tbuckley/cabot-search huggingface dataset:
Response of human intestinal lamina propria T lymphocytes to interleukin 12: additive effects of interleukin 15 and 7
Authors: G Monteleone, T Parrello, F Luzza, F Pallone
Journal: Gut (1998)

Interleukin (IL) 12 is involved in the mucosal response during intestinal inflammation but its role is not fully understood. The response of human lamina propria T lymphocytes (T-LPL) to IL-12 in terms of interferon gamma (IFN-gamma) release and proliferation was investigated, exploring whether IL-15 and IL-7 cooperate with IL-12. The role of accessory molecules (CD2 and CD28) was also investigated.Unstimulated and phytohaemagglutinin preactivated T-LPL cultures were incubated with or without the initial addition of cytokines, anti-CD2 or anti-CD28 antibodies. IFN-gamma mRNA was detected by reverse transcriptase polymerase chain reaction, and protein secretion was measured by enzyme linked immunosorbent assay (ELISA).IFN-gamma mRNA was induced in T-LPLs by IL-12 and IL-15 but not IL-7, whereas IFN-gamma was measured only in IL-12 stimulated T-LPL cultures. IL-12 induced IFN-gamma release was not abrogated by neutralising anti-IL-2 antibody or by cyclosporin A. IL-12 synergised with either anti-CD2 or anti-CD28 antibodies in inducing IFN-gamma synthesis. In preactivated T-LPLs, IL-7 enhanced IFN-gamma release induced by both IL-12 and anti-CD2, whereas IL-15 potentiated only IL-12 induced IFN-gamma synthesis. IL-12 did not induce proliferation of either unstimulated or preactivated T-LPLs and it did not enhance the CD2/CD28 stimulated T-LPL proliferative response. No transcript for IL-12 receptor beta1 subunit was detected in freshly isolated and activated T-LPLs whereas the beta2 subunit mRNA was consistently found in T-LPL samples.IL-12 induces human T-LPLs to produce and release IFN-gamma, and IL-15 and IL-7 cooperate with IL-12 in expanding the IFN-gamma mucosal response.
Prospective Study of Diet and Decline in Lung Function in a General Population
Authors: Tricia M. McKeever, Sarah Scrivener, Emma Broadfield, Zoe Jones, John Britton, Sarah A. Lewis
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

We have investigated the relationship between decline in lung function and dietary intakes of magnesium, vitamin C, and other antioxidant vitamins in a general population cohort in Nottingham, United Kingdom. In 1991, we measured dietary intake by semiquantitative food frequency questionnaire, forced expiratory volume in 1 second (FEV1), and respiratory symptoms in a cross-sectional survey of 2,633 adults aged 18-70. Nine years later we repeated these measures in 1,346 of these individuals. In cross-sectional analyses, after adjustment for smoking and other confounders, higher intakes of vitamin C and magnesium, but not vitamins A or E, were associated with higher levels of FEV1 in both 1991 and 2000. In longitudinal analysis with adjustment for confounders, decline in FEV1 between 1991 and 2000 was lower amongst those with higher average vitamin C intake by 50.8 ml (95% confidence interval, 3.8-97.9) per 100 mg of vitamin C per day, but was unrelated to magnesium intake. There was no relationship between decline in FEV1 and intake of vitamins A or E. This study suggests that a high dietary intake of vitamin C, or of foods rich in this vitamin, may reduce the rate of loss of lung function in adults and thereby help to prevent chronic obstructive pulmonary disease.
Lymphocytes that can't let go
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

On page 1987, Semmrich and colleagues show that immune cells expressing a perpetually activated form of the integrin LFA-1 get traction at the front of the cell, but get stuck from behind. Their lagging ends prevent them from crawling through the endothelium and initiating a normal immune response.

Integrins, such as LFA-1, are adhesive molecules that switch between active and inactive conformations and control migration of circulating immune cells to sites of infection and inflammation. LFA-1 is also required for the formation of stable interactions between T cells and antigen presenting cells (APCs). Previous studies had shown that both tumor-specific T cell responses and neutrophil migration are compromised in the absence of this integrin.






