Boceprevir is highly effective in treatment-experienced hepatitis C virus-positive genotype-1 menopausal women

AIM: To investigate the safety/efficacy of Boceprevirbased triple therapy in hepatitis C virus (HCV)-G1 menopausal women who were historic relapsers, partial-responders and null-responders. METHODS: In this single-assignment, unblinded study, we treated fifty-six menopausal women with HCV-G1, 46% F3-F4, and previous PEG-α/RBV failure (7% null, 41% non-responder, and 52% relapser) with 4 wk lead-in with PEG-IFNα2b/RBV followed by PEGIFNα2b/RBV+Boceprevir for 32 wk, with an additional 12 wk of PEG-IFN-α-2b/RBV if patients were HCV-RNA-positive by week 8. In previous null-responders, 44 wk of triple therapy was used. The primary objective of retreatment was to verify whether a sustained virological response (SVR) (HCV RNA undetectable at 24 wk of follow-up) rate of at least 20% could be obtained. The secondary objective was the evaluation of the percent of patients with negative HCV RNA at week 4 (RVR), 8 (RVR BOC), 12 (EVR), or at the end-of-treatment (ETR) that reached SVR. To assess the relationship between SVR and clinical and biochemical parameters, multiple logistic regression analysis was used. RESULTS: After lead-in, only two patients had RVR; HCV-RNA was unchanged in all but 62% who had ≤ 1 logio decrease. After Boceprevir, HCV RNA became undetectable at week 8 in 32/56 (57.1%) and at week 12 in 41/56 (73.2%). Of these, 53.8% and 52.0%, respectively, achieved SVR. Overall, SVR was obtained in 25/56 (44.6%). SVR was achieved in 55% previous relapsers vs. 41% non-responders (Ρ = 0.250), in 44% F0-F2 vs 54% F3-F4 (Ρ = 0.488), and in 11/19 (57.9%) of patients with cirrhosis. At univariate analysis for baseline predictors of SVR, only previous response to antiviral therapy (OR = 2.662, 95%CI: 0.957-6.881, Ρ= 0.043), was related with SVR. When considering "on treatment" factors, 1 log10 HCV RNA decline at week 4 (3.733, 95%CI: 1.676-12.658, Ρ= 0.034) and achievement of RVR BOC (7.347, 95%CI: 2.156-25.035, Ρ= 0.001) were significantly related with the SVR, al-though RVR BOC only (6.794, 95%CI: 1.596-21.644, Ρ = 0.010) maintained significance at multivariate logistic regression analysis. Anemia and neutropenia were managed with Erythropoietin and Filgrastim supplementation, respectively. Only six patients discontinued therapy. CONCLUSION: Boceprevir obtained high SVR response independent of previous response, RVR or baseline fibrosis or cirrhosis. RVR BOC was the only independent predictor of SVR

The effect of calving in the summer on the hepatic transcriptome of Holstein cows during the peripartal period

The liver is the main metabolic organ coordinating the adaptations that take place during the peripartal period of dairy cows. A successful transition into lactation, rather than management practices alone, depends on environmental factors such as temperature, season of parturition, and photoperiod. Therefore, we analyzed the effect of calving season on the hepatic transcriptome of dairy cows during the transition period. A total of 12 Holstein dairy cows were assigned into 2 groups based on calving season (6 cows March-April, spring; 6 cows June-July, summer, SU). The RNA was extracted from liver samples obtained at -30, 3, and 35 DIM via percutaneous biopsy and hybridized to the Agilent 44K Bovine (V2) Gene Expression Microarray (Agilent Technologies Inc., Santa Clara, CA). A quantitative PCR on 22 target genes was performed to verify and expand the analyses. A total of 4,307 differentially expressed genes were detected (false discovery rate ≤0.05) in SU compared with spring. Furthermore, 73 unique differentially expressed genes were detected in SU compared with spring cows after applying a fold-change threshold ≥3 and ≤-3. For Kyoto Encyclopedia of Genes and Genomes pathways analysis of differentially expressed genes, we used the dynamic impact approach. Ingenuity Pathway Analysis software was used to analyze upstream transcription regulators and perform gene network analysis. Among metabolic pathways, energy metabolism from lipids, carbohydrates, and amino acids was strongly affected by calving in SU, with a reduced level of fatty acid synthesis, oxidation, re-esterification, and synthesis of lipoproteins, leading to hepatic lipidosis. Glycan-synthesis was downregulated in SU cows probably as a mechanism to counteract the progression of this lipidosis. In contrast, calving in the SU resulted in upregulation of gluconeogenesis but also greater use of glucose as an energy source. Among nonmetabolic pathways, the heat-shock response was obviously activated in SU cows but was also associated with inflammatory and intracellular stress response. Furthermore, data support a recent finding that cows experience endoplasmic reticulum stress around parturition. Transcription regulator analysis revealed how metabolic changes are related to important regulatory mechanisms, including epigenetic modification. The holistic analyses of the liver transcriptome response to calving in the summer at high environmental temperatures underscore how transition cows should be carefully managed during this period, as they experience alterations in liver energy metabolism and inflammatory state increasing susceptibility to health disorders in early postpartum

