tbuckley/cabot-search huggingface dataset:
Outdoor fungal spores are associated with child asthma hospitalisations - a case-crossover study
Authors: Rachel Tham, Shyamali Dharmage, Philip Taylor, Ed Newbigin, Mimi L.K. Tang, Don Vicendese, Rob J. Hyndman, Michael J. Abramson, Bircan Erbas
Journal: European Respiratory Journal (2014)

Introduction 

Asthma can be exacerbated by exposure to various fungal spores and Human Rhinovirus [HRV], but current understanding of the importance of fungal exposure to child asthma hospitalisations is limited. Moreover the interaction between HRV and fungal spore exposure on admission has not been examined.

Aim 

To investigate the role of outdoor fungal spores in child asthma hospitalisations and if HRV modifies any such effect.

Methods 

We conducted a case-crossover study of 644 child asthma hospitalisations in Melbourne, Australia (2009–11). On admission, participants had nasal and throat swabs that were tested using a sensitive nested multiplex PCR for HRV infection. Daily ambient spore counts of 14 fungi species were obtained using a Burkard Volumetric spore trap. Conditional logistic regression assessed the role of fungi adjusting for confounders. Interaction terms were included if there was evidence of effect modification from HRV. Results are presented as odds ratios [OR] per unit increase in daily number of fungi spores/m3 of air sampled.

Results 

Overall, higher risk of hospitalisation was observed when participants were exposed to Alternaria (OR=1.011, 95%CI 1.004-1.017), Coprinus (1.009, 1.000-1.017), Leptosphaeria (1.001, 1.000-1.013) independent of air pollution, HRV and sensitization to common allergens. There was evidence of effect modification by HRV in boys exposed to Leptosphaeria (1.028, 1.006-1.050) and Ganoderma (1.320, 1.048-1.660) . No evidence of HRV effect modification in girls.

Conclusion 

Some fungal genera are associated with increased risk of asthma hospitalisation in both sexes but the risk increased with two specific fungal genera in boys infected with HRV.
P15 Multiple defects of the immunoregulatory system contribute to the development of autoimmune hepatitis
Authors: P. Wang, M. S. Longhi, G. Mieli-Vergani, D. Vergani, Y. Ma
Journal: Gut (2011)

<h3>Introduction</h3> Concordance for autoimmune hepatitis (AIH) is rare within families, though non-hepatic autoimmune disorders are frequent among first degree relatives (FDR) of AIH patients. While a defect in immunoregulation has been demonstrated in AIH patients, the mechanism preventing the development of AIH in FDR, who share genetic background, remains to be elucidated. <h3>Aim</h3> To investigate multiple immunoregulatory systems in AIH patients and their FDR. <h3>Method</h3> 44 children with AIH (33 AIH-1 and 11 AIH-2, median age 13.5 yrs, 23 females), 65 FDR from 34 families [23 fathers, 47 yrs (38–58); 28 mothers, 44 yrs (24–53) and 14 siblings, 7 females, 13 yrs (5–24)] and 42 healthy subjects [HS, 36 yrs (22–54), 37 females] were studied. Frequency of conventional CD4<sup>pos</sup>CD25<sup>pos</sup> regulatory T-cells (Tregs), CD4<sup>pos</sup>CD25<sup>high</sup>CD127<sup>neg</sup> True Tregs, CD4<sup>pos</sup>PD-1<sup>pos</sup> and CD8<sup>pos</sup>CD28<sup>neg</sup> T cells, CD3<sup>neg</sup>CD56<sup>pos</sup> natural killer (NK) cells, CD3<sup>pos</sup>TCRVa24<sup>pos</sup>/TCRVb11<sup>pos</sup> invariant NKT cells (iNKT) was defined by flowcytometry. Tregs and CD4<sup>pos</sup>PD-1<sup>pos</sup> T cells were purified from PBMCs using immunomagnetic beads. CD25<sup>neg</sup> and PD-1<sup>neg</sup> cells (responders) were co-cultured for 5 days with cells with regulatory potential and their proliferation was measured by <sup>3</sup>H-thymidine incorporation. <h3>Results</h3> Conventional Tregs were lower in patients (10.5%±1.1) than FDR (15.9%±1.1, p=0.001) and HS (14.7%±1.7, p=0.04), while ‘True’ Tregs were similar in all (6.0%±0.6, 6.3%±0.4 and 6.2%±0.5). CD4<sup>pos</sup>PD-1<sup>pos</sup> T cells were lower in patients (1.7%±0.2) and in FDR (1.9%±0.2) than in HS (3.0%±0.2, p&lt;0.0001 for patients and p=0.0007 for FDR). NK cells were lower in patients (8.6%±1.2) than in FDR (15.8%±1.2, p=0.0004) and HS (12.3%±0.9, p=0.02). CD8<sup>pos</sup>CD28<sup>neg</sup> T cells in patients tended to be lower (8.8%±1.46) than in FDR (12.43%±1.56, p=0.18) and HS (13.1%±1.82, p=0.11). The frequency of iNKT cells was similar in all groups. ‘True’ Tregs decreased CD25<sup>neg</sup> cell proliferation by 13.6% in patients, 28.8% (p=0.007) in FDR and 36.9% (p&lt;0.0001) in HS, while CD4<sup>pos</sup>PD-1<sup>pos</sup> T cells decreased similarly PD-1<sup>neg</sup> cell proliferation in patients (25.4%), FDR (22.5%) and HS (26.8%). <h3>Conclusion</h3> A numerical impairment of CD4<sup>pos</sup>PD-1<sup>pos</sup> T cells in patients and their FDR suggests that these defects are genetically determined and account for family clustering of autoimmune disorders. A numerical impairment of conventional Tregs and functional impairment of CD4<sup>pos</sup>CD25<sup>high</sup>CD127<sup>neg</sup> ‘True’ Tregs, confined to patients with AIH, may be crucial to loss of liver tolerance.
Cost effectiveness of strategies to combat vision and hearing loss in sub-Saharan Africa and South East Asia: mathematical modelling study
Authors: R. Baltussen, A. Smith
Journal: BMJ (2012)

