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Spatial models for areal data are often constructed such that all pairs of adjacent regions are assumed to have near‐identical spatial autocorrelation. In practice, data can exhibit dependence structures more complicated than can be represented under this assumption. In this article, we develop a new model for spatially correlated data observed on graphs, which can flexibly represented many types of spatial dependence patterns while retaining aspects of the original graph geometry. Our method implies an embedding of the graph into Euclidean space wherein covariance can be modeled using traditional covariance functions, such as those from the Matérn family. We parameterize our model using a class of graph metrics compatible with such covariance functions, and which characterize distance in terms of network flow, a property useful for understanding proximity in many ecological settings. By estimating the parameters underlying these metrics, we recover the "intrinsic distances" between graph nodes, which assist in the interpretation of the estimated covariance and allow us to better understand the relationship between the observed process and spatial domain. We compare our model to existing methods for spatially dependent graph data, primarily conditional autoregressive models and their variants, and illustrate advantages of our method over traditional approaches. We fit our model to bird abundance data for several species in North Carolina, and show how it provides insight into the interactions between species‐specific spatial distributions and geography. [ABSTRACT FROM AUTHOR]

Peripheral nerve damage can cause debilitating symptoms ranging from numbness and pain to sensory loss and atrophy. To uncover the underlying mechanisms of peripheral nerve injury, our research aims to develop a relationship between biomechanical peripheral nerve damage and function through finite element modeling. A noncontact, ex vivo electrophysiology chamber, capable of axially stretching explanted nerves while recording electrical signals, was used to investigate peripheral nerve injury. Successive stretch trials were run on eight sciatic nerves (four females and four males) excised from Sprague–Dawley rats. Nerves were stretched until 50% compound action potential (CAP) amplitude reduction was obtained. A constitutive model developed by Raghavan and Vorp was suitable for rat sciatic nerves, with an average α and β of 0.183 MPa and 1.88 MPa, respectively. We then generated 95% confidence intervals for the stretch at which specific CAP amplitude reductions would occur, which compares well to previous studies. We also developed a finite element model that can predict stretch‐induced signaling deficits, applicable for complex nerve geometries and injuries. This relationship between nerve biomechanics and function can be expanded upon to create a clinical model for peripheral nerve dysfunction due to stretch. [ABSTRACT FROM AUTHOR]

Achnatherum inebrians is a perennial grass widely distributed in northwest China. Nearly all wild A. inebrians plants are infected by Epichloë endophytes. In this study, bacteria from the phyllosphere were isolated from leaves of both endophyte‐free and endophyte‐infected A. inebrians and sequenced for identification. Pseudomonas, comprising 48.12% of the culturable bacterial communities, was the most dominant bacterial genus. Thirty‐four strains from 12 Pseudomonas species were used to inoculate A. inebrians seeds and plants. Results indicated that Epichloë significantly increased the diversity and richness index of the phyllosphere. Pseudomonas Sp1, Sp3, Sp5 and Sp7 had a significantly positive effect on plant growth and photosynthesis, whereas Sp10, Sp11 and Sp12 had a significantly negative effect. Whole‐genome and pan‐genome analysis suggested that the variability in the effects of Pseudomonas on A. inebrians was related to differences in genome composition and genomic islands. [ABSTRACT FROM AUTHOR]

Purpose: To determine the number of previous contact lens (CL) wearers who could be comfortably refitted into delefilcon A (DAILIES TOTAL1®) CLs. Methods: This was a 6‐month, three‐visit study that recruited subjects who discontinued CLs within the past 2 years because of discomfort or dryness symptoms. Subjects were required to have Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire scores ≤3 and to be able to wear spherical study CLs. Subjects were asked to complete a ±50 comfort visual analogue scale (VAS) at 1 month and a Likert questionnaire after 1 and 6 months of CL wear to understand the subjects' CL experience. Results: All 60 subjects who were fitted with the study CLs were still wearing them after 1 month, while one subject had dropped out by 6 months. Subjects had a median (interquartile range) age of 24.0 (7.0) years (71.7% female). They reported a median VAS score of 44.0 (8.0) units at the 1‐month visit, with all reporting a comfortable score. At the 1‐month/6‐month visits, 98.3%/93.2%, 86.5%/78.0% and 93.2%/91.5% of subjects responded that they were very satisfied or satisfied with their vision, their end‐of‐day CL comfort and overall CL comfort, respectively. The same subjects responded that they were very likely or likely to continue to wear the study CLs at 1 (89.6%) and 6 months (80.7%) and to recommend the study CLs to a friend at 1 (98.3%) and 6 months (93.2%). Conclusions: The results suggest that when encountering a CL dropout, a practitioner could educate a patient about trying an alternative CL and consider delefilcon A lenses as an option. [ABSTRACT FROM AUTHOR]

