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1.  Indole Alkaloids from Fischerella Inhibit Vertebrate Development in the Zebrafish (Danio rerio) Embryo Model 
Toxins  2014;6(12):3568-3581.
Cyanobacteria are recognized producers of toxic or otherwise bioactive metabolite associated, in particular, with so-called “harmful algal blooms” (HABs) and eutrophication of freshwater systems. In the present study, two apparently teratogenic indole alkaloids from a freshwater strain of the widespread cyanobacterial genus, Fischerella (Stigonemataceae), were isolated by bioassay-guided fractionation, specifically using the zebrafish (Danio rerio) embryo, as a model of vertebrate development. The two alkaloids include the previously known 12-epi-hapalindole H isonitrile (1), and a new nitrile-containing variant, 12-epi-ambiguine B nitrile (2). Although both compounds were toxic to developing embryos, the former compound was shown to be relatively more potent, and to correlate best with the observed embryo toxicity. Related indole alkaloids from Fischerella, and other genera in the Stigonemataceae, have been widely reported as antimicrobial compounds, specifically in association with apparent allelopathy. However, this is the first report of their vertebrate toxicity, and the observed teratogenicity of these alkaloids supports a possible contribution to the toxicity of this widespread cyanobacterial family, particularly in relation to freshwater HABs and eutrophication.
PMCID: PMC4280548  PMID: 25533520
Fischerella; Stigonemataceae; cyanobacteria; hapalindoles; ambiguines; indole alkaloids; zebrafish embryo; teratogenicity; vertebrate toxicity; harmful algal blooms
2.  Polymethoxy-1-alkenes from Aphanizomenon ovalisporum Inhibit Vertebrate Development in the Zebrafish (Danio rerio) Embryo Model 
Marine Drugs  2012;10(10):2322-2336.
Cyanobacteria are recognized producers of a wide array of toxic or otherwise bioactive secondary metabolites. The present study utilized the zebrafish (Danio rerio) embryo as an aquatic animal model of vertebrate development to identify, purify and characterize lipophilic inhibitors of development (i.e., developmental toxins) from an isolate of the freshwater cyanobacterial species, Aphanizomenon ovalisporum.Bioassay-guided fractionation led to the purification, and subsequent chemical characterization, of an apparent homologous series of isotactic polymethoxy-1-alkenes (1–6), including three congeners (4–6) previously identified from the strain, and two variants previously identified from other species (2 and 3), as well as one apparently novel member of the series (1). Five of the PMAs in the series (1–5) were purified in sufficient quantity for comparative toxicological characterization, and toxicity in the zebrafish embryo model was found to generally correlate with relative chain length and/or methoxylation. Moreover, exposure of embryos to a combination of variants indicates an apparent synergistic interaction between the congeners. Although PMAs have been identified previously in cyanobacteria, this is the first report of their apparent toxicity. These results, along with the previously reported presence of the PMAs from several cyanobacterial species, suggest a possibly widespread distribution of the PMAs as toxic secondary metabolites and warrants further chemical and toxicological investigation.
PMCID: PMC3497026  PMID: 23170087
cyanobacteria; Aphanizomenon ovalisporum; toxins; zebrafish (Danio rerio) embryo; polymethoxy-1-alkenes; vertebrate development; harmful algal blooms (HABs)
3.  Toxicity of cylindrospermopsin, and other apparent metabolites from Cylindrospermopsis raciborskii and Aphanizomenon ovalisporum, to the zebrafish (Danio rerio) embryo 
Cyanobacteria produce a diverse array of toxic or otherwise bioactive compounds that pose growing threats to human and environmental health. We utilized the zebrafish (Danio rerio) embryo, as a model of vertebrate development, to investigate the inhibition of development pathways (i.e. developmental toxicity) by the cyanobacterial toxin, cylindrospermopsin (CYN), as well as extracts from various isolates of Cylindrospermopsis raciborskii and Aphanizomenon ovalisporum. CYN was toxic only when injected directly into embryos, but not by direct immersion at doses up to 50 μg/ml. Despite the dose dependency of toxicity observed following injection of CYN, no consistent patterns of developmental defects were observed, suggesting that toxic effects of CYN may not target specific developmental pathways. In contrast, direct immersion of embryos in all of the extracts resulted in both increased mortality and reproducible, consistent, developmental dysfunctions. Interestingly, there was no correlation of developmental toxicity observed for these extracts with the presence of CYN or with previously reported toxicity for these strains. These results suggest that CYN is lethal to zebrafish embryos, but apparently inhibits no specific developmental pathways, whereas other apparent metabolites from C. raciborskii and A. ovalisporum seem to reproducibly inhibit development in the zebrafish model. Continued investigation of these apparent, unknown metabolites is needed.
