Integración de los parámetros de remodelado, sincronía y velocidad máxima de vaciado para evaluar la función sistólica del ventrículo izquierdo / Integration of ventricular remodeling, synchrony and filling rate parameters to improve the assessment of left ventricular systolic function

Objetivos El objetivo es estudiar la relación entre los parámetros estructurales, de remodelado, de sincronía y de función sistólica del ventrículo izquierdo (VI) mediante gSPECT. Obtener los valores de corte del VI para el índice de la forma telediastólica (iFTD), el índice de la forma telesistólica (iFTS), el índice de excentricidad (iEX) y la velocidad máxima de vaciado (VMV). Desarrollar un nuevo índice para evaluar diferentes patrones de función sistólica del VI. Material y métodos Analizamos prospectivamente 238 pacientes (edad: 63,4±13 años) estudiados mediante gSPECT de esfuerzo-reposo (grupo-control, n=148; pacientes con infarto de miocardio [IM] previo, n=90). Estudio aprobado por el Comité de Ética del Hospital (PR[AG]168.2010). Resultados En el grupo-control, el índice del volumen telediastólico (iVTD) y el iEX influyeron en el iFTD (r2: 0,52, p<0,001). El iVTD, la VMV, ser varones y el iEX (r2: 0,44; p<0,001) influyeron en el iFTS. El iFTD, iFTS, la fracción de eyección VI (FEVI) y el volumen de eyección sistólica (r2: 0,62; p<0,001) influyeron en el iEX. La FEVI, la frecuencia cardíaca, el ancho de banda (AB) y la desviación estándar influyeron (r2: 0,76; p<0,001) en la VMV. Los valores de corte para iFTD, iFTS, iEX y VMV fueron 0,59, 0,42, 0,87 y −3,3 respectivamente. La VMV, el iFTS y el AB fueron los parámetros mejor relacionados con los pacientes con IM previo (AUC: 0,89), y sumados a la FEVI permitieron obtener distintos patrones de función sistólica (índice PERRS). Conclusiones Los parámetros de remodelado, sincronía y función sistólica del VI deben interpretarse simultáneamente, ya que esto permite obtener distintos patrones de función sistólica del VI (AU)

Introduction and objectives The aim of this study is to assess the relationship between structural, remodeling, synchrony, and systolic left ventricular (LV) function parameters using gated-SPECT myocardial-perfusion-images (gSPECT-MPI). In addition, obtaining the cut-off values for end-diastolic LV-shape-index (EDLVsi), end-systolic LV-shape-index (ESLVsi), ECC (eccentricity-index) and PER, and developing a new index to evaluate different patterns of the LV systolic function. Methods The study was approved by the Hospital's Ethical-Committee (PR[AG]168.2010), and all patients gave their informed consent. We analyzed prospectively 238 patients (age 63.4±13 years) who underwent stress-rest gSPECT-MPI (control-group, n=148; patients with previous myocardial infarction [MI], n=90). Results In the control group, with regard to remodeling parameters: the end-diastolic-volume-index (EDV) and the ECC were the parameters that influenced the EDLVsi (r2: 0.52, P<.001). EDV, PER, men, and the ECC were the parameters (r2: 0.44; P<.001) which influenced the ESLVsi. EDLVsi, ESLVsi, LVEF and the stroke-volume were the parameters (r2: 0.62; P<.001) which influenced the ECC. With regards to PER: LVEF, heart-rate, bandwidth, and the standard-deviation were the influencing parameters (r2: 0.76; P<.001). The cut-off values for EDLVsi, ESLVsi, ECC, and PER were 0.59, 0.42, 0.87, and 3.3, respectively. The PER, the ESLVsi and the bandwidth were the parameters related to patients with previous MI (AUC: 0.89); and they allow the assessment of different patterns of systolic function (PERRS-index: Peak-Emptying-Rate, left ventricular-Remodeling and Synchrony). Conclusions The remodeling, synchrony and the systolic function parameters of the LV should be interpreted together (PERRS-index). In this way, we obtain different patterns of LV systolic function (AU)

Integration of ventricular remodeling, synchrony and filling rate parameters to improve the assessment of left ventricular systolic function.