Background: Peyronie's disease (PD) has previously been observed to co‐aggregate in a small number of first‐degree relative pairs (e.g., father–son). However, the familial aggregation of PD in more distant relatives, as well as the aggregation of Dupuytren's disease (DD) in probands and relatives, has not been thoroughly investigated. Objective: This study explored the evidence for familial clustering of PD and DD in close and distant relatives. Materials and methods: The Utah Population Database, which includes genealogy information linked to electronic medical records (available since 1995), was used to identify men and their relatives with PD and DD based on ICD9/10 codes. All cases were required to have high‐quality genealogy data. We estimated relative risk (RR) of PD and DD in first‐ through fifth‐degree relatives compared to matched population rates of disease. We also investigated the average relatedness of cases compared to the average relatedness of sets of matched controls. Outcome measures include estimation of relative risk and excessive relatedness as measured by a Genealogical Index of Familiality (GIF) analysis. Results: We analyzed 307 individuals with PD, and their first‐ through fifth‐degree relatives. Approximately 0.12% of the population had PD, 95% of these were diagnosed over the age of 30 years (age range: 10–92 years), and 1.3% of PD probands had a comorbid diagnosis of DD. RR estimates for PD were significant for first‐ and fifth‐degree relatives. RR estimates for DD were significant only for probands. The average relatedness of cases was significantly greater than matched controls, even after removing first‐ and second‐degree relatives. We also found that 74.9% of identified PD probands belonged to pedigrees with a statistical excess of PD. Conclusion: Despite the low prevalence of PD in our healthcare records, the results provide evidence that support a genetic contribution to at least a subset of PD cases. [ABSTRACT FROM AUTHOR]

Abstract: The immense amount of electronic health data (pharmacy and administrative claims, electronic health records, and clinical registries) that is being generated every day in the care of patients has the potential to be leveraged for improving clinical decisions at the point of care, uncovering or validating drug efficacy and drug safety. The potential use of big data for improving safe and effective use of medications is especially important in children because of their low drug exposure relative to adults. Electronic health data is collected primarily for clinical or billing purposes and not for research purposes. The major steps involved in data acquisition, extraction, aggregation, analysis, modeling, and interpretation are discussed. It is important to understand the limitation of big data and utilize appropriate study design and statistical methods. Possible applications are presented along with specific examples of how big data has been used in drug research to find that blip on the radar screen that may give an efficacy or safety signal that can lead to further investigation. [ABSTRACT FROM AUTHOR]

BACKGROUND: The amount of time available to pathologists with which to perform research is becoming limited due to an increasing manpower shortage in pathology, decreased reimbursement, and increased workload. This is occurring at the same time as demands escalate for pathologists to develop new companion tests, correlate the molecular findings with traditional methods, and assist in the development of individualized medicine. This study examined whether cytotechnologists may be integrated into a research team that uses their expertise in understanding pathology and clinical disease to provide interpretations of experiments that traditionally were performed by pathologists. METHODS: Cytotechnologists worked with pathologists to choose blocks for tissue microarrays (TMAs) and to interpret immunohistochemically stained TMA slides. The pathologist met with the cytotechnologist to review the study design. The cytotechnologists reviewed the slides and blocks and chose the most appropriate blocks for the TMA. Either 10% or all of the slides/blocks selected for TMA construction were reviewed by the supervising pathologist. The final selections were given to the TMA technologist to make the TMA. A minimum of 10% of the immunohistochemically stained TMA slides were reviewed by the supervising pathologist. RESULTS: A total of 32 TMAs were created with 6 cytotechnologists collaborating with 6 pathologists. Immunohistochemical stains of 190 TMAs were interpreted by 4 cytotechnologists collaborating with 3 pathologists. All the TMAs and TMA interpretation data were used successfully for the research for which they were designed. CONCLUSIONS: The collaboration of cytotechnologists and pathologists in research can improve the quality of effort and increase satisfaction and productivity. Cancer Cytopathol 2018;126:232‐5. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Abstract: Intensive grazing by large herbivores is known to result in the degeneration of grassland worldwide. However, little is known about how grazing affects the fungi living in roots, especially those with septate hyphae. We investigated grazing intensity effects on culturable root‐associated fungi (c‐RAF) of three dominant plant species; Artemisia capillaris, Lespedeza davurica, and Stipa bungeana, in a semiarid grassland of northwest China. Plant roots were sampled from four grazing intensities at four sampling dates. The total colonization rate of c‐RAF was not affected by grazing intensity, but the diversity of c‐RAF displayed a hump‐shaped trend with grazing intensities. Few c‐RAF were present in all plant species, with most of them being confined to only one or two plant species. The 16 most commonly isolated species were selected to investigate their effects on plant growth and health. Three Fusarium species were most pathogenic c‐RAF. Three dark‐sterile species did not affect growth parameters, regardless of host plants. With A. capillaris, the occurrence of Fusarium spp. was highest in the control plots, while with S. bungeana, the occurrence tended to increase as the grazing intensity increased. Two dark‐sterile species, including Darksidea alpha, in L. davurica roots increased with grazing intensities; in contrast, D. alpha decreased for S. bungeana with grazing intensities. Our results strongly suggest that in grasslands, grazing intensity can lead to changes in the colonization of specific root fungal taxa, and these fungal changes would potentially feed back to plant performance depending on the abundance of host plants. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Cover legend: This cover image, by Katrina Hurst et al., is based on the Research Article A putative lysophosphatidylinositol receptor GPR55 modulates hippocampal synaptic plasticity, DOI: 10.1002/hipo.22747. [ABSTRACT FROM AUTHOR]

