tbuckley/cabot-search huggingface dataset:
Mobilization of potent plasma bactericidal activity during systemic bacterial challenge. Role of group IIA phospholipase A2.
Authors: Y Weinrauch, C Abad, N S Liang, S F Lowry, J Weiss
Journal: Journal of Clinical Investigation (1998)

Extracellular mobilization of Group IIA 14-kD phospholipase A2 (PLA2) in glycogen-induced rabbit inflammatory peritoneal exudates is responsible for the potent bactericidal activity of the inflammatory fluid toward Staphylococcus aureus (1996. J. Clin. Invest. 97:250-257). Because similar levels of PLA2 are induced in plasma during systemic inflammation, we have tested whether this gives rise to plasma bactericidal activity not present in resting animals. Baboons were injected intravenously (i.v.) with a lethal dose of Escherichia coli and plasma or serum was collected before and at hourly intervals after injection. After infusion of bacteria, PLA2 levels in plasma and serum rose > 100-fold over 24 h to approximately 1 microg PLA2/ml. Serum collected at 24 h possessed potent bactericidal activity toward S. aureus, Streptococcus pyogenes, and encapsulated E. coli not exhibited by serum collected from unchallenged animals. Bactericidal activity toward S. aureus and S. pyogenes was nearly completely blocked by a monoclonal antibody to human Group IIA PLA2 and addition of purified human Group IIA PLA2 to prechallenge serum conferred potent antistaphylococcal and antistreptococcal activity equal to that of the 24 h post-challenge serum. PLA2-dependent bactericidal activity was enhanced approximately 10x by factor(s) present constitutively in serum or plasma. Bactericidal activity toward encapsulated E. coli was accompanied by extensive bacterial phospholipid degradation mediated, at least in part, by the mobilized Group IIA PLA2 but depended on the action of other bactericidal factors in the 24-h serum. These findings further demonstrate the contribution of Group IIA PLA2 to the antibacterial potency of biological fluids and suggest that mobilization of this enzyme during inflammation may play an important role in host defense against invading bacteria.
Use of Earth-Observing Satellite Data Helps Predict, Prevent Disease Outbreaks
Authors: Bridget M. Kuehn
Journal: JAMA (2010)

Months before the first human case of Rift Valley fever was identified in Kenya in December 2006, scientists studying satellite data predicted that the Horn of Africa would soon suffer a large outbreak of the viral disease, which can ravage livestock populations and cause severe illness in humans.
OC-119 Mechanistic randomised control trial of mesalazine in symptomatic diverticular disease: Abstract OC-119 Table 1
Authors: J Smith, D Humes, K Garsed, C Lam, A Zaitoun, A Bennett, J Scholefield, R Spiller
Journal: Gut (2012)

<h3>Introduction</h3> Painful symptomatic diverticular disease (SDD) is a common but poorly understood condition. Approximately 20% of patients with diverticulosis complain of pain, but there are currently no effective treatments. We have previously reported peripheral immune activation and alteration in colonic nerve function in SDD. <h3>Aims</h3> To test the significance of this immune activation by performing the first parallel design, double blind, randomised placebo controlled trial of an anti-inflammatory drug, mesalazine in SDD. <h3>Methods</h3> Patients with confirmed SDD underwent an unprepared flexible sigmoidoscopy and biopsies at baseline and after 12 weeks treatment, completing diaries of pain and bowel habit. They were randomised to receive 3 g per day of mesalazine (M) or identical placebo (P) for 12 weeks with follow-up visits at 2 &amp; 4 weeks. RNA from sigmoid biopsies was analysed using a custom made gene card. Gene expression and changes in symptoms were assessed between baseline and final visits using Wilcoxon signed-rank test. <h3>Results</h3> 43 volunteers were recruited (F:M; 24:19), but 11 withdrew during the study resulting in 18 and 14 participants in the P and M groups respectively. M significantly reduced important inflammatory and pain genes including those involved in response to bacterial ligands (Abstract OC-119 table 1), changes not seen with P. M but not P significantly reduced the duration of abdominal pain (Median (range) (hrs/day) P group Pre 1.0 (0–5), Post 0.65 (0–4) p0.1919; M Group Pre 3.0 (0–20), Post 0.125 (0–5.5) p0.0413). <h3>Conclusion</h3> This pilot study suggests that mesalazine significantly alters many of the pathways mediating immune activation by bacteria thought to contribute to pain in SDD and may provide benefit for patients. However further larger studies are required to confirm these mechanisms and efficacy of mesalazine in this group. <h3>Competing interests</h3> J Smith grant/research support from: Wellcome Trust Training Fellowship, Conflict with: £17 000 Gift from Dr Falk Pharma for manufacture of medication for the study, D Humes: None declared, K Garsed: None declared, C Lam: None declared, A Zaitoun: None declared, A Bennett: None declared, J Scholefield: None declared, R Spiller: None declared.
All older people should be guaranteed basic level of care
Authors: Michael Day
Journal: BMJ (2006)