INTRODUCTION AND OBJECTIVES: The aim of this study is to assess the relationship between structural, remodeling, synchrony, and systolic left ventricular (LV) function parameters using gated-SPECT myocardial-perfusion-images (gSPECT-MPI). In addition, obtaining the cut-off values for end-diastolic LV-shape-index (EDLVsi), end-systolic LV-shape-index (ESLVsi), ECC (eccentricity-index) and PER, and developing a new index to evaluate different patterns of the LV systolic function. METHODS: The study was approved by the Hospital's Ethical-Committee (PR[AG]168.2010), and all patients gave their informed consent. We analyzed prospectively 238 patients (age 63.4 ±â€¯13 years) who underwent stress-rest gSPECT-MPI (control-group, n = 148; patients with previous myocardial infarction [MI], n = 90). RESULTS: In the control group, with regard to remodeling parameters: the end-diastolic-volume-index (EDV) and the ECC were the parameters that influenced the EDLVsi (r2: 0.52, p < 0.001). EDV, PER, men, and the ECC were the parameters (r2: 0.44; p < 0.001) which influenced the ESLVsi. EDLVsi, ESLVsi, LVEF and the stroke-volume were the parameters (r2: 0.62; p < 0.001) which influenced the ECC. With regards to PER: LVEF, heart-rate, bandwidth, and the standard-deviation were the influencing parameters (r2: 0.76; p < 0.001). The cut-off values for EDLVsi, ESLVsi, ECC, and PER were 0.59, 0.42, 0.87, and 3.3, respectively. The PER, the ESLVsi and the bandwidth were the parameters related to patients with previous MI (AUC: 0.89); and they allow the assessment of different patterns of systolic function (PERRS-index: peak-emptying-rate, left ventricular-remodeling and synchrony). CONCLUSIONS: The remodeling, synchrony and the systolic function parameters of the LV should be interpreted together (PERRS-index). In this way, we obtain different patterns of LV systolic function.

Comparison of methods to homogenize ricotta cheese samples for total solids determination.

Ricotta cheese is an Italian dairy product obtained by heat-coagulation of the proteins in whey, resulting from cheese production. The homogenization method applied to collect ricotta cheese samples could affect the total solids (TS) contents of the products. The aim of this study was to determine the effects of 5 different homogenization methods of the samples collection applied for the accuracy in TS determination in ricotta cheese, including un-homogenized method (UNH), un-homogenized combined with the Ultra-Turrax (IKA-Werke GmbH & Co. KG) method (UNH-UTX), spoon-homogenized method (SPN), spoon-homogenized combined with Ultra-Turrax method (SPN-UTX), and Ultra-Turrax homogenized method (UTX). The repeatability and the standard deviation of repeatability are indicators of agreement between repeated measures for TS contents. Results reported that UNH ricotta cheese samples showed large variation in TS content with values ranging from 18.31% to 25.85% and a standard deviation of repeatability higher than 1%; SPN samples showed repeatability values higher than 0.35% and standard deviation of repeatability ranged until 1.36%, suggesting large variability even in this case; the Ultra-Turrax homogenization reported repeatability values lower than 0.1% and standard deviation of repeatability lower than 0.05%, indicating that this method provides repeatable measurements that may reduce the sources of uncertainty in TS determination.

Effect of dietary tannin supplementation on cow milk quality in two different grazing seasons.

Extensive farming systems are characterized by seasons with different diet quality along the year, as pasture availability is strictly depending on climatic conditions. A number of problems for cattle may occur in each season. Tannins are natural polyphenolic compounds that can be integrated in cows' diet to overcome these seasonal problems, but little is known about their effect on milk quality according to the season. This study was designed to assess the effects of 150 g/head × day of tannin extract supplementation on proximate composition, urea, colour, cheesemaking aptitude, antioxidant capacity, and fatty acid (FA) profile of cow milk, measured during the wet season (WS) and the dry season (DS) of Mediterranean climate. In WS, dietary tannins had marginal effect on milk quality. Conversely, in DS, the milk from cows eating tannins showed 10% lower urea and slight improvement in antioxidant capacity, measured with FRAP and TEAC assays. Also, tannin extract supplementation in DS reduced branched-chain FA concentration, C18:1 t10 to C18:1 t11 ratio and rumenic to linoleic acid ratio. Tannins effect on rumen metabolism was enhanced in the season in which green herbage was not available, probably because of the low protein content, and high acid detergent fibre and lignin contents in diet. Thus, the integration of tannin in the diet should be adapted to the season. This could have practical implications for a more conscious use of tannin-rich extracts, and other tannin sources such as agro-industrial by-products and forages.

