Enhancing Immunity with Nanomedicine: Employing Nanoparticles to Harness the Immune System.

The failure of immune responses to vaccines and dysfunctional immune responses to viral infection, tumor development, or neoantigens lead to chronic viral infection, tumor progression, or incomplete immune protection after vaccination. Thus, strategies to boost host immunity are a topic of intense research and development. Engineered nanoparticles (NPs) possess immunological properties and can be modified to promote improved local immune responses. Nanoparticle-based approaches have been employed to enhance vaccine efficacy and host immune responses to viral and tumor antigens, with impressive results. In this Perspective, we present an overview of studies, such as the one reported by Alam et al. in this issue of ACS Nano, in which virus-like particles have been employed to enhance immunity. We review the cellular cornerstones of effective immunity and discuss how NPs can harness these interactions to overcome the current obstacles in vaccinology and oncology. We also discuss the barriers to effective NP-mediated immune priming including (1) NP delivery to the site of interest, (2) the quality of response elicited, and (3) the potential of the response to overcome immune escape. Through this Perspective, we aim to highlight the value of nanomedicine not only in delivering therapies but also in coordinating the enhancement of host immune responses. We provide a forward-looking outlook for future NP-based approaches and how they could be tailored to promote this outcome.

Blood analytes of immature Kemp's ridley sea turtles (Lepidochelys kempii) from Georgia, USA: reference intervals and body size correlations.

Health assessments of wildlife species are becoming increasingly important in an ever-changing environment. Kemp's ridley sea turtles (Lepidochelys kempii; hereafter, Kemp's ridleys) are critically endangered and incur several on-going threats to their population recovery; therefore, it is imperative to advance the understanding of baseline blood analyte data as a diagnostic and monitoring tool. For in-water, trawl-captured, immature Kemp's ridleys (minimum N = 31) from Georgia, USA, the objectives of this study were to (1) establish reference intervals (RIs) for packed cell volume (PCV) and 27 plasma biochemistry analytes and (2) determine length-specific relationships in blood analytes. We observed significant positive correlations between minimum straight carapace length and PCV, amylase, calcium:phosphorus ratio, cholesterol, magnesium, triglycerides, total solids, total protein and all protein fractions (e.g. alpha-, beta- and gamma-globulins); aspartate aminotransferase and chloride showed significant negative relationships. These results suggest that certain blood analytes in Kemp's ridleys change as these animals grow, presumptively due to somatic growth and dietary shifts. The information presented herein, in due consideration of capture technique that may have impacted glucose and potassium concentrations, represents the first report of blood analyte RIs for Kemp's ridley sea turtles established by guidelines of the American Society for Veterinary Clinical Pathology and will have direct applications for stranded individuals in rehabilitative care and for future investigations into the health status of wild individuals from this population.

Perfluoroalkyl contaminants in plasma of five sea turtle species: comparisons in concentration and potential health risks.

The authors compared blood plasma concentrations of 13 perfluoroalkyl contaminants (PFCs) in five sea turtle species with differing trophic levels. Wild sea turtles were blood sampled from the southeastern region of the United States, and plasma was analyzed using liquid chromatography tandem mass spectrometry. Mean concentrations of perfluorooctane sulfonate (PFOS), the predominant PFC, increased with trophic level from herbivorous greens (2.41 ng/g), jellyfish-eating leatherbacks (3.95 ng/g), omnivorous loggerheads (6.47 ng/g), to crab-eating Kemp's ridleys (15.7 ng/g). However, spongivorous hawksbills had surprisingly high concentrations of PFOS (11.9 ng/g) and other PFCs based on their trophic level. These baseline concentrations of biomagnifying PFCs demonstrate interesting species and geographical differences. The measured PFOS concentrations were compared with concentrations known to cause toxic effects in laboratory animals, and estimated margins of safety (EMOS) were calculated. Small EMOS (<100), suggestive of potential risk of adverse health effects, were observed for all five sea turtle species for immunosuppression. Estimated margins of safety less than 100 were also observed for liver, thyroid, and neurobehavorial effects for the more highly exposed species. These baseline concentrations and the preliminary EMOS exercise provide a better understanding of the potential health risks of PFCs for conservation managers to protect these threatened and endangered species.

