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For small mammals, such as mice, cannulation procedures can be quite challenging, limiting research associated with tracing isotopically labelled substrates at the whole-animal level. When cannulation in mice is possible, assessment of substrate use is further limited to when mice are either under anesthesia or are at rest, as there are no studies directly quantifying substrate use during exercise in mice. The use of isotopic tracer techniques has greatly advanced our knowledge in understanding how metabolic substrates (carbohydrates, amino acids, and fatty acids) contribute to whole-body metabolism. However, research regarding tissue-specific fuel use contributions to whole-body energy expenditure in mice at varying metabolic intensities (i.e., exercise) is lacking, despite the popularity of using mice in a variety of metabolic models. In this commentary, we briefly discuss the methodologies, advantages, and disadvantages of using radiolabelled, positron emission, and stable isotopes with a specific focus on fatty acids. We highlight recent mouse studies that have used creative experimental designs employing the use of isotopic tracer techniques and we briefly discuss how these methodologies can be further pursued to deepen our understanding of substrate use during exercise. Lastly, we show findings of a recent study we performed using a radiolabelled fatty acid tracer ( 14 C-bromopalmitic acid) to determine fatty acid uptake in 16 muscles, two brown and two white adipose tissue depots during submaximal exercise in deer mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Adult, lab-reared, highland deer mice acclimate to hypoxia by increasing reliance on carbohydrates to fuel exercise. Yet neither the underlying mechanisms for this shift in fuel use nor the impact of lifetime hypoxia exposure experienced in high alpine conditions, are fully understood. Thus, we assessed the use of fuel during exercise in wild highland deer mice running in their native environment. We examined a key step in muscle carbohydrate oxidation - the regulation of pyruvate dehydrogenase (PDH) - during exercise at altitude in wild highlanders and in first generation (G1) lab-born and -raised highlanders acclimated to normoxia or hypoxia. PDH activity was also determined in the gastrocnemius of G1 highlanders using an in situ muscle preparation. We found that wild highlanders had a high reliance on carbohydrates while running in their native environment, consistent with data from hypoxia-acclimated G1 highlanders. PDH activity in the gastrocnemius was similar post exercise between G1 and wild highlanders. However, when the gastrocnemius was stimulated at a light work rate in situ, PDH activity was higher in hypoxia-acclimated G1 highlanders and was associated with lower intramuscular lactate levels. These findings were supported by lower PDH kinase 2 protein production in hypoxia-acclimated G1 mice. Our findings indicate that adult phenotypic plasticity in response to low oxygen is sufficient to increase carbohydrate reliance during exercise in highland deer mice. Additionally, variation in PDH regulation with hypoxia acclimation contributes to shifts in whole-animal patterns of fuel use and is likely to improve exercise performance via elevated energy yield per mole of O2. ., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Adipose tissue was once known as a reservoir for energy storage but is now considered a crucial organ for hormone and energy flux with important effects on health and disease. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted from the small intestinal K cells, responsible for augmenting insulin release, and has gained attention for its independent and amicable effects with glucagon-like peptide 1 (GLP-1), another incretin hormone secreted from the small intestinal L cells. The GIP receptor (GIPR) is found in whole adipose tissue, whereas the GLP-1 receptor (GLP-1R) is not, and some studies suggest that GIPR action lowers body weight and plays a role in lipolysis, glucose/lipid uptake/disposal, adipose tissue blood flow, lipid oxidation, and free-fatty acid (FFA) re-esterification, which may or may not be influenced by other hormones such as insulin. This review summarizes the research on the effects of GIP in adipose tissue (distinct depots of white and brown) using cellular, rodent, and human models. In doing so, we explore the mechanisms of GIPR-based medications for treating metabolic disorders, such as type 2 diabetes and obesity, and how GIPR agonism and antagonism contribute to improvements in metabolic health outcomes, potentially through actions in adipose tissues.

During maximal cold challenge (cold-induced V̇O2,max) in hypoxia, highland deer mice (Peromyscus maniculatus) show higher rates of circulatory fatty acid delivery compared with lowland deer mice. Fatty acid delivery also increases with acclimation to cold hypoxia (CH) and probably plays a major role in supporting the high rates of thermogenesis observed in highland deer mice. However, it is unknown which tissues take up these fatty acids and their relative contribution to thermogenesis. The goal of this study was to determine the uptake of circulating fatty acids into 24 different tissues during hypoxic cold-induced V̇O2,max, by using [1-14C]2-bromopalmitic acid. To uncover evolved and environment-induced changes in fatty acid uptake, we compared lab-born and -raised highland and lowland deer mice, acclimated to either thermoneutral (30°C, 21 kPa O2) or CH (5°C, 12 kPa O2) conditions. During hypoxic cold-induced V̇O2,max, CH-acclimated highlanders decreased muscle fatty acid uptake and increased uptake into brown adipose tissue (BAT) relative to thermoneutral highlanders, a response that was absent in lowlanders. CH acclimation was also associated with increased activities of enzymes citrate synthase and β-hydroxyacyl-CoA dehydrogenase in the BAT of highlanders, and higher levels of fatty acid translocase CD36 (FAT/CD36) in both populations. This is the first study to show that cold-induced fatty acid uptake is distributed across a wide range of tissues. Highland deer mice show plasticity in this fatty acid distribution in response to chronic cold hypoxia, and combined with higher rates of tissue delivery, this contributes to their survival in the cold high alpine environment., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Metabolic diseases, such as obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease, and liver disease, have become increasingly prevalent around the world. As an alternative to bariatric surgery, glucagon-like peptide 1 (GLP-1) receptor agonists have been at the forefront of weight loss medication to combat these metabolic complications. Recently, there has been an exciting rapid emergence of new weight loss medications that combine GLP-1 receptor (GLP-1R) agonists with other gut- and pancreatic-derived hormones, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) receptor agonists. Dual-agonist (GLP-1/GIP and GLP-1/GCG) and tri-agonist (GLP-1/GIP/GCG) administration generally result in greater weight loss, reduction of blood sugar and lipid levels, restoration of tissue function, and improvement in whole-body substrate metabolism compared to when GLP-1R agonists are used alone. The aim of this review is to summarize the recent literature of both preclinical and clinical studies on how these emerging gut-peptide therapies further improve weight loss and metabolic health outcomes for various metabolic diseases., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Highland native deer mice (Peromyscus maniculatus) have greater rates of lipid oxidation during maximal cold challenge in hypoxia (hypoxic cold-induced V̇O2,max) compared with their lowland conspecifics. Lipid oxidation is also increased in deer mice acclimated to simulated high altitude (cold hypoxia), regardless of altitude ancestry. The underlying lipid metabolic pathway traits responsible for sustaining maximal thermogenic demand in deer mice is currently unknown. The objective of this study was to characterize key steps in the lipid oxidation pathway in highland and lowland deer mice acclimated to control (23°C, 21 kPa O2) or cold hypoxic (5°C, 12 kPa O2) conditions. We hypothesized that capacities for lipid delivery and tissue uptake will be greater in highlanders and further increase with cold hypoxia acclimation. With the transition from rest to hypoxic cold-induced V̇O2,max, both highland and lowland deer mice showed increased plasma glycerol concentrations and fatty acid availability. Interestingly, acclimation to cold hypoxia led to increased plasma triglyceride concentrations at cold-induced V̇O2,max, but only in highlanders. Highlanders also had significantly greater delivery rates of circulatory free fatty acids and triglycerides due to higher plasma flow rates at cold-induced V̇O2,max. We found no population or acclimation differences in fatty acid translocase (FAT/CD36) abundance in the gastrocnemius or brown adipose tissue, suggesting that fatty acid uptake across membranes is not limiting during thermogenesis. Our data indicate that circulatory lipid delivery plays a major role in supporting the high thermogenic rates observed in highland versus lowland deer mice., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Background: Component-resolved diagnostics (CRD) help predict hazelnut allergy (HA) in children, but are of unknown diagnostic value in adults. This study aimed to evaluate the diagnostic accuracy of IgE to hazelnut extract and components in adults., Methods: A Dutch population of consecutively presenting adults suspected of HA, who underwent a double-blind placebo-controlled food challenge, were included. Serum IgE to hazelnut extract and Cor a 1, 8, 9, and 14 was measured on ImmunoCAP. Diagnostic accuracy was assessed by area under the curve (AUC) analysis., Results: Of 89 patients undergoing challenge, 46 had challenge-confirmed HA: 17 based on objective and 29 based on subjective symptoms. At commonly applied cutoffs 0.1 and 0.35 kU A /L, high sensitivity was observed for IgE to hazelnut extract and Cor a 1 (range 85-91%), and high specificity for IgE to Cor a 8, 9 and 14 (range 77-95%). However, the AUCs for hazelnut extract and components were too low for accurate prediction of HA (range 0.50-0.56). Combining hazelnut extract and component IgE measurements did not significantly improve accuracy. Higher IgE levels to Cor a 9 and 14 were tentatively associated with HA with objective symptoms, but the corresponding AUCs still only reached 0.68 and 0.63, respectively., Conclusions: Although hazelnut allergic adults are generally sensitized to hazelnut extract and Cor a 1, and hazelnut tolerant adults are usually not sensitized to Cor a 8, 9, or 14, challenge testing is still needed to accurately discriminate between presence and absence of HA in adults from a birch-endemic country., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: It is not well-understood why symptom severity varies between patients with peanut allergy (PA). Objective: To gain insight into the clinical profile of subjects with mild-to-moderate and severe PA, and investigate individual and collective predictive accuracy of clinical background and IgE to peanut extract and components for PA severity. Methods: Data on demographics, patient history and sensitization at extract and component level of 393 patients with probable PA (symptoms ≤ 2 h + IgE sensitization) from 12 EuroPrevall centers were analyzed. Univariable and penalized multivariable regression analyses were used to evaluate risk factors and biomarkers for severity. Results: Female sex, age at onset of PA, symptoms elicited by skin contact with peanut, family atopy, atopic dermatitis, house dust mite and latex allergy were independently associated with severe PA; birch pollen allergy with mild-to-moderate PA. The cross-validated AUC of all clinical background determinants combined (0.74) was significantly larger than the AUC of tests for sensitization to extract (0.63) or peanut components (0.54-0.64). Although larger skin prick test wheal size, and higher IgE to peanut extract, Ara h 1 and Ara h 2/6, were associated with severe PA, and higher IgE to Ara h 8 with mild-to-moderate PA, addition of these measurements of sensitization to the clinical background model did not significantly improve the AUC. Conclusions: Models combining clinical characteristics and IgE sensitization patterns can help establish the risk of severe reactions for peanut allergic patients, but clinical background determinants are most valuable for predicting severity of probable PA in an individual patient., Competing Interests: Outside of submitted work: MF-R reported grants and personal fees from Aimmune Therapeutics and Diater, personal fees from DBV, Allergy Therapeutics, GSK, HAL Allergy, Novartis, ThermoFisher Scientific, and SPRIM. BB-W reported personal fees from ThermoFisher Scientific. FB reported personal fees from Aimmune; grants from Stallergènes Greer, Chiesi, Mundipharma, Novartis, and Regeneron; and board membership for DVB, Stallergènes Greer, Novartis, ALK, Mundipharma, Boehringer, AstraZeneca, Medapharma, and Boston Scientific. JL was an employee of ThermoFisher Scientific. NP reported personal fees from Novartis, Nutricia, HAL Allergy BV, Menarine/Faes Farma, Sanofi, Mylan/Meda, Biomay, AstraZeneca, GSK, MSD, ASIT Biotech, Boehringer Ingelheim; and grants from Gerolymatos International SA, and Capricare. SV reported personal fees from Ärzteverband Deutscher Allergologen, Swiss Society for Allergy and Immunology, Schattauer Allergologie Handbuch, Elsevier Nahrungsmittelallergien und Intoleranzen, Karger Food Allergy: Molecular Basis and Clinical Practice, and Pharmacon. EM reported grants from Reacta Biotech; and was shareholder of Reacta Biotech Ltd. RR reported personal fees from HAL Allergy BV, Citeq BV, Angany Inc., and ThermoFisher Scientific. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Datema, Lyons, Fernández-Rivas, Ballmer-Weber, Knulst, Asero, Barreales, Belohlavkova, de Blay, Clausen, Dubakiene, Fernández-Perez, Fritsche, Gislason, Hoffmann-Sommergruber, Jedrzejczak-Czechowicz, Jongejan, Kowalski, Kralimarkova, Lidholm, Papadopoulos, Popov, Prado, Purohit, Reig, Seneviratne, Sinaniotis, Vassilopoulou, Versteeg, Vieths, Welsing, Mills, Le, Zwinderman and van Ree.)

