Miracle-dz/UniFAR-FTUs huggingface dataset:
Antihormonal activities of 5 alpha-reductase and aromatase inhibitors.

The problem of developing androgen antagonists has been tackled so far only by synthesizing steroids able to displace testosterone and other androgens from their specific receptor sites. The observation that testosterone has to be converted intracellularly either to 5 alpha-reduced metabolites (DHT, 3 alpha-diol, etc.) or to estrogens, in order to become fully active on androgen-dependent structures (both central and peripheral), has opened the possibility of creating molecules which prevent these conversions, and which could then block the actions of testosterone. The availability of these new compounds has allowed a better understanding of the selective physiological role of each of the metabolites of testosterone, and to provide the basis for the development of new hormone antagonists to be used in those clinical conditions for which an inhibition of the actions of testosterone is foreseen. The usefulness of these enzyme inhibitors is underlined by some examples described in this paper. The results obtained may permit the formulation of the following conclusions: (1) The conversion of testosterone to its 5 alpha-reduced metabolites occurring in the neuroendocrine structures may represent an essential step for the appearance of the inhibitory feedback effect testosterone exerts on LH secretion; (2) Testosterone exhibits its negative feedback effect on FSH secretion as such and not following the local aromatization to estrogens; (3) Testosterone exerts its effect on the intrahypothalamic stores of LHRH acting as such and not following its local conversion either to 5 alpha-reduced metabolites or to estrogenic molecules; (4) Some of the new enzyme inhibitors (e.g. 4-OH-A) may represent an interesting tool for the treatment and/or the prevention of BPH and possibly of other androgen-dependent diseases (prostate carcinoma, acne etc.), as shown by their ability to prevent the in vitro conversion of testosterone to its 5 alpha-reduced metabolites both in the normal prostate of the rat and in the human BPH tissue.
Mirtazapine is more effective than trazodone: a double‐blind controlled study in hospitalized patients with major depression

Two hundred hospitalized patients with DSM-III diagnosis of moderate to severe major depressive episode were randomized to receive mirtazapine or trazodone for 6 weeks in a double-blind trial. The dosages were 24–72 mg/day for mirtazapine and 150–450 mg/day for trazodone. The improvement on all depression rating scales used was generally greater for mirtazapine, wish statistically significant differences over trazodone in the Hamilton Psychiatric Rating Scale for Depression total score and two subscores (the Bech melancholia factor and retardation factor), the Brief Psychiatric Rating Scale total score, the General Psychiatric Impression Global Assessment Scale, the Beck score and responder rates. Mirtazapine was well tolerated, while the trazodone-treated patients experienced somnolence more frequently, particularly during the first 2 weeks of treatment. Furthermore, postural symptoms were a clinical problem in >' 6% of the trazodone-treated patients. In this trial, mirtazapine showed significant clinical advantages over trazodone in terms of overall efficacy and tolerability.
NATURAL HISTORY OF SIN NOMBRE VIRUS INFECTION IN DEER MICE IN URBAN PARKS IN OREGON

Sin Nombre virus (SNV), one of at least 45 hantaviruses described worldwide, is hosted by the deer mouse, Peromyscus maniculatus, a common species throughout most of North America. Herein, we describe general life-history characteristics of deer mice and the ways in which these factors relate to the incidence of SNV infections among populations of this host species in and around Portland, Oregon. In total, 3,175 deer mice were captured from October 2002 to September 2005. Transmission of SNV appears to be associated with male breeding behaviors, as more males and adults were infected than expected by capture rate; spring and summer had the highest infection prevalence, as well as scrotal male captures. Wounding rates between infected and uninfected deer mice were not different in any age or sex class. Capture rates were significantly and positively related to the interaction of temperature departure from normal, total precipitation, and number of clear days from two seasons previous (P=0.029), while infection prevalence was significantly and negatively related to the capture rate of juveniles from two seasons previous (P=0.029).
Combining Cross‐Sectional and Prospective Data Methods to Improve Transition Parameter Estimation for Characterizing the Accumulation of HIV‐1 Drug Resistance Mutations

