Miracle-dz/UniFAR-FTUs huggingface dataset:
Translation Control by Protein Kinase R Restricts Minute Virus of Mice Infection: Role in Parvovirus Oncolysis

ABSTRACT The relevance of translational control in the gene expression and oncotropism of the autonomous parvoviruses was investigated with MVMp, the prototype strain of minute virus of mice (MVM), infecting normal and transformed rodent and human cells of different tissue origins. Mouse embryo fibroblasts (MEFs) and NIH 3T3 fibroblasts were resistant to MVMp infection, but 3T3 fibroblasts derived from double-stranded RNA (dsRNA)-dependent protein kinase R (PKR) knockout mice (PKRo/o) behaved in a manner that was highly permissive to productive MVMp replication. NIH 3T3 resistance correlated with significant phosphorylation of eukaryotic translation initiation factor 2 (eIF2) occurring at early time points after infection. Permissive PKRo/o cells were converted to MVMp-restrictive cells after reintroduction of the PKR gene by transfection. Conversely, regulated expression of the vaccinia virus E3 protein, a PKR inhibitor, in MEFs prevented eIF2α phosphorylation and increased MVMp protein synthesis. In vitro-synthesized genome-length R1 mRNA of MVMp was a potent activator of PKR. Virus-resistant primary MEFs and NIH 3T3 cells responded to MVMp infection with significant increases in eIF2α phosphorylation. In contrast, virus-permissive mouse (PKRo/o, BHK21, and A9) and human transformed (NB324K fibroblast, U373 glioma, and HepG2 hepatoma) cells consistently showed no significant increase in the level of eIF2α phosphorylation following MVMp infection. The synthesis of the viral NS1 protein was inversely correlated with the steady-state PKR levels. Our results show that the PKR-mediated antiviral response is an important mechanism for control of productive MVMp infection, and its impairment in human transformed cells allowed efficient MVMp gene expression. PKR translational control may therefore contribute to the oncolysis of MVMp and other autonomous parvoviruses.
International trade in services and inequalities

This study investigates the impact of the international openness in tourism services trade on wage inequality between highly skilled, semi-skilled, and unskilled workers in the tourism industry. The sample covers 10 developed countries and expands over 15 years. A cointegrated panel data model and an error correction model were used to distinguish between the short- and long-run effects. The results are compared to those of openness of business services and manufactured goods. The findings point out that tourism increases wage inequality at the expense of the least skilled workers in the long run and the short run.
Globalization of Equity Markets and the Cost of Capital

This paper examines the impact of globalization on the cost of equity capital. We argue that the cost of equity capital decreases because of globalization for two important reasons. First, the expected return that investors require to invest in equity to compensate them for the risk they bear generally falls. Second, the agency costs which make it harder and more expensive for firms to raise funds become less important. The existing empirical evidence is consistent with the theoretical prediction that globalization decreases the cost of capital, but the documented effects are lower than theory leads us to expect. We discuss various reasons for why this is the case.
Measurement of platelet P-selectin for remote testing of platelet function during treatment with clopidogrel and/or aspirin

