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Objectives: A recent debate in health economics and outcomes research community identified option value as one of the elements warranting consideration in the assessment of medical technologies. To conduct a scoping review of contributions on option value in the healthcare sector and identify relevant conceptual aspects and methods used to incorporate it in standard economic evaluations., Methods: A systematic search was conducted up to July 2020 to identify contributions from electronic bibliographic database and gray literature. Data on the proposed definitions of option value, theoretical implications of its use in economic evaluations, and methods used to estimate it were extracted and analyzed., Results: We found 57 eligible studies. Three different definitions emerged: insurance value, real option value, and option value of survival. Focusing on the latter (24 studies), we analyzed in depth 8 empirical applications across 7 therapeutic areas. The most relevant methodological challenges were on the perspective used in economic evaluations and how to robustly manage forecasting uncertainty, update cost-effectiveness thresholds, and avoid double-counting issues. For empirical studies assessing the total value of the technology, including option value, estimates ranged from +7% to +469% of its conventional value., Conclusions: This review synthesizes theoretical and empirical aspects on option value of healthcare technologies and proposes a terminology to distinguish 3 different concepts identified. Future work should focus primarily on agreeing on whether option value should be included in economic evaluations and, if so, on developing and validating reliable methods for its ex-ante estimation., (Copyright © 2021 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

The complexity of signal transduction resulting from the contact of human immunodeficiency virus type 1 (HIV-1)-infected cells and mucosal cells has hampered our comprehension of HIV-1 mucosal entry. Such process is driven efficiently only by viral synapse contacts, whereas cell-free HIV-1 remains poorly infectious. Using CD4 + T-cells expressing only HIV-1 envelope inoculated on human adult foreskin tissues, we designed methodologies to identify the signals transduced in foreskin keratinocytes following HIV-1-envelope-dependent viral synapse formation. We find that the viral synapse activates the MyD88-independent TLR-4-nuclear factor (NfκB) signaling pathway in keratinocytes and the subsequent secretion of cytokines including thymic stromal lymphopoietin (TSLP), a cytokine linking innate and T-helper type 2-adaptive immune responses. Moreover, the viral synapse upregulates the non-coding microRNA miR-375, known to control TSLP, and transfection of keratinocytes with anti-miR-375 blocks significantly TSLP secretion. Thus, the secretion of TSLP by keratinocytes is induced by the viral synapse in a miR-375 controlled manner. At the tissue level, these signals translate into the epidermal redistribution of Langerhans cells and formation of conjugates with T-cells, recapitulating the initial events observed in human foreskin infection by HIV-1. These results open new possibilities for designing strategies to block mucosal HIV-1 transmission, the major pathway by which HIV-1 spreads worldwide.

