Body composition, gastrointestinal, and reproductive differences between broiler breeders fed using everyday or skip-a-day rearing programs.

Broiler breeder feed restriction practices have intensified as broiler feed efficiency has been improved. Skip-a-day (SAD) rearing regimen has controlled breeder growth, although this practice has become questionable for the modern breeder. We compared everyday (ED) and SAD programs and evaluated their impact on pullet growth performance, body composition, gastrointestinal tract development, and reproduction. At d 0, Ross 708 (Aviagen) pullet chicks (n = 1,778) were randomly assigned to 7 floor pens. Three pens were fed using the ED and 4 pens with SAD program through wk 21 using a chain-feeder system. ED and SAD grower diets were formulated to be isonutritious, with the only difference that ED diets had more crude fiber. Pullets (n = 44 per pen) were moved to 16 hen pens by treatment at wk 21 with 3 YP males (Aviagen) in each pen. All birds were fed common laying diets. In addition to BW data, sampled pullets and hens were scanned using dual energy X-ray absorptiometry (DEXA) to obtain body bone density and composition. Hen performance and hatchery metrics were recorded through wk 60. ED birds were heavier with similar nutrient intake from wk 10 to 45 (P ≤ 0.013). Pullet uniformity was unaffected by feeding method (P ≥ 0.443). SAD pullets had less body fat at wk 19 (P = 0.034) compared to ED pullets, likely as a metabolic consequence of intermittent feeding. SAD birds had lower bone density at wk 7, 15, and 19 (P ≤ 0.026). At 4 wk of age, SAD pullets had less intestinal villi goblet cells compared to ED pullets (P ≤ 0.050), possibly explained by the effect that feed removal has on cell migration rates. Overall egg-specific gravity (P = 0.057) and hatch of fertile % (P = 0.088) tended to be higher in eggs from ED hens. Altogether, ED feeding increased young pullet intestinal goblet cells and increased both bone density and body fat at wk 19. ED program improved pullet feed conversion (2.6% less feed) and increased eggshell quality and hatch of fertile.

Validation of HIV-infected cohort identification using automated clinical data in the Department of Veterans Affairs.

OBJECTIVES: The US Department of Veterans Affairs (VA) is the largest integrated health care provider for HIV-infected patients in the USA. VA data for HIV-specific clinical and quality improvement research are an important resource. We sought to determine the accuracy of using the VA Corporate Data Warehouse (CDW), a fully automated medical records database for all VA users nationally, to identify HIV-infected patients compared with a gold-standard VA HIV Clinical Case Registry (CCR). METHODS: We assessed the test performance characteristics of each of our CDW criteria-based algorithms (presence of one, two or all of the following: diagnostic codes for HIV, positive HIV laboratory tests, and prescription for HIV medication) by calculating their sensitivity (proportion of HIV-positive patients in the CCR accurately detected as HIV-positive by the CDW algorithm) and positive predictive value (PPV; the proportion of patients identified by the CDW algorithm who were classified as HIV-positive from the CCR). RESULTS: We found that using a CDW algorithm requiring two of three HIV diagnostic criteria yielded the highest sensitivity (95.2%) with very little trade-off in PPV (93.5%). CONCLUSIONS: A two diagnostic criteria-based algorithm can be utilized to accurately identify HIV-infected cohorts seen in the nationwide VA health care system.

Hepatitis C virus-related complications are increasing in women veterans: A national cohort study.

There are gender-specific variations in the epidemiology and clinical course of hepatitis C virus (HCV) infection. However, few long-term longitudinal studies have examined trends in the incidence and prevalence of serious liver complications among women compared with men with HCV infection. We used the Veterans Administration Corporate Data Warehouse to identify all veterans with positive HCV viraemia from January 2000 to December 2013. We calculated gender-specific annual incidence and prevalence rates of cirrhosis, decompensated cirrhosis and hepatocellular cancer (HCC) adjusting for age, diabetes, HIV and alcohol use. We also calculated the average annual per cent change (AAPC) for each outcome by gender using piecewise linear regression in the Joinpoint software. We identified 264 409 HCV-infected veterans during 2000-2013, of whom 7162 (2.7%) were women. There were statistically significant increases over time in the incidence rates of cirrhosis, decompensated cirrhosis and HCC for both men and women. The annual-adjusted incidence rates of cirrhosis, decompensated cirrhosis and HCC were higher in men than women for all study years. However, these complications increased at a similar rate in both groups. Specifically, the AAPC for cirrhosis was 13.1 and 15.2, while it was 15.6 and 16.9 for decompensated cirrhosis and 21.0 and 25.3 for HCC in men and women, respectively (all test of parallelism not significant). The results were similar in the prevalence analyses, although AAPCs were slightly smaller for each outcome. In conclusion, we found an ongoing upward trend in the incidence and prevalence of HCV complications in this cohort of HCV-infected women. This increase in cirrhosis complications in women with active HCV infection is similar to those in men. With cure from HCV now becoming a reality, most of the projected burden of HCV is potentially preventable. However, benefits of HCV treatment will need to extend to all patients in order to stem the rising tide of HCV complications.

The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment.