Figure 

T cells that express a constitutively activated form of the integrin LFA-1 (bottom) have restricted mobility compared to those expressing wild-type LFA-1 (top).




The importance of LFA-1 deactivation, however, has been less clear. In vitro studies have shown that locking LFA-1 in its activated conformation impairs both neutrophil chemotaxis and T cell activation. Semmrich et al. now confirm these findings in vivo, and show that lymphocytes from mice expressing a constitutively active LFA-1 moved more slowly than wild-type cells and failed to migrate across endothelial cell monolayers. Video microscopy revealed that these defective movements were due to an inability of the cells to release their trailing edges.

CD4+ T cell proliferation and antibody production were also impaired in these mice. The development of antigen-specific CD8+ cytotoxic T cells, by contrast, was not altered by the mutated LFA-1, but the ability of these cells to lyse target cells was decreased. The authors suggest that defects in T cell activation and function may reflect the need for serial engagement of T cell receptors with peptide–MHC complexes on APCs, a process that may be compromised by the inability to inactivate LFA-1 and thus to terminate cell–cell contacts.

Mice expressing the mutant LFA-1 closely resembled mice lacking the protein completely, suggesting that, for immune cells, letting go is just as important as grabbing on.
The gender imbalance in academic medicine: a study of female authorship in the United Kingdom
Authors: Reena Sidhu, Praveen Rajashekhar, Victoria L Lavin, Joanne Parry, James Attwood, Anita Holdcroft, David S Sanders
Journal: Journal of the Royal Society of Medicine (2009)

A shortfall exists of female doctors in senior academic posts in the United Kingdom. Career progression depends on measures of esteem, including publication in prestigious journals. This study investigates gender differences in first and senior authorship in six peer-reviewed British journals and factors that are associated with publication rates.Data was collected on United Kingdom first and senior authors who had published in the British Medical Journal, Lancet, British Journal of Surgery, Gut, British Journal of Obstetrics and Gynaecology and the Archives of Diseases in Childhood. Authorship and gender were quantified for 1970, 1980, 1990, 2000 and 2004 (n=6457). In addition, selected questions from the Athena Survey of Science Engineering and Technology (ASSET2006), web-based doctor's self-report of publications were also analysed (n=1162).Female first authors increased from 10.5% in 1970 to 36.5% in 2004 (p<0.001) while female senior authors only increased from 12.3% to 16.5% (p=0.046). Within individual journals, the largest rise was in British Journal of Obstetric and Gynaecology with 4.5- and 3-fold increases for first and senior authors, respectively. In contrast, female senior authors marginally declined in Gut and Lancet by 2.8% and 2.2%, respectively. ASSET2006 identified that female respondents who were parents were less likely to have publications as sole (p=0.02) and joint authors (p<0.001) compared to male respondents. Female respondents with care responsibilities for parents/partner also had less publications as lead authors compared to those without carer responsibilities (p<0.001).The increase in UK female first authors is encouraging. In contrast, there is considerable lag and in some specialties a decline in female senior authors. Factors that could narrow the gender gap in authorship should be sought and addressed.
Cumulative effects from repeated exposures to suberythemal doses of UVB and UVA in human skin
Authors: Robert M Lavker, G.Frank Gerberick, Denise Veres, Chris J Irwin, Kays H Kaidbey
Journal: Journal of the American Academy of Dermatology (1995)