Objective: The pathophysiology of giant cell arteritis (GCA) and the mechanisms underlying vascular remodeling, are poorly understood. We aimed to compare vascular smooth muscle cells (VSMCs) from patients with GCA and controls by a proteomic and gene expression profile approach and to identify the signaling pathways involved in proliferation., Methods: VSMCs were cultured from temporal artery biopsies (TABs) from patients with biopsy-proven GCA (TAB + -GCA), biopsy-negative GCA (TAB - -GCA), and diagnosis other than GCA (GCA-control). VSMCs from normal human aorta (HAoSMC) were used as controls. 2D-differential in-gel electrophoresis and Affymetrix chips were used to compare proteomes and gene expression profiles of VSMCs. Proliferation was assessed by BrdU incorporation assay. TAB + -GCA and GCA-control TABs underwent immunohistochemistry staining for endothelin-1 (ET-1) and receptors ET A R and ET B R., Results: We identified 16, 30 and 2 protein spots differentially expressed between TAB + -GCA and GCA-control VSMCs, TAB + -GCA and TAB - -GCA VSMCs and TAB - -GCA and GCA-control VSMCs, respectively (fold change ≥1.5 and p≤0.05). Among the 153 proteins differentially expressed between TAB + -GCA and HAoSMC VSMCs, many were linked with ET-1. Genes differentially expressed between TAB + -GCA and GCA-control VSMCs were involved in proliferation. ET-1 was identified as a link between genes of interest. Proliferation was reduced for TAB + -GCA VSMCs on treatment with the endothelin antagonist macitentan and its active metabolite. Patients showing transmural expression of ET-1 in temporal artery lesions received a significantly higher glucocorticoid daily dose after 6-month follow-up., Conclusion: Inhibiting the proliferation with macitentan, combined with glucocorticoids, might be a promising therapeutic approach for patients with GCA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this article was to compare plasma estrone sulfate (E1SO4), clinical biochemistry, and milk yield of dairy cows carrying a female fetus from a bull (BULL) or from its clone (CLONE), evaluating also the relationship between the former variables and the birth weight of the newborn. Sixteen recipient dairy Friesian heifers (10 BULL and 7 CLONE) received a female embryo, obtained by in vitro embryo production and sexing by polymerase chain reaction with the semen of the BULL or the CLONE. Blood samples on all cows were obtained before feed distribution in the morning from jugular vein from 4 weeks before to 4 weeks after calving, to be analyzed for metabolic profile. The samples from late gestation were also analyzed for E1SO4 concentration. To separately assess the effect of calf birth weight (CBW), data were categorized as follows: low (<39 kg; BWT-A), mid (39-46 kg; BWT-B), and high (>46 kg; BWT-C). The plasma concentrations of β-hydroxybutyric acid (BHB, P=0.019), Na (P=0.002), Cl (P=0.026), strong cation-anion balance (P=0.020), total bilirubin (P=0.054), and α1-globulin (P=0.044) were higher in prepartum BULL recipients than those in CLONE, whereas BHB (P=0.021) and Mg (P=0.090) were higher in postpartum BULL recipients, while no differences were recorded in the remaining postpartum parameters. The CBW class had significant interaction with week of gestation on antepartum plasma estrone sulfate (P=0.021), whereas CBW per se affected antepartum plasma BHB (P=0.021), and nonesterified fatty acids (NEFA; P=0.011) being higher in BWT-C which also had the lower NEFA concentration during postpartum. Milk yield was unaffected by the sire used, both for quantitative and qualitative aspects. Cows carrying heavier fetus (BWT-C) had a different lactation affected by month compared with the other 2 CBW groups. From these results, there were no differences between BULL and CLONE recipients. Estrone sulfate, BHB, and NEFA may be used to predict CBW and provide different nutritional management during gestation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The aim of this paper was to compare body growth, hematological profile development, and clinical biochemistry in the female progeny of a sire with the female progeny of its clone. Sixteen Friesian female calves, 9 daughters from a tested bull (BULL) and 7 from its somatic cell nuclear transfer clone (CLONE) were monitored from birth to 60 wk of life. Body weight (BW), wither height (WH), hip height (HH), body length (BL), and hearth girth (HG) were measured at birth and 4, 8, 12, 16, 20, 24, 36, and 50 wk. Blood samples were taken from jugular vein at 12 to 48 h from birth and 1, 2, 3, 4, 8, 12, 16, 20, 24, and 36 wks of age, to be analyzed for hematological, serum protein, and metabolic profiles. At the same time, rectal temperature (RT) was recorded. Age at puberty was assessed on surviving heifers by measuring weekly plasma progesterone levels. Data were evaluated using a mixed model, taking into account the repeated measures in time on the calf. For each variable, different covariance structures were tested, choosing the best according to the Akaike's Information Criteria. Significant was set at P < 0.05, and a trend was considered for P < 0.10. At 24 wk of age, WH was lower in CLONE daughters than BULL daughters. Around 20 wk of age, there was a trend for lower BW in CLONE daughters than BULL daughters, confirmed from differences in HG. There was no difference in RT due to sire effect. Blood glucose concentration decreased in both groups during the first 4 wk of life; at birth, only a trend for higher blood glucose in CLONE daughters was recorded, whereas an opposite trend was observed for plasma creatinine. Total leukocyte count did not differ between progenies. Circulating lymphocytes tended to be lower in CLONE than BULL daughters. The neutrophil: lymphocyte ratio tended to be higher in CLONE than BULL calves. No difference was demonstrated for erythrocyte features, whereas mean platelet volume tended to be lower in CLONE than BULL progeny. From these results, there were no differences between progenies from BULL and its clone that suggest welfare problems in the first 6 mo of life., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Cigarette smoking is a powerful risk factor for coronary artery disease (CAD), leading to the formation of DNA alterations within blood vessels and heart. However, the degree of smoking-related atherosclerosis varies from individual to individual. Genetic polymorphisms of relevant xenobiotic metabolising enzymes may determine the susceptibility of an individual response to environmental toxicants. The purpose of this study was to test the hypothesis that the inheritance of polymorphic genes encoding cytochrome P450 1A1 (CYP1A1 MspI) and glutathione S-transferases (GSTM1(null) and GSTT1(null)) may be causally associated with the presence and severity of smoking-induced CAD. In a case-only design, 222 (179 male, 57.8+/-10.3 years) consecutive smoker patients who had undergone elective and diagnostic coronary angiography were recruited. We found a group (n=169) of smoker patients with significant CAD, defined as>50% reduction in diameter of at least one major vessel, and a group without obstructive CAD (n=53). No significant differences were observed in CYP1A1 genotypes frequencies between CAD and non-CAD smokers (p=0.1). Homozygous deletion of GSTM1 had a frequency of 58.6% among patients with CAD and 45.3% among those without CAD (p=0.08). The frequency of the GSTT1(null) genotype was 43.8% among the patients with CAD and 24.5% among CAD-free subjects (p=0.01). After adjustment for traditional risk factors, the presence of combined GSTM1(null)GSTT1(null) genotypes was significantly associated with an increased risk of CAD (OR=3.9; 95% CI: 1.3-11.4, p=0.01). Moreover, smokers with combined GSTM1(null)GSTT1(null) genotypes had significantly higher number of stenosed vessels than those with the positive genotype (2.3+/-0.9 versus 1.7+/-0.8, p=0.03). Our findings showed that smokers carrying GST deleted genotypes have an increased susceptibility to the smoking related coronary artery disease. Exploring gene-smoking effect provides an excellent model in order to understand gene-environment toxicants interaction and its implications to cardiovascular disease.