Coste-efectividad de la SPECT de perfusión miocárdica y de la prueba de esfuerzo en relación con la revascularización coronaria, eventos cardíacos y mortalidad total. Registro de 8.496 pacientes / Cost-effectiveness of myocardial perfusion SPECT and stress test according to coronary revascularization therapy, cardiac events and total mortality: Register of 8,496 patients

OBJETIVO: Análisis de la relación coste-efectividad (RCE) del electrocardiograma de esfuerzo y de la SPECT de perfusión miocárdica esfuerzo-reposo en relación con la revascularización coronaria (RC), eventos cardíacos (EC) y mortalidad total (MT). MATERIAL Y MÉTODOS: Se estudiaron 8.496 pacientes con SPECT y seguimiento medio de 5,3±3,5años. Evaluamos la RCE para la RC quirúrgica (RCQ) y percutánea (RCP) (45,6%/54,4%) de acuerdo con los resultados de la isquemia electrocardiográfica y gammagráfica. La efectividad se evaluó como MT, EC, LYSO (life-year-saved-observed) y EC-LYSO. Los análisis de costes se realizaron desde la perspectiva del pagador de atención médica. El análisis de sensibilidad fue considerando las relaciones RCQ/RCP actuales (12%/88%). RESULTADOS: Al combinar los resultados del electrocardiograma de esfuerzo y de la gammagrafía, los valores de coste-efectividad para la RCQ variaron entre 112.589€ (isquemia electrocardiográfica y gammagráfica) y 2.814.715€ (sin isquemia)/evento evitado, y entre 38.664 y 2.221.559€/LYSO; y para la RCP entre 18.824€ (isquemia electrocardiográfica y gammagráfica) y 46.377€ (sin isquemia)/evento evitado, y entre 6.464 y 36.604€/LYSO. Para el EC: los valores de coste-efectividad de la RCQ y RCP en presencia de isquemia electrocardiográfica y gammagráfica fueron de 269.904€/EC evitado y de 24.428€/EC evitado, respectivamente; y los €/LYSO de la RCQ y RCP fueron de 152.488 y 13.801, respectivamente. Se mantuvo la misma RCE para la proporción actual de pacientes revascularizados (12%/88%). CONCLUSIONES: El análisis combinado de las imágenes de la SPECT y del electrocardiograma de esfuerzo permite la diferenciación entre grupos de pacientes en donde la RCP y la RCQ son más rentables. La mayor RCE en relación con la RC, EC y MT se da en los pacientes con isquemia electrocardiográfica y gammagráfica. La RCP es más coste-efectiva que la RCQ

OBJECTIVE: The aim was to analyze the cost-effectiveness ratio (CER) of stress electrocardiogram (ES) and stress myocardial perfusion imaging (SPECT-MPI) according to coronary revascularization (CR) therapy, cardiac events (CE) and total mortality (TM). MATERIAL AND METHODS: A total of 8,496 consecutive patients who underwent SPECT-MPI were followed-up (mean 5.3±3.5years). Cost-effectiveness for coronary bypass (CABG) or percutaneous CR (PCR) (45.6%/54.4%) according to combined electrocardiographic ischemia and scintigraphic ischemia were evaluated. Effectiveness was evaluated as TM, CE, life-year saved observed (LYSO) and CE-LYSO; costs analyses were conducted from the perspective of the health care payer. A sensitivity analysis was performed considering current CABG/PCR ratios (12%/88%). RESULTS: When electrocardiogram and SPECT approaches are combined, the cost-effectiveness values for CABG ranged between 112,589€ (electrocardiographic and scintigraphic ischemia) and 2,814,715€ (without ischemia)/event avoided, 38,664 and 2,221,559€/LYSO; for PCR ranged between 18,824€ (electrocardiographic and scintigraphic ischemia) and 46,377€ (without ischemia)/event avoided, 6,464 and 36,604€/LYSO. To CE: the cost-effectiveness values of the CABG and CPR in presence of electrocardiographic and scintigraphic ischemia were 269,904€/CE-avoided and 24,428€/CE-avoided, respectively; and the €/LYSO of the CABG and PCR were 152,488 and 13,801, respectively. The RCE was maintained for the current proportion of revascularized patients (12%/88%). CONCLUSIONS: Combined ES and SPECT-MPI results, allows differentiation between patient groups, where the PCR and CABG are more cost-effective in different economic frameworks. The major CER in relation to CR, CE and TM occurs in patients with electrocardiographic and scintigraphic ischemia. PCR is more cost-effective than CABG

KRD (carfilzomib and lenalidomide plus dexamethasone) for the treatment of relapsed or refractory multiple myeloma in the real-life: a retrospective survey in 123 patients.

