Azaspiracid substituent at C1 is relevant to in vitro toxicity

The azaspiracids are a group of marine toxins recently described that currently includes 20 analogues. Not much is known about their mechanism of action, although effects on some cellular functions have been found in vitro. We used the reported effects on cell viability, actin cytoskeleton, and caspase activation to study the structure-activity relationship of AZA-1 and AZA-2 and the role of the carboxylic acid moiety in toxicity. AZA-1, AZA-2, and the synthetic AZA-2-methyl ester (AZA-2-ME), where the C1 carboxylic acid moiety of AZA-2 was esterified to the corresponding methyl ester moiety, induced a reduction of cell viability in neuroblastoma and hepatocyte cell lines with similar potency and kinetics. Interestingly, the mast cell line HMC-1 was resistant to AZA-induced cytotoxicity. Actin cytoskeleton alterations and caspase activation appeared after treatment with AZA-1, AZA-2, AZA-2-ME, and biotin-AZA-2 (AZA-2 labeled with biotin at C1) in neuroblastoma cells with similar qualitative, quantitative, and kinetics characteristics. Irreversibility of AZA effects on the actin cytoskeleton and cell morphology after short incubations with the toxin were common to AZA-1, AZA-2, and AZA-2-ME; however, 10-fold higher concentrations of biotin-AZA-2 were needed for irreversible effects. AZA-2-ME was rapidly metabolized in the cell to AZA-2, while transformation of biotin-AZA-2 into AZA-2 was less efficient, which explains the different potency in short exposure times. The moiety present at C1 is related to AZA toxicity in vitro. However, the presence of a methyl moiety at C8 is irrelevant to AZA toxicity since AZA-1 and AZA-2 were equipotent regardless of the readout effect.     

Potent, Plasmodium-selective farnesyltransferase inhibitors that arrest the growth of malaria parasites: structure-activity relationships of ethylenediamine-analogue scaffolds and homology model validation

New chemotherapeutics are urgently needed to combat malaria. We previously reported on a novel series of antimalarial, ethylenediamine-based inhibitors of protein farnesyltransferase (PFT). In the current study, we designed and synthesized a series of second generation inhibitors, wherein the core ethylenediamine scaffold was varied in order to examine both the homology model of Plasmodium falciparum PFT (PfPFT) and our predicted inhibitor binding mode. We identified several PfPFT inhibitors (PfPFTIs) that are selective for PfPFT versus the mammalian isoform of the enzyme (up to 136-fold selectivity), that inhibit the malarial enzyme with IC50 values down to 1 nM, and that block the growth of P. falciparum in infected whole cells (erythrocytes) with ED50 values down to 55 nM. The structure-activity data for these second generation, ethylenediamine-inspired PFT inhibitors were rationalized by consideration of the X-ray crystal structure of mammalian PFT and the homology model of the malarial enzyme.     

Actualizing a provider alliance to expand health services access to a low-income urban community

Social change to facilitate health care access for vulnerable populations sometimes involves model-driven innovative structures and innovative planning and implementation approaches. This paper described and analyzed the rationale, conceptual framework, program components, and implementation of the South Central Health Care Alliance (SCHCA) implemented in South Los Angeles from January 2002 to December 2004. The program development and implementation was guided by an integrated framework linking the Open Systems Theory, the Social Cognitive Theory, the Health Belief Model, and the Preventive Health Education and Medical Home Project. The performance of the SCHCA as a social system, partnership, and participatory implementation program is also presented. While the SCHCA was found to be a dynamic social system that responded well to contingencies, its performance as a partnership and participatory implementation program was wanting in many respects.     

Divalproex in the treatment of posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial in a veteran population

OBJECTIVE: To evaluate the efficacy of divalproex for the treatment of posttraumatic stress disorder (PTSD) hyperarousal symptom cluster. METHOD: Under double-blind conditions, 85 US military veterans with PTSD were randomized to treatment with divalproex or placebo for 8 weeks. All patients who received at least 1 dose of medication and 1 postbaseline assessment (n = 82) were included in the efficacy population. The primary outcome measure was the hyperarousal subscale of the Clinician-Administered PTSD Scale. RESULT: There were no significant intergroup differences in primary or secondary end points. The final mean (SD) divalproex dose and serum valproic acid level were 2309 +/- 507 mg/d and 82 +/- 30 mg/L, respectively. CONCLUSIONS: Divalproex monotherapy was not effective in the treatment of chronic PTSD in predominantly older male combat veterans. Further study is needed to determine the efficacy of divalproex in the management of PTSD in women or civilians or in combination with antidepressants.     

Introducing this Special Issue on the "Mental Health of Asian Americans and Pacific Islanders"

There are approximately 1.4 million Asian American and Pacific Islanders who are suffering from some form of psychiatric disorder. Given the extent of this problem, I wish that we could provide specific epidemiological estimates of psychiatric disorders among Asian Americans. Unfortunately, there are few, if any, reliable and valid community-based epidemiological data on Asian Americans at this point. Given this state of affairs, it is quite important that we continue to do research on the mental needs and problems among Asian Americans so that we can provide the much needed mental health services.     