To assess the impact of acute caloric shortage on reproduction, rabbit does were either fed ad libitum (control, AL), or fasted for 24 (STF) or 48 h (LTF) before induction of ovulation with GnRH injection. Blood samples were collected during the last 3 h of fasting, and the following 4 h after GnRH injection, when feed was provided again, to measure plasma concentrations of LH, estradiol-17beta, leptin, insulin, T3, corticosterone, glucose, and NEFA. Before re-feeding, plasma leptin, insulin, and T3 concentrations were lower (P < or = 0.01) in both fasted groups than in controls, but then gradually increased following realimentation to match those of controls. During fasting, corticosterone levels were higher (P < or = 0.01) in LTF than in STF and AL does, but decreased to control values soon after realimentation. During fasting, plasma glucose concentrations did not differ among groups, but upon re-feeding they markedly increased (P < or= 0.01) both in STF and LTF does. NEFA levels were also more elevated (P < or = 0.01) in fasted rabbits than in controls, and rapidly decreased (P < or = 0.01) after re-feeding. Following GnRH injection, LH peak was lower (P < or = 0.01) in LTF than in AL and STF does. Estradiol-17beta showed higher pulse frequency and amplitude in AL than in STF and LTF does. Compared to controls, receptivity rate of STF and LTF artificially inseminated does declined respectively by -20.5% (P < or = 0.05) and -22.7%, and fertility rate by -23.9% (P < or = 0.05) and 21.4%, but no difference was found in ovulation rate. In summary, nutritional status of does, as modified by fasting, greatly influenced fertility, metabolic and reproductive hormones.