Effect of rating scales on scores given to junior doctors in multi-source feedback.

BACKGROUND: Multi-source feedback (MSF) has an established role in the workplace based assessment of doctors in training. Different models of MSF are currently used in different training programmes and settings. One important way in which these models differ is the rating scale on which assessors score the trainee. The aim of this study was to explore the effect of rating scale on MSF scores. METHODS: Foundation Year 2 trainees in hospitals in the West Midlands underwent MSF using the validated MSF tool, team assessment of behaviour (TAB) in autumn 2005. Trainees were scored with TAB using one of four different rating scales, ranging from 3- to 9-point scales. Each participating hospital used only one rating scale. The proportions of trainees scored as having potential problems were related to the different rating scale used. Similarly, the proportions scored as 'above expectations' were compared. Assessors also completed a short questionnaire regarding the assessment. RESULTS: 245 trainees underwent 2594 assessments. Longer rating scales were associated with a lower proportion of trainees awarded 'problem' scores and higher proportions of trainees scored as 'above expectations'. Assessors generally reported no difficulties whichever rating scale they had used. CONCLUSION: Careful consideration, recognising its potential impact on assessment score, should be given to the rating scale used when instituting MSF within a system of workplace based assessment.

Diabetes care: provider disparities in the US Appalachian region.

INTRODUCTION: Diabetes is a devastating and growing problem in the USA and throughout the world. Parts of Appalachia, especially the most rural and economically 'distressed' areas of the region, have disproportionately high levels of diabetes incidence and have had long-standing problems in healthcare access. PURPOSE: Little is known about the status of public health infrastructures and expertise available to address the diabetes epidemic, whether in Appalachia or elsewhere. This research examines the availability of professional diabetes care in Appalachia, including the economically distressed areas of the region. METHODS: A 2006 cross-sectional survey of healthcare providers in the Appalachian Region identified diabetes service needs and availability in Appalachian healthcare facilities. Survey data and socioeconomic data were combined as a means to assess intra-regional variation in service availability. RESULTS: Participants perceived that diabetes prevalence was growing in Appalachia and that they were seeing increasing numbers of persons with diabetes. Healthcare facilities in the region rarely employed specialized health professional providers and the expertise concerning diabetes in some clinicians may be limited. CONCLUSION: The current and growing diabetes problem in Appalachia underscores the need for appropriate diabetes services and health professionals acquainted with current standards in diabetes care. Such problems in Appalachia have long been identified and linked with insufficient healthcare resources. The identification of ways to assure that local clinicians have current knowledge of diabetes standards of care is warranted.

Diabetes education in the Appalachian region: providers' views.

INTRODUCTION: The aim of this study was to examine provider perceptions concerning the provision and accessibility of diabetes education, according to levels of economic distress and rurality throughout the US Appalachian region. METHODS: A questionnaire regarding diabetes education resources was developed and mailed to all Federally Qualified Health Centers (FQHC), health departments, and known certified diabetes educators (CDEs) in the Appalachian region. Diabetes education was examined according to historical economic distress, distressed/at risk (DAR) versus not DAR (NDAR). RESULTS: Diabetes education classes were offered equally across DAR and NDAR locations and most patients with diabetes had attended. The CDEs and physicians were less common in DAR compared with NDAR sites (adjusted odds ratios [aOR]=0.33 [0.13, 0.85] and 59.1 vs 166.9 per 100 000; p < 0.001). The DAR sites were more likely than NDAR sites to report transportation (aORs 2.19-4.94) as a problem for patients and insufficient staff (aOR=2.50 [1.20, 5.18]) as a problem for diabetes education programs. CONCLUSIONS: Although DAR areas functioned with fewer health professionals than NDAR areas, many of the barriers to providing education affected patients and health professionals in both DAR and NDAR areas.

Predaceous ants, beach replenishment, and nest placement by sea turtles.