GPR55, an orphan G-protein coupled receptor, is activated by lysophosphatidylinositol (LPI) and the endocannabinoid anandamide, as well as by other compounds including THC. LPI is a potent endogenous ligand of GPR55 and neither GPR55 nor LPIs' functions in the brain are well understood. While endocannabinoids are well known to modulate brain synaptic plasticity, the potential role LPI could have on brain plasticity has never been demonstrated. Therefore, we examined not only GPR55 expression, but also the role its endogenous ligand could play in long-term potentiation, a common form of synaptic plasticity. Using quantitative RT-PCR, electrophysiology, and behavioral assays, we examined hippocampal GPR55 expression and function. qRT-PCR results indicate that GPR55 is expressed in hippocampi of both rats and mice. Immunohistochemistry and single cell PCR demonstrates GPR55 protein in pyramidal cells of CA1 and CA3 layers in the hippocampus. Application of the GPR55 endogenous agonist LPI to hippocampal slices of GPR55+/+ mice significantly enhanced CA1 LTP. This effect was absent in GPR55−/− mice, and blocked by the GPR55 antagonist CID 16020046. We also examined paired-pulse ratios of GPR55−/− and GPR55+/+ mice with or without LPI and noted significant enhancement in paired-pulse ratios by LPI in GPR55+/+ mice. Behaviorally, GPR55−/− and GPR55+/+ mice did not differ in memory tasks including novel object recognition, radial arm maze, or Morris water maze. However, performance on radial arm maze and elevated plus maze task suggests GPR55−/− mice have a higher frequency of immobile behavior. This is the first demonstration of LPI involvement in hippocampal synaptic plasticity. [ABSTRACT FROM AUTHOR]

Objective: Cells, scaffold, and surgical approaches are important for regeneration of the lamina propria of the scarred vocal fold (VF). Microendoscopy of Reinke's space (MERS) is a surgical approach used to access the lamina propria. The present study evaluated MERS in the treatment of VF scarring as compared with standardized approaches for the treatment of VF scarring with adipose stem cell constructs.Study Design: Animal study.Setting: Academic center.Subjects and Methods: VF injury was performed bilaterally to induce scarring in 20 pigs. Eight weeks after injury, pigs were classified into no treatment, minithyrotomy, VF injection, VF incision/dissection, and MERS. All groups (except control) were implanted with adipose stem cell and hyaluronan. Four weeks after treatment, histology for collagen, hyaluronan, and fibronectin; mRNA expression for α-smooth muscle actin, tumor growth factor β1, collagen 1α1, collagen 3α1, matrix metalloproteinase 2, basic fibroblast growth factor, and hepatocyte growth factor; and tissue rheology were evaluated.Results: Differences were measured among surgical approaches for protein levels of collagen, hyaluronan, and fibronectin (P = .0133, P < .0001, and P = .0025, respectively). Fibroblast growth factor, collagen 1α1, and matrix metalloproteinase 2 transcript levels were different among treatment groups (P = .003, P = .0086, and P = .014, respectively), while no differences were measured for α-smooth muscle actin, tumor growth factor β1, hepatocyte growth factor, and collagen 3α1. Rheologically, significant differences were not measured between groups.Conclusion: MERS is a promising surgical approach for the treatment of VF scarring, optimizing the placement of implanted biomaterials. [ABSTRACT FROM AUTHOR]

Considerable progress has been made in pediatric drug development. Despite these gains there remain certain therapeutic areas where a high percentage of drugs approved for use in adults do not gain approval for use in children. Lack of sufficient US Food and Drug Administration (FDA)-approved labeling correlates with diminished therapeutic efficacy and increased risk for adverse drug reactions. Despite the increasing prevalence and important clinical challenge with pediatric type 2 diabetes mellitus (T2DM), only 1 drug (metformin) of the first 4 T2DM drugs to complete testing in children gained FDA approval. This analysis reviews 4 pediatric drug development programs for orally administered antidiabetic agents that have undergone FDA review and discusses factors influencing failure to meet specified end points for approval. Recommendations to guide future study are also provided. [ABSTRACT FROM AUTHOR]

