Miracle-dz/UniFAR-FTUs huggingface dataset:
Experimental disseminated strongyloidiasis in Erythrocebus patas. I. Pathology.

Fatal disseminated disease was induced in ten patas monkeys infected with two Southeast Asian strains of Strongyloides stercoralis. While some animals died within 6 weeks after infection, others controlled their infections until placed on high doses of corticosteroids. Larvae were first noted in the stools 11-20 days after transcutaneous exposure to filariform larvae. Daily larval counts tended to increase as the infections progressed, but the number of larvae in the stool was not predictive of whether a monkey would control his infection or succumb to fatal disease. Hyperinfection was confirmed in the six monkeys in which counts were made of the adult female parasites in the duodenum at postmortem, as well as by pathologic findings in all animals. Clinical signs of disease were vague until dyspnea induced by terminal pulmonary hemorrhage occurred. Eosinophilia and/or basophilia were noted intermittently in some infections. Severe necrotizing duodenitis, colitis, and pulmonary hemorrhage were the most conspicuous postmortem findings. Hyperinfection has been predictably induced in a cercopithecoid monkey for the first time; a species which may lend itself to further investigations into the pathogenesis of disseminated strongyloidiasis .
Grey matter brain injuries are common in Ugandan children with cerebral palsy suggesting a perinatal aetiology in full‐term infants

There is limited literature on brain imaging studies of children with cerebral palsy (CP) in low and middle income countries. We investigated neuroimaging patterns of children with CP attending a tertiary referral centre in Uganda to determine how they differed from studies reported from high income countries and their relationship with prenatal and postnatal factors.
Conditional silencing: the HMRE mating-type silencer exerts a rapidly reversible position effect on the yeast HSP82 heat shock gene

The HMRE silencer of Saccharomyces cerevisiae has been previously shown to transcriptionally repress class II and class III genes integrated within the HMR silent mating-type locus up to 2.6 kb away. Here we study the ability of this element to repress at an ectopic position, independent of sequences normally associated with it. When integrated 750 bp upstream of the HSP82 heat shock gene, the silencer represses basal-level transcription approximately 5-fold but has no effect on chemical- or heat-shock-induced expression. Such conditional silencing is also seen when the HMRE/HSP82 allele is carried on a centromeric episome or when the entire HMRa domain is transplaced 2.7 kb upstream of HSP82. Notably, the a1 promoter within the immigrant HMRa locus remains fully repressed at the same time HSP82 is derepressed. The position effect mediated by the E silencer is absolutely dependent on the presence of a functional SIR4 gene product, is lost within 1 min following stress induction, and is fully reestablished within 15 min following a return to nonstressful conditions. Similar kinetics of reestablishment are seen in HMRE/HSP82 and HMRa/HSP82 strains, indicating that complete repression can be mediated over thousands of base pairs within minutes. DNase I chromatin mapping reveals that the ABF1, RAP1, and autonomously replicating sequence factor binding sites within the silencer are constitutively occupied in chromatin, unaltered by heat shock or the presence of SIR4. Similarly, the heat shock factor binding site upstream of HSP82 remains occupied under such conditions, suggesting concurrent occupancy of silencer and activator binding sites. Our results are consistent with a model in which silencing at the HMRE/HSP82 allele is mediated by direct or indirect contacts between the silencer protein complex and heat shock factor.
Brain Metastases: The HER2 Paradigm

Between 100,000 and 170,000 patients with cancer develop central nervous system (CNS) metastases each year in the U.S., of which ∼20% carry a primary diagnosis of breast cancer. As a consequence of improvements in systemic therapy, which have allowed patients to live longer with advanced cancer, CNS metastases are emerging as an important sanctuary site, and the incidence may be increasing in patients with particular tumor subtypes. Unless there are improvements in the treatment of CNS disease, a growing proportion of patients may be at risk of experiencing both morbidity and mortality as a result of uncontrolled CNS progression, often at a time when their extra-CNS disease is apparently under control. This article reviews changes in the epidemiology and natural history of women with brain metastases from HER2-positive breast cancer over the last decade and presents the therapeutic challenges and opportunities that have arisen in this setting. First, the apparent increase in CNS disease among women with HER2-positive breast cancer, relative to historical controls, is discussed, followed by consideration of potential causes of this observation. Next, the implications of CNS disease, in terms of prognosis and the potential development of preventive strategies are considered. Finally, new developments in systemic approaches to the treatment of CNS disease, including cytotoxic chemotherapy and targeted therapy, are explored.
Hyaluronan-containing mouthwash as an adjunctive plaque-control agent.