When at their maximum thermogenic capacity (cold-induced V̇o 2max ), small endotherms reach levels of aerobic metabolism as high, or even higher, than running V̇o 2max . How these high rates of thermogenesis are supported by substrate oxidation is currently unclear. The appropriate utilization of metabolic fuels that could sustain thermogenesis over extended periods may be important for survival in cold environments, like high altitude. Previous studies show that high capacities for lipid use in high-altitude deer mice may have evolved in concert with greater thermogenic capacities. The purpose of this study was to determine how lipid utilization at both moderate and maximal thermogenic intensities may differ in high- and low-altitude deer mice, and strictly low-altitude white-footed mice. We also examined the phenotypic plasticity of lipid use after acclimation to cold hypoxia (CH), conditions simulating high altitude. We found that lipids were the primary fuel supporting both moderate and maximal rates of thermogenesis in both species of mice. Lipid oxidation increased threefold in mice from 30°C to 0°C, consistent with increases in oxidation of [ 13 C]palmitic acid. CH acclimation led to an increase in [ 13 C]palmitic acid oxidation at 30°C but did not affect total lipid oxidation. Lipid oxidation rates at cold-induced V̇o 2max were two- to fourfold those at 0°C and increased further after CH acclimation, especially in high-altitude deer mice. These are the highest mass-specific lipid oxidation rates observed in any land mammal. Uncovering the mechanisms that allow for these high rates of oxidation will aid our understanding of the regulation of lipid metabolism.

