Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparison of the effects of topical administration of a fixed combination of dorzolamide-timolol to monotherapy with timolol or dorzolamide on IOP, pupil size, and heart rate in glaucomatous dogs.

OBJECTIVE To determine whether the combination multiple-dose dorzolamide-timolol administered topically has any greater effects on the reduction of intraocular pressure, pupil size, and heart rate in dogs with glaucoma than do either timolol or dorzolamide alone. PROCEDURE Applanation tonometry, pupil size, and heart rate measurements were made at 7 a.m., 1 p.m. , and 7 p.m. daily of 12 laboratory Beagles with inherited primary open-angle glaucoma during each active phase of this study. Timolol 0.5% was administered first twice daily for 4 consecutive days. Dorzolamide 2.0% was administered next three times daily for 4 consecutive days. The fixed combination of the two (timolol 0.5% and dorzolamide 2.0%) was administered twice daily for 4 consecutive days during the final week of the study. Between administration of each drug, a withdrawal period of at least 10 days was instituted. Statistical comparisons between the effects of the three drugs were performed. RESULTS Intraocular pressure (IOP) was decreased with the administration of all three drugs: timolol alone, dorzolamide alone, and the combination of the two decreased IOP after 1 day of treatment 2.83 +/- 0.70 mmHg, 6.47 +/- 0.32 mmHg, and 6.56 +/- 0.37 mmHg, respectively. After 4 days of treatment, the IOP decreased even further: timolol alone, dorzolamide alone, and the combination of the two decreased IOP 3.75 +/- 0.88 mmHg, 7.50 +/- 0.29 mmHg, and 8.42 +/- 0.58 mmHg, respectively. Heart rate was significantly decreased with timolol (-11.9 +/- 2.0 bpm) and the combination preparation (-8.6 + 2.4 bpm), but not with dorzolamide (-3.7 +/- 1.8 bpm) alone. Pupil size was significantly decreased with timolol (-1.42 + 0.40 mm) and the combination preparation (-1.3 + 0.33 mm), but not with dorzolamide (0.97 +/- 0.36 mm) alone. CONCLUSIONS The combination dorzolamide-timolol appears to be more effective at reducing intraocular pressure in glaucomatous dogs than is either timolol or dorzolamide alone.
Benign and malignant mucocele-like tumors of the breast: mammographic and sonographic appearances.

OBJECTIVE The purpose of this study was to analyze and compare the mammographic and sonographic appearances of benign and malignant mucocele-like tumors. CONCLUSION The mammographic appearance of mucocele-like tumor of the breast is characterized as pleomorphic calcifications, often increasing in number. Microcalcifications in malignant mucocele-like tumors extended over a wider area than those in benign mucocele-like tumors. Sonography often shows cysts with calcified or noncalcified mural nodules.
Expression patterns of beta-catenin in in situ and invasive breast cancer.

BACKGROUND beta-Catenin plays a central role in the E-cadherin/catenin cell-cell adhesion complex and is possibly involved in cellular signalling pathways. In this study, we evaluated the expression patterns of this molecule in in situ and invasive breast cancer. METHODS The expression of beta-catenin was evaluated in 121 breast cancer specimens by immunohistochemistry. Its relationship to clinicopathological features was also investigated. RESULTS Altered beta-catenin expression was found in 68% of tumours. Lobular carcinomas showed abnormal beta-catenin expression more frequently (77%) than ductal carcinomas (64%) with 46% of lobular cases showing complete absence of beta-catenin immunoreactivity. Cytoplasmic beta-catenin localization was seen only in ductal carcinomas. Aberrant beta-catenin expression was observed in 54% of ductal carcinomas in situ with highly concordant beta-catenin expression patterns in the nearby in situ and invasive components. CONCLUSIONS Quantitative and qualitative changes in beta-catenin expression occur in a considerable proportion of in situ and invasive ductal carcinomas and are more prominent in invasive lobular carcinomas.
One-Step Treatment for Patellar Cartilage Defects With a Cell-Free Osteochondral Scaffold: A Prospective Clinical and MRI Evaluation

