tbuckley/cabot-search huggingface dataset:
Latency and Persistence of Respiratory Syncytial Virus Despite T Cell Immunity
Authors: Jurgen Schwarze, Diarmund R. O'Donnell, Angela Rohwedder, Peter J. M. Openshaw
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Respiratory syncytial virus (RSV) causes bronchiolitis in infants, which is associated with recurrent wheezing in later childhood. There is mounting evidence that the virus becomes latent or persists in vivo, but little is known about the mechanisms of its latency, persistence, and immune evasion. We therefore infected BALB/c mice intranasally with human RSV, analyzed sequential tissue samples by direct culture and polymerase chain reaction for viral and messenger RNA, and monitored antiviral immune responses. Virus could not be detected in bronchoalveolar lavage samples beyond Day 14, but viral genomic and messenger RNA was present in lung homogenates for 100 days or more; combined depletion of CD4 and CD8 T cells allowed infective virus to be recovered. Neutralizing antibody and memory cytotoxic T cell responses were intact in mice with latent infections, and latent viral genome contained an authentic nonmutated M2 82-91 K(d) cytotoxic T lymphocyte epitope. A mutation of this epitope, detected in one clone, did not assist evasion. We suggest that RSV latency depends on persistence in privileged sites rather than on viral mutation.
Microsatellite Evolution at Two Hypervariable Loci Revealed by Extensive Avian Pedigrees
Authors: Nadeena R. Beck, Michael C. Double, Andrew Cockburn
Journal: Molecular Biology and Evolution (2003)

Genealogies generated through a long-term study of superb fairy-wrens (Malurus cyaneus) were used to investigate mutation within two hypervariable microsatellite loci. Of 3,230 meioses examined at the tetranucleotide locus (Mcyμ8), 45 mutations were identified, giving a mutation rate of 1.4%. At the dinucleotide locus (Mcyμ4) 30 mutations were recorded from 2,750 meioses giving a mutation rate of 1.1%. Mutations at both loci primarily (80%; 60/75) involved the loss or gain of a single repeat unit. Unlike previous studies, there was no significant bias toward additions over deletions. The mutation rate at Mcyμ8 increased with allele size, and very long alleles (>70 repeats) mutated at a rate of almost 20%. The length of the mutating allele and allele span, however, were strongly correlated so it was not possible to isolate the causative factor. Allele size did not appear to affect mutation rate at Mcyμ4, but the repeat number was considerably lower at this locus. The gender of the mutating parent was significant only at Mcyμ8, where mutations occurred more frequently in maternal alleles. However, at both loci we found that alleles inherited from the mother were on average larger than those from the father, and this in part drove the higher mutation rate among maternally inherited alleles at Mcyμ8.
Cytokeratin-18 Is a Useful Serum Biomarker for Early Determination of Response of Breast Carcinomas to Chemotherapy
Authors: Maria Hägg Olofsson, Takayuki Ueno, Yang Pan, Ren Xu, Feng Cai, Heiko van der Kuip, Thomas E. Muerdter, Maike Sonnenberg, Walter E. Aulitzky, Stephan Schwarz, Elina Andersson, Maria C. Shoshan, Aleksandra Mandic Havelka, Masakazu Toi, Stig Linder
Journal: Clinical Cancer Research (2007)

Abstract Purpose: With a widening arsenal of cancer therapies available, it is important to develop therapy-specific predictive markers and methods to rapidly assess treatment efficacy. We here evaluated the use of cytokeratin-18 (CK18) as a serum biomarker for monitoring chemotherapy-induced cell death in breast cancer. Experimental Design: Different molecular forms of CK18 (caspase cleaved and total) were assessed by specific ELISA assays. Drug-induced release of CK18 was examined from breast carcinoma cells and tissue. CK18 protein composition was examined in serum. CK18 levels were determined in serum from 61 breast cancer patients during docetaxel or cyclophosphamide/epirubicin/5-fluorouracil (CEF) therapy. Results: Caspase-cleaved CK18 molecules were released from monolayer cultures and tumor organ cultures to the extracellular compartment. CK18 was present in complexes with other cytokeratins in serum. Such CK18 protein complexes are remarkably stable, leading to favorable performance of CK18 biomarker assays for clinical investigations. Docetaxel induced increased levels of caspase-cleaved CK18 in serum from breast cancer patients, indicating apoptosis. CEF therapy led to increases predominantly in uncleaved CK18, indicating induction of necrotic cell death in many tumors. The increase in total CK18 at 24 h of the first treatment cycle correlated to the clinical response to CEF therapy (P &amp;lt; 0.0001). Conclusions: Induction of necrotic cell death may explain the clinical efficacy of anthracycline-based therapy for breast carcinomas with defective apoptosis pathways. We suggest that CK18 biomarkers are useful for early prediction of the response to CEF therapy in breast cancer and may be useful biomarkers for clinical trials.
Evaluation and Clinical Analyses of Downstream Targets of the Akt Inhibitor GDC-0068
Authors: Yibing Yan, Violeta Serra, Ludmila Prudkin, Maurizio Scaltriti, Sumati Murli, Olga Rodríguez, Marta Guzman, Deepak Sampath, Michelle Nannini, Yuanyuan Xiao, Marie-Claire Wagle, Jenny Q. Wu, Matthew Wongchenko, Garret Hampton, Vanitha Ramakrishnan, Mark R. Lackner, Cristina Saura, Desamparados Roda, Andrés Cervantes, Josep Tabernero, Premal Patel, José Baselga
Journal: Clinical Cancer Research (2013)

