High deoxynivalenol and ergot alkaloid levels in wheat grain: effects on growth performance, carcass traits, rumen fermentation, and blood parameters of feedlot cattle.

This study was designed to assess the impacts of a mixture of deoxynivalenol (DON) and ergot alkaloids (EAs) on growth performance, rumen function, blood parameters, and carcass traits of feedlot cattle. Forty steers (450 ± 6.0 kg) were stratified by weight and randomly allocated to 1 of 4 treatments; control-low (CON-L), control-high (CON-H) which contained low or high wheat screenings that lacked mycotoxins at the same level as the mycotoxin-low (MYC-L; 5.0 mg/kg DON, 2.1 mg/kg EA), and mycotoxin-high (MYC-H: 10 mg/kg DON, 4.2 mg/kg EA) diets that included wheat screening with mycotoxins. Steers were housed in individual pens for a 112-day finishing trial. Intake was 24.8% lower (P < 0.001) for MYC steers compared to CON steers. As a result, average daily gains of MYC steers were 42.1% lower (P < 0.001) than CON steers. Gain to feed ratio was also lower (P < 0.001) for MYC steers compared to CON steers. Platelets, alanine aminotransferase, globulins, and blood urea nitrogen were lower (P ≤ 0.008), and lymphocytes, glutathione peroxidase activity (GPx), and interleukin-10 (IL-10) were elevated (P ≤ 0.002) in MYC steers compared to CON steers. Hot carcass weights and backfat thickness were reduced (P < 0.001) in MYC steers, resulting in leaner (P < 0.001) carcasses and higher (P < 0.007) meat yield compared to CON steers. Results suggest that a mixture of DON and EAs negatively impacted health, performance, and carcass traits of feedlot steers, with the majority of this response likely attributable to EAs. However, more research is needed to distinguish the relative contribution of each mycotoxin to the specific responses observed.

Investigating anti-D in an individual with the weak D type 2 genotype.

Anti-D in individuals with a weak D phenotype is an unexpected finding that may require additional investigation to determine whether the anti-D is an autoantibody or alloantibody. Further investigation may also include assessment of the patient's RHD genotype and exclusion of anti-G. We present a case of an 84-year-old man with the weak D type 2 genotype who developed an unexpected anti-D along with anti-C. Individuals with the weak D type 2 genotype are thought not to be at risk for developing alloanti-D, although the distinction between alloanti-D and autoanti-D may be difficult to ascertain. Furthermore, investigations may affect transfusion recommendations. This patient was restricted to crossmatch-compatible, D-C- red blood cells even though the clinical significance of the anti-D was uncertain. This report is one of a few reported cases of an individual with the weak D type 2 genotype with demonstrable anti-D but without evidence for alloanti-D.

Long-term clinical, virological and immunological outcomes following planned treatment interruption in HIV-infected children.

OBJECTIVES: Planned treatment interruption (PTI) of antiretroviral therapy (ART) in adults is associated with adverse outcomes. The PENTA 11 trial randomized HIV-infected children to continuous ART (CT) vs. CD4-driven PTIs. We report 5 years' follow-up after the end of main trial. METHODS: Post-trial, all children resumed ART. Clinical, immunological, virological and treatment data were collected annually. A sub-study investigated more detailed immunophenotype. CT and PTI arms were compared using intention-to-treat. Laboratory parameters were compared using linear regression, adjusting for baseline values; mixed models were used to include all data over time. RESULTS: In all, 101 children (51 CT, 50 PTI) contributed a median of 7.6 years, including 5.1 years of post-trial follow-up. Post-trial, there were no deaths, one pulmonary tuberculosis and no other CDC stage B/C events. At 5 years post-trial, 90% of children in the CT vs. 82% in the PTI arm had HIV RNA < 50 copies/mL (P = 0.26). A persistent increase in CD8 cells was observed in the PTI arm. The sub-study (54 children) suggested that both naïve and memory populations contributed to higher CD8 cells following PTI. Mean CD4/CD8 ratios at 5 years post-trial were 1.22 and 1.08 in CT and PTI arms, respectively [difference (CT - PTI) = -0.15; 95% CI: -0.34-0.05), P = 0.14]. The sub-study also suggested that during the trial and at early timepoints after the end of the trial, reduction in CD4 in the PTI arm was mainly from loss of CD4 memory cells. CONCLUSIONS: Children tolerated PTI with few long-term clinical, virological or immunological consequences.

