tbuckley/cabot-search huggingface dataset:
Peak expiratory flow changes during experimental rhinovirus infection
Authors: PG Bardin, DJ Fraenkel, G Sanderson, EM van Schalkwyk, ST Holgate, SL Johnston
Journal: European Respiratory Journal (2000)

Rhinovirus (RV) colds are associated with asthma exacerbations and experimental infections are commonly used to investigate the mechanisms involved. However, a temporal association between experimental RV infections and falls in peak expiratory flow (PEF) have not been demonstrated. PEF was measured in 22 volunteers (11 normal, five atopic, six atopic asthmatic) who developed RV serotype 16 colds after inoculation. PEF was measured twice daily for 2 weeks prior and 6 weeks after RV infection and episodes of respiratory morbidity based on changes in PEF were defined using validated criteria. Six significant reductions in PEF were temporally related to the RV infections (in two (18%) normal, one (20%) atopic, three (50%) atopic asthmatic subjects, p=0.1) and occurred 4-9 days (median 6) after inoculation. Mean+/-SEM PEF at day 6 was 87.8+/-1.8% of the predicted value in the six subjects with reductions versus 99.4+/-1.4% pred in those without (p=0.01). Symptom scores were significantly different at day 6 in the two groups (10.6+/-1.9 versus 6.8+/-1.0, p=0.03), but no differences were noted in the viral culture scores and changes in nasal albumin. In subjects with significant PEF reduction, the decrease in the provocative concentration causing a 20% fall in the forced expiratory volume in one second (FEV1) (PC20) was 1.7+/-1.3 mg x mL(-1) versus 1.2+/-1.1 mg x mL(-1) in the negative group (p=0.06). The degree of seroconversion to RV was significantly higher in the group with reduced PEF (median change dilutions 8 versus 4, p=0.02). The results of the present study suggest that rhinovirus-associated, respiratory morbidity occurs during experimental infection in some but not all normal and asthmatic subjects and also that experimental colds are a valid model for the study of rhinovirus-associated airway symptoms and asthma exacerbations.
Bryostatin-5 Blocks Stromal Cell–Derived Factor-1 Induced Chemotaxis via Desensitization and Down-regulation of Cell Surface CXCR4 Receptors
Authors: Xing He, Liyan Fang, Jue Wang, Yanghua Yi, Shuyu Zhang, Xin Xie
Journal: Cancer Research (2008)

The chemokine receptor CXCR4 and its ligand, stromal cell-derived factor-1 (SDF-1), play important roles in hematopoiesis regulation, lymphocyte activation, and trafficking, as well as in developmental processes, including organogenesis, vascularization, and embryogenesis. The receptor is also involved in HIV infection and tumor growth and metastasis. Antagonists of CXCR4 have been widely evaluated for drugs against HIV and tumors. In an effort to identify novel CXCR4 antagonists, we screened a small library of compounds derived from marine organisms and found bryostatin-5, which potently inhibits chemotaxis induced by SDF-1 in Jurkat cells. Bryostatin-5 is a member of the macrolactones, and its analogue bryostatin-1 is currently being evaluated in clinical trials for its chemotherapeutic potential. The involvement of bryostatins in the SDF-1/CXCR4 signaling process has never been reported. In this study, we found that bryostatin-5 potently inhibits SDF-1-induced chemotaxis but does not affect serum-induced chemotaxis. Further studies indicate that this inhibitory effect is not due to receptor antagonism but rather to bryostatin-5-induced receptor desensitization and down-regulation of cell surface CXCR4. We also show that these effects are mediated by the activation of conventional protein kinase C.
Monoclonal antibodies and synthetic peptides define the active site of Fc<sub>ε</sub>RI and a potential receptor antagonist
Authors: L. J. Rigby, H. Trist, J. Snider, M. D. Hulett, P. M. Hogarth, L. J. Rigby, V. C. Epa
Journal: Allergy (2000)

