tbuckley/cabot-search huggingface dataset:
Probiotics in primary prevention of allergic disease - follow-up at 8-9 years of age
Authors: C. E. West, M.-L. Hammarström, O. Hernell
Journal: Allergy (2013)

Background Long-term effects of probiotics in primary prevention of allergic disease need further evaluation. We previously reported a reduced cumulative incidence of infant eczema by feeding Lactobacillus paracasei ssp paracasei F19 (LF19) during weaning. Therefore, we assessed effects of LF19 on the prevalence of allergic disease at school age. Methods In a double-blind placebo-controlled trial infants were randomized to daily intake of cereals with (n = 89) or without LF19 108 CFU (n = 90) from 4–13 months of age. At age 8–9, we evaluated the prevalence of allergic disease (eczema, allergic rhinitis, asthma, and food allergy) by clinical examination and validated questionnaires. IgE sensitization was assessed by skin prick test (inhalant allergens) and specific IgE levels (food allergens). Lung function was evaluated by a spirometry reversibility test. Fractional exhaled nitric oxide (FENO) was measured. Results Of 171 children that completed the intervention, 121 were assessed at age 8–9. In the probiotic group, 15/59 (25%) were diagnosed with any allergic disease vs 22/62 (35%) in the placebo group [OR (95% CI) 0.62 (0.28–1.36)]. Corresponding numbers for IgE-associated allergic disease were 9/53 (17%) vs 12/59 (20%) [0.80 (0.31–2.09)]. Median (25th-75th percentile) FENO was 9 (8–12) in the probiotic vs 8 (7–12) ppb in the placebo group (P > 0.05). There was no effect of LF19 on lung function measures (P > 0.05). Conclusions There was no long-term effect of LF19 on any diagnosed allergic disease, airway inflammation or IgE sensitization. This suggests delayed eczema onset but to fully examine long-term benefits a larger study population had been needed.
Morphological and cell kinetic effects of dietary manipulation during colorectal carcinogenesis.
Authors: D J Galloway, F Jarrett, P Boyle, M Indran, K Carr, R W Owen, W D George
Journal: Gut (1987)

The effect of dietary manipulation of fat and fibre on the structural and cell kinetic characteristics of colonic mucosa was studied before and during experimental carcinogenesis in 232 male Albino Swiss rats. Carcinogen treated animals were given 12 weekly injections of azoxymethane (10 mg/kg/week). The animals were divided between four dietary groups (1) high fat, high fibre, (2) low fat, high fibre, (3) high fat, low fibre and (4) low fat, low fibre. Pathological and cell kinetic information together with details of certain faecal characteristics was collected when the animals were killed 4, 20, and 28 weeks after starting their experimental diet. Tumour induction was significantly influenced by diet. The highest risk of colorectal tumour development was found in groups fed diet 3: high fat, low fibre (p less than 0.03). In contrast, diet 2: low fat, high fibre was associated with the lowest risk. The proportion of histologically proven colonic tumours occurring in each dietary group was: diet 1-10.9%, diet 2-3.6%, diet 3-63.7%, diet 4-21.8%. Scanning electron microscopic (SEM) studies done on selected samples indicated both dietary and azoxymethane related alterations in crypt unit integrity. The most marked surface architectural changes were seen in carcinogen treated animals maintained on diet 3 (high fat, low fibre). Stathmokinetic analysis revealed considerable intergroup variability. Both fat and fibre produced significant effects, principally during the preneoplastic phase of carcinogenesis. Faster proliferative activity tended to be found in animals at low risk of tumour induction (diet 2), slower proliferation being more characteristic of animals at high risk (p less than 0.05). The findings suggest that both topographical and cell kinetic parameters have an important relationship with promoting and protecting dietary factors during the development of colorectal cancer.
A homeostatic function of CXCR2 signalling in articular cartilage
Authors: Joanna Sherwood, Jessica Bertrand, Giovanna Nalesso, Blandine Poulet, Andrew Pitsillides, Laura Brandolini, Alexandra Karystinou, Cosimo De Bari, Frank P Luyten, Costantino Pitzalis, Thomas Pap, Francesco Dell'Accio
Journal: Annals of the Rheumatic Diseases (2014)