PMCID: PMC3513286  PMID: 19087885
Cyanobacteria; Cylindrospermopsin; Cylindrospermopsis; Aphanizomenon; Zebrafish; Development toxicity
4.  Mode of Communication, Perceived Level of Understanding, and Perceived Quality of Life in Youth Who Are Deaf or Hard of Hearing 
Given the important role of parent–youth communication in adolescent well-being and quality of life, we sought to examine the relationship between specific communication variables and youth perceived quality of life in general and as a deaf or hard-of-hearing (DHH) individual. A convenience sample of 230 youth (mean age = 14.1, standard deviation = 2.2; 24% used sign only, 40% speech only, and 36% sign + speech) was surveyed on communication-related issues, generic and DHH-specific quality of life, and depression symptoms. Higher youth perception of their ability to understand parents’ communication was significantly correlated with perceived quality of life as well as lower reported depressive symptoms and lower perceived stigma. Youth who use speech as their single mode of communication were more likely to report greater stigma associated with being DHH than youth who used both speech and sign. These findings demonstrate the importance of youths’ perceptions of communication with their parents on generic and DHH-specific youth quality of life.
PMCID: PMC3202327  PMID: 21536686
5.  Effects of Cyanobacterial Lipopolysaccharides from Microcystis on Glutathione-Based Detoxification Pathways in the Zebrafish (Danio rerio) Embryo 
Toxins  2012;4(6):390-404.
Cyanobacteria (“blue-green algae”) are recognized producers of a diverse array of toxic secondary metabolites. Of these, the lipopolysaccharides (LPS), produced by all cyanobacteria, remain to be well investigated. In the current study, we specifically employed the zebrafish (Danio rerio) embryo to investigate the effects of LPS from geographically diverse strains of the widespread cyanobacterial genus, Microcystis, on several detoxifying enzymes/pathways, including glutathione-S-transferase (GST), glutathione peroxidase (GPx)/glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT), and compared observed effects to those of heterotrophic bacterial (i.e., E. coli) LPS. In agreement with previous studies, cyanobacterial LPS significantly reduced GST in embryos exposed to LPS in all treatments. In contrast, GPx moderately increased in embryos exposed to LPS, with no effect on reciprocal GR activity. Interestingly, total glutathione levels were elevated in embryos exposed to Microcystis LPS, but the relative levels of reduced and oxidized glutathione (i.e., GSH/GSSG) were, likewise, elevated suggesting that oxidative stress is not involved in the observed effects as typical of heterotrophic bacterial LPS in mammalian systems. In further support of this, no effect was observed with respect to CAT or SOD activity. These findings demonstrate that Microcystis LPS affects glutathione-based detoxification pathways in the zebrafish embryo, and more generally, that this model is well suited for investigating the apparent toxicophore of cyanobacterial LPS, including possible differences in structure-activity relationships between heterotrophic and cyanobacterial LPS, and teleost fish versus mammalian systems.
PMCID: PMC3398417  PMID: 22822454
lipopolysaccharide; cyanobacteria; zebrafish; Microcystis; glutathione; detoxification pathways; oxidative stress
6.  Why Functional Pre-Erythrocytic and Bloodstage Malaria Vaccines Fail: A Meta-Analysis of Fully Protective Immunizations and Novel Immunological Model 
PLoS ONE  2010;5(5):e10685.
Clinically protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants.
Methodology/Principal Findings
We identify and evaluate 1916 immunization studies between 1965-February 2010, and exclude partially or nonprotective results to find 177 completely protective immunization experiments. Detailed reexamination reveals an unexpectedly mundane basis for selective vaccine failure: live malaria parasites in the skin inhibit vaccine function. We next show published molecular and cellular data support a testable, novel model where parasite-host interactions in the skin induce malaria-specific regulatory T cells, and subvert early antigen-specific immunity to parasite-specific immunotolerance. This ensures infection and tolerance to reinfection. Exposure to Plasmodium-infected mosquito bites therefore systematically triggers immunosuppression of endemic vaccine-elicited responses. The extensive vaccine trial data solidly substantiate this model experimentally.
