Molecular epidemiologic studies of polycyclic aromatic hydrocarbon-DNA adducts and breast cancer

We review our studies on the role of polycyclic aromatic hydrocarbon (PAH)-DNA adducts in breast cancer. Additionally we report on analyses of the reliability of the scoring procedures used with immunohistochemical assay for PAH-DNA adducts and of potential bias arising from the use of benign breast disease (BBD) controls. We conducted a case-control study utilizing two control groups: BBD controls who donated tissue and blood samples, and healthy controls who donated blood samples. In comparisons of tumor tissue from cases and benign tissue from BBD controls, increasing adduct levels were significantly associated with case-control status [odds ratio (OR) = 2.40, 95% confidence interval (CI) 1.18-4.92], whereas in comparisons of nontumor tissue from cases and benign tissue from BBD controls the association was nonsignificant (OR = 1.97, 95% CI 0.94-4.17). We also show among cases, but not among BBD controls, that the GSTM1 null genotype is associated with increased adduct levels in breast tissue. Our reliability study found the scoring procedures used with the immunohistochemical assay to have high reliability, 0.93 in nontumor, 0.82 in tumor, and 0.74 in benign tissues. However, we found that the technician significantly contributed to the total variability of a series of data. Finally, we did not find a consistent bias to the null associated with the use of BBD controls; however, BBD controls may overestimate the prevalence of family history of breast cancer compared to that of healthy controls (18% vs.14%). We hypothesize that the higher prevalence results from a referral bias and discuss how this may influence our results.     

Accumulation of a precursor of subunit S1 of pertussis toxin in cell envelopes of Bordetella pertussis in response to the membrane perturbant phenethyl alcohol

Exponential cultures of Bordetella pertussis strain 18334 were treated with the membrane-perturbing agent phenethyl alcohol which, at a concentration of 0.075% v/v, blocked the synthesis of mature subunit S1 of pertussis toxin as revealed by Western blotting. It also caused the accumulation of a precursor, pS1, with an estimated mol. wt of 32 X 10(3), that was located in the cytoplasmic membrane. These findings suggested that subunit S1 of pertussis toxin was exported in a signal peptide-dependent manner.     

Rhodopseudomonas sphaeroides lipid A derivatives block in vitro induction of tumor necrosis factor and endotoxin tolerance by smooth lipopolysaccharide and monophosphoryl lipid A.

Rhodopseudomonas (Rhodobacter) sphaeroides diphosphoryl lipid A is a relatively inert species of lipid A but has been shown to antagonize the effects of toxic lipopolysaccharide (LPS) both in vivo and in vitro. The antagonist and its monophosphoryl derivative were examined for the ability to block tumor necrosis factor synthesis and reverse tolerance induction in vitro in macrophage cultures stimulated with bioactive preparations of smooth LPS, rough LPS, diphosphoryl lipid A, and monophosphoryl lipid A. Inhibition of agonist activity and reversal of tolerance by these novel penta-acylated lipid A antagonists provides new insight into macrophage-LPS interactions.     

Outer membrane proteins from rough strains of four Brucella species.

Outer membrane proteins from 15 rough strains of Brucella abortus, B. ovis, B. canis, and B. melitensis were extracted with a dipolar detergent, and outer membrane proteins from selected strains were purified by anion exchange chromatography and gel filtration (Verstreate et al., Infect. Immun. 35:979-989, 1982). Outer membrane proteins produced two types of profiles on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. One type, demonstrated by B. abortus, B. ovis, and B. canis strains, contained the three predominant protein groups present in smooth B. abortus strains (Verstreate et al., Infect. Immun. 35:979-989, 1982): groups 1, 2 (porin [Douglas et al., Infect. Immun. 44:16-21]), and 3. B. melitensis strains demonstrated the second profile type, in which there was an additional band between groups 1 and 2. The relative proportion of porin was considerably lower in B. ovis, B. canis, and B. melitensis than in B. abortus. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiles could be used to distinguish B. abortus and B. melitensis from each other and from B. canis and B. ovis. The amino acid compositions of groups 2 and 3 from rough strains of B. abortus, B. canis, and B. melitensis were similar to those of corresponding proteins from smooth B. abortus strains. Zwittergent-soluble fractions from most rough strains contained antigen [b], which cross-reacted with group 2 from smooth B. abortus strains, and antigens [c] and [d], which cross-reacted with group 3 from smooth B. abortus strains. Antigen [a], shared by groups 2 and 3 (D. R. Verstreate and A. J. Winter, Infect. Immun. 46:182-187, 1984), was detected in most rough strains. None of these antigens were related to either rough or smooth lipopolysaccharide.     

