tbuckley/cabot-search huggingface dataset:
Specific peripheral B cell tolerance defects in patients with multiple sclerosis
Authors: Tuure Kinnunen, Nicolas Chamberlain, Henner Morbach, Tineke Cantaert, Megan Lynch, Paula Preston-Hurlburt, Kevan C. Herold, David A. Hafler, Kevin C. O’Connor, Eric Meffre
Journal: Journal of Clinical Investigation (2013)

Multiple sclerosis (MS) is a genetically mediated autoimmune disease of the central nervous system. B cells have recently emerged as major contributors to disease pathogenesis, but the mechanisms responsible for the loss of B cell tolerance in patients with MS are largely unknown. In healthy individuals, developing autoreactive B cells are removed from the repertoire at 2 tolerance checkpoints during early B cell development. Both of these central and peripheral B cell tolerance checkpoints are defective in patients with rheumatoid arthritis (RA) and type 1 diabetes (T1D). Here, we found that only the peripheral, but not the central, B cell tolerance checkpoint is defective in patients with MS. We show that this specific defect is accompanied by increased activation and homeostatic proliferation of mature naive B cells. Interestingly, all of these MS features parallel defects observed in FOXP3-deficient IPEX patients, who harbor nonfunctional Tregs. We demonstrate that in contrast to patients with RA or T1D, bone marrow central B cell selection in MS appears normal in most patients. In contrast, patients with MS suffer from a specific peripheral B cell tolerance defect that is potentially attributable to impaired Treg function and that leads to the accumulation of autoreactive B cell clones in their blood.
Vascular Endothelial Growth Factor Receptors VEGFR-2 and VEGFR-3 Are Localized Primarily to the Vasculature in Human Primary Solid Cancers
Authors: Neil R. Smith, Dawn Baker, Neil H. James, Kirsty Ratcliffe, Martin Jenkins, Susan E. Ashton, Graham Sproat, Ruth Swann, Neil Gray, Anderson Ryan, Juliane M. Jürgensmeier, Chris Womack
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Vascular endothelial growth factor (VEGF) signaling is key to tumor angiogenesis and is an important target in the development of anticancer drugs. However, VEGF receptor (VEGFR) expression in human cancers, particularly the relative expression of VEGFR-2 and VEGFR-3 in tumor vasculature versus tumor cells, is poorly defined. Experimental Design: VEGFR-2– and VEGFR-3–specific antibodies were identified and used in the immunohistochemical analysis of human primary cancers and normal tissue. The relative vascular localization of both receptors in colorectal and breast cancers was determined by coimmunofluorescence with vascular markers. Results: VEGFR-2 and VEGFR-3 were expressed on vascular endothelium but not on malignant cells in 13 common human solid tumor types (n &amp;gt; 400, bladder, breast, colorectal, head and neck, liver, lung, skin, ovarian, pancreatic, prostate, renal, stomach, and thyroid). The signal intensity of both receptors was significantly greater in vessels associated with malignant colorectal, lung, and breast than adjacent nontumor tissue. In colorectal cancers, VEGFR-2 was expressed on both intratumoral blood and lymphatic vessels, whereas VEGFR-3 was found predominantly on lymphatic vessels. In breast cancers, both receptors were localized to and upregulated on blood vessels. Conclusions: VEGFR-2 and VEGFR-3 are primarily localized to, and significantly upregulated on, tumor vasculature (blood and/or lymphatic) supporting the majority of solid cancers. The primary clinical mechanism of action of VEGF signaling inhibitors is likely to be through the targeting of tumor vessels rather than tumor cells. The upregulation of VEGFR-3 on tumor blood vessels indicates a potential additional antiangiogenic effect for dual VEGFR-2/VEGFR-3–targeted therapy. Clin Cancer Res; 16(14); 3548–61. ©2010 AACR.
Neuroendocrine tumors of the stomach (gastric carcinoids) are on the rise: small tumors, small problems?
Authors: H. Scherübl, G. Cadiot, R. Jensen, T. Rösch, U. Stölzel, G. Klöppel
Journal: Endoscopy (2010)

