tbuckley/cabot-search huggingface dataset:
Modulation of Immune Complex–induced Inflammation In Vivo by the Coordinate Expression of Activation and Inhibitory Fc Receptors
Authors: Raphael Clynes, Jay S. Maizes, Rodolphe Guinamard, Masao Ono, Toshiyuki Takai, Jeffrey V. Ravetch
Journal: The Journal of Experimental Medicine (1999)

Autoantibodies and immune complexes are major pathogenic factors in autoimmune injury, responsible for initiation of the inflammatory cascade and its resulting tissue damage. This activation results from the interaction of immunoglobulin (Ig)G Fc receptors containing an activation motif (ITAM) with immune complexes (ICs) and cytotoxic autoantibodies which initiates and propagates an inflammatory response. In vitro, this pathway can be interrupted by coligation to FcγRIIB, an IgG Fc receptor containing an inhibitory motif (ITIM). In this report, we describe the in vivo consequences of FcγRII deficiency in the inflammatory response using a mouse model of IC alveolitis. At subthreshold concentrations of ICs that fail to elicit inflammatory responses in wild-type mice, FcγRII-deficient mice developed robust inflammatory responses characterized by increased hemorrhage, edema, and neutrophil infiltration. Bronchoalveolar fluids from FcγRII−/− stimulated mice contain higher levels of tumor necrosis factor and chemotactic activity, suggesting that FcγRII deficiency lowers the threshold of IC stimulation of resident cells such as the alveolar macrophage. In contrast, complement- and complement receptor–deficient mice develop normal inflammatory responses to suprathreshold levels of ICs, while FcRγ−/− mice are completely protected from inflammatory injury. An inhibitory role for FcγRII on macrophages is demonstrated by analysis of FcγRII−/− macrophages which show greater phagocytic and calcium flux responses upon FcγRIII engagement. These data reveal contrasting roles for the cellular receptors for IgG on inflammatory cells, providing a regulatory mechanism for setting thresholds for IC sensitivity based on the ratio of ITIM to ITAM FcγR expression. Exploiting the FcγRII inhibitory pathway could thus provide a new therapeutic approach for modulating antibody-triggered inflammation.
Genetic control of mammalian T-cell proliferation with a synthetic RNA regulatory system - illusion or reality?
Authors: Sang Kil Lee, George A Calin
Journal: Genome Medicine (2010)

Synthetic RNA-based regulatory systems are used to program higher-level biological functions that could be exploited, among many applications, for in vivo diagnostic and therapeutic applications. Chen and colleagues have recently reported a significant technological advance by producing an RNA modular device based on a hammerhead ribozyme and successfully tested its ability to control the proliferation of mammalian T lymphocytes. Like all exciting research, this work raises a lot of significant questions. How quickly will such knowledge be translated into clinical practice? How efficient will this system be in human clinical trials involving adaptive T-cell therapy? We discuss the possible advantages of using such new technologies for specific therapeutic applications.
In memoriam: Frederick E Hargreave (1938-2011)
Authors: P. M. O'Byrne, P. Nair, P. J. Sterk
Journal: Thorax (2011)

![Graphic][1]</img> A wonderful clinical scientist, great friend and mentor to many in the field of respiratory medicine, Frederick E Hargreave (known to everyone as Freddy), died suddenly on 15 June 2011. Freddy was born in Hong Kong and completed his medical school training at the University of Leeds. After completing his initial clinical training, Freddy moved to London to work as a house officer in respiratory medicine with Dr EJ Moran Campbell at the Hammersmith Hospital. A short while later, Moran Campbell accepted the position as the founding chair of the Department of Medicine at the Faculty of Health Sciences at McMaster University in Hamilton, Ontario, a move that was to change Freddy's life both personally and professionally. Subsequently, Freddy began his research training with Professor Jack Pepys at the Brompton Hospital. During this time, Freddy described a new clinical entity, bird fancier's lung disease, a type of allergic alveolitis caused by the inhalation of bird antigens.1 In 1969, Freddy Hargreave joined the Department of Medicine at McMaster University, at the behest of Moran Campbell and Norman Jones (who was the first division director for respiratory medicine at McMaster). Shortly after arriving in Hamilton, he started what was to become a lifelong collaboration and close friendship with Dr Jerry Dolovich and their focus turned to understanding the mechanisms and treatment of asthma. Within 10 years, the studies led by Freddy Hargreave had changed the way that asthma was diagnosed and had paved the way to future studies that have revolutionised its treatment. In particular, Dr Don Cockcroft (who was Freddy's first clinical fellow), who described the methodology for the measurement of airway hyper-responsiveness in asthma,2 had demonstrated that this … [1]: /embed/inline-graphic-1.gif
Acquired resistance of human T cells to sulfasalazine
Authors: D E Furst
Journal: Annals of the Rheumatic Diseases (2004)