Major advances in Human Genome research could significantly change the clinical medical practice, providing new possibilities for both diagnosing and treating common pathologies. Many genetic tests are now commercially available for predicting future risk of common disorders. However, genetic testing has potential benefits but also limitations for the patients, and it should not be used to 'screen' the general population. Diagnostic assays for a predisposition of both venous and arterial thrombosis are among the most requested genetic tests in molecular diagnostics laboratories. However, there is considerable uncertainty as to how this information should be utilized in patient management. Both the medical community and the patients need to obtain accurate information concerning the appropriate use of genetic testing. The purpose of this article is to discuss the usefulness and the practical applications of thrombotic genetic testing in order to define which patients should be tested for both venous and arterial thrombotic risk as well as to have an acceptable cost/benefit ratio and to prevent patients' anxiety.

Recent evidence suggests that somatic mutations in nuclear and mitochondrial DNA accumulated during aging, may significantly contribute to the pathogenesis of chronic-degenerative illness such as coronary artery disease (CAD). Mitochondrial DNA with 4977 bp deletion mutation (mtDNA4977) is a common type of mtDNA alteration in humans. However, little attempt has been made to detect the presence of mtDNA4977 deletion in cells and tissues of cardiovascular patients. This study investigated the presence of mtDNA4977 in blood samples of 65 cardiovascular patients and 23 atherosclerotic plaques of human coronaries with severe atherosclerosis. Moreover, the presence of the deletion has been investigated in blood cells from 22 healthy age-matched subjects. The detection of mtDNA4977 has been performed by using a nested polymerase chain reaction (PCR) protocol and normalized to wild-type mtDNA. A significant higher incidence of mtDNA4977 was observed in CAD patients with respect to healthy subjects (26.2% versus 4.5%; P=0.03). Furthermore, the relative amount of the deletion was significantly higher in the patients compared to the control group (P=0.02). The mtDNA4977 was detected in 17 of the 65 patients blood samples (26.2%) and deletion levels ranged from 0.18 to 0.46% of the total mtDNA (mean: 0.34+/-0.02%). For what concerns atherosclerotic lesions, 5 patients (21.7%) showed the deletion ranging from 0.13 to 0.45% of the total mtDNA (mean: 0.35+/-0.06%). In both samples from patients, the incidence and the relative amount of mtDNA4977 was not significantly influenced by atherogenic risk factors and clinical parameters. The obtained results may suggest that the increase of oxidative stress in cardiovascular disease may be responsible for the accumulation of mtDNA damage in coronary artery disease patients.

Background: A common point mutation (C677T) in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with hyperhomocysteinemia, an independent risk factor and a strong predictor of mortality in patients with coronary artery disease (CAD). The aim of this study was to investigate whether C677T polymorphism can be a predictor of major adverse cardiac events after myocardial revascularization., Methods: We determined MTHFR genotype in 159 patients with CAD undergoing myocardial revascularization [72 percutaneous transluminal coronary angioplasty (PTCA) and 87 coronary artery bypass graft (CABG)]. Recurrent angina, nonfatal myocardial infarction (MI), target vessel revascularization, heart failure and cardiac death were considered major adverse cardiac events that occurred after discharge from index hospitalization., Results: During the follow-up (6.9+/-0.3 months, mean+/-S.E.M.), the composite endpoint accounted for 25.9%, 11.4% and 4.3% for TT, CT and CC genotype (log-rank statistic 5.2, p=0.02), respectively. Subjects with mutant TT genotype had a threefold increase of any cardiac event (hazard ratio [HR]=3.0; 95% [CI], 1.1-8.1). In multiple-variable regression Cox, predictors of events were TT genotype (HR=2.8; 95% CI, 1.01-7.62, p=0.047), low-ejection fraction<40% (HR=4.5; 95% CI, 1.62-12.6, p=0.004) and revascularization procedure (HR=6.1; 95% CI, 1.86-20.34, p=0.003)., Conclusions: These data indicate that the TT genotype seems to be significantly associated with major adverse cardiac events after myocardial revascularization in CAD patients, suggesting a potential pathological influence of homocysteine in the clinical outcome.