Lessons for test and treat in an antiretroviral programme after decentralisation in Uganda: a retrospective analysis of outcomes in public healthcare facilities within the Lablite project.

BACKGROUND: We describe the decentralisation of antiretroviral therapy (ART) alongside Option B+ roll-out in public healthcare facilities in the Lablite project in Uganda. Lessons learned will inform programmes now implementing universal test and treat (UTT). METHODS: Routine data were retrospectively extracted from ART registers between October 2012 and March 2015 for all adults and children initiating ART at two primary care facilities (spokes) and their corresponding district hospitals (hubs) in northern and central Uganda. We describe ART initiation over time and retention and use of Cox models to explore risk factors for attrition due to mortality and loss to follow-up. Results from tracing of patients lost to follow-up were used to correct retention estimates. RESULTS: Of 2100 ART initiations, 1125 were in the north, including 944 (84%) at the hub and 181 (16%) at the spokes; children comprised 95 (10%) initiations at the hubs and 14 (8%) at the spokes. Corresponding numbers were 642 (66%) at the hub and 333 (34%) at the spokes in the central region (77 [12%] and 22 [7%], respectively, in children). Children <3 y of age comprised the minority of initiations in children at all sites. Twenty-three percent of adult ART initiations at the north hub were Option B+ compared with 45% at the spokes (25% and 65%, respectively, in the central region). Proportions retained in care in the north hub at 6 and 12 mo were 92% (95% CI 90 to 93) and 89% (895% CI 7 to 91), respectively. Corresponding corrected estimates in the north spokes were 87% (95% CI 78 to 93) and 82% (95% CI 72 to 89), respectively. In the central hub, corrected estimates were 84% (95% CI 80 to 87) and 78% (95% CI 74 to 82), and were 89% (95% CI 77.9 to 95.1) and 83% (95% CI 64.1 to 92.9) at the spokes, respectively. Among adults newly initiating ART, being older was independently associated with a lower risk of attrition (adjusted hazard ratio [aHR] 0.93 per 5 y [95% CI 0.88 to 0.97]). Other independent risk factors included initiating with a tenofovir-based regimen vs zidovudine (aHR 0.60 [95% CI 0.46 to 0.77]), year of ART initiation (2013 aHR 1.55 [95% CI 1.21 to 1.97], ≥2014 aHR 1.41 [95% CI 1.06 to 1.87]) vs 2012, hub vs spoke (aHR 0.35 [95% CI 0.29 to 0.43]) and central vs north (aHR 2.28 [95% CI 1.86 to 2.81]). Independently, patient type was associated with retention. CONCLUSIONS: After ART decentralisation, people living with human immunodeficiency virus (HIV) were willing to initiate ART in rural primary care facilities. Retention on ART was variable across facilities and attrition was higher among some groups, including younger adults and women initiating ART during pregnancy/breastfeeding. Interventions to support these groups are required to optimise benefits of expanded access to HIV services under UTT.

Acceptability of a first-line anti-tuberculosis formulation for children: qualitative data from the SHINE trial.

SETTING: We conducted a qualitative exploration into the palatability and acceptability of a novel fixed-dose combination (FDC) anti-tuberculosis drug. This study was nested in the SHINE (Shorter treatment for minimal TB in children) trial, which compares the safety and efficacy of treating non-severe drug-susceptible tuberculosis (TB) with a 6 vs. 4 months anti-tuberculosis regimen in children aged 0-16 years. Participants were recruited in Cape Town, South Africa.OBJECTIVE: To describe the palatability and acceptability of a FDC of rifampicin, isoniazid and pyrazinamide among South African children and their caregivers in the SHINE trial.METHODS: We conducted 20 clinic observations of treatment administration, during which we conducted 16 semi-structured interviews with children and their caregivers. Data were organised thematically to report on experiences with administering and ingesting the FDC.RESULTS: Children and caregivers' experiences varied from delight to disgust. In general, participants said that the FDC compared favourably to other formulations. Pragmatic challenges such as dissolving the FDC and the time required to administer the FDC impeded caregivers' ability to integrate treatment into their daily routines. Drug manipulation was common among caregivers to improve TB treatment administration.CONCLUSION: This novel FDC appears acceptable for children, albeit with practical challenges to administration. Scale-up of FDC use should include supplementary intervention components to support caregivers.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life.