PURPOSE Hyaluronan, commonly known as hyaluronic acid, has been shown to have anti-inflammatory action, bacteriostatic effect and antioxidant properties, thus making its use as a long-term anti-plaque and anti-gingivitis agent an appealing proposition. The aim of the present study was to evaluate the efficacy of 0.025% hyaluronan-containing mouthwash in comparison with 0.2% chlorhexidine and a water-based mouthwash and also to evaluate its antibacterial efficacy on isolated strains of periodontopathogens. MATERIALS AND METHODS Forty-five volunteers in a hospital setting were recruited. A single-blinded, parallel design, randomised controlled trial was carried out and the 4-day plaque re-growth model was used to study the efficacy of the three mouthwashes. Microbiological and clinical evaluation was performed by culturing and using dental indices, respectively. The three mouthwashes used in the present study were commercially available 0.025% sodium hyaluronate, 0.2% chlorhexidine and a water-based rinse (negative control). Effects of the three mouthwashes were tested on the growth of isolated strains of Porphyromonas gingivalis (Pg), Aggregatibacter actinomycetemcomitans (Aa) and Prevotella intermedia (Pi). RESULTS In vitro, hyaluronan had a distinct effect on the growth of Aa and Pi with no effect on the growth of Pg. In vivo, the differences between the individual rinse solutions and the water-based solution showed significantly less plaque regrowth with respect to both chlorhexidine (P = 0.033) and hyaluronan (P = 0.045) when compared to the negative control. The difference between chlorhexidine and hyaluronan was not statistically significant (P = 0.69). CONCLUSIONS Hyaluronan (0.025%)-containing mouthwash was comparable to chlorhexidine (0.2%) in inhibiting plaque growth in vivo, and it significantly reduced the growth of Aa and Pi in vitro
Developing Acceptable Surface Limits for Occupational Exposure to Pharmaceutical Substances

Acceptable surface limits (ASLs) are developed in order to establish a quantitative measure for the potential risk from exposure by dermal contact. In the pharmaceuticals industry, ASLs are used for protection against active pharmaceutical ingredients that are known to cause pharmacological or toxicological effects. An ASL can be used, together with appropriate analytical methods and industrial hygiene monitoring, to assess workplaces for potential dermal exposure and to protect the health and safety of individuals who might come in direct contact with contaminated surfaces in the workplace. ASLs are also used to evaluate the adequacy of housekeeping measures and the effectiveness of engineering containment approaches, or to determine whether a chemical is present on surfaces where it is not intended to be (e.g., in lunch rooms or offices, or on the outside surfaces of packaging materials). However, they should not be confused with cleaning limits for the surfaces of manufacturing devices that might come into contact with the drug product, which are set to minimize cross contamination between drug products and to protect end-users (e.g., patients taking drug products) as opposed to workers. A number of parameters must be evaluated in order to accurately develop appropriate and scientifically supportable limits. These include the dose or concentration that will cause the potential effect, the degree of chemical transfer from contaminated surfaces to the skin, and the rate or amount of percutaneous absorption. In practice, this information is usually limited or unavailable. Additionally, there has been very little regulatory guidance on the setting of ASLs. Consequently, in order to calculate an ASL, various assumptions must be made by health and safety professionals regarding how dermal exposures might occur. As quantitative data become available, the ASL can be adjusted accordingly. An overview of the setting of health-based and performance-based ASLs for pharmaceutical substances from animal and human toxicological data is provided.
Understanding and Improving Morphological Learning in the Neural Machine Translation Decoder

