tbuckley/cabot-search huggingface dataset:
Glucopyranosyl Lipid a (GLA) a Toll-like Receptor 4 (TLR4) Agonist for Use As an Adjuvant in Combination with Peanut Allergen Immunotherapy
Authors: Timothy J. Soos, Li Li, Keith Graver, Joanne Schiding, Adrienne Xenos, Dongling Chen, Neil Fitch, El-Bdaoui Haddad, Catherine Jones, Christopher Arendt
Journal: Journal of Allergy and Clinical Immunology (2016)
Diagnosis of Disseminated Histoplasmosis by Detection of<i>Histoplasma capsulatum</i>Antigen in Serum and Urine Specimens
Authors: Lawrence J. Wheat, Richard B. Kohler, Ram P. Tewari
Journal: New England Journal of Medicine (1986)

The diagnosis of Histoplasma capsulatum infection by serologic testing for the presence of antibodies is limited by a high rate of false positive and false negative results and by the requirement that the patient have a normal immune response. We have developed a radioimmunoassay for the detection of H. capsulatum antigen in urine and serum specimens. Antigenuria was noted in 20 of 22 episodes of disseminated histoplasmosis that occurred in 16 patients, in 6 of 32 patients with self-limited infection, in 2 of 32 patients with cavitary histoplasmosis, and in 4 of 8 patients with a sarcoid-like illness caused by H. capsulatum. The detection of antigen in urine was reproducible in 38 of 41 (93 percent) retests of specimens. H. capsulatum antigen was also detected in the serum during 11 of the 22 episodes of disseminated histoplasmosis, in none of the 12 episodes of other types of histoplasmosis in patients with antigenuria, in 1 of the 33 patients with histoplasmosis who lacked the urinary antigen, and in none of the 50 controls. Antigenemia and antigenuria decreased after initiation of antifungal therapy and recurred in patients who had a relapse. We conclude that this radioimmunoassay for H. capsulatum antigen represents a useful new method for the rapid diagnosis of disseminated histoplasmosis.
Associations of wheezing phenotypes with late asthma outcomes in the Avon Longitudinal Study of Parents and Children: A population-based birth cohort
Authors: Raquel Granell, A. John Henderson, Jonathan A. Sterne
Journal: Journal of Allergy and Clinical Immunology (2016)

BackgroundVariable patterns of childhood wheezing might indicate differences in the cause and prognosis of respiratory illnesses. Better understanding of these patterns could facilitate identification of modifiable factors related to development of asthma.ObjectivesWe characterized childhood wheezing phenotypes from infancy to adolescence and their associations with asthma outcomes.MethodsLatent class analysis was used to derive phenotypes based on patterns of wheezing recorded at up to 14 time points from birth to 16½ years among 12,303 participants from the Avon Longitudinal Study of Parents and Children. Measures of lung function (FEV1, forced vital capacity [FVC], and forced expiratory flow between 25% and 75% [FEF25-75]) and fraction of exhaled nitric oxide (Feno) were made at 14 to 15 years of age.ResultsSix wheezing phenotypes were identified: never/infrequent, preschool-onset remitting, midchildhood-onset remitting, school age–onset persisting, late childhood–onset persisting, and continuous wheeze. The 3 persistent phenotypes were associated with bronchodilator reversibility of 12% or greater (BDR) from baseline (odds ratio [OR] range, 2.14-3.34), a Feno value of 35 ppb or greater (OR range, 3.82-6.24), and lung function decrements (mean range of differences: −0.22 to −0.27 SD units (SDU) for FEV1/FVC ratio and −0.21 to −0.33 SDU for FEF25-75) compared with never/infrequent wheeze. Midchildhood-onset (4½ years) remitting wheeze was associated with BDR (OR, 1.77; 95% CI, 1.11-2.82), a Feno value of 35 ppb or greater (OR, 1.72; 95% CI, 1.14-2.59), FEV1/FVC ratio decrements (OR, −0.22 SDU; 95% CI, −0.36 to −0.08 SDU), and FEF25-75 decrements (OR, −0.16 SDU; 95% CI, −0.30 to −0.01 SDU). Preschool-onset (18 months) remitting wheeze was only associated with FEV1/FVC ratio decrements (OR, −0.15 SDU; 95% CI, −0.25 to −0.05 SDU) and FEF25-75 decrements (OR, −0.14 SDU; 95% CI, −0.24 to −0.04 SDU). The persisting phenotypes showed evidence of sex stratification during adolescence.ConclusionsEarly childhood–onset wheezing that persists into adolescence represents the clearest target group for interventions to maximize lung function outcomes.
Care of Civilians Rendered Paraplegic by an Injury to the Spinal Cord or Cauda Equina
Authors: Donald Munro
Journal: New England Journal of Medicine (1959)