Voter studies conducted in the United States during the first decades after World War II transformed social scientific research on democracy. Especially important were the rapid innovations in survey research methods developed by two prominent research centers at Columbia University and the University of Michigan. This article argues that the Columbia and Michigan voter studies presented two visions for research on democracy. Where the Michigan research produced quantitative measures expressing the 'political behavior' of the electorate, the Columbia studies, and especially Paul F. Lazarsfeld, presented an alternative vision for qualitative research on political choice. Largely ignored by later voter studies, this vision prefigured much contemporary research on democracy that embraces a qualitative or interpretive approach. This article reconstructs Lazarsfeld's alternative vision, describes the institutional context in which scholars disregarded it in favor of formal quantitative models, and argues for its recognition as a forerunner to qualitative research on democratic processes. [ABSTRACT FROM AUTHOR]

Background The appropriate management of the neck in patients with regionally advanced head and neck cancer remains controversial. The purpose of this study was to retrospectively analyze our institutional experience with up-front neck dissection followed by definitive chemoradiotherapy. Methods Fifty-five patients with radiographic evidence of large or necrotic lymph nodes underwent up-front neck dissection followed by definitive chemoradiation. Results The 5-year overall survival (OS) and progression-free survival (PFS) rates were estimated at 71.3% and 64.7%, respectively. There were 2 failures in the dissected neck, for a control rate of 96.7%. There were 7 locoregional failures and 12 distant failures, for locoregional and distant control rates of 87.3% and 78.2%, respectively. Conclusion Up-front neck dissection followed by chemoradiotherapy resulted in excellent locoregional control, OS, and PFS. Utilization of this strategy should be considered in carefully selected patients with regionally advanced head and neck cancer. © 2012 Wiley Periodicals, Inc. Head Neck, 2012 [ABSTRACT FROM AUTHOR]

Background Propionibacterium acnes is a major contributing factor to the inflammatory component of acne. The interaction of P. acnes with keratinocytes leads to an innate immune response via activation of toll-like receptors ( TLR2, TLR4) resulting in the production and secretion of pro-inflammatory mediators. SIG1273, an isoprenylcysteine small molecule modulates inflammatory signaling pathways and kills P. acnes. SIG1273 represents a novel cosmetic functional ingredient that provides relief from blemishes in acne prone skin. Objective To assess the keratinocyte response and microbial growth of SIG1273 in vitro and evaluate the tolerability of SIG1273 gel applied topically in acne prone subjects. Methods For in vitro studies, human keratinocytes were exposed in culture to live P. acnes and peptidoglycan ( PGN) to induce IL-8 production. P. acnes were cultured to determine minimal inhibitory concentration and minimal bactericidal concentration values. A total of 30 subjects were randomized in a double-blind controlled trial receiving 3% SIG1273 gel or vehicle for 6 weeks. Evaluation included inflammatory lesions, noninflammatory lesions, microcomedones, Sebutape scores, and P. acnes counts. Results In vitro studies demonstrate SIG1273 inhibits P. acnes-induced IL-8 production and inhibits P. acnes growth. SIG1273 gel was well tolerated with no signs of stinging, redness, or itching. Furthermore, improvement in some aspects of acne was observed in subjects applying SIG1273 gel, including inflammatory lesions, microcomedone counts and Sebutape scores. Facial scrubs taken to measure P. acnes colony-forming units showed those applying SIG1273 gel had ~1.0 Log 10 colony reduction over the length of the study, a statistically significantly improvement when compared with vehicle. No significant effects above vehicle were observed for noninflammatory lesions. Conclusions SIG1273 represents a novel cosmetic functional ingredient that provides a safe dual modulating benefit to individuals with acne prone skin by reducing P. acnes counts and reducing inflammation. [ABSTRACT FROM AUTHOR]

Study Objective. To evaluate the use of enteral fish oil for the treatment of parenteral nutrition-associated liver disease (PNALD). Design. Retrospective case series. Setting. Pediatric academic hospital and outpatient clinic. Patients. Six parenteral nutrition-dependent infants with short-bowel syndrome and PNALD. Measurements and Main Results. The six infants received supplementation with enteral fish oil, and treatment was evaluated over a 12-week period. The PNALD, as reflected by elevated total bilirubin levels, completely reversed in four of the six infants within a mean ± SD of 5 ± 2.6 weeks (range 2-8 wks) after initiation of the enteral fish oil supplementation. In addition, improvement in enteral feedings occurred after starting enteral fish oil therapy. Conclusion. Enteral fish oil may be an effective adjunctive treatment option for infants with PNALD, particularly for those infants with PNALD who are tolerating some amount of enteral nutrition as the result of an adequate amount of small bowel. [ABSTRACT FROM AUTHOR]

