Human skin penetration and local effects of topical nano zinc oxide after occlusion and barrier impairment.

Public health concerns continue to exist over the safety of zinc oxide nanoparticles that are commonly used in sunscreen formulations. In this work, we assessed the effects of two conditions which may be encountered in everyday sunscreen use, occlusion and a compromised skin barrier, on the penetration and local toxicity of two topically applied zinc oxide nanoparticle products. Caprylic/capric triglyceride (CCT) suspensions of commercially used zinc oxide nanoparticles, either uncoated or with a silane coating, were applied to intact and barrier impaired skin of volunteers, without and with occlusion for a period of six hours. The exposure time was chosen to simulate normal in-use conditions. Multiphoton tomography with fluorescence lifetime imaging was used to noninvasively assess zinc oxide penetration and cellular metabolic changes that could be indicative of toxicity. We found that zinc oxide nanoparticles did not penetrate into the viable epidermis of intact or barrier impaired skin of volunteers, without or with occlusion. We also observed no apparent toxicity in the viable epidermis below the application sites. These findings were validated by ex vivo human skin studies in which zinc penetration was assessed by multiphoton tomography with fluorescence lifetime imaging as well as Zinpyr-1 staining and toxicity was assessed by MTS assays in zinc oxide treated skin cryosections. In conclusion, applications of zinc oxide nanoparticles under occlusive in-use conditions to volunteers are not associated with any measurable zinc oxide penetration into, or local toxicity in the viable epidermis below the application site.

Implementation of a pharmacogenomics consult service to support the INGENIOUS trial.

Hospital systems increasingly utilize pharmacogenomic testing to inform clinical prescribing. Successful implementation efforts have been modeled at many academic centers. In contrast, this report provides insights into the formation of a pharmacogenomics consultation service at a safety-net hospital, which predominantly serves low-income, uninsured, and vulnerable populations. The report describes the INdiana GENomics Implementation: an Opportunity for the UnderServed (INGENIOUS) trial and addresses concerns of adjudication, credentialing, and funding.

Opportunities for the replacement of animals in the study of nausea and vomiting.

Nausea and vomiting are among the most common symptoms encountered in medicine as either symptoms of disease or side effects of treatments. Developing novel anti-emetics and identifying emetic liability in novel chemical entities rely on models that can recreate the complexity of these multi-system reflexes. Animal models (especially the ferret and dog) are the current gold standard; however, the selection of appropriate models is still a matter of debate, especially when studying the subjective human sensation of nausea. Furthermore, these studies are associated with animal suffering. Here, following a recent workshop held to review the utility of animal models in nausea and vomiting research, we discuss the limitations of some of the current models in the context of basic research, anti-emetic development and emetic liability detection. We provide suggestions for how these limitations may be overcome using non-animal alternatives, including greater use of human volunteers, in silico and in vitro techniques and lower organisms.

Significance of plasma N-terminal pro-brain natriuretic peptide in patients with systemic sclerosis-related pulmonary arterial hypertension.

OBJECTIVES: A single centre pilot study to investigate the role of the plasma N-terminal pro-brain natriuretic peptide (N-T proBNP) assay to risk stratify patients with suspected pulmonary arterial hypertension (PAH) from a background SSc population. METHODS: Out of 49 SSc patients, 23 had and 26 did not have PAH. Right ventricular haemodynamic variables, six-minute walk test and plasma N-T proBNP levels were recorded from patients catheterised for suspected PAH (23 with PAH and 11/26 without PAH). RESULTS: Mean value of N-T proBNP for SSc patients with PAH was 3365 (standard error 1095) pg/ml compared to 347 (174) pg/ml for patients without PAH. There was a statistically significant correlation (P < 0.05) between N-T proBNP values and (i) mean pulmonary artery pressure (r = 0.53), (ii) right ventricular end diastolic pressure (r = 0.59) and (iii) pulmonary vascular resistance (r = 0.49). Receiver operator characteristic curve analysis showed that a cut-off value of 395.34 pg/ml had a sensitivity of 0.69 and specificity of 1.0. CONCLUSIONS: N-T proBNP estimation in systemic sclerosis-related pulmonary hypertension is a potentially useful diagnostic tool with a high specificity and negative predictive value. This test has the potential to have an important role in risk stratification and monitoring of therapy in the future.