People with a specialty always think they have solved the problem of universality.— DumasTHE purposes of this paper are, first, to call the attention of the medical profession and through them of the public to the present plight of certain patients who have been paralyzed as the result of an injury to the spinal cord and cauda equina; secondly, to illustrate with brief case reports the kind of care provided today for large numbers of these victims, and thus to enter a plea for more effective and better future treatment; thirdly, to point out the minimum standards of . . .
The Many Pitfalls in the Diagnosis of Myeloma
Authors: Thomas P. Duffy
Journal: New England Journal of Medicine (1992)

The step-by-step process of clinical problem-solving is the subject of this new Journal feature. Information about a real patient is presented to an expert clinician in stages (boldface type), to simulate the way such information emerges in everyday clinical practice. In this exercise, the discussant, a nephrologist, was provided with the initial clinical information. Subsequent data were given in response to his specific questions, with the addition of some supplemental related data. A 71-year-old man was admitted to the Yale–New Haven Hospital with a six-month history of sweats, unexplained fever, weight loss of 9 kg (20 lb), and anemia. A . . .
UK could turn to India for new GP recruitment drive
Authors: Adrian O’Dowd
Journal: BMJ (2016)

The United Kingdom may be about to embark on a refreshed recruitment drive for GPs from India to come and work for the NHS, subject to rigorous testing.

Doctors’ leaders have welcomed the contribution that Indian doctors can make to the NHS but criticised the government for its “failure” in attracting enough new doctors from the United Kingdom itself to join the profession.

Health Education England has signed a memorandum of understanding with the Apollo Hospitals Group in India to explore how both countries can benefit from a “mutual exchange of ideas.” Apollo offers a diploma in family medicine that is accredited by the Royal College of General Practitioners.

Pulse magazine has reported that the …
By the Pricking of My Thumbs, Something Wicked This Way Comes: Sporadic Cancers Versus Eponymous Hereditary Cancer Predisposition Syndromes
Authors: Christos Vaklavas, John R. Ross, Lisle M. Nabell, Andres Forero, Martin J. Heslin, Tina E. Wood
Journal: Journal of the National Comprehensive Cancer Network (2012)

Advances in cancer genomics have led to the recognition of a growing number of high-penetrance single-gene cancer predisposition syndromes. Frequently, the suspicion for a hereditary syndrome is raised by a strongly positive family history. However, other features, such as younger-than-usual age at diagnosis and rare histology should also prompt consideration of a genetic syndrome. Common malignancies frequently show a positive family history without an eponymous syndrome being recognized. This article reports on a case with an unusual constellation of malignancies with distinctive pathologies, which raised suspicion for an eponymous cancer pre-disposition syndrome. Absent a positive family history, a de novo mutation—an alteration in a gene that is present for the first time in a family member as a result of a mutation in a germ cell of one of the parents or in the fertilized ovum—was suspected. The authors discuss indications for genetic counseling and testing, limitations, and the evidence that supports the recommendations as formulated by working groups and the NCCN. Most frequently, these recommendations are reasonable statements based on the natural history of the disease, but without population-based studies for many rare syndromes, the actual penetrance, variable expressivity, and actual associated cancer risk are unknown.
Progressive Neurologic Deterioration and Renal Failure Due to Storage of Glutamyl Ribose-5-Phosphate
Authors: Julian C. Williams, Ian J. Butler, Harvey S. Rosenberg, Regina Verani, Charles I. Scott, Susan B. Conley
Journal: New England Journal of Medicine (1984)

A six-year-old boy presented with a history of seizures, progressive neurologic deterioration, and proteinuria. Physical examination revealed mildly coarse facies, failure to thrive, generalized hypotonia with muscle wasting, and optic atrophy; there was no organomegaly. The family history suggested an X-linked recessive inheritance. The electroencephalogram, electroretinogram, evoked potentials, and computed axial tomography of the brain were abnormal. Urine oligosaccharide chromatography, urine amino acids and organic acids, and results of leukocyte and fibroblast lysosomal-enzyme assays for the known storage diseases were normal; however, conjunctival and renal biopsy specimens contained enlarged lysosomes on electron microscopy. The patient had progressive neurologic deterioration and died of renal failure at eight years of age. A compound identified as glutamyl ribose-5-phosphate was purified from the brain (0.96 mumol per gram, wet weight) and kidney (0.60 mumol per gram, wet weight). This compound is the linkage group in ADP-ribosylation of proteins, an important regulatory process in gene expression and DNA repair. We believe this new disorder represents a glycoproteinosis that results in the cytoplasmic storage of glutamyl ribose-5-phosphate.
Auscultation of the Adult Heart by Machine
Authors: Arthur L. Klatsky, Alfred A. Bolomey, A. B. Siegelaub
Journal: New England Journal of Medicine (1968)

