tbuckley/cabot-search huggingface dataset:
Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies
Authors: Andrew T. McGuire, Sam Hoot, Anita M. Dreyer, Adriana Lippy, Andrew Stuart, Kristen W. Cohen, Joseph Jardine, Sergey Menis, Johannes F. Scheid, Anthony P. West, William R. Schief, Leonidas Stamatatos
Journal: The Journal of Experimental Medicine (2013)

Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of inhibiting infection of diverse HIV strains, and have been isolated from HIV-infected individuals. Despite the presence of anti–CD4-BS broadly neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so far failed to elicit such antibodies. Here, we show that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target the CD4-BS. However, we found that the elimination of a conserved glycosylation site located in Loop D and two glycosylation sites located in variable region 5 of Env allows Env-binding to, and activation of, B cells expressing the germline-reverted BCRs of two potent broadly neutralizing antibodies, VRC01 and NIH45-46. Our results offer a possible explanation as to why Env immunogens have been ineffective in stimulating the production of such bNAbs. Importantly, they provide key information as to how such immunogens can be engineered to initiate the process of antibody-affinity maturation against one of the most conserved Env regions.
THE DURATION OF IMMUNE BODIES IN THE BLOOD AFTER ANTITYPHOID INOCULATION
Authors: Martha Wollstein
Journal: The Journal of Experimental Medicine (1912)

In this series of twenty-four persons inoculated with antityphoid vaccine, the immune bodies in the blood reached their height within two months after the first inoculation, or one month after the third, then fell rapidly within the next two months. Only nineteen of the cases could be followed longer, and eight of these were negative for bactericidins within ten months after inoculation, and fifteen were negative after thirteen months. Only one serum reacted in a dilution of 1 to 1,200 at the end of thirteen months. The addition of lecithin to the vaccine did not influence the local reaction after inoculation, nor did it appreciably affect the formation of immune bodies to the typhoid bacillus.
Evaluation of HbA1c determination methods in patients with hemoglobinopathies.
Authors: W J Schnedl, R Krause, G Halwachs-Baumann, M Trinker, R W Lipp, G J Krejs
Journal: Diabetes Care (2000)

OBJECTIVE: To evaluate commercially available determination methods for HbA1c in patients with hemoglobin variants. RESEARCH DESIGN AND METHODS: HbA1c values were determined with various commercially available methods, including ion-exchange high-performance liquid chromatography (HPLC), boronate affinity assay, and immunoagglutination in patients with the hemoglobin mutations Hb Graz, Hb Sherwood Forest, Hb O Padova, Hb D, and Hb S. RESULTS: The effect of hemoglobinopathies on glycohemoglobin measurements was highly method dependent. The HPLC methods for HbA1c determination lacked the resolution necessary to differentiate hemoglobin variants. They demonstrated additional peaks in the chromatograms and HbA1c results either too low or too high compared with the nondiabetic reference range. With all immunoassays, Hb Graz demonstrated falsely low values. The other hemoglobinopathies in our study caused falsely low and/or high HbA1c results in immunoagglutination methods. The boronate affinity method showed values in an acceptable range for all hemoglobin variants. CONCLUSIONS: Because of the local occurrence of Hb variants and the ethnic origin of a given population, every individual laboratory must establish and validate its own assay method. In managing diabetic patients, knowledge of hemoglobinopathies influencing HbA1c determination methods is essential because hemoglobin variants could cause mismanagement of diabetes resulting from false HbA1c determinations.
Predictors of Mortality and Outcomes of Therapy in Low-Flow Severe Aortic Stenosis
Authors: Howard C. Herrmann, Philippe Pibarot, Irene Hueter, Zachary M. Gertz, William J. Stewart, Samir Kapadia, E. Murat Tuzcu, Vasilis Babaliaros, Vinod Thourani, Wilson Y. Szeto, Joseph E. Bavaria, Susheel Kodali, Rebecca T. Hahn, Mathew Williams, D. Craig Miller, Pamela S. Douglas, Martin B. Leon
Journal: Circulation (2013)