ELR+ CXC chemokines are heparin-binding cytokines signalling through the CXCR1 and CXCR2 receptors. ELR+ CXC chemokines have been associated with inflammatory arthritis due to their capacity to attract inflammatory cells. Here, we describe an unsuspected physiological function of these molecules in articular cartilage homeostasis.Chemokine receptors and ligands were detected by immunohistochemistry, western blotting and RT-PCR. Osteoarthritis was induced in wild-type and CXCR2(-/-) mice by destabilisation of the medial meniscus (DMM). CXCR1/2 signalling was inhibited in vitro using blocking antibodies or siRNA. Chondrocyte phenotype was analysed using Alcian blue staining, RT-PCR and western blotting. AKT phosphorylation and SOX9 expression were upregulated using constitutively active AKT or SOX9 plasmids. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay.CXCL6 was expressed in healthy cartilage and was retained through binding to heparan sulfate proteoglycans. CXCR2(-/-) mice developed more severe osteoarthritis than wild types following DMM, with increased chondrocyte apoptosis. Disruption of CXCR1/2 in human and CXCR2 signalling in mouse chondrocytes led to a decrease in extracellular matrix production, reduced expression of chondrocyte differentiation markers and increased chondrocyte apoptosis. CXCR2-dependent chondrocyte homeostasis was mediated by AKT signalling since forced expression of constitutively active AKT rescued the expression of phenotypic markers and the apoptosis induced by CXCR2 blockade.Our study demonstrates an important physiological role for CXCR1/2 signalling in maintaining cartilage homeostasis and suggests that the loss of ELR+ CXC chemokines during cartilage breakdown in osteoarthritis contributes to the characteristic loss of chondrocyte phenotypic stability.
Aldose Reductase Gene Polymorphisms and Diabetic Retinopathy Susceptibility
Authors: Sotoodeh Abhary, Kathryn P. Burdon, Kate J. Laurie, Stacey Thorpe, John Landers, Lucy Goold, Stewart Lake, Nikolai Petrovsky, Jamie E. Craig
Journal: Diabetes Care (2010)

OBJECTIVE Aldose reductase (ALR) is involved in diabetic microvascular damage via the polyol pathway. A recent meta-analysis found genetic variation in the ALR gene (AKR1B1) to be significantly associated with diabetic retinopathy (DR). We investigated the genetic association of AKR1B1 with DR. RESEARCH DESIGN AND METHODS The study enrolled 909 individuals with diabetes. Participants were genotyped for an AKR1B1 (CA)n microsatellite and 14 tag single nucleotide polymorphisms, and ophthalmological assessment was performed. RESULTS A total of 514 individuals were found to have DR. rs9640883 was significantly associated with DR (P = 0.0005). However, AKR1B1 variation was not independently associated with DR development after adjusting for relevant clinical parameters. rs9640883 was associated with duration of diabetes (P = 0.002). CONCLUSION Many previous reports have failed to account for known risk factors for DR. The commonly reported association of AKR1B1 with DR may be due to an association of the gene with younger age at onset of diabetes.
Mycobacterial infection in HIV seropositive and seronegative populations, 1987-93.
Authors: I K Taylor, D J Evans, R J Coker, D M Mitchell, R J Shaw
Journal: Thorax (1995)

Although the causes of the worldwide resurgence of tuberculosis are multifactorial, the HIV epidemic is believed to have had a central role. Control is further threatened by the emergence of multidrug-resistant tuberculosis.A retrospective evaluation was undertaken of trends in pulmonary and extrapulmonary culture positive mycobacterial pathology, and the prevalence of drug-resistant tuberculosis in both HIV seropositive and, presumptively, HIV seronegative patients receiving their clinical care at St Mary's Hospital, London. Five hundred and thirty eight patients (188 of whom were known to be HIV seropositive) with positive mycobacterial isolates between January 1987 and March 1993 were identified from laboratory records. These were cross referenced with drug surveillance records.Overall, between 1987 and 1992 there was a progressive 3.5 fold increase in positive mycobacterial isolates and a 2.5 fold increase in patients with proven mycobacterial infection. This increase was greater within the HIV seropositive population. A total of 663 positive mycobacterial isolates was evaluated; the major pathogen identified was Mycobacterium tuberculosis (379 isolates, 57%). Three hundred and fourteen patients were diagnosed as having M tuberculosis, 49 of whom were HIV seropositive. M tuberculosis was predominantly isolated from the lung. Of 358 positive cultures for M tuberculosis (68 HIV seropositive, 290 presumptively HIV seronegative), only 27 isolates (7.6%), almost exclusively derived from presumed HIV seronegative patients, were resistant to either isoniazid, rifampicin, or both drugs together. No increases in drug-resistant isolates were observed over this period.There has been a considerable increase in the incidence of tuberculosis in both HIV seronegative and seropositive populations during the study period. The emergence of drug-resistant tuberculosis was not observed.
Human Melanoma Metastasis in NSG Mice Correlates with Clinical Outcome in Patients
Authors: Elsa Quintana, Elena Piskounova, Mark Shackleton, Daniel Weinberg, Ugur Eskiocak, Douglas R. Fullen, Timothy M. Johnson, Sean J. Morrison
Journal: Science Translational Medicine (2012)