Background: The treatment of symptomatic cartilage defects of the patella is particularly challenging, and no gold standard is currently available. Purpose: To evaluate the clinical results of a biphasic cell-free collagen-hydroxyapatite scaffold and to evaluate osteochondral tissue regeneration with magnetic resonance imaging (MRI). Study Design: Case series; Level of evidence, 4. Methods: Thirty-four patients (18 men and 16 women; mean ± SD: age, 30.0 ± 10 years) were treated by scaffold implantation for knee chondral or osteochondral lesions of the patella (area, 2.1 ± 1 cm2). The clinical evaluation was performed prospectively at 12 and 24 months via the IKDC (International Knee Documentation Committee; objective and subjective) and Tegner scores. MRI evaluation was performed at both follow-ups in 18 lesions through the MOCART score (magnetic resonance observation of cartilage repair tissue) and specific subchondral bone parameters. Results: A statistically significant improvement in all the scores was observed at 12- and 24-month follow-up as compared with the basal evaluation. The IKDC subjective score improved from 39.5 ± 14.5 to 61.9 ± 14.5 at 12 months (P > .0005) with a further increase to 67.6 ± 17.4 at 24 months of follow-up (12-24 months, P = .020). The MRI evaluation showed a stable value of the MOCART score between 12 and 24 months, with a complete filling of the cartilage in 87.0% of the lesions, complete integration of the graft in 95.7%, and intact repair tissue surface in 69.6% at final follow-up. The presence of osteophytes or more extensive bony overgrowth was documented in 47.8% of the patients of this series, but no correlation was found between MRI findings and clinical outcome. Conclusion: The implantation of a cell-free collagen-hydroxyapatite osteochondral scaffold provided a clinical improvement at short-term follow-up for the treatment of patellar cartilage defects. Women had lower outcomes, and the need for realignment procedures led to a slower recovery. MRI evaluation showed some abnormal findings with the presence of bone overgrowth, but no correlation has been found with the clinical outcome.
Choroid plexus carcinomas are characterized by complex chromosomal alterations related to patient age and prognosis

Choroid plexus carcinoma is a malignant brain tumor predominantly occurring in young children. Only limited data are available regarding the underlying molecular genetic alterations. Therefore, molecular inversion probe single nucleotide polymorphism (MIP SNP) arrays were performed on a series of 26 neuropathologically well‐characterized choroid plexus carcinomas. Recurrent copy number losses of chromosomes 5, 6, 16, 18, 19, and 22 as well as gains of chromosomes 1, 2, 4, 12, and 20 were identified. Furthermore, GISTIC analysis identified significant recurrent gains of 17 genes in 9 regions, and recurrent losses of 96 genes in 14 regions. Clustering analysis separated choroid plexus carcinomas into two groups: one characterized by marked losses and the other characterized by gains across the chromosomes. Chromosomal losses of 9, 19p, and 22q were significantly more frequent in younger children (<36 months), whereas gains on chromosomes 7 and 19, and chromosome arms 8q, 14q, and 21q prevailed in older patients. Multivariate analysis revealed that loss of 12q was associated with shorter survival [12 ± 5 months vs. 86 ± 8 months; (mean ± SD; P = 0.001)] and, in addition, 45 smaller chromosomal regions showing genetic alterations significantly associated with survival could be identified. The MIP SNP array profiles also contributed to the diagnosis of two difficult SMARCB1‐negative tumors as choroid plexus carcinoma and cribriform neuroepithelial tumor (CRINET), respectively. In conclusion, choroid plexus carcinomas are characterized by complex genetic alterations, which are related to patient age and may have prognostic and diagnostic value. © 2014 Wiley Periodicals, Inc.
Macrophage Migration Inhibitory Factor Up-regulates Expression of Matrix Metalloproteinases in Synovial Fibroblasts of Rheumatoid Arthritis*

Neutral matrix metalloproteinases (MMPs) are responsible for the pathological features of rheumatoid arthritis (RA) such as degradation of cartilage. We herein show the up-regulation of MMP-1 (interstitial collagenase) and MMP-3 (stromelysin) mRNAs of cultured synovial fibroblasts retrieved from rheumatoid arthritis (RA) patients in response to macrophage migration inhibitory factor (MIF). The elevation of MMP-1 and MMP-3 mRNA was dose-dependent and started at 6 h post-stimulation by MIF, reached the maximum level at 24 h, and was sustained at least up to 36 h. Interleukin (IL)-1β mRNA was also up-regulated by MIF. These events were preceded by up-regulation of c-jun and c-fos mRNA. Tissue inhibitor of metalloproteinase (TIMP)-1, a common inhibitor of these proteases, was slightly up-regulated by MIF. Similarly, mRNA up-regulation of MMP-1 and MMP-3 was observed in the synovial fibroblasts of patients with osteoarthritis. However, their expression levels were much lower than those of RA synovial fibroblasts. The mRNA up-regulation by MIF was inhibited by the tyrosine kinase inhibitors genestein and herbimycin A, as well as the protein kinase C inhibitors staurosporine and H-7. On the other hand, the inhibition was not seen after the addition of the cyclic AMP-dependent kinase inhibitor, H-8. The mRNA up-regulation of MMPs was also inhibited by curcumin, an inhibitor of transcription factor AP-1, whereas interleukin-1 receptor antagonist, an IL-1 receptor antagonist, failed to inhibit the mRNA up-regulation. Considering these results, it is suggested that 1) MIF plays an important role in the tissue destruction of rheumatoid joints via induction of the proteinases, and 2) MIF up-regulates MMP-1 and MMP-3 via tyrosine kinase-, protein kinase C-, and AP-1- dependent pathways, bypassing IL-1β signal transduction.
Enteropathogens associated with cases of gastroenteritis in a rural population in Jordan.