Tyrosine kinase inhibitor (TKI) therapy results in excellent responses in the majority of patients with chronic myeloid leukaemia. First-line imatinib treatment, with selective switching to nilotinib when patients fail to meet specific molecular targets or for imatinib intolerance, results in excellent overall molecular responses and survival. However, this strategy is less effective in cases of primary imatinib resistance; moreover, 25% of patients develop secondary resistance such that 20-35% of patients initially treated with imatinib will eventually experience treatment failure. Early identification of these patients is of high clinical relevance. Since the drug efflux transporter ABCB1 has previously been implicated in TKI resistance, we determined if early increases in ABCB1 mRNA expression (fold change from diagnosis to day 22 of imatinib therapy) predict for patient response. Indeed, patients exhibiting a high fold rise (⩾2.2, n=79) were significantly less likely to achieve early molecular response (BCR-ABL1IS ⩽10% at 3 months; P=0.001), major molecular response (P<0.0001) and MR4.5 (P<0.0001). Additionally, patients demonstrated increased levels of ABCB1 mRNA before the development of mutations and/or progression to blast crisis. Patients with high fold rise in ABCB1 mRNA were also less likely to achieve major molecular response when switched to nilotinib therapy (49% vs 82% of patients with low fold rise). We conclude that early evaluation of the fold change in ABCB1 mRNA expression may identify patients likely to be resistant to first- and second-generation TKIs and who may be candidates for alternative therapy.

TGF-α and IL-6 plasma levels selectively identify CML patients who fail to achieve an early molecular response or progress in the first year of therapy.

Early molecular response (EMR, BCR-ABL1 (IS)⩽10% at 3 months) is a strong predictor of outcome in imatinib-treated chronic phase chronic myeloid leukemia (CP-CML) patients, but for patients who transform early, 3 months may be too late for effective therapeutic intervention. Here, we employed multiplex cytokine profiling of plasma samples to test newly diagnosed CP-CML patients who subsequently received imatinib treatment. A wide range of pro-inflammatory and angiogenesis-promoting cytokines, chemokines and growth factors were elevated in the plasma of CML patients compared with that of healthy donors. Most of these normalized after tyrosine kinase inhibitor treatment while others remained high in remission samples. Importantly, we identified TGF-α and IL-6 as novel biomarkers with high diagnostic plasma levels strongly predictive of subsequent failure to achieve EMR and deep molecular response, as well as transformation to blast crisis and event-free survival. Interestingly, high TGF-α alone can also delineate a poor response group raising the possibility of a pathogenic role. This suggests that the incorporation of these simple measurements to the diagnostic work-up of CP-CML patients may enable therapy intensity to be individualized early according to the cytokine-risk profile of the patient.

OCT1 and imatinib transport in CML: is it clinically relevant?

Imatinib is a highly effective therapy for chronic phase-chronic myeloid leukaemia (CP-CML) patients; however, responses to frontline imatinib are variable. The human organic cation transporter 1 (OCT1; SLC22A1) has been reported to be the main influx transporter involved in imatinib uptake into CML cells. Furthermore, variation in the efficiency of imatinib influx via OCT1 has been demonstrated to result in the inter-patient variation observed in primary response to imatinib. Although studies have questioned the role of OCT1 in imatinib influx, these have been largely performed in non-clinical settings. Measuring both OCT1 mRNA levels and the functional activity of OCT1 in primary leukaemic cells has been demonstrated to predict molecular response and outcome in imatinib-treated CP-CML patients in several independent studies. Here, the role of OCT1 and OCT1 genetic variants in imatinib uptake and response prediction is summarised and data generated from model systems assessing the role of OCT1 in imatinib transport is discussed.

Sustained inhibition of STAT5, but not JAK2, is essential for TKI-induced cell death in chronic myeloid leukemia.

Kinase inhibitors block proliferative signals in BCR-ABL1+ leukemic cells, but their capacity to induce apoptosis is poorly understood. Initial studies suggested that very brief exposure to kinase inhibitors was sufficient to induce apoptosis in chronic myeloid leukemia (CML) cells. However, flaws in this experimental model have subsequently been identified, leading to the conclusion that apoptosis only occurs with sustained low-level kinase inhibition. Thus, the minimum duration of complete kinase inhibition required to commit CML cells to death is unknown. Here we confirm that <1 h is insufficient to induce significant commitment to death in BCR-ABL1+ cell lines and in primary CD34+ progenitor cells, and establish that commitment to cell death only occurs if kinase inhibition is maintained for 4 h or more. Remarkably, signal transducer and activator of transcription 5 (STAT5) inhibition in combination with transient (<1 h) tyrosine kinase inhibitor (TKI) exposure proved lethal for CML progenitors, despite the reactivation of Bcr-Abl after 1 h. JAK kinase inhibition did not induce cell death in combination with transient TKI exposure. Thus, STAT5 appears to be a critical determinant of the time-dependent sensitivity of CML progenitor cells to TKI treatment in a Bcr-Abl-dependent, but JAK-independent, manner. We conclude that combining kinase inhibition with STAT5 inhibition represents a promising therapeutic approach in BCR-ABL1+ leukemias.