Background: EAACI guidelines emphasize the importance of patient history in diagnosing food allergy (FA) and the need for studies investigating its value using standardized allergy-focused questionnaires., Objective: To determine the contribution of reaction characteristics, allergic comorbidities and demographics to prediction of FA in individuals experiencing food-related adverse reactions., Methods: Adult and school-age participants in the standardized EuroPrevall population surveys, with self-reported FA, were included. Penalized multivariable regression was used to assess the association of patient history determinants with "probable" FA, defined as a food-specific case history supported by relevant IgE sensitization., Results: In adults (N = 844), reproducibility of reaction (OR 1.35 [95% CI 1.29-1.41]), oral allergy symptoms (OAS) (4.46 [4.19-4.75]), allergic rhinitis (AR) comorbidity (2.82 [2.68-2.95]), asthma comorbidity (1.38 [1.30-1.46]) and male sex (1.50 [1.41-1.59]) were positively associated with probable FA. Gastrointestinal symptoms (0.88 [0.85-0.91]) made probable FA less likely. The AUC of a model combining all selected predictors was 0.85 after cross-validation. In children (N = 670), OAS (2.26 [2.09-2.44]) and AR comorbidity (1.47 [CI 1.39-1.55]) contributed most to prediction of probable FA, with a combined cross-validation-based AUC of 0.73. When focusing on plant foods, the dominant source of FA in adults, the pediatric model also included gastrointestinal symptoms (inverse association), and the AUC increased to 0.81., Conclusions: In both adults and school-age children from the general population, reporting of OAS and of AR comorbidity appear to be the strongest predictors of probable FA. Patient history particularly allows for good discrimination between presence and absence of probable plant FA., (© 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: The diagnostic value of peanut components is extensively studied in children, but to a lesser extent in adults with suspected peanut allergy. The use of peanut components in daily practice may reduce the need for double-blind placebo-controlled food challenges (DBPCFCs); however, validation studies are currently lacking., Objective: To evaluate the diagnostic value of (combined) peanut components and validate a previously found Ara h 2 cutoff level with 100% positive predictive value (PPV) in adults with suspected peanut allergy., Methods: Adults who underwent a peanut DBPCFC were included: 84 patients from a previous study (2002-2012) and 70 new patients (2012-2019). Specific IgE (sIgE) to peanut extract, Ara h 1, 2, 3, 6, and 8 was measured using ImmunoCAP. Diagnostic value was assessed with an area under the curve (AUC) analysis., Results: In total, 95 (62%) patients were peanut allergic. sIgE to Ara h 2 and Ara h 6 were the best predictors with an AUC (95% confidence interval) of 0.85 (0.79-0.91) and 0.85 (0.79-0.92), respectively. The Ara h 2 cutoff level with 100% PPV (≥1.75 kU A /L) was validated in the 70 new patients. Thirty percent of all included patients could be classified correctly as peanut allergic using this validated cutoff level., Conclusion: sIgE to Ara h 2 and Ara h 6 have equally high discriminative ability. Peanut allergy can be predicted accurately in one-third of adults using a validated cutoff level of sIgE to Ara h 2., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Walnut allergy is common across the globe, but data on the involvement of individual walnut components are scarce., Objectives: To identify geographical differences in walnut component sensitization across Europe, explore cosensitization and cross-reactivity, and assess associations of clinical and serological determinants with severity of walnut allergy., Methods: As part of the EuroPrevall outpatient surveys in 12 European cities, standardized clinical evaluation was conducted in 531 individuals reporting symptoms to walnut, with sensitization to all known walnut components assessed in 202 subjects. Multivariable Lasso regression was applied to investigate predictors for walnut allergy severity., Results: Birch-pollen-related walnut sensitization (Jug r 5) dominated in Northern and Central Europe and lipid transfer protein sensitization (Jug r 3) in Southern Europe. Profilin sensitization (Jug r 7) was prominent throughout Europe. Sensitization to storage proteins (Jug r 1, 2, 4, and 6) was detected in up to 10% of subjects. The walnut components that showed strong correlations with pollen and other foods differed between centers. The combination of determinants best predicting walnut allergy severity were symptoms upon skin contact with walnut, atopic dermatitis (ever), family history of atopic disease, mugwort pollen allergy, sensitization to cat or dog, positive skin prick test result to walnut, and IgE to Jug r 1, 5, 7, or carbohydrate determinants (area under the curve = 0.81; 95% CI, 0.73-0.89)., Conclusions: Walnut-allergic subjects across Europe show clear geographical differences in walnut component sensitization and cosensitization patterns. A predictive model combining results from component-based serology testing with results from extract-based testing and information on clinical background allows for good discrimination between mild to moderate and severe walnut allergy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The geographical variation and temporal increase in the prevalence of food sensitization (FS) suggest environmental influences., Objective: To investigate how environment, infant diet, and demographic characteristics, are associated with FS in children and adults, focusing on early-life exposures., Methods: Data on childhood and adult environmental exposures (including, among others, sibship size, day care, pets, farm environment, and smoking), infant diet (including breast-feeding and timing of introduction to infant formula and solids), and demographic characteristics were collected from 2196 school-age children and 2185 adults completing an extensive questionnaire and blood sampling in the cross-sectional pan-European EuroPrevall project. Multivariable logistic regression was applied to determine associations between the predictor variables and sensitization to foods commonly implicated in food allergy (specific IgE ≥0.35 kU A /L). Secondary outcomes were inhalant sensitization and primary (non-cross-reactive) FS., Results: Dog ownership in early childhood was inversely associated with childhood FS (odds ratio, 0.65; 95% CI, 0.48-0.90), as was higher gestational age at delivery (odds ratio, 0.93 [95% CI, 0.87-0.99] per week increase in age). Lower age and male sex were associated with a higher prevalence of adult FS (odds ratio, 0.97 [95% CI, 0.96-0.98] per year increase in age, and 1.39 [95% CI, 1.12-1.71] for male sex). No statistically significant associations were found between other evaluated environmental determinants and childhood or adult FS, nor between infant diet and childhood FS, although early introduction of solids did show a trend toward prevention of FS., Conclusions: Dog ownership seems to protect against childhood FS, but independent effects of other currently conceived environmental and infant dietary determinants on FS in childhood or adulthood could not be confirmed., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: For adults, prevalence estimates of food sensitization (FS) and food allergy (FA) have been obtained in a standardized manner across Europe. For children, such estimates are lacking., Objectives: To determine the prevalence of self-reported FA, FS, probable FA (symptoms plus IgE sensitization), and challenge-confirmed FA in European school-age children., Methods: Data on self-reported FA were collected through a screening questionnaire sent to a random sample of the general population of 7- to 10-year-old children in 8 European centers in phase I of the EuroPrevall study. Data on FS and probable FA were obtained in phase II, comprising an extensive questionnaire on reactions to 24 commonly implicated foods, and serology testing. Food challenge was performed in phase III., Results: Prevalence (95% CI) of self-reported FA ranged from 6.5% (5.4-7.6) in Athens to 24.6% (22.8-26.5) in Lodz; prevalence of FS ranged from 11.0% (9.7-12.3) in Reykjavik to 28.7% (26.9-30.6) in Zurich; and prevalence of probable FA ranged from 1.9% (0.8-3.5) in Reykjavik to 5.6% (3.6-8.1) in Lodz. In all centers, most food-sensitized subjects had primary (non-cross-reactive) FS. However, FS due to birch pollen related cross-reactivity was also common in Central-Northern Europe. Probable FA to milk and egg occurred frequently throughout Europe; to fish and shrimp mainly in the Mediterranean and Reykjavik. Peach, kiwi, and peanut were prominent sources of plant FA in most countries, along with notably hazelnut, apple, carrot, and celery in Central-Northern Europe and lentils and walnut in the Mediterranean., Conclusions: There are large geograhical differences in the prevalence of FS and FA in school-age children across Europe. Both primary and cross-reactive FS and FA occur frequently., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Strong school-based vision and eye health systems include 12 key components to be implemented before, during, and after the actual vision screening event. The National Center for Children's Vision and Eye Health (NCCVEH) at Prevent Blindness partnered with the National Association of School Nurses (NASN) to provide guidance for school nurses for each of the 12 key components via a Vision and Eye Health webpage on the NASN website ( https://www.nasn.org/nasn-resources/practice-topics/vision-health ). This online resource is designed to support school nurses accountable for vision screening and maintaining the eye health of preschool- and school-age children. This NCCVEH/NASN webpage addresses key activities that provide overall support for a child's vision and eye health-beginning with parent/caregiver education and ending with an annual evaluation of the school's vision and eye health system. NASN School Nurse is publishing information about each of these 12 components. The May 2019 installment provided details about the 12 Components approach as a whole and Components 1 and 2: Family Education and a Comprehensive Communication/Approval Process. The July 2019 edition described Components 3 and 4: Vision Screening Tools and Procedures and Vision Health for Children With Special Health Care Needs. This article describes Component 5: Standardized Approach for Rescreening.

Deer mice, Peromyscusmaniculatus, live at high altitudes where limited O 2 represents a challenge to maintaining oxygen delivery to tissues. Previous work has demonstrated that hypoxia acclimation of deer mice and low altitude white-footed mice (P. leucopus) increases the force generating capacity of the diaphragm. The mechanism behind this improved contractile function is not known. Within myocytes, the myofilament plays a critical role in setting the rate and level of force production, and its ability to generate force can change in response to changes in physiological conditions. In the current study, we examined how chronic hypobaric hypoxia exposure of deer mice and white-footed mice influences the Ca 2+ activation of force generation by skinned diaphragmatic myofilaments, and the phosphorylation of myofilament proteins. Results demonstrate that myofilament force production, and the Ca 2+ sensitivity of force generation, were not impacted by acclimation to hypobaric hypoxia, and did not differ between preparations from the two species. The cooperativity of the force-pCa relationship, and the maximal rate of force generation were also the same in the preparations from both species, and not impacted by acclimation. Finally, the relative phosphorylation of TnT, and MLC was lower in deer mice than white-footed mice, but was not affected by acclimation. These results indicate that species differences in diaphragm function, and the increase in force production with hypoxia acclimation, are not due to differences, or changes, in myofilament function. However, it appears that diaphragmatic myofilament function in these species is not affected by chronic hypobaric hypoxia exposure.

Successful vision screening efforts require the implementation of 12 key components of a strong vision health system of care. The National Center for Children's Vision and Eye Health (NCCVEH) at Prevent Blindness partnered with the National Association of School Nurses (NASN) to provide guidance around these 12 components via a Vision and Eye Health webpage on the NASN website ( https://www.nasn.org/nasn-resources/practice-topics/vision-health ). This online resource is organized according to the 12 Components of a Strong Vison Health System of Care to support school nurses accountable for screening the vision of preschool and K-12 students. This NCCVEH/NASN webpage addresses key activities that support a child's vision health-beginning with parent/caregiver education and ending with an annual evaluation of the school's vision health system. Each of these 12 components will be described in NASN School Nurse . The May 2019 installment provided information about the 12 components approach as a whole and details on Family Education and a Comprehensive Communication/Approval Process. This installment describes Components 3 and 4: Vision Screening Tools and Procedures and Vision Health for Children with Special Health Care Needs.