The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3 inhibitor, in preclinical models and in patients treated with this compound.We used a reverse phase protein array (RPPA) platform to identify a biomarker set indicative of Akt inhibition in cell lines and human-tumor xenografts, and correlated the degree of pathway inhibition with antitumor activity. Akt pathway activity was measured using this biomarker set in pre- and post-dose tumor biopsies from patients treated with GDC-0068 in the dose escalation clinical trial.The set of biomarkers of Akt inhibition is composed of 10 phosphoproteins, including Akt and PRAS40, and is modulated in a dose-dependent fashion, both in vitro and in vivo. In human-tumor xenografts, this dose dependency significantly correlated with tumor growth inhibition. Tumor biopsies from patients treated with GDC-0068 at clinically achievable doses attained a degree of biomarker inhibition that correlated with tumor growth inhibition in preclinical models. In these clinical samples, compensatory feedback activation of ERK and HER3 was observed, consistent with preclinical observations.This study identified a set of biomarkers of Akt inhibition that can be used in the clinical setting to assess target engagement. Here, it was used to show that robust Akt inhibition in tumors from patients treated with GDC-0068 is achievable, supporting the clinical development of this compound in defined patient populations.
Air trapping in the lungs during cardiopulmonary resuscitation in dogs. A mechanism for generating changes in intrathoracic pressure.
Authors: H R Halperin, R Brower, M L Weisfeldt, J E Tsitlik, N Chandra, L M Cristiano, H Fessler, R Beyar, E Wurmb, A D Guerci
Journal: Circulation Research (1989)

To test the hypothesis that during cardiopulmonary resuscitation, chest compression with an unobstructed trachea raises and maintains intrathoracic pressure by collapsing airways and trapping air in the lung, we studied 11 dogs (20-32 kg). An inflatable vest compressed the thorax after induction of ventricular fibrillation. First, tracheal airflow was measured by a pneumotachometer during vest inflation and deflation in nine of the dogs. As expected, during the initial phase of vest inflation of cycles after ventilation, air moved out of the lungs, but then airflow stopped. After vest deflation, however, more air moved out of the lungs in eight of the nine dogs; this occurrence indicated that a portion of the inspired tidal volume was trapped during vest inflation. During cycles without prior ventilation, the amount of air expired by chest compression decreased, paradoxically, at higher peak vest pressure (p less than 0.002); this occurrence indicated that air was trapped at the higher vest pressures. The change in right atrial pressure was higher on cycles after ventilation than on cycles without prior ventilation (79 +/- 12 vs. 67 +/- 12 mm Hg [mean +/- SEM], p less than 0.005), and lung volume was higher on cycles after ventilation (p less than 0.001). Next, a 5-Fr micromanometer was advanced down the airway in eight of the dogs. With the tip of the micromanometer 5-8 cm distal to the carina, a zone of high pressure was noted in seven dogs; this high pressure suggested a zone of airway collapse distal to the carina.(ABSTRACT TRUNCATED AT 250 WORDS)
ON MEDICO-LEGAL EVIDENCE IN CASES OF INSANITY
Authors: Forbes Winslow
Journal: American Journal of Psychiatry (1853)