Ants known for attacking and killing hatchling birds and reptiles include the red imported fire ant (Solenopsis invicta Buren), tropical fire ant [Solenopsis geminata (Fabr.)], and little fire ant [Wasmannia auropunctata (Roger)]. We tested whether sea turtle nest placement influenced exposure to predaceous ants. In 2000 and 2001, we surveyed ants along a Florida beach where green turtles (Chelonia mydas L.), leatherbacks (Dermochelys coriacea Vandelli), and loggerheads (Caretta caretta L.) nest. Part of the beach was artificially replenished between our two surveys. As a result, mean beach width experienced by nesting turtles differed greatly between the two nesting seasons. We surveyed 1,548 sea turtle nests (2000: 909 nests; 2001: 639 nests) and found 22 ant species. S. invicta was by far the most common species (on 431 nests); S. geminata and W. auropunctata were uncommon (on 3 and 16 nests, respectively). In 2000, 62.5% of nests had ants present (35.9% with S. invicta), but in 2001, only 30.5% of the nests had ants present (16.4% with S. invicta). Turtle nests closer to dune vegetation had significantly greater exposure to ants. Differences in ant presence on turtle nests between years and among turtle species were closely related to differences in nest placement relative to dune vegetation. Beach replenishment significantly lowered exposure of nests to ants because on the wider beaches turtles nested farther from the dune vegetation. Selective pressures on nesting sea turtles are altered both by the presence of predaceous ants and the practice of beach replenishment.

Effects of spontaneous KitlSteel mutations on survival and red blood cells of mice.

Kit ligand (Kitl), which is a member of the helical cytokine superfamily, is encoded by the Steel (Sl) locus of mice and is essential for the development of hematopoietic cells, germ cells, and melanocytes. A large series of Kitl(Sl) alleles has been described, including some that arose spontaneously and others that were induced by either chemical or radiation mutagenesis. Here we describe the nucleotide sequence alterations in two spontaneous Kitl(Sl) alleles. The Kitl(Sl-18R) allele has a point mutation that introduces a premature termination codon, and the encoded protein is expected to be null functionally. The Kitl(Sl-5R) allele has an in-frame deletion that results in deletion of amino acids at position 31 and 32 of Kitl. While both mutations exert severe effects on blood cells and survival of homozygous mice, these effects are slightly milder than those of a previously characterized spontaneous deletion allele, Kitl(Sl-gb). Examination of the survival of compound heterozygotes provided strong genetic evidence that the Kitl(Sl-18R) and Kitl(Sl-5R) mutants are null functionally for mouse survival.

Representation of Long-Time Creep in a Pure-Gum Rubber Vulcanizate.

Creep may be expressed as ΔE/E 1 = A log t + B(t-1) where ΔE is the increase of elongation above E 1 the one-minute value, during the time t. The initial slope of a plot of ΔE/E 1 against log t is A, a measure of physical creep. The limit of the final slope of a plot of ΔE/E 1 against (t-1) is B, a measure of chemical creep. The validity of the equation is determined by the linearity of a plot of (ΔE/E 1 - A log t) against (t-1) after A has been determined by the first plot. B is obtained as the slope. The equation is almost always valid and simultaneous equations can be used to determine A and B from only three observations, if desired. A, usually between 1 and 10 per cent/unit log t, is strongly dependent on cross-linking and nearly independent of temperature. B, ranging from 0.1 × 10-5 to 10,000 × 10-5 per cent/min is nearly independent of cross-linking and strongly dependent on temperature and specimen thickness. With an activation energy of 84-125 kJ (mol)-1 (20-30 kcal (mol)-1) it probably reflects oxidative degradation of the network, often initiated by ozone. The appearance time at which the creep is first observed to exceed A log t can be taken as equal to B -1. At high temperatures B is drastically increased with a corresponding strong reduction in appearance time. Creep in excess of that given by the equation is sometimes observed during a period immediately before rupture.

Molecular Interpretations of Modulus and Swelling Relations in Natural Rubber Cross-Linked by Dicumyl Peroxide.