Stool specimens were collected from 180 patients belonging to a population of recently settled Bedouins in Jordan who presented with acute or persistent diarrhoea and other symptoms, and from 100 non-diarrhoeal controls. All samples were examined for parasites and bacterial pathogens by culture and PCR. Bacterial isolates were tested for their susceptibility to common antimicrobial agents. Pathogens and potential enteropathogens were identified from 140 (77.8%) of the patients, with more than one pathogen being recovered from 67 (37.2%) patients. Potentially pathogenic parasites were observed in 90 (50%) patients; those that were associated significantly with diarrhoea were Giardia lamblia, Blastocystis hominis, Cryptosporidium spp. , Entamoeba histolytica and Cyclospora cayetanensis. Pathogenic bacteria were isolated from 72 (40%) patients, and, of these, 62.5% were resistant to at least one antibiotic, and 30.6% of these were multiresistant. Diarrhoeagenic Escherichia coli strains were found in 14.3% of the patients and 2.9% of the control subjects (not statistically significant). The most common enteropathogenic bacteria found were Shigella spp. , Campylobacter jejuni and Yersinia enterocolitica. Unusual bacterial species were the predominant organisms recovered in a few cases and could represent a possible cause of diarrhoea. Overall, there was a high endemicity of diarrhoeal disease in the area studied. Risk factors that correlated significantly with contracting diarrhoea were socio-economic status, education, use of unchlorinated well or tank water, and a low level of personal hygiene.
Frequencies of circulating B- and T-lymphocytes as indicators for stroke outcomes

Background Stroke has high mortality and morbidity. Biomarkers are required for to predict stroke outcomes, which could help clinicians to provide rationale approaches for patient management. The dynamic changes in circulating immune cells have been reported in stroke patients and animal models of stroke. Aim The aim of this study was to explore biomarkers to predict stroke outcomes by investigating the relationship between the frequencies of circulating immune cells and stroke outcomes. Methods In all, 50 acute ischemic stroke (AIS) patients were enrolled. Their blood samples were collected upon hospital admission and on day 1 and day 7 after stroke, and the leukocyte subsets were analyzed by flow cytometry. The dynamic changes in some types of immune cells in the AIS course and their correlation with clinical parameters were analyzed. Blood samples from 123 age- and gender-matched healthy subjects were used as controls. Results The proportions of T-lymphocytes and NK cells in stroke patients were significantly lower than in healthy controls. The frequencies of B- and T-lymphocytes were negatively correlated with stroke severity at onset, including neurological deficits as assessed by National Institutes of Health Stroke Scale (NIHSS), and infarct volume as measured by the diffusion-weighted images (DWIs) of magnetic resonance (MR). Logistic regression analysis showed that modified Rankin scale (mRs) scores, a score system for the long-term neurological dysfunctions, were negatively correlated with the percentage of B-lymphocytes at stroke onset. Conclusion The proportions of B- and T-lymphocytes are associated with neurological outcomes of stroke patients and might be used as an indicator for severity and prognosis of ischemic stroke.
Scedosporium prolificans sclerokeratitis 10 years after pterygium excision with adjunctive mitomycin C

Scedosporium prolificans is an unusual infection, especially following pterygium surgery. A 63‐year‐old man who developed an uncomfortable, red right eye 10 years after pterygium surgery with adjunctive mitomycin C is described. To the best of the authors’ knowledge, this is the first reported case of S. prolificans sclerokeratitis following pterygium surgery with adjunctive mitomycin C.
Cyclic AMP Analog Blocks Kinase Activation by Stabilizing Inactive Conformation: Conformational Selection Highlights a New Concept in Allosteric Inhibitor Design*

