tbuckley/cabot-search huggingface dataset:
T-Type Ca <sup>2+</sup> Channel Blockade Prevents Sudden Death in Mice With Heart Failure
Authors: Hideyuki Kinoshita, Koichiro Kuwahara, Makoto Takano, Yuji Arai, Yoshihiro Kuwabara, Shinji Yasuno, Yasuaki Nakagawa, Michio Nakanishi, Masaki Harada, Masataka Fujiwara, Masao Murakami, Kenji Ueshima, Kazuwa Nakao
Journal: Circulation (2009)

Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca(2+) channels contributes to the progression of heart failure. The ability of T-type Ca(2+) channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however.We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca(2+) channel blockers, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(-)-isomer of efonidipine, a recently identified, highly selective T-type Ca(2+) channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction.T-type Ca(2+) channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca(2+) channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca(2+) channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.
Translation of a Retained Intron in Tyrosinase-related Protein (TRP) 2 mRNA Generates a New Cytotoxic T Lymphocyte (CTL)-defined and Shared Human Melanoma Antigen Not Expressed in Normal Cells of the Melanocytic Lineage
Authors: Raffaella Lupetti, Patrizia Pisarra, Alessandro Verrecchia, Cinthia Farina, Gabriella Nicolini, Andrea Anichini, Claudio Bordignon, Marialuisa Sensi, Giorgio Parmiani, Catia Traversari
Journal: The Journal of Experimental Medicine (1998)

We report here the identification of a new shared human melanoma antigen recognized by a human leukocyte antigen (HLA)-A*68011–restricted cytotoxic T lymphocyte clone (CTL 128). The cDNA encoding this antigen is composed of a partially spliced form of the melanocyte differentiation antigen tyrosinase-related protein (TRP)-2, containing exons 1–4 with retention of intron 2 and part of intron 4 (TRP-2–INT2). The sequence coding for the antigenic epitope is located at the 5′ end of intron 2 and is available for translation in the same open reading frame of the fully spliced TRP-2 mRNA. This peptide is also recognized by CTL 128 when presented by the HLA-A*3301, a member of the HLA-A3–like supertype that includes the HLA-A*68011. Quantitative reverse transcription PCR analysis carried out on total and/or cytoplasmic mRNA demonstrated that, in contrast to the fully spliced TRP-2 mRNA expressed in melanomas, normal skin melanocytes, and retina, the TRP-2–INT2 mRNA could be detected at significant levels in melanomas but not in normal cells of the melanocytic lineage. Instead, in these normal samples, both the spliced and the unspliced transcript of gp100 were expressed at high levels. Absence of endogenous TRP-2–INT2 expression in melanocytes was also confirmed by lack of recognition of HLA-A*68011–transduced, TRP-2+ melanocyte lines by CTL 128. These results indicate that a partially spliced form of a differentiation antigen mRNA, present in the cytoplasmic compartment of neoplastic but not normal cells of the melanocytic lineage, can be the source of a melanoma-restricted T cell epitope.
Tuberculosis Treatment Outcomes
Authors: Robert M. Jasmer, Christopher B. Seaman, Leah C. Gonzalez, L. Masae Kawamura, Dennis H. Osmond, Charles L. Daley
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Effective treatment of tuberculosis requires adherence to a minimum of 6 months treatment with multiple drugs. To improve adherence and cure rates, directly observed therapy is recommended for the treatment of pulmonary tuberculosis. We compared treatment outcomes among all culture-positive patients treated for active pulmonary tuberculosis (n = 372) in San Francisco County, California from 1998 through 2000. Patients treated by directly observed therapy at the start of therapy (n = 149) had a significantly higher cure rate compared with patients treated by self-administered therapy (n = 223) (the sum of bacteriologic cure and completion of treatment, 97.8% versus 88.6%, p < 0.002), and decreased tuberculosis-related mortality (0% vs. 5.5%, p = 0.002). Rates of treatment failure, relapse, and acquired drug resistance were similar between the two groups. Forty-four percent of patients who received self-administered therapy had risk factors for nonadherence and should have been assigned to directly observed therapy. We conclude that treatment plans that emphasize directly observed therapy from the start of therapy have the greatest success in improving tuberculosis treatment outcomes.
Determinants of the Usage of Splice-Associated<i>cis</i>-Motifs Predict the Distribution of Human Pathogenic SNPs
Authors: XianMing Wu, Laurence D. Hurst
Journal: Molecular Biology and Evolution (2015)