From April 2016, carfilzomib, in combination with lenalidomide and dexamethasone (KRD), became available for use in the daily practice in Italy for patients with relapsed or refractory multiple myeloma (RRMM). We performed a retrospective survey at 14 different institutions from Southern Italy in order to evaluate patient characteristics and treatment results from an unselected series of patients treated accordingly so far. One hundred and twenty-three consecutive patients were included, with a median of 2 previous lines of therapy (range 1-9) and a median age of 63 years (range 39-82). At the time of analysis, median number of courses administered is 11 (range 1-34), and all patients are evaluable for response. Overall response rate including complete remission, very good partial remission, and partial remission is 85%. After a median follow-up of 27 months, median overall and progression-free survival are 33 and 23 months, respectively. Sixty-three patients are alive and between them, 45 (37%) are in continuous remission. Sixty patients have died (49%), mainly from progressive disease. There were 6 treatment-related deaths (5% of the whole patient population). Overall, hematological and non-hematological toxicity were manageable, mostly on outpatient basis. Arterial hypertension has been observed in 43 cases (35%) but did not lead to treatment interruption. Our data demonstrate that in real life, KRD is highly effective and well tolerated in the majority of patients with RRMM.

Cost-effectiveness of myocardial perfusion SPECT and stress test according to coronary revascularization therapy, cardiac events and total mortality: Register of 8,496 patients. / Coste-efectividad de la SPECT de perfusión miocárdica y de la prueba de esfuerzo en relación con la revascularización coronaria, eventos cardíacos y mortalidad total. Registro de 8.496 pacientes.

OBJECTIVE: The aim was to analyze the cost-effectiveness ratio (CER) of stress electrocardiogram (ES) and stress myocardial perfusion imaging (SPECT-MPI) according to coronary revascularization (CR) therapy, cardiac events (CE) and total mortality (TM). MATERIAL AND METHODS: A total of 8,496 consecutive patients who underwent SPECT-MPI were followed-up (mean 5.3±3.5years). Cost-effectiveness for coronary bypass (CABG) or percutaneous CR (PCR) (45.6%/54.4%) according to combined electrocardiographic ischemia and scintigraphic ischemia were evaluated. Effectiveness was evaluated as TM, CE, life-year saved observed (LYSO) and CE-LYSO; costs analyses were conducted from the perspective of the health care payer. A sensitivity analysis was performed considering current CABG/PCR ratios (12%/88%). RESULTS: When electrocardiogram and SPECT approaches are combined, the cost-effectiveness values for CABG ranged between 112,589€ (electrocardiographic and scintigraphic ischemia) and 2,814,715€ (without ischemia)/event avoided, 38,664 and 2,221,559€/LYSO; for PCR ranged between 18,824€ (electrocardiographic and scintigraphic ischemia) and 46,377€ (without ischemia)/event avoided, 6,464 and 36,604€/LYSO. To CE: the cost-effectiveness values of the CABG and CPR in presence of electrocardiographic and scintigraphic ischemia were 269,904€/CE-avoided and 24,428€/CE-avoided, respectively; and the €/LYSO of the CABG and PCR were 152,488 and 13,801, respectively. The RCE was maintained for the current proportion of revascularized patients (12%/88%). CONCLUSIONS: Combined ES and SPECT-MPI results, allows differentiation between patient groups, where the PCR and CABG are more cost-effective in different economic frameworks. The major CER in relation to CR, CE and TM occurs in patients with electrocardiographic and scintigraphic ischemia. PCR is more cost-effective than CABG.

Inflammation and oxidative stress transcription profiles due to in vitro supply of methionine with or without choline in unstimulated blood polymorphonuclear leukocytes from lactating Holstein cows.

Neutrophils are the most important polymorphonuclear leukocytes (PMNL), representing the front-line defense involved in pathogen clearance upon invasion. As such, they play a pivotal role in immune and inflammatory responses. Isolated PMNL from 5 mid-lactating Holstein dairy cows were used to evaluate the in vitro effect of methionine (Met) and choline (Chol) supplementation on mRNA expression of genes related to the Met cycle and innate immunity. The target genes are associated with the Met cycle, cell signaling, inflammation, antimicrobial and killing mechanisms, and pathogen recognition. Treatments were allocated in a 3 × 3 factorial arrangement, including 3 Lys-to-Met ratios (L:M, 3.6:1, 2.9:1, or 2.4:1) and 3 levels of supplemental Chol (0, 400, or 800 µg/mL). Three replicates per treatment group were incubated for 2 h at 37°C and 5% atmospheric CO2. Both betaine-homocysteine S-methyltransferase and choline dehydrogenase were undetectable, indicating that PMNL (at least in vitro) cannot generate Met from Chol through the betaine pathway. The PMNL incubated without Chol experienced a specific state of inflammatory mediation [greater interleukin-1ß (IL1B), myeloperoxidase (MPO), IL10, and IL6] and oxidative stress [greater cysteine sulfinic acid decarboxylase (CSAD), cystathionine gamma-lyase (CTH), glutathione reductase (GSR), and glutathione synthase (GSS)]. However, data from the interaction L:M × Chol indicated that this negative state could be overcome by supplementing additional Met. This was reflected in the upregulation of methionine synthase (MTR) and toll-like receptor 2 (TLR2); that is, pathogen detection ability. At the lowest level of supplemental Chol, Met downregulated GSS, GSR, IL1B, and IL6, suggesting it could reduce cellular inflammation and enhance antioxidant status. At 400 µg/mL Chol, supplemental Met upregulated PMNL recognition capacity [higher TLR4 and L-selectin (SELL)]. Overall, enhancing the supply of methyl donors to isolated unstimulated PMNL from mid-lactating dairy cows leads to a low level of PMNL activation and upregulates a cytoprotective mechanism against oxidative stress. Enhancing the supply of Met coupled with adequate Chol levels enhances the gene expression of PMNL pathogen-recognition mechanism. These data suggest that Chol supply to PMNL exposed to low levels of Met effectively downregulated the entire repertoire of innate inflammatory-responsive genes. Thus, Met availability in PMNL during an inflammatory challenge may be sufficient for mounting an appropriate biologic response.

