tbuckley/cabot-search huggingface dataset:
Pharmacological Enhancement of Mutated α-Glucosidase Activity in Fibroblasts from Patients with Pompe Disease
Authors: Giancarlo Parenti, Alfredo Zuppaldi, M Gabriela Pittis, M Rosaria Tuzzi, Ida Annunziata, Germana Meroni, Caterina Porto, Francesca Donaudy, Barbara Rossi, Massimiliano Rossi, Mirella Filocamo, Alice Donati, Bruno Bembi, Andrea Ballabio, Generoso Andria
Journal: Molecular Therapy (2007)

We investigated the use of pharmacological chaperones for the therapy of Pompe disease, a metabolic myopathy due to mutations of the gene encoding the lysosomal hydrolase α-glucosidase (GAA) and characterized by generalized glycogen storage in cardiac and skeletal muscle. We studied the effects of two imino sugars, deoxynojirimycin (DNJ) and N-butyldeoxynojirimycin (NB-DNJ), on residual GAA activity in fibroblasts from eight patients with different forms of Pompe disease (two classic infantile, two non-classic infantile onset, four late-onset forms), and with different mutations of the GAA gene. We demonstrated a significant increase of GAA activity (1.3-7.5-fold) after imino sugar treatment in fibroblasts from patients carrying the mutations L552P (three patients) and G549R (one patient). GAA enhancement was confirmed in HEK293T cells where the same mutations were overexpressed. No increase of GAA activity was observed for the other mutations. Western blot analysis showed that imino sugars increase the amount of mature GAA molecular forms. Immunofluorescence studies in HEK293T cells overexpressing the L552P mutation showed an improved trafficking of the mutant enzyme to lysosomes after imino sugar treatment. These results provide a rationale for an alternative treatment, other than enzyme replacement, to Pompe disease.
Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease
Authors: Shan Qin, Mary Taglienti, Surya M. Nauli, Leah Contrino, Ayumi Takakura, Jing Zhou, Jordan A. Kreidberg
Journal: Journal of Clinical Investigation (2010)

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that is caused by mutations at two loci, polycystin 1 (PKD1) and polycystin 2 (PKD2). It is characterized by the formation of multiple cysts in the kidneys that can lead to chronic renal failure. Previous studies have suggested a role for hyperactivation of mammalian target of rapamycin (mTOR) in cystogenesis, but the etiology of mTOR hyperactivation has not been fully elucidated. In this report we have shown that mTOR is hyperactivated in Pkd1-null mouse cells due to failure of the HGF receptor c-Met to be properly ubiquitinated and subsequently degraded after stimulation by HGF. In Pkd1-null cells, Casitas B-lineage lymphoma (c-Cbl), an E3-ubiquitin ligase for c-Met, was sequestered in the Golgi apparatus with α₃β₁ integrin, resulting in the inability to ubiquitinate c-Met. Treatment of mouse Pkd1-null cystic kidneys in organ culture with a c-Met pharmacological inhibitor resulted in inhibition of mTOR activity and blocked cystogenesis in this mouse model of ADPKD. We therefore suggest that blockade of c-Met is a potential novel therapeutic approach to the treatment of ADPKD.
Relationship Between Low Cardiorespiratory Fitness and Mortality in Normal-Weight, Overweight, and Obese Men
Authors: Ming Wei, James B. Kampert, Carolyn E. Barlow, Milton Z. Nichaman, Larry W. Gibbons, Ralph S. Paffenbarger, Steven N. Blair
Journal: JAMA (1999)

