tbuckley/cabot-search huggingface dataset:
Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism
Authors: Ighovie F. Onojafe, David R. Adams, Dimitre R. Simeonov, Jun Zhang, Chi-Chao Chan, Isa M. Bernardini, Yuri V. Sergeev, Monika B. Dolinska, Ramakrishna P. Alur, Murray H. Brilliant, William A. Gahl, Brian P. Brooks
Journal: Journal of Clinical Investigation (2011)

Mutation of the tyrosinase gene (TYR) causes oculocutaneous albinism, type 1 (OCA1), a condition characterized by reduced skin and eye melanin pigmentation and by vision loss. The retinal pigment epithelium influences postnatal visual development. Therefore, increasing ocular pigmentation in patients with OCA1 might enhance visual function. There are 2 forms of OCA1, OCA-1A and OCA-1B. Individuals with the former lack functional tyrosinase and therefore lack melanin, while individuals with the latter produce some melanin. We hypothesized that increasing plasma tyrosine concentrations using nitisinone, an FDA-approved inhibitor of tyrosine degradation, could stabilize tyrosinase and improve pigmentation in individuals with OCA1. Here, we tested this hypothesis in mice homozygous for either the Tyrc-2J null allele or the Tyrc-h allele, which model OCA-1A and OCA-1B, respectively. Only nitisinone-treated Tyrc-h/c-h mice manifested increased pigmentation in their fur and irides and had more pigmented melanosomes. High levels of tyrosine improved the stability and enzymatic function of the Tyrc-h protein and also increased overall melanin levels in melanocytes from a human with OCA-1B. These results suggest that the use of nitisinone in OCA-1B patients could improve their pigmentation and potentially ameliorate vision loss.
SOD2 DEFICIENCY-MEDIATED OXIDATIVE STRESS INCREASES ARTERIAL STIFFNESS IN AGED MICE
Authors: Ruihai Zhou, Aleksandr E. Vendrov, Igor Tchivilev, Xi-Lin Niu, Kimberly C. Molnar, Nageswara R. Madamanchi, Marschall S. Runge
Journal: Journal of the American College of Cardiology (2011)
Evaluation of adverse cutaneous reactions to aminopenicillins with emphasis on those manifested by maculopapular rashes
Authors: A. Romano, M. di Fonso, G. Papa, F. Pietrantonio, F. Federico, G. Fabrizi, A. Venuti
Journal: Allergy (1995)

We assessed 195 subjects with histories of adverse reactions to aminopenicillins, using 1) skin tests with penicilloyl polylysine (PPL), minor determinant mixture (MDM), benzylpenicillin (PG), amoxicillin, and ampicillin (read after 20 min and 48 h); 2) patch tests with PG, amoxicillin, and ampicillin; and 3) RAST for penicilloyls G and V. Oral challenges with ampicillin, amoxicillin, and penicillin V were administered to 34/60 patients reporting maculopapular reactions. Immediate hypersensitivity (IH), in most cases for both penicillin and aminopenicillins, was diagnosed (based on skin tests, RAST, or both) in 35 subjects who had suffered anaphylactic shock, or urticaria, angioedema, or both urticaria and angioedema. Thirty‐three of the 60 subjects reporting maculopapular reactions presented delayed intradermal and patch‐test positivity, indicating delayed hypersensitivity (DH), for ampicillin and amoxicillin, and three were also positive for PG. Diagnoses were confirmed with oral challenges in 18/33. The remaining 27/60 were negative in all allergologic tests, with oral‐challenge confirmation in 16. Our findings highlight the importance of the amino group in DH to aminopenicillins. Moreover, the mean time interval between the last reaction and our tests was significantly ( P &lt; 0.01) longer in DH subjects (54.96 months) than in those with IH (18.62 months), suggesting that the time of testing is less important in cases of DH.
The classification criteria for Sjögren syndrome: issues for their improvement from the study of a large Italian cohort of patients
Authors: Luca Quartuccio, Chiara Baldini, Roberta Priori, Elena Bartoloni, Francesco Carubbi, Roberto Giacomelli, Roberto Gerli, Guido Valesini, Salvatore De Vita, Stefano Bombardieri
Journal: Annals of the Rheumatic Diseases (2014)