<b>Objective</b> To determine the relative costs, effects, and cost effectiveness of selected interventions to control cataract, trachoma, refractive error, hearing loss, meningitis and chronic otitis media. <b>Design</b> Cost effectiveness analysis of or combined strategies for controlling vision and hearing loss by means of a lifetime population model. <b>Setting</b> Two World Health Organization sub-regions of the world where vision and hearing loss are major burdens: sub-Saharan Africa and South East Asia. <b>Data sources</b> Biological and behavioural parameters from clinical and observational studies and population based surveys. Intervention effects and resource inputs based on published reports, expert opinion, and the WHO-CHOICE database. <b>Main outcome measures</b> Cost per disability adjusted life year (DALY) averted, expressed in international dollars ($Int) for the year 2005. <b>Results </b>Treatment of chronic otitis media, extracapsular cataract surgery, trichiasis surgery, treatment for meningitis, and annual screening of schoolchildren for refractive error are among the most cost effective interventions to control hearing and vision impairment, with the cost per DALY averted &lt;$Int285 in both regions. Screening of both schoolchildren (annually) and adults (every five years) for hearing loss costs around $Int1000 per DALY averted. These interventions can be considered highly cost effective. Mass treatment with azithromycin to control trachoma can be considered cost effective in the African but not the South East Asian sub-region. <b>Conclusions </b>Vision and hearing impairment control interventions are generally cost effective. To decide whether substantial investments in these interventions is warranted, this finding should be considered in relation to the economic attractiveness of other, existing or new, interventions in health.
The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Induces Apoptosis via Induction of 15-Lipoxygenase-1 in Colorectal Cancer Cells
Authors: Linda C. Hsi, Xiaopei Xi, Reuben Lotan, Imad Shureiqi, Scott M. Lippman
Journal: Cancer Research (2004)

Abstract Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression. HDACs are involved in cell cycle progression and differentiation, and their deregulation is associated with several cancers. HDAC inhibitors have emerged recently as promising chemotherapeutic agents. One such agent, suberoylanilide hydroxamic acid, is a potent inhibitor of HDACs that causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. Because of its low toxicity, suberoylanilide hydroxamic acid is currently in clinical trials for the treatment of cancer. HDAC inhibitors induce the expression of &amp;lt;2% of genes in cultured cells. In this study, we show that low micromolar concentrations of suberoylanilide hydroxamic acid induce the expression of 15-lipoxygenase-1 in human colorectal cancer cells. The expression of 15-lipoxygenase-1 correlates with suberoylanilide hydroxamic acid-induced increase in 13-S-hydroxyoctadecadienoic acid levels, growth inhibition, differentiation, and apoptosis observed with these cells. Furthermore, specific inhibition of 15-lipoxygenase-1 significantly reduced the suberoylanilide hydroxamic acid-induced effects. These novel findings are the first demonstration of a mechanistic link between the induction of 15-lipoxygenase-1 by a HDAC inhibitor and apoptosis in cancer cells. This result has important implications for the study of suberoylanilide hydroxamic acid and other HDAC inhibitors in the prevention and therapy of colorectal cancer and supports future investigations of the mechanisms by which HDAC inhibitors up-regulate 15-lipoxygenase-1.
Circulating Matrix Metalloproteinase-9 Levels as a Biomarker of Disease
Authors: Raquel F. Gerlach, Jose E. Tanus-Santos
Journal: Clinical Cancer Research (2005)