1988 and 1994, the prevalence of obesity in the United States increased substantially, from 14.5% to 22.5%. 1 In 1998, the US National Institutes of Health (NIH) and the World Health Organization published guidelines for the treatment of obesity. 2,3In these reports, overweight and obesity are defined, and treatment guidelines are provided for physicians.It is recommended that clinicians first classify patients by body mass index (BMI), calculated as weight in kilograms divided by the square of height in meters, with overweight defined as a BMI of 25.0 to 29.9 kg/m 2 and obesity as a BMI of at least 30.0 kg/m 2 .Further stratification of risk is recommended by considering the presence of coexisting disease and cardiovascular disease (CVD) risk factors.The NIH guidelines specify that obese persons with established CVD or type 2 diabetes mellitus (DM) are at "very high risk" for death and that patients with 3 or more CVD risk factors are "at high absolute risk." 2 Physical inactivity and serum triglyceride levels of more than 2.3 mmol/L (Ͼ200 mg/dL) are mentioned as "other risk factors" that indicate "incremental absolute risk above that estimated from the preced-
Abstract 4662: Genetic variations in the cell-cycle pathway and survival of patients with advanced non-small cell lung cancer receiving platinum-based chemotherapy
Authors: Jikai Yin, Xifeng Wu, Charles Lu, Joe Chang, Michelle Hildebrandt, David Stewart, Margaret R. Spitz, Jian Gu
Journal: Cancer Research (2010)

Abstract Background: Platinum-based chemotherapy is the main choice of treatment for patients with advanced Non-small cell lung cancer (NSCLC). Platinum agents target DNA preferentially for cytotoxicity, which will lead to DNA damage and cell-cycle arrest. We hypothesize that genetic variations in cell cycle pathway may modulate response to platinum-based chemotherapy. In this study, we utilized a comprehensive pathway-based approach to identify genetic variations in the cell-cycle pathway as predictors of overall survival in NSCLC patients treated with platinum-based chemotherapy. Material and Methods: We genotyped 633 polymorphisms from 105 cell cycle-related genes in 598 advanced NSCLC cases who received first-line platinum-based chemotherapy. All genotypes were analyzed for association with overall survival and evaluated for potential cumulative and gene-gene interactions that further modulated overall survival. Multiple statistic analyses were applied, including individual SNP analysis, cumulative genotype analysis, haplotype analysis, survival tree analysis and Kaplan-Meier survival analysis. Results: 65 SNPs from 40 cell-cycle genes were identified that were significantly associated with NSCLC overall survival (p&amp;lt;0.05) individually. We found that increasing numbers of potential high-risk alleles in any cell-cycle checkpoint would lead to increased risk of death. Compared with other checkpoints, G1/S checkpoint showed more significant associations with patients’ survival. For the combined analysis of unfavorable genotypes in G1/S checkpoint, compared with the referent group (≤20 unfavorable genotypes), the HRs for patients carrying 21-23 and 24-32 unfavorable genotypes were 1.94(95%CI 1.47-2.56) and 3.00(95%CI 2.33-3.85), respectively (p for trend &amp;lt; 0.0001), and also a significant reduction of median survival time from 24.05 to 9.18 months (log-rank p &amp;lt; 0.0001). Heplotype analysis revealed that a TP73 haplotype (GTGTTA) was significantly associated with increased risk of death (p=0.00026). Survival tree analysis of overall cell-cycle pathway indicated G1/S checkpoint genes categorized patients into subgroups with different survival pattern. Conclusions: These results suggest that G1 and G1/S checkpoint genetic variations affect survival of advanced NSCLC patients treated with platinum-based chemotherapy and that there are gene-dosage effect and gene-gene interactions in modulating clinical outcomes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4662.
Advertising of antibiotics.
Authors: J D Williams, A M Geddes
Journal: BMJ (1973)

Advertising of Antibiotics SIR,-We would like to comment on certain aspects of the correspondence which has fol- lowed the publication of our letter on this subject (14 April, p. 116), particularly with reference to amoxycillin and cephradine.We agree with Dr. E. T. Knudsen (28 April, p. 240) that changing a molecule in a compound may alter its action, but this is by no means invariable.For example, the May 1973 issue of MIMS contains 40 prepara- tions of tetracycline and its derivatives which have different formulae but virtually identical antibacterial spectra.We are not opposed to amoxycillin which,
Histamine and histidine decarboxylase are correlated with mucosal repair in rat small intestine after ischemia-reperfusion.
Authors: K Fujimoto, I Imamura, D N Granger, H Wada, T Sakata, P Tso
Journal: Journal of Clinical Investigation (1992)