Studies of human cancer metastasis have been limited by a lack of experimental assays in which cancer cells from patients metastasize in vivo in a way that correlates with clinical outcome. This makes it impossible to study intrinsic differences in the metastatic properties of cancers from different patients. We recently developed an assay in which human melanomas readily engraft in nonobese diabetic/severe combined immunodeficient interleukin-2 receptor-γ chain null (NSG) mice. We show that melanomas from 25 patients exhibited reproducible differences in the rate of spontaneous metastasis after transplantation into NSG mice and that these differences correlated with clinical outcome in the patients. Stage IIIB/C melanomas that formed distant metastases within 22 months in patients also formed tumors that metastasized widely in NSG mice, whereas stage IIIB/C melanomas that did not form distant metastases within 22 to 50 months in patients metastasized more slowly in NSG mice. These differences in the efficiency of metastasis correlated with the presence of circulating melanoma cells in the blood of NSG mice, suggesting that the rate of entry into the blood is one factor that limits the rate of metastasis. The study of NSG mice can therefore yield information about the metastasis of human melanomas in vivo, in this case revealing intrinsic differences among stage III melanomas in their ability to circulate/survive in the blood and to metastasize.
Pneumothorax secondary to septic pulmonary emboli in tricuspid endocarditis.
Authors: J E Corzo, F Lozano de Leon, J Gomez-Mateos, L Lopez-Cortes, R Vazquez, F Garcia-Bragado
Journal: Thorax (1992)

Two cases of pneumothorax secondary to pulmonary septic infarctions occurred in the course of tricuspid endocarditis in intravenous drug misusers. This unusual complication must be considered in patients with right sided endocarditis who develop pleuritic chest pain, haemoptysis, or breathlessness.
Reduced baroreflex sensitivity with volume loading in conscious dogs.
Authors: S F Vatner, D H Boettcher, G R Heyndrickx, R J McRitchie
Journal: Circulation Research (1975)

The Bainbridge reflex, i.e., the effect of rapid saline infusion (1.1 +/- 0.1 liters) on heart rate and arterial and atrial blood pressures, was examined in 12 intact conscious dogs; mean arterial blood pressure rose by 33 +/- 3 (SE) mm Hg, mean atrial pressure by 14 +/- 1 mm Hg, and heart rate by 75 +/- 9 beats/min. After beta-receptor blockade, heart rate rose slightly less (+49 +/- 5 beats/min, P = 0.05). Cholinergic blockade, combined cholinergic and beta-receptor, or beta-receptor blockade after vagotomy blocked the heart rate response to the infusion. The rise in heart rate in the face of an increase in arterial blood pressure with volume loading suggested that the arterial baroreceptor reflex was not responding appropriately to the increase in arterial blood pressure. In conscious dogs after denervation of the arterial baroreceptors, the increase in heart rate with volume loading was no greater than that in those dogs with their arterial baroreceptors intact, suggesting that the baroreceptor reflex was not restraining heart rate in the normal response to volume loading. The relationship between the pulse interval (PI) and the systolic arterial blood pressure (SAP) following an intravenous injection of methoxamine was used to evaluate the sensitivity of the baroreceptor reflex in intact conscious dogs. After a mild amount of volume loading, when atrial pressure was 8 +/- 2 mm Hg, the PI/SAP slope was significantly depressed from normal. When atrial pressure was elevated further to 28 +/- 1 mm Hg by volume loading, the slope was further depressed. Thus, arterial baroreflex sensitivity is reduced progressively as atrial pressure is raised by volume loading, an observation that explains how heart rate can rise strikingly in the face of an elevated arterial blood pressure.
T-cell regulation of antibody responses: demonstration of allotype-specific helper T cells and their specific removal by suppressor T cells.
Authors: L A Herzenberg, K Okumura, H Cantor, V L Sato, F W Shen, E A Boyse, L A Herzenberg
Journal: The Journal of Experimental Medicine (1976)