To the Editor: Nikkola et al. ([1][1]) have recently addressed the prognostic value of serum levels of matrix metalloproteinase 9 (MMP-9), collagenase 1, and collagenase 3 in patients with advanced melanoma. Specifically, the serum levels of MMP-9 were determined by ELISA, Western blot, and gelatin
Sympathetic neural modulation of cardiac impulse initiation and repolarization in the newborn rat.
Authors: G Malfatto, T S Rosen, S F Steinberg, P C Ursell, L S Sun, S Daniel, P Danilo, M R Rosen
Journal: Circulation Research (1990)

We injected neonatal rats with nerve growth factor, the antiserum to nerve growth factor, or placebo for the first 10 days of life. Our goal was to determine the relation between sympathetic innervation of the developing heart, the electrocardiographic expression of cardiac rhythm, and the response of the heart to alpha-adrenergic stimulation with phenylephrine. We were especially interested in the latter area because of the prior demonstration in isolated cell systems of sympathetic neural modulation of a 41-kDa GTP regulatory protein and alpha-adrenergic responsiveness. Ten- to 11-day-old rats treated with nerve growth factor had more complete sympathetic innervation, faster heart rates, and higher levels of the 41-kDa protein than the placebo group. Electrophysiological studies were performed on isolated ventricular septa superfused with Tyrode's solution at 37.0 degrees-37.5 degrees C. The electrophysiological response of septa to 10(-9) and 10(-8) M phenylephrine from the 10-11-day-old nerve growth factor group was comparable with that of 3-week-old control animals. In contrast, 10-11-day-old antiserum-treated rats had an abnormal innervation pattern, lower levels of the 41-kDa protein, and a more immature electrophysiological response to alpha-adrenergic stimulation than the placebo group. In addition, antiserum-treated rats had an abnormally prolonged electrocardiographic QT interval. Our results demonstrate for the first time in intact animals a direct link between sympathetic innervation and alpha-adrenergic receptor-effector coupling as well as the dependence on innervation of the modulation of impulse initiation by alpha-agonists. This sequence of developmental events may be important not only in the regulation of normal cardiac rhythm but also in the expression of certain pathological entities such as the congenital long QT syndrome and the sudden infant death syndrome.
Influence of Cardiac Autonomic Neuropathy on Heart Rate Dependence of Ventricular Repolarization in Diabetic Patients
Authors: Paul E. Valensi, Nicolas B. Johnson, Pierre Maison-Blanche, Fabrice Extramania, Gilbert Motte, Philippe Coumel
Journal: Diabetes Care (2002)

OBJECTIVE—Prolongation of the QT interval and increased QT dispersion are associated with a poor cardiac prognosis. The goal of this study was to assess the long-term influence of the autonomic nervous system on the heart rate dependence of ventricular repolarization in patients with diabetic autonomic neuropathy (DAN). RESEARCH DESIGN AND METHODS—We studied 27 subjects (mean age 51.8 years) divided into three age- and sex-matched groups: nine control subjects, nine diabetic subjects with DAN (mostly at a mild stage; DAN+), and nine diabetic subjects without DAN (DAN−). DAN was assessed on heart rate variations during standard maneuvers (Valsalva, deep-breathing, and lying-to-standing maneuvers). No subject had coronary artery disease or left ventricular dysfunction or hypertrophy, and no subject was taking any drugs known to prolong the QT interval. All subjects underwent electrocardiogram and 24-h Holter recordings for heart rate variations (time and frequency domain) and QT analysis (selective beat averaging QT/RR relation, nocturnal QT lengthening). RESULTS—Rate-corrected QT intervals (Bazett formula) did not differ significantly between the three groups. The diurnal and nocturnal levels of low frequency/high frequency, an index of sympathovagal balance, were significantly reduced in DAN+ subjects. Using the selective beat–averaging technique, a day-night modulation of the QT/RR relation was evidenced in control and DAN− subjects. This long-term modulation was significantly different in DAN+ subjects, with a reversed day-night pattern and an increased nocturnal QT rate dependence. CONCLUSIONS—In diabetic patients with mild parasympathetic denervation, QT heart rate dependence was found to be impaired, as determined by noninvasive assessment using Holter data. Analysis of ventricular repolarization could represent a sensitive index of the progression of neuropathy. The potential prognostic impact of a reversed day-night pattern with steep nocturnal QT/RR relation still remains to be defined.
Evolving general practice consultation in Britain: issues of length and context
Authors: G. K Freeman
Journal: BMJ (2002)