Well differentiated neuroendocrine tumors (NETs) of the stomach (gastric carcinoid tumors) are observed more often, with a tenfold increase in the US in the last 30 – 35 years, and the prognosis has improved greatly in that time. Nowadays most carcinoids of the stomach are diagnosed at an early stage. Four types of gastric NETs have been proposed and recognition of the type is important for defining the diagnostic approach and treatment. Often gastric NETs (especially type 1) are found incidentally during a gastroscopy performed for other reasons; most of these NETs are smaller than 20 mm in size. Conservative management and endoscopic surveillance is adequate for well differentiated, multifocal gastric carcinoids (type 1 or type 2 gastric NETs) that are less than 10 – 20 mm in diameter, unless they show angioinvasion, infiltrate the muscular wall, or have a proliferation rate above 2 %. Endoscopic ultrasound is the method of choice to determine tumor size and depth of infiltration. It is essential to distinguish between multifocal (types 1 and 2) and unifocal type 3 or type 4 gastric NETs, since surgery is indicated for type 3 gastric NETs larger than 10 mm in diameter and for poorly differentiated (localized) neuroendocrine gastric carcinomas (type 4 gastric NET). For optimal management, the type, biology, and stage of the tumor as well as the individual situation of the patient must be considered. Most patients with well differentiated gastric NETs can be treated conservatively and be followed up with endoscopic surveillance.
Estrogen Prophylaxis of Cholesterol-Induced Coronary Atherogenesis in Chicks Given Adrenal Corticoids or ACTH
Authors: JEREMIAH STAMLER, RUTH PICK, LOUIS N. KATZ
Journal: Circulation (1954)

Estrogen prophylaxis of experimental cholesterol-induced coronary atherogenesis in cockerels is unimpaired by the hyperadrenalism and steroid diabetes variously produced by concomitant exhibition of desoxycorticosterone acetate (DCA), hydrocortisone, cortisone or adrenocorticotropic hormone (ACTH).
Beyond arterial remodelling: pulmonary venous and cardiac involvement in patients with systemic sclerosis-associated pulmonary arterial hypertension
Authors: P. Dorfmüller, D. Montani, M. Humbert
Journal: European Respiratory Journal (2009)

Pulmonary arterial hypertension (PAH) represents a heterogeneous group of disorders characterised by elevated pulmonary vascular resistance and a normal pulmonary artery wedge pressure that occurs in the absence of left heart disease, chronic lung diseases/hypoxia or chronic thromboembolic pulmonary disease 1. Entities within the PAH group share not only similar symptoms and haemodynamic profiles but also a common therapeutic approach 2. Unfortunately, outcome among PAH patients remains poor and a cure for the disease remains elusive 3. One additional, although less well described, feature that favours the distinction of a PAH group is the histomorphological correlate of elevated blood pressures within the pulmonary vasculature. Indeed, PAH that is idiopathic, heritable, or associated with anorexigen exposure, HIV infection, portopulmonary hypertension and connective tissue disease (comprising mostly systemic sclerosis (SSc)-associated PAH (SSc-PAH)) appear to have a similar pulmonary arterial and arteriolar remodelling pattern. Typical PAH lesions consist mainly of widely and uniformly distributed vascular alterations, including intimal fibrosis, and endothelial and smooth muscle cell proliferation, without obvious involvement of the bronchoalveolar architecture. These histological features are markedly different from pulmonary hypertension that arises as a consequence of chronic thromboembolic disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and sarcoidosis, in which vascular occlusion develops as a consequence of emboli, arteriolar rarification, interstitial scarring or obstructing granulomas, respectively. Despite similarities in pathological anatomy, clinical management and outcome among the different forms of PAH, there are, nonetheless, important differences that remain unexplained. In patients with SSc, PAH is a leading cause of mortality that requires intensive medical management. However, therapeutic responses are frequently less favourable compared to other forms of PAH 4–6. SSc-PAH treatment with vasodilators such as continuous intravenous epoprostenol is associated with improvements in exercise capacity and cardiopulmonary haemodynamics. However, therapeutic responses using prostanoid therapy in …
Forensic mass spectrometry
Authors: David A. Cowan
Journal: British Journal of Sports Medicine (1988)

This is a reworked edition of Carl Honig's original text with many improvements particularly in terms of clarity.The themes of 'reserve of function' and the 'systems concept' run throughout the book which is divided into five parts.quote from the Preface which states that; 'The first two deal with the biophysical essentials: cardiac mechanics, electrophysiology, and hemodynamics.The third part is concerned with exchanges between blood and tissue, including new concepts in °2 transport.The fourth part describes selected regional circulations.This idiosyncratic material has been simplified by use of a common approach.The final part develops the regulation of pressure, flow, and volume and the integration of cardiovascular controls with voluntary behaviour."Each chapter contains clinical applications which highlight the relevance of the text and concludes with a brief but relevant list of references.The appendices include a number of problems and suggested approaches for solving them which is excellent revisionary material.The figures within the text utilise a full range of techniques including electron micrographs, flow diagrams and models.The book illustrates the importance of the basic physical sciences to full understanding.It will be a valued text for all medical or health science undergraduates and useful in many post-graduate courses.
Thromboxane Mediation of Cardiopulmonary Effects of Embolism
Authors: Takayoshi Utsunomiya, Michael M. Krausz, Lawrence Levine, David Shepro, Herbert B. Hechtman
Journal: Journal of Clinical Investigation (1982)