Background: According to the community-based EuroPrevall surveys, prevalence of self-reported food allergy (FA) in adults across Europe ranges from 2% to 37% for any food and 1% to 19% for 24 selected foods., Objective: To determine the prevalence of probable FA (symptoms plus specific IgE-sensitization) and challenge-confirmed FA in European adults, along with symptoms and causative foods., Methods: In phase I of the EuroPrevall project, a screening questionnaire was sent to a random sample of the general adult population in 8 European centers. Phase II consisted of an extensive questionnaire on reactions to 24 preselected commonly implicated foods, and measurement of specific IgE levels. Multiple imputation was performed to estimate missing symptom and serology information for nonresponders. In the final phase, subjects with probable FA were invited for double-blind placebo-controlled food challenge., Results: Prevalence of probable FA in adults in Athens, Reykjavik, Utrecht, Lodz, Madrid, and Zurich was respectively 0.3%, 1.4%, 2.1%, 2.8%, 3.3%, and 5.6%. Oral allergy symptoms were reported most frequently (81.6%), followed by skin symptoms (38.2%) and rhinoconjunctivitis (29.5%). Hazelnut, peach, and apple were the most common causative foods in Lodz, Utrecht, and Zurich. Peach was also among the top 3 causative foods in Athens and Madrid. Shrimp and fish allergies were relatively common in Madrid and Reykjavik. Of the 55 food challenges performed, 72.8% were classified as positive., Conclusions: FA shows substantial geographical variation in prevalence and causative foods across Europe. Although probable FA is less common than self-reported FA, prevalence still reaches almost 6% in parts of Europe., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Risk-prediction indices are one category of the many tools implemented to guide efforts to decrease readmissions. However, using fied models to predict a complex process can prove challenging. In addition, no risk-prediction index has been developed for patients undergoing colorectal surgery. Therefore, we evaluated the performance of a widely utilized simplified index developed at the hospital level - LACE (length of stay, acute admission, Charlson comorbidity index score, and emergency department visits) and developed and evaluated a novel index in predicting readmissions in this patient population., Methods: Using a retrospective split-sample cohort, patients discharged after colorectal surgery were identified within the inpatient databases of the Healthcare Cost and Utilization Project for the states of New York, California, and Florida (2006-2014). The primary outcome was death or readmission within 30 days after discharge. Multivariable logistic regression models incorporated patient comorbidities, postoperative complications, and hospitalization details, and were evaluated using the C statistic., Results: A total of 440,742 patients met eligibility criteria. The rate of death or readmission within 30 days after discharge was 14.0% (n = 61,757). When applied to surgical patients, the LACE index demonstrated a poor model fit (C = 0.631). The model fit improved significantly-but remained poor (C = 0.654; P < .001)-with the addition of the following variables, which are known to be associated with readmission after colorectal surgery: age, indication for surgery, and creation of a new ostomy. A novel, simplified model also yielded a poor model fit (C = 0.660)., Conclusion: Postdischarge death or readmission after colorectal surgery is not accurately modeled using existing, modified, or novel simplified risk prediction models. Payers and providers must ensure that quality improvement efforts applying simplified models to complex processes, such as readmissions following colorectal surgery, may not be appropriate, and that models reflect the relevant patient population., (Published by Elsevier Inc.)

The National Center for Children's Vision and Eye Health (NCCVEH) at Prevent Blindness partnered with the National Association of School Nurses (NASN) to provide guidance for school nurses responsible for screening the vision of preschool and K-12 students. Goals of this national partnership are to (1) standardize approaches to vision health, (2) facilitate follow up to eye care for students who do not pass vision screening, (3) provide family/caregiver friendly educational information, and (4) consult with leading pediatric eye care experts to promote evidence-based best practices. The NCCVEH/NASN partnership created a Vision and Eye Health page on the NASN website ( https://www.nasn.org/nasn-resources/practice-topics/vision-health ). This resource is organized according to the 12 Components of a Strong Vision Health System of Care. The 12 components emerged as the NCCVEH considered vision screening from a systems perspective. This systems perspective addresses key activities along the entire spectrum of care that supports a child's vision health-beginning with parent/caregiver education and ending with an annual evaluation of the school's vision health system. Each of these 12 components will be described in 4 installments of NASN School Nurse in 2019. This installment describes the first two components: Family Education and a Comprehensive Communication/Approval Process.

In practice, it remains unclear what the best dietary approach is in subjects with pollen-related food allergy (PRFA). Our objective was to evaluate the effect of (1) dietary avoidance advice, (2) oral immunotherapy (OIT), (3) (heat) processing, and (4) consumption of hypoallergenic cultivars on frequency, severity, and eliciting dose of pollen-related food allergic reactions. A systematic search was conducted in PubMed, Embase, and Cochrane. All studies performing an in vivo investigation of one of the four interventions in adults with PRFA were included. Each study was assessed for quality and validity. Available data on frequency, severity, and eliciting dose of allergic reactions were extracted. Ten studies matched the eligibility criteria. No studies were retrieved on dietary avoidance advice. Two studies ( N = 92) on apple OIT reported that tolerance was induced in 63% and 81% of subjects. Four studies (total N = 116) focused on heat processing. Heating was found to completely eradicate symptoms in 15⁻71% of hazelnut allergic and 46% of celery allergic individuals. Four studies ( N = 60) comparing low to high allergenic apple cultivars revealed that Santana (and possibly Elise) apples seemed to cause milder reactions than Golden Delicious. In the awareness that overall level of evidence was low, we conclude that OIT, heat processing, and hypoallergenic cultivars may diminish or completely prevent allergic reactions in some but not all subjects with PRFA.

Aim: We examined the effects of chronic hypoxia on diaphragm function in high- and low-altitude populations of Peromyscus mice., Methods: Deer mice (P. maniculatus) native to high altitude and congeneric mice native to low altitude (P. leucopus) were born and raised in captivity to adulthood and were acclimated to normoxia or hypobaric hypoxia (12 or 9 kPa, simulating hypoxia at 4300 and 7000 m) for 6-8 weeks. We then measured indices of mitochondrial respiration capacity, force production, and fatigue resistance in the diaphragm., Results: Mitochondrial respiratory capacities (assessed using permeabilized fibres with single or multiple inputs to the electron transport system), citrate synthase activity (a marker of mitochondrial volume), twitch force production, and muscle fatigue resistance increased after exposure to chronic hypoxia in both populations. These changes were not well explained by variation in the fibre-type composition of the muscle. However, there were several differences in diaphragm function in high-altitude mice compared to low-altitude mice. Exposure to a deeper level of hypoxia (9 kPa vs 12 kPa) was needed to elicit increases in mitochondrial respiration rates in highlanders. Chronic hypoxia did not increase the emission of reactive oxygen species from permeabilized fibres in highlanders, in contrast to the pronounced increases that occurred in lowlanders. In general, the diaphragm of high-altitude mice had greater capillary length densities, produced less force in response to stimulation and had shorter relaxation times. The latter was associated with higher activity of sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) activity in the diaphragm of high-altitude mice., Conclusion: Overall, our work suggests that exposure to chronic hypoxia increases the capacities for mitochondrial respiration, force production and fatigue resistance of the diaphragm. However, many of these effects are opposed by evolved changes in diaphragm function in high-altitude natives, such that highlanders in chronic hypoxia maintain similar diaphragm function to lowlanders in sea level conditions., (© 2018 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Synopsis: Effective aerobic locomotion depends on adequate delivery of oxygen and an appropriate allocation of metabolic substrates. The use of metabolic substrates during exercise follows a predictive pattern of lipid and carbohydrate oxidation that is similar in lowland native cursorial mammals. We have found that in two highland lineages of mice (Phyllotis and Peromyscus) the fuel use pattern is shifted to a greater reliance on carbohydrates compared to their lowland conspecifics and congenerics. However, there is variation between lineages in the importance of phenotypic plasticity in the expression of this metabolic phenotype. Moreover, this metabolic phenotype is independent of running aerobic capacity and can also be independent of thermogenic capacity. For example, wild-caught mice from a highland population of deer mice (Peromyscus maniculatus) housed in warm normoxic laboratory conditions maintain higher maximum cold-induced oxygen consumption in acute hypoxia than lowland congenerics, but shivering and non-shivering thermogenesis is supported by high rates of lipid oxidation. This is reflected in the consistently higher activities of oxidative and fatty acid oxidation enzymes in the gastrocnemius of highland deer mice compared to lowlanders, which are resistant to hypoxia acclimation. While a fixed trait in muscle aerobic capacity may reflect the pervasive and unremitting low PO2 at high altitudes, muscle capacities for substrate oxidation may be more flexible to match appropriate substrate use with changing energetic demands. How shivering thermogenesis and locomotion potentially interact in the matching of muscle metabolic capacities to appropriate substrate use is unclear. Perhaps it is possible that shivering serves as "training" to ensure muscles have the capacity to support locomotion or visa-versa., (© The Author 2017. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.)