In 1999 Shah1 and others said that the Royal College of General Practitioners should advocate longer consultations in general practice as a matter of policy. The college set up a working group chaired by A P Hungin, and a systematic review of literature on consultation length in general practice was commissioned. The working group agreed that the available evidence would be hard to interpret without discussion of the changing context within which consultations now take place. For many years general practitioners and those who have surveyed patients' opinions in the United Kingdom have complained about short consultation time, despite a steady increase in actual mean length. Recently Mechanic pointed out that this is also true in the United States.2 Is there any justification for a further increase in mean time allocated per consultation in general practice?

We report on the outcome of extensive debate among a group of general practitioners with an interest in the process of care, with reference to the interim findings of the commissioned systematic review and our personal databases. The review identified 14 relevant papers.

#### Summary points

Longer consultations are associated with a range of better patient outcomes

Modern consultations in general practice deal with patients with more serious and chronic conditions

Increasing patient participation means more complex interaction, which demands extra time

Difficulties with access and with loss of continuity add to perceived stress and poor performance and lead to further pressure on time

Longer consultations should be a professional priority, combined with increased use of technology and more flexible practice management to maximise interpersonal continuity

Research on implementation is needed

The systematic review consistently showed that doctors with longer consultation times prescribe less and offer more advice on lifestyle and other health promoting activities. Longer consultations have been significantly associated with better recognition and …
Myocardial kinetics of technetium-99m teboroxime in the presence of postischemic injury, necrosis and low flow reperfusion
Authors: Rob S.B. Beanlands, Robert A. deKemp, Eef Harmsen, John P. Veinot, Neil G. Hartman, Terrence D. Ruddy
Journal: Journal of the American College of Cardiology (1996)
Diagnosis and management of cellulitis
Authors: G. Phoenix, S. Das, M. Joshi
Journal: BMJ (2012)

#### Summary points

Cellulitis is an acute, spreading, pyogenic inflammation of the lower dermis and associated subcutaneous tissue. It is a skin and soft tissue infection that results in high morbidity and severe financial costs to healthcare providers worldwide. Cellulitis is managed by several clinical specialists including primary care physicians, surgeons, general medics, and dermatologists. We assess the most recent evidence in the diagnosis and management of cellulitis.

#### Sources and selection criteria

We searched PubMed and the Cochrane library for recent and clinically relevant cohort studies and randomised controlled trials on cellulitis, using the search terms “cellulitis”, “erysipelas”, “diagnosis”, “investigation”, “recurrence”, “complications” and “management”. For position statements and guidelines we consulted the British Lymphology Society (BLS), National Health Service Clinical Knowledge Summaries (CKS), Clinical Resource Efficiency Support Team (CREST), and Infectious Disease Society of America (IDSA).

In 2008-9 there were 82 113 hospital admissions in England and Wales lasting a mean length of 7.2 days1; an estimated £133m (€170m; $209m) was spent on bed stay alone.2 Cellulitis accounted for 1.6% of emergency hospital admissions during 2008-9.3

In Australia, hospital admissions for cellulitis have risen to 11.5 people …
Investigation of Two Dosing Schedules of Vandetanib (ZD6474), an Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, in Combination with Irinotecan in a Human Colon Cancer Xenograft Model
Authors: Teresa Troiani, Natalie J. Serkova, Daniel L. Gustafson, Thomas K. Henthorn, Owen Lockerbie, Andrea Merz, Michael Long, Mark Morrow, Fortunato Ciardiello, S. Gail Eckhardt
Journal: Clinical Cancer Research (2007)