Humoral factors released from platelets during pulmonary embolism may be the cause of several attendant cardiopulmonary abnormalities. This study examines the role of thromboxanes (Tx) after experimental embolism induced with 0.5 g/kg autologous clot in four groups of five dogs: (a) untreated embolized controls; (b) pretreatment with the Tx synthetase inhibitor, imidazole 25 mg/kg · h i.v., starting 30 min before embolization; (c) pretreatment with the cyclooxygenase inhibitor indomethacin, 5 mg/kg, 12 h per os and 1 mg/kg, 1 h i.v. before the experiment; (d) treatment with prostacyclin (PGI2) 100 ηg/kg · min i.v. for 1 h, 1 h after embolization. Within 30 min, embolization led to increases of 6-keto-PGF1α, the stable hydrolysis product of PGI2, from 0.11±0.08 ηg/ml (mean±SD) to 0.33±0.10 ηg/ml (P < 0.005) and TxB2, the stable product of TxA2, from 0.10±0.04 ηg/ml to 0.38±0.06 ηg/ml (P < 0.001). Increases were observed in total dead space (VD/VT) from 0.46±0.03 to 0.61±0.08 (P < 0.025, physiologic shunting (Q̇S/Q̇T) from 16±4% to 38±9% (P < 0.01), pulmonary vascular resistance (PVR) from 2.27±0.59 mm Hg·min/liter to 9.21±1.90 mm Hg·min/liter (P < 0.005) and mean pulmonary arterial pressure from 14±6 mm Hg to 34±1 mm Hg (P < 0.001). Cardiac index (CI) fell from 139±11 ml/kg·min to 95±17 ml/kg·min in 4 h (P < 0.025). Imidazole pretreatment prevented a rise of TxB2, but not 6-keto-PGF1α; indomethacin blocked both. Both agents maintained VD/VT at base line and limited increases in Q̇S/Q̇T and PVR. CI was higher after imidazole pretreatment compared with controls (P < 0.025). Indomethacin led to intermediate levels of CI. PGI2 lowered TxB2 (P < 0.025), VD/VT (P < 0.025), Q̇S/Q̇T (P < 0.025) and PVR (P < 0.05) within 30 min. During PGI2 infusion, CI was higher than controls. Concentrations of TxB2 correlated with VD/VT, r = 0.79 and Q̇S/Q̇T, r = 0.69 (P < 0.001). Treatment of three dogs with the imidazole derivative ketoconazole, 10 mg/kg IV, 30 min after 0.75 g/kg autologous clot resulted in a lowering of physiologic dead space, but no other improvement of cardiopulmonary function. These results show that a number of cardiopulmonary abnormalities induced by pulmonary embolism are related directly or indirectly to platelet secretions and that VD/VT is closely allied to TxA2 levels.
Complete Lives in the Balance
Authors: Samuel J. Kerstein, Greg Bognar
Journal: The American Journal of Bioethics (2010)

The allocation of scarce health care resources such as flu treatment or organs for transplant presents stark problems of distributive justice. Persad, Wertheimer, and Emanuel have recently proposed a novel system for such allocation. Their "complete lives system" incorporates several principles, including ones that prescribe saving the most lives, preserving the most life-years, and giving priority to persons between 15 and 40 years old. This paper argues that the system lacks adequate moral foundations. Persad and colleagues' defense of giving priority to those between 15 and 40 leaves them open to the charge that they discriminate unfairly against children. Second, the paper contends that the complete lives system fails to provide meaningful practical guidance in central cases, since it contains no method for balancing its principles when they conflict. Finally, the paper proposes a new method for balancing principles of saving the most lives and maximizing life-years.
Phase II Study of Fixed Dose Rate Gemcitabine With Cisplatin for Metastatic Adenocarcinoma of the Pancreas
Authors: Andrew H. Ko, Elizabeth Dito, Brian Schillinger, Alan P. Venook, Emily K. Bergsland, Margaret A. Tempero
Journal: Journal of Clinical Oncology (2005)