The skin is repeatedly exposed to solar UV radiation. Long-term photodamage is a consequence of cumulative UV radiation injury. Hence an examination of the repetitive effects of UV exposure is more likely to yield clues to the early alterations that lead to photoaged skin than a single exposure.We examined the effects of repetitive low-dose UV irradiation on human skin with the aim of identifying UVA-induced effects that may have a different wavelength dependence than acute erythema.Areas on the lower part of the back were each exposed to a suberythemal dose (0.5 minimal erythema dose [MED]) of solar simulated radiation (290 to 400 nm) and of UVA (320 to 400 nm) once daily, 5 days a week, for 28 doses. One site was also treated daily with a sunscreen having a sun protection factor of 22 and then exposed to 11 MEDs of solar simulated radiation for the same duration. Epidermal and dermal changes were analyzed and quantified by histochemical stains in combination with computer-assisted image analysis of tissue sections.At equal 0.5 MED doses, UVA induced greater cumulative changes than solar simulated radiation, as assessed by development of a greater cumulative erythema response in the first week of treatment, the presence of epidermal hyperplasia and stratum corneum thickening, depletion of Langerhans cells, dermal inflammatory infiltrates, and deposition of lysozyme on elastin fibers. These changes were not prevented by the sunscreen. A single short-term dose of UVA did not elicit these changes.These findings suggest that UVA may contribute significantly to long-term actinic damage and that the spectral dependence for cumulative damage does not parallel the action spectrum for acute injury (erythema) in human beings.
Thiopurine Methyltransferase (&lt;EMPH TYPE="ITAL"&gt;TPMT&lt;/EMPH&gt;) Genotype and Early Treatment Response to Mercaptopurine in Childhood Acute Lymphoblastic Leukemia
Authors: Martin Stanulla
Journal: JAMA (2005)

Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for children with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) is involved in the metabolism of mercaptopurine and subject to genetic polymorphism, with heterozygous individuals having intermediate and homozygous mutant individuals having very low TPMT activity.To assess the association of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL.TPMT genotyping of childhood ALL patients (n = 814) in Germany consecutively enrolled in the ALL-BFM (Berlin-Frankfurt-Münster) 2000 study from October 1999 to September 2002. Minimal residual disease was analyzed on treatment days 33 and 78 for risk-adapted treatment stratification. A 4-week cycle of mercaptopurine was administered between these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and consequently deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analyses.Minimal residual disease load before (day 33) and after (day 78) mercaptopurine treatment. Loads smaller than 10(-4) were defined as negative.Patients (n = 55) heterozygous for allelic variants of TPMT conferring lower enzyme activity had a significantly lower rate of minimal residual disease positivity (9.1%) compared with patients (n = 755) with homozygous wild-type alleles (22.8%) on day 78 (P = .02). This translated into a 2.9-fold reduction in risk for patients with wild-type heterozygous alleles (relative risk, 0.34; 95% confidence interval, 0.13-0.86).TPMT genotype has a substantial impact on minimal residual disease after administration of mercaptopurine in the early course of childhood ALL, most likely through modulation of mercaptopurine dose intensity. Our findings support a role for minimal residual disease analyses in the assessment of genotype-phenotype associations in multiagent chemotherapeutic trials.
Positron Emission Tomography in Staging Early Lung Cancer
Authors: Donna E. Maziak
Journal: Annals of Internal Medicine (2009)

Background: Among patients with early-stage non–small cell lung cancer (NSCLC), preoperative imaging tests are important in defining surgical candidates. Objective: To assess whether whole-body positron emission tomography and computed tomography (PET-CT) plus cranial imaging correctly upstages cancer in more patients with NSCLC than does conventional staging plus cranial imaging. Design: Randomized clinical trial with recruitment from June 2004 to August 2007. The centralized, computer-generated, variable block size randomization scheme was stratified by treatment center and cancer stage. Participants, health care providers, and outcome assessors were not blinded to imaging modality assignment. Setting: 8 hospitals and 5 PET-CT centers in academic institutions. Patients: Eligible patients were older than 18 years; had histologic or cytologic proof of stage I, II, or IIIA NSCLC on the basis of chest radiography and thoracic CT; and had a tumor considered to be resectable. Intervention: PET-CT or conventional staging (abdominal CT and bone scan). All patients also had cranial imaging using CT or magnetic resonance imaging. Measurements: The primary outcome was correct upstaging, thereby avoiding stage-inappropriate surgery. Secondary outcomes were incorrect upstaging and incorrect understaging. Results: 170 patients were assigned to PET-CT and 167 to conventional staging. Eight patients (3 who had PET-CT and 5 who had conventional staging) did not have planned surgery. Disease was correctly upstaged in 23 of 167 PET-CT recipients and 11 of 162 conventional staging recipients (13.8% vs. 6.8%; difference, 7.0 percentage points [95% CI, 0.3 to 13.7 percentage points]), thereby sparing these patients from surgery. Disease was incorrectly upstaged in 8 PET-CT recipients and 1 conventional staging recipient (4.8% vs. 0.6%; difference, 4.2 percentage points [CI, 0.5 to 8.6 percentage points]), and it was incorrectly understaged in 25 and 48 patients, respectively (14.9% vs. 29.6%; difference, 14.7 percentage points [CI, 5.7 to 23.4 percentage points]). At 3 years, 52 patients who had PET-CT and 57 patients who had conventional staging had died. Limitation: The relatively small sample and the fact that some patients did not have planned surgery limited the ability to determine precise differences in clinical outcomes that were attributable to testing strategies. Conclusion: Preoperative staging with PET-CT and cranial imaging identifies more patients with mediastinal and extrathoracic disease than conventional staging, thereby sparing more patients from stage-inappropriate surgery, but the strategy also incorrectly upstaged disease in more patients. Primary Funding Source: Ontario Ministry of Health and Long-Term Care, Canadian Institutes of Health Research, and Cancer Care Ontario.
The prevalence of hidradenitis suppurativa in 1093 patients with inflammatory bowel disease
Authors: H.H. Zee, K. Winter, C.J. Woude, E.P. Prens
Journal: British Journal of Dermatology (2014)