Objective: To evaluate the effectiveness of type 1 tympanoplasty with one-piece composite cartilage-perichondrium (CCP) grafts compared to temporalis fascia (TF) grafts for tympanic membrane (TM) closure and hearing improvement in adult patients with a subtotal TM perforation and chronic otitis media (COM)., Data Sources: PubMed, Embase, Cochrane Library., Review Methods: A systematic search was conducted. Relevance and validity of selected articles were assessed. Studies that scored moderate or high on relevance were included, and relevant data for both outcomes were extracted. For the outcome of TM closure, absolute risk differences (RD), relative risks, and number needed to treat with their respective 95% confidence intervals were calculated when possible., Results: We retrieved 3,783 unique studies. Ten studies satisfied the eligibility criteria. Four studies of moderate validity showed RD ranging from 0.08 to 0.13 in favor of the CCP graft compared to the TF graft for TM closure 1 year or more postoperatively, but this was not statistically significant. Five studies of moderate to high validity showed no clinically relevant difference in hearing improvement between both intervention groups at a minimum follow-up of 3 months. The relative air-bone gap closure ranged from 5.7 to 11.5 dB in the TF group and from 8.9 to 12.7 dB in the CCP group., Conclusions: There is no evidence of superiority of one-piece CCP grafting over TF grafting in type 1 tympanoplasty regarding complete closure of a subtotal perforated TM 1 year or more postoperatively or hearing improvement at a minimum of 3 months follow-up. Laryngoscope, 126:1662-1670, 2016., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: The purpose of this study was to investigate the relationship between health literacy and overall medication nonadherence, unintentional nonadherence, and intentional nonadherence. Limited health literacy may be associated with worse diabetes outcomes, but the literature shows mixed results, and mechanisms remain unclear. Medication adherence is associated with diabetes outcomes and may be a mediating factor. Distinguishing between unintentional and intentional nonadherence may elucidate the relationship between health literacy and nonadherence in patients with type 2 diabetes., Methods: Cross-sectional study of 208 patients with type 2 diabetes recruited from a primary care clinic in St. Louis, Missouri. Information was obtained from written questionnaire and patient medical records. Bivariate and multivariable regression were used to examine predictors of medication nonadherence., Results: The majority of patients in the study were low income, publicly insured, and African American, with limited health literacy and a high school/GED education or less. In multivariable models, limited health literacy was significantly associated with increased unintentional nonadherence but not intentional nonadherence., Conclusions: Results suggest differences in factors affecting intentional and unintentional nonadherence. The findings also suggest interventions are needed to decrease unintentional nonadherence among patients with type 2 diabetes and limited health literacy. Efforts to address unintentional medication nonadherence among patients with type 2 diabetes with limited health literacy may improve patient health., (© 2016 The Author(s).)

Data on the national and state levels is often used to inform policy decisions and strategies designed to reduce racial disparities in obesity. Obesity-related health outcomes are realized on the individual level, and policies based on state and national-level data may be inappropriate due to the variations in health outcomes within and between states. To examine county-level variation of obesity within states, we use a small-area analysis technique to fill the void for county-level obesity data by race. Five years of Behavioral Risk Factor Surveillance System data are used to estimate the prevalence of obesity by county, both overall and race-stratified. A modified weighting system is used based on demographics at the county level using 2010 census data. We fit a multilevel reweighted regression model to obtain county-level prevalence estimates by race. We compare the distribution of prevalence estimates of non-Hispanic Blacks to non-Hispanic Whites. For 25 of the 26 states included in our analysis there is a statistically significant difference between within-state county-level average obesity prevalence rates for non-Hispanic Whites and non-Hispanic Blacks. This study provides information needed to target disparities interventions and resources to the local areas with greatest need; it also identifies the necessity of doing so.

The successful delivery of comprehensive pediatric vision care after vision screening referral is a longstanding challenge that has significant implications for child wellness. In response to the many known obstacles that prevent the diagnosis and treatment of vision conditions, School-Based Vision Centers have been established in Framingham, MA and Boston, MA to provide easy access to comprehensive vision care following a failed vision screening. These on-site Vision Centers were developed to improve access to comprehensive vision care and treatment thereby correcting vision conditions that can adversely affect student academic achievement, athletic performance, and self-esteem. This paper highlights the collaboration between two public schools in Massachusetts and The New England Eye Institute and describes a multidisciplinary approach to comprehensive care delivery to high-risk pediatric populations in school-based settings. The ultimate goal of this model is to minimize visual barriers that may impede learning in order to maximize academic success and wellness., (© 2011 - IOS Press and the authors. All rights reserved)

Malignant gliomas have been shown to release glutamate, which kills surrounding brain cells, creating room for tumor expansion. This glutamate release occurs primarily via system xC, a Na+-independent cystine-glutamate exchanger. We show here, in addition, that the released glutamate acts as an essential autocrine/paracrine signal that promotes cell invasion. Specifically, chemotactic invasion and scrape motility assays each show dose-dependent inhibition of cell migration when glutamate release was inhibited using either S-(4)-CPG or sulfasalazine, both potent blockers of system xC. This inhibition could be overcome by the addition of exogenous glutamate (100 micromol/L) in the continued presence of the inhibitors. Migration/invasion was also inhibited when Ca2+-permeable alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPA-R) were blocked using GYKI or Joro spider toxin, whereas CNQX was ineffective. Ca2+ imaging experiments show that the released glutamate activates Ca2+-permeable AMPA-R and induces intracellular Ca2+ oscillations that are essential for cell migration. Importantly, glioma cells release glutamate in sufficient quantities to activate AMPA-Rs on themselves or neighboring cells, thus acting in an autocrine and/or paracrine fashion. System xC and the appropriate AMPA-R subunits are expressed in all glioma cell lines, patient-derived glioma cells, and acute patient biopsies investigated. Furthermore, animal studies in which human gliomas were xenographed into scid mice show that chronic inhibition of system xC-mediated glutamate release leads to smaller and less invasive tumors compared with saline-treated controls. These data suggest that glioma invasion is effectively disrupted by inhibiting an autocrine glutamate signaling loop with a clinically approved candidate drug, sulfasalazine, already in hand.

Although it is presynaptic, short-term plasticity has been shown at some synapses to depend upon the postsynaptic cell type. Previous studies have reported conflicting results as to whether Schaffer collateral axons have target-cell specific short-term plasticity. Here we investigate in detail the short-term dynamics of Schaffer collateral excitatory synapses onto CA1 stratum radiatum interneurones versus pyramidal cells in acute hippocampal slices from juvenile rats. In response to three stimulus protocols that invoke different forms of short-term plasticity, we find differences in some but not all forms of presynaptic short-term plasticity, and heterogeneity in the short term plasticity of synapses onto interneurones. Excitatory synapses onto the majority of interneurones had less paired-pulse facilitation than synapses onto pyramidal cells across a range of interpulse intervals (20-200 ms). Unlike synapses onto pyramidal cells, synapses onto most interneurones had very little facilitation in response to short high-frequency trains of five pulses at 5, 10 and 20 Hz, and depressed during trains at 50 Hz. However, the amount of high-frequency depression was not different between synapses onto pyramidal cells versus the majority of interneurones at steady state during 2-10 Hz trains. In addition, a small subset of interneurones (approximately 15%) had paired-pulse depression rather than paired-pulse facilitation, showed only depression in response to the high-frequency five pulse trains, and had more steady-state high-frequency depression than synapses onto pyramidal cells or the majority of interneurones. To investigate possible mechanisms for these differences in short-term plasticity, we developed a mechanistic mathematical model of neurotransmitter release that explicitly explores the contributions to different forms of short-term plasticity of the readily releasable vesicle pool size, release probability per vesicle, calcium-dependent facilitation, synapse inactivation following release, and calcium-dependent recovery from inactivation. Our model fits the responses of each of the three cell groups to the three different stimulus protocols with only two parameters that differ with cell group. The model predicts that the differences in short-term plasticity between synapses onto CA1 pyramidal cells and stratum radiatum interneurones are due to a higher initial release probability per vesicle and larger readily releasable vesicle pool size at synapses onto interneurones, resulting in a higher initial release probability. By measuring the rate of block of NMDA receptors by the open channel blocker MK-801, we confirmed that the initial release probability is greater at synapses onto interneurones versus pyramidal cells. This provides a mechanism by which both the initial strength and the short-term dynamics of Schaffer collateral excitatory synapses are regulated by their postsynaptic target cell.

