tbuckley/cabot-search huggingface dataset:
Differential effects of interleukin-15 and interleukin-2 on differentiation of bipotential T/natural killer progenitor cells.
Authors: G Leclercq, V Debacker, M de Smedt, J Plum
Journal: The Journal of Experimental Medicine (1996)

Bipotential T/natural killer (NK) progenitor cells are destined to differentiate mainly into T cell receptor (TCR) alpha beta and TCR gamma delta cells in a thymic microenvironment, whereas extrathymically they selectively develop into NK cells. The exact environmental conditions that are required for differentiation into these three leukocyte populations are largely unknown. In this report, we have investigated and compared the effect of interleukin (IL)-15 and IL-2 in this process. The IL-15 receptor is composed of the gamma and beta chains of the IL-2 receptor (IL-2R gamma and IL-2R beta) and of a specific alpha chain (IL-15R alpha). Here, it is shown that IL-15 mRNA is mainly expressed in thymic epithelial stromal cells, whereas IL-2 mRNA is exclusively expressed in thymocytes. IL-2R beta-expressing cells were present in the fetal thymus with a CD25-CD44+Fc gamma R+HSA-/low TCR- phenotype, which is characteristic of progenitor cells. These cells also expressed IL-15R alpha messenger RNA. Sorted IL-2R beta + TCR- cells differentiated into TCR alpha beta and TCR gamma delta cells after transfer to alymphoid thymic lobes, whereas culture of the same sorted cells in cell suspension in the presence of IL-15 resulted in the generation of functional NK cells. This shows that IL-2R beta +TCR- cells of the fetal thymus contain bipotential T/NK progenitors. Addition of low concentrations of IL-15 to fetal thymic organ culture (FTOC) resulted in an increase of all T cell subpopulations. The largest expansion occurred in the TCR gamma delta compartment. In contrast, low concentrations of IL-2 did not result in a higher total cell number and did not induce outgrowth of TCR gamma delta cells. High concentrations of IL-15 blocked TCR alpha beta development and shifted differentiation towards NK cells. Differentiation towards TCR gamma delta cells still proceeded. High concentrations of IL-2 similarly induced development into NK cells, but the cell number was fourfold lower than in IL-15 cultures. Importantly, blocking of IL-2R alpha in IL-2-treated FTOC resulted in a drastic increase in cell number, indicating that IL-2R alpha negatively regulates cell expansion. Collectively, these experiments provide direct evidence that IL-15 and IL-2 differentially affect the differentiation of bipotential T/NK progenitors.
Trends in Otitis Media–Related Health Care Use in the United States, 2001-2011
Authors: Tal Marom, Alai Tan, Gregg S. Wilkinson, Karen S. Pierson, Jean L. Freeman, Tasnee Chonmaitree
Journal: JAMA Pediatrics (2013)

