Miracle-dz/UniFAR-FTUs huggingface dataset:
Circulating myeloid‐derived suppressor cells correlate with clinical outcome in Hodgkin Lymphoma patients treated up‐front with a risk‐adapted strategy

In the attempt to find a peripheral blood biological marker that could mirror the dysregulated microenvironment of Hodgkin Lymphoma (HL), we analysed the amount of myeloid‐derived suppressor cells (MDSC), including the three main sub‐types (monocytic, granulocytic and CD34 + fraction). The absolute MDSC count was investigated in 60 consecutive newly diagnosed HL patients and correlated with clinical variables at diagnosis and outcome. Patients received standard‐of‐care chemotherapy with the exception of interim fluorodeoxyglucose positron emission tomography (PET‐2)‐positive patients, who were switched early to a salvage regimen. All MDSC subsets were increased in HL patients compared to normal subjects (P < 0·0001) and were higher in non‐responders. However, a strong prognostic significance was limited to immature (CD34+) MDSC. A cut‐off level of 0·0045 × 109/l for CD34+MDSC resulted in 89% (95% confidence interval [CI] 52–99%) sensitivity and 92% (95% CI 81–98%) specificity. The positive predictive value to predict progression‐free survival was 0·90 for PET‐2 and 0·98 for CD34+MDSC count; the negative predictive value was 0·57 for PET‐2 and 0·73 for CD34+MDSC. PFS was significantly shorter in patients with more than 0·0045 × 109 CD34+MDSC cells/l at diagnosis and/or PET‐2 positivity (P < 0·0001). In conclusion, all circulating MDSC subsets are increased in HL; CD34+MDSC predict short PFS, similarly to PET‐2 but with the advantage of being available at diagnosis.
Construction of an opal suppressor by oligonucleotide-directed mutagenesis of a Saccharomyces cerevisiae tRNA(Trp) gene

In vitro mutagenesis was used to create putative opal suppressor alleles of a tRNA(Trp) gene of Saccharomyces cerevisiae. The construct with the requisite anticodon change did not result in an active suppressor, whereas when a second change was introduced into the portion of the gene encoding the intron, an active and specific opal suppressor was produced. We propose that the secondary structure of transcripts from the first mutant may prevent efficient pre-tRNA processing, whereas normal processing occurs with the double mutant.
Supply Chain Management of Fresh Products with Producer Transportation

This article considers a class of fresh-product supply chains in which products need to be transported by the upstream producer from a production base to a distant retail market. Due to high perishablility a portion of the products being shipped may decay during transportation, and therefore, become unsaleable. We consider a supply chain consisting of a single producer and a single distributor, and investigate two commonly adopted business models: (i) In the “pull” model, the distributor places an order, then the producer determines the shipping quantity, taking into account potential product decay during transportation, and transports the products to the destination market of the distributor; (ii) In the “push” model, the producer ships a batch of products to a distant wholesale market, and then the distributor purchases and resells to end customers. By considering a price-sensitive end-customer demand, we investigate the optimal decisions for supply chain members, including order quantity, shipping quantity, and retail price. Our research shows that both the producer and distributor (and thus the supply chain) will perform better if the pull model is adopted. To improve the supply chain performance, we propose a fixed inventory-plus factor (FIPF) strategy, in which the producer announces a pre-determined inventory-plus factor and the distributor compensates the producer for any surplus inventory that would otherwise be wasted. We show that this strategy is a Pareto improvement over the pull and push models for both parties. Finally, numerical experiments are conducted, which reveal some interesting managerial insights on the comparison between different business models.
Reasons for Referral for Electroconvulsive Therapy: A Comparison Between Adolescents and Adults

Objective: In order to improve our understanding of the use of electroconvulsive therapy (ECT) in adolescent patients, we aimed to evaluate the reasons for referral for ECT in different age groups. Method: We compared the reasons for adolescent and adult referrals by a retrospective file review of 13 consecutive adolescents and 56 consecutive adults treated in our ECT unit during a 5-year period. Results: There was a significant association between age group and reason for referral. Non-response to pharmacotherapy was a significantly more common reason among adults. Adolescents were mainly referred due to catatonia and suicidal behaviour. Conclusion: Our results support the need to study reasons for referral to ECT, beyond non-response to pharmacotherapy, especially in adolescent patients.
Expression of CHL1 and L1 by Neurons and Glia Following Sciatic Nerve and Dorsal Root Injury