• The relationship between cool-season grasses and fungal endophytes is widely regarded as mutualistic, but there is growing uncertainty about whether changes in resource supply and environment benefit both organisms to a similar extent. • Here, we infected two perennial ryegrass ( Lolium perenne) cultivars (AberDove, Fennema) that differ in carbohydrate content with three strains of Neotyphodium lolii (AR1, AR37, common strain) that differ intrinsically in alkaloid profile. We grew endophyte-free and infected plants under high and low nitrogen (N) supply and used quantitative PCR (qPCR) to estimate endophyte concentrations in harvested leaf tissues. • Endophyte concentration was reduced by 40% under high N supply, and by 50% in the higher sugar cultivar. These two effects were additive (together resulting in 75% reduction). Alkaloid production was also reduced under both increased N supply and high sugar cultivar, and for three of the four alkaloids quantified, concentrations were linearly related to endophyte concentration. • The results stress the need for wider quantification of fungal endophytes in the grassland–foliar endophyte context, and have implications for how introducing new cultivars, novel endophytes or increasing N inputs affect the role of endophytes in grassland ecosystems. [ABSTRACT FROM AUTHOR]

The number of combinations of anthropogenic stressors affecting global change is increasing; however, few studies have empirically tested for their interactive effects on ecosystems. Most importantly, interactions among ecological stressors generate nonadditive effects that cannot be easily predicted based on single-stressor studies. Here, we corroborate findings from an in situ mesocosm experiment with evidence from a whole-ecosystem manipulation to demonstrate for the first time that interactions between climate and acidification determine their cumulative impact on the food-web structure of coldwater lakes. Interactions among warming, drought, and acidification, rather than the sum of their individual effects, best explained significant changes in planktonic consumer and producer biomass over a 23-year period. Further, these stressors interactively exerted significant synergistic and antagonistic effects on consumers and producers, respectively. The observed prevalence of long- and short-term ecological surprises involving the cumulative impacts of multiple anthropogenic stressors highlights the high degree of uncertainty surrounding current forecasts of the consequences of global change. [ABSTRACT FROM AUTHOR]

This study assessed the single- and multiple-dose pharmacokinetics of 3 doses (15 mg, 30 mg, and 45 mg) of pioglitazone in 36 adolescents with type 2 diabetes. Blood samples were obtained over a 48-hour interval after the first dose (day 1) and over a 72-hour interval after the last dose (day 15) of pioglitazone and were assayed for pioglitazone and active metabolites (M-III and M-IV). Pioglitazone systemic exposure increased dose dependently but was less than dose proportional during multiple dosing. The median peak pioglitazone concentration occurred at 2 hours. The mean half-life was 8 to 9 hours for pioglitazone and 24 to 32 hours for M-III and M-IV, with similar values at each dose level. During multiple dosing, accumulation for pioglitazone was negligible, but it reached 2.5- to 3.0-fold for M-III and M-IV. The sustained total serum concentration of active compounds during multiple dosing provides the basis for once-daily dose administration of pioglitazone in adolescents. [ABSTRACT FROM PUBLISHER]

Sumatriptan is a potent and selective vascular 5-HT1receptor agonist effective for the treatment of migraine. In adults, intranasal sumatriptan is well absorbed and tolerated. The authors evaluated the pharmacokinetics and tolerability of a single dose of 20 mg intranasal sumatriptan in healthy adolescent migraineurs ages 12 to 17 years, administered outside of migraine attack. Serum sumatriptan levels were measured by high-performance liquid chromatography (HPLC) with electrochemical detection in serial samples collected over 8 hours. Physical exam, vital signs, clinical laboratory tests, and electrocardiogram measurements were monitored to assess safety and tolerability. A total of 16 subjects (10 males and 6 females) had pharmacokinetic data that could be analyzed, 2 withdrew from the study 30 and 60 minutes after dosing following the loss of venous access for blood sampling, and a bioanalysis failure resulted in loss of data from 3 subjects. Noncompartmental pharmacokinetic parameters (geometric mean and 95% confidence interval) for the remaining 16 subjects were as follows: Cmaxwas 13.9 (11.0, 17.6) ng/mL, AUC∞ was 57.3 (47.6, 69.0) ng/mL•h, and t1/2was 2.0 (1.8, 2.3) hours. Population pharmacokinetic analysis for all subjects (n = 21) showed that clearance and volume of distribution increase slightly with age and body size, but the changes were minimal and would not warrant dose adjustment: CL/F was 316 L (coefficient of variance [CV] = 25%) and Vd/F was 1070 L (CV = 46%). Sumatriptan was well tolerated with only minor adverse events reported, which all resolved spontaneously. The pharmacokinetic parameters in these adolescent subjects were similar to those previously reported in adults, suggesting that adolescents should be dosed similar to adults. [ABSTRACT FROM PUBLISHER]