The regulatory (R) subunit of protein kinase A serves to modulate the activity of protein kinase A in a cAMP-dependent manner and exists in two distinct and structurally dissimilar, end point cAMP-bound “B” and C-subunit-bound “H”-conformations. Here we report mechanistic details of cAMP action as yet unknown through a unique approach combining x-ray crystallography with structural proteomics approaches, amide hydrogen/deuterium exchange and ion mobility mass spectrometry, applied to the study of a stereospecific cAMP phosphorothioate analog and antagonist((Rp)-cAMPS). X-ray crystallography shows cAMP-bound R-subunit in the B form but surprisingly the antagonist Rp-cAMPS-bound R-subunit crystallized in the H conformation, which was previously assumed to be induced only by C-subunit-binding. Apo R-subunit crystallized in the B form as well but amide exchange mass spectrometry showed large differences between apo, agonist and antagonist-bound states of the R-subunit. Further ion mobility reveals the apo R-subunit as an ensemble of multiple conformations with collisional cross-sectional areas spanning both the agonist and antagonist-bound states. Thus contrary to earlier studies that explained the basis for cAMP action through “induced fit” alone, we report evidence for conformational selection, where the ligand-free apo form of the R-subunit exists as an ensemble of both B and H conformations. Although cAMP preferentially binds the B conformation, Rp-cAMPS interestingly binds the H conformation. This reveals the unique importance of the equatorial oxygen of the cyclic phosphate in mediating conformational transitions from H to B forms highlighting a novel approach for rational structure-based drug design. Ideal inhibitors such as Rp-cAMPS are those that preferentially “select” inactive conformations of target proteins by satisfying all “binding” constraints alone without inducing conformational changes necessary for activation.
Effect of single mannitol bolus in intracerebral hemorrhage

Because of existing controversy about use of mannitol in intracerebral hemorrhage (ICH) this open exploratory trial with blinded outcome assessment of single mannitol bolus in ICH was undertaken. CT proven primary supratentorial ICH patients having midline shift of ≥3 mm were randomized into 20% mannitol (1.5 g/kg) and control groups. Clinical evaluation included Glasgow coma scale (GCS) score, Canadian Neurological scale (CNS) score, pupils, breathing, extensor posturing and contra‐lateral pyramidal signs. On cranial MRI horizontal (HS), superior sagittal sinus to pontomesencephalic junction (SSS‐PMJ) distance and edema hematoma complex were measured. Twelve patients each were in mannitol and control groups. The age, sex, GCS score, CNS score, pupillary asymmetry, contra‐lateral pyramidal signs, HS and SSS‐PMJ distance in mannitol and control groups did not differ significantly. Mannitol infusion resulted clinical improvement in five patients, which lasted for 30–60 min. HS and SSS‐PMJ distance in mannitol and control groups did not change at 30 or 60 min from the baseline. The change in HS and SSS‐PMJ distance were also not significantly different between the two groups both at 30 and 60 min. Mannitol led to transient clinical improvement in five patients without significant reduction in HS or SSS‐PMJ distance at 30 and 60 min.
RING Finger Protein RNF207, a Novel Regulator of Cardiac Excitation

Background: A genetic variant within RNF207 is associated with a prolonged QT interval. QT interval prolongation may lead to arrhythmia, a risk factor for sudden cardiac death. Results: RNF207 regulates action potential duration and the repolarizing channel HERG. Conclusion: RNF207 is an important regulator of cardiac excitation. Significance: Understanding the composition and dynamics of membrane complexes is important in unraveling the mechanism of arrhythmias. Two recent studies (Newton-Cheh, C. et al. (2009) Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat. Genet. 41, 399–406 and Pfeufer, A. et al. (2009) Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat. Genet. 41, 407–414) identified an association, with genome-wide significance, between a single nucleotide polymorphism within the gene encoding RING finger protein 207 (RNF207) and the QT interval. We sought to determine the role of RNF207 in cardiac electrophysiology. Morpholino knockdown of RNF207 in zebrafish embryos resulted in action potential duration prolongation, occasionally a 2:1 atrioventricular block, and slowing of conduction velocity. Conversely, neonatal rabbit cardiomyocytes infected with RNF207-expressing adenovirus exhibited shortened action potential duration. Using transfections of U-2 OS and HEK293 cells, Western blot analysis and immunocytochemistry data demonstrate that RNF207 and the human ether-a-go-go-related gene (HERG) potassium channel interact and colocalize. Furthermore, RNF207 overexpression significantly elevated total and membrane HERG protein and HERG-encoded current density by ∼30–50%, which was dependent on the intact N-terminal RING domain of RNF207. Finally, coexpression of RNF207 and HSP70 increased HERG expression compared with HSP70 alone. This effect was dependent on the C terminus of RNF207. Taken together, the evidence is strong that RNF207 is an important regulator of action potential duration, likely via effects on HERG trafficking and localization in a heat shock protein-dependent manner.
Dexamethasone Does Not Modulate Eosinophil Adhesion to Endothelial Cells

