tbuckley/cabot-search huggingface dataset:
Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer’s disease early phenotypes
Authors: Catherine Marquer, Jeanne Laine, Luce Dauphinot, Linda Hanbouch, Camille Lemercier-Neuillet, Nathalie Pierrot, Koen Bossers, Mickael Le, Fabian Corlier, Caroline Benstaali, Frédéric Saudou, Gopal Thinakaran, Nathalie Cartier, Jean-Noël Octave, Charles Duyckaerts, Marie-Claude Potier
Journal: Molecular Neurodegeneration (2014)

It is suspected that excess of brain cholesterol plays a role in Alzheimer's disease (AD). Membrane-associated cholesterol was shown to be increased in the brain of individuals with sporadic AD and to correlate with the severity of the disease. We hypothesized that an increase of membrane cholesterol could trigger sporadic AD early phenotypes.We thus acutely loaded the plasma membrane of cultured neurons with cholesterol to reach the 30% increase observed in AD brains. We found changes in gene expression profiles that are reminiscent of early AD stages. We also observed early AD cellular phenotypes. Indeed we found enlarged and aggregated early endosomes using confocal and electron microscopy after immunocytochemistry. In addition amyloid precursor protein vesicular transport was inhibited in neuronal processes, as seen by live-imaging. Finally transient membrane cholesterol loading lead to significantly increased amyloid-β42 secretion.Membrane cholesterol increase in cultured neurons reproduces most early AD changes and could thus be a relevant model for deciphering AD mechanisms and identifying new therapeutic targets.
Long-term follow-up and prognosis of Reiter's syndrome.
Authors: G.W Csonka
Journal: Annals of the Rheumatic Diseases (1979)

A number of textbooks and articles suggest that the prognosis of Reiter's syndrome (RS), unlike that of ankylosing spondylitis (AS) and rheumatoid arthritis (RA), is good both in the short-and longterm and that the few deaths occur equally from complications and drug side effects, and are in any event very rare.7'I too subscribed to this until I gathered more experience.As I said in my previous paper (see p. 4), a mortality of 0 * 9 % can be expected in venereal RS.The residual disabilities are the main theme of this paper.
More mathematics: Bodily-kinaesthetic intelligence
Authors: Gin McCollum
Journal: Behavioral and Brain Sciences (1997)

Although the idea that cognitive structure changes as we learn is welcome, a variety of mathematical structures are needed to model the neural and cognitive processes involved. A specific example of bodily-kinaesthetic intelligence is given, building on a formalism given elsewhere. As the structure of cognition changes, previous learning can become tacit, adding to the complexity of cognition and its modeling.
Potentiation of induction of apoptosis by sequential treatment with CDDP followed by 5-FU in human oral cancer cells
Authors: Masayuki Azuma
Journal: Cancer Research (2004)

2966   Purpose: Based on evidence that combination chemotherapy with 5-Fluorouracil (5-FU) and Cisplatin (CDDP) has been shown to be highly effective in the treatment of squamous cell carcinoma (SCC) of the head and neck, we examined the mechanism involved in the induction of apoptosis when these agents were combined. Experimental Design: Three different combination administration sequences were evaluated using human oral SCC (B88) cells: (a) 5-FU administered simultaneously with CDDP for 72 h (sequence I); (b) CDDP administered for 24 h before 5-FU treatment for 48 h (sequence II); and (c) 5-FU administered for 24 h before CDDP treatment for 48 h (sequence III). The growth inhibitory response of B88 cells to CDDP and 5-FU was investigated by MTT assay. The apoptotic cascades, including the processing of procaspase 3, procaspase 8, and procaspase 9, the release of cytochrome c from mitochondria, and the expression of inhibitor of cytochrome c release (Bcl-2) were determined by Western blotting. Results: When combining the two drugs at doses 40% of their respective cytotoxicity, the growth-suppressing ratios were 49, 55, and 40% in sequences I, II, and III, respectively. The executioner caspase, caspase 3, was significantly activated in sequence II as compared to its level of activation in sequence I or III, indicating that the degree of growth suppression by anticancer agents with various treatment sequences correlated well with the activation status of caspase 3 in B88 cells. The mitochondrial release of cytochrome c was much greater in sequence II than in sequence III. In addition, activation of caspase 8, which amplifies apoptosis through release of cytochrome c from mitochondria, was most strongly activated in sequence II as compared with sequences I and III. Activation of caspase-9 was also observed in sequence II, and, to a lesser extent, in sequence III. Finally, although a suppressor of cytochrome c release from mitochondria, Bcl-2, was reduced in sequence II, no significant change was observed in sequence III. Conclusions: The data presented here demonstrate a proposed signaling pathway for sequence II-induced apoptosis in B88 cells. Administration of sequence II activates both intrinsic and extrinsic apoptosis pathways, resulting in activation of caspase 8 and caspase 9. Caspase 8 and caspase 9 initiate caspase activation cascades, leading to proteolytic caspase 3 activation, which in turn can directly or indirectly activate caspase 8. Sequence II inhibits Bcl-2 expression, thereby leading to both caspase 8 activation and mitochondrial cytochrome c release. Finally, activated caspase 3 induces apoptosis in B88 cells.
Gastric outlet obstruction caused by tuberculosis and diagnosed by endoscopic ultrasound-guided fine needle aspiration
Authors: S. Rana, D. Bhasin, R. Srinivasan, K. Singh
Journal: Endoscopy (2011)