Defining the structure of the human high-affinity receptor for IgE, Fc,RI, is crucial to understand the receptor:ligand interaction, and to develop drugs to prevent IgE-dependent allergic diseases. To this end, a series of four anti-FcepsilonRI monoclonal antibodies (mAbs), including three new mAbs, 47, 54, and 3B4, were used in conjunction with synthetic FcepsilonRI peptides to define functional regions of the Fc IgE-binding site and identify an antagonist of IgE binding. The spatial orientation of the epitopes detected by these antibodies and their relationship to the IgE-binding region of FcepsilonRI was defined by a homology model based on the closely related FcepsilonRIIa. Using recombinant soluble FcRI-alpha as well as FcepsilonRI-alpha expressed on the cell surface, a series of direct and competitive binding experiments indicated that the mAbs detected nonoverlapping epitopes. One antibody (15-1), previously thought to be located close to the IgE-binding site, was precisely mapped to a single loop within the IgE-binding site by both mutagenesis and overlapping synthetic peptides encompassing the entire extracellular domain. A synthetic peptide epsilonRI-11, containing the amino acids 101-120 and the mAb 15-1 epitope, inhibited IgE binding and may form the basis for the development of a useful receptor-based therapy.
P348Impaired macrophage polarization in endoglin haplo-insufficiency leading to defective tissue repair is recovered by counter balance the TGFbeta pathway
Authors: W Bakker, CKE Dingenouts, K Lodder, MR De Vries, HJ Mager, RJ Snijder, CJ Westerman, P Dijke, PH Quax, MJTH Goumans
Journal: Cardiovascular Research (2014)

Introduction: Endoglin is a co-receptor of Transforming Growth Factorβ (TGFβ) and is crucial for the formation of new blood vessels. Endoglin-haploinsuffiency is the leading cause of the severe vascular disease Hereditary hemorrhagic telangiectasia 1 (HHT-1). The aim of this study is to investigate whether endoglin haplo-insufficiency impairs macrophage polarization towards a regenerative phenotype to induce angiogenesis and tissue repair in ischemic disease. Materials and Methods: HHT-1 was studied in Eng+/- mice and in HHT-1 patients with endoglin mutation. In Eng+/- and Eng+/+ mice, angiogenesis and tissue repair were studied by the induction of hindlimb ischemia, myocardial infarction or in matrigel plugs. Macrophage phenotypes were screened after a differentiation assay in-vitro after stimulation with GM-CSF or in tissue sections with immuno-histochemistry. Results: Angiogenic capacity was impaired in Eng+/- mice, which was associated by the infiltration of macrophages. Ischemic muscle or heart sections of Eng+/- mice showed prolonged inflammation 7 days postischemia. We can explain this by an extended polarization of bone marrow-derived monocytes (BMM) from Eng+/- mice towards pro-inflammatory macrophage (CD11b+/LY6Chi/CD206-) at the expense of regenerative macrophages. In addition, stimulation of macrophages with TGFβ resulted in the polarization of the more regenerative phenotype only in WT BMM-cultures. This TGFβ response was blunted in macrophages from Eng+/- mice, but we were able to rescue it by the inhibition of the Bone Morphogenetic Protein (BMP)-pathway (by LDN-193189). Subsequently, LDN also improved blood flow recovery and myocardial function in Eng+/- mice after hind limb ischemia and MI, respectively. Interestingly, blood monocytes from HHT-1 patients show increased number of CD14+/CD16+ monocytes, which is associated with pro-inflammatory/non-regenerative phenotype. Discussion and Conclusions: Endoglin haplo-insufficiency results in defective tissue repair due to impaired polarization of regenerative macrophages, directed by TGFβ. The defective responses were rescued by the inhibition of another TGFβ familiy member, BMP, and thereby counterbalance its pathway. These results have major implications for the treatment of HHT-1 patients, as we show the same impaired macrophage polarization.
Health Consequences of Contraceptive Use and Reproductive Patterns
Authors: Julie DaVanzo, Allan M. Parnell, William H. Foege
Journal: JAMA (1991)

