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Notes: We study the equilibrium conformations of liquid microstructures on flat but chemically heterogeneous substrates using energy minimization computations. The surface patterns, which establish regions of different surface energy, induce deformations of the liquid–solid contact line. Depending on the geometry, these deformations either promote or impede capillary breakup and bulge formation. The contact angles of the liquid on the hydrophilic and hydrophobic regions, as well as the pattern geometry and volume of liquid deposited, strongly affect the equilibrium shapes. Moreover, due to the small scale of the liquid features, the presence of chemical or topological surface defects significantly influence the final liquid shapes. Preliminary experiments with arrays of parallel hydrophilic strips produce shapes resembling the simulated forms. These encouraging results provide a basis for the development of high resolution lithography by direct wet printing. © 2000 American Institute of Physics.

Notes: We characterize the selective deposition of liquid microstructures on chemically heterogeneous surfaces by means of dip coating processes. The maximum deposited film thickness depends critically on the speed of withdrawal as well as the pattern size, geometry, and angular orientation. For vertically oriented hydrophilic strips, we derive a hydrodynamic scaling relation for the deposited film thickness which agrees very well with interferometric measurements of dip-coated liquid lines. Due to the lateral confinement of the liquid, our scaling relation differs considerably from the classic Landau–Levich formula for chemically homogeneous surfaces. Dip coating is a simple method for creating large area arrays of liquid microstructures for applications involving chemical analysis and synthesis, biochemical assays, or wet printing of liquid polymer or ink patterns. © 2000 American Institute of Physics.

Notes: Antimicrobial peptides are essential to innate host defense as effectors of pathogen clearance and can modify host cell behaviors to promote wound repair. While these two functions appear interrelated, it is unclear whether the ability to aid in wound repair requires inherent antimicrobial function. We hypothesized that the influence of antimicrobial peptides on wound repair is not dependent on antimicrobial function. To explore this, we analyzed the microbial killing activity of peptide fragments and correlated this with the ability to influence wound repair in mice. HB-107, a peptide lacking antimicrobial activity and originally derived from the antimicrobial cecropin B, showed up to 64 percent improvement in wound repair compared to scrambled peptide and vehicle controls, an effect comparable to treatment with recombinant human platelet-derived growth factor-BB (formulated as RegranexTM). Wounds treated with HB-107 showed keratinocyte hyperplasia and increased leukocyte infiltration. Furthermore, HB-107 stimulated interleukin-8 secretion from cultured endothelial cells, an effect that may explain the increase in leukocyte migration. These findings confirm that antimicrobial peptides can function as effectors of cutaneous wound repair. Moreover, this study furthers our understanding of antimicrobial peptides by showing that their wound repair properties can be independent of antimicrobial function.

Notes: Peptides of the innate immune system play a vital role in the protection and repair of almost all biological systems. Such peptides have been implicated in a range of activities associated with prevention of disease and modulation of innate immunity. HB107 is a derivative of one such peptide, Cecropin B, that has demonstrated efficacy in enhancing wound healing in both burn and incision animal models. HB107 has been evaluated for efficacy in a mouse incision model and for safety and efficacy in a pig burn wound model. Topical application of the peptide gives RE50(time needed for 50% re-epithelialization) values of 10.28 days for 500 ug/mL and 12.72 days for 100 ug/mL compared to control 16.45 days. Additionally the peptide was well tolerated in terms of safety both topically and in an IV acute toxicity mouse model with no adverse effects observed. HB107 not only demonstrated efficacy and safety, but due to being a relatively short synthetic peptide, costs significantly less to manufacture than the current approved therapies.

