tbuckley/cabot-search huggingface dataset:
The Effect of Inhaled Budesonide on Symptoms, Lung Function, and Cold Air and Methacholine Responsiveness in 2- to 5-year–old Asthmatic Children
Authors: KIM GJERUM NIELSEN, HANS BISGAARD
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

We hypothesized that measurement of lung function (LF) and bronchial hyperresponsiveness (BHR) could serve as supplemental tools in evaluating the efficacy of treatment with inhaled corticosteroids in asthmatic children aged 2 to 5 yr. We studied 38 children (mean age: 53 mo; range: 35 to 71 mo) with moderately severe asthma in a single-center, randomized, double-blind, parallel-group, placebo-controlled study involving 8 wk of treatment. Budesonide (BUD) 400 μ g twice daily was administered via a pressurized metered-dose inhaler and metal spacer device. Symptom scores (SSc) and use of short-acting β2-agonist were monitored with diary cards. LF in awake children was measured as the specific airway resistance (sRaw), using whole-body plethysmography; as resistance by the interrupter technique (Rint); and as resistance and reactance at 5 Hz (Rrs5, Xrs5) by the impulse oscillation technique. Cold air challenge (CACh) and methacholine challenge (MCh) were used to assess BHR. Children in the BUD group experienced significantly fewer night- and daytime symptoms (p < 0.05) and more symptom-free days (p < 0.05), but not nights (p = 0.07), than children in the placebo group. Daytime (p < 0.05) but not nighttime (p = 0.09) use of rescue medication and asthma exacerbation rates (3.7 versus 9.3 exacerbations/yr) (p = 0.006) were both in favor of BUD. LF measured with the Rint technique, Rrs5, and Xrs5 were significantly improved by BUD. BHR as measured by CACh improved significantly with BUD, whereas no improvement was found on MCh. In conclusion, inhaled BUD at a total dose of 800 μ g daily significantly improved SSc, asthma exacerbation rates, lung function, and BHR as assessed by CACh in asthmatic children aged 2 to 5 yr.
VIRULENCE AND MUTATION OF THE BACILLUS OF RABBIT SEPTICEMIA
Authors: Paul H. De Kruif
Journal: The Journal of Experimental Medicine (1922)

Type D, bacillus of rabbit septicemia, exhibits marked fixity of the character of virulence. This is true for cultures that are regularly transplanted on serum agar or in broth. It is also to be observed when organisms of this variety are subjected to unfavorable conditions; e.g., remaining for 9(1/2) days without transplant in plain broth. Under such conditions no decrease in virulence was observed. G forms which arose in the same culture during this time exhibited characteristic lack of invasibility. Different individuals of a given culture of Type D do not vary to a noticeable extent in virulence. This was ascertained by test of virulence of cultures arising from six individuals fished from Type D cultures by Barber pipette. A Type D culture subjected to passage in plain broth undergoes D --> G mutation. Type D and G individuals can be demonstrated to be present in the same culture. The virulence of such a mixed culture is proportional to the relative member of Microbes D and G present. This throws light on certain mechanisms of attenuation. The virulence of Type G can be raised to a considerable titer by animal passage. Such organisms do not, however, lose their characteristic of granular growth. This last, on the other hand, appears to intensify by animal passage. The acid agglutination zone of Type G strains which have been passed through animals shows a marked broadening. Microbe D owes its superior invasive power at least in part to its antiphagocytic activity, a property apparently not possessed by Microbe G.
Statins and Risk Reduction in Hepatocellular Carcinoma: Fact or Fiction?
Authors: Preet Paul Singh, Siddharth Singh
Journal: Journal of Clinical Oncology (2012)

