Body mass index moderates the association between diabetes distress and objective self-management behaviours in adolescents with type 1 diabetes and elevated A1Cs.

OBJECTIVE: To examine the cross-sectional associations between diabetes distress, BMI (zBMI; BMI z-score), objectively measured mean daily blood glucose readings and insulin boluses administered, and A1C in adolescents with type 1 diabetes (T1D) using insulin pumps. METHODS: T1D self-management behaviour data were downloaded from adolescents' (N = 79) devices and mean daily frequency of blood glucose readings and insulin boluses were calculated. Diabetes distress was measured (Problem Areas in Diabetes-Teen questionnaire [PAID-T]), A1C collected, and zBMI calculated from height and weight. Three multiple linear regressions were performed with blood glucose readings, insulin boluses, and A1C as the three dependent variables and covariates (age, T1D duration), zBMI, diabetes distress, and the diabetes distress x zBMI interaction as independent variables. RESULTS: Participants (55.7% female) were 14.9 ± 1.9 years old with T1D for 6.6 ± 3.4 years. zBMI moderated the relationship between diabetes distress and mean daily insulin boluses administered (b = -0.02, p = 0.02); those with higher zBMI and higher diabetes distress administered fewer daily insulin boluses. zBMI was not a moderator of the association between diabetes distress and blood glucose readings (b = -0.01, p = 0.29) or A1C (b = 0.002, p = 0.81). CONCLUSIONS: Using objective behavioural data is useful for identifying how adolescent diabetes distress and zBMI affect daily bolusing behaviour amongst adolescent insulin pump users. Although distinct interventions exist to improve T1D self-management or diabetes distress, none addresses them together while considering zBMI. Decreasing diabetes distress could be especially important for youth with high zBMI.

Error traps in the perioperative management of children with type 1 diabetes.

Patients with type 1 diabetes mellitus (T1D) require insulin administration at all times to maintain euglycemia and metabolic stability. Insulin administration in the perioperative period is complicated by fasting requirements and perioperative stressors that can change the patient's insulin needs. In addition, many anesthesia providers are not familiar with insulin dosing strategies and technology, such as insulin pumps and continuous glucose monitors (CGMs), that are commonly used by patients with T1D. Errors in perioperative insulin administration can lead to hypoglycemia, hyperglycemia, and diabetic ketoacidosis. This article reviews common errors of associated with the perioperative management of patients with T1D, including failure to assess and coordinate patient care preoperatively; failure to understand diabetes management and technology; failure to monitor blood glucose and recognize dysglycemia; and failure to appropriately administer basal insulin.

Comparison of bupivacaine liposome injectable solution and fentanyl for postoperative analgesia in dogs undergoing limb amputation.

OBJECTIVE: The objectives of the study were to compare the clinical efficacy and adverse effects of two analgesic protocols consisting of bupivacaine liposome injectable solution (BLIS) and 0.5% bupivacaine and fentanyl for postsurgical analgesia in dogs undergoing limb amputation. STUDY DESIGN: Randomized, double-blind, prospective, controlled, intent-to-treat, clinical noninferiority trial. ANIMALS: Forty client-owned dogs. METHODS: Dogs undergoing amputation were randomly assigned to either the BLIS or control group. Postoperative pain, sedation, nausea, and amount eaten were assessed using appropriate scales at 6, 12, 18, and 24 h by trained individuals blinded to the treatment protocol. Rescue analgesia was provided for Glasgow composite measure pain scale (short form) (CMPS-SF) scores of 5 or above. Clients were requested to pain score their dogs at home using a visual analogue scale (VAS) for 48 h following discharge. RESULTS: Forty dogs completed this study (20 control dogs and 20 BLIS dogs). The BLIS and control groups were equivalent for sedation, nausea, amount eaten, and pain, at all time periods except at 6 h (p < .01), when the BLIS group pain score was lower. CONCLUSION: The BLIS provided equivalent analgesia with fewer adverse effects than fentanyl constant rate infusion (CRI) following limb amputation. Rescue analgesia was provided to five dogs in the BLIS group and four in the control group, and there was no statistical difference. Nausea scores did not differ statistically. CLINICAL SIGNIFICANCE: As BLIS provides equivalent analgesia, this may allow for decreased reliance on opioids in the immediate postoperative period.