Journal Article The prevalence of hidradenitis suppurativa in 1093 patients with inflammatory bowel disease Get access H.H. van der Zee, H.H. van der Zee Department of Dermatology Erasmus MC University Medical Center Rotterdam the Netherlands Search for other works by this author on: Oxford Academic Google Scholar K. de Winter, K. de Winter Department of Dermatology Erasmus MC University Medical Center Rotterdam the Netherlands Search for other works by this author on: Oxford Academic Google Scholar C.J. van der Woude, C.J. van der Woude Department of Gastroenterology Erasmus MC University Medical Center Rotterdam the Netherlands Search for other works by this author on: Oxford Academic Google Scholar E.P. Prens E.P. Prens Department of Dermatology Erasmus MC University Medical Center Rotterdam the NetherlandsDepartment of Immunology Erasmus MC University Medical Center Rotterdam the Netherlands Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 171, Issue 3, 1 September 2014, Pages 673–675, https://doi.org/10.1111/bjd.13002 Published: 01 September 2014
Economic Analysis: Randomized Placebo-Controlled Clinical Trial of Erlotinib in Advanced Non-Small Cell Lung Cancer
Authors: P. A. Bradbury, D. Tu, L. Seymour, P. K. Isogai, L. Zhu, R. Ng, N. Mittmann, M.-S. Tsao, W. K. Evans, F. A. Shepherd, N. B. Leighl
Journal: JNCI Journal of the National Cancer Institute (2010)

The NCIC Clinical Trials Group conducted the BR.21 trial, a randomized placebo-controlled trial of erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor) in patients with previously treated advanced non–small cell lung cancer. This trial accrued patients between August 14, 2001, and January 31, 2003, and found that overall survival and quality of life were improved in the erlotinib arm than in the placebo arm. However, funding restrictions limit access to erlotinib in many countries. We undertook an economic analysis of erlotinib treatment in this trial and explored different molecular and clinical predictors of outcome to determine the cost-effectiveness of treating various populations with erlotinib. Resource utilization was determined from individual patient data in the BR.21 trial database. The trial recruited 731 patients (488 in the erlotinib arm and 243 in the placebo arm). Costs arising from erlotinib treatment, diagnostic tests, outpatient visits, acute hospitalization, adverse events, lung cancer–related concomitant medications, transfusions, and radiation therapy were captured. The incremental cost-effectiveness ratio was calculated as the ratio of incremental cost (in 2007 Canadian dollars) to incremental effectiveness (life-years gained). In exploratory analyses, we evaluated the benefits of treatment in selected subgroups to determine the impact on the incremental cost-effectiveness ratio. The incremental cost-effectiveness ratio for erlotinib treatment in the BR.21 trial population was $94 638 per life-year gained (95% confidence interval = $52 359 to $429 148). The major drivers of cost-effectiveness included the magnitude of survival benefit and erlotinib cost. Subgroup analyses revealed that erlotinib may be more cost-effective in never-smokers or patients with high EGFR gene copy number. With an incremental cost-effectiveness ratio of $94 638 per life-year gained, erlotinib treatment for patients with previously treated advanced non–small cell lung cancer is marginally cost-effective. The use of molecular predictors of benefit for targeted agents may help identify more or less cost-effective subgroups for treatment.
The evolution of evolutionary epidemiology: A defense of pluralistic epigenetic modes of transmission
Authors: Daniel R. Wilson
Journal: Behavioral and Brain Sciences (2006)