In school children, cardiac auscultation by machine (Phonocardioscan) has shown promise as a screening procedure. To determine its effectiveness as a screening procedure in adults, results obtained by this means were compared with those obtained by internists, in 456 subjects. The overall sensitivity of the new procedure was 75 per cent (25 per cent false-negative findings), ranging from 47 per cent sensitivity in innocent murmurs to 88 per cent in murmurs of congenital or rheumatic heart disease. Overall specificity was 66 per cent (34 per cent falsely positive). These results were less accurate than those in children reported by others. At its present stage of development, the machine was considered insufficiently sensitive and specific for incorporation into a multiphasic health appraisal examination of adults.
Cost Effectiveness of Oral as Compared with Intravenous Antibiotic Therapy for Patients with Early Lyme Disease or Lyme Arthritis
Authors: Mark H. Eckman, Allen C. Steere, Robert A. Kalish, Stephen G. Pauker
Journal: New England Journal of Medicine (1997)

Lyme disease, which is caused by the tick-transmitted spirochete Borrelia burgdorferi, 1 usually begins with an expanding skin lesion, erythema migrans, accompanied by malaise and fatigue, fever, headache, stiff neck, and myalgias or arthralgias.2,3 Weeks later, some patients have objective neurologic signs, such as meningitis, cranial neuritis, or radiculoneuritis,4 or cardiac abnormalities, particularly atrial–ventricular block.5 Months later, intermittent or chronic episodes of arthritis often develop in untreated patients.6 Months to years later, a small percentage of patients have subtle signs of encephalopathy (memory deficit, irritability, or somnolence), or polyneuropathy characterized by spinal radicular pain or distal paresthesias.7–10 The recommended . . .
Bladder Distention Causing Iliac-Vein Obstruction in the Adult Male
Authors: Carl A. Smith, Morton C. Gluck, Roland G. Kallen
Journal: New England Journal of Medicine (1963)

BLADDER distention has not previously been reported as a cause of iliac-vein obstruction in the adult. On the other hand, a variety of pelvic conditions, such as inflammation, benign and malignant tumors and the gravid and fibroid uterus,1 2 3 4 have been cited as responsible for iliac-vein obstruction and, in many cases, leg edema. It may be that the bladder does not readily come to mind as a cause of such compression because it is anteriorly extraperitoneal and is considered to be a relatively yielding structure remote from the retroperitoneal iliac veins.An adult male, who was admitted to Bellevue Hospital, had . . .
S55 Towards the Clinical Application of Anti-pseudomonal Bacteriophage: Activity is Retained Following Nebulisation with a Range of Commercially Available Nebuliser Systems
Authors: R Pabary, A Alegro, EWFW Alton, D BIlton, S Morales, F Smrekar, JC Davies
Journal: Thorax (2015)

<h3>Background and objectives</h3> We have recently established safety and efficacy of nasally-inhaled bacteriophage (phage) against <i>Pseudomonas aeruginosa </i>in a murine model with reduced infective burden and inflammatory response demonstrated in bronchoalveolar lavage (<i>Thorax </i>2012;67:A50–A51 doi:10.1136/thoraxjnl-2012–202678.108). The aim of this study was to assess titre and activity of four phages following exposure to nebuliser systems more applicable to clinical trial use. <h3>Methods</h3> Four phage strains (1–4) were nebulised through a) Pari LC Plus (LCP), b) Aeroeclipse II (AE) and c) eFlow Rapid for up to 15 min. Phages were collected downstream and quantified by standard plaque assay against Pa01. Results were compared with controls exposed to the nebulisation chambers for 15 min. <h3>Results</h3> All phages retained efficacy post-nebulisation. Nebuliser type affected recovered titres: LCP caused significant decrease in titres of phage 1 and 2 within 5 min and phage 3 within 15 min (p &lt; 0.05). Phage 4 titre did not drop. AE, despite similar mode of action to LCP, was not as detrimental to titres. Decrease in phage 1 titre was seen within 15 min, phage 2 within 10 min (p &lt; 0.05). Phage 3 and 4 did not decrease (p &gt; 0.05). eFlow does not continuously nebulise and recirculate phage, hence changes in titre over time were not recorded. No titre decreases were observed at end of nebulisation (p &gt; 0.05). Morphology may play a role in maintenance of phage titre post-nebulisation (1 and 2 <i>Myoviridae</i>, 3 and 4 <i>Podoviridae</i>). The Figure 1 shows changes in titres of phage 3 over time following nebulisation through each system. <h3>Conclusions</h3> Phage efficacy was retained after nebulisation though titres dropped, greatest for LCP and least for eFlow (which fell within variability of the methodology (± 0.5 log)). We confirm that phage can survive nebulisation and that this mode of administration may therefore be appropriate for future clinical trials.
Pseudohypoparathyroidism Type II: A Possible Defect in the Reception of the Cyclic AMP Signal
Authors: Marc Drezner, Francis A. Neelon, Harold E. Lebovitz
Journal: New England Journal of Medicine (1973)