The NMR-MOUSE is a mobile sensor for single-sided NMR inspection of organic materials which takes advantage of the principles of magnetic resonance and inside-out-NMR. Historical books dating from the 17th century were measured at different points by positioning the NMR-MOUSE on the paper. Different degrees of paper degradation can be discriminated from the regularized inverse Laplace transform of the envelope of the acquired echo signals. For the first time the degradation of historical paper was characterized entirely nondestructively by NMR. As a contribution to current preservation efforts, NMR shows great promise for future use in damage assessment of historical documents.

Human muscle-specific calpain (CAPN3) was expressed in two heterologous systems: Sf9 insect cells and Escherichia coli cells. Polyclonal antibodies were prepared against peptides whose sequences were taken from the three unique regions of human CAPN3, namely NS, IS1, and IS2, which are not found in other members of the calpain family. Western blot analysis using these antibodies revealed that CAPN3 was well expressed in both systems. However, considerable rapid degradation of the expressed CAPN3 was observed in both Sf9 and E. coli cells. These antibodies were therefore also used to detect CAPN3 and its degradation products in human and rat muscles, as well as to detect the protein throughout the purification of the recombinant His-tagged human CAPN3 by Ni2+ affinity chromatography and by immunopurification over immobilized antibody. An alternative purification procedure was used for purification of all putative CAPN3 immunoreactive fragments by combining SDS-PAGE and hydroxyapatite chromatography. Two fragments of CAPN3 of approximately 55 kDa were purified, and their N-terminal amino acid sequencing demonstrated that cleavage of CANP3 occurred between residues 30-31 and 412-413, thus providing the first evidence for the localization of putative autolytic sites in this enzyme., (Copyright 1999 Academic Press.)

Cellulose phosphate (CELLPHOS) was studied as a collector for analytical preconcentration of traces of Cd(II), Cr(III), Cu(II) and Ni(II) from aqueous sample solution. It has been proved that using chromatographic columns packed with CELLPHOS for preconcentration and 1.0 mol 1(-1) HCl for elution the adsorbed analytes are quantitatively enriched. An enrichment factor of 20 (100 ml sample, 5 ml concentrate) was achieved by this separation procedure, which was applied to a series of water analyses (river, sea, bog water).

By using human bone marrow cells enriched for early progenitors by selective immunoadsorption and plated at low cell density (10(3) to 10(4) cells/mL/9.6 cm2) in semisolid methylcellulose culture, we have analyzed the cooperative effects of human colony-stimulating factor 1 (CSF-1), granulocyte-macrophage-CSF (GM-CSF), interleukin-1 alpha (IL-1 alpha), and gibbon as well as human recombinant IL-3 on the formation of monocytic colonies. CSF-1 alone stimulated mature monocytic colony formation by human CFU-M. However, in the presence of IL-3 and erythropoietin, CSF-1 stimulated maximal immature monocytic colony formation at low concentrations and inhibited the formation of granulomonocytic, erythrocytic, and mixed colonies. Cultures with CSF-1 and IL-3 contained more immature monocytic colonies than did cultures with CSF-1 alone. IL-1 alpha alone had little effect. However, IL-1 alpha in combination with optimal concentrations of either CSF-1, GM-CSF, or IL-3 increased the number of colonies containing immature or mature monocytic colonies.