Cell adhesion molecules (CAMs), particularly L1, are important for axonal growth on Schwann cells in vitro. We have used in situ hybridization to study the expression of mRNAs for L1 and its close homologue CHL1, by neurons regenerating their axons in vivo, and have compared CAM expression with that of GAP-43. Adult rat sciatic nerves were crushed (allowing functional regeneration), or cut and ligated to maintain axonal sprouting but prevent reconnection with targets. In other animals lumbar dorsal roots were transected to produce slow regeneration of the central axons of sensory neurons. In unoperated animals L1 and CHL1 mRNAs were expressed at moderate levels by small- to medium-sized sensory neurons and L1 mRNA was expressed at moderate levels by motor neurons. Many large sensory neurons expressed neither L1 nor CHL1 mRNAs and motor neurons expressed little or no CHL1 mRNA. Neither motor nor sensory neurons showed any obvious upregulation of L1 mRNA after axotomy. Increased CHL1 mRNA was found in motor neurons and small- to medium-sized sensory neurons 3 days to 2 weeks following sciatic nerve crush, declining toward control levels by 5 weeks when regeneration was complete. Cut and ligation injuries caused a prolonged upregulation of CHL1 mRNA (and GAP-43 mRNA), indicating that reconnection with target tissues may be required to signal the return to control levels. Large sensory neurons did not upregulate CHL1 mRNA after axotomy and thus regenerated within the sciatic nerve without producing CHL1 or L1. Dorsal root injuries caused a modest, slow upregulation of CHL1 mRNA by some sensory neurons. CHL1 mRNA was also upregulated by many presumptive Schwann cells in injured nerves and by some satellite cells around large sensory neurons after sciatic nerve injuries and was transiently upregulated by some astrocytes in the degenerating dorsal columns after dorsal rhizotomy.
Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions

HIV's shape-shifting envelope protein HIV's envelope protein (Env) coats virus particles and allows HIV to enter host cells. HIV entry is highly dynamic. Env proteins work in groups of three (called trimers), which bind to the viral receptor and co-receptor, both expressed by host cells. Viral receptor binding causes a structural rearrangement in the trimer that allows for co-receptor binding and finally, viral entry. To visualize dynamic changes in Env conformation during viral entry, Munro et al. added differently colored fluorescent tags to two different regions of individual HIV trimers. Single-molecule fluorescence resonance entry transfer revealed three distinct Env conformations before cell entry. Occupation of particular conformations depended on host receptor binding. Science, this issue p. 759 Single-molecule fluorescence studies reveal how HIV’s viral spike protein varies its conformation as it binds to receptors. The HIV-1 envelope (Env) mediates viral entry into host cells. To enable the direct imaging of conformational dynamics within Env, we introduced fluorophores into variable regions of the glycoprotein gp120 subunit and measured single-molecule fluorescence resonance energy transfer within the context of native trimers on the surface of HIV-1 virions. Our observations revealed unliganded HIV-1 Env to be intrinsically dynamic, transitioning between three distinct prefusion conformations, whose relative occupancies were remodeled by receptor CD4 and antibody binding. The distinct properties of neutralization-sensitive and neutralization-resistant HIV-1 isolates support a dynamics-based mechanism of immune evasion and ligand recognition.
Effect of Refrigeration on the Antinematodal Efficacy of Ivermectin