The effects of superoxide dismutase-rich melon pulp concentrate on inflammation, antioxidant status and growth performance of challenged post-weaning piglets.

Piglets can often suffer impaired antioxidant status and poor immune response during post-weaning, especially when chronic inflammation takes place, leading to lower growth rates than expected. Oral administration of dietary antioxidant compounds during this period could be a feasible way to balance oxidation processes and increase health and growth performance. The aim of the trial was to study the effects of an antioxidant feed supplement (melon pulp concentrate) that contains high concentration of the antioxidant superoxide dismutase (SOD) on inflammation, antioxidant status and growth performance of lipopolysaccharide (LPS) challenged weaned piglets. In total, 48 weaned piglets were individually allocated to four experimental groups in a 2×2 factorial design for 29 days. Two different dietary treatments were adopted: (a) control (CTR), fed a basal diet, (b) treatment (MPC), fed the basal diet plus 30 g/ton of melon pulp concentrate. On days 19, 21, 23 and 25 half of the animals within CTR and MPC groups were subjected to a challenge with intramuscular injections of an increasing dosage of LPS from Escherichia coli (serotype 0.55:B5) (+) or were injected with an equal amount of PBS solution (-). Blood samples were collected at the beginning of the trial and under the challenge period for interleukin 1ß, interleukin 6, tumour necrosis factor α, haptoglobin, plasma SOD activity, total antioxidant capacity, reactive oxygen species, red blood cells and plasma resistance to haemolysis, and 8-oxo-7, 8-dihydro-2'-deoxyguanosine. Growth performance was evaluated weekly. A positive effect of melon pulp concentrate was evidenced on total antioxidant capacity, half-haemolysis time of red blood cells, average daily gain (ADG) and feed intake, while LPS challenge increased pro-inflammatory cytokines and haptoglobin serum concentrations, with a reduced feed intake and gain : feed (G : F). The obtained results show that oral SOD supplementation with melon pulp concentrate ameliorates the total antioxidant capacity and the half-haemolysis time in red blood cell of post-weaning piglets, with positive results on growing performance.

Localized morphea after breast implant for breast cancer: A case report.

PURPOSE: Early breast cancer follow-up guidelines for patients who underwent surgery suggest a regular and accurate clinical examination of the breast area, for an early identification of cutaneous or subcutaneous breast cancer relapse. Nonetheless, breast skin lesions arising in patients treated with mastectomy for breast cancer can be caused by several diseases. A series of diagnostic hypotheses should be considered, not only focusing on cutaneous metastasis, but also on dermatologic and systemic diseases. CASE REPORT: In February 2015, a 37-year-old patient underwent a right subcutaneous mastectomy for stage IIA breast cancer. Five months after beginning adjuvant chemotherapy, she noted hyperpigmentation and thickening of the skin on the right breast. Differential diagnosis included local relapse, skin infection, lymphoma, or primary cutaneous disease, and a skin biopsy was performed. The histopathologic specimen showed full-thickness sclerosis, with features of localized morphea. Therapy with clobetasol was prescribed, with progressive resolution of the thickness. The collaboration between many professionals in a multidisciplinary team (oncologist, dermatologist, plastic surgeon, and pathologist) was crucial to achieving the diagnosis. CONCLUSION: In the literature, some articles describe correlation between connective tissue diseases and silicone breast implants, but the pathogenetic mechanisms are unknown. We report a rare case of breast morphea after positioning a silicone implant in a patient who had undergone mastectomy. This clinical report represents an interesting model of multidisciplinary management of a patient with breast cancer who developed an uncommon dermatologic disease. Further studies are needed to clarify the association between silicone implants and breast morphea.