The prognosis and treatment of patients with low-flow (LF) severe aortic stenosis are controversial.The Placement of Aortic Transcatheter Valves (PARTNER) trial randomized patients with severe aortic stenosis to medical management versus transcatheter aortic valve replacement (TAVR; inoperable cohort) and surgical aortic valve replacement versus TAVR (high-risk cohort). Among 971 patients with evaluable echocardiograms (92%), LF (stroke volume index ≤35 mL/m(2)) was observed in 530 (55%); LF and low ejection fraction (<50%) in 225 (23%); and LF, low ejection fraction, and low mean gradient (<40 mm Hg) in 147 (15%). Two-year mortality was significantly higher in patients with LF compared with those with normal stroke volume index (47% versus 34%; hazard ratio, 1.5; 95% confidence interval, 1.25-1.89; P=0.006). In the inoperable cohort, patients with LF had higher mortality than those with normal flow, but both groups improved with TAVR (46% versus 76% with LF and 38% versus 53% with normal flow; P<0.001). In the high-risk cohort, there was no difference between TAVR and surgical aortic valve replacement. In patients with paradoxical LF and low gradient (preserved ejection fraction), TAVR reduced 1-year mortality from 66% to 35% (hazard ratio, 0.38; P=0.02). LF was an independent predictor of mortality in all patient cohorts (hazard ratio, ≈1.5), whereas ejection fraction and gradient were not.LF is common in severe aortic stenosis and independently predicts mortality. Survival is improved with TAVR compared with medical management and similar with TAVR and surgical aortic valve replacement. A measure of flow (stroke volume index) should be included in the evaluation and therapeutic decision making of patients with severe aortic stenosis.URL: http://www.clinicaltrial.gov. Unique identifier: NCT0053089.4.
Clinical Presentation, Investigation, and Management of Pulmonary Vein Stenosis Complicating Ablation for Atrial Fibrillation
Authors: Douglas L. Packer, Paul Keelan, Thomas M. Munger, Jerome F. Breen, Sam Asirvatham, Laura A. Peterson, Kristi H. Monahan, Mary F. Hauser, K. Chandrasekaran, Lawrence J. Sinak, David R. Holmes
Journal: Circulation (2005)

Although segmental or circumferential ablation is effective in eliminating pulmonary vein (PV)-mediated atrial fibrillation (AF), this procedure may be complicated by the occurrence of PV stenosis.To establish the clinical presentation, diagnostic manifestations, and interventional management of PV stenosis, 23 patients with stenosis of 34 veins complicating ablation of AF were evaluated. Each patient became symptomatic 103+/-100 days after undergoing ablation. In 8 veins, the ablation producing the PV stenosis was a repeated procedure for continued AF. Nineteen patients presented with dyspnea on exertion, 7 with dyspnea at rest, 9 with cough, and 6 with chest pain. On multirow spiral computed tomography examination, the narrowest lumen of the affected PVs measured 3+/-2 mm compared with 13+/-3 mm at baseline (P< or =0.001). The relative perfusion of affected lung segments on isotope scans was reduced to 4+/-3% of total perfusion compared with 22+/-10% in unaffected segments. At percutaneous intervention, these veins showed 80+/-13% stenosis, with a mean gradient of 12+/-5 mm Hg. This was significantly reduced to a residual stenosis of 9+/-8% (P< or =0.001) and a residual gradient of 3+/-4 mm Hg (P< or =0.001). Twenty veins were treated with balloon dilatation alone, whereas 14 veins were stented with standard 10-mm-diameter bare-metal stents. Although the symptomatic response was nearly immediate and impressive, 14 patients developed in-stent or in-segment restenosis, requiring repeated interventions in 13.Percutaneous intervention produces rapid and dramatic symptom relief in patients with highly symptomatic PV stenosis after radiofrequency ablation for AF. Nevertheless, alternative treatment methods will be required to decrease recurrent in-stent or in-segment restenosis.
Imaging Response in the Primary Index Lesion and Clinical Outcomes Following Transarterial Locoregional Therapy for Hepatocellular Carcinoma
Authors: Ahsun Riaz
Journal: JAMA (2010)

