Teaching behavioral medicine using individual coronary heart disease risk factors

Two hundred twenty-one first-year medical students participated in a voluntary coronary heart disease risk factor self-change project designed to teach the principles of behavioral change. Blood pressure, serum lipids, percentage body fat, cardiovascular fitness, and smoking status were measured prior to the project. Students designed their own programs of behavior modification and, after 8 weeks, repeat measurements were obtained in students whose projects related to coronary heart disease risk (56% of entire group). Despite generally low initial coronary heart disease risk factors, most risk factor groups successfully altered the targeted risk factors. The subgroup attempting to lower serum cholesterol (n = 49) reduced total cholesterol 15 +/- 24 mg/dl (mean +/- SD) and low-density lipoprotein cholesterol 11 +/- 20 mg/dl (P less than 0.001 for both). The blood pressure group (n = 9) decreased systolic blood pressure 8 +/- 10 mm Hg (P less than 0.05), and the weight-loss group (n = 33) lost 3.0 +/- 2.9 kg (P less than 0.001), reducing estimated percentage body fat 1.7 +/- 1.8 (P less than 0.001). The self-change project was well received by the students and appears to be a useful technique for introducing the principles of behavioral medicine to first-year medical students.     

Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition

Background: Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thoroughly evaluated for their inhibitory effects on AChE activity. AChE inhibitors can have therapeutic applications (e.g., tacrine and donepezil) or neurotoxic consequences (e.g., insecticides and nerve agents).Objectives: The objective of the current study was to identify environmental chemicals that inhibit AChE activity using in vitro and in silico models.Methods: To identify AChE inhibitors rapidly and efficiently, we have screened the Toxicology in the 21st Century (Tox21) 10K compound library in a quantitative high-throughput screening (qHTS) platform by using the homogenous cell-based AChE inhibition assay and enzyme-based AChE inhibition assays (with or without microsomes). AChE inhibitors identified from the primary screening were further tested in monolayer or spheroid formed by SH-SY5Y and neural stem cell models. The inhibition and binding modes of these identified compounds were studied with time-dependent enzyme-based AChE inhibition assay and molecular docking, respectively.Results: A group of known AChE inhibitors, such as donepezil, ambenonium dichloride, and tacrine hydrochloride, as well as many previously unreported AChE inhibitors, such as chelerythrine chloride and cilostazol, were identified in this study. Many of these compounds, such as pyrazophos, phosalone, and triazophos, needed metabolic activation. This study identified both reversible (e.g., donepezil and tacrine) and irreversible inhibitors (e.g., chlorpyrifos and bromophos-ethyl). Molecular docking analyses were performed to explain the relative inhibitory potency of selected compounds.Conclusions: Our tiered qHTS approach allowed us to generate a robust and reliable data set to evaluate large sets of environmental compounds for their AChE inhibitory activity. https://doi.org/10.1289/EHP6993     

A new way of looking at Caesarean section births

AIMS: To implement the Robson Ten Group Classification System (TGCS) at the Royal Women's Hospital (RWH), Melbourne, in order to determine the main contributors to the rising Caesarean section (CS) rate. METHODS: The TGCS divides women into ten groups according to parity, past obstetric history, singleton or multiple pregnancy, fetal presentation, gestational age and mode of onset of labour/delivery. The TGCS was applied retrospectively to the population of women who had a registered birth at the RWH between January 2005 and 31 December 2005. RESULTS: A total of 5833 women gave birth to 6011 babies during the study period. A total of 1651 women (28.3%) had a CS birth. The total CS rates ranged from 3.7% (group 3) to 100% (group 9). Women in groups 1 and 2 were the greatest contributors to the emergency CS rate, 4.2% and 4.9%, respectively. Women in group 5 were the single greatest contributor to both the elective CS rate and the total CS rate. CONCLUSIONS: The TGCS was successfully implemented at the RWH in 2005. The TGCS is ongoing, enabling monitoring of CS rates. The Robson TGCS demonstrates the need to focus on the care of women in groups 1, 2 and 5 in particular, if CS rates are to be reduced.     

Co-targeting bromodomain and extra-terminal proteins and MCL1 induces synergistic cell death in melanoma

