tbuckley/cabot-search huggingface dataset:
Long-term efficacy of antifungals in toenail onychomycosis: a critical review
Authors: B.J. Cribier, C. Paul
Journal: British Journal of Dermatology (2001)

Modern antifungal drugs achieve high mycological and clinical cure rates in onychomycosis of the toes, but little is known about the long-term evolution of the treated patients.The aim of this review was to analyse the therapeutic results recorded more than 1 year after initiation of therapy.We used two endpoints for the analysis: EP1 (the number of patients with negative mycology after follow-up, divided by the number of patients included at day 0, including all patients lost to follow-up), and EP2 (the number of patients with negative mycology after follow-up divided by the number of patients with negative mycology at week 48). Clinical cure rate (EPclin) was the number of patients clinically cured or with minimal residual lesions divided by the number of patients included at day 0.From a Medline search we identified 17 studies providing results beyond 48 weeks. Ketoconazole 200 mg d(-1) up to 1 year resulted in EP1 of 11% at 18 months, and EP2 of 43%. Griseofulvin 1 g d(-1) for 1 year allowed an EP1 of 43% at 18 months, and EP2 of 71%. The mean EP1 after fluconazole once weekly up to 1 year was 49% at 18 months, and EP2 was 91%. With itraconazole 200 mg d(-1) or 400 mg d(-1) for 1 week each month for 3-4 months, EP1 was 37% at 18 months, and 53% at 2 years; EP2 was 76% at 4 years. Terbinafine 250 mg d(-1) for 12-16 weeks achieved an EP1 of 62% at 18 months, 72% at 2 years, and 60% at 4 years; EP2 was 80% at 18 months, 81% at 2 years, and 71% at 4 years. In the only study planned to compare the long-term efficacy of terbinafine and itraconazole, EP1 at 18 months was significantly higher with continuous terbinafine than with intermittent itraconazole (66% vs. 37%, P < 0.001). The clinical cure rates were 21% at 60 weeks and 37% at 72 weeks with fluconazole. EPclin was 27% at 18 months and 35% at 2 years with itraconazole. EPclin was 48% at 18 months, 69% at 2 years and 50% at 4 years with terbinafine.Considering the stringency of the criteria we used, this critical review suggests that the long-term efficacy achieved with terbinafine is superior to that obtained with griseofulvin, ketoconazole, fluconazole or itraconazole.
St John's wort for depression
Authors: P. J Houghton
Journal: BMJ (1996)

Table 1-Cost per life year gained with diuretic and 3 blocker treatment (thousands of Swedish crowns at 1992 prices; 10 Swedish crowns = £1).With permission3 Age (years) <45 45-69 ¢70 Diastolic blood pressure (mm Hg) Men Women Men Women
Protective Efficacy of Haemophilus influenzae Type b Polysaccharide and Conjugate Vaccines in Children 18 Months of Age and Older
Authors: David P. Greenberg
Journal: JAMA (1991)

To evaluate the protective efficacy of polyribosylribitol phosphate (PRP) and polyribosylribitol phosphate-diphtheria toxoid (PRP-D) vaccines in children 18 to 59 months of age, we conducted a case-control study in Los Angeles (Calif) County between July 1, 1988, and July 31, 1989. Seventy-nine children with invasive Haemophilus influenzae type b disease 18 to 59 months of age were identified, and 212 controls were selected by random-digit telephone dialing methods. Cases and controls were stratified by age and month of disease onset of the case. Seventeen PRP vaccine failures and two PRP-D vaccine failures occurred more than 2 weeks after vaccination. The PRP vaccine was shown not to be effective (point estimate--47%; 95% confidence interval,--307% to 47%), but the PRP-D vaccine was 88% protective (95% confidence interval, 42% to 97%). Adjustment of the efficacy estimates for potential confounding variables did not change the results significantly. The PRP-D vaccine provided significantly better protection than the PRP vaccine against invasive H influenzae type b disease in this population.
Lesson of the week: Deaths from low dose paracetamol poisoning
Authors: S Bridger, K Henderson, E Glucksman, A J Ellis, J A Henry, R. Williams
Journal: BMJ (1998)