CD38 plays an age-related role in cholinergic deregulation of airway smooth muscle contractility.

BACKGROUND: Allergen-induced airway hyperresponsiveness in neonatal mice, but not adult mice, is caused by elevated innervation and consequent cholinergic hyperstimulation of airway smooth muscle (ASM). Whether this inflammation-independent mechanism contributes to ASM hypercontraction in childhood asthma warrants investigation. OBJECTIVE: We aimed to establish the functional connection between cholinergic stimulation and ASM contractility in different human age groups. METHODS: First, we used a neonatal mouse model of asthma to identify age-related mediators of cholinergic deregulation of ASM contractility. Next, we conducted validation and mechanistic studies in primary human ASM cells and precision-cut lung slices from young (<5 years old) and adult (>20 years old) donor lungs. Finally, we evaluated the therapeutic potential of the identified cholinergic signaling mediators using culture models of human ASM hypercontraction. RESULTS: ASM hypercontraction due to cholinergic deregulation in early postnatal life requires CD38. Mechanistically, cholinergic signaling activates the phosphatidylinositol 3-kinase/protein kinase B pathway in immature ASM cells to upregulate CD38 levels, thereby augmenting the Ca2+ response to contractile agonists. Strikingly, this early-life, CD38-mediated ASM hypercontraction is not alleviated by the ß-agonist formoterol. CONCLUSIONS: The acetylcholine-phosphatidylinositol 3-kinase/protein kinase B-CD38 axis is a critical mechanism of airway hyperresponsiveness in early postnatal life. Targeting this axis may provide a tailored treatment for children at high risk for allergic asthma.

Proteomic and Low-Polar Metabolite Profiling Reveal Unique Dynamics in Fatty Acid Metabolism during Flower and Berry Development of Table Grapes.

Grapevine development and ripening are complex processes that involve several biochemical pathways, including fatty acid and lipid metabolism. Fatty acids are essential components of lipids, which play crucial roles in fruit maturation and flavor development. However, the dynamics of fatty acid metabolism in grape flowers and berries are poorly understood. In this study, we present those dynamics and investigate the mechanisms of fatty acid homeostasis on 'Thompson Seedless' berries using metabolomic and proteomic analyses. Low-polar metabolite profiling indicated a higher abundance of fatty acids at the pre-flowering and pre-veraison stages. Proteomic analyses revealed that grape flowers and berries display unique profiles of proteins involved in fatty acid biosynthesis, triacylglycerol assembly, fatty acid ß-oxidation, and lipid signaling. These findings show, for the first time, that fatty acid metabolism also plays an important role in the development of non-oil-rich tissues, opening new perspectives about lipid function and its relation to berry quality.

Making Diabetes Electronic Medical Record Data Actionable: Promoting Benchmarking and Population Health Improvement Using the T1D Exchange Quality Improvement Portal.

This article describes how the T1D Exchange Quality Improvement Collaborative leverages an innovative web platform, the QI Portal, to gather and store electronic medical record (EMR) data to promote benchmarking and population health improvement in a type 1 diabetes learning health system. The authors explain the value of the QI Portal, the process for mapping center-level data from EMRs using standardized data specifications, and the QI Portal's unique features for advancing population health.

Worldwide differences in childhood type 1 diabetes: The SWEET experience.