The treatment of melanoma has been markedly improved by the introduction of targeted therapies and checkpoint blockade immunotherapy. Unfortunately, resistance to these therapies remains a limitation. Novel anticancer therapeutics targeting the MCL1 anti-apoptotic protein have shown impressive responses in haematological cancers but are yet to be evaluated in melanoma. To assess the sensitivity of melanoma to new MCL1 inhibitors, we measured the response of 51 melanoma cell lines to the novel MCL1 inhibitor, S63845. Additionally, we assessed combination of this drug with inhibitors of the bromodomain and extra-terminal (BET) protein family of epigenetic readers, which we postulated would assist MCL1 inhibition by downregulating anti-apoptotic targets regulated by NF-kB such as BCLXL, BCL2A1 and XIAP, and by upregulating pro-apoptotic proteins including BIM and NOXA. Only 14% of melanoma cell lines showed sensitivity to S63845, however, combination of S63845 and I-BET151 induced highly synergistic apoptotic cell death in all melanoma lines tested and in an in vivo xenograft model. Cell death was dependent on caspases and BAX/BAK. Although the combination of drugs increased the BH3-only protein, BIM, and downregulated anti-apoptotic proteins such as BCL2A1, the importance of these proteins in inducing cell death varied between cell lines. ABT-199 or ABT-263 inhibitors against BCL2 or BCL2 and BCLXL, respectively, induced further cell death when combined with S63845 and I-BET151. The combination of MCL1 and BET inhibition appears to be a promising therapeutic approach for metastatic melanoma, and presents opportunities to add further BCL2 family inhibitors to overcome treatment resistance.     

Vasopressin in the treatment of milrinone-induced hypotension in severe heart failure

The use of phosphodiesterase inhibitors such as milrinone in the treatment of severe heart failure is frequently restricted because they cause vasodilation and hypotension. In patients with decompensated heart failure with hypotension after treatment with milrinone, low doses of vasopressin restored blood pressure without inhibiting the inotropic effect of milrinone.     

Renal medullary carcinoma: prolonged remission with chemotherapy, immunohistochemical characterisation and evidence of bcr/abl rearrangement

BACKGROUND: Renal medullary carcinoma (RMC), an extremely rare tumour of the kidney, carries a dismal prognosis, with no reports to date of significant response to chemotherapy or radiotherapy. A case of this tumour in a male child, who showed a dramatic response to chemotherapy, is described. PROCEDURE: A detailed histological evaluation of the tumour and cytogenetic analysis using fluorescent in situ hybridisation (FISH) was carried out. The child was treated with multiagent chemotherapy, followed by abdominal radiotherapy. RESULTS: A detailed histopathological and immunohistochemical portrait of this tumour is described, and FISH studies confirmed the presence of a bcr/abl rearrangement. The child obtained complete radiological remission following chemotherapy, although he later relapsed and died of progressive disease despite further attempts at treatment with chemotherapy. CONCLUSIONS: Although there are no previous reports of response of this tumour to chemotherapy, this case illustrates that treatment of this disease is justified. The responses of other cases to similar drug regimens would be of interest to confirm whether the encouraging response described for this case could be reproduced. Cytogenetic analysis of other cases of RMC may clarify whether the abnormalities seen in this case are typical.     

Elevated high-density lipoprotein cholesterol in endurance athletes is related to enhanced plasma triglyceride clearance

We compared the clearance rate (K2) of plasma triglycerides (TG) following the intravenous (IV) infusion of a fat emulsion in 13 male endurance athletes (age 33 +/- 5.6 years, mean +/- SD) and 12 sedentary men (33 +/- 5.6 years). The athletes had lower fasting triglycerides (TG) (75 +/- 30.4 mg/dL v 125 +/- 52.5 mg/dL) and higher high-density lipoprotein (HDL) cholesterol concentrations (64 +/- 16.2 mg/dL v 42 +/- 9.4 mg/dL) than the sedentary subjects (P less than .01 for all). The higher HDL concentrations were due to increases in both the HDL2 and HDL3 subfractions. K2 in the athletes was 92% higher than that in the sedentary men (4.8 +/- 2.3%/min v 2.5 +/- 0.7%/min, P less than .01), but there was no difference in postheparin lipoprotein lipase activity (LPLA) between the groups (P greater than .05). K2 was positively correlated with LPLA (r = .51) and inversely related to fasting TG concentrations (r = -.73, P less than .01 for both). Furthermore, K2 was directly related to HDL (r = .75), HDL2 (r = .72), and HDL3 (r = .60) cholesterol concentrations (P less than .01 for all). These data suggest that the low TG levels in endurance athletes result at least in part from increased TG removal and that the elevated HDL concentrations of endurance athletes are related to enhanced fat clearance.     

Small group health insurance: ranking the states on the depth of reform, 1999

States are ranked based on the potential of their small group health insurance reforms to enhance health insurance uptake. Reforms were quantified based on their market impact potential. Five dimensions of reforms were identified, Access Improvement, Premium Reduction, Premium Differential Reduction, Continuity of Coverage, and Enhancing Valued Plan Features. The reform indices representing these dimensions were developed based on document review of state statutes, combined with actuarial judgment to identify and assign scores to market-relevant regulations in line with their impact potential. The distribution of the states' reform scores and rankings show wide variation in the depth and focus of their reforms. Only seven of the top ten states on the Total Reform index had consistently higher scores on two or more reform dimensions. The conceptual linkages between specific regulations and the documented small group market problems lead to normative expectations of an association between the depth of state reforms and the prevalence of uninsurance.