and the Risk of Hepatocellular Carcinoma in Patients With Hepatitis B Virus Infection.” In this population-based cohort study that used the Taiwan National Health Insurance Research Database, the authors reported that statin use may reduce the risk of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) infection. Tsan et al 1 followed 33,413 patients with HBV infection from 1997 to 2008, of which 8.3% used statins and noted 1,021 incident HCC cases in this HBV cohort. The incidence rate (per 100,000 person-years) of HCC in patients on statins was 210.9, compared with an incidence rate of 319.5 in nonusers (P .001). The crude and adjusted hazard ratios (95% CIs) for HCC in statin users compared with nonusers was 0.66 (0.51 to 0.86) and 0.47 (0.36 to 0.61), respectively. The authors appropriately adjusted for potential confounders (age, sex, cirrhosis, diabetes, and medications such as anti-HBV treatment, aspirin, and angiotensin converting enzyme inhibitors) and acknowledged unmeasured confounders (alcohol intake, smoking status, and body mass index) as a limitation of their study. However, in their analysis, Tsan et al 1 failed to account for the impact of antidiabetic medications on altering the risk of HCC. It is now well established that diabetes is an independent risk factor for HCC as reported in several observational studies from Asia, Europe, and North America and subsequent metaanalyses. 2-4 Interestingly, recent studies have reported that antidiabetic medications also alter the risk of multiple cancers, including HCC. Population- and hospital-based observational studies in patients with diabetes have shown that metformin and thiazolidinediones are associated with reduced risk of HCC. 5-7 In a
Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation
Authors: Heeyoung Yang, Quan Qiu, Beixue Gao, Sinyi Kong, Zhenghong Lin, Deyu Fang
Journal: The Journal of Experimental Medicine (2014)

The ubiquitin pathway plays critical roles in antigen presentation. However, the ubiquitin ligases that regulate MHC gene transcription remain unidentified. We showed that the ubiquitin ligase Hrd1, expression of which is induced by Toll-like receptor (TLR) stimulation, is required for MHC-II but not MHC-I transcription in dendritic cells (DCs). Targeted Hrd1 gene deletion in DCs diminished MHC-II expression. As a consequence, Hrd1-null DCs failed to prime CD4+ T cells without affecting the activation of CD8+ T cells. Hrd1 catalyzed ubiquitination and degradation of the transcriptional suppressor B lymphocyte–induced maturation protein 1 (BLIMP1) to promote MHC-II expression. Genetic suppression of Hrd1 function in DCs protected mice from myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis (EAE). We identified Hrd1-mediated BLIMP1 ubiquitination as a previously unknown mechanism in programming DC for CD4+ T cell activation during inflammation.
Alveolate Mitochondrial Metabolic Evolution: Dinoflagellates Force Reassessment of the Role of Parasitism as a Driver of Change in Apicomplexans
Authors: Jillian C. Danne, Sebastian G. Gornik, James I. MacRae, Malcolm J. McConville, Ross F. Waller
Journal: Molecular Biology and Evolution (2012)

Mitochondrial metabolism is central to the supply of ATP and numerous essential metabolites in most eukaryotic cells. Across eukaryotic diversity, however, there is evidence of much adaptation of the function of this organelle according to specific metabolic requirements and/or demands imposed by different environmental niches. This includes substantial loss or retailoring of mitochondrial function in many parasitic groups that occupy potentially nutrient-rich environments in their metazoan hosts. Infrakingdom Alveolata comprises a well-supported alliance of three disparate eukaryotic phyla—dinoflagellates, apicomplexans, and ciliates. These major taxa represent diverse lifestyles of free-living phototrophs, parasites, and predators and offer fertile territory for exploring character evolution in mitochondria. The mitochondria of apicomplexan parasites provide much evidence of loss or change of function from analysis of mitochondrial protein genes. Much less, however, is known of mitochondrial function in their closest relatives, the dinoflagellate algae. In this study, we have developed new models of mitochondrial metabolism in dinoflagellates based on gene predictions and stable isotope labeling experiments. These data show that many changes in mitochondrial gene content previously only known from apicomplexans are found in dinoflagellates also. For example, loss of the pyruvate dehydrogenase complex and changes in tricarboxylic acid (TCA) cycle enzyme complement are shared by both groups and, therefore, represent ancestral character states. Significantly, we show that these changes do not result in loss of typical TCA cycle activity fueled by pyruvate. Thus, dinoflagellate data show that many changes in alveolate mitochondrial metabolism are independent of the major lifestyle changes seen in these lineages and provide a revised view of mitochondria character evolution during evolution of parasitism in apicomplexans.
Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer
Authors: Beatrice Rondinelli, Dalia Rosano, Elena Antonini, Michela Frenquelli, Laura Montanini, DaChuan Huang, Simona Segalla, Kosuke Yoshihara, Samir B. Amin, Dejan Lazarevic, Bin Tean The, Roel G.W. Verhaak, P. Andrew Futreal, Luciano Di Croce, Lynda Chin, Davide Cittaro, Giovanni Tonon
Journal: Journal of Clinical Investigation (2015)