Summary The order and rate of acquisition of HIV drug resistance mutations have been estimated from longitudinal and cross‐sectional data using Markov models and branching trees, respectively. This article proposes methods that make use of both longitudinal and cross‐sectional data simultaneously by employing link functions between the two parameter sets. Most functions that link the two parameter sets also depend on the time on treatment before the start of the study—information that may not be available. Nonetheless, under certain assumptions, some link functions eliminate the dependence on time. Using such functions, the two sources of information can be combined to improve the precision of parameter estimation. The method also accommodates error in the link functions from uncertainty in the assumptions required for the links or other reasons. These methods are applied to data from AIDS Clinical Trial Group protocol 398, a randomized comparison of mono‐ versus dual‐protease inhibitor use in heavily treatment experienced HIV patients. Combining the two sources of information allows detection of differences between rates of transition that are not detectable using prospective data alone.
Treatment of refractory coccidioidomycosis with voriconazole or posaconazole.

BACKGROUND Coccidioidomycosis is a fungal infection of the desert southwestern United States. It may be self-limited or may require antifungal therapy. Currently used triazoles (eg, fluconazole and itraconazole) have largely supplanted amphotericin B, which is fraught with adverse effects. Limited case reports and small open-label trials show that voriconazole and posaconazole benefit patients with coccidioidomycosis refractory to first-line agents. METHODS We conducted a retrospective review of patients prescribed voriconazole or posaconazole for coccidioidomycosis at our institution between 1 January 2006 and 1 August 2010. Outcomes were assessed with both a retrospectively applied Mycosis Study Group score (ie, a composite score for symptoms, serology, and radiographic findings) and the documented impressions of treating medical practitioners. RESULTS Twenty-one patients who received voriconazole and 16 who received posaconazole met study criteria. After a median duration of 6 months of voriconazole treatment, 14 of 21 patients (67%) were improved in overall status, 5 were unchanged, and 2 were unresponsive to voriconazole. After a median of 17 months of posaconazole treatment, 12 of 16 patients (75%) showed improvement, 1 was unchanged, and 3 were unresponsive due to medication intolerance or relapsed infection. CONCLUSIONS Voriconazole and posaconazole are reasonable but not infallible options for salvage treatment of refractory coccidioidomycosis. Prospective comparative trials are required to provide further insights into their efficacy and utility.
Numerous FUS‐positive inclusions in an elderly woman with motor neuron disease

We report an autopsy case of a 75‐year‐old Japanese woman with motor neuron disease (MND) showing numerous neuronal and glial inclusions immunostained with anti‐fused in sarcoma (FUS) antibody. At 73 years, she received a diagnosis of MND and died of respiratory insufficiency 2 years later. No mutation was found in all exons of the FUS gene. Neuropathological examination revealed a reduced number of anterior horn cells and degeneration of the pyramidal tracts. Neither Bunina bodies nor inclusions positive for ubiquitin/phosphorylated TAR DNA binding protein of 43 kD (pTDP‐43), such as skein‐like or round inclusions, were observed. However, basophilic inclusions (BIs) were frequently observed in the remaining neurons of the anterior horns, facial nuclei, hypoglossal nuclei, vestibular nuclei, dentate nuclei and inferior olivary nuclei. In an immunohistochemical analysis, the BIs showed strong immunoreactivity with anti‐FUS and anti‐ubiquitin‐binding protein p62 (p62) antibodies. The nuclear staining of FUS was preserved in some neurons with FUS‐positive inclusions, and a few FUS‐positive glial inclusions were found. FUS‐positive inclusions were more common than p62‐positive inclusions in some anatomical regions, and in some neurons, p62 immunoreactivity was observed in only parts of the BIs. These results suggest that BI formation and TDP‐43 aggregation have different pathogenic mechanisms, and FUS may play an important role in the pathogenesis of MND with BIs. This patient has the oldest reported age of onset for MND with BIs, and clinical features observed in this patient were indistinguishable from those of classic sporadic MND. Therefore, we consider that the age of onset and clinical features of FUS‐related disorders may be variable.
Classification of peripheral nerve fibres