OBJECTIVE: To study worldwide differences in childhood diabetes, comparing relevant indicators among five regions within the SWEET initiative. SUBJECTS: We investigated 26 726 individuals with type 1 diabetes (T1D) from 54 centers in the European region; 7768 individuals from 30 centers in the Asia/Middle East/Africa region; 2642 people from five centers in Australia/New Zealand; 10 839 individuals from seven centers in North America, and 1114 patients from five centers in South America. METHODS: The SWEET database was analyzed based on the following inclusion criteria: T1D, time period 2015-2019, and age < 21 years, with analysis of the most recent documented year of therapy. For the statistical analysis, we used multivariable linear and logistic regression models to adjust for age (<6 years, 6- < 12 years, 12- < 18 years, 18- < 21 years), gender, and duration of diabetes (<2 years, 2- < 5 years, 5- < 10 years, ≥10 years). RESULTS: Adjusted HbA1c means ranged from 7.8% (95%-confidence interval: 7.6-8.1) in Europe to 9.5% (9.2-9.8) in Asia/Middle East/Africa. Mean daily insulin dose ranged from 0.8 units/kg in Europe (0.7-0.8) and Australia/New Zealand (0.6-0.9) to 1.0 unit/kg 0.9-1.1) in Asia/Middle East/Africa. Percentage of pump use was highest in North America (80.7% [79.8-81.6]) and lowest in South America (4.2% [3.2-5.6]). Significant differences between the five regions were also observed with regards to body mass index SD scores, frequency of blood glucose monitoring and presence of severe hypoglycaemia. CONCLUSIONS: We found significant heterogeneity in diabetes care and outcomes across the five regions. The aim of optimal care for each child remains a challenge.

Increasing Insulin Pump Use Among 12- to 26-Year-Olds With Type 1 Diabetes: Results From the T1D Exchange Quality Improvement Collaborative.

Insulin pump therapy in pediatric type 1 diabetes has been associated with better glycemic control than multiple daily injections. However, insulin pump use remains limited. This article describes an initiative from the T1D Exchange Quality Improvement Collaborative aimed at increasing insulin pump use in patients aged 12-26 years with type 1 diabetes from a baseline of 45% in May 2018 to >50% by February 2020. Interventions developed by participating centers included increasing in-person and telehealth education about insulin pump technology, creating and distributing tools to assist in informed decision-making, facilitating insulin pump insurance approval and onboarding processes, and improving clinic staff knowledge about insulin pumps. These efforts yielded a 13% improvement in pump use among the five participating centers, from 45 to 58% over 22 months.

Quality Improvement in Diabetes Care: A Review of Initiatives and Outcomes in the T1D Exchange Quality Improvement Collaborative.

Despite immense strides in therapeutic advances, clinical outcomes continue to be less than ideal for people with type 1 diabetes. This discrepancy has prompted an outpouring of quality improvement (QI) initiatives to address the medical, psychosocial, and health equity challenges that complicate ideal type 1 diabetes care and outcomes. This article reviews a framework for QI in diabetes care that guided the development of the T1D Exchange Quality Improvement Collaborative to improve care delivery and health outcomes in type 1 diabetes. Evaluation of the methodology, outcomes, and knowledge gained from these initiatives will highlight the importance of continued QI initiatives in diabetes care.

Multi-Clinic Quality Improvement Initiative Increases Continuous Glucose Monitoring Use Among Adolescents and Young Adults With Type 1 Diabetes.

Continuous glucose monitoring (CGM) use is associated with improved A1C outcomes and quality of life in adolescents and young adults with diabetes; however, CGM uptake is low. This article reports on a quality improvement (QI) initiative of the T1D Exchange Quality Improvement Collaborative to increase CGM use among patients in this age-group. Ten centers participated in developing a key driver diagram and center-specific interventions that resulted in an increase in CGM use from 34 to 55% in adolescents and young adults over 19-22 months. Sites that performed QI tests of change and documented their interventions had the highest increases in CGM uptake, demonstrating that QI methodology and sharing of learnings can increase CGM uptake.

AGK-BRAF is associated with distant metastasis and younger age in pediatric papillary thyroid carcinoma.