Impact of Seasonal Conditions on Quality and Pathogens Content of Milk in Friesian Cows

Heat stress negatively affects milk quality altering its nutritive value and cheese making properties. This study aimed at assessing the impact of seasonal microclimatic conditions on milk quality of Friesian cows. The study was carried out in a dairy farm from June 2013 to May 2014 at Beni-Suef province, Egypt. Inside the barn daily ambient temperature and relative humidity were recorded and used to calculate the daily maximum temperature-humidity index (mxTHI), which was used as indicator of the degree of heat stress. The study was carried out in three periods according to the temperature-humidity index (THI) recorded: from June 2013 to September 2013 (mxTHI>78), from October 2013 to November 2013 (mxTHI 72–78) and from December 2013 to April 2014 (mxTHI78 was observed. In addition, the isolation rate of both S. aureus and E. coli increased when the mxTHI increased. The results of this study show the seriousness of the negative effects of hot conditions on milk composition and mammary gland pathogens. These facts warrant the importance of adopting mitigation strategies to alleviate negative consequences of heat stress in dairy cows and for limiting related economic losses

Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis C.

BACKGROUND AND AIMS: Chronic hepatitis C (CHC) and liver fibrosis progress more rapidly in men and menopausal women than in women of reproductive age. We investigated the associations among menopause, sustained virologic response (SVR), and liver damage in patients with CHC. METHODS: We performed a prospective study of 1000 consecutive, treatment-naïve patients 18 years of age and older with compensated liver disease from CHC. Liver biopsy samples were analyzed (for fibrosis, inflammation, and steatosis) before patients received standard antiviral therapy. From women (n = 442), we collected data on the presence, type, and timing of menopause; associated hormone and metabolic features; serum levels of interleukin-6; and hepatic tumor necrosis factor (TNF)-α. RESULTS: Postmenopausal women achieved SVRs less frequently than women of reproductive age (46.0% vs 67.5%; P < .0001) but as frequently as men (51.1%; P = .283). By multivariate regression analysis, independent significant predictors for women to not achieve an SVR were early menopause (odds ratio [OR], 8.055; 95% confidence interval [CI], 1.834-25.350), levels of γ-glutamyl transpeptidase (OR, 2.165; 95% CI, 1.364-3.436), infection with hepatitis C virus genotype 1 or 4 (OR, 3.861; 95% CI, 2.433-6.134), and cholesterol levels (OR, 0.985; 95% CI, 0.971-0.998). Early menopause was the only independent factor that predicted lack of an SVR among women with genotype 1 hepatitis C virus infection (OR, 3.933; 95% CI, 1.274-12.142). Baseline levels of liver inflammation, fibrosis, steatosis, serum interleukin-6 (P = .04), and hepatic TNF-α (P = .007) were significantly higher among postmenopausal women than women of reproductive age. CONCLUSIONS: Among women with CHC, early menopause was associated with a low likelihood of SVR, probably because of inflammatory factors that change at menopause

A neural tracking and motor control approach to improve rehabilitation of upper limb movements