Otitis media (OM) is a leading cause of pediatric health care visits and the most frequent reason children consume antibiotics or undergo surgery. During recent years, several interventions have been introduced aiming to decrease OM burden.To study the trend in OM-related health care use in the United States during the pneumococcal conjugate vaccine (PCV) era (2001-2011).An analysis of an insurance claims database of a large, nationwide managed health care plan was conducted. Enrolled children aged 6 years or younger with OM visits were identified.Annual OM visit rates, OM-related complications, and surgical interventions were analyzed.Overall, 7.82 million unique children (5.51 million child-years) contributed 6.21 million primary OM visits; 52% were boys and 48% were younger than 2 years. There was a downward trend in OM visit rates from 2004 to 2011, with a significant drop that coincided with the advent of the 13-valent vaccine (PCV-13) in 2010. The observed OM visit rates in 2010 (1.00/child-year) and 2011 (0.81/child-year) were lower than the projected rates based on the 2005-2009 trend had there been no intervention (P < .001). Recurrent OM (≥3 OM visits within 6-month look-back) rates decreased at 0.003/child-year (95% CI, 0.002-0.004/child-year) in 2001-2009 and at 0.018/child-year (95% CI, 0.008-0.028/child-year) in 2010-2011. In the PCV-13 premarket years, there was a stable rate ratio (RR) between OM visit rates in children younger than 2 years and in those aged 2 to 6 years (RR, 1.38; 95% CI, 1.38-1.39); the RR decreased significantly (P < .001) during the transition year 2010 (RR 1.32; 95% CI, 1.31-1.33) and the postmarket year 2011 (RR 1.01; 95% CI, 1.00-1.02). Tympanic membrane perforation/otorrhea rates gradually increased (from 3721 per 100,000 OM child-years in 2001 to 4542 per 100,000 OM child-years in 2011; P < .001); the increase was significant only in the older children group. Mastoiditis rates substantially decreased (from 61 per 100,000 child-years in 2008 to 37 per 100,000 child-years in 2011; P < .001). Ventilating tube insertion rate decreased by 19% from 2010 to 2011 (P = .03).There was an overall downward trend in OM-related health care use from 2001 to 2011. The significant reduction in OM visit rates in 2010-2011 in children younger than 2 years coincided with the advent of PCV-13. Although tympanic membrane perforation/otorrhea rates steadily increased during that period, mastoiditis and ventilating tube insertion rates decreased in the last years of the study.
Equity in the new NHS: hard lessons from implementing a local healthcare policy on donepezil
Authors: Y. Doyle
Journal: BMJ (2001)

Restricting access to expensive drugs that have modest benefits often leads to public protest. One such drug is donepezil, which is recommended for treating mild to moderate Alzheimer's dementia. Initial enthusiasm for the drug was dampened by revelations about the select nature of the study population, sharp marketing practices, and the unsatisfactory process during licensing.1 Nevertheless, somehow the public debate shifted to the problems of funding the drug. The National Institute for Clinical Excellence issued guidance on the drug early in 2001, stating that it has limited benefit in certain carefully assessed patients.2

#### Summary points

Debate is needed about the merit of open access to expensive treatments for many people to identify the few who gain marginal benefit

An evidence based approach can conflict with perceptions of fair access by patients and carers

This conflict poses a challenge to independent local advisory forums proposed under the NHS plan

Since blanket bans on access to treatments are legally indefensible, the process of decision making must be reasonable and transparent

Merton, Sutton and Wandsworth Health Authority devised its first policy on donepezil in 1997 in response to national and local consumer interest in the treatment. Having assessed the evidence in various prescribing and effectiveness groups, the authority concluded that the drug's benefits were insufficient to warrant funding. The majority of consultants agreed with the decision, although there was some dissent, particularly among doctors treating elderly patients. The drug was not placed in the formularies of any of the authority's hospitals and was consequently not prescribed in secondary care. The appearance of guidance from the Standing Medical Advisory Committee in 19983 did not change clinical opinion or the policy.

Between 1997 and 2000 various inconsistencies became apparent. Firstly, some general practitioners were prescribing the drug in primary care. At any time since …
Air Sampling for Legionella-Reply
Authors: Robert F. Breiman
Journal: JAMA (1990)

<h3>In Reply.—</h3> In their letter, Dr Zingeser and colleagues have provided further evidence that detection of the causative agent by air sampling complements epidemiologic investigations of legionnaires' disease. Since legionellae are widely distributed in water, the significance of isolating the bacteria from water reservoirs of aerosol-producing devices is often uncertain<sup>1</sup>; however, we suspect that legionellae are not frequently present in air. In our<i>JAMA</i>study, which associated legionnaires' disease with shower use, legionellae were isolated after, but not before, water was turned on in a shower. In another investigation associating legionnaires' disease with exposure to one area of a building in close proximity to a device that produced contaminated aerosol, legionellae were isolated from air samples collected in that area, but not in other areas of the same building unexposed to the contaminated aerosol.<sup>2</sup>Thus, using selective air sampling to detect legionellae within respirable-sized droplets in aerosols
Association Between Pulse Pressure and Mortality in Patients Undergoing Maintenance Hemodialysis
Authors: Preston S. Klassen
Journal: JAMA (2002)