THERE has been widespread support by governments and international donors for family planning to provide people with a means to achieve the number of children they desire and reduce unwanted pregnancy, to contribute to slower population growth and more rapid economic development, and to improve the health of women and children. The health rationale is increasingly being used to organize program activities and argue for more resources. However, there has been concern about the safety of the contraceptive methods women use to control their fertility. At the request of the US Agency for International Development, and through its support, as well as support from the Rockefeller Foundation and the William and Flora Hewlett Foundation, the National Research Council's Committee on Population appointed the Working Group on the Health Consequences of Contraceptive Use and Controlled Fertility to assess the scientific evidence of the health risks and benefits of contraceptive methods and
Ocular and Optic Nerve Hemorrhages in Abused Infants with Intracranial Injuries
Authors: Donald L. Budenz, Martha G. Farber, Haresh G. Mirchandani, Hydow Park, Lucy B. Rorke
Journal: Ophthalmology (1994)

Purpose: To ascertain whether the pathology of the eye and optic nerve might be useful in determining the manner of death in infants who died after sustaining apparent nonaccidental intracranial injury.Methods: Complete autopsies were performed on 13 infants who died of acute intracranial injuries after nonaccidental trauma.The infants were divided into two groups: nine with physical evidence of blunt trauma to the head, and four without detectable scalp or skull injury whose intracranial injuries were attributed to violent shaking (shaken baby syndrome).Six infants with no intracranial injuries who died suddenly from unidentifiable causes (the so-called sudden infant death syndrome) served as controls.Results: Optic nerve sheath hemorrhage, most prominent in the subdural space, was present in all 13 infants with nonaccidental intracranial injury.Multilayered retinal hemorrhage was present in at least one eye of 11 of these 13 infants.The location and quantity of the intraocular and optic nerve sheath hemorrhages did not differ in those with external head trauma and those without scalp or skull lesions.A single control infant had a few erythrocytes in the nerve fiber layer of the anterior optic nerve of one eye.The remainder of the control infants did not have evidence of hemorrhage in the eye or optic nerve sheath.Conclusion: Histopathologic analysis of optic nerve sheath and intraocular hemorrhages may be helpful in distinguishing traumatic from non-traumatic causes of death in infants.
Acute and chronic immunological response to dietary antigen.
Authors: P J Gallagher, N J Goulding, M J Gibney, D B Jones, J Morgan
Journal: Gut (1983)

On separate mornings at 14 day intervals groups of six to eight healthy fasting male volunteers drank a 5.5 MJ test meal containing 20% milk, egg or soya protein, or a control protein free preparation. Using a Clq binding test, marked but transient rises in circulating immune complexes were detected 30-120 minutes after the milk and egg meals but not with soya or the control. No such changes were seen when complexes were measured by Raji cell immunoassay. Food antigen specific antibodies were present in the plasma of all subjects but showed no consistent pattern of variation in the postprandial period. In most volunteers a chronic increase in milk (three weeks) or soya (six weeks) consumption produced no changes in circulating immune complexes or antibodies to dietary protein. Although two of 16 milk and six of 52 soya volunteers had substantial rises of one or more classes of plasma food antigen specific antibodies they were matched by a similar number in which a decrease was recorded. These results indicate that the formation of circulating immune complexes may be a physiological response to a large load of dietary antigen but that in most adults a chronic increase of milk or soya consumption does not affect food antibody or immune complex concentrations.
Minor Ailments of the Feet--II
Authors: N. C. Lake
Journal: BMJ (1951)

Hallux ValgusHallux valgus is a very common cause of disability in the feet.Except in certain congenital cases, when the deformity may affect the interphalangeal instead of Fio.5.-Extreme degree of hallux valgus.The splaying of the feet and the rotation of the great toe are well shown.
Points from Letters: Registrable Qualifications
Authors: N. Marsden
Journal: BMJ (1975)

vogue in the future should Parliament as at present constituted beconme too unwieldy to function effectively.Moreover, the medical profession would be freer to set up and supervise what mtust surely come, and that is a body of aware persons to interview at regular intervals all persons in paid authority above a certain level of responsibility, in- cluding doctors, lawyers, M.P.s, teachers, etc., regairding their continuing suitability to hold such authority.Under the pro- fession's present subservience to politics this would be difficult to implement, if at all."What shall it profit a man if he shall gain the whole world and lose his own soul?"And as a profession we are in grave danger of doing just that.-I am, etc.,
Food Fortification to Prevent Neural Tube Defects
Authors: James L. Mills, Lucinda England
Journal: JAMA (2001)