The aim of this experiment was to demonstrate whether histamine and histidine decarboxylase (HDC) contribute to mucosal repair in small intestine subjected to ischemia-reperfusion (I/R). The superior mesenteric artery was occluded for 15 min followed by reperfusion. In jejunal mucosa, histamine content and HDC activity increased after I/R. Histamine output in mesenteric lymph was also elevated after I/R. These increases in HDC activity, and mucosal and lymph histamine levels were suppressed by pretreatment of alpha-fluoromethylhistidine (alpha-FMH), a suicide inhibitor of HDC. alpha-FMH also attenuated the increase of ornithine decarboxylase (ODC) activity normally observed after I/R. Transport of dietary lipid into lymph markedly decreased at 24 h after I/R, yet it was restored to normal at 48 h after I/R. alpha-FMH inhibitor led to a sustained deficit in lipid transport at 48 h after I/R. This sustained functional impairment in alpha-FMH treated animals was associated with blunted responses of HDC activity and histamine content to I/R. Our results suggest that histamine and HDC contribute to the restoration in mucosal function observed at 48 h after I/R. This response may be related, at least in part, to stimulation of ODC activity by histamine.
712-4 Role of Intraoperative Transesophageal Echocardiography in Patients with Hypertrophic Obstructive Cardiomyopathy
Authors: Seong H. Park, Roger L. Click, William K. Freeman, Jae K. Oh, Hartzell V. Schaff, Gordon K. Danielson, Donald J. Hagler, A. Jamil Tajik, James B. Seward
Journal: Journal of the American College of Cardiology (1995)
Studies on the Control of Hypertension
Authors: H. MITCHELL PERRY, HENRY A. SCHROEDER
Journal: Circulation (1956)

Because doses of antihypertensive agents necessary to control human arterial hypertension at relatively normotensive levels were observed to decrease with time, records of all patients in our series receiving oral hexamethonium chloride and hydralazine (but no other drugs) were analyzed (114 cases). After two years of therapy, those patients maintaining average diastolic pressures below 100 mm. Hg were found to require considerably less methonium ion while those unable or unwilling to control their pressures to this degree needed approximately their initial doses. Further decreases in drug requirements for the well-controlled group occurred after three years. Ten were able to discontinue all medication eventually and nine others needed only smaller doses of hydralazine; in these reversal of secondary changes was sometimes observed. Prolonged, continuous and adequate drug therapy is apparently associated with a change in the basic process producing hypertension.
Movement arousals and sleep-related disordered breathing in adults.
Authors: P Collard, M Dury, P Delguste, G Aubert, D O Rodenstein
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Sleep fragmentation (an increase in the number of short EEG arousals) is considered a major determinant of excessive daytime sleepiness but is seldom quantified in sleep studies, and reference values are scarce at best. We present data on the movement arousal index (MAI) in five groups of subjects: normals, simple snorers, patients with the sleep apnea-hypopnea syndrome (SAHS), and patients with sleep-related oxygen desaturations due to chronic obstructive pulmonary disease or neuromusculoskeletal disorders. In normal subjects, the MAI was 13 +/- 7 (mean +/- SD). MAI was distinctly increased in most patients with SAHS and was strongly correlated with the apnea-hypopnea index and loss of both slow wave and REM sleep. It was corrected to normal by nasal continuous positive airway pressure (CPAP). There was some overlap of MAI between SAHS patients and snorers, suggesting that a minority of nonapneic snorers may suffer from daytime sleepiness due to upper airway dysfunction. Sleep fragmentation is not a feature of sleep-related hypoventilation due to COPD or neuromusculoskeletal disorders, and an increase of the number of movement arousals (MA) is very suggestive of upper airway dysfunction and of potential success of CPAP. Quantification of sleep fragmentation is feasible and clinically useful; it should be included in the assessment of sleep-related breathing disorders.
Report shows health disparities in American Indians and Alaska Natives
Authors: U. Tayal
Journal: BMJ (2003)