Although gemcitabine remains the standard of care for patients with advanced pancreatic cancer, additional improvements may be realized by combining therapeutic agents with synergistic activity, and optimizing drug delivery using pharmacokinetic principles such as fixed dose rate (FDR) infusion. The objectives of this study were to determine safety and efficacy in patients with metastatic pancreatic cancer treated with FDR gemcitabine in combination with low-dose cisplatin.Chemotherapy-naive patients with metastatic pancreatic adenocarcinoma were treated with a combination of gemcitabine 1,000 mg/m2 at 10 mg/m2/min together with cisplatin 20 mg/m2 on days 1 and 8 of a 21-day cycle. Patient follow-up was performed using computerized tomographic scans and serial CA 19-9 measurements.A total of 51 patients were enrolled onto the study, with a median follow-up time of 215 days. Twenty-two of 40 patients (55.0%) with a baseline serum CA 19-9 level > or = 2x the upper limit of normal demonstrated a > or = 50% biomarker decline during treatment. Nine of 47 patients (19.1%) with measurable disease achieved a partial response, and 28 patients (59.6%) had disease stabilization for at least two treatment cycles. Median time to progression was 3.9 months and median survival was 7.1 months, with an estimated 1-year survival rate of 29%. The most frequently reported grade 3 or 4 adverse events were neutropenia (52.9%) and thrombocytopenia (15.7%). Most patients were switched to an every-other-week dosing schedule.The combination of FDR gemcitabine and cisplatin is well tolerated and appears to be an acceptable, albeit not clearly superior, alternative to other gemcitabine/platinum regimens for the treatment of metastatic pancreatic cancer.
Spermine decreases peripheral vascular resistance in the dog and relaxes the isolated aorta of the guinea pig
Authors: E. W CHIDECKEL, H. H DEDHIA, J. S FEDAN, L. TEBA, A. JAIN
Journal: Cardiovascular Research (1986)

Polyamines, found in all nucleated cells, have been shown to relax uterine, gastrointestinal, and respiratory tract smooth muscle. When parenterally administered to the rat or dog they cause hypotension. To determine the range of the relaxing effect of polyamines on smooth muscle and the mechanism of the hypotensive effect anaesthetised dogs were infused with increasing intravenous bolus doses of spermine while cardiovascular measurements were made. At doses of ≤2 mg·kg−1spermine a reversible hypotensive effect was produced that is accounted for by changes in peripheral vascular resistance. It is unlikely that this effect was due to the known propensity of polyamines to release histamine because the hypotensive action of 2 mg·kg−1 spermine was unaltered by pretreatment with the H1 and H2 blockers, diphenhydramine and cimetidine. Evidence that the spermine effect is not mediated by circulating agents was shown by the ability of spermine to relax the precontracted guinea pig isolated aorta. These results in vascular smooth muscle may be added to those in other types of smooth muscle shown to be relaxed by polyamines; the polyamine effect on smooth muscle may be ubiquitous. These data also raise the possibility that changing concentrations of tissue polyamines may play a role in the regulation of tissue blood flow.
Phase I/II trial of bortezomib in patients with unresectable hepatocellular carcinoma (HCC)
Authors: S. Hegewisch-Becker, M. Sterneck, U. Schubert, X. Rogiers, R. Guerciolini, J. E. Pierce, D. K. Hossfeld
Journal: Journal of Clinical Oncology (2004)