There is great interest in assessing the efficacy of treatment with clopidogrel and aspirin in patients with cardiovascular disease using procedures that can be used in a remote setting. Here we have established methods to assess the effects of clopidogrel and aspirin on platelets based on measurements of platelet P-selectin. Platelets were stimulated in whole blood by adding the combination of adenosine diphosphate and the TXA2 mimetic U46619 (ADP/U4, designed to assess P2Y12 inhibition) or the combination of arachidonic acid and epinephrine (AA/Epi, designed to assess COX-1 inhibition). The stimulated samples were then fixed using a fixative solution that provides stability for at least 9 days, and sent to a central laboratory for analysis of P-selectin by flow cytometry. Measurements were performed in blood from healthy volunteers and patients with cardiovascular disease. The inhibitory effects of clopidogrel and aspirin were assessed ex vivo and the effects of the direct acting P2Y12 antagonist cangrelor and aspirin were assessed in vitro. Measurements of platelet aggregation were also performed for comparison. In healthy volunteers clopidogrel ex vivo and cangrelor in vitro markedly inhibited P-selectin expression induced by ADP/U4. Aspirin did not inhibit and did not interfere with the effects of clopidogrel or cangrelor using this test. There was very little overlap of results obtained in the absence and presence of clopidogrel or cangrelor. In contrast, over half of 42 patients with cardiovascular disease did not respond well to clopidogrel treatment, although cangrelor was still effective. Aspirin markedly inhibited P-selectin expression induced by AA/Epi. Clopidogrel had much less effect and did not interfere with the effects of aspirin. There was no overlap of results obtained in the absence and presence of aspirin. Aspirin provided near-complete inhibition in 29 of 30 patients with cardiovascular disease. Aggregometry measurements agreed well with the P-selectin data obtained ex vivo following both clopidogrel and aspirin treatment. It is concluded that measurements of P-selectin performed on fixed blood samples following platelet stimulation in whole blood in a remote setting can be used effectively to monitor the effects of clopidogrel and aspirin.
Cellular benign mesenchymal tumors of the uterus. A comparative morphologic and immunohistochemical analysis of 33 highly cellular leiomyomas and six endometrial stromal nodules, two frequently confused tumors.

Thirty-three highly cellular leiomyomas of the uterus from patients 29 to 65 (mean, 46) years of age and six endometrial stromal nodules from patients 41 to 53 (mean, 46) years of age are described. The patients usually presented with irregular uterine bleeding. Twenty-eight of the leiomyomas were intramural and five, submucosal. Eleven of 18 whose consistency is known were soft, fish-flesh, or rubbery, 10 were yellow or yellow-tan; one had a prominent cystic component. The tumors ranged from 0.5 to 15 cm (mean, 4.6 cm) in maximum dimension. On microscopic examination, they were densely cellular and composed of cells that ranged from round to spindle-shaped and had scanty cytoplasm. A focal fascicular pattern was present in all of the cases. Blood vessels were typically large; thick muscular walls and focally dilated lumens were a conspicuous feature of the majority of the neoplasms. Arterioles were evident focally in most of the tumors but were prominent in only one of them. Cleft-like spaces, some representing compressed vessels, others due to internodular edema, were present in 24 of the tumors and were conspicuous in 15 of them. The neoplasms typically exhibited focal irregular extension into the adjacent myometrium, and this feature was conspicuous in 18 of them. They often merged almost imperceptibly with the adjacent myometrium. All tumors were immunoreactive for desmin and 32 of 32 for alpha-smooth muscle actin. Two of the stromal nodules were polypoid intracavitary masses, three were submucosal, and one intramural. Five were completely or predominantly solid with cysts present focally in three of them; one tumor was predominantly cystic. The solid tissue was frequently yellow. Microscopic examination disclosed a diffuse growth of closely packed small cells with scanty cytoplasm and nuclei that lacked atypia. Three neoplasms contained cells with abundant foamy cytoplasm that were immunoreactive for CD68, indicating that they were histiocytes and not neoplastic cells. All the neoplasms had a prominent component of arterioles, which in one tumor had hyalinized walls. Five tumors were entirely well circumscribed and one predominantly well circumscribed with limited extension into the adjacent myometrium. The tumors were immunohistochemically negative for desmin. (ABSTRACT TRUNCATED AT 400 WORDS)
Osteoarthritis of the knee and hip. Part II: therapy with ibuprofen and a review of clinical trials

Objectives We review the pharmacological properties and clinical evidence pertaining to the efficacy of ibuprofen as a first‐line treatment in hip and knee osteoarthritis (OA). In the context of our previous paper's exploration of the aetiology and pathogenesis of OA as a basis for pharmacotherapy, we discuss the pharmacokinetics (PK) and clinical pharmacodynamics (PD) of ibuprofen relevant to OA.
Testing the role of preBötzinger Complex somatostatin neurons in respiratory and vocal behaviors