The controversial policy of means testing elderly people who need long term care must end, says a new report. Under radical proposals set out by Sir Derek Wanless, the number of people in England required to sell their homes to pay for personal care would be slashed—but at a price.

Sir Derek, who produced the 2002 Treasury report calling for a massive rise in NHS funding, now advocates a near doubling of social care spending over the next 20 years, from 1.1% …
Role of Protoplasts in Pathogenesis of Pyelonephritis
Authors: George M. Kalmanson, Lucien B. Guze
Journal: JAMA (1964)

The present experiments were designed to study the host-parasite-drug relationship in "protoplast" infection. Protoplasts are a form of bacteria characterized by loss of cell wall and consequent increased osmotic fragility. Because of this, protoplasts are not readily cultured on standard bacteriological media unless precautions are taken to osmotically stabilize the media. Protoplasts were isolated from renal tissue, following apparent cure of experimental pyelonephritis. Ureteral ligation, dehydration, or mannitol-induced diuresis did not cause exacerbation of protoplast infection. Erythromycin, an inhibitor of protein synthesis, while ineffective against the bacterial form of infection was successful in killing protoplasts in vivo.
Acromegaly and Galactorrhea-Amenorrhea with Two Pituitary Adenomas Secreting Growth Hormone or Prolactin
Authors: GEORGE TOLIS
Journal: Annals of Internal Medicine (1978)

A prolactinoma was removed from a nulliparous woman who had acromegaly, galactorrhea-amenorrhea, elevated serum growth hormone and prolactin, and hypogonadotropinism. Postoperatively galactorrhea decreased and cyclic vaginal bleeding ensued; serum prolactin concentration was normal but growth hormone remained elevated and the acromegalic complex was unchanged, even after subsequently administered bromocriptine. At a second transsphenoidal operation, an adenoma of somatotropes was removed; improvement in symptoms and signs and normalisation of pituitary function, including growth hormone, followed. The possible presence of distinctly separate pituitary adenomas should be considered in patients with galactorrhea associated with acromegaly.
Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners.
Authors: E Leitersdorf, D R Van der Westhuyzen, G A Coetzee, H H Hobbs
Journal: Journal of Clinical Investigation (1989)

Familial hypercholesterolemia (FH), an autosomal dominant disease caused by mutations in the LDL receptor gene, is five times more frequent in the Afrikaner population of South Africa than it is in the population of the United States and Europe. It has been proposed that the high frequency is due to a founder effect. In this paper, we characterized 24 mutant LDL receptor alleles from 12 Afrikaner individuals homozygous for FH. We identified two mutations that together makeup greater than 95% of the mutant LDL receptor genes represented in our sample. Both mutations were basepair substitutions that result in single-amino acid changes. Each mutation can be detected readily with the polymerase chain reaction and restriction analysis. The finding of two common LDL receptor mutations in the Afrikaner FH homozygotes predicts that these mutations will predominate in the Afrikaner population and that the high frequency of FH is due to a founder effect. The increased incidence of ischemic heart disease in the Afrikaner population may in part be due to the high frequency of these two mutations in the LDL receptor gene.
Clinimetrics and Clinical Psychometrics: Macro- and Micro-Analysis
Authors: Elena Tomba, Per Bech
Journal: Psychotherapy and Psychosomatics (2012)

