NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir.

Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.

A review of phosphorus homeostasis and the impact of different types and amounts of dietary phosphate on metabolism and renal health in cats.

Elevated concentrations of serum phosphate are linked with progression and increased case fatality rate in animals and humans with chronic kidney disease. Elevated concentrations of serum phosphate can be a risk factor for development of renal and cardiovascular diseases or osteoporosis in previously healthy people. In rodents, an excess intake of dietary phosphorus combined with an inverse dietary calcium : phosphorus ratio (<1 : 1) contributes to renal calcification. Renal injury also has occured in cats fed experimental diets supplemented with highly soluble phosphate salts, especially in diets with inverse calcium : phosphorus ratios. However, not all phosphorus sources contribute similarly to this effect. This review, which focuses on cats, summarizes the published evidence regarding phosphorus metabolism and homeostasis, including the relative impact of different dietary phosphorus sources, and their impact on the kidneys. No data currently shows that commercial cat foods induce renal injury. However, some diets contain high amounts of phosphorus relative to recommendations and some have inverse Ca : P ratios and so could increase the risk for development of kidney disease. While limiting the use of highly soluble phosphates appears to be important, there are insufficient data to support a specific upper limit for phosphate intake. This review also proposes areas where additional research is needed in order to strengthen conclusions and recommendations regarding dietary phosphorus for cats.

Health Disparities in the Relationship of Neighborhood Greenness to Mental Health Outcomes in 249,405 U.S. Medicare Beneficiaries.

Prior studies suggest that exposure to the natural environment may be important for optimal mental health. The present study examines the association between block-level greenness (vegetative presence) and mental health outcomes, in a population-based sample of 249,405 U.S. Medicare beneficiaries aged ≥65 years living in Miami-Dade County, Florida, USA, whose location did not change from 2010 to 2011. Multilevel analyses examined relationships between greenness, as measured by mean Normalized Difference Vegetation Index from satellite imagery at the Census block level, and each of two mental health outcomes; Alzheimer's disease and depression, respectively, after statistically adjusting for age, gender, race/ethnicity, and neighborhood income level of the individuals. Higher block-level greenness was linked to better mental health outcomes: There was a reduced risk of Alzheimer's disease (by 18%) and depression (by 28%) for beneficiaries living in blocks that were 1 SD above the mean for greenness, as compared to blocks that were 1 SD below the mean. Planned post-hoc analyses revealed that higher levels of greenness were associated with even greater mental health benefits in low-income neighborhoods: An increase in greenness from 1 SD below to 1 SD above the mean was associated with 37% lower odds of depression in low-income neighborhoods, compared to 27% and 21% lower odds of depression in medium- and high-income neighborhoods, respectively. Greenness may be effective in promoting mental health in older adults, particularly in low-income neighborhoods, possibly as a result of the increased opportunities for physical activity, social interaction, or stress mitigation.

Mixed reality virtual pets to reduce childhood obesity.

Novel approaches are needed to reduce the high rates of childhood obesity in the developed world. While multifactorial in cause, a major factor is an increasingly sedentary lifestyle of children. Our research shows that a mixed reality system that is of interest to children can be a powerful motivator of healthy activity. We designed and constructed a mixed reality system that allowed children to exercise, play with, and train a virtual pet using their own physical activity as input. The health, happiness, and intelligence of each virtual pet grew as its associated child owner exercised more, reached goals, and interacted with their pet. We report results of a research study involving 61 children from a local summer camp that shows a large increase in recorded and observed activity, alongside observational evidence that the virtual pet was responsible for that change. These results, and the ease at which the system integrated into the camp environment, demonstrate the practical potential to impact the exercise behaviors of children with mixed reality.

Fractionated photothermal antitumor therapy with multidye nanoparticles.

PURPOSE: Photothermal therapy is an emerging cancer treatment paradigm which involves highly localized heating and killing of tumor cells, due to the presence of nanomaterials that can strongly absorb near-infrared (NIR) light. In addition to having deep penetration depths in tissue, NIR light is innocuous to normal cells. Little is known currently about the fate of nanomaterials post photothermal ablation and the implications thereof. The purpose of this investigation was to define the intratumoral fate of nanoparticles (NPs) after photothermal therapy in vivo and characterize the use of novel multidye theranostic NPs (MDT-NPs) for fractionated photothermal antitumor therapy. METHODS: The photothermal and fluorescent properties of MDT-NPs were first characterized. To investigate the fate of nanomaterials following photothermal ablation in vivo, novel MDT-NPs and a murine mammary tumor model were used. Intratumoral injection of MDT-NPs and real-time fluorescence imaging before and after fractionated photothermal therapy was performed to study the intratumoral fate of MDT-NPs. Gross tumor and histological changes were made comparing MDT-NP treated and control tumor-bearing mice. RESULTS: The dual dye-loaded mesoporous NPs (ie, MDT-NPs; circa 100 nm) retained both their NIR absorbing and NIR fluorescent capabilities after photoactivation. In vivo MDT-NPs remained localized in the intratumoral position after photothermal ablation. With fractionated photothermal therapy, there was significant treatment effect observed macroscopically (P = 0.026) in experimental tumor-bearing mice compared to control treated tumor-bearing mice. CONCLUSION: Fractionated photothermal therapy for cancer represents a new therapeutic paradigm enabled by the application of novel functional nanomaterials. MDT-NPs may advance clinical treatment of cancer by enabling fractionated real-time image guided photothermal therapy.