A 5 year old girl with tuberculous meningitis developed progressive visual failure during in-patient anti-tuberculous chemotherapy due to an ophthochiasmatic tuberculoma. This was successfully managed by prolonged high-dose corticosteroids and continued anti-tuberculous therapy resulting in complete visual and psychosocial recovery.
Inhibition of Inositol(1,4,5)Trisphosphate Generation by Endothelin-1 During Postischemic Reperfusion
Authors: Elizabeth A. Woodcock, Nancy Reyes, Alexander N. Jacobsen, Xiao-Jun Du
Journal: Circulation (1999)

Background —Reperfusion of ischemic rat hearts in the presence of thrombin or norepinephrine but not endothelin-1 causes the generation of inositol 1,4,5-trisphosphate (Ins 1,4,5P 3 ) and arrhythmias. The present study investigates the effect of endothelin-1 on these responses. Methods and Results —Ins 1,4,5P 3 generation was quantified by use of [ 3 H] labeling and high-performance liquid chromatography as well as by mass analysis. Twenty minutes of global ischemia followed by 2 minutes of reperfusion increased [ 3 H]Ins 1,4,5P 3 from 2828±265 to 5033±650 cpm/g tissue in the presence of thrombin 2.5 IU/mL and to 4561±286 cpm/g tissue in response to release of norepinephrine (n=4, P &lt;0.01) in both cases. Reperfusion in the presence of endothelin-1 alone caused no change in Ins 1,4,5P 3 (2762±240 cpm/g tissue), but when added together with thrombin or norepinephrine, endothelin-1 reduced the Ins 1,4,5P 3 responses to 2313±197 and 1764±168 cpm/g tissue, respectively (n=4, P &lt;0.01 in both cases). Similar inhibitory interactions between endothelin-1 10 nmol/L and thrombin 2.5 IU/mL were observed under normoxic conditions in nonperfused ventricle, eliminating the possibility that excessive vasoconstriction was responsible. In parallel studies, endothelin-1 suppressed the development of reperfusion arrhythmias initiated by either thrombin (ventricular fibrillation, 75% to 39%, n=16 to 18) or norepinephrine (83% to 8%, n=12 to 22) ( P &lt;0.01 in both cases). Conclusions —Inhibition of Ins 1,4,5P 3 generation during myocardial reperfusion by endothelin-1 represents a novel antiarrhythmic mechanism.
Intra‐aortic balloon counterpulsation as a bridge to heart transplantation does not impair long‐term survival
Authors: Ola Gjesdal, Einar Gude, Satish Arora, Torbjørn Leivestad, Arne K. Andreassen, Lars Gullestad, Lars Aaberge, Harald Brunvand, Thor Edvardsen, Odd R. Geiran, Svein Simonsen
Journal: European Journal of Heart Failure (2009)
Distribution and clinical significance of blood dendritic cells in children with juvenile idiopathic arthritis
Authors: E Smolewska, J Stanczyk, H Brozik, M Biernacka-Zielinska, B Cebula, T Robak, P Smolewski
Journal: Annals of the Rheumatic Diseases (2007)

A role for dendritic cells (DC) in the development of adult rheumatoid arthritis has been suggested. To date, this problem has been poorly explored in juvenile idiopathic arthritis (JIA).To analyse distribution and maturation status of blood DC (BDC) in JIA.Absolute BDC counts were assessed by the "single platform" method in peripheral blood (PB) of 47 untreated children with JIA and 32 healthy controls. Moreover, BDC were investigated in JIA synovial fluid (SF). When the panel of monoclonal antibodies against BDC antigens (BDCA) was used, three BDC subpopulations were determined: myeloid type 1 (mDC1; BDCA-1+/HLA-DR+/CD19-), myeloid type 2 (mDC2; BDCA-3+/HLA-DR+/CD14-) and plasmacytoid (pDC; BDCA-2+/HLA-DR+/CD123+).A considerable deficiency of all subtypes of BDC was found in the PB of children with JIA. BDC counts in JIA SF were significantly higher than in PB both from children with JIA (p<0.001) and healthy children (p<0.001). SF BDC, especially mDC1 and mDC2 subtypes, had significantly higher expression of maturation markers (CD40, CD80, CD86 or CD83 antigens) than those from PB. A smaller number of PB BDC at diagnosis correlated significantly with poor response to treatment.A deficiency of BDC in PB is accompanied by enrichment of SF with those cells. Probably, circulating BDC migrate to joints where they undergo maturation and help to mediate and maintain the local immune response. Interestingly, the level of PD BDC deficiency seems to influence the outcome in children with JIA.
Type A Behaviour, Attention, and the Report of Subjective Arousal
Authors: F.H. Roldan
Journal: Psychotherapy and Psychosomatics (1987)