4089 Background: Bortezomib (Velcade) is a potent and reversible inhibitor of the proteasome and causes apoptotic cell death in a dose dependent matter in the human malignant hepatoma cell line HepG2. Available chemotherapeutic agents offer limited benefit to patients (pts) with HCC. The primary objective of this phase I/II study was to assess the dose limiting (DLT) and maximum tolerated dose (MTD) of bortezomib given as an iv bolus on days 1, 4, 8 and 11 of a 3 week cycle. Secondary objectives included response assessment, safety and pharmacodynamics of bortezomib. Methods: Eligibility criteria included histologically documented or diagnostic evidence of diagnosis of hepatocellular carcinoma and measurable surgically unresectable disease. So far 18 pts have been accrued to the study (17 male/1 female; Child-Pugh score A/B - 13/5 pts), median age 62 (range 33–82), a median KPS 80% (range 70–100). A prior history of hepatitis B and/or C or alcoholic cirrhosis was present in 39% and 17%, respectively.The DLT was defined on toxicities which occurred in cycle 1. Responses were evaluated every 4 cycles by CT scan using RECIST criteria. Results: A mean of 4.5 cycles (range 1–12) has been administered to these pts, 28 cycles at dose level 1 (1 mg/m2, 6 pts) and 54 cycles at dose level 2 (1.3 mg/m2, 12 pts).No grade III/IV DLTs in cycle 1 occurred. Grade II/III toxicities per pt included thrombocytopenia (7/3, respectively), fatigue (5/3), neuropathy (2/1), loss of appetite (6/2), hypotension (0/2), and abdominal cramps (2/1). 1 grade IV thrombocytopenia was observed. 5 pts required dose reduction. Based on observed toxicities in all cycles 1.3 mg/m2 was considered the MTD. SD has been observed in 7/15 evaluable pts lasting for 21, 14, 36+, 22+, 16+, 12+ and 9+ weeks, 8 pts progressed. Pharmacodynamics of bortezomib were similar to findings in pts without compromised liver function. Conclusions: Bortezomib appeared to be well tolerated in pts with HCC. Doxorubicin is considered standard treatment in HCC. Since proteasome inhibitors attenuate certain pathways implicated in resistance to anthracyclines further study of bortezomib in combination with doxorubicin may be warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millenium Pharmaceuticals Millenium Pharmaceuticals Millenium Pharmaceuticals Millennium Pharmaceuticals
2× genomes - depth does matter
Authors: Michel C Milinkovitch, Raphaël Helaers, Eric Depiereux, Athanasia C Tzika, Toni Gabaldón
Journal: Genome biology (2010)

Given the availability of full genome sequences, mapping gene gains, duplications, and losses during evolution should theoretically be straightforward. However, this endeavor suffers from overemphasis on detecting conserved genome features, which in turn has led to sequencing multiple eutherian genomes with low coverage rather than fewer genomes with high-coverage and more even distribution in the phylogeny. Although limitations associated with analysis of low coverage genomes are recognized, they have not been quantified. Here, using recently developed comparative genomic application systems, we evaluate the impact of low-coverage genomes on inferences pertaining to gene gains and losses when analyzing eukaryote genome evolution through gene duplication. We demonstrate that, when performing inference of genome content evolution, low-coverage genomes generate not only a massive number of false gene losses, but also striking artifacts in gene duplication inference, especially at the most recent common ancestor of low-coverage genomes. We show that the artifactual gains are caused by the low coverage of genome sequence per se rather than by the increased taxon sampling in a biased portion of the species tree. We argue that it will remain difficult to differentiate artifacts from true changes in modes and tempo of genome evolution until there is better homogeneity in both taxon sampling and high-coverage sequencing. This is important for broadening the utility of full genome data to the community of evolutionary biologists, whose interests go well beyond widely conserved physiologies and developmental patterns as they seek to understand the generative mechanisms underlying biological diversity.
Diagnostic value of anti-cyclic citrullinated peptide antibodies to detect rheumatoid arthritis in patients with Sjogren's syndrome
Authors: C van Noord
Journal: Annals of the Rheumatic Diseases (2004)

No patient had a history of a male twin or a solid organ transplant at the time of biopsy.SLE, systemic lupus erythematosus; CLE, cutaneous lupus erythematosus; DM, dermatomyositis; MF, mycosis fungoides.
Identification of Functions of Peroxisome Proliferator-Activated Receptor α in Proximal Tubules
Authors: Yuji Kamijo, Kazuhiko Hora, Naoki Tanaka, Nobuteru Usuda, Kendo Kiyosawa, Tamie Nakajima, Frank J. Gonzalez, Toshifumi Aoyama
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Peroxisome proliferator-activated receptor α(PPARα) is a member of the steroid/nuclear receptor superfamily that is intensively expressed in the kidney, but its physiologic function is unknown. In this study, PPARα-null mice were used to help clarify the function. Starved PPARα -null mice were found to secrete significantly more quantities of urine albumin than starved wild-type mice. Furthermore, the appearance of giant lysosomes, marked accumulation of albumin, and an impaired ability concerning albumin digestion were found only in proximal tubules of the starved PPARα-null mice. These abnormalities were probably derived from ATP insufficiency as a result of the starvation-induced decline of carbohydrate metabolism and a lack of PPARα-dependent fatty acid metabolism. It is interesting that these abnormalities disappeared when glucose was administered. Taken together, these findings demonstrate important functions of PPARα in the proximal tubules, the dynamic regulation of the protein-degradation system through maintenance of ATP homeostasis, and emphasize the importance of the fatty acid metabolism in renal physiology.