What should be reported in a methods section on utility assessment?

BACKGROUND: The measurement of utilities, or preferences, for health states may be affected by the technique used. Unfortunately, in papers reporting utilities, it is often difficult to infer how the utility measurement was carried out. PURPOSE: To present a list of components that, when described, provide sufficient detail of the utility assessment. METHODS: An initial list was prepared by one of the authors. A panel of 8 experts was formed to add additional components. The components were drawn from 6 clusters that focus on the design of the study, the administration procedure, the health state descriptions, the description of the utility assessment method, the description of the indifference procedure, and the use of visual aids or software programs. The list was updated and redistributed among a total of 14 experts, and the components were judged for their importance of being mentioned in a Methods section. RESULTS: More than 40 components were generated. Ten components were identified as necessary to include even in an article not focusing on utility measurement: how utility questions were administered, how health states were described, which utility assessment method(s) was used, the response and completion rates, specification of the duration of the health states, which software program (if any) was used, the description of the worst health state (lower anchor of the scale), whether a matching or choice indifference search procedure was used, when the assessment was conducted relative to treatment, and which (if any) visual aids were used. The interjudge reliability was satisfactory (Cronbach's alpha = 0.85). DISCUSSION: The list of components important for utility papers may be used in various ways, for instance, as a checklist while writing, reviewing, or reading a Methods section or while designing experiments. Guidelines are provided for a few components.

Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1.

This study examines endothelin-induced modulation of extracellular matrix synthesis and remodeling by fibroblasts, and its potential role in the pathogenesis of systemic sclerosis (scleroderma). Endothelin-1 promoted fibroblast synthesis of collagen types I and III, but not fibronectin, by a mechanism dependent upon both ETA and ETB receptors. Conversely, endothelin-1 inhibited both protein expression of matrix metalloproteinase 1 and zymographic activity exclusively via ETA receptors. A dual regulatory role for endothelin-1 in transcriptional regulation was suggested by the ability of endothelin-1 to enhance steady-state levels of collagen mRNA and activate the proalpha2(I) collagen (Col1a2) promoter, but in contrast to reduce matrix metalloproteinase 1 transcript expression and suppress transcription of a human matrix metalloproteinase 1 promoter reporter construct in transient transfection assays. Although endothelin-1 significantly enhanced remodeling of three-dimensional collagen lattices populated by normal fibroblasts, this was not observed for lattices populated by systemic sclerosis fibroblasts. Promotion of matrix remodeling was dependent upon ETA receptor expression and was blocked by specific inhibitors of tyrosine kinases or protein kinase C. Reverse transcriptase polymerase chain reaction, S1 nuclease, and functional cell surface binding studies showed that normal and systemic sclerosis fibroblasts express both ETA and ETB receptors (predominantly ETA), but that ETA receptor mRNA levels and ETA binding sites on fibroblasts cultured from systemic sclerosis skin biopsies are reduced by almost 50%. Endothelin-1 is thus able to induce a fibrogenic phenotype in normal fibroblasts that is similar to that of lesional systemic sclerosis fibroblasts. Moreover, reduced responsiveness to exogenous endothelin-1 in systemic sclerosis suggests that downstream pathways may have already been activated in vivo. These data further implicate dysregulated endothelin-receptor pathways in fibroblasts in the pathogenesis of connective tissue fibrosis.

Crystallization of agGST1-6, a recombinant glutathione S-transferase from a DDT-resistant strain of Anopheles gambiae.