BACKGROUND: The incidence of thyroid carcinoma has increased in most populations, including pediatric patients. The increase is almost exclusively due to an increase in the incidence of papillary thyroid carcinoma (PTC). Genetic alterations leading to mitogen-activated protein kinase (MAPK) pathway activation are highly prevalent in PTC, with BRAF V600E mutation being the most common event in adult PTC. Although a lower prevalence of BRAF V600E had been reported among pediatric patients, a higher prevalence of BRAF fusion has been identified in both radiation-exposed and sporadic pediatric PTC. However, little is known about the prognostic implications of BRAF fusions in pediatric PTC. PROCEDURE: In this study, we investigated the prevalence of BRAF alterations (AGK-BRAF fusion and BRAF V600E mutation) in a large set of predominantly sporadic pediatric PTC cases and correlate with clinicopathological features. Somatic AGK-BRAF fusion was investigated by RT-PCR and confirmed by FISH break-apart. The BRAF V600E mutation was screened using Sanger sequencing. RESULTS: AGK-BRAF fusion, found in 19% of pediatric PTC patients, was associated with distant metastasis and younger age. Conversely, the BRAF V600E, found in 15% of pediatric PTC patients, was correlated with older age and larger tumor size. CONCLUSION: Collectively, our results advance knowledge concerning genetic bases of pediatric thyroid carcinoma, with potential implications for diagnosis, prognosis, and therapeutic approaches.

Misdiagnosis and Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes: Patient and Caregiver Perspectives.

IN BRIEF Diabetic ketoacidosis (DKA) is a life-threatening complication that frequently occurs at diagnosis of type 1 diabetes, occurs more commonly when a patient is misdiagnosed, is the leading cause of death in children with type 1 diabetes, and is associated with worse long-term outcomes. Our retrospective online survey found that 25% of all participants were misdiagnosed and that misdiagnosis was associated with an 18% increased risk for DKA compared to those correctly diagnosed. Adult providers should consider type 1 diabetes when diagnosing type 2 diabetes, and pediatric providers should rule out type 1 diabetes when a patient reports nonspecific viral symptoms.

CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms.

Asthma is an inflammatory disease in which proinflammatory cytokines have a role in inducing abnormalities of airway smooth muscle function and in the development of airway hyperresponsiveness. Inflammatory cytokines alter calcium (Ca2+) signaling and contractility of airway smooth muscle, which results in nonspecific airway hyperresponsiveness to agonists. In this context, Ca2+ regulatory mechanisms in airway smooth muscle and changes in these regulatory mechanisms encompass a major component of airway hyperresponsiveness. Although dynamic Ca2+ regulation is complex, phospholipase C/inositol tris-phosphate (PLC/IP3) and CD38-cyclic ADP-ribose (CD38/cADPR) are two major pathways mediating agonist-induced Ca2+ regulation in airway smooth muscle. Altered CD38 expression or enhanced cyclic ADP-ribosyl cyclase activity associated with CD38 contributes to human pathologies such as asthma, neoplasia, and neuroimmune diseases. This review is focused on investigations on the role of CD38-cyclic ADP-ribose signaling in airway smooth muscle in the context of transcriptional and posttranscriptional regulation of CD38 expression. The specific roles of transcription factors NF-kB and AP-1 in the transcriptional regulation of CD38 expression and of miRNAs miR-140-3p and miR-708 in the posttranscriptional regulation and the underlying mechanisms of such regulation are discussed.

[Total parathyroidectomy, autoimplant and cryopreservation for the treatment of hyperparathyroidism of renal origin in children and young adults]. / Paratiroidectomía total, autoimplante y criopreservación para el tratamiento del hiperparatiroidismo de origen renal en pediatría y adultos jóvenes.