We read with great interest the article by Rasmussen et al ,1 which compared the performance of the new ACR2 and the AECG3 classification criteria for Sjogren syndrome (SS) showing that they led to similar results when applied to a well characterised cohort of patients with sicca symptoms. More specifically, no clear evidence for an increased value of the new ACR criteria2 over the old AECG criteria3 from the clinical or biological perspective was suggested by the authors. In addition, when compared to the ACR criteria, the AECG criteria gave more space to patients’ subjective symptoms which …
Effect of Treatment with Dornase Alpha on Airway Inflammation in Patients with Cystic Fibrosis
Authors: Karl Paul, Ernst Rietschel, Manfred Ballmann, Matthias Griese, Dieter Worlitzsch, Janis Shute, Christiane Chen, Tanja Schink, Gerd Döring, Silke van Koningsbruggen, Ulrich Wahn, Felix Ratjen
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Recombinant human deoxyribonuclease (rhDNase) has been shown to improve lung function and reduce the number of pulmonary exacerbations in patients with cystic fibrosis (CF), but its long-term effect on airway inflammation remains unknown. In this study, we used bronchoalveolar lavage (BAL) to investigate the long-term effect of rhDNase on inflammation in patients with CF having mild lung disease. A total of 105 patients with CF (> or =5 years of age) having normal lung function were randomized to receive rhDNase (2.5 mg/day) or no rhDNase. Patients with a normal percentage of neutrophils in BAL fluid at baseline were not randomized and served as the control group. The percentage of neutrophils in the pooled BAL sample was similar in both randomized groups at baseline. A significant increase in neutrophils was observed over the 3-year study period in both untreated patients and control subjects, whereas neutrophils remained unchanged in patients treated with rhDNase. Elastase activities and interleukin-8 concentrations also increased in untreated patients and remained stable in patients on rhDNase. We conclude that in patients with CF, an increase in neutrophilic airway inflammation is found that is positively influenced by rhDNase treatment.
Adrenergic effects on reentrant ventricular rhythms in subacute myocardial infarction.
Authors: G S Butrous, W B Gough, M Restivo, H Yang, N el-Sherif
Journal: Circulation (1992)

BACKGROUND Reentry has been shown to be a mechanism of ventricular arrhythmias elicited by programmed premature stimulation in the subacute ischemic period of dogs subjected to myocardial infarction. The spatial distribution of refractoriness in these hearts has been shown to play an important part in the formation of functional arcs of conduction block during programmed ventricular stimulation. Because the adrenergic nervous system influences cardiac arrhythmias and myocardial infarction can directly affect sympathetic innervation in the heart, we investigated the role of the sympathetic nervous system on reentry in the canine heart 4 days after infarction. METHODS AND RESULTS The influences of adrenergic stimuli on the initiation of reentrant ventricular excitation were studied using a 128-channel computerized recording system in the canine heart 4 days after ligation of the left anterior descending coronary artery. Bilateral stimulation of the ansae subclavia preferentially improved conduction of premature beats in the normal zones. This corresponded to an improvement in excitability, as measured by a decrease in stimulus strength at the same premature coupling interval as control. Consequently, the effective refractory period was preferentially shortened at normal sites but not at ischemic sites. Both of these changes contributed to a shift of the arc of functional conduction block toward more normal tissue. As a result, sites proximal to the arc of functional conduction block had more time to recover excitability and thereby were available to be reexcited by the distal activation wave front. Conversely, intravenous infusion of norepinephrine preferentially shortened the effective refractory period of sites in the ischemic zone, thereby indicating that denervation hypersensitivity had occurred at these sites. The spatial dispersion of refractoriness and the arc of functional conduction block were significantly reduced in size. As a consequence, previously inducible reentrant rhythms were no longer inducible. CONCLUSIONS Sympathetic stimulation can be considered an arrhythmogenic intervention, whereas norepinephrine infusion may be considered antiarrhythmic in this experimental model.
IFN Regulatory Factor 8 Sensitizes Soft Tissue Sarcoma Cells to Death Receptor–Initiated Apoptosis via Repression of FLICE-like Protein Expression
Authors: Dafeng Yang, Suizhao Wang, Craig Brooks, Zheng Dong, Patricia V. Schoenlein, Vijay Kumar, Xinshou Ouyang, Huabao Xiong, Guy Lahat, Andrea Hayes-Jordan, Alexander Lazar, Raphael Pollock, Dina Lev, Kebin Liu
Journal: Cancer Research (2009)