End-to-end training makes the neural machine translation (NMT) architecture simpler, yet elegant compared to traditional statistical machine translation (SMT). However, little is known about linguistic patterns of morphology, syntax and semantics learned during the training of NMT systems, and more importantly, which parts of the architecture are responsible for learning each of these phenomenon. In this paper we i) analyze how much morphology an NMT decoder learns, and ii) investigate whether injecting target morphology in the decoder helps it to produce better translations. To this end we present three methods: i) simultaneous translation, ii) joint-data learning, and iii) multi-task learning. Our results show that explicit morphological information helps the decoder learn target language morphology and improves the translation quality by 0.2–0.6 BLEU points.
Joint estimation of Down syndrome risk and ascertainment rates: a meta‐analysis of nine published data sets

In this paper we present an analysis of nine data sets in which ascertainment and maternal age risk of Down syndrome are estimated jointly using maximum likelihood. We include data on 4825 Down syndrome cases from nine previously published data sets. These include data from studies carried out before the introduction of prenatal screening and from recent studies involving women who had not received prenatal testing. Our results show that, allowing for under‐ascertainment, there is a good degree of consistency between the different data sets. We compare the three‐ and five‐parameter constant plus exponential model with a three‐parameter logistic model for maternal age‐specific risk. We show that the three‐parameter logistic model provides a good fit to the data and compare rates from this model with those derived from published studies of uncertain completeness (Cuckle et al., 1987) and those from data sets believed to be complete (Halliday et al., 1995; Hecht and Hook, 1994, 1996). In general, our results agree closely with those of the latter, but achieve greater precision because of the inclusion of additional data. Our derived rates are considerably higher than those of Cuckle et al. (1987), which are embedded in many computer systems for generating risks. © 1998 John Wiley & Sons, Ltd.
Wegener's granulomatosis: inflammatory cells and markers of repair and fibrosis in renal biopsies--a clinicopathological study.

OBJECTIVE This study aimed to quantitate inflammatory cells in renal biopsies from patients with Wegener's granulomatosis (WG) and to identify cells participating in early fibrogenesis. The goal was to determine whether these cells correlated with the severity of renal disease and whether their presence had a bearing on renal prognosis. MATERIAL AND METHODS Sixty-one patients with WG who had a renal biopsy taken at the time of diagnosis were included in the study. Immunostaining with monoclonal antibodies towards macrophages (CD68), T- and B-lymphocytes, alpha-smooth muscle actin (alpha-SMA) and vimentin was done. RESULTS The dominating intraglomerular leucocytes were macrophages (29.9 +/- 15 cells/glomerular cross-section) and to a lesser extent T-cells (2.57 +/- 1.8 cells/glomerular cross-section). No B-lymphocytes were detected in the glomeruli. More than two-thirds of the T-cells were CD8+ (cytotoxic) cells. Macrophages and T-lymphocytes were distributed equally in the renal interstitium and were numerous around crescentic glomeruli. Glomerular and interstitial macrophages and interstitial T-cells correlated significantly with serum (S-) creatinine at the time of biopsy but not after 1 year. S-creatinine at the time of biopsy and after 1 year differed significantly among the three levels of interstitial alpha-SMA staining. S-creatinine at biopsy was highest when tubular vimentin staining was strongest, and tubular vimentin staining was strongest in patients with acute tubular damage. CONCLUSIONS Evidence was found for a cellular type IV immune response in WG, with CD8+ T-lymphocytes and macrophages dominating the cellular infiltrate. The detection of interstitial alpha-SMA, probably staining myofibroblasts implicated in renal fibrogenesis, indicated a low glomerular filtration rate 1 year after renal biopsy.
DECAY RATES FOR SOLUTIONS TO THERMOELASTIC BRESSE SYSTEMS OF TYPES I AND III

In this article, we study the energy decay for the thermoelastic Bresse system in the whole line with two dissipative mechanisms, given by heat conduction (Types I and III). We prove that the decay rate of the solutions are very slow. More precisely, we show that the solutions decay with the rate of (1+t)−1/8 in the L2-norm, whenever the initial data belongs to L1(R)∩Hs(R) for a suitable s. The wave speeds of propagation have influence on the decay rate with respect to the regularity of the initial data. This phenomenon is known as regularity-loss. The main tool used to prove our results is the energy method in the Fourier space.
Flow Cytometric Detection of Activated Platelets: Comparison of Determining Shape Change, Fibrinogen Binding, and P-Selectin Expression