Patients with serum paracetamol concentrations below the standard treatment line may develop acute liver failure Paracetamol is the most commonly used substance in self poisoning (about 70 000 cases annually in Britain1) and is the most frequent subject of inquiries to the National Poisons Information Services.2 Paracetamol overdose is the commonest cause of acute liver failure in the United Kingdom,3 accounting for at least half of all cases sent to tertiary referral units. To decrease the chance of liver damage in cases of paracetamol overdose, protocols and guidelines for treating patients with an antidote before referral to specialist care have been drawn up. The antidote acetylcysteine should be given to all patients with a serum paracetamol concentration >200 mg/l four hours after ingestion of the drug. A nomogram in which this value is joined to an end point of 25 mg/l at 16 hours allows identification over this period of the patients who should receive the antidote.4 If the antidote is not given, over 60% of patients with serum paracetamol concentrations above the treatment line may develop serious liver damage, and of these about 5% will die.5 Recent studies also suggest that acetylcysteine given after 16 hours, even at the stage of encephalopathy, can reduce the frequency of multiorgan failure and improve survival. 6 7 Factors that have been reported to enhance hepatotoxicity include chronic alcohol misuse,8 eating disorders,9 and enzyme inducing drugs,10 and in each of these contexts treatment is advisable below the treatment line.

No deaths have been reported in any of the major treatment trials of paracetamol overdose,11 12 13 14 however high the initial serum paracetamol concentration, provided acetylcysteine was given within 10 hours of the drug's ingestion. Furthermore, there was only a 2% incidence of serious …
Three phenotypes of adult‐onset asthma
Authors: M. Amelink, S. B. de Nijs, J. C. de Groot, P. M. B. van Tilburg, P. I. van Spiegel, F. H. Krouwels, R. Lutter, A. H. Zwinderman, E. J. M. Weersink, A. ten Brinke, P. J. Sterk, E. H. Bel
Journal: Allergy (2013)

Abstract Rationale Adult‐onset asthma differs from childhood‐onset asthma in many respects. It is more heterogeneous, often severe and frequently associated with loss of lung function. To identify underlying mechanisms of adult‐onset asthma and to capture predictors of disease progression, detailed characterization and phenotyping is necessary. Objectives To characterize adult‐onset asthma and identify subphenotypes of adult‐onset asthma. Methods A cohort of 200 patients with adult‐onset (&gt;18 year) asthma (age 54 (26–75) year) was recruited from one academic and three nonacademic pulmonary outpatient clinics in Amsterdam, the Netherlands. These patients were fully characterized with respect to clinical, functional and inflammatory markers. After data reduction, K‐means nonhierarchical cluster analysis was performed to identify clusters of adult‐onset asthma. Measurements and main results Patients with adult‐onset asthma were predominately female (61%) and nonatopic (55%). Within this group of patients were identified three clusters of adult‐onset asthma. Cluster 1 ( n = 69) consisted of patients with severe eosinophilic inflammation‐predominant asthma and persistent airflow limitation despite high‐intensity anti‐inflammatory treatment, with relatively low symptom scores. The second cluster was characterized by obese women with frequent symptoms, high healthcare utilization and low sputum eosinophils. The third cluster consisted of patients with mild‐to‐moderate, well‐controlled asthma with normal lung function and low inflammatory markers. Repeatability accuracy was 98.2%. Conclusions Amongst patients with adult‐onset asthma, three subphenotypes can be identified with distinct clinical and inflammatory characteristics. These subphenotypes help to understand the underlying pathobiology and provide clinicians with directions for personalized management.
Graves Thyrotoxicosis Following Primary Thyroid Failure
Authors: William J. Bremner
Journal: JAMA (1976)

THE DEVELOPMENT of primary nongoitrous hypothyroidism is usually associated with idiopathic atrophy of the thyroid or chronic thyroiditis.<sup>1</sup>In both of these conditions, normal thyroid tissue is largely or completely replaced by fibrous tissue and lymphocytic and plasma cell infiltrates. It is characteristic of these conditions that serum levels of endogenous thyroid-stimulating hormone (TSH) are elevated<sup>2</sup>and that administration of exogenous TSH does not cause a normal response in terms of thyroid hormone production or iodine uptake.<sup>3</sup>The clinical course is not characterized by improvement of the thyroid disease, and lifelong thyroid replacement therapy is usually required.<sup>4</sup> Recently, we have cared for a patient who, two years after the diagnosis of primary nongoitrous hypothyroidism confirmed by lack of responsiveness to TSH stimulation, manifested hyperthyroidism with a diffuse goiter. This unique sequence implies that (1) the development of primary nongoitrous hypothyroidism may not necessarily require lifelong thyroid
Anemia with spur cells: a red cell defect acquired in serum and modified in the circulation
Authors: R. A. Cooper
Journal: Journal of Clinical Investigation (1969)