Naratriptan is a novel 5-HT1 agonist developed to treat acute migraine. The study objective was to characterize the pharmacokinetics of oral naratriptan in adolescent migraine patients outside a migraine attack. Subjects received a single 2.5 mg naratriptan tablet. Serial serum samples for naratriptan concentrations were collected over 24 hours. Blood pressure, pulse rate, and 12-lead ECG were recorded at baseline and at regular intervals after dosing. Seven patients—3 males and 4 females, 12 to 16 years of age—received drug and completed the study. The geometric mean and 95% confidence interval maximum concentration (Cmax) was 8.0 ng/mL (5.9-10.7), elimination half-life (t1/2) was 4.9 hours (4.5-5.4), area under the concentration-time curve (AUC) was 74.6 ng•h/mL (56.6-98.2), and apparent total clearance (Cl/F) was 558.8 mL/min (424.3-735.9). The median time to maximal concentration (tmax) was 4 hours, with a range of 1.5 to 4. Blood pressure, pulse rate, and ECG parameters did not change significantly from baseline. No serious adverse events or subject withdrawal after drug administration occurred. Oral naratriptan pharmacokinetic parameters in adolescents were similar to values reported in adults. Naratriptan doses for adolescents older than 12 years of age would be expected to be similar to adult doses. [ABSTRACT FROM PUBLISHER]

Abstract: Tacrolimus is an immunosuppressant used to prevent rejection of transplanted organs. It is metabolized in both the gut and the liver by the cytochrome P450 (CYP) 3A4 enzyme system and is a substrate for the P‐glycoprotein (P‐gp) drug efflux pump. As CYP3A4 enzymes and P‐gp are present at differing concentrations throughout the gastrointestinal tract, the bioavailability of tacrolimus may be influenced by changes in gastrointestinal transit time in addition to changes in hepatic metabolism. We report the case of a pediatric renal transplant patient who experienced a three‐fold increase in serum tacrolimus concentrations during an episode of gastroenteritis with chronic diarrhea. [ABSTRACT FROM AUTHOR]

Repaglinide is a novel insulin secretagogue developed in response to the need for a fast-acting, oral prandial glucose regulator for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Repaglinide is metabolized mainly in the liver; its pharmacokinetics may therefore be altered by hepatic dysfunction. This open, parallel-group study compared the pharmacokinetics and tolerability of a single 4 mg dose of repaglinide in healthy subjects (n = 12) and patients with chronic liver disease (CLD) (n = 12). Values forAUC and Cm,, were significantly higher in CLD patients compared with healthy subjects, and the MRT was prolonged in CLD patients. Values for tmax did not differ between the groups, but t1/2 was significantly prolonged in CLD patients compared with previously determined values in healthy subjects. AUC was inversely correlated with caffeine clearance in CLD patients but not in healthy subjects. Blood glucose profiles were similar in both groups. Adverse events (principally hypoglycemia) were similar in the two groups; none was serious. Repaglinide clearance is significantly reduced in patients with hepatic impairment; the agent should be used with caution in this group. [ABSTRACT FROM PUBLISHER]

The objective of this study was to determine if the positional structure of dietary triacylglycerol affected lipidemic responses. Thirty healthy adults (16 men and 14 postmenopausal women) with low-density lipoprotein cholesterol (LDL-C) concentrations >3.37 mM (130 mg/dl) enrolled in a prospective, single-blind, cross-over outpatient clinical trial that consisted of two 5-wk dietary phases. After baseline screening, subjects were instructed to follow individualized meal plans (weight maintenance diets with 36% of total energy from fat, half of which was from a test oil) and randomized to receive either butter (B) or an interesterified mixture (IM) of butter, medium-chain triacylglycerol (MCI), and safflower oils. Blood drawn during weeks 5 and 10 of feeding was analyzed for total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), LDL-C, and triacylglycerols (TAG). Mean plasma levels of TC (B, 6.98±1.06 mM; IM, 7.09±1.20 mM), HDL-C (B,1.30±0.35 mM; IM, 1.29±0.34 mM), and LDL-C (B, 4.91±0.95 mM; IM, 492±1.10 mM) were not significantly different between the two dietary treatments. Mean TAG levels were higher for the interesterified B-MCT mixture (B, 1.75±0.72 mM; IM, 1.96±0.86 mM, P<0.05). We conclude that an IM of B, MCT and safflower oils as compared to native B has no appreciable effect on plasma cholesterol concentrations but is associated with a modest rise in plasma TAG. [ABSTRACT FROM AUTHOR]

Genetically sterile male Norway rats, Rattus norvegicus, were tested in the laboratory to determine both 1) behavioral characteristics, and 2) the ability of sterile males to compete aggressively and sexually with wild Norway rat males. Sterile males were larger in weight, more frequently dominant, won as many fighting encounters, were as aggressive as wild males, and mounted females more frequently. Behavioral activities were similar for both strains when compared under laboratory conditions with no apparent abnormal behavior exhibited by the sterile males. Use of sterile males in biological control programs is discussed. [ABSTRACT FROM AUTHOR]