Over-treatment of carbapenemase-producing Enterobacteriaceae.

OBJECTIVES: To describe the treatment and outcomes of patients with carbapenemase-producing Enterobacteriaceae and evaluate whether these cases represented active infection requiring antibiotic therapy or colonization. METHODS: Adult inpatients with carbapenemase-producing Enterobacteriaceae were retrospectively evaluated. Cases were classified as colonization versus infection by 2 infectious diseases physicians. Multiple cultures that grew in the same patient within a 2-week period were evaluated as a single case. RESULTS: A total of 42 cases among 35 patients were identified. The mean age of the cohort was 67.7 ± 13.7 y, mean APACHE II score was 17.9 ± 8.6, and 77% of patients were in the intensive care unit when the carbapenem-producing Enterobacteriaceae was isolated. Klebsiella pneumoniae (84%) was the predominant organism; urine (36%), tissue/wound/drainage (25%), and blood (20%) were the most common sites of collection. Though 43% of cases were classified as colonization, 56% of these cases were treated with antibiotics. Only 1 patient characterized as colonized subsequently developed infection, 29 days later. Among infected cases, colistin (55%), meropenem (41%), aminoglycosides (32%), and tigecycline (27%) were used for treatment, and combination antimicrobial therapy was common (55%). Clinical and microbiological success was higher in patients receiving combination therapy (83% vs 60%, p = 0.35). Colistin monotherapy was only successful in urinary infections. All-cause hospital mortality was 29%. CONCLUSIONS: Nearly half of cases represented colonization, yet the majority were treated with broad-spectrum antibiotics. Determining infection versus colonization is a critical first step in managing patients with carbapenemase-producing Enterobacteriaceae. The risk of not treating apparent colonization appears low.

Increasing capacity: practice effects in absolute identification.

In most of the long history of the study of absolute identification--since Miller's (1956) seminal article--a severe limit on performance has been observed, and this limit has resisted improvement even by extensive practice. In a startling result, Rouder, Morey, Cowan, and Pfaltz (2004) found substantially improved performance with practice in the absolute identification of line lengths, albeit for only 3 participants and in a somewhat atypical paradigm. We investigated the limits of this effect and found that it also occurs in more typical paradigms, is not limited to a few virtuoso participants or due to relative judgment strategies, and generalizes to some (e.g., line inclination and tone frequency) but not other (e.g., tone loudness) dimensions. We also observed, apart from differences between dimensions, 2 unusual aspects of improvement with practice: (a) a positive correlation between initial performance and the effect of practice and (b) a large reduction in a characteristic trial-to-trial decision bias with practice.

Healthy skepticism: assessing realistic model performance.

Although the development of computational models to aid drug discovery has become an integral part of pharmaceutical research, the application of these models often fails to produce the expected impact on productivity. One reason for this may be that the expected performance of many models is simply not supported by the underlying data, because of often neglected effects of assay and prediction errors on the reliability of the predicted outcome. Another significant challenge to realizing the full potential of computational models is their integration into prospective medicinal chemistry campaigns. This article will analyze the impact of assay and prediction error on model quality, and explore scenarios where computational models can expect to have a significant influence on drug discovery research.

Application of belief theory to similarity data fusion for use in analog searching and lead hopping.

A wide variety of computational algorithms have been developed that strive to capture the chemical similarity between two compounds for use in virtual screening and lead discovery. One limitation of such approaches is that, while a returned similarity value reflects the perceived degree of relatedness between any two compounds, there is no direct correlation between this value and the expectation or confidence that any two molecules will in fact be equally active. A lack of a common framework for interpretation of similarity measures also confounds the reliable fusion of information from different algorithms. Here, we present a probabilistic framework for interpreting similarity measures that directly correlates the similarity value to a quantitative expectation that two molecules will in fact be equipotent. The approach is based on extensive benchmarking of 10 different similarity methods (MACCS keys, Daylight fingerprints, maximum common subgraphs, rapid overlay of chemical structures (ROCS) shape similarity, and six connectivity-based fingerprints) against a database of more than 150,000 compounds with activity data against 23 protein targets. Given this unified and probabilistic framework for interpreting chemical similarity, principles derived from decision theory can then be applied to combine the evidence from different similarity measures in such a way that both capitalizes on the strengths of the individual approaches and maintains a quantitative estimate of the likelihood that any two molecules will exhibit similar biological activity.

