated with an increased risk of hepatocellular carcinoma (HCC). The hepatocarcinogenesis is initiated by covalent binding of AFB1 to cellular DNA. To determine whether nutritional factors and hormonal status may influence the binding of AFB1 to hepatic DNA, a cross- sectional study was performed on a total of 42 male asymptomatic hepatitis B surface antigen (HBsAg) carriers and 43 male non-carriers in a cohort study on the multistage development of HCC in Taiwan. The major AFB1-DNA adduct in vivo, AFB1-N7-guanine, was measured by high- performance liquid chromatography in urine. Urinary AFB1-N7-guanine was detectable in 40% of the subjects. HBsAg carriers had a higher detection rate of urinary AFB1-DNA adducts than non-carriers and the difference was statistically significant after multivariate adjustment. After taking into account the total AFB1 urinary metabolite level, chronic HBsAg carrier status, and other potential confounders, plasma levels of cholesterol, alpha-tocopherol, and alpha- and beta-carotene were positively associated with the detection rate of the AFB1-DNA adducts in a dose-dependent manner, whereas plasma lycopene level was inversely related to the presence of the adducts in urine. The association of urinary AFB1-DNA adducts with the plasma levels of cholesterol, alpha-tocopherol, lycopene, and alpha- and beta-carotene was observed at both low and high exposure levels of AFB1. There was a synergistic interaction of plasma alpha-tocopherol with alpha- and beta- carotene on the adduct levels. No association with the adducts was found for plasma levels of retinol and testosterone. This study demonstrated different associations of antioxidant vitamins with AFB1- DNA adduct formation. The data consistent with our previous finding in cultured woodchuck hepatocytes that alpha-tocopherol and beta-carotene enhanced AFB1-DNA adduct formation suggest that prospective investigation of the relationship between plasma micronutrients and risk of AFB1-related HCC is warranted.      

Palpable lymph nodes of the neck in Swedish schoolchildren

We studied 3592 Swedish schoolchildren, 8 or 9 years old, examined for palpable submandibular, cervical and supraclavicular lymph nodes. All children were skin tested with 2 TU PPD RT23 and with 0.1 μ g of Mycobacterium avium sensitin or 0.1 μ g of M. scrofulaceum sensitin. A total of 991 children had palpable lymph nodes in any of the three locations. Among them, 811 had lymph nodes in one location, 162 in two locations and 18 in three. In 312 children, the lymph nodes were ± 5 mm in size in any location. The most common location was submandibular. Boys had a significantly higher prevalence of palpable lymph nodes than girls. There was also seasonal variation. Children infected by atypical mycobacteria (sensitin reaction ±6 mm) did not have a higher prevalence of palpable lymph nodes than those not infected.     

The deep inspiration breath-hold technique in the treatment of inoperable non-small-cell lung cancer

PURPOSE: Conventional radiotherapeutic techniques are associated with lung toxicity that limits the treatment dose. Motion of the tumor during treatment requires the use of large safety margins that affect the feasibility of treatment. To address the control of tumor motion and decrease the volume of normal lung irradiated, we investigated the use of three-dimensional conformal radiation therapy (3D-CRT) in conjunction with the deep inspiration breath-hold (DIBH) technique. METHODS AND MATERIALS: In the DIBH technique, the patient is initially maintained at quiet tidal breathing, followed by a deep inspiration, a deep expiration, a second deep inspiration, and breath-hold. At this point the patient is at approximately 100% vital capacity, and simulation, verification, and treatment take place during this phase of breath-holding. RESULTS: Seven patients have received a total of 164 treatment sessions and have tolerated the technique well. The estimated normal tissue complication probabilities decreased in all patients at their prescribed dose when compared to free breathing. The dose to which patients could be treated with DIBH increased on average from 69.4 Gy to 87.9 Gy, without increasing the risk of toxicity. CONCLUSIONS: The DIBH technique provides an advantage to conventional free-breathing treatment by decreasing lung density, reducing normal safety margins, and enabling more accurate treatment. These improvements contribute to the effective exclusion of normal lung tissue from the high-dose region and permit the use of higher treatment doses without increased risks of toxicity.     

Lack of effect of a low-molecular-weight heparin (nadroparin) on mortality in bedridden medical in-patients: a prospective randomised double-blind study

Background Hospitalised medical patients are at significant risk of venous thromboembolic disease through fatal pulmonary embolism; low-molecular-weight heparins have been proved efficient in preventing deep venous thrombosis in surgical and medical patients, but their effect on mortality in bedridden medical patients remains unknown.Methods In a multi-centre, randomised, double-blind, placebo-controlled study, 2,474 consecutive patients aged over 40 years admitted to internal medicine departments in the last 24 h and unable to move alone were randomised to receive 0.3 ml nadroparin (7,500 anti-Xa units) or placebo for up to 21 days. The primary end-point was overall mortality at day 21.Results There were no significant differences between the patients characteristics. Overall mortality between the two groups was not statistically different [10.08% (124 of 1,230) versus 10.29% (128 of 1,244), respectively, in the nadroparin and in the placebo groups; relative risk reduction 0.02, CI (–0.27, +0.25), P=0.89]. An autopsy was performed in 123 of the 252 patients who died (49%). Pulmonary embolism was discovered at autopsy in 10 of 63 patients in the nadroparin group and in 17 of 60 in the placebo group [relative risk reduction 0.38, CI (–0.27, +0.70), P=0.13].Conclusion Nadroparin does not have a significant effect on mortality in bedridden medical patients, based on the study results. The study provides no data suggesting that low-molecular-weight heparins might reduce the incidence of thromboembolic in-patients hospitalised for an acute medical disease.The full list of investigators involved in the CY 216 study are given in Appendix A.     