Allotype suppressor T cells (Ts) generated in SJL X BALB/c mice specifically suppress production of antibodies marked with the Ig-1a allotype. The studies presented here show that allotypes Ts suppress by specifically removing helper T cell (Th) activity required to facilitate differentiation and expansion of B cells to Ig-1b antibody-forming cells. We show first that Ts and Th belong to different T-cell subclasses as defined by Ly surface antigens. Ts are Ly2+Lyl- and thus belong to the same subclass as cytotoxic precursor and effector cells; Th are Lyl+Ly2- cells and thus belong to the subclass containing cells which can exert helper functions and initiate delayed hypersensitivity reactions. Placing these cells in these two subclasses shows that Th are different from Ts and suggests that they play different roles in regulating antibody responses. The difference in these roles is defined by the evidence presented here showing that Ts attack Th and regulate the antibody response by specifically regulating the availability of Th activity. We show that in allotype suppressed mice, Ts which suppress Ig-1b antibody production have completely removed the Th activity of helping Ig-1b cells without impairing Th activity which helps other IgB B cells. These findings imply the existence of allotype-specific Th for Ig-1b cells (Ig-1b Th). We directly establish that Ig-1b cells require such help by showing that carrier-primed spleen cells from Iga/Iga congenic hybrids help Ig-1a B cells from hapten-primed Igb/Iga donors but do not help Ig-1b B cells from the same donor in the same adoptive recipient.
PKC-θ knockout mice are protected from fat-induced insulin resistance
Authors: Jason K. Kim, Jonathan J. Fillmore, Mary Jean Sunshine, Bjoern Albrecht, Takamasa Higashimori, Dong-Wook Kim, Zhen-Xiang Liu, Timothy J. Soos, Gary W. Cline, William R. O’Brien, Dan R. Littman, Gerald I. Shulman
Journal: Journal of Clinical Investigation (2004)

Insulin resistance plays a primary role in the development of type 2 diabetes and may be related to alterations in fat metabolism. Recent studies have suggested that local accumulation of fat metabolites inside skeletal muscle may activate a serine kinase cascade involving protein kinase C–θ (PKC-θ), leading to defects in insulin signaling and glucose transport in skeletal muscle. To test this hypothesis, we examined whether mice with inactivation of PKC-θ are protected from fat-induced insulin resistance in skeletal muscle. Skeletal muscle and hepatic insulin action as assessed during hyperinsulinemic-euglycemic clamps did not differ between WT and PKC-θ KO mice following saline infusion. A 5-hour lipid infusion decreased insulin-stimulated skeletal muscle glucose uptake in the WT mice that was associated with 40–50% decreases in insulin-stimulated tyrosine phosphorylation of insulin receptor substrate–1 (IRS-1) and IRS-1–associated PI3K activity. In contrast, PKC-θ inactivation prevented fat-induced defects in insulin signaling and glucose transport in skeletal muscle. In conclusion, our findings demonstrate that PKC-θ is a crucial component mediating fat-induced insulin resistance in skeletal muscle and suggest that PKC-θ is a potential therapeutic target for the treatment of type 2 diabetes.
NCOA1 Directly Targets <i>M-CSF1</i> Expression to Promote Breast Cancer Metastasis
Authors: Li Qin, Ye-Lin Wu, Michael J. Toneff, Dabing Li, Lan Liao, Xiuhua Gao, Fiona T. Bane, Jean C.-Y. Tien, Yixiang Xu, Zhen Feng, Zhihui Yang, Yan Xu, Sarah M. Theissen, Yi Li, Leonie Young, Jianming Xu
Journal: Cancer Research (2014)