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Human suicide: a biological perspective
Authors: Denys deCatanzaro
Journal: Behavioral and Brain Sciences (1980)

Abstract Human suicide presents a fundamental problem for the scientific analysis of behavior. This problem has been neither appreciated nor confronted by research and theory. Almost all other behavior exhibited by humans and nonhumans can be viewed as supporting the behaving organism's biological fitness and advancing the welfare of its genes. Yet suicide acts against these ends, and does so more directly and unequivocally than any other form of maladaptive behavior. Four heuristic models are presented here to account for suicide in an evolutionary and sociobiological framework. The first model attributes suicide to the extraordinary development of learning and cultural evolution in the human species. Learning may make human behavior so independent of biological constraints that it can occasionally assume a form entirely contrary to the principles of biological evolution. The second model attributes suicide to a breakdown of adaptive mechanisms in extremely stressful novel environments. The third model involves kin and group selection, arguing that in limited circumstances suicide may occur because of beneficial effects it has on other, surviving individuals who share the suicidal individual's genes. The last model suggests that suicide should be tolerated by evolution when it has no effect on the gene pool. This model holds particular promise in accounting for aspects of suicide not attributable to culture. The evidence indicates that suicide is most common in individuals who are unlikely to reproduce and unable to engage in productive activity; such individuals are least capable of promoting their genes. A complete explanation of suicide may derive only from an analysis of its biological significance.
84. Assessing Hemostatic Efficacy of Continuous Expression of Factor VIIa after AAV-Mediated, Liver-Directed Gene Transfer in Hemophilia A and B Mice
Authors: Alexander Schlachterman, Paris Margaritis, Majed Aljamali, Jianhua Liu, Valder Arruda, Katherine High
Journal: Molecular Therapy (2005)

We have shown that portal vein infusion of an AAV vector expressing an engineered secreted activated murine factor VIIa (mFVIIa) results in long-term phenotypic correction of murine hemophilia B (HB) mice, as judged by shortening of the prothrombin time (PT), activated partial thromboplastin time (aPTT), and the tail-clip bleeding time (J Clin Invest. 2004; 113: 1025). We sought to compare endpoints for hemostasis in hemophilia A and B mice infused with AAV-mFVIIa, analyzing VIIa levels, the tail-clip assay, the FeCl3-carotid artery model, and real-time imaging of clot formation utilizing the cremasteric muscle arteriole. Twenty-two (N=22) Hemophilia A (HA) and forty-eight (N=48) HB mice were injected with AAV-mFVIIa via the portal vein at doses ranging from 1.0|[times]|10^8 to 4.8|[times]|10^12 vg/mouse. Based on a PT assay we observed a dose response with circulating VIIa levels ranging from 11 ng/ml for the untreated and the lowest dose to 1000 ng/ml for the higher doses. In HB mice (N=15) injected at 1.2|[times]|10^12 vg/mouse, the mean PT shortened from 23 to 17 sec, and the aPTT from 86 to 43 seconds, 8 weeks post vector injection. Measurement of the blood loss post tail-clip was documented as a statistically significant reduction in blood loss in HB AAV-mFVIIa-treated mice (N=5) relative to the untreated HB mice (N=10) * [P-value  25ug/kg), animals developed complete, albeit transient, occlusion, but neither FVIIa protein (>90ug/kg) nor AAV-mFVIIa mice exhibited formation of an occlusive thrombus in HB mice. Similar results have been obtained in hemophilia A mice. Together these data suggest that 1) AAV-mFVIIa is functional in supporting hemostasis as judged by in vitro coagulation assays and by some but not all in vivo hemostasis challenges; and 2) results in these hemostasis assays may vary as a function of the diameter of the vessel that is injured. Which of these endpoints most faithfully reflects hemostasis in humans is not yet clear, but the major morbidity of hemophilia is from joint bleeds which likely begin as bleeding in the microcirculation. Our studies provide clear evidence of improvement of in vivo hemostasis and support continuous expression of FVIIa as an alternative strategy for the treatment of hemophilia.
Tissue factor pathway inhibitor-2 as a frequently silenced tumor suppressor gene in hepatocellular carcinoma
Authors: Chun‐Ming Wong, Yeung‐Lam Ng, Joyce Man‐Fong Lee, Carmen Chak‐Lui Wong, Oi‐Fung Cheung, Chung‐Yiu Chan, Edmund Kwok‐Kwan Tung, Yick‐Pang Ching, Irene Oi‐Lin Ng
Journal: Hepatology (2007)