The sera and red cells of three patients with severe liver disease and "spur cells" were studied. In each case the per cent of serum cholesterol which was free (unesterified) was elevated, and the serum lecithin: cholesterol acyltransferase activity was depressed. Lipoproteins with beta mobility were increased, but exhibited immune reactivity with antisera to both alpha- and beta-lipoproteins. Serum bile salt concentrations were markedly elevated and consisted primarily of chenodeoxycholic acid, with small amounts of lithocholic acid present as well.SPUR CELLS MANIFESTED A STRIKING INCREASE IN CHOLESTEROL CONTENT AND IN THE CHOLESTEROL: phospholipid ratio, but a normal osmotic fragility. When incubated in heated normal serum, spur cells lost their excess cholesterol and became spherocytic and osmotically fragile. Conversely, sera from patients with spur cells readily transferred up to one-third of their free cholesterol to normal red cells, causing normal cells to become resistant to osmotic lysis. In addition, these sera caused normal red cells to acquire thorny membrane projections. Cholesterol transfer to normal cells also occurred from normal serum which had previously been incubated with spur cells. Changes in cell cholesterol were induced by all of the lipoprotein fractions of spur serum. When transfused into a patient with spur cells, normal red cells became more resistant to osmotic lysis over the course of 24 hr. However, over the subsequent 7 days they underwent a progressive increase in osmotic fragility. These normal cells, as well as the patient's own cells, had a shortened survival. Correlating with the moderate decrease in the filterability of red cells spurred in vitro, red cell destruction occurred predominently in the spleen. Red cells in this disorder appear to serve as repositories for free cholesterol loosely bound to serum lipoproteins. Cholesterol acquisition by the red cell membrane increases its surface area and causes the red cell to be resistant to osmotic lysis. The associated alteration in red cell shape leads to further changes in the cell membrane during circulation in vivo resulting in the loss of membrane surface area and culminating in the cell's premature destruction in the spleen.
Duty Hour Reforms and Patient Outcomes—Reply
Authors: Mitesh S. Patel, Dylan S. Small, Jeffrey H. Silber
Journal: JAMA (2015)

In Reply We evaluated the association of the 2011 Accreditation Council for Graduate Medical Education duty hour reforms with 30-day all-location mortality and 30-day all-cause readmissions. This nationwide study evaluated 6 384 273 admissions from 2 790 356 patients at 3104 hospitals.
Phosphatidylinositol-3-Kinase-γ Is Integral to Homing Functions of Progenitor Cells
Authors: Emmanouil Chavakis, Guillaume Carmona, Carmen Urbich, Stephan Göttig, Reinhard Henschler, Josef M. Penninger, Andreas M. Zeiher, Triantafyllos Chavakis, Stefanie Dimmeler
Journal: Circulation Research (2008)

Endothelial progenitor cells (EPCs) and hematopoietic progenitor cells are recruited to ischemic regions, improving neovascularization. beta1 and beta2 integrins play a crucial role for progenitor cell homing to ischemic tissues. Integrin activity is regulated by chemokines and their respective G protein-coupled receptors. The phosphatidylinositol-3-kinase catalytic subunit gamma (PI3Kgamma) is the PI3K isoform that selectively transduces signals from G protein-coupled receptors. Here, we investigated the role of PI3Kgamma as a signaling intermediate in the chemokine-induced integrin-dependent homing functions of progenitor cells. A pharmacological PI3Kgamma inhibitor significantly reduced chemokine-induced chemotaxis and stromal cell-derived factor (SDF)1alpha-induced transmigration of human EPCs. Moreover, the PI3Kgamma inhibitor significantly reduced SDF1alpha-induced adhesion of EPCs to intercellular adhesion molecule-1 and human umbilical vein endothelial cell monolayers. These findings were corroborated with Lin(-) bone marrow-derived progenitor cells from PI3Kgamma-deficient mice that displayed reduced SDF1alpha-induced migration and intercellular adhesion molecule-1 adhesion as compared with wild-type cells. Pharmacological inhibition or genetic ablation of PI3Kgamma reduced SDF1alpha-induced integrin activation in human EPCs and in murine Lin(-) BM-derived progenitor cells, respectively. In vivo, the homing of PI3Kgamma-deficient Lin(-) progenitor cells to ischemic muscles after intravenous infusion in the model of hindlimb ischemia and their neovascularization-promoting capacity was reduced as compared with wild-type cells. In conclusion, PI3Kgamma is integral to the integrin-dependent homing of progenitor cells.
FALSE POSITIVE RESULTS FOR CORONARY ARTERY DISEASE IN LEFT BUNDLE BRANCH BLOCK PATIENTS UNDERGOING DIPYRIDAMOLE MYOCARDIAL PERFUSION SCINTIGRAPHY
Authors: R. J. Campeau, LJ. Percy, F. Sierra, O. A. Correa, O. M. Garcla
Journal: Clinical Nuclear Medicine (1994)