<p>Abstract</p> <p>Background</p> <p>Restoration of upper limb movements in subjects recovering from stroke is an essential keystone in rehabilitative practices. Rehabilitation of arm movements, in fact, is usually a far more difficult one as compared to that of lower extremities. For these reasons, researchers are developing new methods and technologies so that the rehabilitative process could be more accurate, rapid and easily accepted by the patient. This paper introduces the proof of concept for a new non-invasive FES-assisted rehabilitation system for the upper limb, called smartFES (sFES), where the electrical stimulation is controlled by a biologically inspired neural inverse dynamics model, fed by the kinematic information associated with the execution of a planar goal-oriented movement. More specifically, this work details two steps of the proposed system: an <it>ad hoc </it>markerless motion analysis algorithm for the estimation of kinematics, and a neural controller that drives a synthetic arm. The vision of the entire system is to acquire kinematics from the analysis of video sequences during planar arm movements and to use it together with a neural inverse dynamics model able to provide the patient with the electrical stimulation patterns needed to perform the movement with the assisted limb.</p> <p>Methods</p> <p>The markerless motion tracking system aims at localizing and monitoring the arm movement by tracking its silhouette. It uses a specifically designed motion estimation method, that we named Neural Snakes, which predicts the arm contour deformation as a first step for a silhouette extraction algorithm. The starting and ending points of the arm movement feed an Artificial Neural Controller, enclosing the muscular Hill's model, which solves the inverse dynamics to obtain the FES patterns needed to move a simulated arm from the starting point to the desired point. Both position error with respect to the requested arm trajectory and comparison between curvature factors have been calculated in order to determine the accuracy of the system.</p> <p>Results</p> <p>The proposed method has been tested on real data acquired during the execution of planar goal-oriented arm movements. Main results concern the capability of the system to accurately recreate the movement task by providing a synthetic arm model with the stimulation patterns estimated by the inverse dynamics model. In the simulation of movements with a length of ± 20 cm, the model has shown an unbiased angular error, and a mean (absolute) position error of about 1.5 cm, thus confirming the ability of the system to reliably drive the model to the desired targets. Moreover, the curvature factors of the factual human movements and of the reconstructed ones are similar, thus encouraging future developments of the system in terms of reproducibility of the desired movements.</p> <p>Conclusion</p> <p>A novel FES-assisted rehabilitation system for the upper limb is presented and two parts of it have been designed and tested. The system includes a markerless motion estimation algorithm, and a biologically inspired neural controller that drives a biomechanical arm model and provides the stimulation patterns that, in a future development, could be used to drive a smart Functional Electrical Stimulation system (sFES). The system is envisioned to help in the rehabilitation of post stroke hemiparetic patients, by assisting the movement of the paretic upper limb, once trained with a set of movements performed by the therapist or in virtual reality. Future work will include the application and testing of the stimulation patterns in real conditions.</p

A biologically inspired neural network controller for ballistic arm movements

<p>Abstract</p> <p>Background</p> <p>In humans, the implementation of multijoint tasks of the arm implies a highly complex integration of sensory information, sensorimotor transformations and motor planning. Computational models can be profitably used to better understand the mechanisms sub-serving motor control, thus providing useful perspectives and investigating different control hypotheses. To this purpose, the use of Artificial Neural Networks has been proposed to represent and interpret the movement of upper limb. In this paper, a neural network approach to the modelling of the motor control of a human arm during planar ballistic movements is presented.</p> <p>Methods</p> <p>The developed system is composed of three main computational blocks: 1) a parallel distributed learning scheme that aims at simulating the internal inverse model in the trajectory formation process; 2) a pulse generator, which is responsible for the creation of muscular synergies; and 3) a limb model based on two joints (two degrees of freedom) and six muscle-like actuators, that can accommodate for the biomechanical parameters of the arm. The learning paradigm of the neural controller is based on a pure exploration of the working space with no feedback signal. Kinematics provided by the system have been compared with those obtained in literature from experimental data of humans.</p> <p>Results</p> <p>The model reproduces kinematics of arm movements, with bell-shaped wrist velocity profiles and approximately straight trajectories, and gives rise to the generation of synergies for the execution of movements. The model allows achieving amplitude and direction errors of respectively 0.52 cm and 0.2 radians.</p> <p>Curvature values are similar to those encountered in experimental measures with humans.</p> <p>The neural controller also manages environmental modifications such as the insertion of different force fields acting on the end-effector.</p> <p>Conclusion</p> <p>The proposed system has been shown to properly simulate the development of internal models and to control the generation and execution of ballistic planar arm movements. Since the neural controller learns to manage movements on the basis of kinematic information and arm characteristics, it could in perspective command a neuroprosthesis instead of a biomechanical model of a human upper limb, and it could thus give rise to novel rehabilitation techniques.</p