Several observations have suggested that the anthelmintic ivermectin can affect nematodes by non-oral entry into the nematode body. To investigate this possibility further, we refrigerated Caenorhabditis elegans at 5 C to prevent its locomotion and to block the pharyngeal pumping that is so prominent a feature of its feeding. Worms were exposed to ivermectin (1–25 µg/ml) at that temperature for 1 hr, after which the medium was replaced by unmedicated medium at room temperature. After 1 hr at room temperature the worms were examined and counted to determine the degree to which irreversible immobilization had occurred. The drug was significantly less effective at 5 C than at room temperature. This reduction in potency could be attributed to a general cold-induced decline in the rate of the biochemical processes involved in drug action. Alternatively, the reduction could be attributed to the cold-induced blockade of pharyngeal pumping, which would suggest that the efficacy of ivermectin is partially the result of oral intake of drug. The fact that antinematodal efficacy was not entirely abrogated and reached a significant level despite blockade of pharyngeal pumping supports the former interpretation and is in accord with earlier indications that ivermectin can enter by non-oral routes. This conclusion is further supported by the observation that ivermectin is active against the nonfeeding third-stage larva of Haemonchus contortus.
Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjögren's syndrome.

PURPOSE The authors demonstrated that immunoglobulin G, present in the sera of patients with primary Sjögren syndrome (pSS), could recognize and activate muscarinic acetylcholine receptors (mAChRs) of rat exorbital acrimal gland. METHODS Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), immunoblotting, and radioligand binding and biologic assays were used to demonstrate autoantibodies against mAChRs. RESULTS These autoantibodies recognized by means of SDS-PAGE and immunoblotting assay a band of approximately 70 kDa expressed on lacrimal gland membranes that comigrated with the peak of labeled mAChRs. Moreover, pSS IgG were able to inhibit, in an irreversible manner, the binding of [3H]quinuclidinyl benzilate to mAChRs of rat exorbital lacrimal glands and to simulate the biologic effect of mAChR agonists, because they trigger the activation of phosphoinositide turnover. Atropine and 4-diphenylacetoxy-N-methylpiperidine methiodide blocked the effect and carbachol mimicked it, confirming that the M3 subtype mAChRs mediated pSS IgG action. As control, IgG from sera of women without pSS gave negative results on immunoblotting, binding, and biologic assays, thus demonstrating the specificity of the reaction. CONCLUSIONS Autoantibodies against mAChRs may be considered among the serum factors implicated in the pathophysiology of the development of pSS dry eyes.
Teratogenicity of Artemether–Clindamycin Nanostructured Lipid Carriers in Rats

Currently, artemisinin-based combination therapy is considered the best option in the treatment of malaria. However, toxicity of artemisinins limits their use in pregnancy. In the absence of sufficient toxicity data, the World Health Organization recommends that artemisinins are not to be used in the first trimester of pregnancy and can be used only in second and third trimesters, when other treatments are not available. We have recently observed that drugs loaded in nanolipid carriers are selectively taken up in Plasmodium-infected erythrocytes with a concomitant reduction in the dose required to cure animals. Thus, 20% of the therapeutic dose of artemether–clindamycin (ARM-CP) loaded in nanostructured lipid carriers (NLCs; mean particle size 55 ± 10 nm) resulted in complete parasite clearance and 100% survival of infected mice. Here, we investigate the teratogenicity of this formulation in rodents (dosing on alternate days from 6th day to 18th day of gestation; 12-15 animals/group). The teratogenicity of drug-free NLCs and artesunate–clindamycin (ARS-CP) solution was also evaluated. We found that the therapeutic dose of ARS-CP caused fetal resorptions (87.5% resorptions in 8 litters), suggesting its unsuitability for use in pregnancy. Artesunate–clindamycin NLCs at therapeutic doses also resulted in ∼90% fetal resorptions in 10 litters examined. However, postimplantation losses or fetal malformations were not observed at the dose of ARM-CP NLCs that was required for complete parasite clearance in preclinical trials (ie, 20% of the therapeutic dose). Our data suggest that the NLCs loaded with 20% of the therapeutic dose of ARM-CP may have potential in treating malaria during pregnancy.
Vocabulary size, translation equivalents, and efficiency in word recognition in very young bilinguals