Where in genes do pathogenic mutations tend to occur and does this provide clues as to the possible underlying mechanisms by which single nucleotide polymorphisms (SNPs) cause disease? As splice-disrupting mutations tend to occur predominantly at exon ends, known also to be hot spots of cis-exonic splice control elements, we examine the relationship between the relative density of such exonic cis-motifs and pathogenic SNPs. In particular, we focus on the intragene distribution of exonic splicing enhancers (ESE) and the covariance between them and disease-associated SNPs. In addition to showing that disease-causing genes tend to be genes with a high intron density, consistent with missplicing, five factors established as trends in ESE usage, are considered: relative position in exons, relative position in genes, flanking intron size, splice sites usage, and phase. We find that more than 76% of pathogenic SNPs are within 3–69 bp of exon ends where ESEs generally reside, this being 13% more than expected. Overall from enrichment of pathogenic SNPs at exon ends, we estimate that approximately 20–45% of SNPs affect splicing. Importantly, we find that within genes pathogenic SNPs tend to occur in splicing-relevant regions with low ESE density: they are found to occur preferentially in the terminal half of genes, in exons flanked by short introns and at the ends of phase (0,0) exons with 3′ non-"AGgt" splice site. We suggest the concept of the "fragile" exon, one home to pathogenic SNPs owing to its vulnerability to splice disruption owing to low ESE density.
Sindbis viral vector induced apoptosis requires translational inhibition and signaling through Mcl-1 and Bak
Authors: Lisa Venticinque, Daniel Meruelo
Journal: Molecular Cancer (2010)

Sindbis viral vectors are able to efficiently target and kill tumor cells in vivo, as shown using pancreatic and ovarian cancer models. Infection results in apoptosis both in vitro and in vivo. Sindbis vector uptake is mediated by the LAMR, which is upregulated on a number of different tumor types, thus conferring specificity of the vector to a wide range of cancers. In this study we elucidate the mechanism of apoptosis in two tumor cell lines, MOSEC, derived from the ovarian epithelium and Pan02, derived from a pancreatic adenocarcinoma. A comprehensive understanding of the mechanism of apoptosis would facilitate the design of more effective vectors for cancer therapy. The initial phase of Sindbis vector induced apoptosis in MOSEC and Pan02 models reconfirms that viral infection is sensed by PKR due to double-stranded RNA intermediates associated with genomic replication. PKR activation results in translation inhibition through eIF2α phosphorylation and initiation of the stress response. Our studies indicate that the roles of two proteins, Mcl-1 and JNK, intimately link Sindbis induced translational arrest and cellular stress. Translational arrest inhibits the synthesis of anti-apoptotic Bcl-2 protein, Mcl-1. JNK activation triggers the release of Bad from 14-3-3, which ultimately results in apoptosis. These signals from translational arrest and cellular stress are propagated to the mitochondria where Bad and Bik bind to Bcl-xl and Mcl-1 respectively. Formation of these heterodimers displaces Bak, which results in caspase 9 cleavage and signaling through the mitochondrial pathway of apoptosis. The host cell response to Sindbis is triggered through PKR activation. Our studies demonstrate that PKR activation and subsequent translational arrest is linked to both cellular stress and apoptosis. We have also found the linkage point between translational arrest and apoptosis to be Mcl-1, a protein whose constant translation is required for inhibition of apoptosis. With this information vectors can be designed, which express or repress proteins implicated in this study, to enhance their therapeutic potential.
Time course of exhaled hydrogen peroxide and nitric oxide during chemotherapy
Authors: A. R. Wewel, J. A. M. Crusius, U. Gatzemeier, M. Heckmayr, G. Becher, H. Magnussen, R. A. Jörres, O. Holz
Journal: European Respiratory Journal (2006)