Clinical features and comorbidity pattern of HCV infected migrants compared to native patients in care in Italy: A real-life evaluation of the PITER cohort

Background: Direct-acting antivirals are highly effective for the treatment of hepatitis C virus (HCV) infection, regardless race/ethnicity. We aimed to evaluate demographic, virological and clinical data of HCV-infected migrants vs. natives consecutively enrolled in the PITER cohort. Methods: Migrants were defined by country of birth and nationality that was different from Italy. Mann-Whitney U test, Chi-squared test and multiple logistic regression were used. Results: Of 10,669 enrolled patients, 301 (2.8%) were migrants: median age 47 vs. 62 years, (p &lt; 0.001), females 56.5% vs. 45.3%, (p &lt; 0.001), HBsAg positivity 3.8% vs. 1.4%, (p &lt; 0.05). Genotype 1b was prevalent in both groups, whereas genotype 4 was more prevalent in migrants (p &lt; 0.05). Liver disease severity and sustained virologic response (SVR) were similar. A higher prevalence of comorbidities was reported for natives compared to migrants (p &lt; 0.05). Liver disease progression cofactors (HBsAg, HIV coinfection, alcohol abuse, potential metabolic syndrome) were present in 39.1% and 47.1% (p &gt; 0.05) of migrants and natives who eradicated HCV, respectively. Conclusion: Compared to natives, HCV-infected migrants in care have different demographics, HCV genotypes, viral coinfections and comorbidities and similar disease severity, SVR and cofactors for disease progression after HCV eradication. A periodic clinical assessment after HCV eradication in Italians and migrants with cofactors for disease progression is warranted

Molecular Signatures Reveal Circadian Clocks May Orchestrate the Homeorhetic Response to Lactation

Genes associated with lactation evolved more slowly than other genes in the mammalian genome. Higher conservation of milk and mammary genes suggest that species variation in milk composition is due in part to the environment and that we must look deeper into the genome for regulation of lactation. At the onset of lactation, metabolic changes are coordinated among multiple tissues through the endocrine system to accommodate the increased demand for nutrients and energy while allowing the animal to remain in homeostasis. This process is known as homeorhesis. Homeorhetic adaptation to lactation has been extensively described; however how these adaptations are orchestrated among multiple tissues remains elusive. To develop a clearer picture of how gene expression is coordinated across multiple tissues during the pregnancy to lactation transition, total RNA was isolated from mammary, liver and adipose tissues collected from rat dams (n = 5) on day 20 of pregnancy and day 1 of lactation, and gene expression was measured using Affymetrix GeneChips. Two types of gene expression analysis were performed. Genes that were differentially expressed between days within a tissue were identified with linear regression, and univariate regression was used to identify genes commonly up-regulated and down-regulated across all tissues. Gene set enrichment analysis showed genes commonly up regulated among the three tissues enriched gene ontologies primary metabolic processes, macromolecular complex assembly and negative regulation of apoptosis ontologies. Genes enriched in transcription regulator activity showed the common up regulation of 2 core molecular clock genes, ARNTL and CLOCK. Commonly down regulated genes enriched Rhythmic process and included: NR1D1, DBP, BHLHB2, OPN4, and HTR7, which regulate intracellular circadian rhythms. Changes in mammary, liver and adipose transcriptomes at the onset of lactation illustrate the complexity of homeorhetic adaptations and suggest that these changes are coordinated through molecular clocks

The application of omics in ruminant production: a review in the tropical and sub-tropical animal production context

The demand for animal products (e.g. dairy and beef) in tropical regions is expected to increase in parallel with the public demand for sustainable practices, due to factors such as population growth and climate change. The necessity to increase animal production output must be achieved with better management and production technologies. For this to happen, novel research methodologies, animal selection and postgenomic tools play a pivotal role. Indeed, improving breeder selection programs, the quality of meat and dairy products as well as animal health will contribute to higher sustainability and productivity. This would surely benefit regions where resource quality and quantity are increasingly unstable, and research is still very incipient, which is the case of many regions in the tropics. The purpose of this review is to demonstrate how omics-based approaches play a major role in animal science, particularly concerning ruminant production systems and research associated to the tropics and developing countriesinfo:eu-repo/semantics/acceptedVersio