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

Risk in the "Red Zone": Outcomes for Children Admitted to Ebola Holding Units in Sierra Leone Without Ebola Virus Disease.

We collected data on 1054 children admitted to Ebola Holding Units in Sierra Leone and describe outcomes of 697/1054 children testing negative for Ebola virus disease (EVD) and accompanying caregivers. Case-fatality was 9%; 3/630 (0.5%) children discharged testing negative were readmitted EVD-positive. Nosocomial EVD transmission risk may be lower than feared.

Clinical Status of Adolescents with Perinatal HIV at Transfer to Adult Care in the UK/Ireland.

Background: Increasing numbers of children infected perinatally with human immunodeficiency virus (HIV) are surviving to adolescence and transitioning to adult care, yet there are scarce data on their clinical status at transfer. Methods: We analyzed prospective cohort data from the UK/Ireland national Collaborative HIV Pediatric Study (CHIPS). Clinical status at last pediatric clinic visit prior to transfer was described. Factors associated with higher CD4 cell count and viral load (VL) suppression<400 c/mL among patients on antiretroviral therapy (ART) at transfer were assessed using linear and logistic regression, respectively. Data were matched with the UK HIV Drug Resistance Database (UKHIVDRB) to assess cumulative resistance profiles at transfer. Results: Of 1,907 children followed in CHIPS from 1996 to November 2014, 644 (34%) transferred to adult care: 53% were female, 62% born outside the UK/Ireland, 75% black African. At last pediatric follow-up, median age was 17.4 years [interquartile range 16.5,18.1], 27% had previous AIDS diagnosis, CD4 was 444 cells/mm3 [280, 643], 76% were on ART, 13% off-ART, and 11% ART-naive. Among patients on ART, 74% had VL<400 c/mL. In multivariable analysis, higher CD4 at transfer was associated with younger age, higher CD4 at ART initiation and lower VL at transfer (P ≤ .001). Predictors of viral suppression include no AIDS diagnosis and later year of transfer (P ≤ .05). Of 291 patients with resistance data, 82% had resistance to ≥1 drug class, 56% to ≥2 classes and 12% had triple-class resistance. Conclusion: Three-quarters of adolescents were on stable ART at transfer, of whom 74% were virologically suppressed. The prevalence of triple-class resistance was relatively low at 12%.

Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe.

OBJECTIVES: The aim of the study was to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection. METHODS: We analysed individual patient data from cohorts in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). A total of 5972 participants starting antiretroviral therapy (ART) from 1998, aged < 20 years at the start of ART for those with perinatal infection and 15-29 years for those with heterosexual infection, with ART containing at least two nucleoside reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (bPI), were followed from ART initiation until the most recent viral load (VL) measurement. Virological failure of a drug was defined as VL > 500 HIV-1 RNA copies/mL despite ≥ 4 months of use. TCVF was defined as cumulative failure of two NRTIs, an NNRTI and a bPI. RESULTS: The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall [17 (interquartile range (IQR) 4-111) vs. 8 (IQR 2-38) weeks, respectively], and highest in perinatally infected participants aged 10-14 years [49 (IQR 9-267) weeks]. The cumulative proportion with TCVF 5 years after starting ART was 9.6% [95% confidence interval (CI) 7.0-12.3%] in participants with perinatally acquired infection and 4.7% (95% CI 3.9-5.5%) in participants with heterosexually acquired infection, and highest in perinatally infected participants aged 10-14 years when starting ART (27.7%; 95% CI 13.2-42.1%). Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10-14 years, African origin, pre-ART AIDS, NNRTI-based initial regimens, higher pre-ART viral load and lower pre-ART CD4. CONCLUSIONS: The results suggest a beneficial effect of starting ART before adolescence, and starting young people on boosted PIs, to maximize treatment response during this transitional stage of development.

Improved Adherence to Antiretroviral Therapy Observed Among HIV-Infected Children Whose Caregivers had Positive Beliefs in Medicine in Sub-Saharan Africa.