Full-left-full-right split liver transplantation for adult recipients: a systematic review and meta-analysis

Full-left-full-right split liver transplantation (FSLT) for adult recipients, may increase the availability of liver grafts, reduce waitlist time, and benefit recipients with below-average body weight. However, FSLT may lead to impaired graft and patient survival. This study aims to assess outcomes after FSLT. Five databases were searched to identify studies concerning FSLT. Incidences of complications, graft- and patient survival were assessed. Discrete data were pooled with random-effect models. Graft and patient survival after FSLT were compared with whole liver transplantation (WLT) according to the inverse variance method. Vascular complications were reported in 25/273 patients after FSLT (Pooled proportion: 6.9%, 95%CI: 3.1–10.7%, I²: 36%). Biliary complications were reported in 84/308 patients after FSLT (Pooled proportion: 25.6%, 95%CI: 19–32%, I²: 44%). Pooled proportions of graft and patient survival after 3 years follow-up were 72.8% (95%CI: 67.2–78.5, n = 231) and 77.3% (95%CI: 66.7–85.8, n = 331), respectively. Compared with WLT, FSLT was associated with increased graft loss (pooled HR: 2.12, 95%CI: 1.24–3.61, P = 0.006, n = 189) and patient mortality (pooled HR: 1.81, 95%CI: 1.17–2.81, P = 0.008, n = 289). FSLT was associated with high incidences of vascular and biliary complications. Nevertheless, long-term patient and graft survival appear acceptable and justify transplant benefit in selected patients.     

Health-related quality of life,uncertainty and coping strategies in solid organ transplant recipients during shielding for the COVID-19 pandemic

Strict isolation of vulnerable individuals has been a strategy implemented by authorities to protect people from COVID-19. Our objective was to investigate health-related quality of life (HRQoL), uncertainty and coping behaviours in solid organ transplant (SOT) recipients during the COVID-19 pandemic. A cross-sectional survey of adult SOT recipients undergoing follow-up at our institution was performed. Perceived health status, uncertainty and coping strategies were assessed using the EQ-5D-5L, Short-form Mishel Uncertainty in Illness Scale (SF-MUIS) and Brief Cope, respectively. Interactions with COVID-19 risk perception, access to health care, demographic and clinical variables were assessed. The survey was completed by 826 of 3839 (21.5%) invited participants. Overall, low levels of uncertainty in illness were reported, and acceptance was the major coping strategy (92%). Coping by acceptance, feeling protected, self-perceived susceptibility to COVID-19 were associated with lower levels of uncertainty. Health status index scores were significantly lower for those with mental health illness, compromised access to health care, a perceived high risk of severe COVID-19 infection and higher levels of uncertainty. A history of mental health illness, risk perceptions, restricted healthcare access, uncertainty and coping strategies was associated with poorer HRQoL in SOT recipients during strict isolation. These findings may allow identification of strategies to improve HRQoL in SOT recipients during the pandemic.     

The mitogenic effects of isologous nuclear material

The nuclear material from human lymphocytes stimulated with phytohaemagglutinin (PHA) will produce a marked increase of DNA synthesis in unstimulated isologous lymphocytes which is far in excess of the normal response to PHA by the same lymphocytes. It is postulated that release of nuclear complexes from a few lymphocytes transformed in response to a specific stimulus is responsible for the transformation produced in surrounding lymphocytes which are non-responsive to the initial antigenic challenge.     