SpecUic Functions of the -!If-odico-ljegctt' Witness in Cases of 7?Ma!/.&mdash;I have selected for my third and concluding Lettsomian Lecture a subject of great, of vast, and, I may add, of daily increasing magnitude and importance, not only if viewed in relation to our position as citizens, privileged to live under the protection of a monarchical government and a constitutional sovereign, but as members of an honourable and learned pro- fession, exercising, and rightly, justly, and advantageously exercising, an incalculable degree of moral influence through all sections of society, and over all departments of art, science, and philosophy.Is it possible for me to over-estimate, to exaggerate the interest of the subject now under our consideration?It will be my duty to submit to your critical judgment a sketch of our high and responsible vocation as medico-legal witnesses-to suggest for adoption certain general principles of evidence, which may serve to guide us when called upon to give testimony in difficult, doubtful, and disputed cases of insanity.The position * Lord Brougham, in his celebrated speech on the Queen's trial, thus describes the duty of an advocate to his client:-" An advocate, by the sacred duty of bis connexion with his client, knows, in the discharge of that office, but one person in the world-that client, and none other.To save that client by all expedient means-to protect that client at all hazards and costs to all others, and among others, to himself, is the highest and most D
Cost-Effectiveness of Preparticipation Screening for Prevention of Sudden Cardiac Death in Young Athletes
Authors: Matthew T. Wheeler
Journal: Annals of Internal Medicine (2010)

Inclusion of 12-lead electrocardiography (ECG) in preparticipation screening of young athletes is controversial because of concerns about cost-effectiveness.To evaluate the cost-effectiveness of ECG plus cardiovascular-focused history and physical examination compared with cardiovascular-focused history and physical examination alone for preparticipation screening.Decision-analysis, cost-effectiveness model.Published epidemiologic and preparticipation screening data, vital statistics, and other publicly available data.Competitive athletes in high school and college aged 14 to 22 years.Lifetime.Societal.Nonparticipation in competitive athletic activity and disease-specific treatment for identified athletes with heart disease.Incremental health care cost per life-year gained.Addition of ECG to preparticipation screening saves 2.06 life-years per 1000 athletes at an incremental total cost of $89 per athlete and yields a cost-effectiveness ratio of $42 900 per life-year saved (95% CI, $21 200 to $71 300 per life-year saved) compared with cardiovascular-focused history and physical examination alone. Compared with no screening, ECG plus cardiovascular-focused history and physical examination saves 2.6 life-years per 1000 athletes screened and costs $199 per athlete, yielding a cost-effectiveness ratio of $76 100 per life-year saved ($62 400 to $130 000).Results are sensitive to the relative risk reduction associated with nonparticipation and the cost of initial screening.Effectiveness data are derived from 1 major European study. Patterns of causes of sudden death may vary among countries.Screening young athletes with 12-lead ECG plus cardiovascular-focused history and physical examination may be cost-effective.Stanford Cardiovascular Institute and the Breetwor Foundation.
Quality of Diabetes Care Predicts the Development of Cardiovascular Events: Results of the AMD-QUASAR Study
Authors: Maria C.E. Rossi, Giuseppe Lucisano, Marco Comaschi, Carlo Coscelli, Domenico Cucinotta, Patrizia Di Blasi, Giovanni Bader, Fabio Pellegrini, Umberto Valentini, Giacomo Vespasiani, Antonio Nicolucci
Journal: Diabetes Care (2011)

OBJECTIVE The QUASAR (Quality Assessment Score and Cardiovascular Outcomes in Italian Diabetes Patients) study aimed to assess whether a quality-of-care summary score predicted the development of cardiovascular (CV) events in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In 67 diabetes clinics, data on randomly selected patients were extracted from electronic medical records. The score was calculated using process and outcome indicators based on monitoring, targets, and treatment of A1C, blood pressure, LDL cholesterol, and microalbuminuria. The score ranged from 0 to 40. RESULTS Overall, 5,181 patients were analyzed; 477 (9.2%) patients developed a CV event after a median follow-up of 28 months. The incidence rate (per 1,000 person-years) of CV events was 62.4 in patients with a score of &amp;lt;15, 41.0 in those with a score between 20 and 25 and 36.7 in those with a score of &amp;gt;25. Multilevel analysis, adjusted for clustering and case-mix, showed that the risk to develop a new CV event was 84% higher in patients with a score of &amp;lt;15 (incidence rate ratio [IRR] = 1.84; 95% confidence interval [CI] 1.29–2.62) and 17% higher in those with a score between 15 and 25 (IRR = 1.17; 95% CI 0.93–1.49) compared with those with a score of &amp;gt;25. Mean quality score varied across centers from 16.5 ± 7.5 to 29.1 ± 6.3. When the score was tested as the dependent variable, it emerged that 18% of the variance in the score could be attributed to setting characteristics. CONCLUSIONS Our study documented a close relationship between quality of diabetes care and long-term outcomes. A simple score can be used to monitor quality of care and compare the performance of different centers/physicians.
Relationship between landing strategy and patellar tendinopathy in volleyball
Authors: Rob W Bisseling, At L Hof, Steef W Bredeweg, Johannes Zwerver, Theo Mulder
Journal: British Journal of Sports Medicine (2007)