Platelet activation plays an important role in the pathomechanisms of arterial vascular disorders including stroke, peripheral arterial disease (PAD), and myocardial infarction. Circulating activated platelets may be useful markers of local thrombotic events occurring in these diseases. Using flow cytometry circulating activated platelets can be detected by determining: 1. the platelets' shape change on the basis of the different light scatter properties of discocytes and spherocytes, 2. the expression of platelet bound fibrinogen or conformation specific neoantigens on fibrinogen and on its platelet receptor, and 3. the exposure of granule membrane proteins such as P-selectin as a result of platelet secretion. The concentration-effect relationships were determined for the ADP and U46619 induced shape change, fibrinogen binding, and expression of P-selectin. The EC50 for the shape change was 4 times lower than the EC50 for the fibrinogen binding and 29 times lower than the EC50 for the expression of P-selectin. These data clearly demonstrate that the shape change is a more sensitive indicator of platelet activation in vitro than fibrinogen binding or P-selectin expression. Both the shape change and fibrinogen binding were reversible, whereas the expression of P-selectin was irreversible upon stimulation. Reversibility of the shape change may be responsible for the fact that in patients with stroke or PAD the fraction of discocytes did not differ from controls, whereas more than 80% of them revealed a significantly higher fraction of P-selectin positive platelets. Thus the determination of the P-selectin expression reveals a higher diagnostic sensitivity for detecting a platelet activation in vivo than the determination of the shape change.
Cost-effectiveness of levodopa/carbidopa/entacapone (Stalevo*) compared to standard care in UK Parkinson's disease patients with wearing-off

ABSTRACT Background and methods: A Markov model was developed to evaluate the cost-effectiveness of levodopa/carbidopa/entacapone (LCE;Stalevo*), in the treatment of patients with Parkinson's disease (PD) and end-of-dose motor fluctuations (wearing-off). LCE, with or without other antiparkinsonian medications, was compared to UK standard care, comprising traditional levodopa/dopa-decarboxylase inhibitor (DDCI) with other antiparkinsonian medications (e.g. selegiline or dopamine agonists) added as needed. The costs and outcomes of both treatments were projected over a period of 10 years from the perspective (a) of society as a whole and (b) of the UK National Health Service (NHS). Sensitivity analyses, including second-order Monte Carlo simulations, were performed to assess the confidence level of the primary results. Results: Treatment with LCE produced an average gain of +1.04 quality-adjusted life-years (QALYs) per patient (2.57 vs. 1.53) in the base-case analysis (discount rate 3.5%). This gain was accompanied by a reduction in the total 10-year direct cost of care to society of £10 198 per patient (~ ¤14 800). From the societal perspective, therefore, LCE was dominant, producing better clinical outcomes with lower costs. This dominance was reiterated in all sensitivity analyses of society-focused analysis, including a shortening of the time-frame to 5 years. Although treatment with LCE resulted in an increase in direct costs per patient of £3239 (£25 756 versus £22 517) to the NHS over the 10-year period analysed, the incremental cost-effectiveness ratio (ICER) of LCE was only £3105 per QALY gained (~ ¤4500). All ICERs to the NHS remained below £3800 per QALY gained in univariate sensitivity analyses applying different discount rates. When a shorter, 5-year, time-horizon was analysed, the NHS-related ICER for LCE was £6526 per QALY gained. All these ICERs are within the range usually considered to indicate acceptable or highly acceptable cost effectiveness (defined as < £30 000 per QALY gained). The results of the Monte Carlo simulations indicated that the likelihood of LCE being either ‘dominant’ or more effective at an ‘acceptable cost’ from either the societal or the NHS perspective was high, exceeding 96% in the base-case sensitivity analysis, and was 93% even when all the uncertainties associated with the model were taken into consideration simultaneously. In particular, compared to standard care, the probability that LCE would provide better outcomes at a lower cost to society as a whole was 77% in the base-case sensitivity analysis and 72% in the scenario involving the highest degree of uncertainty. Conclusions: In the UK the use of LCE to treat PD patients with wearing-off is beneficial to individual patients and likely to offer money savings to society as a whole, compared with UK standard therapy. The added cost of the medication itself is exceeded by the savings made in other direct costs of PD, mainly those relating to social care or PD-related private expenditures.
Suppressors of Cytokine Signaling-1 and -3 Regulate Osteoclastogenesis in the Presence of Inflammatory Cytokines1

