tbuckley/cabot-search huggingface dataset:
Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance
Authors: S. Dillon
Journal: Journal of Clinical Investigation (2006)

Emerging evidence suggests critical roles for APCs in suppressing immune responses. Here, we show that zymosan, a stimulus for TLR2 and dectin-1, regulates cytokine secretion in DCs and macrophages to induce immunological tolerance. First, zymosan induces DCs to secrete abundant IL-10 but little IL-6 and IL-12(p70). Induction of IL-10 is dependent on TLR2- and dectin-1–mediated activation of ERK MAPK via a mechanism independent of the activation protein 1 (AP-1) transcription factor c-Fos. Such DCs stimulate antigen-specific CD4+ T cells poorly due to IL-10 and the lack of IL-6. Second, zymosan induces F4-80+ macrophages in the splenic red pulp to secrete TGF-β. Consistent with these effects on APCs, injection of zymosan plus OVA into mice results in OVA-specific T cells that secrete little or no Th1 or Th2 cytokines, but secrete robust levels of IL-10, and are unresponsive to challenge with OVA plus adjuvant. Finally, coinjection of zymosan with OVA plus LPS suppresses the response to OVA via a mechanism dependent on IL-10, TGF-β, and lack of IL-6. Together, our data demonstrate that zymosan stimulates IL-10+IL-12(p70)–IL-6low regulatory DCs and TGF-β+ macrophages to induce immunological tolerance. These data suggest several targets for pharmacological modulation of immune responses in various clinical settings.
Invasive Pneumococcal Disease Among Infants Before and After Introduction of Pneumococcal Conjugate Vaccine
Authors: Katherine A. Poehling, Thomas R. Talbot, Marie R. Griffin, Allen S. Craig, Cynthia G. Whitney, Elizabeth Zell, Catherine A. Lexau, Ann R. Thomas, Lee H. Harrison, Arthur L. Reingold, James L. Hadler, Monica M. Farley, Bridget J. Anderson, William Schaffner
Journal: JAMA (2006)

Streptococcus pneumoniae is a serious infection in young infants. A heptavalent pneumococcal conjugate vaccine (PCV7) was licensed in 2000 and recommended for all children aged 2 to 23 months.To determine the rates of invasive pneumococcal disease (IPD) in young infants before and after PCV7 was incorporated into the childhood immunization schedule in June 2000.A prospective, population-based study of infants aged 0 to 90 days who resided in areas in 8 US states with active laboratory surveillance for invasive S pneumoniae infections from July 1, 1997, to June 30, 2004.Rates of laboratory-confirmed IPD before (July 1, 1997-June 30, 2000) and after (July 1, 2001-June 30, 2004) PCV7 introduction, excluding a transition year (July 1, 2000-June 30, 2001).There were 146 cases of IPD, 89 before and 57 after PCV7 introduction. Isolated bacteremia occurred in 94 cases (64%), pneumonia in 27 (18%), meningitis in 22 (15%), and septic arthritis and/or osteomyelitis in 3 (2%). Mean rates of IPD for infants aged 0 to 90 days decreased 40% from 11.8 (95% confidence interval [CI], 9.6-14.5) to 7.2 (95% CI, 5.6-9.4; P = .004) per 100 000 live births following PCV7 introduction. Among black infants, mean rates of IPD decreased significantly from 17.1 (95% CI, 11.9-24.6) to 5.3 (95% CI, 2.8-10.1; P = .001) per 100,000 live births, with a nonsignificant decrease from 9.6 (95% CI, 7.3-12.7) to 6.8 (95% CI, 4.9-9.4) per 100,000 live births for white infants. Rates of PCV7-serotype isolates decreased significantly from 7.3 (95% CI, 5.3-10.1) to 2.4 (95% CI, 1.6-3.8; P<.001) per 100,000 live births, while rates of non-PCV7 serotypes remained stable (P = .55).Since PCV7 introduction, rates of IPD in young infants have decreased significantly, providing evidence that vaccinating children aged 2 to 23 months has led to changes in pneumococcal carriage in infants too young to receive PCV7. With a significant decrease in rates of IPD among black infants, the previous racial difference has been eliminated.
5-Fluorouracil, Doxorubicin, and Mitomycin (FAM) Combination Chemotherapy for Advanced Gastric Cancer
Authors: JOHN S. MACDONALD
Journal: Annals of Internal Medicine (1980)