ABSTRACT The present study examined early vocabulary development in fifty-nine French monolingual and fifty French–English bilingual infants (1;4–1;6). Vocabulary comprehension was assessed using both parental report (MacArthur-Bates Communicative Development Inventory; CDI) and the Computerized Comprehension Task (CCT). When assessing receptive vocabulary development using parental report, the bilinguals knew more words in their L1 versus their L2. However, young bilinguals were as accurate in L1 as they were in L2 on the CCT, and exhibited no difference in speed of word comprehension across languages. The proportion of translation equivalents in comprehension varied widely within this sample of young bilinguals and was linked to both measures of vocabulary size but not to speed of word retrieval or exposure to L2. Interestingly, the monolinguals outperformed the bilinguals with respect to accuracy but not reaction time in their L1 and L2. These results highlight the importance of using multiple measures to assess early vocabulary development.
Services of General Economic Interest: Towards Common Values?

The aim of the article is to analyse the concept of services of general economic interest (SGEI). It tries to answer the questions whether there are common values for such services and whether such services can be universally defined. Such analysis starts with concepts that originated with the European lawmaker when it introduced SGEI. Later, the article focuses on the rationale for introducing this concept. The main part of the article analyses the EU case law concerning different sectors of the economy, in which specific services were recognized as SGEI to find some common values that such services share. In the end, the article focuses on the borders of freedom of the Member States to determine such services.
Low-dose monitored mitotane treatment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer.

Eight patients with adrenocortical cancer were treated with low doses of mitotane (2-3 g daily) while monitoring drug plasma levels. When the mitotane concentrations reached the therapeutic range (defined as mitotane plasma levels between 14-20 microg/mL), a dose reduction was performed to avoid toxicity. Thereafter, the mitotane dose was tailored according to plasma levels. A progressive increase in plasma mitotane concentrations was observed during treatment, and a highly significant linear correlation was found between plasma drug levels and the total mitotane dose. The therapeutic threshold was reached in all patients after 3-5 months and a total mitotane dose of 283-387 g/days (median, 363). The duration of treatment was 8-40 months (median, 9). Toxicity was manageable in all but one patient, who discontinued treatment. It is therefore possible to design a standard low dose schedule, e.g. 3 g/daily for about 3-4 months with following dose adjustments guided by the monitoring of plasma mitotane levels. This approach is able to provide therapeutic mitotane concentrations and limit the unwanted effects. The present data provide a rationale to change the approach to mitotane treatment in patients with adrenocortical carcinoma from high dose to low dose regimens.
Intermittent Antegrade Warm Blood Cardioplegia in Aortic Valve Replacement

Abstract Background: Intermittent antegrade warm blood cardioplegia (IAWBC) is a well established technique of myocardial protection for coronary artery surgery, with metabolic and experimental basis. Methods: To evaluate its effectiveness in aortic valve replacement (AVR), we compared 171 consecutive patients who underwent first AVR using IAWBC (group A) with the last 100 consecutive patients who underwent first AVR using intermittent antegrade cold blood cardioplegia (IACBC) (group B). The endpoints considered were myocardial protection related (recovery of spontaneous rhythm, need for mechanical support, incidence of low‐output syndrome, perioperative Q wave myocardial infarct, CK‐MB levels, ventricular arryhthmias and lidocaine infusion requirement, cardiac‐related deaths, and death for any cause) and temperature perfusion related (bleeding, awaking time, time to extubation, and cerebrovascular accidents). Results: Mortality was similar in both groups, but no patient in group A died for cardiac‐related cause (0 vs 4, p < 0.01). More patients in group A recovered a spontaneous rhythm (144 vs 47, p < 0.0001). Incidence of low‐output syndrome was higher in group B (16 vs 3, p < 0.0005), as well as ventricular arryhthmias incidence and need for lidocaine infusion (respectively 15 vs 2, p < 0.0001, and 10 vs 1, p < 0.0005). Awaking time was shorter in warm patients (2.5 ± 2.5 hours vs 4.4 ± 3.7 hours, p < 0.0005), as the extubation time (9.4 ± 7.7 hours vs 13.5 ± 11.7 hours, p < 0.0005) and bleeding (803 ± 714 mL/24 hours vs 1051 ± 1375 mL/24 hours, p < 0.05). As a consequence, the intensive care unit and the postoperative hospital stays were shorter in group A (32 ± 27 hours vs 48 ± 20 hours, p < 0.0005, and 7.2 ± 3.1 days vs 11.3 ± 5.4 days, p < 0.0001, respectively). Conclusions: IAWBC provides lower cardiac‐related mortality and morbidity in patients who undergo AVR in comparison with IACBC.
Retinal and choroidal changes observed with ‘En face’ enhanced-depth imaging OCT in central serous chorioretinopathy