OBJECTIVES: To describe our initial experience in the treatment of hyperparathyroidism (HPP) of renal cause using total or subtotal parathyroidectomy, autoimplant and cryopreservation in pediatric patients. Secondary HPP is the increased function of the parathyroid hormone (PTH) due to an abnormal phosphocalcic metabolism in patients with chronic renal failure (CRF). This situation produces increased bone resorption resulting in osteodystrophy and endovascular calcifications. Surgical treatment is aimed to diminish the level of PTH in CRF patients, to avoid HPP complications. METHODS AND MATERIALS: Descriptive, monocentric and retrospective study of a case series of patients with secondary and tertiary hyperparathyroidism, who went through total or subtotal parathyroidectomy, autoimplant and cryopreservation between 2009 and 2016. We analyzed the following variables: age, calcemia, PTH, phosphatemia, alkaline phosphatase (ALP), follow-up and complications. The continuous variables are expressed in median and interquartile range or in mean and SD, according to their distribution. The categorical variables were expressed in percentages and frequencies (repeated sentence). RESULTS: Number of patients included: 13. Mean age of the patients was 16.7 years old. Preoperative median calcium dosage was 9.1 mg/dl (IQR: 8.9-9.5). Median PTH was 2,600 pg/ml (IQR: 1,400 pg/ml to 2,785 pg/ml). Intraoperatory dosage of PTH reported a median drop of 86.6% in the first 15 minutes (IQR: 80.5-95.9). After the first 48 hours, median calcemia was 9 mg/dl (IQR: 7.7-9.4) and median PTH was 40 pg/ml (IQR: 20-113). We did not identify intraoperatory complications. In the immediate post operatory stage, mean IV calcium therapy was 4 days (SD: 2.39). Median time of follow-up was 18 months (IQR 9-36). Two patients had hungry bone syndrome and one patient had a recurrence of the pathology as remote post operatory complications. After a year, median calcemia, was 9 mg/dl (IQR: 7.6-9.3) and median PTH was 50 pg/ml (IQR: 28.5-108). The decrease in PTH and ALP were statistically significant with p value < 0.05. CONCLUSION: In our study, total parathyroidectomy with auto implant is a safe and effective option for the treatment of secondary and tertiary hyperparathyroidism in pediatric patients. This could also prevent bone complications.

OBJETIVOS: Describir la experiencia en el tratamiento del hiperparatiroidismo (HPP) de origen renal con la técnica de la paratiroidectomía total o subtotal, autoimplante y criopreservación en pacientes pediátricos y adultos jóvenes. El HPP secundario es el aumento de la función de las hormonas paratiroideas debido a una alteración en el metabolismo fosfocálcico a partir de la insuficiencia renal crónica (IRC). Esto produce una mayor resorción ósea, provocando alteraciones en los huesos y calcificaciones en el endotelio vascular. El tratamiento quirúrgico se indica para disminuir el nivel de parathormona (PTH), y así prevenir las complicaciones del hiperparatiroidismo en pacientes con IRC terminal. MATERIAL Y METODOS: Estudio descriptivo, retrospectivo, monocéntrico de una serie de pacientes con diagnóstico de HPP secundario y terciario sometidos a paratiroidectomía total, autoimplante y criopreservación entre 2009 y 2016. Se analizaron las siguientes variables: Edad, Calcemia, PTH, Fosfatemia, Fosfatasa alcalina (FAL), tiempo de seguimiento y complicaciones. Las variables continuas se expresan en mediana y rango intercuartil o en media y DS, según su distribución. Las variables categóricas se expresaron en porcentajes y frecuencias. RESULTADOS: Se incluyeron 13 pacientes. La edad media fue 16,7 años (R= 11:24). La mediana de calcemia preoperatoria fue 9,1 mg/dl (RIQ: 8,9-9,5). La mediana preoperatoria de PTH fue 2.600 pg/ml (RIQ: 1.400-2.785). La medición del descenso porcentual de PTHi ultrarrápida informó una mediana de 86,6% en los primeros 15 minutos (RIQ: 80,5-95,9). No se identificaron complicaciones intraoperatorias. A las 48 horas posquirúrgicas, la mediana de calcemia fue de 9 mg/dl (RIQ: 7,7-9,4) y la mediana de PTH de 40 pg/ml (RIQ: 20-113). La media de aporte de calcio endovenoso posquirúrgico fue de 4 días (DS 2,39). La mediana de seguimiento fue de 18 meses (RIQ 9-36). Como complicaciones posoperatorias tardías se identificaron dos pacientes con síndrome de hueso hambriento y un paciente con recidiva de la enfermedad. Al año postoperatorio la mediana de calcemia, fue de 9 mg/dl (RIQ: 7,6-9,3). La mediana de PTH fue de 50 pg/ml (RIQ: 28,5-108)y la de FAL fue de 116 UI/L (RIQ 102:273). El descenso de PTH y de FAL fueron estadísticamente significativos con p valor < 0,05. CONCLUSIONES: En nuestro estudio, la paratiroidectomía total con autoimplante es una alternativa segura y efectiva para el tratamiento del hiperparatiroidismo secundario y terciario en pediatría, permitiendo prevenir así complicaciones óseas y cardiovasculares.