A high level of adherence to antiretroviral treatment is essential for optimal clinical outcomes in HIV infection, but measuring adherence is difficult. We investigated whether responses to a questionnaire eliciting caregiver beliefs in medicines were associated with adherence of their child (median age 2.8 years), and whether this in turn was associated with viral suppression. We used the validated beliefs in medicine questionnaire (BMQ) to measure caregiver beliefs, and medication event monitoring system caps to measure adherence. We found significant associations between BMQ scores and adherence, and between adherence and viral suppression. Among children initiating Antiretroviral therapy (ART), we also found significant associations between BMQ 'necessity' scores, and BMQ 'necessity-concerns' scores, and later viral suppression. This suggests that the BMQ may be a valuable tool when used alongside other adherence measures, and that it remains important to keep caregivers well informed about the long-term necessity of their child's ART.

When information does not suffice: young people living with HIV and communication about ART adherence in the clinic.

Despite mounting evidence recommending disclosure of human immunodeficiency virus (HIV) status to young people with perinatally acquired HIV as a central motivating factor for adherence to antiretroviral therapy, many young people continue to experience disclosure as a partial event, rather than a process. Drawing from two longitudinal, interview-based qualitative studies with young people living with HIV (aged 10-24) in five different countries in low and high income settings, we present data regarding disclosure and information about HIV in the clinic. The article highlights the limits of discussions framing disclosure and patient literacy, and young people's reluctance to voice their adherence difficulties in the context of their relationships with clinical care teams. We suggest that a clinician-initiated, explicit acknowledgment of the social and practical hurdles of daily adherence for young people would aid a more transparent conversation and encourage young people to disclose missed doses and other problems they may be facing with their treatment. This may help to reduce health harms and poor adherence in the longer-term.

Population level usage of health services, and HIV testing and care, prior to decentralization of antiretroviral therapy in Agago District in rural Northern Uganda.

BACKGROUND: Decentralization of ART services scaled up significantly with the country wide roll out of option B plus in Uganda. Little work has been undertaken to examine population level access to HIV care particularly in hard to reach areas in rural Africa. Most work on ART scale up has been done at health facility level which omits people not accessing healthcare in the community. This study describes health service usage, particularly HIV testing and care in 2/6 parishes of Lapono sub-county of northern Uganda, prior to introduction of ART services in Lira Kato Health Centre (a local lower-level health centre III), as part of ART decentralization. METHODS: Household and individual questionnaires were administered to household members (aged 15-59 years). Logit random effects models were used to test for differences in proportions (allowing for clustering within villages). RESULTS: 2124 adults from 1351 households were interviewed (755 [36%] males, 1369 [64 %] females). 2051 (97%) participants reported seeking care locally for fever, most on foot and over half at Lira Kato Health Centre. 574 (76%) men and 1156 (84%) women reported ever-testing for HIV (P < 0.001 for difference); 34/574 (6%) men and 102/1156 (9%) women reported testing positive (P = 0.04). 818/850 (96%) women who had given birth in the last 5 years had attended antenatal care in their last pregnancy: 7 women were already diagnosed with HIV (3 on ART) and 790 (97%) reported being tested for HIV (34 tested newly positive). 124/136 (91%) HIV-positive adults were in HIV-care, 123/136 (90 %) were taking cotrimoxazole and 74/136 (54%) were on ART. Of adults in HIV-care, most were seen at Kalongo hospital (n = 87), Patongo Health Centre (n = 7) or Lira Kato Health Centre (n = 23; no ART services). 58/87, 5/7 and 20/23 individuals walked to Kalongo hospital (56 km round-trip, District Health Office information), Patongo Health Centre (76 km round-trip, District Health Office information) and Lira Kato Health Centre (local) respectively. 8 HIV-infected children were reported; only 2 were diagnosed aged <24 months: 7/8 were in HIV-care including 3 on ART. CONCLUSIONS: Higher proportions of women compared to men reported ever-testing for HIV and testing HIV-positive, similar to other surveys. HIV-infected men and women travelled considerable distances for ART services. Children appeared to be under-accessing testing and referral for treatment. Decentralization of ART services to a local health facility would decrease travel time and transport costs, making care and treatment more easily accessible.

The EPIICAL project: an emerging global collaboration to investigate immunotherapeutic strategies in HIV-infected children.