Glutathione S-transferases (GSTs) belong to a family of detoxification enzymes that conjugate glutathione to various xenobiotics, thus facilitating their expulsion from the cell. GST activity is elevated in many insecticide-resistant insects, including the DDT-resistant malaria vector Anopheles gambiae. Crystals of the recombinant form of a GST from A. gambiae, agGST1-6, have been grown in at least five different crystal forms, with a broad range of diffraction resolution limits. A complete 2.0 A data set has been collected on a C-centered orthorhombic crystal form with unit-cell parameters a = 99.0, b = 199.4, c = 89.6 A. A search for heavy-atom derivatives has been initiated, along with phase-determination efforts by molecular replacement.

Estimates of use and costs of behavioural health care: a comparison of standard and finite mixture models.

Estimates of health care demand are known to depend on the empirical specification used in the analysis. In this paper, an innovative specification, the finite mixture model (FMM), is employed to estimate the utilization of and expenditures on behavioural health care. Unlike standard specifications, the FMM has the ability to distinguish between distinct classes of users of behavioural health care (e.g. the 'worried well' and the severely mentally ill). This new model is tested against standard empirical specifications using data from the National Medical Expenditure Survey. Using common risk stratifiers, estimates of utilization and costs are generated with each specification. It is found that the FMM provides a much better fit of both expenditure and utilization data than standard specifications, particularly among high intensity users that standard models have been unable to represent adequately. Furthermore, the results provide preliminary evidence that there are (at least) two distinct groups of users of behavioural health care. The empirical advantages of the FMM translate into superior estimates of mean costs and utilization that have widespread application in rate-setting exercises.

Cost-utility of one-time colonoscopic screening for colorectal cancer at various ages.

OBJECTIVE: One-time colonoscopy has been recommended as a possible colorectal cancer (CRC) screening strategy. Because the incidence of colorectal neoplasia increases with age, the effectiveness and cost of this strategy depend on the age at which screening occurs. The purpose of this study was to investigate the age-dependent cost-utility of one-time colonoscopic screening. METHODS: We constructed a computer simulation model of the natural history of colorectal neoplasia. This model was used to compare the cost-utility of no screening and age-based strategies employing one-time colonoscopic screening (age ranges evaluated: 45-49, 50-54, 55-59, and 60-64 yr). RESULTS: We determined that one-time colonoscopic screening in men age <60 yr and in women age <65 yr dominates never screening and screening at older ages. For both sexes, one-time colonoscopic screening between 50 and 54 yr of age is associated with a marginal cost-utility of less than $10,000 per additional quality-adjusted life-year compared to screening between 55 and 60 yr of age. One-time colonoscopic screening between 45 and 49 yr of age is either dominated (women) or associated with a marginal cost-utility of $69,000/per quality-adjusted life-year (men) compared to screening between 50 and 54 yr of age. The marginal cost-utility of one-time colonoscopic screening is relatively insensitive to plausible changes in the cost of colonoscopy, the cost of CRC treatment, the sensitivity of colonoscopy for colorectal neoplasia, the utility values representing the morbidity associated with the CRC-related health states, and the discount rate. CONCLUSIONS: One-time colonoscopic screening between 50 and 54 yr of age is cost-effective compared to no screening and screening at older ages in both men and women. Screening in men between 45 and 49 yr of age may be cost-effective compared to screening between 50 and 54 yr of age depending on societal willingness to pay.

Particle clearance and histopathology in lungs of C3H/HeJ mice administered beryllium/copper alloy by intratracheal instillation.