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Clinimetrics was introduced three decades ago to specify the domain of clinical markers in clinical medicine (indexes or rating scales). In this perspective, clinical validity is the platform for selecting the various indexes or rating scales (macro-analysis). Psychometric validation of these indexes or rating scales is the measuring aspect (micro-analysis). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Clinical judgment analysis by experienced psychiatrists is included in the macro-analysis and the item response theory models are especially preferred in the micro-analysis when using the total score as a sufficient statistic. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Clinical assessment tools covering severity of illness scales, prognostic measures, issues of co-morbidity, longitudinal assessments, recovery, stressors, lifestyle, psychological well-being, and illness behavior have been identified. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; The constructive dialogue in clinimetrics between clinical judgment and psychometric validation procedures is outlined for generating developments of clinical practice in psychiatry.
Cardiac transplants and the artificial heart: ethical considerations.
Authors: J C Fletcher
Journal: Circulation (1983)

THE ETHICAL CONSIDERATIONS relevant to car- diac transplantation and the artificial heart have evolved with intensity since the first human tissue transplant nearly 40 years ago.Ethical issues raised have led to an ongoing debate that permeates our entire society.Recent implantation of an artificial heart in a human being has made these issues even more cogent.A brief historical perspective and some definitions may be useful.The ethical framework in which medi- cal decisions relevant to cardiac transplantation and the artificial heart are made is evolving constantly.Typically, ethics help us make such decisions i.e., deci- sions occasioned by changing technology.Should we choose A (the old way), B (the new way), C (seek yet another way), or D (elect not to decide)?Ethics pro- vide protection against special threats to moral life, such as partiality and tendentious consideration of one- self or one's group as being exempt from moral rules.Ethical issues develop generally in four stages: threshold, conflict, debate, and adaptation.In the first stage, conditions for moral conflict are present.Isolated individuals may anticipate problems that later be- come more widely recognized.In the conflict stage, a number of significant or notorious cases arise, con- firming predicted inconsistencies and leading to emo- tional polarization.In the third stage, social debate becomes widespread.Ethical principles are applied, solutions are tested, and evidence is gathered to sup- port various alternatives.In the fourth stage, moral adaptations and the development and implementation of public policies with administrative and legislative formulations occur in this climate of socioethical debate.
Abstract 2553: Inhibition of γ-secretase in combination with Lapatinib induces tumor regression <i>in vivo</i>
Authors: Kinnari Pandya, Kathleen Meeke, Allison Rogowski, Anthony Clementz, Clodia Osipo
Journal: Cancer Research (2011)

Abstract Amplification, over-expression, and/or hyperactivity of ErbB-2 occur in 15-30% of breast tumors which include both luminal B and the HER2+ subtypes. Metastatic breast tumors that overexpress ErbB-2 are difficult to treat and generally resistant to trastuzumab. Lapatinib, a dual EGFR/ErbB-2 tyrosine kinase inhibitor, is approved for the treatment of ErbB-2-positive breast cancer that has advanced during or after trastuzumab treatment. However, resistance to lapatinib occurs in cell culture models in vitro. We have recently published that overexpression of ErbB-2 suppresses Notch-1 activity and this is reversed by inhibitors of ErbB-2, trastuzumab or a tyrosine kinase inhibitor. Furthermore, we demonstrated that trastuzumab resistance is reversed when Notch-1 is downregulated by siRNA or when cells are treated with a gamma-secretase inhibitor (MRK-003, GSI). Additionally, in an independent study we showed that GSI also prevented resistance to lapatinib. Since lapatinib is a very potent inhibitor of ErbB-2 tyrosine kinase activity in vitro, we asked whether a combination therapy based on lapatinib and GSI can prevent the resistant phenotype by using a pre-clinical in vivo model. BT474 breast tumor xenografts were generated in athymic mice and randomized to vehicle, GSI, lapatinib, or lapatinib plus a GSI. Tumor size was measured up to 13 weeks with treatments. The xenograft studies using BT474 lapatinib sensitive cells demonstrated that lapatinib treatment alone inhibited tumor growth by 40%. GSI alone had no effect on growth of tumors compared to vehicle control. However, GSI plus lapatinib significantly reduced tumor growth where regression was observed. Tumor histology of lapatinib plus GSI-treated tumors displayed a significant decrease in Ki67, a proliferation marker, and an increase in apoptotic cells as measured by TUNEL. Furthermore, both ERK1/2 and AKT1 phosphorylated proteins were undetectable by western blot in tumors treated with lapatinib plus GSI. These results suggest that both ErbB-2 and Notch activities must be inhibited to induce tumor regression of ErbB-2 positive breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2553. doi:10.1158/1538-7445.AM2011-2553
Blood is thicker than lymph
Authors: Mark L. Kahn
Journal: Journal of Clinical Investigation (2007)