The historical development of the nomenclature used to describe peripheral nerve fibres is described. Some of the properties of nerve fibres and their maturation are discusses. It is suggested that when grouping fibres by their conduction velocities the original terminology introduced by Erlanger and Gasser41 (i.e. A-alpha, beta, gamma, delta, B and C) should be used for efferent nerve fibres, while the nomenclature introduced by Lloyd44 (i.e. groups I,II, III and IV) should be applied to afferent fibres. The terms B, 'gamma efferent', Ia and Ib have specific implications with regard to their source or distribution irrespective of the conduction velocities of the fibres contributing to these groups.
Evaluation of Replication and Pathogenicity of Avian Influenza A H7 Subtype Viruses in a Mouse Model

ABSTRACT Avian influenza A H7 subtype viruses pose a significant threat to human health because of their ability to transmit directly from domestic poultry to humans and to cause disease and, sometimes, death. Although it is important to develop vaccines against viruses of this subtype, very limited information is available on the immune response and pathogenesis of H7 viruses in animal models such as mice and ferrets. Ten H7 viruses were selected for possible vaccine development on the basis of their phylogenetic relationships and geographical locations. The virulence of the 10 viruses for mice and the immunogenicity of the viruses in mice and ferrets were evaluated to study the extent of antigenic relatedness and the level of cross-reactivity of antibodies. Most of the viruses showed similar patterns of cross-reactivity with mouse and ferret antisera. The Eurasian viruses elicited broadly cross-reactive antibodies that neutralized viruses from both Eurasian and North American lineages, but the converse was not true. A subset of the viruses was also evaluated for the ability to replicate and cause disease in BALB/c mice following intranasal administration. H7 subtype viruses were able to infect mice without adaptation and manifested different levels of lethality and kinetics of replication. On the basis of phylogenetic data, induction of broadly cross-neutralizing antibodies in mouse and ferret antisera, and their ability to replicate in mice, we have selected A/Netherlands/219/03 (subtype H7N7) and A/chicken/BC/CN-7/04 (subtype H7N3) viruses for vaccine development. The mouse model can be used for the preclinical evaluation of these vaccines against H7 subtype viruses.
Neuronal binucleation in Alzheimer disease hippocampus

Aims: The literature and teachings instruct that neurones in the adult brain are fully differentiated, quiescent cells that never divide. Somewhat surprisingly, and counter to such dogma, susceptible neurones in Alzheimer disease display an activated cell cycle phenotype. However, whether this leads to a coordinated procession through the cell cycle is unclear, particularly whether neurones enter anaphase and beyond. To begin to address this issue, in this study we sought to determine whether nuclear division occurs in these neurones. Methods: We examined a series of 101 archived, routinely stained hippocampal sections collected at post mortem for neuropathological evaluation for evidence of neuronal binucleation. Results: We report for the first time, binucleated neurones within the hippocampus in cases of Alzheimer disease but not in control cases (P < 0.05). Conclusions: While a relatively rare event, occurring once every 20 000 neurones, this morphological evidence that neuronal cells within the cortical regions of the adult human brain in Alzheimer disease contain two nuclei supports the hypothesis that neuronal cells can re‐enter into a coordinated cell cycle that culminates in nuclear division.
Drugs in Sport: Justifying Paternalism on the Grounds of Harm

The use of drugs by athletes is not a new phenomenon, but in the last decade or so the issue has received much public attention. This has resulted in a renewed focus on the question of whether the use of performance-enhancing substances in sport ought to be prohibited. (We need to be aware of the distinction between the question of whether it is wrong to use performance-enhancing substances in sport, and the question of whether the use of these sub stances in sport ought to be prohibited. Prohibition does not necessarily follow from "wrongness.") In this paper I will argue that a certain class of performance-enhancing substances should be banned. In doing this, I shall first define performance-enhancing substances and then focus on arguments concerning self-harm and harm to others. The notions of coercion and subtle pressure will be exam ined, and this will serve as an attempt at justifying paternalism. If one were to ask the proverbial "man in the street" whether the use of performance-enhancing substances in sport ought to be banned, it is likely that the majority of responses would be affirmative. If one were then to ask why, the answer would probably be justified by one of two lines of reasoning. Reason A would be that it is cheating, and this is contrary to the nature of sport. Reason B would be that the use of performance-enhancing substances should be prohibited because it is a harmful practice.
Propagation of Epileptiform Activity Can Be Independent of Synaptic Transmission, Gap Junctions, or Diffusion and Is Consistent with Electrical Field Transmission

