The objective of this observational study was to compare the metabolic status of dairy cows during the last 6 wk of gestation based on colostrum volume and immunoglobulin content. For this, healthy ...Holstein cows were randomly selected from 3 commercial herds in Michigan. In each farm, 4 cohorts of 21 cows (1 per season), stratified by parity, were enrolled (n = 228). Cows were blood sampled weekly during the last 6 wk of gestation, and biomarkers related to nutrient utilization, oxidant status, and inflammation were quantified in serum. Cows were milked within 6 h of calving, and the volume of colostrum produced was recorded and an aliquot collected. Concentration of IgG, IgA, and IgM were measured by radial immunodiffusion. Cows were grouped into high or low colostrum producer, high or low IgG, high or low IgA, and high or low IgM. For volume category, we arbitrarily defined 6 L of colostrum (4 L for first and 2 L for second feeding of calves) as the cutoff point, whereas for IgG we used the industry standard of ≥50 g/L. To create groups of low and high IgM or IgA, we used the median of these immunoglobulin as the cutoff point. Colostrum volume was lowest in winter, but no differences were observed among parity groups. Conversely, colostrum IgG concentration was highest in fall and winter, but colostrum IgM was lowest at these seasons. However, colostrum immunoglobulin content only showed a negative weak correlation with volume (Spearman's correlation coefficient < −0.28). Compared with low colostrum producer, high colostrum producer cows had higher concentrations of antioxidant potential and β-hydroxybutyrate, and lower cholesterol and oxidant status index. Cows with high IgG showed higher concentrations of glucose compared with low IgG. Cows with high IgA had higher concentrations of cholesterol, reactive oxygen and nitrogen species, oxidant status index, and total protein, whereas β-hydroxybutyrate and glucose were lower compared with low IgA. Biomarkers of metabolic stress were not significantly different between high IgM and low IgM. Nevertheless, the differences observed did not result in differences in inflammatory status between animals in any of the colostrum variable categories analyzed, suggesting that physiological homeostasis was not disrupted during late gestation in association with the colostrum variables studied. Overall, the great variability observed in colostrum variables suggests that colostrogenesis is a complex and multifactorial process. However, our results suggest that greater availability of antioxidants during late gestation could support the production of higher volumes of colostrum, which needs to be explored in future trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
In patients intubated for hypoxemic acute respiratory failure (ARF) related to novel coronavirus disease (COVID-19), we retrospectively compared two weaning strategies, early extubation with ...immediate non-invasive ventilation (NIV) versus standard weaning encompassing spontaneous breathing trial (SBT), with respect to IMV duration (primary endpoint), extubation failures and reintubations, rate of tracheostomy, intensive care unit (ICU) length of stay and mortality (additional endpoints). All COVID-19 adult patients, intubated for hypoxemic ARF and subsequently extubated, were enrolled. Patients were included in two groups, early extubation followed by immediate NIV application, and conventionally weaning after passing SBT. 121 patients were enrolled and analyzed, 66 early extubated and 55 conventionally weaned after passing an SBT. IMV duration was 9 6–11 days in early extubated patients versus 11 6–15 days in standard weaning group (
p
= 0.034). Extubation failures 12 (18.2%) vs. 25 (45.5%),
p
= 0.002 and reintubations 12 (18.2%) vs. 22 (40.0%)
p
= 0.009 were fewer in early extubation compared to the standard weaning groups, respectively. Rate of tracheostomy, ICU mortality, and ICU length of stay were no different between groups. Compared to standard weaning, early extubation followed by immediate NIV shortened IMV duration and reduced the rate of extubation failure and reintubation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In the dairy industry, individual diseases and their effects are normally studied independently. However, in many cases the diseases are all related. The diverse effects of these diseases provide the ...foundation for creating a measure that incorporates morbidity and removal (death or culling) measures and evaluates the impact diseases can have during lactation. This summary health measure is called the disease-adjusted lactation (DALact) and it represents time lost due to disease and injury. The DALact is a time-based