Sixty-two patients with advanced measurable gastric cancer were treated with a combination chemotherapy program of 5-fluorouracil, doxorubicin, and mitomycin (FAM). Forty-two percent of patients achieved an objective partial response. The median duration of remission was 9 months and the median survival for responding patients, 12.5 months. The median survival for nonresponding patients was 3.5 months; all patients were dead by 8 months after initiation of therapy. The median survival of all 62 patients treated with FAM was 5.5 months. An analysis of possible prognostic variables including initial performance status, resectability of the primary gastric tumor, and histologic differentiation of the neoplasm failed to account for differences in patient response and survival. The FAM regimen was well tolerated, producing only moderate bone marrow suppression. These results show that patients with metastatic gastric cancer can be effectively palliated with FAM chemotherapy. The efficacy of this regimen should now be tested in patients with less advanced stages of this disease.
Defects in Macrophage Recruitment and Host Defense in Mice Lacking the CCR2 Chemokine Receptor
Authors: Takao Kurihara, Glenn Warr, James Loy, Rodrigo Bravo
Journal: The Journal of Experimental Medicine (1997)

Chemokines are a structurally related family of cytokines that are important for leukocyte trafficking. The C-C chemokine monocyte chemoattractant protein-1 (MCP-1) is a potent monocyte activator in vitro and has been associated with monocytic infiltration in several inflammatory diseases. One C-C chemokine receptor, CCR2, has been identified that mediates in vitro responses to MCP-1 and its close structural homologues. CCR2 has also recently been demonstrated to be a fusion cofactor for several HIV isolates. To investigate the normal physiological function of CCR2, we generated mice with a targeted disruption of the ccr2 gene. Mice deficient for CCR2 developed normally and had no hematopoietic abnormalities. However, ccr2(-/-) mice failed to recruit macrophages in an experimental peritoneal inflammation model. In addition, these mice were unable to clear infection by the intracellular bacteria, Listeria monocytogenes. These results suggest that CCR2 has a nonredundant role as a major mediator of macrophage recruitment and host defense against bacterial pathogens and that MCP-1 and other CCR2 ligands are effectors of those functions.
Platelet-activating factor and the release of a platelet-derived coronary artery vasodilator substance in the canine.
Authors: C V Jackson, W A Schumacher, S L Kunkel, E M Driscoll, B R Lucchesi
Journal: Circulation Research (1986)

Platelet-activating factor (acetyl-glyceryl-ether-phosphorylcholine; 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphorylcholine), which is released by stimulated neutrophils and platelets, possesses the ability to alter vascular tone and permeability and to activate various formed blood elements. We have characterized the hemodynamic effects of intracoronary injections of platelet-activating factor and the influences of pharmacological blockade and platelet depletion on its activity. Intracoronary injections of platelet-activating factor produced maximum increases in left circumflex coronary artery blood flow of 55 +/- 8, 52 +/- 8, and 52 +/- 7 ml/min at 0.5, 1.0, and 2.0 nM, respectively. Only modest changes in systemic arterial blood pressure and regional developed isometric contractile force were associated with the intracoronary artery administration of platelet-activating factor over the range of doses studied. The increase in left circumflex coronary artery blood flow in response to platelet-activating factor was attenuated (44%), but not prevented, by pretreatment with diphenhydramine, (4 mg/kg, iv), and was not affected by pretreatment with aspirin (20 mg/kg, iv) or the systemic administration of the serotonin receptor antagonist, methysergide. The coronary vasodilator response to platelet-activating factor was reduced significantly by the induction of thrombocytopenia (95 +/- 3% platelet depletion) through the administration of sheep-derived canine platelet antiserum. The intracoronary artery injection of platelet-rich plasma activated with platelet-activating factor into thrombocytopenic dogs produced a significantly greater increase in coronary artery blood flow than the injection of either non-activated platelet-rich plasma or platelet-depleted plasma to which platelet-activating factor was added. Similar changes in coronary artery blood flow could be obtained with the intracoronary artery injection of cell-free supernates from washed platelets activated with platelet-activating factor. The observed results suggest that circulating platelets, when exposed to platelet-activating factor, can release a coronary dilator substance, and that the coronary artery dilation is not prevented by pharmacological receptor antagonists for histamine, serotonin, or inhibitors of cyclooxygenase.
Brain Natriuretic Peptide Enhances Renal Actions of Furosemide and Suppresses Furosemide-Induced Aldosterone Activation in Experimental Heart Failure
Authors: Alessandro Cataliotti, Guido Boerrigter, Lisa C. Costello-Boerrigter, John A. Schirger, Toshihiro Tsuruda, Denise M. Heublein, Horng H. Chen, Lorenzo S. Malatino, John C. Burnett
Journal: Circulation (2004)