The EPIICAL (Early-treated Perinatally HIV-infected Individuals: Improving Children's Actual Life with Novel Immunotherapeutic Strategies) project arises from the firm belief that perinatally infected children treated with suppressive antiretroviral therapy (ART) from early infancy represent the optimal population model in which to study novel immunotherapeutic strategies aimed at achieving ART-free remission. This is because HIV-infected infants treated within 2-3 months of life have a much reduced viral reservoir size, and rarely show HIV-specific immunity but preserve normal immune development. The goal of EPIICAL is the establishment of an international collaboration to develop a predictive platform using this model to select promising HIV therapeutic vaccine candidates, leading to prioritisation or deprioritisation of novel immunotherapeutic strategies. To establish this platform, the EPIICAL Consortium aims to: develop predictive models of virological and immunological dynamics associated with response to early ART and to treatment interruption using available data from existing cohorts/studies of early-treated perinatally HIV-infected children; optimise methodologies to better characterise immunological, virological and genomic correlates/profiles associated with viral control; test novel immunotherapeutic strategies using in vivo proof-of-concept (PoC) studies with the aim of inducing virological, immunological and transcriptomic correlates/profiles equivalent to those defined by the predictive model. This approach will strengthen the capacity for discovery, development and initial testing of new therapeutic vaccine strategies through the integrated efforts of leading international scientific groups, with the aim of improving the health of HIV-infected individuals.

Feeding behavior and ruminal pH of corn silage, barley grain, and corn dried distillers' grain offered in a total mixed ration or in a free-choice diet to beef cattle.

Seventy-nine continental crossbred beef heifers (524.4 ± 41.68 kg BW), 16 of which were ruminally cannulated, were used in a 53-d experiment with a generalized randomized block design to assess the effects of barley grain (BG), corn silage (CS), and corn distillers' grain (DG) offered in a free-choice diet on feeding behavior and ruminal fermentation. Treatments were total mixed ration (TMR) consisting of 85% BG, 10% CS, and 5% supplement or free-choice (i.e., self-selection) diets of BG and CS (BGCS), BG and corn dry DG (BGDG), or CS and corn DG (CSDG). Heifers were housed in groups of 9 or 10 in 8 pens and weighed 2 h before feed delivery at d 0, 21, 42, and 52 of the study. Pens were equipped with an electronic feed bunk monitoring system enabling feed intake and feeding behavior to be continuously monitored. Each of these pens was randomly allocated 2 cannulated heifers equipped with indwelling pH probes for continuous measurement of ruminal pH during wk 1, 2, 4, and 7. Blood and rumen contents were taken from cannulated heifers 2 h after feed delivery on d -3, 0, 7, 8, 42, and 49. Cattle fed either TMR or free-choice diets had similar (P > 0.10) ruminal fermentation, blood profile, and growth performance, with the exception of the CSDG diet, for which ruminal pH levels were consistently greater (P < 0.01) and performance was lower (P < 0.01). When DG was a component in free-choice diets, heifers reduced its inclusion in the diet (P < 0.05) over the experiment without affecting growth rate or ruminal fluid pH. Finishing feedlot cattle fed BG and CS separately selected a diet with a greater proportion of BG (85% DMI) compared to the TMR with no signs of acidosis. When cattle were given free-choice access to corn dry DG as an alternative to CS, they consumed levels up to 30% of their total daily DMI. Under the conditions of our experiment cattle can effectively self-select diets without increasing the risk of subclinical acidosis and still maintain similar levels of growth and feed efficiency compared with a TMR.

Pharmacokinetics of antiretroviral drug varies with formulation in the target population of children with HIV-1.

The bioequivalence of formulations is usually evaluated in healthy adult volunteers. In our study in 19 HIV-1-infected Ugandan children (1.8-4 years of age, weight 12 to <15 kg) receiving zidovudine, lamivudine, and abacavir solutions twice a day for ≥24 weeks, the use of scored tablets allowed comparison of plasma pharmacokinetics of oral solutions vs. tablets. Samples were collected 0, 1, 2, 4, 6, 8, and 12 h after each child's last morning dose of oral solution before changing to scored tablets of Combivir (coformulated zidovudine + lamivudine) and abacavir; this was repeated 4 weeks later. Dose-normalized area under curve (AUC)(0-12) and peak concentration (C(max)) for the tablet formulation were bioequivalent with those of the oral solution with respect to zidovudine and abacavir (e.g., dose-normalized geometric mean ratio (dnGMR) (tablet:solution) for zidovudine and abacavir AUC(0-12) were 1.01 (90% confidence interval (CI) 0.87-1.18) and 0.96 (0.83-1.12), respectively). However, lamivudine exposure was ~55% higher with the tablet formulation (AUC(0-12) dnGMR = 1.58 (1.37-1.81), C(max) dnGMR = 1.55 (1.33-1.81)). Although the clinical relevance of this finding is unclear, it highlights the impact of the formulation and the importance of conducting bioequivalence studies in target pediatric populations.