<h3>Context</h3>Response Evaluation Criteria in Solid Tumors (RECIST) (unidimensional), World Health Organization (WHO) (bidimensional), and European Association for Study of the Liver (EASL) (necrosis) guidelines are commonly used to assess response following therapy for hepatocellular carcinoma (HCC). No universally accepted standard exists.<h3>Objectives</h3>To evaluate intermethod agreement between these 3 imaging guidelines and to introduce the concept of the “primary index lesion” as a biomarker for response.<h3>Design, Setting, and Participants</h3>Single-center comprehensive imaging analysis including 245 consecutive patients with HCC who were treated with chemoembolization or radioembolization between January 2000 and December 2008. Computed tomography and magnetic resonance imaging scans (N = 1065) were reviewed to assess response in the “primary index lesion,” defined as the largest tumor targeted during first treatment.<h3>Main Outcome Measures</h3>Intermethod agreement (κ statistics) between RECIST, WHO, and EASL guidelines response; correlation of WHO and EASL response in the primary index lesion with time to progression and survival.<h3>Results</h3>κ Coefficients were 0.86 (95% confidence interval [CI], 0.80-0.92) between the WHO and RECIST guidelines, 0.24 (95% CI, 0.16-0.33) between RECIST and EASL, and 0.28 (95% CI, 0.19-0.36) between WHO and EASL. Disease progressed in 96 patients; 113 died. The hazard ratio for time to progression in responders compared with nonresponders was 0.36 (95% CI, 0.23-0.57) for WHO, 0.38 (95% CI, 0.24-0.58) for RECIST, and 0.38 (95% CI, 0.22-0.64) for EASL. Hazard ratios for survival in responders compared with nonresponders in univariate and multivariate analyses were 0.46 (95% CI, 0.32-0.67) and 0.55 (95% CI, 0.35-0.84) for WHO and 0.36 (95% CI, 0.22-0.57) and 0.54 (95% CI, 0.34-0.85) for EASL. Hazard ratios for survival in responders vs nonresponders in patients with solitary and multifocal HCC were 0.39 (95% CI, 0.19-0.77) and 0.51 (95% CI, 0.32-0.82) for WHO and 0.26 (95% CI, 0.10-0.67) and 0.47 (95% CI, 0.28-0.79) for EASL.<h3>Conclusions</h3>Among a group of patients with HCC, agreement for classification of therapeutic response was high between the RECIST and WHO guidelines but low between each of these and EASL. Application of these methods to measure response in a primary index lesion resulted in statistically significant correlations with disease progression and survival.
Agalsidase-Beta Therapy for Advanced Fabry Disease
Authors: Maryam Banikazemi, Jan Bultas, Stephen Waldek, William R. Wilcox, Chester B. Whitley, Marie McDonald, Richard Finkel, Seymour Packman, Daniel G. Bichet, David G. Warnock, Robert J. Desnick
Journal: Annals of Internal Medicine (2007)

Background: Fabry disease (α-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement. Objective: To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease. Design: Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial. Setting: 41 referral centers in 9 countries. Patients: 82 adults with mild to moderate kidney disease; 74 of whom were protocol-adherent. Intervention: Intravenous infusion of agalsidase beta (1 mg per kg of body weight) or placebo every 2 weeks for up to 35 months (median, 18.5 months). Measurements: The primary end point was the time to first clinical event (renal, cardiac, or cerebrovascular event or death). Six patients withdrew before reaching an end point: 3 to receive commercial therapy and 3 due to positive or inconclusive serum IgE or skin test results. Three patients assigned to agalsidase beta elected to transition to open-label treatment before reaching an end point. Results: Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). Secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.034). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, 0.19 [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or moderate infusion-associated reactions, reported by 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group. Limitations: The study sample was small. Only one third of the patients experienced clinical events, and some patients withdrew before experiencing any event. Conclusions: Agalsidase-beta therapy slowed progression to the composite clinical outcome of renal, cardiac, and cerebrovascular complications and death compared with placebo in patients with advanced Fabry disease. Therapeutic intervention before irreversible organ damage may provide greater clinical benefit. *For a list of members of the Fabry Disease Clinical Trial Study Group, see the Appendix. ClinicalTrials.gov identifier: NCT00074984.
Association Between Early Administration of High-Dose Erythropoietin in Preterm Infants and Brain MRI Abnormality at Term-Equivalent Age
Authors: Russia Ha-Vinh Leuchter, Laura Gui, Antoine Poncet, Cornelia Hagmann, Gregory Anton Lodygensky, Ernst Martin, Brigitte Koller, Alexandra Darqué, Hans Ulrich Bucher, Petra Susan Hüppi
Journal: JAMA (2014)

<h3>Importance</h3> Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies. <h3>Objective</h3> To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age. <h3>Design, Setting, and Participants</h3> A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age. <h3>Interventions</h3> Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth. <h3>Main Outcomes and Measures</h3> The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome. <h3>Results</h3> At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89). <h3>Conclusions and Relevance</h3> In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00413946
Atopy and house dust mite sensitization as risk factors for asthma in children
Authors: M. Miraglia del Giudice, M. Pedullà, G.L. Piacentini, C. Capristo, F. P. Brunese, F. Decimo, N. Maiello, A.F. Capristo
Journal: Allergy (2002)