First kudos, followed by some friendly badinage, and then renewed appreciation and a look ahead. This commentary is meant to clarify main arguments, redress incorrect attributions, and strengthen an excellent contribution that draws further attention to the importance of evolutionary epidemiology. Keller &amp; Miller (K&amp;M), despite significant errors, have done well to further systematize the evolutionary epidemiology of psychopathology.
Endogenous Inhibitors of Angiogenesis
Authors: Pia Nyberg, Liang Xie, Raghu Kalluri
Journal: Cancer Research (2005)

Angiogenesis, the formation of new blood vessels, is required for many pathologic processes, including invasive tumor growth as well as physiologic organ/tissue maintenance. Angiogenesis during development and adulthood is likely regulated by a balance between endogenous proangiogenic and antiangiogenic factors. It is speculated that tumor growth requires disruption of such balance; thus, the angiogenic switch must be turned "on" for cancer progression. If the angiogenic switch needs to be turned on to facilitate the tumor growth, the question remains as to what the physiologic status of this switch is in the adult human body; is it "off," with inhibitors outweighing the stimulators, or maintained at a fine "balance," keeping the proangiogenic properties of many factors at a delicate "activity" balance with endogenous inhibitors of angiogenesis. The physiologic status of this balance is important to understand as it might determine an individual's predisposition to turn the switch on during pathologic events dependent on angiogenesis. Conceivably, if the physiologic angiogenesis balance in human population exists somewhere between off and even balance, an individual's capacity and rate to turn the switch on might reflect their normal physiologic angiogenic status. In this regard, although extensive knowledge has been gained in our understanding of endogenous growth factors that stimulate angiogenesis, the activities associated with endogenous inhibitors are poorly understood. In this review, we will present an overview of the knowledge gained in studies related to the identification and characterization of 27 different endogenous inhibitors of angiogenesis.
Tainted Glory — Doping and Athletic Performance
Authors: Timothy D Noakes
Journal: New England Journal of Medicine (2004)

Is it possible for the “natural” athlete who competes without chemical assistance to achieve record-breaking performances in sports requiring strength, power, speed, or endurance? Because doping tests are infrequently positive in international sports, it has been widely believed that the answer is yes — and that few athletes competing in major sporting events, including the Olympic Games and the Tour de France, use performance-enhancing drugs. But multiple sources of evidence, including personal testimony1,2 and an ever-increasing incidence of doping scandals, suggest the opposite: that widespread use of performance-enhancing drugs has fundamentally distorted the upper range of human athletic performance. . . .
BCG vaccination by multipuncture method
Authors: L P. ORMEROD;
Journal: Thorax (2000)

I write in response to the article by Al Jarad et al 1 on this topic. The first study to compare the efficacy of BCG vaccination and its side effects using the Bignal multipuncture device with the reusable handle and disposable heads was the pilot study of neonatal BCG vaccination carried out in 1992 for the Department of Health in our health authority.2 In previous studies in neonates and children under two, referenced in the paper by Al Jarad et al ,1an 18–20 needle percutaneous head gave approximately the same degree of tuberculin conversion as did intradermal vaccination but, to achieve this in older children and adults, 36–40 punctures were required. This would require either a 40 needle head or a double vaccination with two × 18–20 needles. This is why percutaneous BCG is currently only … Dr N Al Jarad