In HCC, inactivation of tumor suppressor genes plays a significant role in carcinogenesis. Apart from deletions and mutations, growing evidence has indicated that epigenetic alterations including aberrant promoter methylation and histone deacetylation are also implicated in inactivation of tumor suppressor genes. The goal of this study was to identify epigenetically silenced candidate tumor suppressor genes in human HCC by comparing the changes in oligonucleotide microarray gene expression profiles in HCC cell lines upon pharmacological treatment with the demethylating agent 5-Aza-2′-deoxycytidine (5-Aza-dC). By analyzing the gene expression profiles, we selected tissue factor pathway inhibitor-2 (TFPI-2), a Kunitz-type serine protease inhibitor, for validation and further characterization. Our results showed that TFPI-2 was frequently silenced in human HCC and HCC cell lines. TFPI-2 was significantly underexpressed in approximately 90% of primary HCCs when compared with their corresponding nontumorous livers. TFPI-2 promoter methylation was detected in 80% of HCC cell lines and 47% of human HCCs and was accompanied by reduced TFPI-2 messenger RNA expression. In addition, TFPI-2 expression in HCC cell lines can be robustly restored by combined treatment with 5-Aza-dC and histone deacetylase inhibitor trichostatin A. These findings indicate that TFPI-2 is frequently silenced in human HCC via epigenetic alterations, including promoter methylation and histone deacetylation. Moreover, ectopic overexpression of TFPI-2 significantly suppressed the proliferation and invasiveness of HCC cells. Conclusion: Our findings suggest that TFPI-2 is a candidate tumor suppressor gene in human HCC. (HEPATOLOGY 2007;45:1129–1138.)
Medical corruption in the UK
Authors: F. Godlee
Journal: BMJ (2015)

Last year The BMJ launched an international campaign against corruption in healthcare. A single article was the spark: a personal view about the endemic culture of kickbacks to doctors in India (doi:10.1136/bmj.g3169). The campaign received widespread support from Indian doctors and the media, and it seems to have led to some positive change, if not yet enough. In an unprecedented move India’s then health minister acknowledged that corruption was a big problem. The government set up a special committee and has banned gifts to doctors and conference sponsorship by drug companies. The Indian Medical Association is working on a new code of medical ethics for private hospitals. And the Medical …
Linkage and association of HLA class II genes with vitiligo in a Dutch population
Authors: M. Zamani, M. Spaepen, S.S. Sghar, C. Huang, W. Westerhof, L. Nieuweboer-Krobotova, J.J. Cassiman
Journal: British Journal of Dermatology (2001)

Serological typing of HLA has shown discrepancies in HLA associations with vitiligo in different ethnic populations.To perform genotyping of HLA class II genes on a Dutch vitiligo population in order clearly to identify susceptible and protective HLA alleles in vitiligo.HLA typing was carried out by amplifying genomic DNA by polymerase chain reaction (PCR) followed by dot-blot hybridization with sequence-specific oligonucleotides (SSO). Fifty Dutch vitiligo probands, and their parents (150 individuals) and 204 healthy controls were studied.Family-based case-control association studies and linkage disequilibrium analysis showed the linkage and association of DRB4*0101 allele with vitiligo (P(c) = 0.0016, relative risk = 2.21). The family-based association study also provided evidence for linkage and association of DQB1*0303 allele with vitiligo (chi(2) = 7.36, P = 0.006). We measured the clinical relevance of the test by calculating the prevalence corrected positive predictive values (PcPPV). The PcPPV of disease for the DRB4*0101 allele was 0.017 and for the DRB4*0101/0101 genotype was 0.0358. In other words, a DRB4*0101/0101 genotype carries a 3.58% risk of developing vitiligo.Both DRB4*0101 and DQB1*0303 alleles provide significant susceptibility for vitiligo.