The propagation of activity in neural tissue is generally associated with synaptic transmission, but epileptiform activity in the hippocampus can propagate with or without synaptic transmission at a speed of ∼0.1 m/s. This suggests an underlying common nonsynaptic mechanism for propagation. To study this mechanism, we developed a novel unfolded hippocampus preparation, from CD1 mice of either sex, which preserves the transverse and longitudinal connections and recorded activity with a penetrating microelectrode array. Experiments using synaptic transmission and gap junction blockers indicated that longitudinal propagation is independent of chemical or electrical synaptic transmission. Propagation speeds of 0.1 m/s are not compatible with ionic diffusion or pure axonal conduction. The only other means of communication between neurons is through electric fields. Computer simulations revealed that activity can indeed propagate from cell to cell solely through field effects. These results point to an unexpected propagation mechanism for neural activity in the hippocampus involving endogenous field effect transmission.
Prévention, contrôle et maîtrise du risque d’aspergillose invasive au Groupement Hospitalier Edouard Herriot lors de travaux : apport de la surveillance et de l’alerte environnementale et épidémiologique

Lors de travaux, la mise en suspension des spores d’Aspergillus constitue un facteur de risque reconnu dans le developpement d’une aspergillose invasive. Durant l’annee 2015, un pavillon de 6000 m2 (60 lits) de notre etablissement a ete entierement deconstruit. L’objectif principal de cette etude a ete d’evaluer l’association entre la concentration des spores d’Aspergillus fumigatus (AF) dans l’environnement exterieur et interieur des pavillons, mais egalement avec la coexistence de cas cliniques, afin de proposer des recommandations d’amelioration (pratiques & techniques). Pour cela, durant 11 mois, une surveillance prospective de la contamination a Aspergillus fumigatus (AF) de l’air exterieur et interieur par impaction sur gelose, mais aussi une investigation epidemiologique des patients a risque ont ete mis en place. Au total, 3885 prelevements d’air ont ete realises (1744 exterieurs et 2141 interieurs) permettant, par calcul des ratios de contamination (exterieurs vs interieurs), de confirmer une efficacite des mesures de precautions pour reduire l’aerocontamination. Des prelevements exterieurs continus des spores d’Aspergillacees (spore/m3/jour) ont egalement ete realises par un capteur Hirst. Ce capteur, mais aussi le suivi des conditions meteorologiques se sont reveles etre des systemes d’alerte utiles pour prevenir les pics de contamination. Enfin, 394 (383 environnementaux, 11 cliniques) isolats d’AF sensibles aux antifongiques ont ete genotypes (MLVA). L’analyse des genotypes a montre 7 genotypes similaires entre des isolats d’AF cliniques et environnementaux confirmant un role de l’environnement hospitalier dans l’infection ou la colonisation des patients
Detection and Quantification of Minor Human Immunodeficiency Virus Type 1 Variants Harboring K103N and Y181C Resistance Mutations in Subtype A and D Isolates by Allele-Specific Real-Time PCR

ABSTRACT Nevirapine (single dose), commonly used to prevent the mother-to-child transmission of human immunodeficiency virus (HIV) in developing countries, frequently induces viral resistance. Even mutations which occur only in a minor population of the HIV quasispecies (<20%) are associated with subsequent treatment failure but cannot be detected by population-based sequencing. We developed sensitive allele-specific real-time PCR (ASPCR) assays for two key resistance mutations of nevirapine. The assays were specifically designed to analyze HIV-1 subtype A and D isolates accounting for the majority of HIV infections in Uganda. Assays were evaluated using DNA standards and clinical samples of Ugandan women having preventively taken single-dose nevirapine. Lower detection limits of drug-resistant HIV type 1 (HIV-1) variants carrying reverse transcriptase mutations were 0.019% (K103N [AAC]), 0.013% (K103N [AAT]), and 0.29% (Y181C [TGT]), respectively. Accuracy and precision were high, with coefficients of variation (the standard ratio divided by the mean) of 0.02 to 0.15 for intra-assay variability and those of 0.07 to 0.15 (K103N) and 0.28 to 0.52 (Y181C) for inter-assay variability. ASPCR assays enabled the additional identification of 12 (20%) minor drug-resistant HIV variants in the 20 clinical Ugandan samples (3 mutation analyses per patient; 60 analyses in total) which were not detectable by population-based sequencing. The individual patient cutoff derived from the clinical baseline sample was more appropriate than the standard-based cutoff from cloned DNA. The latter is a suitable alternative since the presence/absence of drug-resistant HIV-1 strains was concordantly identified in 92% (55/60) of the analyses. These assays are useful to monitor the emergence and persistence of drug-resistant HIV-1 variants in subjects infected with HIV-1 subtypes A and D.
The superfamily of heme-copper respiratory oxidases