The aetiology of patellar tendinopathy (jumper's knee) remains unclear. To see whether landing strategy might be a risk factor for the development of this injury, this study examined whether landing dynamics from drop jumps differed among healthy volleyball players (CON) and volleyball players with a jumper's knee. The patients with jumper's knee were divided into an asymptomatic group with a previous jumper's knee (PJK) and a symptomatic group with a recent jumper's knee (RJK).Inverse dynamics analyses were used to estimate lower extremity joint dynamics from 30, 50 and 70 cm drop jumps in the three groups (CON, n = 8; PJK, n = 7; RJK, n = 9). A univariate repeated measures analysis of variance was used to compare the different landing techniques.Data analysis of the landing dynamics revealed that PJK showed higher knee angular velocities (p<0.01), and higher ankle plantar flexion moment loading rate (p<0.01). Furthermore, strong tendencies of higher loading rate of vertical ground reaction force (p = 0.05) and higher knee extensor moment loading rate (p = 0.08) were found compared with CON. Higher values for peak knee moment, peak knee power and knee work (all p<0.01) were found for CON compared with RJK. The comparison of the two jumper's knee groups yielded higher knee angular velocities (p<0.01), together with higher ankle plantar flexion and knee extensor moment loading rate (p<0.01 and p<0.05, respectively).Where RJK used a landing technique to avoid high patellar tendon loading, PJK used a stiffer landing strategy, which may be a risk factor in the development of patellar tendinopathy.
Hospital Ward Antibiotic Prescribing and the Risks of<i>Clostridium difficile</i>Infection
Authors: Kevin Brown, Kim Valenta, David Fisman, Andrew Simor, Nick Daneman
Journal: JAMA Internal Medicine (2015)

Only a portion of hospital-acquired Clostridium difficile infections can be traced back to source patients identified as having symptomatic disease. Antibiotic exposure is the main risk factor for C difficile infection for individual patients and is also associated with increased asymptomatic shedding. Contact with patients taking antibiotics within the same hospital ward may be a transmission risk factor for C difficile infection, but this hypothesis has never been tested.To obtain a complete portrait of inpatient risk that incorporates innate patient risk factors and transmission risk factors measured at the hospital ward level and to investigate ward-level rates of antibiotic use and C difficile infection risk.A 46-month (June 1, 2010, through March 31, 2014) retrospective cohort study of inpatients 18 years or older in a large, acute care teaching hospital composed of 16 wards, including 5 intensive care units and 11 non-intensive care unit wards.Patient-level risk factors (eg, age, comorbidities, hospitalization history, antibiotic exposure) and ward-level risk factors (eg, antibiotic therapy per 100 patient-days, hand hygiene adherence, mean patient age) were identified from hospital databases.Incidence of hospital-acquired C difficile infection as identified prospectively by hospital infection prevention and control staff.A total of 255 of 34 298 patients developed C difficile (incidence rate, 5.95 per 10,000 patient-days; 95% CI, 5.26-6.73). Ward-level antibiotic exposure varied from 21.7 to 56.4 days of therapy per 100 patient-days. Each 10% increase in ward-level antibiotic exposure was associated with a 2.1 per 10,000 (P < .001) increase in C difficile incidence. The association between C difficile incidence and ward antibiotic exposure was the same among patients with and without recent antibiotic exposure, and C difficile risk persisted after multilevel, multivariate adjustment for differences in patient-risk factors among wards (relative risk, 1.34 per 10% increase in days of therapy; 95% CI, 1.16-1.57).Among hospital inpatients, ward-level antibiotic prescribing is associated with a statistically significant and clinically relevant increase in C difficile risk that persists after adjustment for differences in patient-level antibiotic use and other patient- and ward-level risk factors. These data strongly support the use of antibiotic stewardship as a means of preventing C difficile infection.
Singapore's multibillion dollar gamble
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