Abstract In breast cancer, overexpression of the nuclear coactivator NCOA1 (SRC-1) is associated with disease recurrence and resistance to endocrine therapy. To examine the impact of NCOA1 overexpression on morphogenesis and carcinogenesis in the mammary gland (MG), we generated MMTV-hNCOA1 transgenic [Tg(NCOA1)] mice. In the context of two distinct transgenic models of breast cancer, NCOA1 overexpression did not affect the morphology or tumor-forming capability of MG epithelial cells. However, NCOA1 overexpression increased the number of circulating breast cancer cells and the efficiency of lung metastasis. Mechanistic investigations showed that NCOA1 and c-Fos were recruited to a functional AP-1 site in the macrophage attractant CSF1 promoter, directly upregulating colony-simulating factor 1 (CSF1) expression to enhance macrophage recruitment and metastasis. Conversely, silencing NCOA1 reduced CSF1 expression and decreased macrophage recruitment and breast cancer cell metastasis. In a cohort of 453 human breast tumors, NCOA1 and CSF1 levels correlated positively with disease recurrence, higher tumor grade, and poor prognosis. Together, our results define an NCOA1/AP-1/CSF1 regulatory axis that promotes breast cancer metastasis, offering a novel therapeutic target for impeding this process. Cancer Res; 74(13); 3477–88. ©2014 AACR.
Choriocarcinoma with lung metastases during pregnancy with successful delivery and outcome after chemotherapy.
Authors: J Nabers, T A Splinter, H C Wallenburg, F J ten Kate, R Oosterom, C Hilvering
Journal: Thorax (1990)

A patient with an intrauterine pregnancy of 27 weeks had a coexisting pulmonary metastatic choriocarcinoma. On the chest radiograph the lung metastases appeared as pulmonary infiltrates, simulating atypical pneumonia. Serum human chorionic gonadotrophin levels were normal for gestational age. Treatment with methotrexate was successful. This is the first reported case of choriocarcinoma in a woman with a pregnancy of less than 35 weeks in which both mother and child survived. The case emphasises the need to consider choriocarcinoma in any pregnant woman who presents with haemoptysis and pulmonary nodules or infiltrates.
Troponin I gene expression during human cardiac development and in end-stage heart failure.
Authors: S Sasse, N J Brand, P Kyprianou, G K Dhoot, R Wade, M Arai, M Periasamy, M H Yacoub, P J Barton
Journal: Circulation Research (1993)

Recent reports have demonstrated the presence of two isoforms of troponin I in the human fetal heart, namely, cardiac troponin I and slow skeletal muscle troponin I. Structural and physiological considerations indicate that these isoforms would confer differing contractile properties on the myocardium, particularly on the phosphorylation-mediated regulation of contractility by adrenergic agonists. We have investigated the developmental expression of these isoforms in the human heart from 9 weeks of gestation to 9 months of postnatal life, using Western blots revealed with troponin I antibodies to detect troponin protein isoforms and Northern blots to detect the corresponding mRNAs. The results show the following: 1) Slow skeletal muscle troponin I is the predominant isoform throughout fetal life. 2) After birth, the slow skeletal isoform is lost, with cardiac troponin I being the only isoform detectable by 9 months of postnatal development. 3) The protein isoforms and their corresponding mRNAs follow the same pattern of accumulation, suggesting that the transition in troponin expression is regulated at the level of gene transcription. The developmental transition in troponin I isoform content has implications for contractility of the fetal and postnatal myocardium. We further analyzed right and left ventricular muscle samples from 17 hearts in end-stage heart failure resulting from pulmonary hypertension, ischemic heart disease, or dilated cardiomyopathy. Cardiac troponin I mRNA remained abundant in each case, and slow skeletal muscle troponin I mRNA was not detectable in any of sample. We conclude that alterations in troponin I isoform content do not therefore contribute to the altered contractile characteristics of the adult failing ventricle.
Cardiac Events in Patients Undergoing Noncardiac Surgery: Shifting the Paradigm from Noninvasive Risk Stratification to Therapy
Authors: Paul A. Grayburn, L David Hillis
Journal: Annals of Internal Medicine (2003)

Internists and cardiologists are often asked to estimate the risk for perioperative myocardial infarction or cardiac death in patients being considered for noncardiac surgery. Estimating this risk in an individual patient is difficult and complex. Although noninvasive imaging tests are often used for this purpose, a review of the literature reveals that the positive predictive value of noninvasive imaging tests is uniformly low and that they do not provide information beyond that obtained by assessing simple clinical risk variables. Moreover, no evidence exists that noninvasive imaging tests lead to a therapeutic strategy that reduces the risk for perioperative myocardial infarction or cardiac death. Since the publication of guidelines for preoperative risk stratification by the American College of Cardiology/American Heart Association in 1996 and the American College of Physicians in 1997, three clinical trials have shown that -blocker therapy reduces the risk for perioperative cardiac events. This paper focuses on the relationship between risk stratification and subsequent therapy to minimize or eliminate risk. In short, the paradigm is shifting from predicting which patient is at high risk for having a perioperative cardiac event to minimizing the likelihood of such an event with specific perioperative pharmacologic therapy.