Aims To describe retinal and choroidal changes in acute and quiescent central serous chorioretinopathy (CSC) observed with ‘En face’ spectral domain optical coherence tomography (SD OCT) combined with enhanced-depth imaging (EDI). Methods A prospective and descriptive study at the Rothschild Ophthalmologic Foundation (Paris, France) between September 2011 and February 2012. Eyes with a clinical diagnosis of CSC were examined using SD OCT with EDI, fluorescein and indocyanine green angiography. 3D reconstruction of 197 transverse sections with SD OCT, spaced of 30 μ, provided a virtual macular brick through which 496 sections in the coronal plane resulted in a C-scan or En face OCT image. Results 23 of 29 eyes (79%) had serous retinal detachment (all active CSC) and 22 had pigment epithelial detachment (75%). Pigment epithelial hyperplasia was visualised in nine eyes (31%). Posterior cystoid retinal degenerations were present in five eyes (17%). The mean choroidal thickness was 491.5 μ. In 11 eyes (38%), En face OCT showed multiple hyper reflective points located at the level of the choriocapillary layer and choroidal cavitations were found in two patients. Conclusions En face OCT imaging using SD OCT is an easy, reproducible, non-invasive and effective tool to understand choroidal changes in acute and quiescent CSCR. It provides complementary morphological information, describes new semiological entities and might substitute other exams in the future.
Identification and characterization of antibiotic resistance genes in Lactobacillus reuteri and Lactobacillus plantarum

Aims: The study aimed to identify the resistance genes mediating atypical minimum inhibitory concentrations (MICs) for tetracycline, erythromycin, clindamycin and chloramphenicol within two sets of representative strains of the species Lactobacillus reuteri and Lactobacillus plantarum and to characterize identified genes by means of gene location and sequencing of flanking regions.
The cardiovascular effects of glucagon‐like peptide‐1 receptor agonists: a trial sequential analysis of randomized controlled trials

Glucagon‐like peptide‐1 (GLP‐1) receptor agonists are a new class of antidiabetic drugs. Their wider use for the treatment of patients with type 2 diabetes mellitus has led to concerns about its cardiovascular effects. However, the robustness of data leading to those concerns is unclear. The purpose of this study is to systematically assess the robustness of the available evidence on the adverse cardiovascular effects of GLP‐1 receptor agonists in patients with type 2 diabetes.
Cox Regression and Parametric Models: Comparison of How They Determine Factors Influencing Survival of Patients with Non-Small Cell Lung Carcinoma

Background and objectives: The present study of survival rate of patients with non-small cell carcinoma (NSCLC) compared the efficiency of Cox semi-parametric vs. parametric models in determination of influencing factors. Methods: In this retrospective cohort study, data were gathered from 190 patients with a confirmed diagnosis of NSCLC referred to Shahid Sadoughi and Shohadaye Kargar Hospitals in Yazd, Iran during 2005 to 2014. To identify and compare factors influencing the survival rate, a Cox semi-parametric model was fitted to the data. Data analysis was performed using the R software version R3.3. 1, and the significance level was set at 0.05. Results: The average age was 64.5 years. About 40% of patients had stage 4 disease. The median survival was 8 months. After comparing the models, the more efficient was the log-normal distribution (AIC=889.3829), with which disease stage, type of therapy, and age were significant factors. Among the different types of therapy, chemotherapy and radiotherapy yielded higher survival rates, and increased age was associated with lower survival. Conclusion: The most efficient model was a log-normal model. Implementation of optimal therapies at early stages can improve the survival of patients.