Figure 1Biopolis, Singapore's futuristic research hub.How does a country one-fourth the size of Rhode Island with little history in biomedical science become one of the world's biomedical research giants? The answer: with a pile of money and a large dose of chutzpah. Since 2000, Singapore has dumped more than US$2 billion into developing a biomedical research industry-from scratch. Is the gamble paying off?
Mechanical assessment of elastin integrity in fibrillin-1-deficient carotid arteries: implications for Marfan syndrome
Authors: Jacopo Ferruzzi, Melissa J. Collins, Alvin T. Yeh, Jay D. Humphrey
Journal: Cardiovascular Research (2011)

Elastin is the primary component of elastic fibres in arteries, which contribute significantly to the structural integrity of the wall. Fibrillin-1 is a microfibrillar glycoprotein that appears to stabilize elastic fibres mechanically and thereby to delay a fatigue-induced loss of function due to long-term repetitive loading. Whereas prior studies have addressed some aspects of ageing-related changes in the overall mechanical properties of arteries in mouse models of Marfan syndrome, we sought to assess for the first time the load-carrying capability of the elastic fibres early in maturity, prior to the development of ageing-related effects, dilatation, or dissection. We used elastase to degrade elastin in common carotid arteries excised, at 7–9 weeks of age, from a mouse model (mgR/mgR) of Marfan syndrome that expresses fibrillin-1 at 15–25% of normal levels. In vitro biaxial mechanical tests performed before and after exposure to elastase suggested that the elastic fibres exhibited a nearly normal load-bearing capability. Observations from nonlinear optical microscopy suggested further that competent elastic fibres not only contribute to load-bearing, they also increase the undulation of collagen fibres, which endows the normal arterial wall with a more compliant response to pressurization. These findings support the hypothesis that it is an accelerated fatigue-induced damage to or protease-related degradation of initially competent elastic fibres that render arteries in Marfan syndrome increasingly susceptible to dilatation, dissection, and rupture.
Dissociation of Insulin Absorption and Blood Flow During Massage of a Subcutaneous Injection Site
Authors: B Linde
Journal: Diabetes Care (1986)

Nine healthy volunteers with normal body weights were injected subcutaneously with 125I-labeled soluble human insulin (10 U) in one thigh and 133Xe in the contralateral thigh for the measurement of subcutaneous blood flow on 2 consecutive mornings. On one of the days, standardized massage of both injection sites was performed for 30 min starting 30 min after insulin injection. Serum insulin and plasma glucose were determined intermittently before, during, and after massage, and elimination of radioactivities was monitored continuously by external detectors. During massage, the first-order elimination rate constants of l25I increased approximately sixfold compared with the rise during control (0.19 ± 0.04 to 0.88 ± 0.15%/min during the last 15 min of the massage vs. 0.21 ± 0.03 to 0.32 ± 0.03%/min during control). Serum insulin increased from 13.8 ± 1.8 mU/L before massage to a maximal value of 56.4 ± 8.7 mU/L 10 min after massage (vs. 15.3 ± 3.0 and 19.7 ± 2.2 mU/L during control). Plasma glucose fell significantly faster on the massage day, from 10 min after massage onward. No significant alteration in the subcutaneous blood flow was found during or after massage. The results suggest that the pronounced enhancement of insulin absorption induced by massage of the injection site is mainly not blood flow mediated.
Virus‐associated haemophagocytic syndrome caused by rubella in an adult
Authors: None Takenaka, None Kishimoto, None Ichikawa, None Shibagaki, None Kubota, None Yamagata, None Gotoh, None Fujita, None Yasuno
Journal: British Journal of Dermatology (1998)

Haemophagocytic syndrome is a systemic clinicopathological entity characterized by systemic proliferation of benign haemophagocytic histiocytes, fever, cytopenia, abnormal liver function and, frequently, coagulopathy and hepatosplenomegaly. Its occurrence has been documented in association with viral, bacterial, fungal and parasitic infections, a wide spectrum of malignant neoplasms, autoimmune diseases and drugs. We report a case of rubella virus‐associated haemophagocytic syndrome in a previously healthy 29‐year‐old woman. Blood tests showed cytopenia, especially severe thrombocytopenia, liver dysfunction, hyperferritinaemia and hypercytokinaemia. Bone marrow examination showed many mature histiocytes with active haemophagocytosis. A skin biopsy from the rash revealed perivascular lymphohistiocytic infiltrates with haemophagocytic histiocytes in the upper and mid‐dermis. The patient was treated with antibiotics and immunoglobulin, and by supportive measures including platelet transfusion, and recovered completely.