IFN regulatory factor 8 (IRF8) has been shown to suppress tumor development at least partly through regulating apoptosis of tumor cells; however, the molecular mechanisms underlying IRF8 regulation of apoptosis are still not fully understood. Here, we showed that disrupting IRF8 function resulted in inhibition of cytochrome c release, caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase cleavage in soft tissue sarcoma (STS) cells. Inhibition of the mitochondrion-dependent apoptosis signaling cascade is apparently due to blockage of caspase-8 and Bid activation. Analysis of signaling events upstream of caspase-8 revealed that disrupting IRF8 function dramatically increases FLIP mRNA stability, resulting in increased IRF8 protein level. Furthermore, primary myeloid cells isolated from IRF8-null mice also exhibited increased FLIP protein level, suggesting that IRF8 might be a general repressor of FLIP. Nuclear IRF8 protein was absent in 92% (55 of 60) of human STS specimens, and 99% (59 of 60) of human STS specimens exhibited FLIP expression, suggesting that the nuclear IRF8 protein level is inversely correlated with FLIP level in vivo. Silencing FLIP expression significantly increased human sarcoma cells to both FasL-induced and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, and ectopic expression of IRF8 also significantly increased the sensitivity of these human sarcoma cells to FasL- and TRAIL-induced apoptosis. Taken together, our data suggest that IRF8 mediates FLIP expression level to regulate apoptosis and targeting IRF8 expression is a potentially effective therapeutic strategy to sensitize apoptosis-resistant human STS to apoptosis, thereby possibly overcoming chemoresistance of STS, currently a major obstacle in human STS therapy.
Endothelial Mitochondria
Authors: Sean M. Davidson, Michael R. Duchen
Journal: Circulation Research (2007)

Disturbances in vascular function contribute to the development of several diseases of increasing prevalence and thereby contribute significantly to human mortality and morbidity. Atherosclerosis, diabetes, heart failure, and ischemia with attendant reperfusion injury share many of the same risk factors, among the most important being oxidative stress and alterations in the blood concentrations of compounds that influence oxidative stress, such as oxidized low-density lipoprotein. In this review, we focus on endothelial cells: cells in the frontline against these disturbances. Because ATP supplies in endothelial cells are relatively independent of mitochondrial oxidative pathways, the mitochondria of endothelial cells have been somewhat neglected. However, they are emerging as agents with diverse roles in modulating the dynamics of intracellular calcium and the generation of reactive oxygen species and nitric oxide. The mitochondria may also constitute critical “targets” of oxidative stress, because survival of endothelial cells can be compromised by opening of the mitochondrial permeability transition pore or by mitochondrial pathways of apoptosis. In addition, evidence suggests that endothelial mitochondria may play a “reconnaissance” role. For example, although the exact mechanism remains obscure, endothelial mitochondria may sense levels of oxygen in the blood and relay this information to cardiac myocytes as well as modulating the vasodilatory response mediated by endothelial nitric oxide.
From De Novo Mutations to Personalized Therapeutic Interventions in Autism
Authors: William M. Brandler, Jonathan Sebat
Journal: Annual Review of Medicine (2015)

The high heritability, early age at onset, and reproductive disadvantages of autism spectrum disorders (ASDs) are consistent with an etiology composed of dominant-acting de novo (spontaneous) mutations. Mutation detection by microarray analysis and DNA sequencing has confirmed that de novo copy-number variants or point mutations in protein-coding regions of genes contribute to risk, and some of the underlying causal variants and genes have been identified. As our understanding of autism genes develops, the spectrum of autism is breaking up into quanta of many different genetic disorders. Given the diversity of etiologies and underlying biochemical pathways, personalized therapy for ASDs is logical, and clinical genetic testing is a prerequisite.
Prospects for Building Large Timetrees Using Molecular Data with Incomplete Gene Coverage among Species
Authors: A. Filipski, O. Murillo, A. Freydenzon, K. Tamura, S. Kumar
Journal: Molecular Biology and Evolution (2014)