Background— The renal actions of brain natriuretic peptide (BNP) in congestive heart failure (CHF) are associated with increased diuresis and natriuresis, preserved glomerular filtration rate (GFR), and lack of activation of the renin-angiotensin-aldosterone system (RAAS). In contrast, diuretic-induced natriuresis may be associated with reduced GFR and RAAS activation. The objective of this study was to test the hypothesis that exogenous BNP enhances the renal diuretic and natriuretic actions of furosemide (Fs) and retards the activation of aldosterone in a model of CHF. Methods and Results— CHF was produced in 2 groups of dogs by ventricular pacing. One group received continuous (90-minute) intravenous Fs (1 mg · kg −1 · h −1 ). A second group (Fs+BNP) received 45-minute intravenous coinfusion of Fs (1 mg · kg −1 · h −1 ) and low-dose (2 pmol · kg −1 · min −1 ) BNP followed by 45-minute coinfusion of Fs (1 mg · kg −1 · h −1 ) and high-dose (10 pmol · kg −1 · min −1 ) BNP. Fs increased urinary flow, but the effect of Fs+BNP was greater. Similarly, urinary sodium excretion was higher in the Fs+BNP group. Although GFR tended to decrease in the Fs group, it increased in the Fs+BNP group (35±3 to 56±4*) (* indicates P &lt;0.05 versus baseline) ( P &lt;0.0001 between groups). Plasma aldosterone increased with Fs (41±10 to 100±11* ng/dL) but was attenuated in the Fs+BNP group (44±11 to 54±9 ng/dL low-dose and to 47±7 ng/dL high-dose) ( P =0.0007 between groups). Conclusions— Fs+BNP has more profound diuretic and natriuretic responses than Fs alone and also increases GFR without activation of aldosterone. Coadministration of BNP and loop diuretic is effective in maximizing natriuresis and diuresis while preserving renal function and inhibiting activation of aldosterone.
Management of the Difficult Airway in Children
Authors: Robert W M Walker
Journal: Journal of the Royal Society of Medicine (2001)

Airway management and endotracheal intubation in children usually present no difficulties for the experienced anaesthetist. In infants, access may be slightly more problematic because of certain anatomical variations: the tongue is large relative to the mandible and the larynx is more cephalad than in the older child. In infants below the age of four months the epiglottis is at the level of the first cervical vertebra; at six months it has moved down to the level of the third cervical vertebra. Unlike the epiglottis in adults, the epiglottis in infants is hard and narrow and is folded into an inverted U shape. These features together give rise to what many people refer to as the ‘anterior larynx’, but in fact are just due to the relative macroglossia and the higher placement of the larynx. The anatomical variations between infants, children and adults should be easily overcome by use of straight-bladed laryngoscopes which can pick up the epiglottis and reveal the larynx.

The children who present major difficulties for the anaesthetist are not easily missed. In this paper I focus on congenital causes. Others are retropharyngeal abscess, burns, trauma and Still's disease.
Heterogeneous Patterns of Gene-Expression Diversification in Mammalian Gene Duplicates
Authors: D. Farre, M. M. Alba
Journal: Molecular Biology and Evolution (2009)