summary measure that represents a new approach to assess the impact of diseases in a lactation. The objective of this study was to evaluate the association between time lost due to specific diseases and total time lost due to diseases in two consecutive lactations using the DALact. Health and removal (culling and death) data were obtained from a Colorado dairy with approximately 1,400 lactating cows. A total of 803 cows in their second or greater lactation that calved, were sold, or died from July 1, 2015, through June 30, 2016, were selected. Health data were collected from Dairy Comp 305 for each most recently completed lactation and from the previous lactation. Health events included calving injury, displaced abomasum, diarrhea, hypocalcemia, ketosis, lameness, mastitis, metritis, musculoskeletal injuries, pneumonia, and retained placenta. All cow-level data were imported into SAS ® for validation, calculation of DALact and modeling. The DALact was calculated by adding the Days Lost due to Premature Death or Culling (DLRD) and the Days Lost due to Illness (DLI). DLRD was calculated as the difference between the average completed lactation days in milk for that herd and the days in milk at culling or death. The DLI was the product of the number of cases multiplied by previously established disability weights and estimated disease durations (days) for a specific disease. The PROC GLM procedure was used to model the association of DALacts between the 2 consecutive lactations. A p-value of ≤0.05 was considered significant. Positive significant associations (P<0.001) were found between the DALact of the previous lactation and the current lactation for lameness and mastitis. The total DALact of the previous lactation was significantly associated (P<0.001) with the total DALact of the current lactation. Significant associations (P<0.001) were also found between the mastitis and lameness DALact of the precious lactation with the total DALact of the current lactation. Identification of diseases and reasons for removal that significantly affect time lost during two consecutive lactations will help producers focus management and preventive measures on diseases having the greatest impact on future productivity and wellbeing.
Galectin-1 (GAL1), a β-galactoside-binding protein abundantly expressed in the tumor microenvironment, has emerged as a key mechanism of chemoresistance developed by different tumors. Although ...increased expression of GAL1 is a hallmark of hepatocellular carcinoma (HCC) progression, aggressiveness and metastasis, limited information is available on the role of this endogenous lectin in HCC resistance to chemotherapy. Moreover, the precise mechanisms underlying this effect are uncertain. HCC has evolved different mechanisms of resistance to chemotherapy including those involving the P-glycoprotein (P-gp), an ATP-dependent drug efflux pump, which controls intracellular drug concentration. Here, we investigated the molecular mechanism underlying GAL1-mediated chemoresistance in HCC cells, particularly the involvement of P-gp in this effect. Our results show that GAL1 protected HepG2 cells from doxorubicin (DOX)- and sorafenib-induced cell death in vitro. Accordingly, GAL1-overexpressing HepG2 cells generated DOX-resistant tumors in vivo. High expression of GAL1 in HepG2 cells reduced intracellular accumulation of DOX likely by increasing P-gp protein expression rather than altering its membrane localization. GAL1-mediated increase of P-gp expression involved activation of the phosphatidylinositol-3 kinase (PI3K) signaling pathway. Moreover, 'loss-of-function' experiments revealed that P-gp mediates GAL1-driven resistance to DOX, but not to sorafenib, in HepG2 cells. Conversely, in PLC/PRF/5 cells, P-gp protein expression was undetectable and GAL1 did not control resistance to DOX or sorafenib, supporting the critical role of P-gp in mediating GAL1 effects. Collectively, our findings suggest that GAL1 confers chemoresistance in HCC through mechanisms involving modulation of P-gp, thus emphasizing the role of this lectin as a potential therapeutic target in HCC.
Monoclonal antibodies (mAbs) are currently among the most investigated targets for potential disease-modifying therapies in Alzheimer's disease (AD).
Our objectives were to identify all registered ...trials investigating mAbs in MCI due to AD or AD at any stage, retrieve available published and unpublished data from all registered trials, and analyze data on safety and efficacy outcomes.
A systematic search of all registered trials on ClinicalTrials.gov and EUCT was performed. Available results were searched on both platforms and on PubMed, ISI Web of Knowledge, and The Cochrane Library.