Scientists are assembling sequence data sets from increasing numbers of species and genes to build comprehensive timetrees. However, data are often unavailable for some species and gene combinations, and the proportion of missing data is often large for data sets containing many genes and species. Surprisingly, there has not been a systematic analysis of the effect of the degree of sparseness of the species–gene matrix on the accuracy of divergence time estimates. Here, we present results from computer simulations and empirical data analyses to quantify the impact of missing gene data on divergence time estimation in large phylogenies. We found that estimates of divergence times were robust even when sequences from a majority of genes for most of the species were absent. From the analysis of such extremely sparse data sets, we found that the most egregious errors occurred for nodes in the tree that had no common genes for any pair of species in the immediate descendant clades of the node in question. These problematic nodes can be easily detected prior to computational analyses based only on the input sequence alignment and the tree topology. We conclude that it is best to use larger alignments, because adding both genes and species to the alignment augments the number of genes available for estimating divergence events deep in the tree and improves their time estimates.
Neutral Effect on Markers of Heart Failure, Inflammation, Endothelial Activation and Function, and Vagal Tone After High-Dose HMG-CoA Reductase Inhibition in Non-Diabetic Patients With Non-Ischemic Cardiomyopathy and Average Low-Density Lipoprotein Level
Authors: Barry E. Bleske, John M. Nicklas, Robert L. Bard, Robert D. Brook, Paul A. Gurbel, Kevin P. Bliden, Sanjay Rajagopalan, Bertram Pitt
Journal: Journal of the American College of Cardiology (2005)
Social Phobia Subtypes in the National Comorbidity Survey
Authors: Ronald C. Kessler, Murray B. Stein, Patricia Berglund
Journal: American Journal of Psychiatry (1998)

This article presents epidemiologic data on the distinction between social phobia characterized by pure speaking fears and that characterized by other social fears.The data come from the National Comorbidity Survey (N = 8,098). Social phobia was assessed with a revised version of the Composite International Diagnostic Interview.Latent class analysis showed that the brief set of social fears assessed in the survey can be disaggregated into a class characterized largely by speaking fears and a second class characterized by a broader range of social fears. One-third of the people with lifetime social phobia exclusively reported speaking fears, while the other two-thirds also had at least one of the other social fears assessed. The vast majority of the latter had multiple social fears including, in most cases, both performance and interactional fears. The two subtypes were similar in age at onset distribution, family history, and certain sociodemographic correlates. However, the social phobia characterized by pure speaking fears was less persistent, less impairing, and less highly comorbid with other DSM-III-R disorders than was social phobia characterized by other social fears.Further general population research assessing more performance and interaction fears is needed to determine whether social phobia subtypes can be refined and whether the subtypes are better conceptualized as distinct disorders. In the meantime, people who have social phobia with multiple fears, some of which are nonspeaking fears, appear to have the most impairment and should be the main focus of prevention and intervention efforts.
Poor Pregnancy Outcome in Women With Type 2 Diabetes
Authors: Tine D. Clausen, Elisabeth Mathiesen, Pia Ekbom, Ellinor Hellmuth, Thomas Mandrup-Poulsen, Peter Damm
Journal: Diabetes Care (2005)

OBJECTIVE— To evaluate the perinatal outcome and the frequency of maternal complications in pregnancies of women with type 2 diabetes during 1996–2001. RESEARCH DESIGN AND METHODS— Medical records of 61 consecutive singleton pregnancies in women with type 2 diabetes from 1996 to 2001 were studied. Pregnancy outcome was compared with that of pregnant women with type 1 diabetes during 1996–2000, the background population, and pregnant women with type 2 diabetes during 1980–1992 from the same department. RESULTS— The perinatal mortality in pregnancies complicated by type 2 diabetes (4/61, 6.6%) was increased four- and ninefold, respectively, and the rate of major congenital malformations (4/60, 6.7%) was more than doubled, although not statistically significant, compared with type 1 diabetic pregnancies and the background population. The glycemic control was similar or better in women with type 2 diabetes compared with women with type 1 diabetes. Multivariate logistic regression analysis in the pooled group of pregnancies with pregestational diabetes from 1996 to 2001 showed that high HbA1c at admission and type 2 diabetes were independently associated with a serious adverse fetal outcome (perinatal mortality and/or major congenital malformations). The perinatal mortality and the rate of major congenital malformations in type 2 diabetic pregnancies have increased during the last decade. CONCLUSIONS— The perinatal outcome of pregnancies in women with type 2 diabetes during 1996–2001 is poor. It is worse than the outcome of pregnancies in women with type 1 diabetes and the background population in the same period, as well as in women with type 2 diabetes studied during 1982–1990.
Inducible nitric oxide synthase colocalizes with signs of lipid oxidation/peroxidation in human atherosclerotic plaques
Authors: K Cromheeke
Journal: Cardiovascular Research (1999)