A 34-year-old man presented with a 3-month history of recurrent episodes of vomiting, anorexia, and weight loss of 16 kg. There was no history of ingestion of nonsteroidal anti-inflammatory drugs and clinical examination was unremarkable. Laboratory investigations revealed hemoglobin of 9.6 g/dL (normal range: 12 – 18 g/dL) with an erythrocyte sedimentation rate (ESR) of 46 mm/h. Upper gastrointestinal endoscopy revealed an impassable stricture with mucosal ulceration at the junction of the first and second parts of duodenum. An antral biopsy showed Helicobacter pylori, so the patient was started on a proton pump inhibitor (PPI) with antibiotics to eradicate H. pylori. There was no improvement in his symptoms, and repeat endoscopy was performed 4 weeks later, which revealed similar features ([Fig. 1]).
Frizzled 4 Regulates Arterial Network Organization Through Noncanonical Wnt/Planar Cell Polarity Signaling
Authors: Betty Descamps, Raj Sewduth, Nancy Ferreira Tojais, Béatrice Jaspard, Annabel Reynaud, Fabien Sohet, Patrick Lacolley, Cécile Allières, Jean-Marie Daniel Lamazière, Catherine Moreau, Pascale Dufourcq, Thierry Couffinhal, Cécile Duplàa
Journal: Circulation Research (2011)

A growing body of evidence supports the hypothesis that the Wnt/planar cell polarity (PCP) pathway regulates endothelial cell proliferation and angiogenesis, but the components that mediate this regulation remain elusive.We investigated the involvement of one of the receptors, Frizzled4 (Fzd4), in this process because its role has been implicated in retinal vascular development.We found that loss of fzd4 function in mice results in a striking reduction and impairment of the distal small artery network in the heart and kidney. We report that loss of fzd4 decreases vascular cell proliferation and migration and decreases the ability of the endothelial cells to form tubes. We show that fzd4 deletion induces defects in the expression level of stable acetylated tubulin and in Golgi organization during migration. Deletion of fzd4 favors Wnt noncanonical AP1-dependent signaling, indicating that Fzd4 plays a pivotal role favoring PCP signaling. Our data further demonstrate that Fzd4 is predominantly localized on the top of the plasma membrane, where it preferentially induces Dvl3 relocalization to promote its activation and α-tubulin recruitment during migration. In a pathological mouse angiogenic model, deletion of fzd4 impairs the angiogenic response and leads to the formation of a disorganized arterial network.These results suggest that Fzd4 is a major receptor involved in arterial formation and organization through a Wnt/PCP pathway.
Blindness in Saudi Arabia
Authors: Alfred Sommer
Journal: JAMA (1986)

Depending on definitions and how you count, an estimated 42 million people are blind. Over 80% reside in developing countries, where blindness rates are often five to 20 times those of wealthier industrialized nations.<sup>1,2</sup>The majority of Third World blindness is caused by cataract<sup>3,4</sup>; the rest, depending upon local conditions, by trachoma,<sup>5</sup>onchocerciasis (river blindness),<sup>6</sup>malnutrition (xerophthalmia),<sup>7,8</sup>trauma, and glaucoma.<sup>2,3</sup>It is concentrated in the elderly, particularly women. Most importantly, it can be prevented or reversed with existing technology. In a carefully conducted nationwide prevalence survey reported in this issue, Tabbara and Ross-Degnan<sup>9</sup>document the magnitude and causes of blindness in Saudi Arabia, confirming findings of similar surveys in Nepal<sup>10</sup>and Malawi<sup>11</sup>and more modest investigations elsewhere. These have revealed the unacceptable burden of this avoidable disability, with its economic and human costs, and enabled governments with severely limited resources to
The Integrin Inhibitor Cilengitide Affects Meningioma Cell Motility and Invasion
Authors: Annette Wilisch-Neumann, Nadine Kliese, Doreen Pachow, Thomas Schneider, Jan-Peter Warnke, Werner EK Braunsdorf, Frank-Dietmar Böhmer, Peter Hass, Diana Pasemann, Cornelia Helbing, Elmar Kirches, Christian Mawrin
Journal: Clinical Cancer Research (2013)