We investigated the influence of the intramolecular fatty acid distribution of dietary triacyl- sn-glycerols (TAG) rich in n-3 polyunsaturated fatty acids (PUFA) on the structure of chylomicron TAG. Fish oil and seal oil, comparable in fatty acid compositions but with different contents of major n-3 PUFA esterified at the sn-2 position (20:5n-3, 46.6%, and 5.3%; 22:6n-3, 75.5%, and 3.8%, respectively), were fed to rats. Mesenteric lymph was collected and the chylomicrons were isolated by ultracentrifugation. The fatty acid composition of chylomicrons largely reflected the fatty acid composition of the oils administered. The intramolecular fatty acid distributions of the TAG fed were reflected in the chylomicron TAG as the fraction of the total contents observed in the sn-2 position of 20:5n-3 were 23.6 and 13.3%, and of 22:6n-3 were 30.6 and 5.4% for resultant chylomicrons following fish oil and seal oil administration, respectively. Thus, after seal oil administration, significant higher load of n-3 PUFA was esterified in the sn-1,3 positions of chylomicron TAG compared with fish oil administration ( P<0.05). [ABSTRACT FROM AUTHOR]

Fat absorption may be compromised by pancreatic or bile insufficiency, resulting in low uptake of essential fatty acid and energy. Using a rat model of malabsorption, we examined the absorption of defined triglycerides with medium-chain fatty acids (MCFA) in the sn-1,3 positions and essential fatty acids in the sn-2 position (MLM) compared to other fats. The thoracic duct was cannulated for collection of lymph, and the common bile and pancreatic duct was cannulated to divert both the pancreatic juice and bile. The rats were given a single bolus of triglyceride as a taurocholate emulsion. Fat absorption was measured from collected lymph samples. The triglycerides administered were a defined triglyceride, MLM [mainly (8∶0/10∶0)-(18∶2n−6)-(8∶0/10∶0)], a similar triglyceride subjected to chemical randomization, a mixture of medium-chain triglycerides and soybean oil, and soybean oil, respectively. The first three triglycerides had approximately 36 wt% linoleic acid (18∶2n−6) content. Administration of defined triglyceride was followed by significantly higher lymphatic level (wt%) of 18∶2n−6 ( P<0.01) as well as a relative enhancement in mol% of 18∶2n−6 ( P<0.05) compared to the other triglycerides. Lymphatic absorption of MCFA was similar in the three first groups but not as efficient as for long-chain fatty acids. Our results indicate that defined triglycerides thus may provide a means to increase absorption of essential fatty acids in fat malabsorption, such as that seen in cystic fibrosis, or for pre-term infants. [ABSTRACT FROM AUTHOR]

Teniposide is a widely used anticancer drug that is extensively bound to plasma proteins (> 95%). We evaluated the drug's plasma protein binding in nine patients with acute lymphocytic leukemia who were in their first complete remission, and in a second group of nine patients at the time of relapse and subsequently after achieving another complete remission. Plasma protein binding was assessed by equilibrium dialysis, with direct high-performance liquid chromatographic measurement of total and free teniposide. The mean unbound fraction was 0.44% (0.21-0.88%) in the plasma of patients in first remission. It was significantly higher in patients at the time of relapse (mean = 0.86%; range 0.68-1.08%) and after achieving another complete remission (mean = 1.25%; range 0.51-2.11%). Serum albumin values were significantly lower at the time of relapse (mean = 4.6 vs 4.0 mg/dl; p<0.014), and decreased further during intensive postremission therapy containing l-asparaginase (mean = 3.2; p<0.05). For all 18 patients, a significant negative correlation (r2=0.667; p<0.001) was found between serum albumin and unbound teniposide, with low albumin being associated with higher unbound fraction. Such patients have higher systemic exposure to unbound (presumably active) teniposide at any given total plasma concentration of the agent. [ABSTRACT FROM AUTHOR]

Aim: Renal fibrosis plays a pivotal role in the development and progression of chronic kidney disease, which affects 10% of the adult population. Previously, it has been demonstrated that the cyclooxygenase‐2 (COX‐2)/prostaglandin (PG) system influences the progression of renal injury. Here, we evaluated the impact of butaprost, a selective EP2 receptor agonist, on renal fibrosis in several models of kidney injury, including human tissue slices. Methods: We studied the anti‐fibrotic efficacy of butaprost using Madin‐Darby Canine Kidney (MDCK) cells, mice that underwent unilateral ureteral obstruction and human precision‐cut kidney slices. Fibrogenesis was evaluated on a gene and protein level by qPCR and Western blotting. Results: Butaprost (50 μM) reduced TGF‐β‐induced fibronectin (FN) expression, Smad2 phosphorylation and epithelial‐mesenchymal transition in MDCK cells. In addition, treatment with 4 mg/kg/day butaprost attenuated the development of fibrosis in mice that underwent unilateral ureteral obstruction surgery, as illustrated by a reduction in the gene and protein expression of α‐smooth muscle actin, FN and collagen 1A1. More importantly, a similar anti‐fibrotic effect of butaprost was observed in human precision‐cut kidney slices exposed to TGF‐β. The mechanism of action of butaprost appeared to be a direct effect on TGF‐β/Smad signalling, which was independent of the cAMP/PKA pathway. Conclusion: In conclusion, this study demonstrates that stimulation of the EP2 receptor effectively mitigates renal fibrogenesis in various fibrosis models. These findings warrant further research into the clinical application of butaprost, or other EP2 agonists, for the inhibition of renal fibrosis. [ABSTRACT FROM AUTHOR]