Objective: Advanced human atherosclerotic plaques are characterized by the abundant presence of the autofluorescent non-soluble lipid pigment ceroid, consisting of oxidized lipoproteins. The aim of the present study was to examine the topographical and cellular distribution of inducible nitric oxide synthase (iNOS or NOS II) within different stages of atherosclerosis and its colocalization with ceroid deposits and nitrotyrosine. Methods and results: Different stages of atherosclerosis were studied by immunohistochemistry on whole-mount longitudinal sections of carotid endarterectomy specimens. In the adaptive intimal thickening the predominant cell type were smooth muscle cells. The fatty streaks contained both smooth muscle cells and macrophages with an extremely low NOS II immunoreactivity. The advanced atherosclerotic plaques however, showed a very dense infiltration by macrophages, of which a subpopulation expressed NOS II as a vesicular immunoreactivity in their cytoplasm. These were mainly present around the necrotic core, in association with ceroid accumulation and nitrotyrosine. Fluorescence quenching microscopy showed the presence of NOS II on autofluorescent ceroid vesicles in the macrophages. Large extracellular ceroid granules were not NOS II immunoreactive. NOS II mRNA was detected by RT-PCR and the protein by Western blot in the plaque tissue but not in mammary arteries used as controls. Conclusion: Ceroid, nitrotyrosine and NOS II colocalized in late stages of atherosclerosis and were found around the necrotic core in the plaque. This could suggest that NOS II expression in macrophages is involved in oxidation and peroxidation of lipids, leading to ceroid formation.
L-4F, an Apolipoprotein A-1 Mimetic, Restores Nitric Oxide and Superoxide Anion Balance in Low-Density Lipoprotein-Treated Endothelial Cells
Authors: Zhijun Ou, Jingsong Ou, Allan W. Ackerman, Keith T. Oldham, Kirkwood A. Pritchard
Journal: Circulation (2003)

Low-density lipoprotein (LDL) impairs endothelial cell function by uncoupling endothelial nitric oxide synthase (eNOS) activity, which allows superoxide anion (O2*-)) to be generated rather than nitric oxide (*NO). Recent reports indicate that apolipoprotein (apo) A-1 mimetics inhibit the development of atherosclerotic lesions in LDL receptor-null mice. Here we hypothesize that L-4F, an apoA-1 mimetic that inhibits atherosclerosis induced by hypercholesterolemia, protects endothelial cell function by preventing LDL from uncoupling eNOS activity.Bovine aortic endothelial cells were incubated with LDL+/-L-4F, and changes in A23187-stimulated.NO and O2*- generation were determined by ozone chemiluminescence and superoxide dismutase-inhibitable ferricytochrome c reduction, respectively. Western analysis of eNOS immunoprecipitates was used to determine effects of LDL and L-4F on heat shock protein 90 (hsp90) interactions with eNOS. LDL decreased.NO production and increased eNOS-dependent O2*- generation. Pretreatment of LDL with L-4F increased.NO and decreased O2*- generation. By itself, L-4F had no effect on O2*- but did increase *NO generation. Stimulation of endothelial cells incubated with LDL decreased the association of hsp90 with eNOS. Pretreatment of LDL with L-4F prevented a decrease in hsp90 association with eNOS and often enhanced association on stimulation.These data demonstrate that L-4F protects endothelial cell function by preventing LDL from uncoupling eNOS activity. L-4F allows endothelial cell to maintain coupled eNOS activity to generate.NO even in the face of atherogenic concentrations of LDL.