Epstein-Barr virus lytic infection promotes activation of Toll-like receptor 8 innate immune response in systemic sclerosis monocytes.

BACKGROUND: Monocytes/macrophages are activated in several autoimmune diseases, including systemic sclerosis (scleroderma; SSc), with increased expression of interferon (IFN)-regulatory genes and inflammatory cytokines, suggesting dysregulation of the innate immune response in autoimmunity. In this study, we investigated whether the lytic form of Epstein-Barr virus (EBV) infection (infectious EBV) is present in scleroderma monocytes and contributes to their activation in SSc. METHODS: Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) depleted of the CD19+ cell fraction, using CD14/CD16 negative-depletion. Circulating monocytes from SSc and healthy donors (HDs) were infected with EBV. Gene expression of innate immune mediators were evaluated in EBV-infected monocytes from SSc and HDs. Involvement of Toll-like receptor (TLR)8 in viral-mediated TLR8 response was investigated by comparing the TLR8 expression induced by infectious EBV to the expression stimulated by CL075/TLR8/agonist-ligand in the presence of TLR8 inhibitor in THP-1 cells. RESULTS: Infectious EBV strongly induced TLR8 expression in infected SSc and HD monocytes in vitro. Markers of activated monocytes, such as IFN-regulated genes and chemokines, were upregulated in SSc- and HD-EBV-infected monocytes. Inhibiting TLR8 expression reduced virally induced TLR8 in THP-1 infected cells, demonstrating that innate immune activation by infectious EBV is partially dependent on TLR8. Viral mRNA and proteins were detected in freshly isolated SSc monocytes. Microarray analysis substantiated the evidence of an increased IFN signature and altered level of TLR8 expression in SSc monocytes carrying infectious EBV compared to HD monocytes. CONCLUSION: This study provides the first evidence of infectious EBV in monocytes from patients with SSc and links EBV to the activation of TLR8 and IFN innate immune response in freshly isolated SSc monocytes. This study provides the first evidence of EBV replication activating the TLR8 molecular pathway in primary monocytes. Immunogenicity of infectious EBV suggests a novel mechanism mediating monocyte inflammation in SSc, by which EBV triggers the innate immune response in infected cells.

EBV early lytic protein BFRF1 alters emerin distribution and post-translational modification.

The nuclear envelope (NE), a structural element of fundamental importance for the cell, is the first barrier that meets a virus in the early stages of viral maturation. Therefore, in order to allow the passage of nucleocapsids, viruses are known to modulate the architecture of the nuclear membrane to permit a proficient viral infection. Epstein-Barr Virus (EBV), a pathogen from Herpesvirus family, possesses two well conserved proteins, BFRF1 and BFLF2, which together form the heterodimeric nuclear egress complex (NEC) that is involved in the early steps of nuclear egress. Here we show that EBV replication causes the delocalization of emerin, a cellular LEM-domain protein normally distributed on the nuclear rim. We also demonstrate that the early lytic protein BFRF1 is responsible for emerin delocalization. Expression of BFRF1 alone or in combination with BFLF2 induces emerin hyperphosphorylation. Altogether, these results suggest a novel mechanism by which EBV exploits the cellular machinery for nucleocapsid egress.

Far-off and close-up dry matter intake modulate indicators of immunometabolic adaptations to lactation in subcutaneous adipose tissue of pasture-based transition dairy cows.

The common practice of increasing dietary energy density during the close-up dry period (last ∼3 wk prepartum) has been recently associated with a higher incidence of metabolic disorders after calving. Despite these reports, over-feeding of metabolizable energy (ME) during the far-off, nonlactating period is a common management policy aimed at achieving optimum calving body condition score (BCS) in pasture-based systems, as cows are generally thinner than total mixed ration cows at the end of lactation. Our hypothesis was that both far-off and close-up overfeeding influence the peripartum adipose tissue changes associated with energy balance and inflammatory state. Sixty mid-lactation, grazing dairy cows of mixed age and breed were randomly allocated to 1 of 2 groups that were managed through late lactation to achieve a low and high BCS (approximately 4.25 and 5.0 on a 10-point scale) at dry-off. The low BCS cows were then overfed ME to ensure that they achieved the same BCS as the higher BCS group by calving. Within each rate of BCS gain treatment, cows were offered 65, 90, or 120% of their pre-calving ME requirements for 3 wk pre-calving in a 2 × 3 factorial arrangement of treatments (i.e., 10 cows/treatment). Subcutaneous adipose tissue was collected via biopsy at -1, 1, and 4 wk relative to parturition. Quantitative PCR was used to measure mRNA and microRNA expression of targets related to adipogenesis and inflammation. Cows overfed in the far-off period had increased expression of miR-143 and miR-378 prepartum (-1 wk) indicating greater adipogenesis, consistent with their rapid gain in BCS following dry-off. Furthermore, the lower postpartum expression of IL6, TNF, TLR4, TLR9, and miR-145, and a higher abundance of miR-99a indicated lower body fat mobilization in early lactation in the same group. In the close-up period, feeding either 65 or 120% of ME requirements caused changes in FASN, IL1B, IL6R, TLR9, and the microRNA miR-143, miR-155, and miR-378. Their respective expression patterns indicate a tentative negative-feedback mechanism in metabolically compromised, feed-restricted cows, and a possible immune-related stimulation of lipolysis in apparently static adipocytes in overfed cows. Data from cows fed 90% of ME requirements indicate the existence of a balance between lipolytic (inflammatory-related) and anti-lipolytic signals, to prime the mobilization machinery in light of imminent lactation. Overall, results indicate that far-off dry cow nutrition influences peripartum adipose tissue metabolism, with neither strategy negatively affecting the physiological adaptation to lactation. Furthermore, to ensure a favorable transition, cows should be subjected to a small feed restriction in the close-up period, irrespective of far-off nutritional management.