Metformin is today the first choice treatment for type‐2 diabetes, but has also protective effects in several renal disease models. Previously, we have demonstrated that the protective effects in response to unilateral ureteral obstruction (UUO) are independent of organic cation transporters (OCTs), the transporters responsible for the metformin uptake into the renal cells. The mechanisms behind the renoprotective effects are incompletely understood, but our previous results indicate that the renoprotective effects at least partly could be dependent on actions of metformin outside the renal cells. In this study, we investigate whether the renoprotective effects of metformin can be mediated via systemic immunomodulatory actions. We demonstrated that metformin can affect the immune system in the kidney as well as in the peripheral blood and spleen following UUO. UUO kidneys showed infiltration of immune cells including monocytes, B cells, and T cells, but metformin limited infiltration of all cell types. UUO animals had increased spleen sizes, but this increase was attenuated by metformin. Metformin treatment surprisingly resulted in a higher proportion of monocytes with infiltratory capacity 7 days after UUO. Other studies have suggested that metformin regulates monocyte maturation through signal transducer and activator of transcription 3 (STAT3) activation, as also indicated by our results. In conclusion, our results demonstrate that metformin limits the infiltration of immune cells into the kidney, as well as modulates immune cell composition at a systemic level. [ABSTRACT FROM AUTHOR]

Background: The purpose of the study is to examine the effect of metformin on oxygen metabolism and mitochondrial function in the kidney of an animal model of insulinopenic diabetes in order to isolate any renoprotective effect from any concomitant effect on blood glucose homeostasis.Methods: Sprague-Dawley rats were injected with streptozotocin (STZ) (50 mg kg-1 ) and when stable started on metformin treatment (250 mg kg-1 ) in the drinking water. Rats were prepared for in vivo measurements 25 to 30 days after STZ injection, where renal function, including glomerular filtration rate and sodium transport, was estimated in anesthetized rats. Intrarenal oxygen tension was measured using oxygen sensors. Furthermore, mitochondrial function was assessed in mitochondria isolated from kidney cortex and medulla analysed by high-resolution respirometry, and superoxide production was evaluated using electron paramagnetic resonance.Results: Insulinopenic rats chronically treated with metformin for 4 weeks displayed improved medullary tissue oxygen tension despite of no effect of metformin on blood glucose homeostasis. Metformin reduced UCP2-dependent LEAK and differentially affected medullary mitochondrial superoxide radical production in control and diabetic rats.Conclusions: Metformin attenuates diabetes-induced renal medullary tissue hypoxia in an animal model of insulinopenic type 1 diabetes. The results suggest that the mechanistic pathway to attenuate the diabetes-induced medullary hypoxia is independent of blood glucose homeostasis and includes reduced UCP2-mediated mitochondrial proton LEAK. [ABSTRACT FROM AUTHOR]

Aim: Renal fibrosis plays a pivotal role in the development and progression of chronic kidney disease, which affects 10% of the adult population. Previously, it has been demonstrated that the cyclooxygenase-2 (COX-2)/prostaglandin (PG) system influences the progression of renal injury. Here, we evaluated the impact of butaprost, a selective EP 2 receptor agonist, on renal fibrosis in several models of kidney injury, including human tissue slices., Methods: We studied the anti-fibrotic efficacy of butaprost using Madin-Darby Canine Kidney (MDCK) cells, mice that underwent unilateral ureteral obstruction and human precision-cut kidney slices. Fibrogenesis was evaluated on a gene and protein level by qPCR and Western blotting., Results: Butaprost (50 μM) reduced TGF-β-induced fibronectin (FN) expression, Smad2 phosphorylation and epithelial-mesenchymal transition in MDCK cells. In addition, treatment with 4 mg/kg/day butaprost attenuated the development of fibrosis in mice that underwent unilateral ureteral obstruction surgery, as illustrated by a reduction in the gene and protein expression of α-smooth muscle actin, FN and collagen 1A1. More importantly, a similar anti-fibrotic effect of butaprost was observed in human precision-cut kidney slices exposed to TGF-β. The mechanism of action of butaprost appeared to be a direct effect on TGF-β/Smad signalling, which was independent of the cAMP/PKA pathway., Conclusion: In conclusion, this study demonstrates that stimulation of the EP 2 receptor effectively mitigates renal fibrogenesis in various fibrosis models. These findings warrant further research into the clinical application of butaprost, or other EP 2 agonists, for the inhibition of renal fibrosis., (© 2019 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiology Society.)