Identifying neurons essential for the generation of breathing and related behaviors such as vocalisation is an important question for human health. The targeted loss of preBötzinger Complex (preBötC) glutamatergic neurons, including those that express high levels of somatostatin protein (SST neurons), eliminates normal breathing in adult rats. Whether preBötC SST neurons represent a functionally specialised population is unknown. We tested the effects on respiratory and vocal behaviors of eliminating SST neuron glutamate release by Cre‐Lox‐mediated genetic ablation of the vesicular glutamate transporter 2 (VGlut2). We found the targeted loss of VGlut2 in SST neurons had no effect on viability in vivo, or on respiratory period or responses to neurokinin 1 or μ‐opioid receptor agonists in vitro. We then compared medullary SST peptide expression in mice with that of two species that share extreme respiratory environments but produce either high or low frequency vocalisations. In the Mexican free‐tailed bat, SST peptide‐expressing neurons extended beyond the preBötC to the caudal pole of the VII motor nucleus. In the naked mole‐rat, however, SST‐positive neurons were absent from the ventrolateral medulla. We then analysed isolation vocalisations from SST‐Cre;VGlut2F/F mice and found a significant prolongation of the pauses between syllables during vocalisation but no change in vocalisation number. These data suggest that glutamate release from preBötC SST neurons is not essential for breathing but play a species‐ and behavior‐dependent role in modulating respiratory networks. They further suggest that the neural network generating respiration is capable of extensive plasticity given sufficient time.
Benign paroxysmal positional vertigo of the posterior semicircular canal: efficacy of Santiago treatment protocol, long-term follow up and analysis of recurrence

Abstract Objectives: To evaluate the efficacy of the Santiago treatment protocol for benign paroxysmal positional vertigo of the posterior semicircular canal, to analyse recurrence and to establish prognostic factors. Material and methods: Four hundred and twelve patients with unilateral benign paroxysmal positional vertigo of the posterior semicircular canal were treated with the Semont manoeuvre and, if symptoms did not resolve, successive application of three Epley manoeuvres plus Brandt–Daroff exercises. Results: Symptoms resolved in 404 patients (98.1 per cent); a single Semont manoeuvre was sufficient in 334 (81.2 per cent). Aetiology had no impact on resolution of symptoms or number of manoeuvres required. The estimated likelihood of recurrence was 14 per cent in the first year and 27 per cent after 10 years. The only factor indicating a worse prognosis was recurrence. Conclusion: In unilateral benign paroxysmal positional vertigo of the posterior semicircular canal, the above treatment protocol cured 98 per cent of patients. More than half of recurrences occurred in the first year. None of the analysed factors increased the likelihood of recurrence.
MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement

The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the “molar tooth sign”, a midbrain‐hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel‐like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene‐phenotype correlates in JSRDs. © 2008 Wiley‐Liss, Inc.
Assessment and valuation of forest ecosystem services: State of the science review

This review focuses on the assessment and economic valuation of ecosystem services from forest ecosystems—that is, our ability to predict changes in the quantity and value of ecosystem services as a result of specific forest management decisions. It is aimed at forest economists and managers and intended to provide a useful reference to those interested in developing the practice of integrated forest modeling and valuation. We review examples of ecosystem services associated with several broad classes of potentially competing forest uses—production of timber, sequestration of carbon, regulation of the quality and quantity of water, provision of residential and recreational amenities, and protection of endangered species. For each example considered, we briefly describe what is known about ecological production functions and economic benefits functions. We also highlight the challenges and best practices in the creation and use of this knowledge. In the final section, we discuss the process, strengths, pitfalls, and limitations of utilizing integrated models for benefit-cost analysis of proposed forest management activities.
Determination of the effects of aflatoxin B1 given in ovo on the proximal tibial growth plate of broiler chickens: histological, histometric and immunohistochemical findings