This study was designed to assess the effect of differential leukocyte depletion during chemotherapy by monitoring the levels of exhaled hydrogen peroxide H 2 O 2 and nitric oxide ( F eNO ) present. In 39 patients with lung cancer (chronic obstructive pulmonary disorder up to stage II, median forced expiratory volume in one second 78% predicted), measurements were performed before a cycle of therapy (day 1), at least once during the cycle (day 8: n = 34; day 15: n = 19), and afterwards (days 21–29). There were significant changes in the level of H 2 O 2 , F eNO and peripheral blood cell differentials over the visits. The level of H 2 O 2 was decreased only on day 15, with a median (difference between the upper and lower quartiles) fall of 31 (57)%, while F eNO was reduced only on day 8, by 22 (40)%. Neutrophil numbers were unchanged on day 8 and decreased by 59 (48)% on day 15, while monocyte numbers were decreased on day 8 by 87 (39)%. On days 21–29, values had returned to baseline. Taken together with previous findings, the parallel course of levels of exhaled hydrogen peroxide and neutrophil counts suggests that a major part of exhaled hydrogen peroxide is due to neutrophils via the conducting airways. In contrast, the production of exhaled nitric oxide seems to be primarily associated with monocytes.
N-Terminal Pro-Brain Natriuretic Peptide Levels and Risk of Death in Sickle Cell Disease
Authors: Roberto F. Machado, Anastasia Anthi, Martin H. Steinberg, Duane Bonds, Vandana Sachdev, Gregory J. Kato, Angelo M. Taveira-DaSilva, Samir K. Ballas, William Blackwelder, Xiuli Xu, Lori Hunter, Bruce Barton, Myron Waclawiw, Oswaldo Castro, Mark T. Gladwin, for the MSH Investigators
Journal: JAMA (2006)

ContextThirty percent of patients with sickle cell disease (SCD) develop pulmonary hypertension, a major risk factor for death in this population. A validated blood biomarker of pulmonary hypertension in SCD could provide important prognostic and diagnostic information and allow the exploration of the prevalence of pulmonary hypertension in participants in the 1996 Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) Patients' Follow-up Study. Levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) provide such information in patients with idiopathic pulmonary arterial hypertension.ObjectiveTo determine the relationship between NT-proBNP levels and severity of pulmonary hypertension and prospective mortality in patients with SCD.Design, Setting, and ParticipantsNT-proBNP levels were measured in 230 participants in the National Institutes of Health (NIH) Sickle Cell Disease–Pulmonary Hypertension Screening Study (enrollment between February 2001 and March 2005) and in 121 samples from patients enrolled starting in 1996 in the MSH Patients' Follow-up Study. A threshold level predictive of high pulmonary artery pressure and mortality was identified in the NIH Sickle Cell Disease–Pulmonary Hypertension Screening Study and used to define an a priori analytical plan to determine the prevalence and associated mortality of pulmonary hypertension in the MSH follow-up study.Main Outcome MeasuresSeverity of pulmonary hypertension and risk of all-cause mortality.ResultsNT-proBNP levels were higher in patients with sickle cell pulmonary hypertension and correlated directly with tricuspid regurgitant jet velocity in the NIH cohort (R = 0.50, P&lt;.001). An NT-proBNP level of 160 pg/mL or greater had a 78% positive predictive value for the diagnosis of pulmonary hypertension and was an independent predictor of mortality (21 deaths at 31 months' median follow-up; risk ratio, 5.1; 95% confidence interval, 2.1-12.5; P&lt;.001; 19.5% absolute increase in risk of death). In the MSH cohort, 30% of patients had an NT-proBNP level of 160 pg/mL or greater. An NT-proBNP level of 160 pg/mL or greater in the MSH cohort was independently associated with mortality by Cox proportional hazards regression analysis (24 deaths at 47 months' median follow-up; risk ratio, 2.87; 95% confidence interval, 1.2-6.6; P = .02; 11.9% absolute increase in risk of death).ConclusionsPulmonary hypertension, as indicated by an NT-proBNP level of 160 pg/mL or greater, was very common in patients in the NIH study and in the MSH cohort. The MSH analysis suggests that rates of vaso-occlusive pain episodes in these patients were unrelated to risk of death; this risk was largely determined by occult hemolytic anemia–associated pulmonary hypertension.
Advances in recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency
Authors: B.C.J.M. Fauser, B.M.J.L. Mannaerts, P. Devroey, A. Leader, I. Boime, D.T. Baird
Journal: Human Reproduction Update (2009)