A22 month old boy with grand-mal seizures and hypocalcemia, had an elevated serum concentration of parathyroid hormone, increased urinary excretion of cyclic AMP, and a marked rise in urinary cyclic AMP in response to exogenously administered parathyroid extract. However, neither the renal tubular handling of phosphate nor the serum calcium concentration responded appropriately to administered parathyroid hormone. This defect appears to represent a failure of intracellular reception of the cyclic AMP message, and the disorder might be called pseudohypoparathyroidism Type II. (N Engl J Med 289:1056–1060, 1973)
Hedgehog Pathway Inhibitor Therapy for Locally Advanced and Metastatic Basal Cell Carcinoma
Authors: Audrey A. Jacobsen, Adam S. Aldahan, Olivia B. Hughes, Vidhi V. Shah, John Strasswimmer
Journal: JAMA Dermatology (2016)

<h3>Importance</h3> Hedgehog pathway inhibitors (HPIs) were made available by US Food and Drug Administration approval in 2012 for vismodegib and 2015 for sonidegib. Both target the Smoothened molecule and are indicated for locally advanced basal cell carcinoma (laBCC) and metastatic basal cell carcinoma (mBCC). <h3>Objective</h3> To evaluate clinical experience with HPIs, including efficacy and adverse effects. <h3>Data Sources</h3> We conducted a systematic review in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and EMBASE, using search terms “vismodegib,” “sonidegib,” “Erivedge,” “Odomza,” “basal cell carcinoma,” and “BCC.” <h3>Study Selection</h3> We included clinical trials, retrospective medical record reviews, and prospective case series that used HPIs for the treatment of laBCC or mBCC in human subjects. Individual case reports and limited, retrospective case series were excluded from our review. <h3>Data Extraction and Synthesis</h3> Data were extracted independently by 2 reviewers on a predesigned, standardized form. <h3>Main Outcomes and Measures</h3> The following data were recorded: number of patients with laBCC or mBCC, dose and frequency of drug administration, median duration of treatment, clearance and recurrence rates, and adverse effects. <h3>Results</h3> Eleven vismodegib articles (published between 2009 and 2015) met criteria for inclusion, and 8 articles were able to be pooled for analysis. The 8 pooled articles included 744 total patients with 704 patients clinically evaluable. Sonidegib did not yield enough publications for a formal analysis. Objective response to vismodegib for laBCC had a weighted average of 64.7% (95% CI, 63.7%-65.6%); complete response averaged 31.1% (95% CI, 30.4%-31.8%). Objective response for mBCC was 33.6% (95% CI, 33.1%-34.2%); complete response averaged 3.9% (95% CI, 3.3%-4.4%). Median duration of therapy was 35.8 weeks (95% CI, 35.1-36.5 weeks). <h3>Conclusions and Relevance</h3> In a systematic review of HPIs for laBCC and mBCC, vismodegib, but not sonidegib, had enough studies to warrant a pooled analysis. Vismodegib was identified to have a significant, consistent effect on the median duration of therapy of laBCC and mBCC. While mBCC responses are superior to any traditional approach, the response rate for laBCC might be considered in the context of other standard treatment options including surgery and radiation therapy.
The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis
Authors: Luisana Astudillo, Thiago G. Da Silva, Zhiqiang Wang, Xiaoqing Han, Ke Jin, Jeffrey VanWye, Xiaoxia Zhu, Kelly Weaver, Taiji Oashi, Pedro E.M. Lopes, Darren Orton, Leif R. Neitzel, Ethan Lee, Ralf Landgraf, David J. Robbins, Alexander D. MacKerell, Anthony J. Capobianco
Journal: Cancer Research (2016)