Campeau, R. J.; Percy, LJ.; Sierra, F.; Correa, O. A.; Garcla, O. M. Author Information
Seizure Disorders Among Prisoners
Authors: Alfred P. French
Journal: JAMA (1978)

To the Editor.—  Drs King and Young relied on the rates that anticonvulsant medications were actually prescribed by the physicians who provide medical care in various correctional institutions and concluded that the incidence of seizure disorders is increased among prisoners. Unfortunately, the authors have failed to consider several of the following possible sources of bias: (1) As a generalization, prisoners are skilled at manipulating others to get what they want. (2) One might anticipate a certain willingness by prisoners to go to some lengths to obtain a sedative, and phenobarbital, commonly used in the treatment of seizure disorders, is a coveted downer. (3) A false-negative error in the treatment of a seizure disorder would be highly visible to many members of a prison community and possibly highly embarrassing for a prison physician, while a false-positive error would not be noticed in an environment wherein the watchword must be don't rock
B cells blunt neonatal immunity
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2007)

Infants are easy targets for viruses and bacteria, as their immune responses lack the punch to ward off pathogens. Zhang et al. (page 1107) now find that young immune systems are well developed but are sabotaged by a group of childish B cells.

In adults, microbes trigger defense responses by activating Toll-Like Receptors (TLRs) on dendritic cells (DCs). The DCs then ramp up defense by secreting Interferons α and β (IFN α/β), which are toxic to pathogens, and pro-inflammatory TNF and interleukin-12 (IL-12), which reinforce inflammation by activating T cells.

In newborns, however, TNF and IL-12 are only weakly produced during inflammation, even though neonatal DCs produce these cytokines when stimulated in vitro. To identify the in vivo roadblock, Zhang et al. focused on the anti-inflammatory cytokine IL-10, as it is a known inhibitor of TNF and IL-12 production. In an earlier study, the group found that IL-10 is produced by a subset of B cells that are more abundant in newborns than in adults.

The team now shows that these B cells overwhelm inflammatory responses in newborn mice. Pathogens triggered TLRs on both B cells and DCs. The B cells responded by producing IL-10, while the DCs made IFNα/β. But instead of stoking inflammation, the IFNα/β enhanced B cell IL-10 production, which then blocked DC secretion of TNF/IL-12. This regulatory loop sabotaged anti-microbial immunity in newborns, but it also had a positive effect: it allowed young mice to avoid overenthusiastic and potentially lethal inflammatory responses. The team speculates that this mechanism might also prevent human infants from succumbing to inflammation. Adults do not get the same benefit, as their IL-10-secreting B cells are vastly out-numbered by inflammatory DCs.
ASSOCIATION BETWEEN DETECTABLE CARDIAC TROPONIN, ABNORMAL MYOCARDIAL CORONARY FLOW RESERVE AND ADVERSE CLINICAL OUTCOMES IN PATIENTS WITHOUT OVERT CORONARY ARTERY DISEASE
Authors: Viviany Taqueti, Venkatesh Murthy, Brendan Everett, Sharmila Dorbala, Ron Blankstein, Masanao Naya, Jon Hainer, Courtney Foster, Marcelo Di Carli
Journal: Journal of the American College of Cardiology (2013)
Cognitive Distraction Worsens Endovascular Performance: Effects Related to Experience
Authors: T.T. Wang, P. Naughton, R. Aggarwal, I. Van Herzeele, A.N. Keeling, A. Choong, K. O'Donoghue, K. Sahnan, A. Darzi, P. Gaines, N. Cheshire
Journal: International Journal of Surgery (2010)
Abstract 3104: Genome-wide screen for modulators of cell death induced by the NEDD8-activating enzyme inhibitor MLN4924
Authors: Kat Cosmopoulos, Jonathan Blank, Xiaozhen Liu, David Bouck, Khristofer Garcia, Hua Liao, Hughes Bernard, Olga Tayber, Greg Hather, Ray Liu, Eric Lightcap
Journal: Cancer Research (2012)