From the Bench to the Trench: A Comparison of Sertraline Treatment of Major Depression in Clinical and Research Patient Samples

BACKGROUND: New medications that enter the marketplace have been tested almost exclusively in controlled clinical trials conducted in specialty research settings. There is some concern that these carefully selected patient samples may not provide information generalizable to the "real world" clinical population. The purpose of this investigation was to compare results from a large, open-label study of sertraline in the treatment of major depression in the clinical practice setting with pooled results from 2 multicenter, double-blind, placebo-controlled studies conducted in specialty research settings. METHOD: Clinical practice patients (N = 1482), aged 21 to 65 years, from 228 psychiatric clinical practice sites across the United States participated in the open-label treatment study (Clinical Practice sample). Patients who met DSM-III-R criteria for moderate-to-severe unipolar major depression (i.e., had pretreatment Hamilton Rating Scale for Depression [HAM-D] scores >/= 18) were treated for 8 weeks with sertraline in a flexible dosing fashion (50-200 mg daily). Outcomes on the HAM-D and Clinical Global Impressions-Improvement scale (CGI-I) were compared with the pooled results from 2 previously published placebo-controlled, multicenter treatment studies of sertraline in outpatients with major depression (N = 280). The overall response to sertraline in the Clinical Practice sample was compared with the outcome from the research study patient sample (Clinical Research sample). Additionally, comparison of outcomes of patients with common depressive subtypes (double depression, anxious depression, and melancholic ["endogenous"] depression) were examined. RESULTS: The percentage of sertraline-treated patients rated as responders on the CGI-I was significantly higher in the Clinical Practice sample compared with the Clinical Research sample (87% vs. 73%; p <.001). Sertraline was also much better tolerated in the Clinical Practice sample than in the Clinical Research sample as evidenced by significantly lower overall reports of adverse events (9.4% vs. 13.2%; p <.05) and lower patient dropout rates (17.5% vs. 34.3%; p <.01). Among clinical practice patients, sertraline was found to be equally effective in treating endogenous/melancholic and anxious subtypes and only mildly less effective in achieving a response in patients with double depression (chronic low-grade depression with a superimposed major depression). A regression analysis identified older age and double depression as being predictors of a slower time to response. More than 70% of patients who reported nonresponse to previous treatment with fluoxetine or a tricyclic antidepressant responded to sertraline. CONCLUSION: The effectiveness and tolerability of sertraline treatment was found to be significantly better in the Clinical Practice sample, suggesting that the results from controlled studies in research settings may represent an underestimate of the benefits of a drug. More effectiveness research is needed to confirm and extend these findings.     

Synthesis of deuterium‐labeled 3‐O‐methyldopa and 4‐O‐methyldopa

Concise methods for the synthesis of 4‐hydroxy‐3‐[²H₃]‐methoxyphenylalanine (3‐O‐[²H₃]‐methydopa) and 3‐hydroxy‐4‐[²H₃]‐methoxyphenylalanine (4‐O‐[²H₃]‐methydopa) are described. The 3‐O‐[²H₃]‐methydopa is a valuable internal standard for the tandem MS quantification of 3‐O‐methyldopa, a metabolite of value in the diagnosis of aromatic l‐amino acid decarboxylase (AADC) deficiency. Copyright © 2003 John Wiley & Sons, Ltd.     

Reduction of atherosclerosis in cholesterol-fed rabbits and decrease of expressions of intracellular adhesion molecule-1 and vascular endothelial growth factor in foam cells by a water-soluble fraction of Polygonum multiflorum

Polygonum multiflorum stilbeneglycoside （PMS） is a water-soluble fraction of Polygonum multiflorum Thunb. , one of the most famous tonic traditional Chinese medicines, that has protective effects on the cardiovascular system. The purpose of the present study is to elucidate the effects of PMS on macrophage-derived foam cell functions and the reduction of severity of atherosclerosis in hypercholesterolemic New Zealand White （NZW） rabbits. NZW rabbits were fed for 12 weeks with a normal diet, a high cholesterol diet, or a high cholesterol diet associated with irrigation with different doses of PMS （25, 50, or 100 mg/kg）. Treatment of NZW rabbits fed with high cholesterol diet with 100 mg/kg PMS attenuated the increase in plasma cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and plasma triglyceride. Treatment with 50 and 100 mg/kg PMS caused 43% and 60% decrease in atherosclerotic lesioned area ratio to total surface area, respectively. In U937 foam cells, PMS could decrease the high expression of intercellular adhesion molecule （ICAM）-1 protein and the vascular endothelial growth factor （VEGF） protein levels in the medium induced by oxidized lipoprotein when analyzed by flow cytometry. The results proved that PMS is a powerful agent against atherosclerosis and that PMS action could possibly be through the inhibition of the expression of ICAM-1 and VEGF in foam cells.