Bone metabolism and the immune system have a correlative relationship, and both are controlled by various common cytokines, such as IFNs and ILs, produced in the bone microenvironments. The suppressor of cytokine signaling-1 (SOCS1) and SOCS3 are negative regulators of such cytokines. Although SOCSs are shown to be induced during osteoclast differentiation, their physiological roles in osteoclast differentiation and function have not been clarified. Thus, we examined the roles of SOCS1 and SOCS3 in osteoclastogenesis using SOCS1- and SOCS3-deficient mice. IFN-γ-mediated inhibition of osteoclast differentiation from bone marrow-derived monocytes (BMMs) was strongly enhanced in SOCS1-deficient BMMs, but was diminished in SOCS1-overexpressing BMMs. Moreover, LPS-induced osteoclastogenesis and bone destruction in vivo were suppressed in SOCS1+/− mice compared with those in wild-type mice, suggesting that SOCS1 antagonizes the inhibitory effect of IFN-γ on osteoclastogenesis. SOCS3 did not alter the inhibitory effect of IFNs in osteoclastogenesis in both gain and loss of functional assays; however, the suppressive effect of IL-6 on osteoclast differentiation was greater in SOCS3-deficient BMMs than in wild-type BMMs in vitro. In addition, IL-6 significantly prevented LPS-induced bone destruction in SOCS3-deficient mice, although it failed in wild-type mice in vivo. In SOCS3-deficient BMMs, expression levels of TNF-receptor-associated factor-6 and IκB were drastically reduced and receptor activator of the NF-κB ligand-induced IκB phosphorylation was severely impaired in the presence of IL-6. These data suggest that both SOCS1 and SOCS3 regulate osteoclastogenesis by blocking the inhibitory effect of inflammatory cytokines on receptor activator of the NF-κB ligand-mediated osteoclast differentiation signals. Selective suppression of SOCS1 and SOCS3 in osteoclast precursors may be a possible therapeutic strategy for inflammatory bone destruction.
An E3 Ligase Affects the NLR Receptor Stability and Immunity to Powdery Mildew1

The barley MIR1 E3 ubiquitin ligase interacts with MLA immune receptors to promote their ubiquitination and proteasomal degradation, thus regulating receptor stability and immunity. Following the detection of pathogen cognate effectors, plant Nod-like receptors (NLRs) trigger isolate-specific immunity that is generally associated with cell death. The regulation of NLR stability is important to ensure effective immunity. In barley (Hordeum vulgare), the allelic Mildew locus A (MLA) receptors mediate isolate-specific disease resistance against powdery mildew fungus (Blumeria graminis f. sp. hordei). Currently, how MLA stability is controlled remains unknown. Here, we identified an MLA-interacting RING-type E3 ligase, MIR1, that interacts with several MLAs. We showed that the carboxyl-terminal TPR domain of MIR1 mediates the interaction with the coiled-coil domain-containing region of functional MLAs, such as MLA1, MLA6, and MLA10, but not with that of the nonfunctional MLA18-1. MIR1 can ubiquitinate the amino-terminal region of MLAs in vitro and promotes the proteasomal degradation of MLAs in vitro and in planta. Both proteasome inhibitor treatment and virus-induced gene silencing-mediated MIR1 silencing significantly increased MLA abundance in barley transgenic lines. Furthermore, overexpression of MIR1 specifically compromised MLA-mediated disease resistance in barley, while coexpression of MIR1 and MLA10 attenuated MLA10-induced cell death signaling in Nicotiana benthamiana. Together, our data reveal a mechanism for the control of the stability of MLA immune receptors and for the attenuation of MLA-triggered defense signaling by a RING-type E3 ligase via the ubiquitin proteasome system.