Growth of blood and lymphatic vessels is essential in the developing embryo and in the pathogenesis of human diseases such as cancer, but the signaling pathways that regulate vessel growth and function are not yet well characterized. In this issue of the JCI, studies by Fritz-Six et al. and Ichikawa-Shindo et al. demonstrate that loss of signaling by the adrenomedullin peptide results in embryonic edema and death (see the related articles beginning on pages 40 and 29, respectively). Remarkably, this phenotype is attributed to defects in lymphatic vessels by one group and to defects in blood vessels by the other. In addition to defining what I believe to be a novel angiogenic signaling pathway, these studies demonstrate the intricate molecular, genetic, and physiologic relationships between blood and lymphatic vessels that must be considered by investigators of vascular biology.
MSF challenges Novartis's action over Indian patent for imatinib
Authors: Ganapati Mudur
Journal: BMJ (2007)

The international aid organisation Medicins Sans Frontieres has called on the Swiss pharmaceutical company Novartis to withdraw its challenge to the Indian government, which has refused to give the company a patent on its leukaemia drug imatinib (Glivec). 

In a case scheduled to be heard in an Indian court next week, Novartis has challenged sections of the Indian patent laws that are seen as an important public health tool by Medicins Sans Frontieres, doctors, lawyers, and health activists, because they ensure cheap access to …
Athol Noble Hepburn
Authors: A. L. N. Hepburn
Journal: BMJ (2013)

Athol Hepburn was born and educated in Aberdeen. After house appointments he joined the Royal Navy for a short service commission. After two years at sea, including the Gulf and East Indies, he moved to the Fleet Air Arm at Lossiemouth, specialising in aviation medicine. He then transferred to the Royal Naval Reserve, based at HMS President in London, where he served for a further 24 years.

In 1960 he won a scholarship to study the …
The dermatology-industry interface: Defining the boundaries
Authors: W.Mitchell Sams, Irwin M. Freedberg
Journal: Journal of the American Academy of Dermatology (2000)

Support from industry has become an important factor in the growth of the dermatologic profession. However, the relationship creates inevitable conflicts of interest. This article explores these potential conflicts, including (1) giving and receiving of gifts, (2) conduct of clinical trials, (3) appearance of advertisements in professional journals, (4) continuing medical education programs and educational grants to societies and departments, and (5) drug sampling.
Mononuclear Leukocytes Invade Rabbit Arterial Intima During Thickening Formation via CD18- and VLA-4–Dependent Mechanisms and Stimulate Smooth Muscle Migration
Authors: Dorothee Kling, Jürgen Fingerle, John M. Harlan, Roy R. Lobb, Florian Lang
Journal: Circulation Research (1995)

Abstract The role of mononuclear leukocytes for the migration of smooth muscle cells (SMCs) during intimal thickening was investigated in the rabbit model of electrically stimulated carotid artery. The approach was to inhibit leukocyte entry into the arterial intima with antibodies against the adhesion molecules very late activation antigen-4 (VLA-4) and CD11/CD18. In electrically stimulated control rabbits treated either with saline or a nonspecific antibody, all types of granulocytes, monocytes, and lymphocytes migrated across an intact endothelium into the acellular subendothelial space, followed by the movement of SMCs from the media into the intima within 36 hours of applying electrical current. Treatment of the rabbits with monoclonal antibody (mAb) HP1/2 directed toward the α 4 subunit (CD49d) of VLA-4 inhibited mononuclear leukocyte invasion (consisting of monocytes and lymphocytes) by ≈70% compared with the IgG-treated control rabbits and completely abolished the minimal influx of basophils and eosinophils after 36 hours. Neutrophil infiltration, however, remained unaffected by anti–VLA-α 4 treatment. Under these conditions, SMC migration across the internal elastic lamina was reduced by 50%. The use of mAb HP1/2 together with mAb 60.3 (directed to the β 2 chain of CD11/CD18) completely abolished the influx of monocytes, lymphocytes, and all types of granulocytes into the arterial intima. This complete blockade of leukocyte infiltration resulted in a 70% reduction of intimal SMC accumulation. Together with our previous findings excluding neutrophils as stimulators of SMC migration, the present results indicate that mononuclear leukocytes promote lesion development by stimulating SMC migration.
The molecular basis for adhesion-mediated suppression of reactive oxygen species generation by human neutrophils
Authors: Tieming Zhao, Valerie Benard, Benjamin P. Bohl, Gary M. Bokoch
Journal: Journal of Clinical Investigation (2003)