Interaction of the efflux transporters ABCB1 and ABCG2 with imatinib, nilotinib, and dasatinib.

The efflux transporters adenosine triphosphate (ATP)-binding cassette (ABC)B1 and ABCG2 have been demonstrated to interact with the tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, and dasatinib. However, although some studies conclude that TKIs are substrates of one or both transporters, other studies demonstrate only an inhibitory function. This variation is probably due to differences in the concentration of TKIs assayed and the experimental systems used. This article examines the evidence for clinically relevant interactions between three currently approved TKIs and ABCB1/ABCG2.

The association between serological and dietary vitamin D levels and hepatitis C-related liver disease risk differs in African American and white males.

BACKGROUND: Vitamin D may affect the severity of HCV-related liver disease. AIM: To examine the association between serum vitamin D levels and advanced liver disease in a multiethnic US cohort of HCV patients, and account for dietary and supplemental intake. METHODS: We measured serum 25-hydroxyvitamin D levels and used FibroSURE-ActiTest to assess hepatic pathology in a cohort of HCV-infected male veterans. We estimated and adjusted for daily intake of vitamin D from diet using a Dietary History Questionnaire, and dispensed prescriptions prior to study enrolment. We used race-stratified logistic regression analyses to evaluate the relationship between serum vitamin D levels and risk of advanced fibrosis (F3/F4-F4) and advanced inflammation (A2/A3-A3). RESULTS: A total of 163 African American (AA) and 126 White non-Hispanics were studied. Overall, ~44% of AAs and 15% of Whites were vitamin D deficient (<12 ng/mL) or insufficient (12-19 ng/mL); 4% of AAs and 9% of White patients had an elevated level (>50 ng/mL). Among AAs, patients with elevated serum vitamin D levels had significantly higher odds of advanced fibrosis (OR = 12.91, P = 0.03) than those with normal levels. In contrast, AAs with insufficient or deficient levels had > two-fold excess risk of advanced inflammation (P = 0.06). Among White males there was no association between vitamin D levels and advanced fibrosis (F3/F4-F4) or inflammation (A2/A3-A3) risk. CONCLUSIONS: We observed potential differences in the association between vitamin D levels and degree of HCV-related hepatic fibrosis between White and African American males. Additional research is necessary to confirm that high serum vitamin D levels may be associated with advanced fibrosis risk in African American males, and to evaluate whether racial differences exist in HCV-infected females.

Sleep duration and incidence of colorectal cancer in postmenopausal women.

BACKGROUND: Sleep duration is dependent on circadian rhythm that controls a variety of key cellular functions. Circadian disruption has been implicated in colorectal tumorigenesis in experimental studies. We prospectively examined the association between sleep duration and risk of colorectal cancer (CRC). METHODS: In the Women's Health Initiative Observational Study, 75 828 postmenopausal women reported habitual sleep duration at baseline 1993-1998. We used Cox proportional hazards regression model to estimate the hazard ratio (HR) of CRC and its associated 95% confidence interval (CI). RESULTS: We ascertained 851 incident cases of CRC through 2010, with an average 11.3 years of follow-up. Compared with 7 h of sleep, the HRs were 1.36 (95% CI 1.06-1.74) and 1.47 (95% CI 1.10-1.96) for short (≤5 h) and long (≥9 h) sleep duration, respectively, after adjusting for age, ethnicity, fatigue, hormone replacement therapy (HRT), physical activity, and waist to hip ratio. The association was modified by the use of HRT (P-interaction=0.03). CONCLUSION: Both extreme short and long sleep durations were associated with a moderate increase in the risk of CRC in postmenopausal women. Sleep duration may be a novel, independent, and potentially modifiable risk factor for CRC.

Contrasting effects of diclofenac and ibuprofen on active imatinib uptake into leukaemic cells.

BACKGROUND: The human organic cation transporter-1 (OCT-1) is the primary active protein for imatinib uptake into target BCR-ABL-positive cells. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used by chronic myeloid leukaemia (CML) patients on imatinib to manage musculoskeletal complaints. METHODS: Here we investigated the impact of NSAIDs on functional activity of the OCT-1 (OCT-1 activity; OA) in CML cells. RESULTS: Although ten of twelve NSAIDs tested had no significant impact on OA (P>0.05), we observed increased OA (27% increase in K562; 22% increase in KU812 cells, P<0.05) and reduced IC50(imatinib) when treated with diclofenac. Co-incubation with imatinib and diclofenac resulted in a significantly lower viable cell number compared with imatinib alone. In contrast, ibuprofen led to a significant decrease in OA, an increase in IC50(imatinib) and thus reduced the cytotoxicity of imatinib. In primary CML samples, diclofenac significantly increased OA, particularly in patients with low OA (<4 ng per 200 000 cells), and significantly decreased IC50(imatinib). Ibuprofen induced significant decreases in OA in CML samples and healthy donors. CONCLUSION: On the basis of the expected impact of these two drugs on OA, ibuprofen should be avoided in combination with imatinib. Further studies are warranted regarding the potential benefit of diclofenac to improve OA in a clinical setting.