Mutations in genes encoding chromatin-remodeling proteins are often identified in a variety of cancers. For example, the histone demethylase JARID1C is frequently inactivated in patients with clear cell renal cell carcinoma (ccRCC); however, it is largely unknown how JARID1C dysfunction promotes cancer. Here, we determined that JARID1C binds broadly to chromatin domains characterized by the trimethylation of lysine 9 (H3K9me3), which is a histone mark enriched in heterochromatin. Moreover, we found that JARID1C localizes on heterochromatin, is required for heterochromatin replication, and forms a complex with established players of heterochromatin assembly, including SUV39H1 and HP1α, as well as with proteins not previously associated with heterochromatin assembly, such as the cullin 4 (CUL4) complex adaptor protein DDB1. Transcription on heterochromatin is tightly suppressed to safeguard the genome, and in ccRCC cells, JARID1C inactivation led to the unrestrained expression of heterochromatic noncoding RNAs (ncRNAs) that in turn triggered genomic instability. Moreover, ccRCC patients harboring JARID1C mutations exhibited aberrant ncRNA expression and increased genomic rearrangements compared with ccRCC patients with tumors endowed with other genetic lesions. Together, these data suggest that inactivation of JARID1C in renal cancer leads to heterochromatin disruption, genomic rearrangement, and aggressive ccRCCs. Moreover, our results shed light on a mechanism that underlies genomic instability in sporadic cancers.
Regulation of immune responses by I-J gene products. II. Presence of Both I-Jb and I-Jk suppressor factors in (nonsuppressor x nonsuppressor) F1 mice.
Authors: H Y Lei, M E Dorf, C Waltenbaugh
Journal: The Journal of Experimental Medicine (1982)

Antigen-specific suppression to poly(Glu50-Tyr50) (GT) is under the control of two complementary immune suppressor (Is) genes located in the major histocompatibility (H-2) complex of the mouse. Suppressor strains of mice produce both suppressor T (Ts) cells and Ts-derived suppressor factors (TsF) that bear antigenic determinants of the I-J subregion of the H-2 complex. Nonsuppressor strains of mice, on the other hand, are not suppressed by GT preimmunization. These nonsuppressor mice, however, can be classified according to those that lack the ability to make GT-specific T cell-derived suppressor factor (GT-TsF) after GT injection (i.e., H-2a, I-Jk mice) and those that lack the ability to be suppressed by the appropriate GT-TsF (i.e., H-2b,g2, I-Jb mice). In the present study, we demonstrate that (H-2a x H-2b,g2)F1 hybrid mice produce distinct GT-specific suppressor factors of both parental I-J haplotypes. Moreover, only the I-Jb-bearing GT-TsF derived from these F1 hybrid mice is able to induce second-order suppressor cells (Ts2). This is consistent with the observation that injection of GT-TsF1 derived from C57BL/6 (I-Jb) mice into A/J (I-Jk) mice leads to the production of an antigen-specific I-Jk GT-TsF2. Our results suggest that Is gene complementation occurs through a different cellular mechanism that was previously observed for Ir gene complementation. Further, we show that complementing (non-suppressor X nonsuppressor)F1 hybrid mice produce an I-Jb (and not an I-Jk) GT-TsF1 and an I-Jk (not an I-Jb) GT-TsF2, thus suggesting a heterogeneity of Ia loci within the I-J subregion. Data presented in the present study suggest that there may be even more heterogeneity within the I-J subregion than has has been heretofore reported with regard to I-J expression on Ts.
Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines
Authors: Kai Kisand, Anette S. Bøe Wolff, Katarina Trebušak Podkrajšek, Liina Tserel, Maire Link, Kalle V. Kisand, Elisabeth Ersvaer, Jaakko Perheentupa, Martina Moter Erichsen, Nina Bratanic, Antonella Meloni, Filomena Cetani, Roberto Perniola, Berrin Ergun-Longmire, Noel Maclaren, Kai J. E. Krohn, Mikuláš Pura, Berthold Schalke, Philipp Ströbel, Maria Isabel Leite, Tadej Battelino, Eystein S. Husebye, Pärt Peterson, Nick Willcox, Anthony Meager
Journal: The Journal of Experimental Medicine (2010)

Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A–producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in &amp;gt;150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis.
Waist Girth Does Not Predict Metabolic Complications in Severely Obese Men
Authors: Isabelle Lemieux, Vicky Drapeau, Denis Richard, Jean Bergeron, Picard Marceau, Simon Biron, Pascale Mauriège
Journal: Diabetes Care (2006)

The epidemic of obesity has received considerable attention because of its increasing prevalence and its deleterious impact on health (1–6). In this regard, the metabolic syndrome has been recognized as a prevalent cause of cardiovascular disease, and the National Cholesterol Education Program Adult Treatment Panel III guidelines (7) have proposed clinical tools for the identification of individuals characterized by this syndrome. However, there is considerable metabolic heterogeneity among equally overweight/obese individuals. While some patients show a relatively “normal” metabolic risk profile despite being obese, others who are moderately overweight can nevertheless be characterized by metabolic complications (8,9).

Thus, it is not uncommon to find severely obese patients with minimal changes in their metabolic risk profile, suggesting that they may be at lower cardiovascular disease risk than what could be expected from their massive obesity. Therefore, the aim of the present study was to examine the relationships between selected features of the metabolic syndrome and waist circumference as a crude marker of abdominal obesity in moderately and severely obese men.

Informed written consent was obtained from all patients, and studies were conducted according to the Helsinki Declaration. The reference group consisted of moderately obese men ( n = 97) of …
Echocardiographic Definition and Surgical Decision-Making in Unbalanced Atrioventricular Septal Defect
Authors: Anusha Jegatheeswaran, Christian Pizarro, Christopher A. Caldarone, Meryl S. Cohen, Jeanne M. Baffa, David B. Gremmels, Luc Mertens, Victor O. Morell, William G. Williams, Eugene H. Blackstone, Brian W. McCrindle, David M. Overman
Journal: Circulation (2010)

Background— Although identification of unbalanced atrioventricular septal defect (AVSD) is obvious when extreme, exact criteria to define the limits of unbalanced are not available. We sought to validate an atrioventricular valve index (AVVI) (left atrioventricular valve area/total atrioventricular valve area, centimeters squared) as a discriminator of balanced and unbalanced forms of complete AVSD and to characterize the association of AVVI with surgical strategies and outcomes. Methods and Results— Diagnostic echocardiograms and hospital records of 356 infants with complete AVSD at 4 Congenital Heart Surgeons’ Society (CHSS) institutions (2000–2006) were reviewed and AVVI measured (n=315). Patients were classified as unbalanced if AVVI≤0.4 (right dominant) or ≥0.6 (left dominant). Surgical strategy and outcomes were examined across the range of AVVI. Competing risks analysis until the time of commitment to a surgical strategy examined 4 end states: biventricular repair (BVR), univentricular repair (UVR), pulmonary artery banding (PAB), and death before surgery. A prediction nomogram for surgical strategy based on AVVI was developed. The majority of patients had balanced AVSD (0.4&lt;AVVI&lt;0.6) and underwent BVR. Patients with AVVI&lt;0.19 uniformly underwent UVR. Heterogeneous repair strategies were found when 0.19≤AVVI≤0.39 (UVR and BVR), with a disproportionate number of deaths in this range. AVVI≥0.6 (left dominant) was less common. The proportion of subjects predicted for the end states at 12 months after diagnosis are: BVR, 86%; UVR, 7%; PAB, 1%; death without surgery, 1%; alive without surgery, 5%. Conclusions— AVVI effectively characterizes the transition between balanced and unbalanced AVSD with important correlation to anatomic substrate and selected surgical strategy.
Functional Recovery in a Friedreich's Ataxia Mouse Model by Frataxin Gene Transfer Using an HSV-1 Amplicon Vector
Authors: Filip Lim, Gloria M Palomo, Christina Mauritz, Alfredo Giménez-Cassina, Belen Illana, Francisco Wandosell, Javier Díaz-Nido
Journal: Molecular Therapy (2007)