Human neutrophil adherence to ECMs induces an initial inhibition of stimulated reactive oxygen species (ROS) formation, followed by an enhanced phase of oxidant production. The initial integrin-mediated suppression of ROS constitutes a mechanism to prevent inappropriate tissue damage as leukocytes migrate to inflammatory sites. The Rac2 guanosine 5′-triphosphatase (GTPase) is a critical regulatory component of the phagocyte NADPH oxidase. We show that activation of Rac2 is inhibited in adherent neutrophils, correlating with inhibition of ROS formation. Conversely, NADPH oxidase components p47 and p67 assemble normally, suggesting a specific action of adhesion on the Rac2 molecular switch. Reconstitution with activated Rac2 restored rapid NADPH oxidase activation kinetics to adherent neutrophils, establishing that inhibition was due to defective Rac2 activity. We provide evidence that integrins inhibit Rac2 activation via a membrane-associated guanine nucleotide exchange factor, likely to be Vav1. Activation of Vav1, but not its upstream activator, Syk, is suppressed by cell adhesion. Vav1 activity is inhibited due to dephosphorylation of the regulatory Tyr174 via enhanced tyrosine phosphatase activity in adherent cells. These studies identify an integrin-mediated pathway in which Vav1 is as a strong candidate for the critical regulatory point in suppression of Rac2 activation and ROS generation during inflammatory responses.
Phosphoinositide 3-Kinase Inhibitors Combined with Imatinib in Patient-Derived Xenograft Models of Gastrointestinal Stromal Tumors: Rationale and Efficacy
Authors: Thomas Van Looy, Agnieszka Wozniak, Giuseppe Floris, Raf Sciot, Haifu Li, Jasmien Wellens, Ulla Vanleeuw, Jonathan A. Fletcher, Paul W. Manley, Maria Debiec-Rychter, Patrick Schöffski
Journal: Clinical Cancer Research (2014)

The PI3K signaling pathway drives tumor cell proliferation and survival in gastrointestinal stromal tumor (GIST). We tested the in vivo efficacy of three PI3K inhibitors (PI3Ki) in patient-derived GIST xenograft models.One hundred and sixty-eight nude mice were grafted with human GIST carrying diverse KIT genotypes and PTEN genomic status. Animals were dosed orally for two weeks as follows: control group (untreated); imatinib (IMA); PI3Ki (BKM120-buparlisib, BEZ235, or BYL719) or combinations of imatinib with a PI3Ki. Western blotting, histopathology, and tumor volume evolution were used for the assessment of treatment efficacy. Furthermore, tumor regrowth was evaluated for three weeks after treatment cessation.PI3Ki monotherapy showed a significant antitumor effect, reflected in tumor volume reduction or stabilization, inhibitory effects on mitotic activity, and PI3K signaling inhibition. The IMA+PI3Ki combination remarkably improved the efficacy of either single-agent treatment with more pronounced tumor volume reduction and enhanced proapoptotic effects over either single agent. Response to IMA+PI3Ki was found to depend on the KIT genotype and specific model-related molecular characteristics.IMA+PI3Ki has significant antitumor efficacy in GIST xenografts as compared with single-agent treatment, resulting in more prominent tumor volume reduction and enhanced induction of apoptosis. Categorization of GIST based on KIT genotype and PI3K/PTEN genomic status combined with dose optimization is suggested for patient selection for clinical trials exploring such combinations.