A survey of published experimental work on the modulus of natural rubber cross-linked by dicumyl peroxide permits a comparison with the results and molecular interpretations obtained in recent NBS work [J. Res. NBS 76A, No. 1, 51 (1972), 77A, No. 1, 171 (1973) and 80A, No. 3, 451 (1976)]. Excellent agreement was found among values of the shear modulus G at the same cross-linking when the cross-linking is calculated from the amount of decomposed dicumyl peroxide. The types of deformation included torsion as well as uniaxial extension and compression. G increases linearly with cross-linking (except at the lowest degrees) with a slope from 5 to 15 percent greater than that predicted by the simple statistical theory. Data of Mullins demonstrated that at each degree of cross-linking the value of G is intermediate between 2C 1 and 2(C 1 + C 2) where C 1 and C 2 are the Mooney-Rivlin constants. Measurements of equilibrium swelling at a given degree of cross-linking are in reasonable agreement with each other. However the entropy components of the modulus and the sub-chain density calculated from swelling measurements are appreciably greater than those calculated from cross-linking or from direct mechanical measurements. They increase linearly with cross-linking. It is concluded that the number of sub-chains effective in limiting swelling is greater than that effective in direct mechanical measurements.

Uniaxial Extension and Compression in Stress-Strain Relations of Rubber.

A survey of experimental data from the literature in cases where the deformation of a specimen is varied continuously from uniaxial compression to tensile deformation shows that Young's Modulus M, defined as the limit of stress to strain in the undeformed state, is independent of the direction of approach to the limit. The normalized stress-strain relation of Martin, Roth, and Stiehler (MRS, 1956) is F/M = (L-1 - L-2) exp A (L - L-1) where F is the stress on the undeformed section, L is the extension ratio, and M and A are constants. Values of M and A are obtained from the intercept and slope of a graph of experimental observations of log F/(L-1 - L-2) against (L - 1-1) including observations of uniaxial compression if available. They found the value of A to he about 0.38 for pure-gum vulcanizates of natural rubber and several synthetics. In later work several observers have now found that the equation is also valid for vulcanizates containing a filler, but A is higher, reaching a value of about 1 for large amounts of filler. In extreme cases A is not constant at low deformations. The range of applicability in many cases now is found to extend from the compressive region where L = 0.5 up to the point of tensile rupture or to a point where A increases abruptly because of crystallization. Taking A as a constant parameter in the range 0.36 to 1, graphs are presented showing calculated values of (1) F/M as a function of L and (2) the normalized Mooney-Rivlin plot of F/[2M(L - L-2)] against L-1. Each of the latter graphs has only a limited region of linearity corresponding to constant values of the Mooney-Rivlin coefficients C1 and C2. Since this region does not include the undeformed state, where L = 1, or any of the compression region, the utility of the Mooney-Rivlin equation is extremely limited, since it can not be used at low elongations. The coefficients are dramatically altered for rubbers showing different values of the MRS constant A. For rubbers showing the higher values of A, the coefficients are radically altered and the region of approximate linearity is drastically reduced.

Modulus of Natural Rubber Cross-Linked by Dicumyl Peroxide III. Some Molecular Interpretations, Possible Refinements of Theory, and Conclusions.

The shear modulus G = 5.925 × 10 - 3(fp - 0.45)T+G* (Part I), its energy component G* = 0.0684 (fp - 0.45)+ 2.70 (Part II), and the number of effective suh-chains per unit volume ve = (G - G*)/RT are given detailed molecular consideration. G is given in Mdyn cm-2 for rubber cross-linked by adding p parts of dicumyl peroxide per hundred of rubber, and heating until a fraction f of the peroxide is decomposed. ve is found to be approximately twice the density of cross-links, after a correction for impurities and chain ends is made. It can not be computed as G/RT since only the entropy component of modulus is related to ve. The sub-chains for the most highly cross-linked rubbers studied had a molecular weight of about 575 g mol-1, corresponding to about 8 isoprene units. The modulus corresponding to no added cross-links is not zero. It is determined chiefiy by the energy component of the modulus; it does not arise from entanglements. The "front factor" is found to be unity. An extensive literature survey yields values of the quantity RTΨ(v 2), where Ψ (v 2) is the Flory- Rehner equation function of v 2, the equilibrium volume fraction obtained by swelling the cross-linked rubber. RTψ (v 2) is found to be greater than G - G* but not as large as G itself.

Long-Time Creep in a Pure-Gum Rubber Vulcanizate: Influence of Humidity and Atmospheric Oxygen.