Feeding difficulties are common in long chain 3-hydroxyacyl-CoA dehydrogenase deficiency in early childhood and are not associated with developmental disability, metabolic abnormalities, or the overnight feeding regimen. They are an inherent part of the phenotype and it is important to recognise them because of the distress and disruption they cause.
Role for Cathepsin F in Invariant Chain Processing and Major Histocompatibility Complex Class II Peptide Loading by Macrophages
Authors: Guo-Ping Shi, Rebecca A.R. Bryant, Richard Riese, Steven Verhelst, Christoph Driessen, Zhenqiang Li, Dieter Bromme, Hidde L. Ploegh, Harold A. Chapman
Journal: The Journal of Experimental Medicine (2000)

The major histocompatibility complex (MHC) class II-associated invariant chain (Ii) regulates intracellular trafficking and peptide loading of MHC class II molecules. Such loading occurs after endosomal degradation of the invariant chain to a approximately 3-kD peptide termed CLIP (class II-associated invariant chain peptide). Cathepsins L and S have both been implicated in degradation of Ii to CLIP in thymus and peripheral lymphoid organs, respectively. However, macrophages from mice deficient in both cathepsins S and L can process Ii and load peptides onto MHC class II dimers normally. Both processes are blocked by a cysteine protease inhibitor, indicating the involvement of an additional Ii-processing enzyme(s). Comparison of cysteine proteases expressed by macrophages with those found in splenocytes and dendritic cells revealed two enzymes expressed exclusively in macrophages, cathepsins Z and F. Recombinant cathepsin Z did not generate CLIP from Ii-MHC class II complexes, whereas cathepsin F was as efficient as cathepsin S in CLIP generation. Inhibition of cathepsin F activity and MHC class II peptide loading by macrophages exhibited similar specificity and activity profiles. These experiments show that cathepsin F, in a subset of antigen presenting cells (APCs), can efficiently degrade Ii. Different APCs can thus use distinct proteases to mediate MHC class II maturation and peptide loading.
Dendritic cells freshly isolated from human blood express CD4 and mature into typical immunostimulatory dendritic cells after culture in monocyte-conditioned medium.
Authors: U O'Doherty, R M Steinman, M Peng, P U Cameron, S Gezelter, I Kopeloff, W J Swiggard, M Pope, N Bhardwaj
Journal: The Journal of Experimental Medicine (1993)

A procedure has been developed to isolate dendritic cells to a high degree of purity from fresh blood. Prior enrichment methods have relied upon an initial 1-2-d culture period. Purified fresh isolates lack the characteristic morphology, phenotype, and immunostimulatory function of dendritic cells. The purified cells have the appearance of medium sized lymphocytes and express substantial levels of CD4, but lack the T cell molecules CD3, CD8, and T cell receptor. When placed in culture, the cells mature in a manner resembling the previously described, cytokine-dependent maturation of epidermal dendritic cells (Langerhans cells). The cells enlarge and exhibit many cell processes, express much higher levels of major histocompatibility complex class II and a panel of accessory molecules for T cell activation, and become potent stimulators of the mixed leukocyte reaction. Among the many changes during this maturation process are a fall in CD4 and the appearance of high levels of B7/BB1, the costimulator for enhanced interleukin 2 production in T cells. These changes are not associated with cell proliferation, but are dependent upon the addition of monocyte-conditioned medium. We suggest that the freshly isolated CD4-positive blood dendritic cells are recent migrants from the bone marrow, and that subsequent maturation of the lineage occurs in tissues in situ upon appropriate exposure to cytokines.
Reception of the stethoscope and Laennec's book.
Authors: P J Bishop
Journal: Thorax (1981)