Glial cells play an important role in sequestering neuronally released glutamate via Na+-dependent transporters. Surprisingly, these transporters are not operational in glial-derived tumors (gliomas). Instead, gliomas release glutamate, causing excitotoxic death of neurons in the vicinity of the tumor. We now show that glutamate release from glioma cells is an obligatory by-product of cellular cystine uptake via system xc-, an electroneutral cystine-glutamate exchanger. Cystine is an essential precursor for the biosynthesis of glutathione, a major redox regulatory molecule that protects cells from endogenously produced reactive oxygen species (ROS). Glioma cells, but not neurons or astrocytes, rely primarily on cystine uptake via system xc- for their glutathione synthesis. Inhibition of system xc- causes a rapid depletion of glutathione, and the resulting loss of ROS defense causes caspase-mediated apoptosis. Glioma cells can be rescued if glutathione status is experimentally restored or if glutathione is substituted by alternate cellular antioxidants, confirming that ROS are indeed mediators of cell death. We describe two potent drugs that permit pharmacological inhibition of system xc-. One of these drugs, sulfasalazine, is clinically used to treat inflammatory bowel disease and rheumatoid arthritis. Sulfasalazine was able to reduce glutathione levels in tumor tissue and slow tumor growth in vivo in a commonly used intracranial xenograft animal model for human gliomas when administered by intraperitoneal injection. These data suggest that inhibition of cystine uptake into glioma cells through the pharmacological inhibition of system xc- may be a viable therapeutic strategy with a Food and Drug Administration-approved drug already in hand.

Many mosquito control agencies use carbon dioxide-baited traps as surveillance tools for adult vector populations. However, decisions regarding the number and location of trap sites and the frequency of collections are often based on logistical issues, and not on the bionomics or spatial distribution of the target species. Therefore, with the aim of providing practical information for adult mosquito surveillance programs, we used an array of 81 carbon dioxide- and octenol-baited lights traps to obtain weekly samples of adult mosquitoes in Redland Shire in southeastern Queensland, Australia. The spatial patterns of four different mosquito species were examined, and positive spatial autocorrelation in trap counts was evident for Ochlerotatus vigilax (Skuse), Coquillettidia linealis (Skuse), and Culex annulirostris Skuse, but not for the container species Ochlerotatus notoscriptus (Skuse). Of the three species that exhibited spatially correlated trap counts, the autocorrelation was greatest in Oc. vigilax at a lag distance of 0-1.5 km, with Moran's I values of 0.30-0.64. Moran's I indices were also positive and statistically significant (P < 0.05) at lag distances of 1.5-3.0 and 3.0-4.5 km on each of the 15 sampling occasions. However, at 3.0-4.5 km the Moran's I values were low, which indicated only weak spatial autocorrelation in trap counts. Universal kriging was used to estimate the numbers of each species at unsampled locations throughout the study area, and leave-one-out cross validation analyses indicated that this was a robust method for Cq. linealis and Oc. vigilax. In contrast, trap counts for the container-breeding species Oc. notoscriptus were randomly distributed and the interpolated counts were not reliable. Comparisons of weekly contour maps of adult mosquito counts indicated a consistent spatial pattern for Oc. vigilax and Cq. linealis. Particular geographic areas had consistently high or low numbers of vectors, and these patterns were stable from year to year. Definition of geographic areas with consistently high or low numbers of vectors may allow control activities to be focused in areas with the greatest risk of arbovirus transmission.

The role of monocytes and macrophages during EBV infection is not clear. The interaction of EBV with human monocytes was investigated in terms of cell survival and morphological and phenotypic changes to gain a better understanding of the role of these cells during EBV infection. We show that EBV infection of PBMCs rescues monocytes from undergoing spontaneous apoptosis and dramatically enhances their survival. Results obtained with heat-inactivated virus, neutralizing anti-EBV mAb 72A1 and recombinant gp350, suggest that enhancement of viability by EBV requires both infectious virus and interaction between gp350 and its receptor. IFN-alpha either secreted within 24 h from PBMCs upon infection with EBV or exogenously added to unstimulated monocytes inhibited spontaneous apoptosis, indicating that induction of IFN-alpha is an early important survival signal responsible for the delay in the apoptosis of monocytes. EBV infection also induced acute maturation of monocytes to macrophages with morphological and phenotypic characteristics of potent APCs. Monocytes exposed to EBV became larger in size with increased granularity and expressed considerably higher levels of membrane HLA classes I and II, ICAM-1, CD80, CD86, and CD40 compared with uninfected cultures. These observations provide the first immunoregulatory links among EBV, IFN-alpha, and monocyte survival and maturation and importantly raise the possibility that these cells may serve as a vehicle for the dissemination of the virus as well as being active participants in eliciting anti-EBV T cell responses during acute infection.

Background: Prescribing philosophies for hyperopic refractive error in symptom-free children vary widely because relatively little information is available regarding the natural history of hyperopic refractive error in children and because accommodation and binocular function closely related to hyperopic refractive error vary widely among children. We surveyed pediatric optometrists and ophthalmologists to evaluate typical prescribing philosophies for hyperopia., Methods: Practitioners were selected from the American Academy of Optometry Binocular Vision, Perception, and Pediatric Optometry Section; the College of Vision Development; the pediatric and binocular vision faculty members of the colleges of optometry; and the American Association for Pediatric Ophthalmology and Strabismus. Surveys were mailed to 314 participants: 212 optometrists and 102 ophthalmologists., Results: A total of 161 (75%) of the optometrists and 59 (57%) of the ophthalmologists responded. About one-third of optometrists surveyed prescribe optical correction for symptom-free 6-month-old infants with +3.00 D to +4.00 D hyperopia, but fewer than 5% of ophthalmologists prescribe at this level. Most eye care practitioners prescribe optical correction for symptom-free 2-year-old children with +5.00 D of hyperopia, and this criterion for hyperopia decreases with age. Most ophthalmologists (71.4%) prescribe the full amount of astigmatism and less than the full amount of cycloplegic spherical component, and most optometrists (71.6%) prescribe less than the full amount of both components. When prescribing less than the full amount of astigmatism, eye care practitioners do not tend to prescribe a specific proportion of the cycloplegic refractive error., Conclusion: Pediatric eye care providers show a lack of consensus on prescribing philosophies for hyperopic children.

Voltage-gated chloride channels have recently been implicated as being important for cell proliferation and invasive cell migration of primary brain tumors cells. In the present study we provide several lines of evidence that glioma Cl- currents are primarily mediated by ClC-2 and ClC-3, two genes that belong to the ClC superfamily. Transcripts for ClC-2 thru ClC-7 were detected in a human glioma cell line by PCR, whereas only ClC-2, ClC-3, and ClC-5 protein could be identified by Western blot. Prominent ClC-2, -3, and -5 channel expression was also detected in acute patient biopsies from low- and high-grade malignant gliomas. Immunogold electron microscopic studies as well as digital confocal imaging localized a portion of these ClC channels to the plasma membrane. Whole-cell patch-clamp recordings show the presence of two pharmacologically and biophysically distinct Cl- currents that could be specifically reduced by 48 hr exposure of cells to channel-specific antisense oligonucleotides. ClC-3 antisense selectively and significantly reduced the expression of outwardly rectifying current with pronounced voltage-dependent inactivation. Such currents were sensitive to DIDS (200-500 microm) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (165 microm). ClC-2 antisense significantly reduced expression of inwardly rectifying currents, which were potentiated by hyperpolarizing prepulses and inhibited by Cd2+ (200-500 microm). Currents that were mediated by ClC-5 could not be demonstrated. We suggest that ClC-2 and ClC-3 channels are specifically upregulated in glioma membranes and endow glioma cells with an enhanced ability to transport Cl-. This may in turn facilitate rapid changes in cell size and shape as cells divide or invade through tortuous extracellular brain spaces.

Highly migratory neuroectodermal cells share a common embryonic origin with cells of the central nervous system (CNS). They include enteric, parasympathetic, sympathoadrenal, and sensory neurons of the peripheral nervous system, Schwann cells, melanocytes, endocrine cells, and cells forming connective tissue of the face and neck. Because of their common embryologic origin, these cells and the tumors that derive from them can share genetic and antigenic phenotypes with gliomas, tumors derived from CNS glia. We recently discovered that chlorotoxin (ClTx), a 4-kD peptide purified from Leiurus quinquestriatus scorpion, is a highly specific marker for glioma cells in biopsy tissues (Soroceanu et al. Cancer Res 58:4871-4879, 1998) that can target tumors in animal models. We report on the specificity of ClTx as a marker for tumors of neuroectodermal origin that include peripheral neuroectodermal tumors (PNET) and gliomas. Specifically, we histochemically stained frozen and paraffin tissue sections of human biopsy tissues from 262 patients with a synthetically manufactured and biologically active ClTx bearing an N-terminal biotin. The vast majority (74 of 79) of primary human brain tumors investigated showed abundant binding of ClTx with greater than 90% ClTx-positive cells in each section. By comparison, 32 biopsies of uninvolved brain used for comparison were largely ClTx-negative, with only a few isolated reactive astrocytes showing some ClTx binding. However, as with gliomas, the vast majority of PNETs examined showed specific ClTx binding (31 of 34). These include medulloblastomas (4 of 4), neuroblastomas (6 of 7), ganglioneuromas (4 of 4), melanomas (7 of 7), adrenal pheochromocytomas (5 of 6), primitive PNET (1), small cell lung carcinoma (2 of 3), and Ewing's sarcoma (2 of 2). Under identical staining conditions, normal tissues from brain, skin, kidney, and lung were consistently negative for ClTx. These results suggest that chlorotoxin is a reliable and specific histopathological marker for tumors of neuroectodermal origin and that chlorotoxin derivatives with cytolytic activity may have therapeutic potential for these cancers., (Copyright 2002 Wiley-Liss, Inc.)

