Life cycle of a minimal protocell--a dissipative particle dynamics study

Cross-reactions and other systematic difficulties generated by the coupling of functional chemical subsystems pose the largest challenge for assembling a viable protocell in the laboratory. Our current work seeks to identify and clarify such key issues as we represent and analyze in simulation a full implementation of a minimal protocell. Using a 3D dissipative particle dynamics simulation method, we are able to address the coupled diffusion, self-assembly, and chemical reaction processes required to model a full life cycle of a protocell composed of coupled genetic, metabolic, and container subsystems. Utilizing this minimal structural and functional representation of the constituent molecules, their interactions, and their reactions, we identify and explore the nature of the many linked processes for the full protocellular system. Obviously the simplicity of this simulation method combined with the inherent system complexity prevents us from expecting quantitative simulation predictions from these investigations. However, we report important findings on systemic processes, some previously predicted and some newly discovered, as we couple the protocellular self-assembly processes and chemical reactions.     

Recombinant protein-based assays for detection of antibodies to severe acute respiratory syndrome coronavirus spike and nucleocapsid proteins

Recombinant severe acute respiratory syndrome (SARS) nucleocapsid and spike protein-based immunoglobulin G immunoassays were developed and evaluated. Our assays demonstrated high sensitivity and specificity to the SARS coronavirus in sera collected from patients as late as 2 years postonset of symptoms. These assays will be useful not only for routine SARS coronavirus diagnostics but also for epidemiological and antibody kinetic studies.     

The contribution of gene-environment interaction to psychopathology

The study of gene-environment interaction (G x E) constitutes an area of significant social and clinical significance. Different types of research study designs are being used to investigate the contribution of G x E to psychopathology, although the term G x E has also been used and interpreted in different ways. Despite mixed evidence that G x E contributes to psychopathology, some promising and consistent findings are emerging. Evidence is reviewed in relation to depression, antisocial behavior, schizophrenia, and attention-deficit/hyperactivity disorder. Although findings from various research designs have different meaning, interestingly much of the evidence with regard to the contribution of G x E that has arisen from twin and adoption studies has been for antisocial behavior and depression. It is for these same forms of psychopathology that molecular genetic evidence of G x E has also been most convincing. Finally, current and anticipated methodological challenges and implications for future research in this area are considered.     

Colesevelam hydrochloride: reducing atherosclerotic coronary heart disease risk factors

Colesevelam HCl is a bile acid sequestrant (BAS) which has been specifically designed with a unique structure for the purpose of improving tolerability and reducing potential drug interactions compared to older BAS, such as cholestyramine and colestipol. As a class, BAS are known to reduce cholesterol and glucose levels, and to reduce atherosclerotic coronary heart disease (CHD) risk as monotherapy, and in combination with other lipid-altering drug therapies. Colesevelam HCl has specifically been shown to reduce total and low-density lipoprotein (LDL) cholesterol levels, and has been approved as a cholesterol-lowering drug since year 2000. It has also been shown to reduce glucose levels. This discussion reviews mechanisms by which BAS lower cholesterol, and potential mechanisms by which BAS lower glucose levels in patients with type 2 diabetes mellitus. Finally this paper specifically reviews colesevelam HCl's pharmacology, lipid and glucose efficacy, safety/tolerability, and clinical use.     

California's county and city environmental health services delivery system

The purpose of the authors' research was to assess the current status of county and city environmental health service delivery in California with the aim of providing a foundation for informed decision making about environmental health service delivery. Standardized interviews were conducted from March 2005 to May 2005 with 55 (88 percent) of the 62 county and city directors of environmental health; their jurisdictions represented 90 percent of the state's population and 94 percent of the landmass. Relevant databases and other publicly available information germane to project goals were also evaluated. The directors who were interviewed reported a total of 2,477 professional environmental health staff employed in county and city agencies, complemented by 520 support personnel. Percentages of respondents reporting technical-training needs were greatest for Certified Unified Program Agency (CUPA) activities (60 percent), dairy programs (57 percent), and septic-system programs (55 percent), while nontechnical training was desired in conflict resolution (55 percent), written/oral communication (49 percent), and problem solving (49 percent). Sixty-seven percent (67 percent) of directors reported difficulty in recruiting qualified applicants. Fifty-six percent (56 percent) were familiar with the 10 essential services of environmental health, while only 11 percent collected and reported health outcome measures to demonstrate agency effectiveness. The study team concluded that at the local level, environmental health services are largely provided as a reflection of local need; however, this tendency toward customization leads to stakeholder confusion about the purpose and value of environmental health services. The authors offer seven recommendations for improving environmental health services in California. Many of these recommendations can be generalized to the nation at large.     

First-in-Human Phase 1b Trial of Quinacrine Plus Capecitabine in Patients With Refractory Metastatic Colorectal Cancer

BackgroundQuinacrine plus a fluoropyrimidine has in vivo efficacy against metastatic colorectal cancer (mCRC). This phase 1b trial evaluated the combination of quinacrine plus capecitabine in patients with treatment-refractory mCRC.Patients and MethodsUsing a modified Simon accelerated titration design, adults with treatment-refractory mCRC were treated with capecitabine 1000 mg/m² twice daily for 14/21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg twice daily, and 200 mg twice daily for 21 days. The primary endpoint was identifying the maximum tolerated dose, determining tolerability and safety. In an expansion cohort, it was overall response rate and time to tumor progression (TTP).ResultsTen patients (median age of 60 years) were treated in phase 1b. The first 2 quinacrine dosing levels were well tolerated. Dose-limiting toxicities were seen in 3 patients treated with quinacrine 200 mg twice daily. Five additional patients tolerated quinacrine 100 mg twice daily without further dose-limiting toxicities, thus establishing the maximum tolerated dose. Seven additional expansion-cohort patients enrolled onto the study before quinacrine manufacturing ceased within the United States. Five patients experienced stable disease, 1 partial response, and 10 disease progression. Median TTP overall was 2.12 months and median overall survival 5.22 months for the 17 patients.ConclusionCapecitabine and quinacrine can be safely administered at the maximum tolerated dose of capecitabine 1000 mg/m² by mouth twice daily on days 1-14 and quinacrine 100 mg by mouth twice daily on days 1-21 of a 21-day cycle in mCRC patients. Although the expansion study was halted early, TTP was in line with other studies of refractory mCRC, suggesting activity of this regimen in heavily pretreated patients.