We conclude skinstage-initiated immunosuppression, unassociated with bloodstage parasites, systematically blocks vaccine function in the field. Our model exposes novel molecular and procedural strategies to significantly and quickly increase protective efficacy in both pipeline and currently ineffective malaria vaccines, and forces fundamental reassessment of central precepts determining vaccine development. This has major implications for accelerated local eliminations of malaria, and significantly increases potential for eradication.
PMCID: PMC2873430  PMID: 20502667
7.  The zebrafish (Danio rerio) embryo as a model system for identification and characterization of developmental toxins from marine and freshwater microalgae☆ 
The zebrafish (Danio rerio) embryo has emerged as an important model of vertebrate development. As such, this model system is finding utility in the investigation of toxic agents that inhibit, or otherwise interfere with, developmental processes (i.e. developmental toxins), including compounds that have potential relevance to both human and environmental health, as well as biomedicine. Recently, this system has been applied increasingly to the study of microbial toxins, and more specifically, as an aquatic animal model, has been employed to investigate toxins from marine and freshwater microalgae, including those classified among the so-called “harmful algal blooms” (HABs). We have developed this system for identification and characterization of toxins from cyanobacteria (i.e. “blue-green algae”) isolated from the Florida Everglades and other freshwater sources in South and Central Florida. Here we review the use of this system as it has been applied generally to the investigation of toxins from marine and freshwater microalgae, and illustrate this utility as we have applied it to the detection, bioassay-guided fractionation and subsequent characterization of developmental toxins from freshwater cyanobacteria.
PMCID: PMC2573033  PMID: 17020820
Zebrafish; Danio rerio; Vertebrate development; Toxins; Algae; Model system; Cyanobacteria; Everglades
8.  Disablement and care: a comparison of patient views and general practitioner knowledge 
A questionnaire was used to assess general practitioners' knowledge of handicaps and service use among disabled patients in a group practice. The disabled patients were identified by a postal screening questionnaire. Sixty-eight were subsequently interviewed to assess the severity of restrictions on their activities and to collect information about informal support and use of community or hospital services. The areas of life in which the disabled were most affected by their medical conditions were sleep and rest, household management, emotion and mood. Relatives assisted the disabled considerably with all daily activities but more help was requested. Most disabled patients had consulted their general practitioner or attended casualty and outpatient clinics, but only a minority had used other community services. Prescription of drugs was considered the most important service the doctor provided. A second questionnaire, which the general practitioners completed with the help of their records, revealed that they knew of only 50 per cent of the difficulties with daily living reported by the disabled and even less of the aids, appliances and services used. A better awareness of these facilities among general practitioners might lead to a more effective distribution of resources among their patients.
PMCID: PMC1972508  PMID: 6214627
10.  NHS priorities and RAWP 
British Medical Journal  1978;2(6149):1446-1447.
PMCID: PMC1608593  PMID: 20792757
11.  Use of multivariate measures of disability in health surveys. 
It has been claimed that the aggregation of information from several areas of life into a small set of global measures has certain advantages for describing disability. Global measures of disability were constructed from a modified version of an existing health survey instrument and the sickness impact profile (SIP) and their properties were tested. The disability items grouped satisfactorily into five global measures (physical, psychosocial, eating, communication, and work). All disability measures (global and original category scores) were poor predictors of service use by individuals but were related as expected to age and number of medical conditions. The global measures generally had lower standard errors and better repeatability. All scores exhibit J-shaped distributions for cross sectional data but the change in global measures over time was consistent with the normal distribution. Preferably, both global and category measures should be used for comparing changes over time between groups of individuals.