Recombinant DNA technologies have been used to develop longer-acting therapeutic proteins. One approach is to introduce sequences containing additional glycosylation sites. Using this technique, a new chimeric gene has been developed containing the coding sequences of the FSH β-subunit and the C-terminal peptide of the hCG β-subunit, which bears four O-linked oligosaccharide binding sites. Co-expression of the α-subunit and the chimeric FSH β-subunit produces a new recombinant molecule, named corifollitropin alfa, with a prolonged elimination half-life and enhanced in vivo bioactivity compared with wild-type FSH. Medline searches by subject and additional searching by hand. Initial studies in pituitary suppressed female volunteers confirmed the extended half-life of the compound. Phase II studies have shown that corifollitropin alfa is able to induce and sustain multi-follicular growth for an entire week in women undergoing ovarian stimulation using GnRH antagonist co-treatment for IVF. Corifollitropin alfa regimens have been developed with dosages of 100 and 150 µg, for patients with body weight ≤60 and >60 kg, respectively. Corifollitropin alfa is the first long-acting hybrid molecule with sustained follicle-stimulating activity developed for the induction of multi-follicular growth along with GnRH antagonist co-treatment for IVF. This new treatment option may be simpler and more convenient for patients compared with conventional long protocols of daily FSH injections in combination with GnRH agonist co-treatment. The safety and efficacy of such regimens is currently being evaluated in large comparative phase III clinical trials. The development of corifollitropin alfa is the first step towards a new generation of recombinant gonadotrophins.
Activation of Protein Kinase C-α and Src Kinase Increases Urea Transporter A1 α-2, 6 Sialylation
Authors: Xuechen Li, Baoxue Yang, Minguang Chen, Janet D Klein, Jeff M Sands, Guangping Chen
Journal: Journal of the American Society of Nephrology (2014)

The urea transporter A1 (UT-A1) is a glycosylated protein with two glycoforms: 117 and 97 kD. In diabetes, the increased abundance of the heavily glycosylated 117-kD UT-A1 corresponds to an increase of kidney tubule urea permeability. We previously reported that diabetes not only causes an increase of UT-A1 protein abundance but also, results in UT-A1 glycan changes, including an increase of sialic acid content. Because activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway is elevated in diabetes and PKC-α regulates UT-A1 urea transport activity, we explored the role of PKC in UT-A1 glycan sialylation. We found that activation of PKC specifically promotes UT-A1 glycan sialylation in both UT-A1-MDCK cells and rat kidney inner medullary collecting duct suspensions, and inhibition of PKC activity blocks high glucose-induced UT-A1 sialylation. Overexpression of PKC-α promoted UT-A1 sialylation and membrane surface expression. Conversely, PKC-α-deficient mice had significantly less sialylated UT-A1 compared with wild-type mice. Furthermore, the effect of PKC-α-induced UT-A1 sialylation was mainly mediated by Src kinase but not Raf-1 kinase. Functionally, increased UT-A1 sialylation corresponded with enhanced urea transport activity. Thus, our results reveal a novel mechanism by which PKC regulates UT-A1 function by increasing glycan sialylation through Src kinase pathways, which may have an important role in preventing the osmotic diuresis caused by glucosuria under diabetic conditions.
Planning and controlling action in a structured environment: Visual illusion without dorsal stream
Authors: Yann Coello, Yves Rossetti
Journal: Behavioral and Brain Sciences (2004)

Some data concerning visual illusions are hardly compatible with the perception–action model, assuming that only the perception system is influenced by visual context. The planning–control dichotomy offers an alternative that better accounts for some controversy in experimental data. We tested the two models by submitting the patient I. G. to the induced Roelofs effect. The similitude of the results of I. G. and control subjects favoured Glover's model, which, however, presents a paradox that needs to be clarified.
Long-term follow-up of 287 meningiomas in neurofibromatosis type 2 patients: clinical, radiological, and molecular features
Authors: S. Goutagny, A. B. Bah, D. Henin, B. Parfait, A. B. Grayeli, O. Sterkers, M. Kalamarides
Journal: Neuro-Oncology (2012)