Background: Recent evidence suggests that asthma is not invariably related to atopy. The aim of this study was to evaluate the frequency of atopy, asthma and sensitization to eight common allergens in a large group of children with allergic symptoms. Methods: 1426 children referred to our Paediatric Asthma and Allergy Center because of allergic symptoms were examined. Bronchial asthma, allergic rhino‐conjunctivitis, food allergy and atopic dermatitis were diagnosed with standardized methods. Atopy was diagnosed if at least one skin test was positive. Results: Of the 1426 children examined, 629 (44%) were atopic and 769 (56%) were non‐atopic. Asthma was diagnosed in the same proportion (i.e., 64%) of atopic and non‐atopic children. However, after division into age groups, non‐atopic asthma was significantly more prevalent (χ 2 = 8.46) in children between 0 and 3 years old (group 1). On the other hand, atopy was significantly associated with asthma only in group 3 (odds ratio 1.85). Furthermore, a significant association with asthma symptoms was found for house dust mite (HDM) in group 3 (odds ratio 4.8). Conclusions: Asthma is related to atopy in pre‐selected children only from the age of 7 years. House dust mite sensitization seems to be an important determinant of asthma in these “older” children.
Chest radiography in children aged 2-59 months diagnosed with non-severe pneumonia as defined by World Health Organization: descriptive multicentre study in Pakistan
Authors: Tabish Hazir, Yasir Bin Nisar, Shamim A Qazi, Shazia F Khan, Mujahid Raza, Shehla Zameer, Syed Asif Masood
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objectives</b> To evaluate the chest radiographs of children diagnosed with non-severe pneumonia on the basis of the current World Health Organization guidelines (fast breathing alone) for radiological evidence of pneumonia. <b>Design</b> Descriptive analysis. <b>Setting</b> Outpatient departments of six hospitals in four cities in Pakistan. <b>Participants</b> 2000 children with non-severe pneumonia were enrolled; 1932 children were selected for chest radiography. <b>Interventions</b> Two consultant radiologists used standardised WHO definitions to evaluate chest radiographs; no clinical information was made available to them. If they disagreed, the radiographs were read by a third radiologist; the final classification was based on agreement between two of the three radiologists. <b>Main outcome measures</b> Presence or absence of pneumonia on radiographs. <b>Results</b> Chest radiographs were reported normal in 1519 children (82%). Radiological evidence of pneumonia was reported in only 263 (14%) children, most of whom had interstitial pneumonitis. Lobar consolidation was present in only 26 children. The duration of illness did not correlate significantly with the presence of radiological changes (relative risk 1.17, 95% confidence interval 0.91 to 1.49). <b>Conclusion</b> Most children diagnosed with non-severe pneumonia on the basis of the current WHO definition had normal chest radiographs.
Optimization and Functional Effects of Stable Short Hairpin RNA Expression in Primary Human Lymphocytes via Lentiviral Vectors
Authors: Dong Sung An, F. Xiao-Feng Qin, Vincent C. Auyeung, Si Hua Mao, Sam K.P. Kung, David Baltimore, Irvin S.Y. Chen
Journal: Molecular Therapy (2006)

Specific, potent, and sustained short hairpin RNA (shRNA)-mediated gene silencing is crucial for the successful application of RNA interference technology to therapeutic interventions. We examined the effects of shRNA expression in primary human lymphocytes (PBLs) using lentiviral vectors bearing different RNA polymerase III promoters. We found that the U6 promoter is more efficient than the H1 promoter for shRNA expression and for reducing expression of CCR5 in PBLs. However, shRNA expression from the U6 promoter resulted in a gradual decline of the transduced cell populations. With one CCR5 shRNA this decline could be attributed to elevated apoptosis but another CCR5 shRNA that caused cytotoxicity did not show evidence of apoptosis, suggesting sequence-specific mechanisms for cytotoxicity. In contrast to the U6 promoter, PBLs transduced by vectors expressing shRNAs from the H1 promoter could be maintained without major cytotoxic effects. Since a lower level of shRNA expression appears to be advantageous to maintaining the shRNA-transduced population, lentiviral vectors bearing the H1 promoter are more suitable for stable transduction and expression of shRNA in primary human T lymphocytes. Our results suggest that functional shRNA screens should include tests for both potency and adverse metabolic effects upon primary cells.
Acute Anticholinergic Syndrome Due to Jimson Seed Ingestion
Authors: J. RONALD MIKOLICH
Journal: Annals of Internal Medicine (1975)

Ten patients presented with acute anticholinergic syndrome secondary to Jimson seed (Datura stramonium) ingestion. Six of the 10 patients required hospitalization because of hyperpyrexia and severe neurologic derangement. Electroencephalograms recorded immediately after admission showed [1] slow wave activity, and [2] bizarre rhythmical bursts of high-voltage sharp wave activity; both of which rapidly resolved during the next 24 hours, as did the associated clinical findings of hyperreflexia, bilateral dorsiflexor Babinski responses, and decerebrate posturing. Previously unreported elevation of serum glutarnic-oxalacetic transaminase and lactic dehydrogenase and prothrombin time prolongation are documented. The pathogenic mechanism accounting for abberation of these laboratory values remains undefined. All patients showed rapid clinical improvement; follow-up neurologic evaluation and electroencephalograms have been within normal limits. Because of the widespread availability and potential abuse of the Jimson seed, the clinical syndrome associated with its toxicity merits recognition.