Detrimental effects of aflatoxin B1 (AFB1) on the embryonic development of broiler tibia and its proximal growth plate were determined by means of histological, histometric and immunohistochemical methods. For this, 420 fertile eggs from parent stocks of Ross 308 broiler chickens were divided into five groups according to the proposed treatment: a control untreated group, a group injected with 30% ethanol and three further groups to be injected with 5, 15 or 40 ng AFB1. The eggs were injected into the air space prior to incubation. Five eggs from each group were opened at 9, 11, 13, 17, 19 and 21 days of incubation and tibial tissue samples were removed, dissected of muscle and connective tissues, and processed by means of routine histological techniques. The cell proliferation rate of the epiphyseal growth plate cells was determined by immunohistochemical assay of proliferating cell nuclear antigen (PCNA) expression. The results showed that both proliferative and hypertrophic zones narrowed significantly (P<0.05), when compared with the controls, in all of the AFB1-treated groups whereas the transitional zone thickened, especially in the group given 40 ng AFB1 group. The PCNA positivity indices of 15 and 40 ng AFB1-treated groups were significantly higher (P<0.05) on days 11, 13, 17, 19 and 21 of incubation. It was concluded that in ovo-administered AFB1 adversely affected embryonic development of the tibial growth plate, and that affected hatched broilers might also be more susceptible to skeletal disorders during growth.
Penetrating Keratoplasty in Young Children with Congenital Hereditary Endothelial Dystrophy

Purpose. To report the visual results and success rate of penetrating keratoplasty (PKP) in a series of young children with congenital hereditary endothelial dystrophy (CHED). Methods. This is a retrospective study on twenty-four eyes of 15 patients (seven male and eight female) operated on for CHED. Children less than 12 years of age at the time of surgery who were followed for at least 6 months were recalled. Characteristics of the patients, indications for PKP, final visual outcome, and graft clarity were evaluated. The following tests were employed: McNemmar test for evaluating visual results, Kaplan-Meyer analysis for determination of graft survival, and Mann-Whitney U test for evaluating the relationship between visual outcome and age at PKP. Results. Patients' age at diagnosis and at initial PKP was 6.5 ± 3.6 and 8.1 ± 2.5 years, respectively. Follow-up period was 35.5 ± 36.2 months. Visual acuity could be evaluated by Snellen chart in 19 eyes. Preoperative visual acuity was less than 20/80 in all of these. Postoperatively, visual acuity was less than 20/80 in nine eyes (47.4%) (P < 0.002). Visual acuity improved in 18 (94.7%) of 19 eyes. There was no relationship between age at initial PKP and final visual outcome (P = 0.35). At the last examination (24 grafts), 19 were clear (79.1%), two were hazy (8.3%), and three were opaque (12.5%). Allograft rejection was seen in 10 eyes (43.4%), seven of which were endothelial. Excluding one case of trauma, all graft failures resulted from endothelial rejection. The probability of primary graft survival was 88% at 3 years and 74% at 5 years. Conclusion. Regarding the difficulties in pediatric keratoplasty and the absence of a relationship between postoperative visual outcome and age at keratoplasty, a conservative approach and careful risk-benefit ratio evaluation are recommended in patients with CHED.
Increased Level and Longevity of Protective Immune Responses Induced by DNA Vaccine Expressing the HIV-1 Env Glycoprotein when Combined with IL-21 and IL-15 Gene Delivery1

We investigated the ability of a plasmid-derived IL-21 delivered alone or in combination with the IL-15 gene to regulate immune responses to the HIV-1 envelope (Env) glycoprotein induced by DNA vaccination. Mice were injected with the gp140ΔCFIHXB2/89.6 vector expressing a modified Env glycoprotein with C-terminal mutations intended to mimic a fusion intermediate, in which the most divergent region encoding the variable V1, V2, and V3 domains of CXCR4-tropic HxB2 virus was replaced with the dual-tropic 89.6 viral strain. Using a recombinant vaccinia virus expressing 89.6 Env glycoprotein (vBD3) in a mouse challenge model, we observed that IL-21 plasmid produced sustained resistance to viral transmission when injected 5 days after DNA vaccination. Moreover, IL-21 in a synergistic manner with IL-15 expression vector augmented the vaccine-induced recall responses to the vBD3 challenge compared with those elicited by immunization in the presence of either cytokine alone. The synergistic combination of IL-21 and IL-15 plasmids promoted expansion of CD8+CD127+ memory T cell pools specific for a subdominant HLA-A2-restricted Env121–129 epitope (KLTPLCVTL). Our results also show that coimmunization with IL-21 and IL-15 plasmid combination resulted in enhanced CD8+ T cell function that was partially independent of CD4+ T cell help in mediating protection against vBD3 challenge. Furthermore, the use of IL-21 and IL-15 genes was able to increase Ab-dependent cellular cytotoxicity and complement-dependent lysis of Env-expressing target cells through augmentation of Env-specific IgG Ab levels. These data indicate that the plasmid-delivered IL-21 and IL-15 can increase the magnitude of the response to DNA vaccines.
Determinants of burden in those who care for someone with dementia