ContextAlthough increased blood pressure is associated with adverse outcomes in the general population, elevated blood pressure is associated with decreased mortality in patients with end-stage renal disease undergoing maintenance hemodialysis. Recent investigations in the general population have demonstrated the predictive utility of pulse pressure (systolic minus diastolic blood pressure), a measure reflecting the pulsatile nature of the cardiac cycle.ObjectivesTo estimate the relationship between pulse pressure and mortality in patients undergoing maintenance hemodialysis and to test our hypothesis that an increasing pulse pressure would be associated with increased risk of death up to 1 year despite the inverse relationship between conventional blood pressure measures and mortality in patients with end-stage renal disease.Design, Setting, and PatientsRetrospective cohort investigation of patients with end-stage renal disease undergoing maintenance hemodialysis at 782 hemodialysis facilities throughout the United States. Of 44 069 eligible patients as of January 1, 1998, 37 069 with complete demographic data were included in the analyses of clinical and laboratory data collected from October 1 through December 31, 1997. Patients were followed up through December 31, 1998.Main Outcome MeasuresThe primary study outcome was death at 1 year. A secondary outcome was the magnitude of the pulse pressure.ResultsThe final patient cohort was similar to national averages with respect to age, sex, race, and diabetic status. Mean (SD) pulse pressures before dialysis were 75.0 (15.0) mm Hg and 66.9 (13.9) mm Hg after dialysis. By the end of the 1-year follow-up, 5731 patients (18.4%) died. After adjusting for level of systolic blood pressure, multivariable Cox proportional hazards modeling showed a direct and consistent relationship between increasing pulse pressure and increasing death risk. Each incremental elevation of 10 mm Hg in postdialysis pulse pressure was associated with a 12% increase in the hazard for death (hazard ratio, 1.12; 95% confidence interval, 1.06-1.18). Postdialysis systolic blood pressure was inversely related to mortality with a 13% decreased hazard for death for each incremental elevation of 10 mm Hg (hazard ratio, 0.87; 95% confidence interval, 0.84-0.90). In a multivariable linear regression model, important variables directly associated with elevated pulse pressure included age, diabetes, white race, female sex, and number of years receiving dialysis (all P<.001).ConclusionsPulse pressure is associated with risk of death in a large, nationally representative sample of patients undergoing maintenance hemodialysis. The recognition of pulse pressure as an important correlate of mortality in patients receiving dialysis highlights the need to investigate the relationship between potential therapeutic implications of conduit vessel function and clinical outcomes in patients with end-stage renal disease.
Endothelium-Derived Hyperpolarizing Factor Determines Resting and Stimulated Forearm Vasodilator Tone in Health and in Disease
Authors: Muhiddin A. Ozkor, Jonathan R. Murrow, Ayaz M. Rahman, Nino Kavtaradze, Ji Lin, Amita Manatunga, Arshed A. Quyyumi
Journal: Circulation (2011)