Shared random effects analysis of multi-state Markov models: application to a longitudinal study of transitions to dementia

Multi-state models are appealing tools for analysing data about the progression of a disease over time. In this paper, we consider a multi-state Markov chain with two competing absorbing states: dementia and death and three transient non-demented states: cognitively normal, amnestic mild cognitive impairment (amnestic MCI), and non-amnestic mild cognitive impairment (non-amnestic MCI). The likelihood function for the data is derived and estimates for the effects of the covariates on transitions are determined when the process can be viewed as a polytomous logistic regression model with shared random effects. The presence of a shared random effect not only complicates the formulation of the likelihood but also its evaluation and maximization. Three approaches for maximizing the likelihood are compared using a simulation study; the first method is based on the Gauss-quadrature technique, the second method is based on importance sampling ideas, and the third method is based on an expansion by Taylor series. The best approach is illustrated using a longitudinal study on a cohort of cognitively normal subjects, followed annually for conversion to mild cognitive impairment (MCI) and/or dementia, conducted at the Sanders Brown Center on Aging at the University of Kentucky.     

Stereoselective synthesis of beta-lactams with polyaromatic imines: entry to new and novel anticancer agents

We present herein stereoselective synthesis of novel beta-lactams using polyaromatic imines following the Staudinger reaction. Consistent mechanisms for these results have been advanced. As a measure of cytotoxicity, some of these compounds have been assayed against nine human cancer cell lines. Structure-activity study has revealed that 1-N-chrysenyl and 1-N-phenanthrenyl 3-acetoxy-4-aryl-2-azetidinones have potent anticancer activity. The presence of the acetoxy group at C(3) of the beta-lactams has proven to be obligatory for their anticancer activity.     

Physical symptoms in long-term survivors of rare cancer

Purpose

Advances in cancer detection and treatment have resulted in a growing population of long-term survivors, but even years after treatment has concluded, many survivors report physical symptoms that interfere with daily living. While there are studies of late effects following common cancers, less is known about these complications in rare cancers. This study focuses on the physical symptoms reported by long-term survivors enrolled in the NIH-sponsored Rare Cancer Genetics Registry.

Methods

The Rotterdam Symptom Checklist-Modified was administered to evaluate the severity of physical symptoms commonly reported by long-term cancer survivors. Logistic regression was used to assess association between symptoms and demographic and clinical factors.

Results

In 309 subjects with a median time of 7.6 years from a diagnosis of one or more rare cancers, the median number of symptoms present per participant was 7. The most prevalent symptom reported was tiredness/lack of energy, which was present/very bothersome in 70%/25% of registrants. Women, non-whites, current smokers, and upper GI cancer survivors are particularly affected. Overall, symptom prevalence was similar across rare cancer types, time since diagnosis, and type of treatment.

Conclusions

Rare cancer survivors continue to experience troublesome symptoms many years after diagnosis, regardless of cancer type or treatment modality.

Implications for Cancer Survivors

There is a need for continued emphasis on smoking cessation in cancer survivors as well as enhanced monitoring of long-term complications in female, non-white, and upper GI cancer survivors.

     

Developmental selenomethionine and methylmercury exposures affect zebrafish learning

Methylmercury (MeHg) is a ubiquitous environmental pollutant and has been shown to affect learning in vertebrates following relatively low exposures. Zebrafish were used to model long-term learning deficits after developmental MeHg exposure. Selenomethionine (SeMet) co-exposure was used to evaluate its role in neuroprotection. Embryos were exposed from 2 to 24 h post fertilization to (1) MeHg without SeMet, (2) SeMet without MeHg and (3) in combination of MeHg and SeMet. In case (1), the levels of MeHg were 0.00, 0.01, 0.03, 0.06, 0.10, and 0.30 μM. In case (2), the levels of SeMet were 0.00. 0.03, 0.06, 0.10, and 0.30 μM. In case (3), co-exposure levels of (MeHg, SeMet) were (0.03, 0.03), (0.03, 0.06), (0.03, 0.10), (0.03, 0.30), (0.10, 0.03), (0.10, 0.06), (0.10, 0.10), and (0.10, 0.30) μM. Learning functions were tested in individual adults, 4 months after developmental exposure using a spatial alternation paradigm with food delivery on alternating sides of the aquarium. Low levels of MeHg (< 0.1 µM) exposure delayed learning in treated fish; fish exposed to higher MeHg levels were unable to learn the task; SeMet co-exposure did not prevent this deficit. These data are consistent with findings in laboratory rodents. The dorsal and lateral telencephalon are the primary brain regions in fish involved in spatial learning and memory. Adult telencephalon cell body density decreased significantly at all MeHg exposures > 0.01 μM MeHg. SeMet co-exposure ameliorated but did not prevent changes in telencephalon cell body density. In summary, MeHg affected both learning and brain structure, but SeMet only partially reversed the latter.