Decision-making criteria for optimal management of meningiomas in neurofibromatosis type 2 (NF2) patients is hampered by lack of robust data, particularly long-term natural history. Seventy-four NF2 patients harboring 287 cranial meningiomas followed up for a mean period of 110.2 months were studied retrospectively. The median number of meningiomas per patient was 3. The mean maximum diameter of meningiomas at diagnosis was 14.3 mm, with a mean annual growth rate of 1.5 mm. Sixty-six percent of tumors showed no or minimal growth. In a subgroup of patients with 3D MRI, 7.3% of meningiomas (28% of patients) had a volumetric growth rate 20% or more per year. Twenty-five de novo meningiomas appeared during the follow-up (8.7%) and demonstrated a higher growth rate than other meningiomas (6.6 mm/year). Fifty-six meningiomas (23%) in 34 NF2 patients (45.9%) were operated on during the follow-up period. Among symptomatic resected meningiomas, grades II and III tumors were found in 29% and 6% of cases, respectively, with a remarkable intratumor histological heterogeneity. Single nucleotide polymorphism array analysis of 22 meningioma samples in 14 NF2 patients showed increasing chromosome instability with increasing grade, the most frequent losses being on 22q, 1p, 18q, and 6p. This study provides clues to improve tailored treatment of meningiomas: de novo and brain edema-associated meningiomas require active treatment. Future clinical trials in NF2 need to focus specifically on meningiomas as the primary endpoint and should include patients with meningiomas growing 20% or more per year in order to assess new treatments.
Insurance Coverage of Emergency Care for Young Adults under Health Reform
Authors: Andrew Mulcahy, Katherine Harris, Kenneth Finegold, Arthur Kellermann, Laurel Edelman, Benjamin D. Sommers
Journal: New England Journal of Medicine (2013)

The Affordable Care Act (ACA) established nationwide eligibility for young adults 19 to 25 years of age to retain coverage under their parents' private health plans. We conducted a study to determine how the implementation of this provision changed rates of insurance coverage for young adults seeking medical care for major emergencies.We evaluated more than 480,000 nondiscretionary visits made to emergency departments from 2009 through 2011, as recorded in a large, geographically diverse data set of hospital claims, to estimate how the ACA provision affected private insurance coverage of such visits by young adults (19 to 25 years of age). To adjust for underlying trends in insurance coverage, we compared changes in the target age group with changes among adults 26 to 31 years of age, who were unaffected by the provision (control group).After the ACA provision took effect, private coverage of nondiscretionary visits to emergency departments by young adults increased by 3.1 percentage points (95% confidence interval [CI], 2.3 to 3.9; relative increase, 5.2%; P<0.001), as compared with similar visits in the control group. The percentage of visits by uninsured young adults also fell significantly (-1.7 percentage points; 95% CI, -2.8 to -0.7; relative decrease, 9.1%; P<0.001). The rates of nondiscretionary visits that were covered by Medicaid or other nonprivate insurers remained relatively steady throughout the study period. The coverage expansion led to an estimated 22,072 visits to emergency departments by newly insured young adults and $147 million in associated costs that were covered by private insurance plans during a 1-year period.Enactment of the dependent-coverage provision was associated with a significant increase in the proportion of young adults who were protected from the financial consequences of a serious medical emergency. (Funded by the Office of the Assistant Secretary for Planning and Evaluation, Department of Health and Human Services.).
WHO publishes the third edition of guidelines for the prevention and control of air-travel-associated tuberculosis
Authors: I Abubakar, K Fernandez de la Hoz
Journal: Eurosurveillance (2008)

Air travel has increased over the last few decades resulting in greater risk of the spread of infectious diseases carried by infectious travellers. The risk of transmission of pathogens is particularly important for airborne organisms raising concern among public health agencies and the public. Despite limited research on the risk of tuberculosis associated with air travel, several reports have published evidence of the transmission of tuberculosis infection, including multidrug-resistant tuberculosis (MDR-TB) [1, 2].