PMCID: PMC1052928  PMID: 6655420
12.  Measuring quality of life in clinical trials: a taxonomy and review. 
Measurement of quality of life is becoming increasingly relevant to controlled clinical trials. Two basic types of instrument are available: generic instruments, which include health profiles and utility measurements based on the patient's preferences in regard to treatment and outcome; and specific instruments, which focus on problems associated with individual diseases, patient groups or areas of function. The two approaches are not mutually exclusive; each has its strengths and weaknesses and may be suitable under different circumstances. We surveyed 75 randomized trials published in three medical journals in 1986 and categorized them according to the importance of quality of life as a measure of outcome and the extent to which quality of life was actually measured. Although a number of the investigators used quality-of-life instruments in a sophisticated manner, in only 10 of 55 trials in which the measurement had been judged to be crucial or important were instruments with established validity and responsiveness used. We conclude that although accurate measurement of quality of life in randomized trials is now feasible it is still not widely done. Using the framework we have outlined, investigators can choose generic or specific instruments according to the purpose and the focus of their trial.
PMCID: PMC1269981  PMID: 2655856
13.  Measuring the "managedness" and covered benefits of health plans. 
Health Services Research  2000;35(3):707-734.
STUDY AIMS: (1) To develop indexes measuring the degree of managedness and the covered benefits of health insurance plans, (2) to describe the variation in these indexes among plans in one health insurance market, (3) to assess the validity of the health plan indexes, and (4) to examine the association between patient characteristics and the health plan indexes. Measures of the "managedness" and covered benefits of health plans are requisite for studying the effects of managed care on clinical practice and health system performance, and they may improve people's understanding of our complex health care system. DATA SOURCES/STUDY SETTING: As part of our larger Physician Referral Study, we collected health insurance information for 189 insurance product lines and 755 products in the Seattle, Washington metropolitan area, which we linked with the study's data for 2,277 patients recruited in local primary care offices. STUDY DESIGN: Managed care and benefit variables were constructed through content analysis of health plan information. Principal component analysis of the variables produced a managedness index, an in-network benefits index, and an out-of-network benefits index. Bivariable analyses examined associations between patient characteristics and the three indexes. PRINCIPAL FINDINGS: From the managed care variables, we constructed three provider-oriented indexes for the financial, utilization management, and network domains of health plans. From these, we constructed a single managedness index, which correlated as expected with the individual measures, with the domain indexes, with plan type (FFS, PPO, POS, HMO), with independent assessments of local experts, and with patients' attitudes about their health insurance. For benefits, we constructed an in-network benefits index and an out-of-network benefits index, which were correlated with the managedness index. The personal characteristics of study patients were associated with the managed care and benefit indexes. Study patients in more managed plans reported somewhat better health than patients in less managed plans. CONCLUSIONS: Indexes of the managedness and benefits of health plans can be constructed from publicly available information. The managedness and benefit indexes are associated with the personal characteristics and health status of study patients. Potential uses of the managed care and benefits indexes are discussed.
PMCID: PMC1089144  PMID: 10966092
14.  Estimating the prevalence of disability in the community: the influence of sample design and response bias. 
An estimate of the prevalence of physical disability in the community based upon a sample survey may be influenced by the sample design and the response to the method of data collection employed. In this paper we describe a postal survey of a sample of households in the London borough of Lambeth and the procedures used for calculating the influence of these factors on the estimate produced. These procedures can be used to adjust the estimate to take account of the relative chance of households falling into the sample and to correct for non-response bias.
PMCID: PMC1052159  PMID: 6460072
15.  Screening for disability in the inner city. 
A 10% sample of private households on the electoral register of the London borough of Lambeth was screened for disable persons aged 16 and over, using a postal questionnaire. After three mailings and individual follow-up of non-responders, 87% of the sample households returned questionnaires. Disability was defined in the screening questionnaire as functional limitations or activity restrictions consequent upon disease or impairment. The overall point prevalence of disability was estimated at 15.4% and the most frequently reported impairments were those of the sense organs, bones, central nervous, circulatory, and respiratory systems. Hearing difficulties were the single most frequently reported functional limitation. A log-linear modelling procedure identified age, marital status, and working status as the factors most strongly associated with disability for both men and women. In addition, men aged 50-64 and not working, and men in manual occupations and living alone, were more likely to report disability. These findings indicate that some population groups are disable by functional limitations and activity restrictions not included in office criteria of identification and assessment. These criteria might be broadened, and serves planned for those population groups with higher rates of reported disability.
PMCID: PMC1052122  PMID: 6455485

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