Abstract The NEDD8-activating enzyme (NAE) is an E1 involved in the activation of a large family of ubiquitin E3 ligases termed the cullin-RING ligases (CRLs) through conjugation of the cullin proteins with the ubiquitin-like modifier NEDD8. Polyubiquitination of CRL substrate proteins targets them for degradation by the proteasome. In this way, NAE regulates the stability of proteins required for cancer cell growth and survival. MLN4924 is an investigational small molecule that is a potent and selective inhibitor of NAE in Phase I clinical trials. In order to investigate the primary genetic determinants that confer sensitivity of cells to NAE inhibition, we have performed a genome-wide synthetic lethal RNAi screen using MLN4924 in the A375 melanoma cell line. We have also investigated the biological consequences of NAE inhibition by studying the regulation of protein and transcript levels in MLN4924-treated A375 cells using large-scale quantitative proteomics and gene expression profiling, respectively. The RNAi screen has identified 123 genes whose down-regulation modulates MLN4924-induced cell death, and approximately one-third of these interfere with components of the NEDD8 pathway itself, the cell cycle and apoptotic machinery, and DNA damage-response pathways. Of these genes, 99 were subsequently assessed using high throughput FACS analysis for their contribution to the major phenotype induced by MLN4924. The results emphasize replication, p53, BRCA1/BRCA2, and transcription-coupled repair as being particularly important for MLN4924-induced cell death. In addition, the interactions of 80 genes with roles in cell cycle and DNA damage repair were explored with proteasome inhibitors and 12 DNA damaging agents, demonstrating that MLN4924 induces DNA damage by a distinct mechanism. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3104. doi:1538-7445.AM2012-3104
429. AAV5-Mediated Delivery of Human Aryl Sulfatase A (hARSA) Prevents Sufatide Storage and Neuropathological Phenotype in Metachromatic Leukodystrophy (MLD) Mice
Authors: Nathalie Cartier, Caroline Sevin, Abdellatif Benraiss, Peter DeDeyn, Delphine Bonnin, Marie-T Vanier, Moullier Philippe, Volkmar Gieselmann, Patrick Aubourg
Journal: Molecular Therapy (2005)

Metachromatic leukodystrophy (MLD) is an inborn lysosomal storage disease caused by arylsulfatase A (ARSA) enzyme deficiency. Lack of ARSA results in the storage of galactosyl-3-sulfate ceramide (sulfatide) in neurons and glial cells that leads to progressive demyelination and neuronal damage in the CNS. The most severe form of MLD is the late infantile form that results in rapid loss of motor and cognitive functions and death within 2-5 years. No efficient therapy is available in infantile form of MLD and allogeneic hematopoietic cell transplantation has limited effects in the juvenile forms of MLD. MLD mice exhibit phenotypic abnormalities reminiscent of the human disease that include sulfatide storage in neurons and glial cells and neuromotor impairment. AAV5 vector encoding human ARSA was injected in the internal capsules and cerebellum of 3 month-old MLD mice (3 x109 vp /injection; n= 14) at the time they are beginning to develop CNS disease. Treated mice and mock-treated mice (AAV5-LacZ) were sacrificed at 6 and 18 months of age. Functional recombinant hARSA was detected in almost all areas of the forebrain, cerebellum and brainstem of AAV5-hARSA treated mice, using an ELISA assay that recognizes specifically the hARSA, immunohistochemistry and measurement of hARSA activity with the artificial substrate p-nitrocatechol sulfate. As expected, hARSA was mostly expressed in neurons, but also in a significant percentage of astrocytes (up to 14% arround the injection site) and in microglial cells. The widespread diffusion of hARSA resulted from both vector and enzyme diffusion within the CNS. Quantitative PCR in AAV5-ARSA vector showed that vector genomes were concentrated at the injection sites but spreads over a distance from injection sites. ARSA expression using ELISA test was proportional to the number of vector genomes but extended far beyond PCR-positive brain regions. The increase of ARSA positive neurons and astrocytes from 6 to 18 months of age confirmed that a significant amount of AAV5-encoded ARSA was secreted by transduced cells and captured by neurons and astrocytes. ARSA delivery prevented sulfatide deposits and reversed the galactosyl ceramide/sulfatide abnormal ratio that reflects sulfatide storage and loss of oligodendrocytes. Eighteen-month old treated mice showed a nearly absence of neuropathological abnormalities (Purkinje cell loss, astrogliosis, microglial activation) and normal motor behavior (at the rotarod test). These results indicate that ARSA delivery from intracerebral sources has the capacity to alleviate most disease manifestation in the MLD model.