Growth performance, carcass characteristics and meat composition of Milanino chickens fed on diets with different protein concentrations.

Milanino is a heavy Italian chicken breed included in a conservation project of the University of Milan and is an important genetic resource for alternative production systems. This research was aimed to study the effect of the dietary protein concentration on growth, slaughter performance and meat composition in free-range reared Milanino chickens. A total of 120 Milanino chickens were fed on different protein concentrations (HP = 20% CP and LP = 16% CP), reared according to a free-range system and slaughtered at 150 and 180 d of age. Growth, slaughter performance and meat (breast and thigh) composition were recorded. The protein concentration of the diet did not affect the overall Milanino mean body weight recorded in the straight-run group in the whole rearing period. However, the growth rate within sex was significantly different between the dietary treatments: heavier females were found in the HP group from 125 d onwards, while no differences were recorded in male body weights. The protein concentration of the diet did not affect carcass weight data or meat composition. The present results suggest the use of a low-protein diet for rearing straight-run Milanino chickens for long rearing periods. However, in females, a high-protein diet is recommended from 125 d of age onwards.

El patrón de discordancia motilidad-perfusión en la gated-SPECT de reposo sugiere necrosis no transmural en la resonancia magnética cardiaca / Motion-perfusion mismatch-pattern on rest-gated SPECT suggests non-transmural necrosis on cardiac magnetic resonance

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Fresh Insights into Disease Etiology and the Role of Microbial Pathogens.

Pathogens have been implicated in the initiation and/or promotion of systemic sclerosis (scleroderma, SSc); however, no evidence was found to substantiate the direct contribution to this disease in past years. Recently, significant advances have been made in understanding the role of the innate immune system in SSc pathogenesis, supporting the idea that pathogens might interact with host innate immune-regulatory responses in SSc. In light of these findings, we review the studies that identified the presence of pathogens in SSc, along with studies on pathogens implicated in driving the innate immune dysregulation in SSc. The goal of this review is to illustrate how these pathogens, specifically viruses, may play important role both as triggers of the innate immune system, and critical players in the development of SSc disease.

The HLA-B*35 allele modulates ER stress, inflammation and proliferation in PBMCs from Limited Cutaneous Systemic Sclerosis patients.

INTRODUCTION: HLA-B*35 is associated with increased risk of developing pulmonary hypertension in SSc patients. We previously reported that HLA-B*35 induces endothelial cell dysfunction via activation of ER stress/UPR and upregulation of the inflammatory response. Because PBMCs from lcSSc-PAH patients are also characterized by activation of ER stress/UPR and inflammation, the goal of this study was to assess whether the presence of HLA-B*35 contributes to those characteristics. METHODS: PBMCs were purified from healthy controls (n = 49 HC) and lcSSc patients, (n = 44 with PAH, n = 53 without PAH). PBMCs from each group were stratified for the presence of HLA-B*35. Global changes in gene expression in response to HLA-B*35, HLA-B*8 or empty lentivirus were investigated by microarray analysis in HC PBMCs. Total RNA was extracted and qPCR was performed to measure gene expression. RESULTS: ER stress markers, in particular the chaperones BiP and DNAJB1 were significantly elevated in PBMC samples carrying the HLA-B*35 allele. IL-6 expression was also significantly increased in HLA-B*35 lcSSc PBMCs and positively correlated with ER stress markers. Likewise, HMGB1 was increased in HLA-B*35-positive lcSSc PBMCs. Global gene expression analysis was used to further probe the role of HLA-B*35. Among genes downregulated by HLA-B*35 lentivirus were genes related to complement (C1QB, C1QC), cell cycle (CDNK1A) and apoptosis (Bax, Gadd45). Interestingly, complement genes (C1QC and C1QB) showed elevated expression in lcSSc without PAH, but were expressed at the low levels in lcSSc-PAH. The presence of HLA-B*35 correlated with the decreased expression of the complement genes. Furthermore, HLA-B*35 correlated with decreased expression of cyclin inhibitors (p21, p57) and pro-apoptotic genes (Bax, Gadd45) in lcSSc B35 subjects. FYN, a tyrosine kinase involved in proliferation of immune cells, was among the genes that were positively regulated by HLA-B*35. HLA-B*35 correlated with increased levels of FYN in lcSSc PBMCs. CONCLUSIONS: Our study demonstrates that HLA-B*35 contributes to the dysregulated expression of selected ER stress, inflammation and proliferation related genes in lcSSc patient PBMCs, as well as healthy individuals, thus supporting a pathogenic role of HLA-B*35 in the development of PAH in SSc patients.