Notes: Genetic differences (polymorphisms) among members of a population are thought to influence susceptibility to various environmental exposures. In practice, however, this information is rarely incorporated into quantitative risk assessment and risk management. We describe an analytic framework for predicting the risk reduction and value-of-information (VOI) resulting from specific risk management applications of genetic biomarkers, and we apply the framework to the example of occupational chronic beryllium disease (CBD), an immune-mediated pulmonary granulomatous disease. One described Human Leukocyte Antigen gene variant, HLA-DPβ1*0201, contains a substitution of glutamate for lysine at position 69 that appears to have high sensitivity (∼94%) but low specificity (∼70%) with respect to CBD among individuals occupationally exposed to respirable beryllium. The expected postintervention CBD prevalence rates for using the genetic variant (1) as a required job placement screen, (2) as a medical screen for semiannual in place of annual lymphocyte proliferation testing, or (3) as a voluntary job placement screen are 0.08%, 0.8%, and 0.6%, respectively, in a hypothetical cohort with 1% baseline CBD prevalence. VOI analysis is used to examine the reduction in total social cost, calculated as the net value of disease reduction and financial expenditures, expected for proposed CBD intervention programs based on the genetic susceptibility test. For the example cohort, the expected net VOI per beryllium worker for genetically based testing and intervention is $13,000, $1,800, and $5,100, respectively, based on a health valuation of $1.45 million per CBD case avoided. VOI results for alternative CBD valuations are also presented. Despite large parameter uncertainty, probabilistic analysis predicts generally positive utility for each of the three evaluated programs when avoidance of a CBD case is valued at $1 million or higher. Although the utility of a proposed risk management program may be evaluated solely in terms of risk reduction and financial costs, decisions about genetic testing and program implementation must also consider serious social, legal, and ethical factors.

Notes: This article presents a general model for estimating population heterogeneity and “lack of knowledge” uncertainty in methylmercury (MeHg) exposure assessments using two-dimensional Monte Carlo analysis. Using data from fish-consuming populations in Bangladesh, Brazil, Sweden, and the United Kingdom, predictive model estimates of dietary MeHg exposures were compared against those derived from biomarkers (i.e., [Hg]hair and [Hg]blood). By disaggregating parameter uncertainty into components (i.e., population heterogeneity, measurement error, recall error, and sampling error) estimates were obtained of the contribution of each component to the overall uncertainty. Steady-state diet:hair and diet:blood MeHg exposure ratios were estimated for each population and were used to develop distributions useful for conducting biomarker-based probabilistic assessments of MeHg exposure. The 5th and 95th percentile modeled MeHg exposure estimates around mean population exposure from each of the four study populations are presented to demonstrate lack of knowledge uncertainty about a best estimate for a true mean. Results from a U.K. study population showed that a predictive dietary model resulted in a 74% lower lack of knowledge uncertainty around a central mean estimate relative to a hair biomarker model, and also in a 31% lower lack of knowledge uncertainty around central mean estimate relative to a blood biomarker model. Similar results were obtained for the Brazil and Bangladesh populations. Such analyses, used here to evaluate alternative models of dietary MeHg exposure, can be used to refine exposure instruments, improve information used in site management and remediation decision making, and identify sources of uncertainty in risk estimates.

Notes: Topical prophylaxis against wound infection by an agent that is active against multi-resistant bacteria does not generate resistance and is rapidly cidal would be of great clinical benefit. Peptides of the innate immune system have long been known to protect a wide range of organisms from attack by bacterial and fungal pathogens. Helix BioMedix Inc. has developed a short bioactive peptide antimicrobial modeled after these peptides. HB-50 is an amphipathic cationic alpha-helical peptide that has broad spectrum activity and is rapidly microbicidal. These attributes make HB-50 an ideal candidate for wound infection prophylaxis. In vitro studies have demonstrated HB-50 to be active against both gram-positive and gram-negative bacteria killing 5–7 log orders of bacteria within minutes. In addition, this peptide has potent activity against Vancomycin and Mupirocin resistant S. aureus. Preliminary testing of the peptide in a rat abraded skin infection model has shown the peptide’s effectiveness in preventing wound infection while not inhibiting wound healing. Additionally, the HB-50 sequence has been specifically developed to be cost effective to manufacture and therefore is well suited for use as a topical antimicrobial agent.