Gene duplication is a major mechanism for molecular evolutionary innovation. Young gene duplicates typically exhibit elevated rates of protein evolution and, according to a number of recent studies, increased expression divergence. However, the nature of these changes is still poorly understood. To gain novel insights into the functional consequences of gene duplication, we have undertaken an in-depth analysis of a large data set of gene families containing primate- and/or rodent-specific gene duplicates. We have found a clear tendency toward an increase in protein, promoter, and expression divergence with increasing number of duplication events undergone by each gene since the human–mouse split. In addition, gene duplication is significantly associated with a reduction in expression breadth and intensity. Interestingly, it is possible to identify three main groups regarding the evolution of gene expression following gene duplication. The first group, which comprises around 25% of the families, shows patterns compatible with tissue-expression partitioning. The second and largest group, comprising 33–53% of the families, shows broad expression of one of the gene copies and reduced, overlapping, expression of the other copy or copies. This can be attributed, in most cases, to loss of expression in several tissues of one or more gene copies. Finally, a substantial number of families, 19–35%, maintain a very high level of tissue-expression overlap (>0.8) after tens of millions of years of evolution. These families may have been subject to selection for increased gene dosage.
Factors Associated With Remission From Alcohol Dependence in an American Indian Community Group
Authors: David A. Gilder, Philip Lau, Linda Corey, Cindy L. Ehlers
Journal: American Journal of Psychiatry (2008)

This study identified factors associated with remission from DSM-III-R alcohol dependence in an American Indian community group.Participants were assessed by using the Semi-Structured Assessment for the Genetics of Alcoholism.Five hundred eighty participants were assessed for alcohol use and alcohol use symptoms; 254 participants were found to have alcohol dependence. The rate of remission in this group was 59%. Thirty-four percent of remitters and 39% of nonremitters had received treatment for alcohol problems. Remission from alcohol dependence was associated with being female, older, and married; an earlier age of onset of alcohol dependence; and self-reported depression symptoms from drinking. Absence of remission was associated with continuing to drink despite knowing one had medical problems from drinking and self-reported anxiety symptoms from drinking.Attention to factors associated with remission from alcohol dependence may be important in designing more effective treatment and prevention programs in this high-risk population.
Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care
Authors: J. R. Feary, L. C. Rodrigues, C. J. Smith, R. B. Hubbard, J. E. Gibson
Journal: Thorax (2010)

Comorbidities associated with systemic inflammation including cardiovascular disease (CVD), stroke and diabetes mellitus (DM) are common among individuals with chronic obstructive pulmonary disease (COPD). A study was undertaken to quantify the burden of comorbidity and to determine the risk of first acute arteriovascular events among individuals with COPD.The computerised primary care records of 1,204,100 members of the general population aged ≥ 35 years on 25 February 2005 were searched for recordings of each disease. Data were analysed using multivariate logistic regression. Cox regression was used to determine whether individuals with COPD were at increased risk of acute myocardial infarction (MI) and stroke.Cross-sectional analyses showed that physician-diagnosed COPD was associated with increased risks of CVD (OR 4.98, 95% CI 4.85 to 5.81; p<0.001), stroke (OR 3.34, 95% CI 3.21 to 3.48; p<0.001) and DM (OR 2.04, 95% CI 1.97 to 2.12; p<0.001). In the follow-up analyses, after adjusting for confounding by sex and smoking status and stratifying for age, the greatest increase in the rate of acute arteriovascular events was found in the youngest age groups; the HR for acute MI was 10.34 (95% CI 3.28 to 32.60; p<0.001) and for stroke the HR was 3.44 (95% CI 0.85 to 13.84; p<0.001) compared with the oldest age group.Individuals with COPD are substantially more likely to have pre-existing CVD, DM or a previous stroke and are at high risk of acute arteriovascular events. National COPD guidelines and models of care need to adapt to provide an integrated approach to addressing these comorbidities.
A randomized clinical trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients
Authors: Sylvie Naveau, Gilles Pelletier, Thierry Poynard, Pierre Attali, Alain Poitrine, Catherine Buffet, Jean-Pierre Etienne, Jean-Claude Chaput
Journal: Hepatology (1986)