Oxidative stress and chronic kidney disease.

Slowing the rate of progression of chronic kidney disease (CKD) is a critical part of the management of affected dogs and cats. Renal oxidant stress is a previously unrecognized factor in the progression of canine CKD and is likely to be similarly important in feline CKD. Renin-angiotensin antagonism, calcium channel antagonism, n-3 polyunsaturated fatty acid, and antihypertensive and antiproteinuric therapy are commonly recommended for dogs and cats with CKD. These therapies would be expected to reduce renal oxidant stress by decreasing reactive oxygen species generation. Newer data indicate that dietary supplementation with specific antioxidants is an important consideration for limiting renal oxidant stress and progression of CKD.

Retinoid requirements in the reproduction of zebrafish.

This study examines whether retinoids are essential in the reproduction of zebrafish. Using RT-PCR, it was shown that the ovaries and testes express enzymes that synthesize and metabolize the hormone retinoic acid (RA) (raldh2 and cyp26a, respectively), and RA receptors (raraa, rarga, rxrba, rxrbb, rxrga but not rxrab). Three new isoforms of rxrba were also observed in a variety of tissues. In other experiments, zebrafish were exposed for 11 d to diethylaminobenzaldehyde (DEAB), an inhibitor of RA synthesis, or fed a retinoid deficient diet for 130 d in order to evaluate the functional requirements of retinoids in reproduction. DEAB altered cyp26a transcript numbers in the gonads, suggesting an impact on RA, and decreased the number of spawned eggs by 95%. The retinoid deficient diet decreased whole body retinoids (retinol and retinal) by 68% in females and 33% in males. Females fed the retinoid deficient diet also produced 73% fewer eggs that contained 78% less retinal than controls. Fertilization rates were not affected. These studies have shown that the RA receptors are expressed in zebrafish gonads, and RA is required for the spawning of eggs. Dietary retinoid content influences reproduction, while retinyl ester storage levels appear to be of little significance. Females were more susceptible to retinoid perturbation than males, likely due to the cost of retinal deposition in the eggs. Overall, these studies have shown retinoids play a fundamental role in the reproduction of zebrafish, and the lack of retinyl ester stores in controls that successfully spawned illustrates that we have only a limited understanding of the retinoid physiology and requirements of fish.

The effect of an amethystic product on ethanol in humans.

A putative amethystic product was studied in two cohorts of human subjects. The amethystic product (Sobrietol) was applied according to the manufacturer's instructions while control subjects received water in place of the Sobrietol solution. The two cohorts were challenged with 1.2 ml/lb and 1.4 ml/lb of 80 proof liquor, respectively, with subsequent breath alcohol (BrAC) measurement. In cohort 1, Sobrietol reduced the area under the BrAC curve (AUC) by 15.1% (p = 0.003) relative to controls; in cohort 2 the AUC was reduced by 12.5% (p = 0.011) relative to controls. It appears that the amethystic product Sobrietol can eliminate significantly greater ethanol than ethanol eliminated by similar controls.

The effects of copper and benzo[a]pyrene on retinoids and reproduction in zebrafish.

This study examines whether a link exists between toxicant exposure, retinoids and reproduction in fish. Zebrafish were fed a control diet (8.1 microg Cu/g diet, 0 microg benzo[a]pyrene/g diet) or diets containing elevated copper (100 microg, 500 microg and 1000 microg Cu/g diet) or benzo[a]pyrene (B[a]P; 30 and 150 microg B[a]P/g diet) for 260 days. Toxicant-supplemented diets did not affect growth or mortality rates. While whole body retinoid levels in control zebrafish decreased during the experiment, females exposed to Cu or B[a]P for 200 days or more experienced additional losses of retinyl esters (45-100% depleted) and retinal (45% depleted in B[a]P-fed fish). Despite the reduced retinoids, Cu and B[a]P did not effect reproduction with respect to the number of eggs spawned, fertilization rates or egg retinal content (retinal was instead increased 55-65% in eggs from B[a]P-fed fish). There were no apparent deformities observed in 36 h post fertilization embryos from any treatment. It appears that although internal retinoid stores were depleted in adults, dietary retinoids were sufficient to meet the daily requirement for retinal deposition in the eggs and retinoic acid synthesis. This study has shown that retinoid levels in female zebrafish are sensitive to Cu and B[a]P, and are a good indicator of long-term exposure. It also brings to light the resiliency of the retinoid system in fish and the importance of the diet on the toxicological response. Specifically that dietary retinoids appear to support normal reproduction in the absence of internal retinoid stores.

Research strategies for safety evaluation of nanomaterials. Part VI. Characterization of nanoscale particles for toxicological evaluation.