A study of contemporary book reviews and other notices enables us to trace the reception of the stethoscope and Laënnec9s book between 1816 and 1826. It is quite clear from these that the stethoscope was welcomed with enthusiasm by most people who saw it as the first major diagnostic tool medicine had ever had. Laënnec9s book was recognised as being the most important, interesting, accurate, and complete work on diseases of the chest that had ever been published.
Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child
Authors: Markus Schuelke, Kathryn R. Wagner, Leslie E. Stolz, Christoph Hübner, Thomas Riebel, Wolfgang Kömen, Thomas Braun, James F. Tobin, Se-Jin Lee
Journal: New England Journal of Medicine (2004)

uscle wasting and weakness are among the most common inherited and acquired disorders and include the muscular dystrophies, cachexia, and age-related wasting.Since there is no generally accepted treatment to improve muscle bulk and strength, these conditions pose a substantial burden to patients as well as to public health.Consequently, there has been considerable interest in a recently described inhibitor of muscle growth, myostatin, or growth/ differentiation factor 8 (GDF-8), which belongs to the transforming growth factor b superfamily of secreted proteins that control the growth and differentiation of tissues throughout the body.The myostatin gene is expressed almost exclusively in cells of skeletal-muscle lineage throughout embryonic development as well as in adult animals and functions as a negative regulator of muscle growth. 1,2Targeted disruption of the myostatin gene in mice doubles skeletal-muscle mass. 1 Conversely, systemic overexpression of the myostatin gene leads to a wasting syndrome characterized by extensive muscle loss. 3In adult animals, myostatin appears to inhibit the activation of satellite cells, which are stem cells resident in skeletal muscle. 4,5he potential relevance of myostatin to the treatment of disease in humans has been suggested by studies involving mdx mice, which carry a mutation in the dystrophin gene and therefore serve as a genetic model of Duchenne's and Becker's muscular dystrophy. 6For example , mdx mice that lacked myostatin were found not only to be stronger and more muscular than their mdx counterparts with normal myostatin, but also to have reduced fibrosis and fatty remodeling, suggesting improved regeneration of muscle. 7Furthermore, injection of neutralizing monoclonal antibodies directed against myostatin into either wild-type or mdx mice increases muscle mass and specific force, suggesting that myostatin plays an important role in regulating muscle growth in adult animals. 8,91][12][13] The phenotypes of mice and cattle lacking myostatin and the high degree of sequence conservation of the predicted myostatin protein in many mammalian species have raised the possibility that myostatin may help regulate muscle growth in humans.We report the identification of a myostatin mutation in a child with muscle hypertrophy, thereby providing strong evidence that myostatin does play an important role in regulating muscle mass in humans.A healthy woman who was a former professional athlete gave birth to a son after a normal pregnancy.The identity of the child's father was not revealed.The child's birth weight was in the 75th percentile.Stimulus-induced myoclonus developed several m case report
Fibroblast Growth Factor 21 Prevents Atherosclerosis by Suppression of Hepatic Sterol Regulatory Element-Binding Protein-2 and Induction of Adiponectin in Mice
Authors: Zhuofeng Lin, Xuebo Pan, Fan Wu, Dewei Ye, Yi Zhang, Yu Wang, Leigang Jin, Qizhou Lian, Yu Huang, Hong Ding, Chris Triggle, Kai Wang, Xiaokun Li, Aimin Xu
Journal: Circulation (2015)

Background— Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. It acts as a key downstream target of both peroxisome proliferator-activated receptor α and γ, the agonists of which have been used for lipid lowering and insulin sensitization, respectively. However, the role of FGF21 in the cardiovascular system remains elusive. Methods and Results— The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apolipoprotein E −/− mice. FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E −/− mice, which is accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment of FGF21 protects against atherosclerosis in apolipoprotein E −/− mice via 2 independent mechanisms, inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibit neointima formation and macrophage inflammation, and suppressing the hepatic expression of the transcription factor sterol regulatory element-binding protein-2, thereby leading to reduced cholesterol synthesis and attenuation of hypercholesterolemia. Chronic treatment with adiponectin partially reverses atherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apolipoprotein E −/− mice. By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of sterol regulatory element-binding protein-2. Conclusions— FGF21 protects against atherosclerosis via fine tuning the multiorgan crosstalk among liver, adipose tissue, and blood vessels.
Acute Metabolic Responses in Myxedema to Large Doses of Intravenous L-Thyroxine
Authors: E. CHESTER RIDGWAY
Journal: Annals of Internal Medicine (1972)