Abstract In many cancers, aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of the neoplastic phenotype and in cancer stem cells, which may allude to its additional involvement in metastasis and resistance to therapy. Therefore, Notch is an exceedingly attractive therapeutic target in cancer, but the full range of potential targets within the pathway has been underexplored. To date, there are no small-molecule inhibitors that directly target the intracellular Notch pathway or the assembly of the transcriptional activation complex. Here, we describe an in vitro assay that quantitatively measures the assembly of the Notch transcriptional complex on DNA. Integrating this approach with computer-aided drug design, we explored potential ligand-binding sites and screened for compounds that could disrupt the assembly of the Notch transcriptional activation complex. We identified a small-molecule inhibitor, termed Inhibitor of Mastermind Recruitment-1 (IMR-1), that disrupted the recruitment of Mastermind-like 1 to the Notch transcriptional activation complex on chromatin, thereby attenuating Notch target gene transcription. Furthermore, IMR-1 inhibited the growth of Notch-dependent cell lines and significantly abrogated the growth of patient-derived tumor xenografts. Taken together, our findings suggest that a novel class of Notch inhibitors targeting the transcriptional activation complex may represent a new paradigm for Notch-based anticancer therapeutics, warranting further preclinical characterization. Cancer Res; 76(12); 3593–603. ©2016 AACR.
A New Web Site and a New Policy
Authors: Edward W. Campion, Kent R. Anderson, Jeffrey M. Drazen
Journal: New England Journal of Medicine (2001)

The Journal has been on the World Wide Web for more than five years.1 During that time, rapid, global dissemination of new scientific information has come to be expected. Broad searches of the medical literature and of scientific data bases are now possible. Information on line is becoming highly interlinked and increasingly is available in multimedia formats. To serve the diverse needs of our readers, we are taking steps to use the technology of electronic publication to enhance and complement the print version of the Journal. However, the many new electronic possibilities must not obscure our fundamental goal: to . . .
90-Yttrium-DOTA-octreotate for the treatment of advanced neuroendocrine tumors
Authors: C. Toumpanakis, A. Quigley, R. Srirajaskanthan, L. Marelli, T. Singhrao, T. Meyer, J. Buscombe, M. E. Caplin
Journal: Journal of Clinical Oncology (2009)

4594 Background: The expression of somatostatin receptors (SSTR) on Neuroendocrine Tumors (NETs) has led not only to tumour visualization utilizing SSTR scintigraphy, but also to the development of receptor-targeted radionuclide therapy. Isotopes such as 111-Indium, 90-Yttrium and 177-Lutetium are linked to somatostatin analogues and then internalized by tumour cells. The recent development of the peptide Octreotate has higher affinity for type 2 SSTR than Octreotide. Aim: to estimate efficacy and tolerability of 90-Yttrium-tyr3-DOTA-octreotate in patients with metastatic progressive NETs. Methods: 89 patients (median age: 51.5 years) with metastatic NETs were studied. All patients had shown signs of progression despite previous treatments. In all patients, the tumours had shown good uptake either in the OctreoScan or in the Ga-68 octreotate PET scan. 64 patients received 3 cycles and 25 patients received 2 cycles of 90-Yttrium-tyr3-DOTA-octreotate. The mean i.v. dose/cycle was 3100 MBq. 29/89 patients included a cycle of intra-arterial therapy with mean dose/cycle 2090 MBq for large volume liver disease. Symptomatic response to treatment was defined as the reduction of &gt;50% to the symptom score and radiological response utilized RECIST criteria. Results: In all patients the post treatment scintigraphy demonstrated good uptake and localization by the tumors. In 59/89 (66%) symptomatic response was achieved. Utilizing RECIST criteria, 50/89 (56%) had disease stabilization (SD) of previously progressive disease and 7 (8%) had partial response (PR). 31/89 (35%) had continued tumor progression. The SD/PR (n=57) group had sustained response for median 17.2 months. Bone marrow toxicity (WHO grade II) was noted in 15/89 (16.8%), persistent in 4 patients with significant bone metastases. Four patients developed mild renal failure (WHO grade II), that was irreversible in one of them. Conclusions: 90Y-DOTA-octreotate is a well-tolerated and safe treatment for patients with progressive neuroendocrine tumors. Early results regarding efficacy are promising. No significant financial relationships to disclose.
Focus Formation by Japanese Quail Cells Infected With Rous Sarcoma Virus&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Gustave Freeman
Journal: JNCI Journal of the National Cancer Institute (1963)

Embryonic Japanese quail and chick fibroblasts in secondary cultures were equally efficient in forming foci when infected with Rous sarcoma virus. However, quail monolayers stained with neutral red were more homogeneous and paler than chick monolayers and afforded greater contrast to the deeply stained sarcoma cells. This facilitated identification of foci at low magnification (20 X) and reduced scanning time when large numbers of cultures were handled. These infected quail cells appeared to release Rous sarcoma virus.