Long-time creep of natural rubber cured with a sulfur-accelerator recipe containing no filler can be conveniently represented by a plot of (E - E 1)/E 1 = ΔE/E 1 with a double-abscissa scale showing log t and t. E is the elongation at any time t, after application of the load, and E 1 its value at unit time. Experimental data conform to the equation except for a more rapid rise preceding rupture. The constants A and B can be evaluated from only three observations-at the longest time (about 70 days), at one minute, and at an intermediate time. ΔE/E 1 is approximately linear with log t when t is less than 0.1(A/B) and approximately linear with t when t is greater than 4.343(A/B). The observed modulus was about 1.4 MPa and A was about 2.4 percent/(unit log t) when the atmosphere was a vacuum, dry N2, or dry air. The modulus was lowered very slightly and A became about 4 percent/(unit log t) when the air was saturated with water. B was raised from about 2 × 10-5 percent/min to about 20 × 10-5 percent/min when the vacuum or dry N2 was replaced by dry air and to about 50 × 10-5 percent/min when the air was saturated with moisture. A is considered to be related to physical relaxation, while B corresponds to a chemical reaction, probably oxidative degradation.

Modulus of Natural Rubber Cross-Linked by Dicumyl Peroxide II. Comparison With Theory.

Thermodynamics and molecular considerations are applied to an examination of the equation G = S(fp + B)T + H(fp + B) + A = 5.925 × 10-3(fp - 0.45)T + 0.0684(fp - 0.45) + 2.70, found experimentally in Part I. G is the shear modulus in Mdyn cm-2 at a temperature T for natural rubber cross-linked by adding p parts of dicumyl peroxide per hundred of rubber (phr) and heating until a fraction f of the peroxide is decomposed. G*, the energy component of the modulus, is H(fp + B) + A. The ratio G*/G decreases from 1.00 at the gel point (fp = 0.45 phr) to 0.5 near 2 phr and to 0.09 at 23.8 phr. The modulus G is related to ν e , the number of moles of effective sub-chains per cm3, by the equation G - G* = v e RT where R is the gas constant. If each molecule of decomposed dicumyl peroxide of molecular weight M d produces one cross-link in the rubber of specific volume υ ¯ r , then it is predicted that S = 2 R ( 100 M d υ ¯ r ) - 1 = 5.5535 × 10 - 3 Mdyn cm-2 phr-1 K-1, as compared with the experimental value 5.925 × 10-3. Theory gives no prediction of the values of A, or of H. The gel point may be located experimentally as the point where the slope of the modulus-temperature relation is zero. The value of G at the gel point is the energy component G*. The experimental value of fp at the gel point permits a calculation of the molecular weight of the rubber before cross-linking as 193,000. The results afford a very satisfactory confirmation of the essential validity of the statistical theory of rubber elasticity in its simplest form, if due regard is paid to G*, the energy component of the modulus.

Modulus of Natural Rubber Cross-Linked by Dicumyl Peroxide. I. Experimental Observations.

Natural rubber mixed with varying amounts of dicumyl peroxide was cross-linked by heating 120 min at 149 °C. The quantitative measure of cross-linking was taken as the amount fp of decomposed dicumyl peroxide, the product of p, the number of parts added per hundred of rubber and f the fraction decomposed during the time of cure. The shear creep modulus G was calculated from measurements of the indentation of a flat rubber sheet by a rigid sphere. The glass transition temperature T g , was raised about 1.2 °C for each part of decomposed dicumyl peroxide. Above (T g + 12) the modulus-temperature relations were linear with a slope that increased with increasing cross-linking. The creep rate was negligible except near the glass transition and at low values of fp. Values of G, read from these plots at seven temperatures, were plotted as a function of fp. The linearity of the two plots permits the derivation of the general relation: G = S(fp + B)T + H(fp + B) + A where A, B, H, and S are constants. The lines representing G as a function of fp at each temperature all intersected near the point, fp = 0.45 phr, G = 2.70 Mdyn cm-2 (0.270 MN m-2). The constants were evaluated as A = 2.70 Mdyn cm-2, B = -0.45 phr, S = 5.925 × 10-3 Mdyn cm-2(phr)-1K-1 and H = 0.0684 (Mdyn cm-2) (phr)-1. This equation represented satisfactorily all the data obtained at temperatures from -50 to +100 °C for values of fp from about 1 to 24 phr.