We assessed the contribution of endothelium-derived hyperpolarizing factors to resting and agonist-stimulated vasodilator tone in health and disease. Tetraethylammonium chloride (TEA) was used to inhibit K(+)(Ca) channel activation and fluconazole was used to inhibit cytochrome P450 2C9-mediated epoxyeicosatrienoic acid synthesis. We hypothesized that endothelium-derived hyperpolarizing factors contribute to resting vascular tone by K(+)(Ca) channel activation and epoxyeicosatrienoic acid release and that endothelium-derived hyperpolarizing factors compensate for reduced nitric oxide bioavailability at rest and with endothelium-dependent vasodilators.In 103 healthy subjects and 71 nonhypertensive subjects with multiple risk factors, we measured resting forearm blood flow (FBF) using venous occlusion plethysmography before and after intra-arterial infusions of N(G)-monomethyl-l-arginine (L-NMMA), TEA, fluconazole, and their combination. The effects of these antagonists on resting FBF and on bradykinin- and acetylcholine-mediated vasodilation were studied. Resting FBF decreased with TEA and L-NMMA in all subjects (P<0.001); however, the vasoconstrictor response to L-NMMA was greater (P=0.04) and to TEA was lower (P=0.04) in healthy subjects compared with those with risk factors. Fluconazole decreased resting FBF in all subjects, and the addition of TEA further reduced FBF after fluconazole, suggesting that cytochrome P450 metabolites and other hyperpolarizing factor(s) activate K(+)(Ca) channels. Both L-NMMA and TEA attenuated bradykinin-mediated vasodilation in healthy and hypercholesterolemic subjects (P<0.001). In contrast, acetylcholine-mediated vasodilation remained unchanged with TEA in healthy subjects but was significantly attenuated in hypercholesterolemia (P<0.04).First, by activating TEA-inhibitable K(+)(Ca) channels, endothelium-derived hyperpolarizing factors, together with nitric oxide, contribute to resting microvascular dilator tone. The contribution of K(+)(Ca) channel activation compared with nitric oxide is greater in those with multiple risk factors compared with healthy subjects. Second, activation of K(+)(Ca) channels is only partly through epoxyeicosatrienoic acid release, indicating the presence of other hyperpolarizing mechanisms. Third, bradykinin, but not acetylcholine, stimulates K(+)(Ca) channel-mediated vasodilation in healthy subjects, whereas in hypercholesterolemia, K(+)(Ca) channel-mediated vasodilation compensates for the reduced nitric oxide activity. Thus, enhanced endothelium-derived hyperpolarizing factor activity in conditions of nitric oxide deficiency contributes to maintenance of resting and agonist-stimulated vasodilation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00166166.
Goodpasture's Syndrome: Recovery from Severe Pulmonary Hemorrhage After Bilateral Nephrectomy
Authors: Andrew Nowakowski, Robert B. Grove, Leroy H. King, Tatiana T. Antonovych, Robert W. Fortner, Martial R. Knieser, Charles B. Carter, James H. Knepshield
Journal: Annals of Internal Medicine (1971)

A case of Goodpasture's syndrome is presented wherein life-threatening pulmonary hemorrhage, refractory to immunosuppressive drug therapy, rapidly resolved after bilateral nephrectomy. This experience, although not unprecedented, is reported here for the first time in a patient not in end-stage renal failure. During the 12 months that have elapsed since nephrectomy, there has been no recurrence of the patient's original disease; circulating antiglomerular basement membrane antibodies, present before nephrectomy, have become undetectable; and the patient has received a related living donor renal allograft. Electron microscopic studies of this patient's renal tissue showed effacement of the lamina rara interna, a previously unreported observation, and virus-like particles within glomerular endothelial cells. Based on the evidence for the immunopathogenesis of Goodpasture's syndrome and recent experiments with animal models for this disease, we offer an explanation of how nephrectomy may reverse pulmonary hemorrhage in Goodpasture's syndrome.
Late Results of Pediatric Cardiac Surgery in Finland
Authors: Heta P. Nieminen, Eero V. Jokinen, Heikki I. Sairanen
Journal: Circulation (2001)

Background This population-based study characterizes the history and progress of pediatric cardiac surgery in Finland. For the first time, all defects and procedures are included in an outcome study, reflecting the true effectiveness of operative treatment. Methods and Results All data relating to the operations were collected retrospectively from hospital records. Current patient status was obtained from the population registry. Survival was evaluated with the Kaplan-Meier method applied to all patients and separately to subgroups of patients with the most common defects. The survival rates were compared with those of an age- and sex-matched general population. During the 37 years (1953 to 1989), 6461 patients underwent surgery; 96% of them were traced. The number of operations and the constellation of defects treated increased dramatically over time. Actuarial survival for the 45 years ended October 28, 1998 (the ending date of this study) was 78% for patients versus 93% for the general population. Survival and the number of operations per patient varied widely with the defect. The survival of patients with a surgically closed atrial septal defect was comparable to that of the general population, and such patients rarely needed a reoperation, whereas only 15% of patients with univentricular heart survived for 34 years, and almost all needed at least 2 operations. Conclusions The overall survival of patients with cardiac defects corrected surgically in childhood is good compared with their estimated natural course. The increasing number of surgically treatable defects and the growing number of operations per patient reflect the increasing ability to treat more difficult cases.
On Cigarette Smoking, Bronchial Carcinoma and Ciliary Action
Authors: A. C. Hilding
Journal: New England Journal of Medicine (1956)