This study details the novel application of predacious copepods, genus Mesocyclops, for control of Ochlerotatus tremulus (Theobald) group and Aedes aegypti (L.) mosquito larvae in subterranean habitats in north Queensland, Australia. During June 1997, 50 Mesocyclops sp. 1 were inoculated into one service manhole in South Townsville. Wet season rainfall and flooding in both 1998 and 2000 was responsible for the dispersal of copepods via the underground pipe system to 29 of 35 manholes over an area of 1.33 km2. Significant reductions in Aedes and Ochlerotatus larvae ensued. In these habitats, Mesocyclops and Metacyclops were able to survive dry periods, when substrate moisture content ranged from 13.8 to 79.9%. At the semiarid inland towns of Hughenden and Richmond, cracking clay soil prevents drainage of water from shallow service pits where Oc. tremulus immatures numbered from 292-18,460 per pit. Introduction of Mesocyclops copepods into these sites during May 1999 resulted in 100% control of Oc. tremulus for 18 mo. One uninoculated pit subsequently became positive for Mesocyclops with resultant control of mosquito larvae.

At semiarid Charters Towers, north Queensland, Australia, the importance of Aedes aegypti (L.) in wells was assessed in relation to the colonization of surface habitats during the wet season. From April to July 1999, 10 wells (five positive for Ae. aegypti) were monitored to assess their status and larvae population numbers therein. All surface containers located within a 100 m radius of each well were removed, treated with s-methoprene or sealed to prevent the utilization of these containers by mosquitoes. These inner cores were surrounded by outer zones for a further 100 m in which surface containers were left untreated but all subterranean habitats were treated. Ovitraps were monitored monthly in the inner cores for 36 wk from August 1999 to April 2000 and differences in the proportions of ovitraps positive for Ae. aegypti and Ochlerotatus notoscriptus (Skuse) were analyzed by logistic regression. Analysis of the proportions of ovitraps positive for Ae. aegypti near positive wells indicated significantly greater colonization from November to March (the wet season), compared with those situated near Ae. aegypti negative wells. As Oc. notoscriptus were not produced from subterranean sites, comparisons of the proportions of ovitraps positive for Oc. notoscriptus in positive and negative inner cores provided an indication of the relative productivity of the uncontrolled surface containers in the outer zones. Differences in the utililization of ovitraps by Oc. notoscriptus among positive and negative cores were observed during only one month (March), when oviposition was greater in ovitraps in the negative cores, compared with the positive cores. Best subsets linear regression analysis of the proportion of ovitraps positive forAe. aegypti against meteorological variables (rainfall, mean wind speed, mean relative humidity, mean minimum, and maximum temperature) during the week of ovitrapping indicated that minimum temperature and wind speed accounted for 63.4% of the variability. This study confirms that for semiarid towns such as Charters Towers, the practice of treating a relatively small number of key subterranean habitats during winter will significantly affect Ae. aegypti recolonization of surface container habitats during summer, the period of greatest risk for dengue.

Overexpression of the 5T4 transmembrane glycoprotein can have marked effects on both the actin cytoskeleton and cell migration. Using a yeast two-hybrid approach, we describe a novel interaction between 5T4 and TIP-2/GIPC, a cytoplasmic interacting protein containing a PDZ domain. The cytoplasmic tail of 5T4 contains a class I PDZ-binding motif (Ser-Asp-Val) and we demonstrate that this region, in particular the terminal valine, is required for 5T4 interaction with TIP-2/GIPC. HeLa cells expressing hemagglutinin-tagged TIP-2/GIPC (HA-TIP-2/GIPC) have an altered distribution of endogenous 5T4, which colocalizes with HA-TIP-2/GIPC, thus supporting an interaction. Furthermore, TIP-2/GIPC can be coimmunoprecipitated with 5T4 from HeLa cell lysates. Identification of the 5T4 and TIP-2/GIPC interaction provides the first link between 5T4 and the actin cytoskeleton. Since other proteins, like 5T4, associate with TIP-2/GIPC and are linked with cancer, we explore the possibility that TIP-2/GIPC may be a common factor involved in the cancer process.

Neocortical freeze lesions have been widely used to study neuronal mechanisms underlying hyperexcitability in dysplastic cortex. Comparatively little attention has been given to biophysical changes in the surrounding astrocytes that show profound morphological and biochemical alterations, often referred to as reactive gliosis. Astrocytes are thought to aid normal neuronal function by buffering extracellular K(+). Compromised astrocytic K(+) buffering has been proposed to contribute to neuronal dysfunction. Astrocytic K(+) buffering is mediated, partially, by the activity of inwardly rectifying K(+) channels (K(IR)) and may involve intracellular redistribution of K(+) through gap-junctions. We characterized K(+) channel expression and gap-junction coupling between astrocytes in freeze-lesion-induced dysplastic neocortex. Whole cell patch-clamp recordings were obtained from astrocytes in slices from postnatal day (P) 16--P24 rats that had received a freeze-lesion on P1. A marked increase in glial fibrillary acidic protein immunoreactivity was observed along the entire length of the freeze lesion. Clusters of proliferative (bromo-deoxyuridine nuclear staining, BrdU+) astrocytes were seen near the depth of the microsulcus. Astrocytes in cortical layer I surrounding the lesion were characterized by a significant reduction in K(IR). BrdU-positive astrocytes near the depth of the microsulcus showed essentially no expression of K(IR) channels but markedly enhanced expression of delayed rectifier K(+) (K(DR)) channels. These proliferative cells showed virtually no dye coupling, whereas astrocytes in the hyperexcitable zone adjacent to the microsulcus displayed prominent dye-coupling as well as large K(IR) and outward K(+) currents. These findings suggest that reactive gliosis is accompanied by a loss of K(IR) currents and reduced gap junction coupling, which in turn suggests a compromised K(+) buffering capacity.

The authors investigated the time course of leukocyte infiltration compared with microglial activation in adult rat brain slices after permanent middle cerebral artery occlusion (MCAO). To distinguish peripheral leukocytes from microglia, the blood cells were prelabeled in vivo with Rhodamine 6G (Rhod6G) i.v. before induction of ischemia. At specific times after infarct, invading leukocytes, microglia, and endothelial cells were labeled in situ with isolectin (IL)B4-FITC (ILB4). Six hours after MCAO only a few of the ILB4+ cells were colabeled by Rhod6G. These cells expressed the voltage-gated inwardly and outwardly rectifying K+ currents characteristic of macrophages. The majority of the ILB4+ cells were Rhod6G- and expressed a lack of voltage-gated channels, recently described for ramified microglial cells in brain slices, or exhibited only an inward rectifier current, a unique marker for cultured (but unstimulated) microglia. Forty-eight hours after MCAO, all blood-borne and the majority of Rhod6G- cells expressed outward and inward currents indicating that the intrinsic microglial population exhibited physiologic features of stimulated, cultured microglia. The ILB4+/Rhod6G- intrinsic microglial population was more abundant in the border zone of the infarct and their morphology changed from radial to ameboid. Within this zone, the authors observed rapidly migrating cells and recorded this movement by time-lapse microscopy. The current findings indicate that microglial cells acquire physiologic features of leukocytes at a later time point after MCAO.