Meningiomas are frequent intracranial or spinal neoplasms, which recur frequently and can show aggressive clinical behaviour. We elucidated the impact of the integrin inhibitor cilengitide on migration, proliferation, and radiosensitization of meningioma cells.We analyzed integrin expression in tissue microarrays of human meningiomas and the antimeningioma properties of cilengitide in cell cultures, subcutaneous and intracranial nude mouse models by measuring tumor volumes and survival times.αvβ5 was the predominantly expressed integrin heterodimer in meningiomas, whereas αvβ3 was mainly detected in tumor blood vessels. Application of up to 100 μg/mL cilengitide resulted in only mildly reduced proliferation/survival of meningioma cell lines. Effects on cell survival could be enhanced by irradiation. One μg/mL cilengitide was sufficient to significantly inhibit meningioma cell migration and invasion in vitro. A daily dosage of 75 mg/kg did neither affect tumor volumes nor overall survival (P = 0.813, log-rank test), but suppressed brain invasion in a significant fraction of treated animals. A combination of 75 mg/kg cilengitide daily and irradiation (2 × 5 Gy) led to a 67% reduction of MRI-estimated tumor volumes in the intracranial model (P < 0.01), whereas the corresponding reduction reached by irradiation alone was only 55% (P < 0.05).These data show that a monotherapy with cilengitide is not likely to achieve major responses in rapidly growing malignant meningiomas, although brain invasion may be reduced because of the strong antimigratory properties of the drug. The combination with radiotherapy warrants further attention.
Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells
Authors: Göran Carlsson, Andrew A. G. Aprikyan, Ramin Tehranchi, David C. Dale, Anna Porwit, Eva Hellström-Lindberg, Jan Palmblad, Jan-Inge Henter, Bengt Fadeel
Journal: Blood (2004)
Ventricular tachycardia rate and morphology determine energy and current requirements for transthoracic cardioversion.
Authors: R E Kerber, M G Kienzle, B Olshansky, A L Waldo, D Wilber, M D Carlson, A M Aschoff, S Birger, L Fugatt, S Walsh
Journal: Circulation (1992)

BACKGROUND The electrical current and energy required to terminate ventricular tachyarrhythmias are known to vary by arrhythmia: Ventricular tachycardia (VT) is generally considered to require less energy than ventricular fibrillation (VF). The hypothesis of our study was that current requirements for transthoracic termination of VT are further determined by VT rate and QRS complex morphology. METHODS AND RESULTS We prospectively studied 203 patients who received a total of 569 shocks for VT or VF by following a current-based protocol. This protocol recommended shocks for VT beginning at 18 A (70 +/- 22 J) and shocks for VF beginning at 25 or 30 A (137 +/- 52 J or 221 +/- 70 J). The ventricular tachyarrhythmias were subclassified as monomorphic VT (MVT): uniform QRS complex morphology on surface electrocardiogram and heart rate greater than 100 beats per minute; polymorphic VT (PVT): nonuniform QRS complex morphology and heart rate less than or equal to 300 beats per minute; or VF: nonuniform QRS complex morphology and heart rate greater than 300 beats per minute. We found that shocks of 18 A and 25 A for terminating MVT had success rates of 69% and 82%, respectively, whereas such low-current shocks were less successful for PVT (33% at 18 A) and for VF (19% at 18 A, 53% at 25 A). High-current shocks of 35 A and 40 A were equally successful for the three ventricular tachyarrhythmias. Subdividing MVT revealed that slower MVT (heart rate less than 200 beats per minute) had a significantly better success rate with low-current shocks of 18 A and 25 A than did faster MVT (greater than 200 beats per minute) (89% versus 72% success, p less than 0.01). Bundle branch block morphology, QRS axis, and duration of ventricular tachyarrhythmia did not alter current requirements. CONCLUSIONS Heart rate and electrocardiographic degree of organization of ventricular tachycardia are important determinants of transthoracic energy and current requirements for cardioversion and defibrillation. Transthoracic termination of MVT requires relatively low current or energy, but PVT behaves more like VF and requires higher electrical current or energy.
Negative selection, not receptor editing, is a physiological response of autoreactive thymocytes
Authors: Taras Kreslavsky, Hye-Jung Kim, Sergei B. Koralov, Dvora Ghitza, Thorsten Buch, Harvey Cantor, Klaus Rajewsky, Harald von Boehmer
Journal: The Journal of Experimental Medicine (2013)