Early antiretroviral treatment reduces risk of bacille Calmette-Guérin immune reconstitution adenitis.

SETTING: Two centres in Soweto and Cape Town, South Africa. OBJECTIVE: To assess the effects of timing of initiation of antiretroviral treatment (ART) and other factors on the risk of bacille Calmette-Guérin (BCG) related regional adenitis due to immune reconstitution inflammatory syndrome (BCG-IRIS) in human immunodeficiency virus (HIV) infected infants. DESIGN: HIV-infected infants aged 6-12 weeks with CD4 count ≥25% enrolled in the Children with HIV Early Antiretroviral Therapy (CHER) Trial received early (before 12 weeks) or deferred (after immunological or clinical progression) ART; infants with CD4 count <25% all received early ART. All received BCG vaccination after birth. Reactogenicity to BCG was assessed prospectively during routine study follow-up. RESULTS: Of 369 infants, 32 (8.7%) developed BCG-IRIS within 6 months of starting ART, 28 (88%) within 2 months after ART initiation. Of the 32 cases, 30 (93.8%) had HIV-1 RNA > 750 000 copies/ml at initiation. Incidence of BCG-IRIS was 10.9 and 54.3 per 100 person-years (py) among infants with CD4 count ≥25% at enrolment receiving early (at median age 7.4 weeks) vs. deferred (23.2 weeks) ART, respectively (HR 0.24, 95%CI 0.11-0.53, P < 0.001). Infants with CD4 count <25% receiving early ART had intermediate incidence (41.7/100 py). Low CD4 counts and high HIV-1 RNA at initiation were the strongest independent risk factors for BCG-IRIS. CONCLUSIONS: Early ART initiation before immunological and/or clinical progression substantially reduces the risk of BCG-IRIS regional adenitis.

A potential new target for asthma therapy: a disintegrin and metalloprotease 10 (ADAM10) involvement in murine experimental asthma.

BACKGROUND: Elevated levels of CD23, a natural regulator of IgE production, have been shown to decrease the signs of lung inflammation in mice. The aim of this study was to study the involvement of ADAM10, the primary CD23 sheddase, in experimental asthma. METHODS: ADAM10 was blocked either by using mice with a B-cell-specific deletion of the protease or pharmacologically by intranasal administration of selective ADAM10 inhibitors. Airway hypersensitivity (AHR) and bronchoaveolar lavage fluid (BALF) eosinophilia and select BALF cytokine/chemokine levels were then determined. RESULTS: Using an IgE and mast cell-dependent mouse model, B-cell-specific ADAM10(-/-) mice (C57B/6 background) exhibited decreased eosinophilia and AHR when compared with littermate (LM) controls. Treatment of C57B/6 mice with selective inhibitors of ADAM10 resulted in an even further decrease in BALF eosinophilia, as compared with the ADAM10(-/-) animals. Even in the Th2 selective strain, Balb/c, BALF eosinophilia was reduced from 60% to 23% respectively. In contrast, when an IgE/mast cell-independent model of lung inflammation was used, the B-cell ADAM10(-/-) animals and ADAM10 inhibitor treated animals had lung inflammation levels that were similar to the controls. CONCLUSIONS: These results thus show that ADAM10 is important in the progression of IgE-dependent lung inflammation. The use of the inhibitor further suggested that ADAM10 was important for maintaining Th2 levels in the lung. These results thus suggest that decreasing ADAM10 activity could be beneficial in controlling asthma and possibly other IgE-dependent diseases.

Relationship between feeding behavior and performance of feedlot steers fed barley-based diets.