Abstract Purpose: This in vivo study was designed to determine the optimal doses and schedules of vandetanib, a dual epidermal growth factor receptor (EGFR)-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in combination with irinotecan in a murine xenograft model of human colon cancer. Experimental Design: HT-29 tumor-bearing nude mice were treated with two doses of vandetanib (12.5 and 25 mg/kg/d) with or without irinotecan (100 mg/kg) using either sequential or concurrent schedules for 30 days. Tumor size was measured using standard variables, whereas the antiangiogenic response was evaluated using dynamic contrast-enhanced magnetic resonance imaging. Additionally, effects on EGFR-dependent signal transduction pathways and proliferation were assessed using immunohistochemistry. These pharmacodynamic end points were then evaluated for associations with antitumor efficacy and/or to plasma/tumor concentrations of vandetanib. Results: The greatest antitumor efficacy was observed in the groups receiving the highest dose of vandetanib given continuously (concurrent schedule), alone or in combination with irinotecan. These dosing schedules resulted in significant effects on tumor vasculature, with decreased volume transfer constants, area under the curve, and permeability surface factor as well as increased gadolinium clearance after 30 days of treatment. In addition, these groups showed the greatest inhibition of EGFR signaling. Interestingly, tumor concentrations of vandetanib were increased by irinotecan in the concurrent schedule, possibly due to decreased tumor perfusion in this group. Conclusions: These data suggest that higher, sustained concentrations of vandetanib (versus intermittent), alone and in combination with irinotecan, result in optimal antitumor efficacy in this model and may have implications for the design of future clinical studies with this drug.
Family history of breast cancer and cost of life assurance: a test case comparison of current UK industry practice
Authors: A Hunter, S E Humphries
Journal: BMJ (2005)

Previous work has considered a relation of offspring sex ratio with time to pregnancy. 5A slightly reduced sex ratio was found in infertile couples (time to pregnancy > 1 year).Comparison with the current findings, however, is complicated by the fact that no adjustments or subdivisions were made for assisted reproduction and the prevalence of reported infertility in the study population was unusually high (18%).Contributors: LS had the idea for the study, analysed the statistics, and wrote the final manuscript.
N-Acetylcysteine potentiates inhibition of platelet aggregation by nitroglycerin.
Authors: J Loscalzo
Journal: Journal of Clinical Investigation (1985)

Platelet aggregation is currently felt to play an important role in the pathogenesis of ischemic vascular disorders. The smooth muscle relaxant, nitroglycerin, has been shown to inhibit platelet aggregation in vitro, but at concentrations that were felt to be unattainable in vivo. Because the in vivo action of nitroglycerin on smooth muscle cells has been shown to depend on the presence of reduced cytosolic sulfhydryl groups, the inhibitory effect of nitroglycerin on platelet aggregation was examined in the presence of the reduced thiol, N-acetylcysteine. Millimolar concentrations of N-acetylcysteine potentiated markedly the inhibitory effect of nitroglycerin on platelet aggregation induced by ADP, epinephrine, collagen, and arachidonate, decreasing the 50% inhibitory concentration (IC50) approximately 50-fold for each of these agents. Other guanylate cyclase activators inhibited ADP-induced aggregation similarly and this inhibition was likewise potentiated by N-acetylcysteine. Platelet guanosine 3',5'-cyclic monophosphate content increased fivefold in the presence of nitroglycerin and N-acetylcysteine 2 min before maximal inhibition of ADP-induced aggregation was achieved, while simultaneously measured cyclic AMP did not change relative to base-line levels. In the absence of N-acetylcysteine, nitroglycerin induced a marked decrease in platelet-reduced glutathione content as S-nitroso-thiol adducts were produced. The synthetic S-nitroso-thiol, S-nitroso-N-acetylcysteine, markedly inhibited platelet aggregation with an IC50 of 6 nM. These data show that N-acetylcysteine markedly potentiates the inhibition of platelet aggregation by nitroglycerin and likely does so by inducing the formation of an S-nitrosothiol adduct(s), which activate guanylate cyclase.
developmental systems, evolutionarily stable strategies, and population laterality
Authors: michael b. casey
Journal: Behavioral and Brain Sciences (2005)

multiple endogenous and exogenous prenatal influences interact to form a system that induces the development of individual lateralization across a range of perceptual and motor abilities in precocial birds. as these influences are nearly invariant for all species members, they produce a phylogenetic influence that creates high levels of population laterality and social cohesion in the postnatal state.