Overall, 101 studies were identified on 27 mAbs. Results were available for 50 trials investigating 12 mAbs. For 18 trials, data were available from both published and unpublished sources, for 21 trials only from published sources, and for 11 trials only from unpublished sources. Meta-analyses of amyloid-related imaging abnormalities (ARIA) events showed overall risk ratios of 10.65 for ARIA-E and of 1.75 for ARIA-H. The meta-analysis of PET-SUVR showed an overall significant effect of mAbs in reducing amyloid (SMD -0.88), but when considering clinical efficacy, data on CDR-SB showed that treated patients had a statistically significant but clinically non-relevant lower worsening (MD -0.15).
Our results suggest that the risk-benefit profile of mAbs remains unclear. Research should focus on clarifying the effect of amyloid on cognitive decline, providing data on treatment response rate, and accounting for minimal clinically important difference. Research on mAbs should also investigate the possible long-term impact of ARIA events, including potential factors predicting their onset.
Older people living in nursing homes (NHs) are particularly vulnerable in the ongoing COVID-19 pandemic, due to the high prevalence of chronic diseases and disabilities (e.g., dementia). The ...phenomenon of adverse events (AEs), intended as any harm or injury resulting from medical care or to the failure to provide care, has not yet been investigated in NHs during the pandemic. We performed a national survey on 3,292 NHs, either public or providing services both privately and within the national health system, out of the 3,417 NHs covering the whole Italian territory. An online questionnaire was addressed to the directors of each facility between March 24 and April 27, 2020. The list of NHs was provided by the Dementia Observatory, an online map of Italian services for people with dementia, which was one of the objectives of the implementation of the Italian National Dementia Plan. About 26% of residents in the Italian NHs for older people listed within the Dementia Observatory site had dementia. The objective of our study was to report the frequency of AEs that occurred during the months when SARS-CoV-2 spreading rate was at its highest in the Italian NHs and to identify which conditions and attributes were most associated with the occurrence of AEs by means of multivariate regression logistic analysis. Data are referred to 1,356 NHs that participated in the survey. The overall response rate was 41.2% over a time-period of six weeks (from March 24 to May 5). About one third of the facilities (444 out of 1,334) (33.3%) reported at least 1 adverse event, with a total of 2,000 events. Among the included NHs, having a bed capacity higher than the median of 60 beds (OR=1.57, CI95% 1.17-2.09; p=0.002), an observed increased in the use of psychiatric drugs (OR=1.80, CI95% 1.05-3.07; p=0.032), adopting physical restraint measures (OR=1.97, CI95% 1.47-2.64; p<0.001), residents hospitalized due to flu-like symptoms (OR =1.73, CI95% 1.28-2.32; p<0.001), and being located in specific geographic areas (OR=3.59, CI95% 1.81-7.08; OR = 2.90, CI95% 1.45-5.81 and OR = 4.02, CI05% 2.01-8.04 for, respectively, North-West, North-East and Centre vs South, p<0.001) were all factors positively associated to the occurrence of adverse events in the facility. Future recommendations for the management and care of residents in NHs during the COVID-19 pandemic should include specific statements for the most vulnerable populations, such as people with dementia.
The relationship between cancer and dementia is triggering growing research interest. Several preclinical studies have provided the biological rationale for the repurposing of specific anticancer ...agents in Alzheimer's disease (AD), and a growing number of research protocols are testing their efficacy and safety/tolerability in patients with AD.
The aim of the present systematic review was to provide an overview on the repurposing of approved anticancer drugs in clinical trials for AD by considering both ongoing and completed research protocols in all phases. In parallel, a systematic literature review was conducted on PubMed, ISI Web, and the Cochrane Library to identify published clinical studies on repurposed anticancer agents in AD.
Based on a structured search on the ClinicalTrials.gov and the EudraCT databases, we identified 13 clinical trials testing 11 different approved anticancer agents (five tyrosine kinase inhibitors, two retinoid X receptor agonists, two immunomodulatory agents, one histone deacetylase inhibitor, and one monoclonal antibody) in the AD continuum. The systematic literature search led to the identification of five published studies (one phase I, three phase II, and one phase IIb/III) reporting the effects of antitumoral treatments in patients with mild cognitive impairment or AD dementia. The clinical findings and the methodological characteristics of these studies are described and discussed.