Between March 1982 and September 1983, 40 inpatients (25 men and 15 women, mean age 53 years) with alcoholic cirrhosis and total serum bilirubin ≥5 mg per dl were studied. Those with hepatocellular carcinoma, renal failure, hyponatremia, septicemia, spontaneous bacterial peritonitis, gastrointestinal bleeding, and hepatic coma were excluded. Patients were studied for 28 days. The two groups were offered an oral diet containing 40 kcal per kg per day. Patients in the supplementary parenteral nutrition group received 40 kcal per kg per day and 200 mg nitrogen per kg per day using a central catheter. The major endpoint was total serum bilirubin on Day 28. On admission, serum bilirubin was not significantly different in the two groups: oral group, 12.5 ± 6.6 mg per dl; supplementary parenteral nutrition group, 12.3 ± 8.5 mg per dl. On Day 28, serum bilirubin was lower in the supplementary parenteral nutrition group (2.5 ± 1.4 mg per dl) than in the oral group (4.1 ± 2.2 mg per dl) (p &lt; 0.02). Serum bilirubin was also lower in the supplementary parenteral nutrition group than in the oral group on Days 7, 14and 21 (p &lt; 0.05). Analysis of covariance, considering serum bilirubin on admission and at randomization and time between admission and randomization, confirmed these results. On Day 28, anthropometric parameters, serum transferrin, prealbumin and retinol–binding protein were higherin the supplementary parenteral nutrition group, but the differences were not significant. Serum albumin was significantly lower in the supplementary parenteral nutrition group. The incidence of encephalopathy and sepsis was not significantly different between the two groups.
Changes in B-Type Natriuretic Peptide and BMI Following Roux-en-Y Gastric Bypass Surgery
Authors: Annis M. Marney, Nancy J. Brown, Robyn Tamboli, Naji Abumrad
Journal: Diabetes Care (2014)

Obesity and attendant complications including type 2 diabetes mellitus, hypertension (HTN), and heart disease are worldwide epidemics with incompletely understood associations. Mechanisms underlying the association of HTN and obesity include upregulation of the renin-angiotensin-aldosterone system, sympathetic nervous system, insulin resistance, and adipose tissue activity, but a paradoxically downregulated cardiac natriuretic peptide system, cardiovascular system, and altered renal function (1). Recent studies suggest that natriuretic peptide deficiency may provide a link between obesity-related HTN and insulin resistance (2). Weight loss through bariatric surgery has reduced or eliminated HTN in multiple randomized controlled trials, perhaps through decreased plasma volume, but other mechanisms including changes in the cardiac natriuretic peptide system and lipolysis remain obscure (3). Understanding natriuretic peptide concentration changes following Roux-en-Y gastric bypass (RYGB) surgery may help elucidate the mechanism and impact of paradoxically low concentrations in obesity. We characterized changes in B-type natriuretic peptide (BNP) and N-telopeptide pro-BNP …
Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice
Authors: Jin Hu, Chia-Chen Liu, Xiao-Fen Chen, Yun-wu Zhang, Huaxi Xu, Guojun Bu
Journal: Molecular Neurodegeneration (2015)

Human apolipoprotein E (apoE) exists in three major isoforms: apoE2, apoE3 and apoE4. In the brain, apoE is produced mostly by astrocytes and transports cholesterol to neurons via apoE receptors. Among the gene alleles encoding the three isoforms, the APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), whereas APOE2 is protective. ApoE4 confers a gain of toxic function, a loss of neuroprotective function or a combination of both in AD pathogenesis. Given that therapeutic impacts of modulating apoE expression may be isoform-dependent, we sought to investigate the relationship between overexpressing apoE isoform and apoE-related functions in apoE-targeted replacement (TR) mice. Specifically, apoE isoform expression driven by the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter was built into an adeno-associated virus serotype 8 (AAV8) vector and injected into the ventricles of postnatal day 2 (P2) apoE3-TR or apoE4-TR mice. Upon confirmation of apoE isoform expression, effects on apoE lipidation and the levels of amyloid-β (Aβ) in the brain were assessed. AAV8-GFAP-apoE isoforms were specifically expressed in astrocytes throughout all brain regions, which led to overall increased apoE levels in the brain. Viral mediated overexpression of apoE4 in the apoE4-TR background increased poorly-lipidated apoE lipoprotein particles and decreased apoE-associated cholesterol in apoE4-TR mice. Conversely, apoE2 overexpression in apoE4-TR mice enhanced apoE lipidation and associated cholesterol. Furthermore, overexpression of apoE4 elevated the levels of endogenous Aβ, whereas apoE2 overexpression trended to lower endogenous Aβ. Overexpression of apoE isoforms induces differential effects in the apoE4-TR background: apoE4 decreases apoE lipidation and enhances Aβ accumulation, whereas apoE2 has the opposite effects. Our findings suggest that increasing apoE2 in APOE4 carriers is a beneficial strategy to treat AD, whereas increasing apoE4 in APOE4 carriers is likely harmful. We have also established novel methods to express apoE isoforms in mouse brain to study apoE-related pathways in AD and related dementia.