To properly assign mechanisms or causes for toxic effects of nanoscale materials, their properties and characteristics both outside and within the biological environment must be well understood. Scientists have many tools for studying the size, shape, and surface properties of particulates outside of the physiological environment; however, it is difficult to measure many of these same properties in situ without perturbing the environment, leading to spurious findings. Characterizing nanoparticle systems in situ can be further complicated by an organism's active clearance, defense, and/or immune responses. As toxicologists begin to examine nanomaterials in a systematic fashion, there is consensus that a series of guidelines or recommended practices is necessary for basic characterization of nanomaterials. These recommended practices should be developed jointly by physical scientists skilled in nano characterization and biological scientists experienced in toxicology research. In this article, basic nanoparticle characterization techniques are discussed, along with the some of the issues and implications associated with measuring nanoparticle properties and their interactions with biological systems. Recommendations regarding how best to approach nanomaterial characterization include using proper sampling and measurement techniques, forming multidisciplinary teams, and making measurements as close to the biological action point as possible.

Dietary retinoic acid induces hindlimb and eye deformities in Xenopus laevis.

This study investigated the effects of dietary retinoic acid (RA) on frog hindlimb development. Xenopus laevis (African clawed frog) tadpoles were fed a diet supplemented with 0, 1, 10, or 100 microg of RA/g of food for 2 or 5 d at different stages of metamorphosis. Hindlimb deformities were induced in the group fed 100 microg of RA/g of diet for 5 d. Exposures beginning at mid-hindlimb bud development induced bilaterally bent tibiafibula (bony triangles), while exposures later in hindlimb development induced deformities of the feet, including fusion of the 1st and 2nd clawed digits and reduced length of the 4th and 5th digits (due to reduced, missing, or misplaced phalanges). There were also cases of extra phalanges in the 5th digit. The eye was another target of RA exposure. In one experiment, 58% of the tadpoles fed 10 microg of RA/g had a smaller or absent right eye. Additionally, 11% of the tadpoles fed 100 microg of RA/g of diet developed a smaller or absent left eye. Waterborne heavy metals (Zn or Cu) modified RA effects on the hindlimb and eye. Co-exposure to metals and RA resulted in cases of unilateral bony triangles and reduced rates of smaller eyes. There were also cases of extra hindlimb digits in Zn-exposed animals. Dietary RA exposure in tadpoles can cause some deformities that differ from waterborne RA exposures in previous studies. RA also induced deformities that resemble those in affected wild frog populations (bony triangles), although the patterns of other deformities and missing segments (phalanges and metatarsals) are not similar to those documented in the wild.

Effects of dietary sodium chloride intake on renal function and blood pressure in cats with normal and reduced renal function.

OBJECTIVE: To determine effects of variations in dietary intake of sodium chloride (NaCl) on systemic arterial blood pressure (ABP) in cats with normal and reduced renal function. ANIMALS: 21 adult cats (7 with intact kidneys [control cats; group C], 7 with unilateral renal infarction with contralateral nephrectomy [remnant-kidney model; group RK], and 7 with unilateral renal infarction and contralateral renal wrapping and concurrent oral administration of amlodipine [remnant-wrap model; group WA]). PROCEDURE: All cats were sequentially fed 3 diets that differed only in NaCl content (50, 100, or 200 mg of Na/kg); each diet was fed for 7 days. The ABP was recorded continuously by radiotelemetry, and renal function (glomerular filtration rate [GFR]) was determined on the sixth day of each feeding period. RESULTS: Dietary supplementation with NaCl did not affect ABP, but it increased GFR in groups C and WA. The renin-angiotensin-aldosterone axis was activated in groups RK and WA at the lowest NaCl intake, but supplementation with NaCl suppressed this activation in group WA. The lowest NaCl intake was associated with hypokalemia and a high fractional excretion of potassium that decreased in response to supplementation with NaCl. Arterial baroreceptor resetting was evident after chronic hypertension but was not modified by dietary supplementation with NaCl. CONCLUSIONS AND CLINICAL RELEVANCE: Low NaCl intake was associated with inappropriate kaliuresis, reduced GFR, and activation of the renin-angiotensin-aldosterone axis without evidence of a beneficial effect on ABP. Therefore, this common dietary maneuver could contribute to hypokalemic nephropathy and progressive renal injury in cats.

Functional foods and the urinary tract.

There is no universally accepted definition of a commonly used term for a functional food: nutraceutical. For the purposes of this article, a nutraceutical is any ingredient found in foods that has a demonstrated (or proposed) physiologic benefit. Although a nutraceutical is generally taken to be an ingredient that can be isolated or purified from food, plants, or marine products and made available in medicinal form, this article also considers claims of benefit to the urinary tract for foods or food supplements in which the active ingredient has not yet been characterized or isolated.