In north Queensland, 14 localities were surveyed for mosquito larvae (third and fourth instar) during summer/autumn and winter from 1996 to 1999. Absolute population numbers in subterranean habitats, mainly service manholes and pits (97%) but also some wells, septic tanks, storm drains, and sumps, were expressed as a proportion of total numbers in these sites plus surface sites within a 100-m radius. When correction factors were applied to subterranean samples, the 472,477 larvae mainly of Aedes tremulus (Theobald) group, Aedes notoscriptus (Skuse), and Aedes aegypti (L.) comprised 78% of the total population. In relation to the proportion of the overall immature mosquito population from subterranean habitats (propsub), linear regression coefficients for minimum temperature, relative humidity, and Mesocyclops copepod prevalence were significant for winter data; but for summer, only relative humidity was significant. Linear regression coefficients for Mesocyclops prevalence approached significance (P = 0.061) in summer. When multiple linear regression was used to model propsub, 68% of the variation was accounted for by relative humidity and the prevalence of Mesocyclops. In the drier and cooler towns, increased use of subterranean sites during winter was caused by reduced availability of surface oviposition sites because of the dry season. In the wetter coastal towns, no such restrictions applied and ambient conditions remained more equitable all year round. Mesocyclops were surprisingly common, particularly in these coastal towns. Release of known numbers of Mesocyclops indicated that 3-sweep netting in service manholes was sensitive down to densities of one Mesocyclops per 10 liters, and overall recovery varied from 1 to 4%. In relation to control, service manholes represent a stable habitat for mosquito (7% positive overall) and Mesocyclops populations. If they remained wet, service manholes positive for mosquito immatures or Mesocyclops during summer/autumn had 96% and 85% chance, respectively, of being positive the following winter. Even allowing for the effect of drying, a mosquito-positive manhole had a 79% chance of remaining positive the following winter. In view of the importance of these sites as refuges from adverse ambient conditions, it is proposed that a winter control strategy using Mesocyclops presents a cost-effective control option to reduce the recolonization of surface sites when conditions become more suitable.

Objective: To evaluate the safety, immunogenicity, pharmacokinetics, and efficacy of intravenous administration of tumor necrosis factor binding protein (TNFbp) dimer in patients with rheumatoid arthritis (RA)., Methods: This phase I/II study was a multicenter, randomized, double blind, placebo controlled, ascending dose study evaluating TNFbp dimer administered by i.v. infusion. Thirty-three patients with RA divided into 3 cohorts received TNFbp dimer (30, 100, 300 microg/kg) or placebo during a 5 min infusion at baseline and at 3 and 6 weeks; patients were followed at routine intervals after each infusion through 77 days postinfusion. Pharmacokinetics were analyzed using a log-linear regimen and comparisons were made between half-life after first, 2nd, and 3rd doses. Plasma TNFbp dimer concentrations and serum antibody levels were used in the measurement of pharmacokinetics., Results: Administration of 30 microg/kg of TNFbp dimer was generally well tolerated; the maximum tolerated dose was 100 microg/kg. No serious adverse events were reported. A significant antibody response affected the half-life and clearance of TNFbp dimer at each dose group. Anti-TNFbp antibodies were noncytotoxic and nonagonistic. Clinical evaluations provided evidence of in vivo activity of TNFbp dimer in these patients., Conclusion: TNFbp dimer administered to patients with long standing RA resulted in significant antibody production to the study drug. This effect reduced the half-life and clearance of the TNFbp. This TNFbp will not be a viable option for treating patients with RA secondary to immunogenicity.

Background: A 44-year-old woman came to us with a chief symptom of "jumping letters side-to-side, which is most noticeable while reading." The onset occurred after she had experienced a closed head traumatic brain injury 3 years earlier. Several neuro-ophthalmologists diagnosed a fixational instability secondary to saccadic intrusions and prescribed Gabapentin, which provided minimal relief., Methods: The term saccadic intrusions refers to an inappropriate saccade with a disrupting effect on fixation. Our examination revealed a myopic anisometropia. Motility testing confirmed saccadic intrusions that lessened on occlusion of either eye and superior gaze. A plano spectacle with six-prism diopter-yoked base down was used to position the eyes in the superior null point. Electro-oculography, using the Visagraph II, demonstrated pre and post changes with the prism. The uncorrected anisometropia allowed the patient to be monocular under binocular viewing conditions., Case Report: The case report focuses on fixational problems that may occur secondary to traumatic brain injuries. There is evidence that the origin of the problem may be from uninhibited brain stem circuits. Pharmacological treatment may only offer transient improvement. The responsibility of a functional cure is often placed on the optometrist., Conclusion: This case demonstrates how an alternative use of prism and prescription application can play an important role in the management of fixation dysfunctions.

Background: Hyperopia is the most common refractive error of children. Children with mild (or even moderate) levels of hyperopia usually do not experience visual problems resulting from this hyperopia. However, children with moderate-to-high degrees of hyperopia are at significantly increased risk for the development of amblyopia and strabismus. It is this association with these visually threatening disorders that makes hyperopia in children an important public health problem. In addition, even lesser degrees of hyperopia may affect the child's ability to perform well in near-related tasks, such as reading. The effect hyperopia has on an individual child is dependent on a variety of factors, including the magnitude of hyperopia, the age of the individual, the status of the accommodative and convergence system, and the demands placed on the visual system. Early detection and treatment of hyperopia may help prevention of potential complications from adversely impacting the child's vision. Although much is known about childhood hyperopia and its effects on vision, there is also much that is not known. The natural history, ocular biometry, relationship to accommodative function, the indications for treatment, and the most effective treatment modalities are among the underlying issues and clinical considerations awaiting more complete understanding.

The major classes of glial cells, namely astrocytes, oligodendrocytes, and microglial cells were compared in parallel for their susceptibility to damage after combined hypoxia and hypoglycemia or hypoxia alone. The three glial cell types were isolated from neonatal rat brains, separated, and incubated in N2/CO2-gassed buffer-containing glucose or glucose substitutes, 2-deoxyglucose or mannitol (both nonmetabolizable sugars). The damage to the cells after 6 hours' exposure was determined at 0, 1, 3, 7 days based on release of lactate dehydrogenase and counting of ethidium bromide-stained dead cells, double-stained with cell-type specific markers. When 2-deoxyglucose replaced glucose during 6 hours of hypoxia, both oligodendrocytes and microglia rarely survived (18% and 12%, respectively). Astroglia initially increased the release of lactate dehydrogenase but maintained 98% to 99% viability. When mannitol, a radical scavenger and osmolarity stabilizer, replaced glucose during 6 hours of hypoxia, oligodendrocytes rarely survived (10%), astroglia survival remained at 99%, but microglia survival increased to 50%. After exposure to 6 and 42 hours, respectively, of hypoxic conditions alone, oligodendrocytes exhibited 10% survival whereas microglia and astroglia were only temporarily stressed and subsequently survived. In conclusion, oligodendrocytes, then microglia, are the most vulnerable glial cell types in response to hypoxia or hypoglycemia conditions, whereas astrocytes from the same preparations recover.

The cytokine, interleukin (IL)-15, and the T cell growth factor, IL-2, exhibit a similar spectrum of immune effects and share the IL-2 receptor (IL-2R) subunits IL-2Rbeta and IL-2Rgamma for signaling in hematopoietic cells. Numerous neuroregulatory activities of IL-2 have been suggested, but its expression in the normal central nervous system (CNS) is apparently very low and regionally restricted. We show by RNA and protein detection that IL-15, its specific receptor molecule, IL-15Ralpha, and the signal-transducing receptor subunits, IL-2Rbeta and IL-2Rgamma, are constitutively present in various regions of the developing and adult mouse brain. We further demonstrate, also at the single-cell level, that IL-15 and the components for IL-15Ralpha/IL-2Rbetagamma receptors are expressed by microglia. Tyrosine phosphorylation data are presented showing that IL-15 signaling in microglia involves Janus kinase 1 activity. At doses of 0.1-10 ng/ml, IL-15 affected functional properties of these cells, such as the production of nitric oxide, and supported their growth in culture, suggestive of a role as an autocrine growth factor. Microglial IL-15 could thus play a pivotal role in the CNS and may participate in certain CNS and neuroendocrine functions previously ascribed to IL-2.

We addressed the question of whether glial cells in intact white matter tracts express neurotransmitter receptors and we used Ca+2 signalling as a probe to detect the receptor activation. Corpus callosum slices from postnatal mice were bulk-loaded with the Ca+2-sensitive fluorescent dye fluo-3, and confocal microscopy was used to measure Ca+2 transients in response to neuroligands. Glial cell bodies were intensely dye-loaded and could be discriminated from the diffuse fluorescence of axons. Subpopulations of glial cells from slices obtained at postnatal days 3 to 7 responded with Ca+2 signals to ATP, glutamate, histamine, GABA, norepinephrine, serotonin, angiotensin II, bradykinin, and substance P. These subpopulations showed a distinct overlap; cells which were responsive to substance P always showed Ca+2 signalling in response to histamine, ATP, GABA and high K+ (membrane depolarization). GABA-responsive cells almost always showed a [Ca+2]i increase after membrane depolarization. In brain slices from postnatal day 11 to 18 animals, the Ca+2 responses were evident for glutamate, ATP, and norepinephrine, while GABA, substance P, serotonin, histamine, or angiotensin II rarely elicited a response. This study demonstrates that white matter glial cells in slices exhibit a large repertoire of neurotransmitter responses linked to Ca+2 signalling and that these receptor systems are differentially distributed on sub-populations of glial cells.