It has been estimated that about 90% of the reduction of molecular oxygen in the biosphere is catalyzed by respiratory oxidases (95). Much of this is accomplished by a wide variety of bacterial oxidases. It has long been recognized that bacterial respiratory systems are branched, having a number of distinct terminal oxidases, rather than the single cytochrome c oxidase present in most eukaryotic mitochondrial systems. This multiplicity of oxidases in bacteria has long been a source of confusion, both in terms of the nature of the enzymes themselves and in terms of the rationale for such complex systems. During the past several years, it has been recognized that most of the bacterial oxidases, despite differences in their substrates (quinol versus cytochrome c), oxygen affinities, and heme types and metal compositions, are closely related members of a single superfamily called the heme-copper oxidase superfamily. A large number of enzymes which just a few years ago were considered to be totally unrelated are now known to be close relatives. This recognition has provided considerable order to a chaotic field, and the research that has been stimulated in this field has generated new insights into heme biosynthesis and the evolution of respiratory systems. The heme-copper oxidase superfamily also includes the eukaryotic mitochondrial oxidases. Much of the impetus for pursuing the study of the bacterial oxidases has been to exploit the experimental advantages offered by the prokaryotic systems to learn about the structures and the functional mechanisms common to the members of the superfamily. The mitochondrial cytochrome c oxidase (primarily the bovine oxidase) has long been the object of intensive study (for reviews, see references 6, 10, 17, 20, 42, 59, and 86). This enzyme catalyzes the four-electron reduction of molecular oxygen to two molecules of water and utilizes the free energy available from this reaction to pump protons (one per electron) across the mitochondrial inner membrane, thus generating a transmembrane proton electrochemical gradient, or proton motive force (118). Although they typically contain only 3 or 4 subunits, in contrast to the 13-subunit mammalian enzyme, the bacterial oxidases catalyze the reduction of dioxygen and pump protons as efficiently as the mitochondrial oxidases do (39). Studies of several of the bacterial oxidases have made a very significant contribution to our knowledge of
Radioimmunotherapy of Relapsed Non-Hodgkin's Lymphoma with Zevalin, a 9~ Anti-CD20 Monoclonal Antibody 1

Approximately 55,400 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed each year, with the overall prevalence of the disease now estimated to be 243,000. Until recently, treatment alternatives for advanced disease included chemotherapy with or without external beam radiation. Based on the results of several clinical trials, the chimeric monoclonal antibody Rituximab has now been approved by the United States Food and Drug Administration as a treatment for patients with relapsed or refractory, low-grade or follicular, B-cell NHL. Several other monoclonal antibodies in conjugated and unconjugated forms have been evaluated in the treatment of NHL. Ibritumomab, the murine counterpart to Rituximab, radiolabeled with 9Oy (Zevalin), is presently being evaluated in clinical trials. The success of radioimmunotherapy is dependent upon the appropriate choice of antibody, isotope, and chelator-linker. The Ibritumomab antibody targets the CD20 antigen. The antibody is covalently bound to the chelator-linker tiuxetan (MX-DTPA), which tightly chelates the isotope 9Oy. To date, two Phase I/II Zevalin clinical trials have been completed in patients with low-grade, intermediate-grade, and mantle cell NHL. The overall response rate was 64% in the first trial and 67% in the later trial. Phase II and III trials are ongoing.