THE New York Times published a story in February, 1955, stating that bronchogenic carcinoma never develops in the Yemen Jews.1 They smoke a great deal of strong tobacco but pass the smoke through water in a special type of pipe.One wonders what becomes of the smoke after it leaves the proximal end of American cigarettes. It passes directly, of course, into the mouth. Hansel2 has described the effects of tobacco smoking on the upper respiratory tract. Proetz3 has studied the irritating effects on the pharyngeal mucosa and has demonstrated tar deposit in the noses of experimental animals. So-called smoker's . . .
A LONG-ACTING PHENOTHIAZINE IN OFFICE PRACTICE
Authors: NATHAN S. KLINE, GEORGE M. SIMPSON
Journal: American Journal of Psychiatry (1964)

Fluphenazine enanthate is a useful and potent medication with a clinically effective range of 10 to 20 days from a single depot injection. The usefulness of this preparation in preventing the hospitalization or re-hospitalization of extremely psychotic patients is illustrated and discussed.
STUDIES ON ANTIBODY AFFINITY AT THE CELLULAR LEVEL
Authors: Birger Andersson
Journal: The Journal of Experimental Medicine (1972)

Heterogeneity with regard to affinity of anti-hapten antibody was demonstrated at the cellular level in mice. The heterogeneity was shown at the level of single antibody-forming cells using hapten inhibition of hemolytic antibody plaque formation as a measure of affinity. The affinity increased with time after immunization. A high antigen dose initially resulted in relatively low affinity antibody production as compared to the affinity of the antibody production in animals immunized with a low dose. Affinity specialization of immunological memory cells was demonstrated, since it was possible to specifically fractionate such cells with regard to affinity on hapten-protein-coated plastic bead columns. High affinity memory cells showed a higher tendency to become retained in the columns than did low affinity memory cells. The data in a direct way demonstrate that memory cells carrying membrane-associated receptors of a certain affinity for the antigen are determined to release antibody of a similar affinity after stimulation with antigen.
Terbinafine: Mode of action and properties of the squalene epoxidase inhibition
Authors: N.S. RYDER
Journal: British Journal of Dermatology (1992)

Terbinafine (Lamisil) has primarily fungicidal action against many fungi as a result of its specific mechanism of squalene epoxidase inhibition. Treated fungi accumulate squalene while becoming deficient in ergosterol, an essential component of fungal cell membranes. The cidal action is closely associated with the development of high intracellular squalene concentrations, which are believed to interfere with fungal membrane function and cell wall synthesis. In the case of Candida albicans, growth inhibition with terbinafine appears to result from the ergosterol deficiency. The filamentous form of this fungus is more susceptible than the yeast form. Measurement of ergosterol biosynthesis by incorporation of radiolabelled precursors indicates a correlation between inhibition of growth and ergosterol biosynthesis in a range of pathogenic fungi. Terbinafine is a potent non-competitive inhibitor of squalene epoxidase from Candida (Ki = 30 nM). In contrast, inhibition of rat liver squalene epoxidase only occurs at higher drug concentrations (Ki = 77 microM), and is competitive with squalene. Thus, terbinafine has no effect on cholesterol biosynthesis in vivo. Squalene epoxidase is not an enzyme of the cytochrome P-450 type, thereby avoiding potential inhibition of this class of enzymes.
Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease
Authors: Byoung Dae Lee, Joo-Ho Shin, Jackalina VanKampen, Leonard Petrucelli, Andrew B West, Han Seok Ko, Yun-Il Lee, Kathleen A Maguire-Zeiss, William J Bowers, Howard J Federoff, Valina L Dawson, Ted M Dawson
Journal: Nature Medicine (2010)
Translating Biomedical Research to the Bedside
Authors: Roger N. Rosenberg
Journal: JAMA (2003)

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