Previous research has indicated a tendency among type A individuals to report less subjective arousal than type B individuals. Differences in attentional style between type A and type B individuals have been suggested to account for this tendency. The present paper describes a study which employed adult male subjects to examine this notion. The results of this study replicated previous findings of symptom underreport by type A subjects, but findings pertaining to the role of attention in this phenomenon were ambiguous. These data are discussed in the light of previous studies.
Allele diversity of the H-ras-1 variable number of tandem repeats in Norwegian lung cancer patients.
Authors: D Ryberg, T Tefre, V Skaug, L Stangeland, S Ovrebø, A Naalsund, A L Børresen, A Haugen
Journal: Environmental Health Perspectives (1992)

We have examined restriction fragment length polymorphisms of the H-ras-1 gene in germ-line DNA from 214 lung cancer patients and 309 unaffected controls. When DNA samples were digested with MspI/HpaII, Southern blot analysis revealed at least 22 different alleles, grouped according to their frequencies as common, intermediate, and rare. The frequency of rare alleles in lung cancer patients (16/428) is significantly different (p = 0.002) from that in the control group (5/618). Individuals with rare alleles were found to be at 4.7-fold greater risk of lung cancer than those with no rare alleles.
PHYSICOCHEMICAL CHARACTERIZATION OF MOUSE MYELOMA PROTEINS: DEMONSTRATION OF HETEROGENEITY FOR EACH MYELOMA GLOBULIN
Authors: John L. Fahey
Journal: The Journal of Experimental Medicine (1961)

Physicochemical characterization of mouse myeloma proteins revealed the individuality of each myeloma protein. When the myeloma proteins are considered collectively a wide range of individual properties were represented, including electrophoretic mobilities varying from the gamma to alpha region, hexose contents from 1 to 4 per cent, and ultracentrifugal components from 6.5 to 13 S. The 20 myeloma proteins could be divided into groups, the gamma type and the beta type myeloma globulins, on the basis of physicochemical, as well as immunoelectrophoretic, studies. Two gamma type myeloma proteins (5563, MPC-11) resembled normal gamma globulins, sedimenting as a single 6.5 S peak in the ultracentrifuge, and having a relatively low hexose content (1 per cent). Eighteen beta type mouse myeloma proteins differed from gamma myeloma proteins and, typically, were found on ultracentrifugal analysis to have multiple components with sedimentation coefficients of 6.5, 9, 11, and 13 S, having a higher hexose content (2 to 4 per cent) as well as distinctive chromatographic and starch gel electrophoretic properties. All of the mouse myeloma proteins were heterogeneous and heterogeneity of two types was observed. Polymer formation was responsible for the 9, 11, and/or 13 S components seen on ultracentrifugation of the beta type myeloma proteins. Starch gel electrophoresis revealed this type of heterogeneity as relatively widely separated myeloma protein components, presumably owing to the retardation effect of starch gel on the electrophoretic migration of the larger polymers. Starch gel electrophoresis revealed a different type of heterogeneity for the two gamma type myeloma proteins, each of these being shown to contain 5 or more components differing only in electrophoretic properties. The physicochemical characteristics of the gamma-type and beta-type myeloma proteins in the mouse indicated the close similarity of these proteins to the gamma- and beta-(2A)-myeloma proteins in man.
A Case of Recalcitrant DRESS Syndrome With Multiple Autoimmune Sequelae Treated With Intravenous Immunoglobulins
Authors: Elisha M. Singer, Karolyn A. Wanat, Misha A. Rosenbach
Journal: JAMA Dermatology (2013)

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