Two comparable groups of noncomatose hypothyroid patients were given large doses of intravenous L-thyroxine. Group I was given an initial mean injection of 428 µg L-thyroxine and then 100 µg daily for 9 days; group II was given 750 µg initially and 200 µg each day thereafter for 9 days. A fall in serum thyrotrophin was the first metabolic response observed, occurring within the first 24 hours before changes in the basal metabolic rate, serum cholesterol, and creatine phosphokinase were observed. Peripheral conversion of L-thyroxine to triiodothyronine occurred during the first week. Plasma cortisol and human growth-hormone responses to insulin-induced hypoglycemia were blunted before therapy and remained abnormal after 10 days of intravenous L-thyroxine therapy.
Brain PPAR-γ promotes obesity and is required for the insulin–sensitizing effect of thiazolidinediones
Authors: Min Lu, David A Sarruf, Saswata Talukdar, Shweta Sharma, Pingping Li, Gautam Bandyopadhyay, Sarah Nalbandian, WuQiang Fan, Jiaur R Gayen, Sushil K Mahata, Nicholas J Webster, Michael W Schwartz, Jerrold M Olefsky
Journal: Nature Medicine (2011)
Accessory Kvβ <sub>1</sub> Subunits Differentially Modulate the Functional Expression of Voltage-Gated K <sup>+</sup> Channels in Mouse Ventricular Myocytes
Authors: Franck Aimond, Seung P. Kwak, Kenneth J. Rhodes, Jeanne M. Nerbonne
Journal: Circulation Research (2005)

Voltage-gated K+ (Kv) channel accessory (beta) subunits associate with pore-forming Kv alpha subunits and modify the properties and/or cell surface expression of Kv channels in heterologous expression systems. There is very little presently known, however, about the functional role(s) of Kv beta subunits in the generation of native cardiac Kv channels. Exploiting mice with a targeted disruption of the Kvbeta1 gene (Kvbeta1-/-), the studies here were undertaken to explore directly the role of Kvbeta1 in the generation of ventricular Kv currents. Action potential waveforms and peak Kv current densities are indistinguishable in myocytes isolated from the left ventricular apex (LVA) of Kvbeta1-/- and wild-type (WT) animals. Analysis of Kv current waveforms, however, revealed that mean+/-SEM I(to,f) density is significantly (P< or =0.01) lower in Kvbeta1-/- (21.0+/-0.9 pA/pF; n=68), than in WT (25.3+/-1.4 pA/pF; n=42), LVA myocytes, and that mean+/-SEM I(K,slow) density is significantly (P< or =0.01) higher in Kvbeta1-/- (19.1+/-0.9 pA/pF; n=68), compared with WT (15.9+/-0.7 pA/pF; n=42), LVA cells. Pharmacological studies demonstrated that the TEA-sensitive component of I(K,slow), I(K,slow2,) is selectively increased in Kvbeta1-/- LVA myocytes. In parallel with the alterations in I(to,f) and I(K,slow2) densities, Kv4.3 expression is decreased and Kv2.1 expression is increased in Kvbeta1-/- ventricles. Taken together, these results demonstrate that Kvbeta1 differentially regulates the functional cell surface expression of myocardial I(to,f) and I(K,slow2) channels.
Refinement of primate copy number variationhotspots identifies candidate genomic regions evolving under positive selection
Authors: Omer Gokcumen, Paul L Babb, Rebecca C Iskow, Qihui Zhu, Xinghua Shi, Ryan E Mills, Iuliana Ionita-Laza, Eric J Vallender, Andrew G Clark, Welkin E Johnson, Charles Lee
Journal: Genome biology (2011)