A survey of youth with new onset type 1 diabetes: Opportunities to reduce diabetic ketoacidosis.

OBJECTIVE: Pediatric patients in Colorado with new onset type 1 diabetes (T1D) presenting with diabetic ketoacidosis (DKA) increased from 29.9% to 46.2% from 1998 to 2012. The purpose of this study was to compare differences between patients with newly diagnosed T1D who presented in DKA with those who did not across three domains: sociodemographic factors, access to medical care, and medical provider factors, aiming to identify potential targets for intervention. METHODS: Sixty-one patients <17 years of age with T1D duration <6 months completed the questionnaire. Groups were compared using Fisher's exact test or the Kruskal-Wallis test. RESULTS: Parents of 28% of patients researched their child's symptoms on the Internet prior to diagnosis. At the first healthcare visit for symptoms of T1D, 23% were not diagnosed. There were no significant differences between groups (DKA vs non-DKA) in demographics, first healthcare setting for T1D symptoms, provider type at first visit or at diagnosis, insurance status, or specific barriers to care. DKA patients had a longer interval between previous well visit to diagnosis (median 172 vs 263 days, P = 0.01). Non-DKA patients were more likely to have blood glucose measured at P = 0.02, and had fewer symptoms prior to (P = 0.01) the first visit for diabetes symptoms. Parents of non-DKA patients were more likely to be familiar with symptoms of diabetes (P < 0.001) and to suspect diabetes (P = 0.01). CONCLUSION: Targets for campaigns to prevent DKA include increasing provider glucose and ketone testing, increasing public knowledge about diabetes, and understanding how socio-demographic factors may delay T1D diagnosis.

Educational strategies and atraumatic restorative treatment effect on salivary characteristics: A controlled clinical trial.

OBJECTIVE: To evaluate educational strategies and atraumatic restorative treatment (ART)-restoration impact on salivary physicochemical and microbiological characteristics. DESIGN: Two groups of 6- to 7-year-old children were included: GART , with at least one decayed primary molar (n = 36), submitted to four sessions of oral health educational strategy (OHES) and ART restoration; GC , a paired caries-free group (n = 36), submitted to four sessions of OHES. Three evaluations were carried out: baseline, 1 week after OHES, and 1 month after OHES or ART, when biofilm and gingivitis frequencies, salivary flow, pH, buffer capacity, calcium and phosphorus concentrations were assessed. Total bacteria and Streptococcus mutans were quantified in unstimulated saliva (qPCR). RESULTS: Improvement in biofilm and gingivitis scores, salivary pH, and buffering capacity after OHES was observed in GC , with a decrease in total bacteria and S. mutans counts. GART also showed changes in salivary parameters, even before ART restoration was delivered, and total bacteria count remained lower than baseline 1 month after ART restoration, although a trend to increase the proportion of S. mutans was observed. CONCLUSION: Improvements in salivary physicochemical and microbiological characteristics were observed after educational strategies, thus reducing the caries risk of children with decayed teeth, although a trend to increase the S. mutans percentage was observed 1 month after ART restoration.

Comparison between the effects of postanesthetic xylazine and dexmedetomidine on characteristics of recovery from sevoflurane anesthesia in horses.