Are orgasms in the mind or the body? Psychosocial versus physiological correlates of orgasmic pleasure and satisfaction

We investigated the hypothesis that the subjective experience of orgasmic pleasure and satisfaction depends more on psychological and psychosocial than on physical factors. Male and female participants rated adjectives to describe orgasm attained during either solitary masturbation (n = 356) or sex with a partner (n = 442). Orgasmic pleasure and satisfaction were related more to (a) the cognitive-affective than sensory aspects of the orgasm experience; (b) the overall physical and psychological intensity of orgasm but not to anatomical location of orgasm sensations; and (d) relationship satisfaction. These findings emphasize the importance of psychosocial determinants of the orgasm experience.     

Platelet transfusion containing ABO-incompatible plasma and hepatic veno-occlusive disease after hematopoietic transplantation in young children

BACKGROUND: Hepatic veno-occlusive disease is a major limiting factor of high-dose chemotherapy in children. The cells lining the hepatic vascular endothelium express blood group A and/or B antigens according to the patient's blood group. We designed a study evaluating the impact of platelet concentrates containing ABO-incompatible plasma transfused to young children with a high risk of hepatic veno-occlusive disease. METHODS: In all, 186 consecutive children (median age: 4 years, range: 0.75-17 years), treated with high-dose chemotherapy containing busulfan followed by hematopoietic stem cell transplantation for neuroblastoma (n=112) or brain tumor (n=74) between 1988 and 1998, were investigated. The main endpoint was the occurrence of hepatic veno-occlusive disease. Multivariate analysis was performed using a Cox's regression model with transfusion of platelet concentrates containing ABO-incompatible plasma as a time-dependent covariate. RESULTS: We found that 73 out of 186 (39%) children developed hepatic veno-occlusive disease after transplantation. Multivariate analysis demonstrated that two factors significantly increased the risk of hepatic veno-occlusive disease occurrence: transfusion of platelet concentrates containing ABO-incompatible plasma (P=0.003) and use of melphalan in the conditioning regimen (P=0.006). Conversely, the number of platelet concentrates transfusions per week, child's age, weight, sex, and use of cyclophosphamide in the conditioning regimen had no effect. CONCLUSIONS: Transfusion of platelet concentrates containing ABO-incompatible plasma increases the risk of hepatic veno-occlusive disease in young children treated with a busulfan-containing regimen. Binding of A and/or B antigens expressed on the surface of hepatic endothelial cells may promote this complication. Transfusion of platelet concentrates containing ABO-incompatible plasma should be avoided in these children.     

Age, an independent risk factor for thrombosis. Epidemiologic data

The incidence of thrombosis--arterial and venous--increases with age. This is the case for atheromatous diseases, atrial fibrillation and even venous thromboembolic disease. Ischemic heart disease is the most common cause of death in the elderly. Atrial fibrillation, an independent risk factor for cerebral vascular accidents, affects around 10% of persons older than 80 years. The incidence of venous thromboembolic disease increases with age, reaching 12.5 per 1000 people older than 75 years, compared with 5 per 1000 aged 60-75 and 2.5 per 1000 aged 40-59. Elderly persons often have two or more cardiovascular or venous thromboembolic risk factors and thus a still higher risk of thrombotic events. Their risk of thrombosis justifies the systematic search for acquired risk factors to assess the level of risk and take appropriate prevention measures.     

Random effects survival models gave a better understanding of heterogeneity in individual patient data meta-analyses

BACKGROUND AND OBJECTIVE: Individual patient data meta-analysis consists in combining data from all available trials dealing with a therapeutic problem in order to increase the power of statistical analyses. A key issue when analyzing these pooled data sets is intertrial heterogeneity. In survival data, heterogeneity manifests itself either by differing treatment effects between the included trials or by a baseline hazard that differs between studies. One way to investigate and accommodate this heterogeneity is to use models that include random effects. METHODS: We apply this class of models to the Meta-Analysis of Chemotherapy in Head and Neck Cancers, in which strong heterogeneity is exhibited. This meta-analysis pooled 63 trials involving 10,741 patients. RESULTS: We show that such modeling permits a better understanding of heterogeneity in the MACH-NC data, both from a frequentist and from a Bayesian point of view. In particular, the modeling suggests the presence of two outlying sets of trials whose baseline risk could explain the apparent efficacy or inefficacy of some treatment protocols. CONCLUSION: We conclude that this family of random-effects models is a useful tool for exploring heterogeneity in meta-analyses of time-to-event data, and that its features can be applied to a very wide range of studies.