The relationship between feeding behavior and performance of 274 feedlot cattle was evaluated using Charolais cross steers from 2 consecutive years averaging 293 ± 41 kg for yr 1 (n = 115) and 349 ± 41 for yr 2 (n = 159). Steers were blocked by BW and assigned to 3 (yr 1) or 4 (yr 2) feedlot pens equipped with a radio frequency identification system (GrowSafe Systems). Each pen contained 5 feeding stalls that allowed individual animal access to a feed tub suspended on load cells. The system recorded animal identification, duration, and frequency of feedings as well as the amount of feed consumed during each visit. Daily variation in DMI (DVI), calculated as the absolute difference in DMI from one day to the next, as well as eating rate were determined for each steer. Barley-based diets were delivered to meet steer ad libitum intake over the 213- and 181-d feeding periods for yr 1 and 2 of the study, respectively. The backgrounding periods included the first 85 and 56 d of yr 1 and 2, respectively, in which steers were fed a 14 to 30% concentrate diet, whereas the finishing periods included the last 116 and 101 d of feeding in yr 1 and 2, respectively, with the diet consisting of 77.9% concentrate. Steers were weighed individually every 14 d. To relate feeding behavior to performance, steers were grouped by ADG and G:F and categorized as high, average, or low (based on 1 SD greater than and less than the mean). In the backgrounding and finishing periods of both years of the study, steers classified as having high ADG exhibited greater (P < 0.001) DVI than steers classified as having average or low ADG. Total daily DMI was also greater (P < 0.001) for steers in the high ADG group than those in the low ADG group. Overall, those steers with the greatest G:F also tended (P = 0.15) to have greater DVI than average or low G:F steers. Compared with average or low G:F steers, DMI by high G:F steers in both years of the study was less during backgrounding, finishing, and overall (P = 0.02). Bunk visits and bunk attendance duration were less frequent and shorter (P ≤ 0.01) overall for high compared with low G:F steers. In this study, steers with more variable eating patterns exhibited greater ADG and tended to have greater G:F, a finding that is contrary to industry perception.

Feeding behavior and ruminal acidosis in beef cattle offered a total mixed ration or dietary components separately.

Eighty continental crossbred beef heifers (414.9 ± 37.9 kg of BW), 16 of which were ruminally cannulated, were used in a 52-d experiment with a generalized randomized block design, to assess if self-selection of dietary ingredients modulates ruminal pH and improves rumen function of feedlot finishing cattle. Treatments were total mixed ration [TMR; 85% barley grain (BG), 10% corn silage (CS), 5% supplement]; or free-choice (self-selection; FC) diets of barley grain and corn silage (BGCS), barley grain and wheat distillers grain (BGDG), or corn silage and wheat distillers grain (CSDG). Heifers were housed in groups of 10 in 8 pens equipped with the GrowSafe System (Airdrie, AB, Canada) enabling feed intake and feeding behavior to be continuously monitored. Two cannulated heifers were randomly assigned to each pen and equipped with indwelling pH probes for continuous measurement of ruminal pH during 4 periods (d 1 to 4, d 7 to 14, d 21 to 28, and d 42 to 49). Rumen fluid samples were collected from cannulated heifers on d 7 and 42 before feed delivery, and on d 4 and 49 at 2 h post-feed delivery for determination of VFA. Heifers fed the TMR had shorter (P = 0.01) and smaller (P = 0.03) meals than those fed the FC diets. Cattle fed BGCS and BGDG increased (P < 0.01) intake of BG over time by up to 80 and 70%, respectively. Increased consumption of BG arose from an increase (P < 0.01) in eating rate over the same (P > 0.10) feeding time, which was accompanied by an increase (P < 0.05) in eating rate but a decrease (P < 0.05) in feeding time of either CS or DG. Even with increased BG consumption, ruminal pH and VFA profiles were not different (P > 0.10) among FC diets or compared with the TMR. Cattle fed FC CSDG consumed DG at 60% of dietary DM over the trial, resulting in greater (P < 0.05) mean ruminal pH and acetate-to-propionate ratio and less (P < 0.05) area under the curve than those given the other FC diets or the TMR. Finishing feedlot cattle fed FC diets containing BG self-regulate intake of diets that have a similar composition, intake level, and ruminal fermentation profile to those fed a TMR.