Notes: Risks associated with toxicants in food are often controlled by exposure reduction. When exposure recommendations are developed for foods with both harmful and beneficial qualities, however, they must balance the associated risks and benefits to maximize public health. Although quantitative methods are commonly used to evaluate health risks, such methods have not been generally applied to evaluating the health benefits associated with environmental exposures. A quantitative method for risk-benefit analysis is presented that allows for consideration of diverse health endpoints that differ in their impact (i.e., duration and severity) using dose-response modeling weighted by quality-adjusted life years saved. To demonstrate the usefulness of this method, the risks and benefits of fish consumption are evaluated using a single health risk and health benefit endpoint. Benefits are defined as the decrease in myocardial infarction mortality resulting from fish consumption, and risks are defined as the increase in neurodevelopmental delay (i.e., talking) resulting from prenatal methylmercury exposure. Fish consumption rates are based on information from Washington State. Using the proposed framework, the net health impact of eating fish is estimated in either a whole population or a population consisting of women of childbearing age and their children. It is demonstrated that across a range of fish methylmercury concentrations (0–1 ppm) and intake levels (0–25 g/day), individuals would have to weight the neurodevelopmental effects 6 times more (in the whole population) or 250 times less (among women of child-bearing age and their children) than the myocardial infarction benefits in order to be ambivalent about whether or not to consume fish. These methods can be generalized to evaluate the merits of other public health and risk management programs that involve trade-offs between risks and benefits.

Notes: One-week treatment with the benzodiazepine (BZ) flurazepam (FZP), results in anticonvulsant tolerance, associated with reduced GABAA receptor (GABAR) subunit protein and miniature inhibitory post-synaptic current (mIPSC) amplitude in CA1 neurons of rat hippocampus. Because protein kinase A (PKA) has been shown to modulate GABAR function in CA1 pyramidal cells, the present study assessed whether GABAR dysfunction is associated with changes in PKA activity. Two days after 1-week FZP treatment, there were significant decreases in basal (− 30%) and total (− 25%) PKA activity, and a 40% reduction in PKA RIIβ protein in the insoluble fraction of CA1 hippocampus. The soluble component of CA1 showed a significant increase in basal (100%) but not total PKA activity. Whole-cell recording in vitro showed a 50% reduction in mIPSC amplitude in CA1 pyramidal cells, with altered sensitivity to PKA modulators. Neurons from FZP-treated rats responded to 8-bromo-cAMP with a significant increase (31%) in mIPSC amplitude. Likewise, vasoactive intestinal polypeptide (VIP), an endogenous PKA activator, caused a significant 36% increase in mIPSC amplitude in FZP-treated cells. Neither agent had a significant effect on mIPSC amplitude in control cells. This study supports a role for PKA in GABAR dysfunction after chronic FZP treatment.

Notes: Although the toxin 6-hydroxydopamine (6-OHDA) is utilized extensively in animal models of Parkinson's disease, the underlying mechanism of its toxic effects on dopaminergic neurons is not completely understood. We examined the effects of 6-OHDA on the CNS-derived tyrosine hydroxylase expressing B65 cell line, with particular attention to the regulation of the extracellular signal-regulated protein kinases (ERK). 6-OHDA elicited a dose-dependent cytotoxicity in B65 cells. Toxic doses of 6-OHDA also elicited a biphasic pattern of ERK phosphorylation with a prominent sustained phase, a pattern that differed from that observed with hydrogen peroxide (H2O2) treatment. 6-OHDA-elicited ERK phosphorylation was blocked by PD98059, an inhibitor of the upstream mitogen activated protein kinase kinase (MEK) that phosphorylates and activates ERK. PD98059 also conferred protection against 6-OHDA cytotoxicity, but did not affect H2O2 toxicity in B65 cells. These results suggest that ERK activation plays a direct mechanistic role in 6-OHDA toxicity, rather than representing a protective compensatory response, and raise the possibility that abnormal patterns of ERK activation may contribute to dopaminergic neuronal cell death.