Caregiver burden is a key measure in caregiver research and is frequently used as a baseline measure in intervention studies. Previous research has found numerous factors associated with caregiver burden such as the relationship quality between carer and patient, the patient's cognitive ability, behavioural and psychological symptoms displayed by the patient, caregiver gender, adverse life events to name a few. Many studies have investigated these factors singularly however current thought suggests a multi‐factorial role and inter‐dependence of these factors. Based on this it was decided to investigate factors associated with caregiver burden using a multiple regression analysis in order to ascertain the predictive quality of these factors of caregiver burden.
Antimicrobial Selection for Hospitalized Patients with Presumed Community-Acquired Pneumonia: A Survey of Nonteaching US Community Hospitals

OBJECTIVE: To describe and evaluate empiric antimicrobial regimens chosen for hospitalized patients with presumed community-acquired pneumonia (CAP) in US hospitals, including compliance with the American Thoracic Society (ATS) guidelines. Secondary outcomes included length of stay (LOS) and mortality associated with the choice of therapy. METHODS: A nonrandomized, prospective, observational study was performed in 72 nonteaching hospitals affiliated with a national group purchasing organization. Patients with an admission diagnosis of physician-presumed CAP and an X-ray taken within 72 hours of admission were eligible for the study. Demographic, antibiotic selection, and outcomes data were collected prospectively from patient charts. RESULTS: 3035 patients were enrolled; 2963 were eligible for analysis. Compliance with the ATS guidelines was 81% in patients with nonsevere CAP. The most common antibiotic regimen used for empiric treatment was ceftriaxone alone or in combination with a macrolide (42%). The overall mortality rate was 5.5%. The addition of a macrolide to either a second- or third-generation cephalosporin or a β-lactam/β-lactamase inhibitor was associated with decreased mortality and reduced LOS. CONCLUSIONS: Most hospitalized patients with CAP receive antimicrobial therapy consistent with the ATS guidelines. The addition of a macrolide may be associated with improved patient outcomes.
Relapse-related molecular signature in lung adenocarcinomas identifies patients with dismal prognosis.

PURPOSE In order to aid the development of patient-tailored therapeutics, we attempted to identify a relapse-related signature that allows selection of a group of adenocarcinoma patients with a high probability of relapse. PATIENTS AND METHODS Whole-genome expression profiles were analyzed in 117 lung adenocarcinoma samples using microarrays consisting of 41,000 probes. A weighted voting classifier for identifying patients with a relapse-related signature was constructed with an approach that allowed no information leakage during each training step, using 10-fold cross-validation and 100 random partitioning procedures. RESULTS We identified a relapse-related molecular signature represented by 82 probes (RRS-82) through genome-wide expression profiling analysis of a training set of 60 patients. The robustness of RRS-82 in the selection of patients with a high probability of relapse was then validated with a completely blinded test set of 27 adenocarcinoma patients, showing a clear association of high risk RRS-82 with very poor patient prognosis regardless of disease stage. The discriminatory power of RRS-82 was further validated using an additional independent cohort of 30 stage I patients who underwent surgery at a distinct period of time as well as with the Duke data set on a different platform. Furthermore, completely separate training and validation procedures using another data set recently reported by the Director's Challenge Consortium also successfully confirmed the predictive power of the genes comprising RRS-82. CONCLUSION RRS-82 may be useful for identifying adenocarcinoma patients at very high risk for relapse, even those with cancer in the early stage.