OBJECTIVE: To compare postanesthetic xylazine and dexmedetomidine on recovery characteristics from sevoflurane anesthesia in horses. STUDY DESIGN: Randomized, crossover study. ANIMALS: Six geldings, mean±standard deviation (SD) (range), 17±4 (11-24) years and 527±80 (420-660) kg. METHODS: Horses were anesthetized with sevoflurane for 60 minutes under standardized conditions for a regional limb perfusion study. In recovery, horses were administered either xylazine (200 µg kg-1) or dexmedetomidine (0.875 µg kg-1) intravenously. Recoveries were unassisted and were video-recorded for later evaluation of recovery events and quality by two individuals unaware of treatment allocation. Recovery quality was assessed using a 100 mm visual analog scale (VAS) (0=poor recovery, 100=excellent recovery), the Edinburgh Scoring System (ESS) (0-100; 100=excellent recovery) and the mean attempt interval (MAI) (longer=better). Data are mean±SD. RESULTS: All recovery quality assessments (xylazine and dexmedetomidine, respectively: VAS: 71±21 mm, 84±13 mm; ESS: 65±22, 67±30; MAI: 52±24 minutes, 60±32 minutes) and events (first limb movement: 37±8 minutes, 42±10 minutes; first attempt to lift head: 44±12 minutes, 48±9 minutes; first attempt to sternal posture: 57±28 minutes, 50±7 minutes; number of head bangs: 2.0±3.0, 0.5±0.5; time to first attempt to stand: 72±6 minutes, 78±13 minutes; time to standing: 79±14 minutes, 84±13 minutes) did not differ significantly between treatments (p>0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Recovery characteristics did not differ significantly between postanesthetic xylazine and dexmedetomidine following 1 hour of sevoflurane anesthesia in horses in this study. Further evaluations in more horses and in younger horses are required to confirm these results.

Airway responsiveness in CD38-deficient mice in allergic airway disease: studies with bone marrow chimeras.

CD38 is a cell-surface protein involved in calcium signaling and contractility of airway smooth muscle. It has a role in normal airway responsiveness and in airway hyperresponsiveness (AHR) developed following airway exposure to IL-13 and TNF-α but appears not to be critical to airway inflammation in response to the cytokines. CD38 is also involved in T cell-mediated immune response to protein antigens. In this study, we assessed the contribution of CD38 to AHR and inflammation to two distinct allergens, ovalbumin and the epidemiologically relevant environmental fungus Alternaria. We also generated bone marrow chimeras to assess whether Cd38(+/+) inflammatory cells would restore AHR in the CD38-deficient (Cd38(-/-)) hosts following ovalbumin challenge. Results show that wild-type (WT) mice develop greater AHR to inhaled methacholine than Cd38(-/-) mice following challenge with either allergen, with comparable airway inflammation. Reciprocal bone marrow transfers did not change the native airway phenotypic differences between WT and Cd38(-/-) mice, indicating that the lower airway reactivity of Cd38(-/-) mice stems from Cd38(-/-) lung parenchymal cells. Following bone marrow transfer from either source and ovalbumin challenge, the phenotype of Cd38(-/-) hosts was partially reversed, whereas the airway phenotype of the WT hosts was preserved. Airway inflammation was similar in Cd38(-/-) and WT chimeras. These results indicate that loss of CD38 on hematopoietic cells is not sufficient to prevent AHR and that the magnitude of airway inflammation is not the predominant underlying determinant of AHR in mice.

CD38 and airway hyper-responsiveness: studies on human airway smooth muscle cells and mouse models.

Asthma is an inflammatory disease in which altered calcium regulation, contractility, and airway smooth muscle (ASM) proliferation contribute to airway hyper-responsiveness and airway wall remodeling. The enzymatic activity of CD38, a cell-surface protein expressed in human ASM cells, generates calcium mobilizing second messenger molecules such as cyclic ADP-ribose. CD38 expression in human ASM cells is augmented by cytokines (e.g., TNF-α) that requires the activation of MAP kinases and the transcription factors, NF-κB and AP-1, and is post-transcriptionally regulated by miR-140-3p and miR-708 by binding to 3' Untranslated Region of CD38 as well as by modulating the activation of signaling mechanisms involved in its regulation. Mice deficient in Cd38 exhibit reduced airway responsiveness to inhaled methacholine relative to the response in wild-type mice. Intranasal challenge of Cd38-deficient mice with TNF-α or IL-13, or the environmental fungus Alternaria alternata, causes significantly attenuated methacholine responsiveness compared with wild-type mice, with comparable airway inflammation. Reciprocal bone marrow transfer studies revealed partial restoration of airway hyper-responsiveness to inhaled methacholine in the Cd38-deficient mice. These studies provide evidence for CD38 involvement in the development of airway hyper-responsiveness; a hallmark feature of asthma. Future studies aimed at drug discovery and delivery targeting CD38 expression and (or) activity are warranted.