Anticancer agents are triggering growing interest in the context of repurposed therapies in AD. Several clinical trials are underway, and data are expected to be available in the near future. To date, data emerging from published clinical studies are controversial. The promising results emerging from preclinical studies and identified research protocols should be confirmed and extended by larger, adequately designed, and high-quality clinical trials.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
On the basis of recent clinical and experimental data, natural killer (NK) cells appear to play a crucial role in eradication of acute myeloid leukemias. In the present study, by exploiting our ...current knowledge on NK receptors and their ligands on target cells, we investigated the interactions between NK and leukemic cells. We show that the size of the NK cell subset expressing the killer immunoglobulin-like receptor (KIR) not engaged by the HLA-class I alleles of the patient parallels the degree of NK cytotoxicity against leukemic cells. A sharp down-regulation of HLA-class I molecules has been detected in various leukemias and it was more frequent in myeloid than in lymphoblastic leukemias. Analysis of the ligands for triggering NK receptors revealed the consistent expression of Poliovirus receptor (PVR) and Nectin-2 in myeloid leukemias. In contrast, major histocompatibility complex class I-related chain molecules A/B (MICA/B) and UL1b-binding protein (ULBPs) were either absent or weakly expressed. Accordingly, NK-mediated lysis of these leukemias was dependent on DNAM-1 but not NKG2D. The major role of NKp46 and NKp30 was also confirmed. The expression of PVR and/or Nectin-2 was less frequent in lymphoblastic leukemias. In most leukemias, both CD48 and NTBA were down-regulated. The correlation found between marker expression and susceptibility to lysis may reveal useful information for NK-based immunotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Forty adults aged 28 to 73 years were entered into a prospective trial of imatinib for the treatment of steroid-refractory chronic graft-versus-host disease (SR-cGVHD). After 6 months, ...intention-to-treat (ITT) analysis of 39 patients who received the drug, regardless of the duration of treatment, revealed 14 partial responses (PR), 4 minor responses (MR) with relevant steroid sparing (46%) according to Couriel criteria, and 20 ≥ PR (51.3%), as per the National Institutes of Health (NIH) criteria and NIH severity score changes. The best responses were seen in the lungs, gut, and skin (35%, 50%, and 32%, respectively). After a median follow-up of 40 months, 28 patients were alive, with a 3-year overall survival (OS) and event-free survival of 72% and 46%, respectively. The 3-year OS was 94% for patients responding at 6 months and 58% for nonresponders according to NIH response, suggesting that these criteria represent a reliable tool for predicting OS after second-line treatment. Monitoring of anti–platelet-derived growth factor receptor (PDGF-R) antibodies showed a significant decrease in PDGF-R stimulatory activity in 7 responders, whereas it remained high in 4 nonresponders. This study confirms the efficacy of imatinib against SR-cGVHD and suggests that the response at 6 months significantly predicts long-term survival. This study is registered at https://eudract.ema.europa.eu/ (EUDRACT number: 2009-012927-27).
•Efficacy of imatinib in steroid-refractory chronic GVHD was prospectively compared across 3 different response systems, with high agreement.•Validity of quantitative-based assessment of response with NIH criteria was confirmed by its prognostic impact on long-term survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Allogeneic hematopoietic stem cell transplantation (allo-SCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and ...mortality. Crucial questions in clinical decision-making include the definition of optimal timing of the procedure and the benefit of cytoreduction before transplant in high-risk patients. We carried out a decision analysis on 1728 MDS who received supportive care, transplantation or hypomethylating agents (HMAs). Risk assessment was based on the revised International Prognostic Scoring System (IPSS-R). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of different treatment policies on survival. Life expectancy increased when transplantation was delayed from the initial stages to intermediate IPSS-R risk (gain-of-life expectancy 5.3, 4.7 and 2.8 years for patients aged ⩽55, 60 and 65 years, respectively), and then decreased for higher risks. Modeling decision analysis on IPSS-R versus original IPSS changed transplantation policy in 29% of patients, resulting in a 2-year gain in life expectancy. In advanced stages, HMAs given before transplant is associated with a 2-year gain-of-life expectancy, especially in older patients. These results provide a preliminary evidence to maximize the effectiveness of allo-SCT in MDS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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