Beryllium/copper (BeCu) alloys are commonly used in the electronics, automotive, consumer, defense, and aerospace industries. Some individuals exposed occupationally to BeCu alloys have developed chronic beryllium disease. However, little is known of the toxicity and fate of BeCu alloys in the respiratory tract. To begin to address this question, we investigated the pulmonary toxicity and clearance of BeCu alloy (2% Be; 98% Cu) in mice. Groups of 40 female C3H/HeJ mice were administered 12.5, 25, and 100 microg BeCu alloy or 2 and 8 microg Be metal by intratracheal instillation. Mice were sacrificed at 1 h and 1, 7, 14, and 28 days postinstillation. Left lungs were evaluated for histopathological change. Right lungs were analyzed for Be and Cu content. Twenty-five percent of the high-dose BeCu mice and 7.5% of the mid-dose BeCu mice died within 24 h of dosing. Acute pulmonary lesions included acute alveolitis and interstitial inflammation. Type II epithelial cell hyperplasia and centriacinar fibrosis were present by 7 days after dosing. Lesions persisted through 28 days after instillation. No lesions attributable to alloy exposure were present in liver or kidney. Be metal instillation caused no deaths and minimal pulmonary changes over the time studied, indicating that the pulmonary lesions were due to Cu rather than Be. Cu cleared the lung with a half-time of 0. 5-2 days. Be cleared with a half-time of several weeks or longer. Results of this study suggest that exposure to BeCu alloy is more acutely toxic to lung than Be metal. The results of tissue analyses also indicate that, while the Cu component of the alloy clears the lung rapidly, Be is retained and may accumulate upon repeated exposure.

Utility valuations for outcome states of colorectal cancer.

OBJECTIVE: Utilities for the outcome states of colorectal cancer (CRC) must be measured to evaluate the cost-utility of screening and surveillance strategies for this disease. We sought to measure utilities for stage-dependent outcome states of CRC. METHODS: We identified persons who had previously undergone removal of colorectal adenoma. We conducted individual interviews in which these participants were presented with stage-dependent outcome states and were asked to assess utilities for them using the standard gamble technique. RESULTS: A total of 90 participants were interviewed; nine were excluded, leaving 81 for analysis. We obtained the following utility valuations: stage I rectal or stage I/II colon cancer (mean 0.74, median 0.75); stage III colon cancer (mean 0.67, median 0.75); stage II/III rectal cancer without ostomy (mean 0.59, median 0.60), stage II/III rectal cancer with ostomy (mean 0.50, median 0.55), stage IV rectal or colon cancer (mean 0.25, median 0.20). These valuations were statistically different from each other. CONCLUSIONS: We measured utilities for stage-dependent outcome states of CRC in a sample of persons who had previously undergone removal of colorectal adenoma. We found that our participants were able to differentiate between the presented outcome states and assigned lower utility to increasingly morbid states. Our results show that stage-dependent morbidity is an important consideration in CRC and should be incorporated into any decision analysis model evaluating the cost-effectiveness of CRC screening or surveillance.

Double-strand break repair in yeast requires both leading and lagging strand DNA polymerases.

Mitotic double-strand break (DSB)-induced gene conversion at MAT in Saccharomyces cerevisiae was analyzed molecularly in mutant strains thermosensitive for essential replication factors. The processivity cofactors PCNA and RFC are essential even to synthesize as little as 30 nucleotides following strand invasion. Both PCNA-associated DNA polymerases delta and epsilon are important for gene conversion, though a temperature-sensitive Pol epsilon mutant is more severe than one in Pol delta. Surprisingly, mutants of lagging strand replication, DNA polymerase alpha (pol1-17), DNA primase (pri2-1), and Rad27p (rad27 delta) also greatly inhibit completion of DSB repair, even in G1-arrested cells. We propose a novel model for DSB-induced gene conversion in which a strand invasion creates a modified replication fork, involving leading and lagging strand synthesis from the donor template. Replication is terminated by capture of the second end of the DSB.

Provider choice and use of mental health care: implications for gatekeeper models.