Background: Glucocorticoids are representative agents in the anti-inflammatory treatment of allergic airway diseases. Although they reduce the number of tissue eosinophils, its exact mechanism has not been completely established. Objective: The present study was undertaken to evaluate whether dexamethasone modulates the adhesive property of eosinophils. The effect on the expression of endothelial adhesion molecules was also evaluated. Methods: Blood eosinophils from healthy subjects were incubated in the presence or absence of 0.1–1 µM of dexamethasone for 6 h at 37°C. Eosinophil chemotaxis and adhesion to paraformaldehyde-fixed human pulmonary vascular endothelial cells (HPMEC) were then examined. The effects of dexamethasone on the expression of VCAM-1 and ICAM-1 on HPMEC were examined by cell ELISA. Results: 1 µM dexamethasone significantly inhibited the chemotactic response of eosinophils to 1 µM formyl-methionyl-leucyl-phenylalanine (FMLP). On the other hand, dexamethasone did not modify either the spontaneous or FMLP-stimulated adhesion of eosinophils to resting HPMEC. Similarly, dexamethasone did not alter either the spontaneous adhesion of eosinophils to or the expression of VCAM-1 or ICAM-1 on HPMEC stimulated with IL-4 + TNF-α. Conclusion: Dexamethasone does not modify the adhesive property of eosinophils or the expression of adhesion molecules on endothelial cells. Thus, it is unlikely that glucocorticoids directly modulate the adhesive interaction between eosinophils and endothelial cells.
Prognosis in Patients with Non-Small Cell Lung Cancer Who Received Erlotinib Treatment and Subsequent Dose Reduction due to Skin Rash

Background: Severe skin rash as toxicity of erlotinib has been reported in relation to better response and survival. However, some patients require dose reduction due to skin toxicities, and their prognosis remains uncertain. We retrospectively evaluated the clinical course of non-small cell lung cancer patients receiving erlotinib at a reduced dose because of skin rash. Patients and Methods: Among 76 patients treated with erlotinib, 55 patients who developed skin rash severer than grade 2 were divided into 2 groups: 24 patients treated with erlotinib with dose reduction because of skin rash (dose reduction group) and 31 patients without any dose reduction (non-dose reduction group). Results: The median progression-free survival in the dose reduction and non-dose reduction groups was 341 and 70 days, respectively, and the median overall survival was 566 and 202 days, respectively (p < 0.001). In the dose reduction group, no smoking history, female sex, epidermal growth factor receptor gene mutation, and grade 3 skin rash were significant baseline factors. Conclusions: Patients who received erlotinib at a reduced dose following skin rash showed better survival than those without reduction. In cases of intolerable skin rash, patients may benefit from continuous treatment with a reduced dose of erlotinib.
Parallelism, uniqueness, and large‐sample asymptotics for the Dantzig selector

The Dantzig selector (Candès & Tao, 2007) is a popular $\ell^{1}$‐regularization method for variable selection and estimation in linear regression. We present a very weak geometric condition on the observed predictors which is related to parallelism and, when satisfied, ensures the uniqueness of Dantzig selector estimators. The condition holds with probability 1, if the predictors are drawn from a continuous distribution. We discuss the necessity of this condition for uniqueness and also provide a closely related condition which ensures the uniqueness of lasso estimators (Tibshirani, 1996). Large sample asymptotics for the Dantzig selector, that is, almost sure convergence and the asymptotic distribution, follow directly from our uniqueness results and a continuity argument. The limiting distribution of the Dantzig selector is generally non‐normal. Though our asymptotic results require that the number of predictors is fixed (similar to Knight & Fu, 2000), our uniqueness results are valid for an arbitrary number of predictors and observations. The Canadian Journal of Statistics 41: 23–35; 2013 © 2012 Statistical Society of Canada