Rice and soy protein isolate in pre-starter diets for broilers.

Although most industries use a specific diet for the pre-starter phase, ingredients are used in the later phases, primarily corn and soybean meal, which at this stage do not have high digestibility. Three experiments : Exp : were carried out to evaluate the substitution of corn by white or parboiled rice : WR, PR : and the inclusion of 6% soy protein isolate : SPI : in pre-starter diets (1 to 7 d). In Exp 1 (1 to 21 d), WR, PR, and SPI were added to the diets until the birds were 21-day-old, whereas in Exps 2 and 3 (1 to 33 d), only until birds were 7-day-old. Birds were fed a basal diet based on corn and soybean meal until the end of the experimental period. In Exp 1, the coefficients of total tract apparent retention : CTTAR : of the pre-starter and the starter diets, ileal and jejunal digestibility of starch in the starter diets, and broiler performance were measured. Subsequently, the same pre-starter diets Exp 1 were evaluated in pellet (Exp 2) or mash (Exp 3) form and different oil percentage (Exp 2) or not (Exp 3). We hypothesized that the ingredients particle size (Exp 2) and fat content (Exp 3) could influence feed intake. There was no interaction among the evaluated factors (P > 0.05). Rice (WR or PR) promoted better results than corn in terms of CTTAR of dietary components, jejunal and ileal starch digestibility, and broiler performance (P < 0.01). In Exp 1, diets with 6% SPI presented better CTTAR, except Nitrogen ( N: ), but lower feed intake, which negatively affected broiler performance (P < 0.01). In Exps 1, 2, and 3, the inclusion of SPI did not improve broiler performance (P > 0.05), so that SPI may not be the best choice for pre-starter diets. The study also suggests that better growth performance and nutrient digestibility can be obtained in broiler chickens if corn is replaced by rice in pre-starter diets.

Value of KRAS as prognostic or predictive marker in NSCLC: results from the TAILOR trial.

BACKGROUND: The prognostic and predictive role of KRAS mutations in advanced nonsmall-cell lung cancer (NSCLC) is still unclear. TAILOR prospectively assessed the prognostic and predictive value of KRAS mutations in NSCLC patients treated with erlotinib or docetaxel in second line. PATIENTS AND METHODS: NSCLC patients from 52 Italian hospitals were genotyped for KRAS and EGFR mutational status in two independent laboratories. Wild-type EGFR patients (N = 218) received first-line platinum-based chemotherapy and were randomly allocated at progression to erlotinib or docetaxel. Overall survival (OS) according to KRAS mutational status was the primary end point. RESULTS: KRAS mutations were present in 23% of TAILOR randomized cases. The presence of a KRAS mutation did not adversely affect progression-free (PFS) or overall (OS) survival [hazard ratio (HR) PFS = 1.01, 95% confidence interval (CI) 0.71-1.41, P = 0.977; OS = 1.24, 95% CI 0.87-1.77, P = 0.233], nor influenced treatment outcome (test for interaction: OS P = 0.965; PFS P = 0.417). Patients randomized to docetaxel treatment experienced longer survival independently from the KRAS mutational status of their tumors (HR: mutated KRAS 0.81, 95% CI 0.45-1.47; wild-type KRAS 0.79, 95% CI 0.57-1.10). CONCLUSION: In TAILOR, KRAS was neither prognostic nor predictive of benefit for either docetaxel or erlotinib. Docetaxel remains superior independently from KRAS status for second-line treatment in EGFR wild-type advanced NSCLC patients. CLINICAL TRIAL REGISTRATION: NCT00637910.