There is currently no effective treatment for Friedreich's ataxia (FA), the most common of the hereditary ataxias. The disease is caused by mutations in FRDA that drastically reduce expression levels of the mitochondrial protein frataxin. In FA animal models, a key difficulty is obtaining the precise levels of frataxin expression in the appropriate tissues to provoke pathology without early lethality. To develop strategies to circumvent these problems, conditional frataxin transgenic mice have been generated. We now show that frataxin expression can be eliminated in neurons from these loxP[frda] mice by infection with CRE-expressing herpes simplex virus type 1 (HSV-1) amplicon vectors. We have also achieved in vivo delivery by stereotaxic injection of these CRE-expressing vectors into the brainstem of loxP[frda] mice to generate a localized gene knockout model. These mice develop a behavioral deficit in the rotarod assay detectable after 4 weeks, and when re-injected with HSV-1 amplicon vectors expressing human frataxin complementary DNA (cDNA) exhibit behavioral recovery as early as 4 weeks after the second injection. To the best of our knowledge, this is the first proof of principle of recovery of neurological function by a therapeutic agent aimed at correcting frataxin deficiency.
TWO CASES OF PARATYPHOID INFECTION; ONE CAUSED BY AN ABERRANT ORGANISM.
Authors: G. BERTNARD SMITH
Journal: JAMA (1903)

Cases of paratyphoid fever, both sporadic and epidemic,<sup>1</sup>have been reported so frequently of late that perhaps some special reason should be given for calling attention to any more isolated cases. In the present instance the author believes that the bacteriologic findings are of sufficient interest to warrant a brief presentation: <h3>Case 1.</h3> —The patient, a man aged 58 years, entered the Presbyterian Hospital, Oct. 22, 1902. His temperature by mouth was 102.2, and he complained of frontal headache and severe abdominal pain. The abdomen was tender everywhere, but the liver and spleen were not palpable and no rose spots were visible. November 1 the patient had two hemorrhages from the bowels. The first was slight and only a small amount of blood was cast out. About three pints of liquid blood containing some clots were discharged with the second hemorrhage. The abdominal distress and headache continued
Effects of a motilin receptor agonist (ABT-229) on upper gastrointestinal symptoms in type 1 diabetes mellitus: a randomised, double blind, placebo controlled trial
Authors: N J Talley
Journal: Gut (2001)

<h3>INTRODUCTION</h3> Erythromycin, a motilin agonist, is a potent prokinetic. ABT-229 is a specific motilin agonist that dose dependently accelerates gastric emptying. Dyspepsia and gastroparesis are common problems in type 1 diabetes mellitus. We aimed to evaluate the efficacy of ABT-229 in symptomatic diabetic patients with and without delayed gastric emptying. <h3>METHODS</h3> Patients with type 1 diabetes and postprandial symptoms were randomised (n=270). Based on a validated C<sup>13</sup> octanoic acid breath test, patients were assigned to either the delayed or normal gastric emptying strata. Patients received one of four doses of ABT-229 (1.25, 2.5, 5, or 10 mg twice daily before breakfast and dinner) or placebo for four weeks following a two week baseline. A self report questionnaire measured symptoms on visual analogue scales; the primary outcome was assessment of change in the total upper abdominal symptom severity score (range 0–800 mm) from baseline to the final visit. <h3>RESULTS</h3> The treatment arms were similar regarding baseline characteristics. There was symptom improvement on placebo and a similar level of improvement on active therapy for the upper abdominal discomfort severity score (mean change from baseline −169, −101, −155, −143, and −138 mm for placebo, and 1.25, 2.5, 5, and 10 mg ABT-229, respectively, at four weeks by intent to treat). The results were not significantly different in those with and without delayed gastric emptying. The severity of bloating, postprandial nausea, epigastric discomfort, heartburn, and acid regurgitation worsened dose dependently in a greater number of patients receiving ABT-229 than placebo. Overall, 63% of patients on placebo reported a good or excellent global response, and this was not different from the active treatment arms. <h3>CONCLUSIONS</h3> The motilin agonist ABT-229 was not efficacious in the relief of postprandial symptoms in diabetes mellitus in the presence or absence of delayed gastric emptying.