OBJECTIVE: To examine the ways in which the costs of nonresidential mental health care depend on (1) the type of provider who initiates the treatment episode and (2) the level of cost sharing imposed on the patient. STUDY SETTING: The 1987 National Medical Expenditure Survey, a national probability sample of the U.S. civilian, noninstitutionalized population. DATA COLLECTION: Data were collected during four personal interviews conducted during 1987 and 1988. Key variables include the type of provider contacted at the beginning of treatment (psychiatrist, other physician, nonmedical mental health care specialist) and the cost (total actual payments from all sources) for the treatment episode. METHODS OF ANALYSIS: An episodic model of demand for mental health care is estimated using a two-step procedure. Multinomial probit analysis is first used to determine the factors that influence the choice of initial provider type. Right-censored Tobit analysis is used to determine the factors that affect the costs of care, including the type of provider who initiates the care episode. PRINCIPAL FINDINGS: Results indicate that out-of-pocket price does significantly (p < .05) affect the patient's initial choice of provider type but that, after controlling for the endogeneity of provider choice, price is no longer significant in explaining overall treatment costs. After controlling for selection effects, care episodes initiated by nonspecialist physicians are found to be as expensive as those initiated by psychiatrists and significantly more expensive than episodes initiated by nonphysicians. CONCLUSIONS: The results suggest that nonmedical mental health care specialists may be more effective than physicians in controlling costs when used as case managers in the care of persons with mental illnesses.

The formal mental health care burden among recently deinstitutionalized patients.

This article examines the extent to which the costs of formal health care are shifted from third-party payers to the patient and his or her family, especially during the transition to the community after discharge from a state hospital. Findings indicate that patients residing in the community are as likely to receive some care as their counterparts in institutions, but are at higher risk for uncovered care. Uncovered care is more likely to manifest as an unmet need for patients who have been recently discharged, especially for racial minorities, and as an out-of-pocket expense for patients who are established in the community.

Substitution of physicians and other providers in outpatient mental health care.

This paper evaluates the extent to which patients may substitute physician and non-physician outpatient mental health services in response to insurance coverage which differs by provider type. Using data from the National Medical Expenditure Survey, a semi-flexible two-stage demand specification is used to estimate substitution elasticities. Our results indicate that insurance coverage significantly affects the choice of provider from whom care is sought and, for individuals who seek care from both provider types, that physician and non-physician services are substitutes. Our elasticity estimates provide a welfare economic argument supporting coverage parity of physician and non-physician mental health services.

Measurement of short term health effects in economic evaluations.

Short term health effects can significantly impact health-related quality of life (HR-QOL). Appropriate healthcare priorities can be set only if they are based on health status measurements which are consistent with how people value both short and long term health effects. This article discusses methods by which such health effects may be measured using health state utilities. The standard discounted quality-adjusted life-year model, in which the values of the various health states are weighted by the time spent in each state, generally fails to capture the true impact of temporary ill health on HR-QOL. Instead, a scenario approach is recommended in which valuations are based on holistic descriptions of health states which include all short and long term health effects experienced.

Electrophoretic mobility and zeta potential of lysozyme crystals.

Using free-solution capillary electrophoresis, the electrophoretic mobility of micro m-sized lysozyme crystals in their growth solution at 283 K, 1.5%(w/v) NaC1, and over a range of pH values between 3.59 and 5.70 has been measured. Under these conditions, the mobility is independent of crystal size, while the calculated zeta potential increases from +8 to +24 mV as the pH decreases. Since the pH dependence of the zeta potential mirrors the pH dependence of charge on the free molecule, as determined by acid titration, it is concluded that the charge on the crystal is a result of H(+) adsorption from solution.

A method to elicit utilities for interpersonal comparisons.

This paper examines how values should be assigned to health states when policy decisions must be made about who should receive treatment. The paper demonstrates that, if priority were to be assigned to those people who would benefit most from treatment, standard health-state utilities might fail to identify resource allocations that would maximize total health-related well-being in society. A new measurement instrument is proposed that is based on the direct comparison of the well-being achieved by different people in various health states and thus captures such community priorities. A sample of 72 health administration students used the instrument to evaluate speech and mobility dysfunctions as they afflicted hypothetical people who differed by gender, family status, and occupational type. This preliminary analysis indicates that the instrument is feasible to use, and that the valuations of respondents did, for some health conditions, significantly depend on the type of person afflicted.