Copy number variants (CNVs), defined as losses and gains of segments of genomic DNA, are a major source of genomic variation. In this study, we identified over 2,000 human CNVs that overlap with orthologous chimpanzee or orthologous macaque CNVs. Of these, 170 CNVs overlap with both chimpanzee and macaque CNVs, and these were collapsed into 34 hotspot regions of CNV formation. Many of these hotspot regions of CNV formation are functionally relevant, with a bias toward genes involved in immune function, some of which were previously shown to evolve under balancing selection in humans. The genes in these primate CNV formation hotspots have significant differential expression levels between species and show evidence for positive selection, indicating that they have evolved under species-specific, directional selection. These hotspots of primate CNV formation provide a novel perspective on divergence and selective pressures acting on these genomic regions.
Seborrhoeic wart or basal cell papilloma: what's in a name?
Authors: A.C. Pembroke
Journal: British Journal of Dermatology (2002)

Journal Article Seborrhoeic wart or basal cell papilloma: what's in a name? Get access A.C. Pembroke A.C. Pembroke 28 Dartford Road, Sevenoaks, Kent TN13 3TQ, U.K. E‐mail: family@pembroke28.freeserve.co.uk Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 147, Issue 5, 1 November 2002, Page 1020, https://doi.org/10.1046/j.1365-2133.2002.49581.x Published: 01 November 2002
Re: Oral Contraceptives and the Risk of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers
Authors: J. L. Hopper, J. A. Baron
Journal: JNCI Journal of the National Cancer Institute (2003)

In a recent issue of the Journal, Narod et al. (1) reported findings from a large sample of 2611 BRCA1 and BRCA2 germline mutation carriers regarding the association of oral contraceptive use with the risk of breast cancer. An interesting feature of this report— not commented on by the authors—is data regarding cigarette smoking. The proportion of breast cancer case subjects who ever smoked was 39%, and the proportion among control subjects was 41%. These data clearly suggest no material association between cigarette smoking and breast cancer risk, a finding in agreement with a recent pooled analysis of major breast cancer studies (2). In 1998, Narod et al. published in the Journal an earlier report from the same study (3). By contrast with the current data, that analysis, based on only 372 subjects, suggested that smoking reduced the risk of breast cancer in women known to carry a germline mutation in BRCA1 or BRCA2. In that analysis, the proportion of case subjects who had ever smoked was 39% (as in the current report), whereas the proportion among control subjects was 52% (higher than in the current, larger report). With a higher smoking prevalence among the control subjects, an adjusted odds ratio of 0.54 (P .007) was found. It is not clear what might explain the difference in findings between the two analyses. Certainly the use of clinicbased data introduces potential problems in design and interpretation (4,5). Indeed, the two different prevalences of smoking among the control samples could be the result of seemingly subtle differences in participation in genetic counseling clinics and the studies conducted there. The differences in the smoking findings may also illustrate a possible pitfall of studies with continuing enrollment. Premature or repeated analyses of evolving data may lead to a decision to publish apparently “significant” findings that have actually emerged by chance. It is also possible that the statistics generated from the matched analyses do not appropriately reflect the association in the whole study sample. The methodology used by Narod et al. (1)—matching on mutated gene, age, and country of residence—reduces the potential for bias. However, this approach does not optimize the use of the data because a large proportion of carriers with and without breast cancer are not included. It would be interesting to see analyses that are based on less stringent matching criteria, greater control-to-case matching ratios, and/or modeling of possible confounding effects.
Topical monobenzyl ether of hydroquinone is an effective and safe treatment for depigmentation of extensive vitiligo in the medium term: a retrospective cohort study of 53 cases
Authors: E.S.-T. Tan, R. Sarkany
Journal: British Journal of Dermatology (2014)

Funding sources: None. Conflicts of interest: None declared. Dear Editor, Monobenzyl ether of hydroquinone (MBEH) is presently the only depigmenting agent approved by the U.S. Food and Drug Administration for use in patients with extensive vitiligo.1 The paucity of studies on this treatment means that its efficacy and safety are poorly understood. We have evaluated the safety and efficacy of topical MBEH in a cohort of patients. We performed a retrospective cohort study of all patients with vitiligo treated with MBEH at St John's Institute of Dermatology in London over a 6·5‐year period from 1 January 2008 to 30 June 2014 (excluding patients who started treatment in the final 6 months of the period, given their uninformatively short follow‐up period). Similarly, we also excluded patients who defaulted follow‐up after the first visit, as we were unable to assess their response to treatment. We reviewed clinical letters, case notes and clinical photographs where available, inclusive of follow‐up data until 30 June 2014.