Antigen receptor editing—a process of secondary rearrangements of antigen receptor genes in autoreactive lymphocytes—is a well-established tolerance mechanism in B cells, whereas its role in T cells remains controversial. Here, we investigated this issue using a novel Tcra knock-in locus, which ensured appropriate timing of TCRα expression and allowed secondary rearrangements. Under these conditions the only response to self-antigen that could be unambiguously identified was negative selection of CD4/CD8 double positive thymocytes. No evidence could be obtained for antigen-induced TCR editing, whereas replacement of the transgenic TCRα chain by ongoing gene rearrangement occurred in some cells irrespective of the presence or absence of self-antigen.
Air pollution and the elderly: oxidant/antioxidant issues worth consideration
Authors: F.J. Kelly, C. Dunster, I. Mudway
Journal: European Respiratory Journal (2003)

The elderly are frequently classified as being particularly susceptible to air pollution. The basis of this increased sensitivity is not known but it is likely that it is linked to age-related impaired function of the lung. However, given this uncertainty and increased impact of air pollution of this section of the community there is a need to explore the mechanisms involved. Gaseous air pollutants such as ozone and nitrogen dioxide, or many of the components adsorbed onto the surface of respirable particles, are either powerful oxidants or capable of generating free radicals. If unabated, oxidants can cause injury to the delicate cells that line the respiratory tract. Small molecular weight antioxidant defences present in respiratory tract lining fluid (RTLF) represent the first line of defence against a range of oxidants that enter the lung. The quantity and quality of the RTLF airways antioxidant network are, therefore, likely to be important determinants of the impact of the oxidant challenge on the underlying respiratory epithelium. As yet, comprehensive information on the distribution and variability of respiratory tract lining fluid antioxidant defences is only available in young, mainly healthy volunteers. Studies undertaken in patients with a range of respiratory diseases suggest that marked changes in the distribution of respiratory tract lining fluid antioxidants can occur. Information is not currently available on the impact of ageing on the respiratory tract lining fluid antioxidant defence network. As several respiratory tract lining fluid antioxidants are of dietary origin, the elderly, who often have different dietary patterns to younger individuals, may have decreased availability of important antioxidants. Given these possibilities, a better understanding of respiratory tract lining fluid antioxidant defences in the aged lung is warranted.
Th9 Cells: A Novel CD4 T-cell Subset in the Immune War against Cancer
Authors: Frédérique Végran, Lionel Apetoh, François Ghiringhelli
Journal: Cancer Research (2015)

CD4 T cells are key components of the immune system that shape the anticancer immune response in animal models and in humans. The biology of CD4 T cells is complex because naïve T cells can differentiate into various subpopulations with various functions. Recently, a new population called Th9 cells was described. These cells are characterized by their ability to produce IL9 and IL21. They were first described in the context of parasite infections and allergic processes. However, some reports described their presence in the tumor bed in mice and humans. Their high secretion of IL9 and IL21 in the tumor bed contributes to their anticancer functions. Indeed, these cytokines trigger the activation of dendritic cells, mast cells, natural killer cells, and CD8 T cells to mount an antitumor immune response, thus explaining the remarkable ability of Th9 cells to control tumor growth. This review summarizes the latest advances in the Th9 field in cancer and focuses on their potential role as new tool for cell therapy.
Mechanisms of activation of mouse and human enteroendocrine cells by nutrients
Authors: Erin L Symonds, Madusha Peiris, Amanda J Page, Bridgette Chia, Harween Dogra, Abigail Masding, Vasileios Galanakis, Michael Atiba, David Bulmer, Richard L Young, L Ashley Blackshaw
Journal: Gut (2014)

<h3>Objective</h3> Inhibition of food intake and glucose homeostasis are both promoted when nutrients stimulate enteroendocrine cells (EEC) to release gut hormones. Several specific nutrient receptors may be located on EEC that respond to dietary sugars, amino acids and fatty acids. Bypass surgery for obesity and type II diabetes works by shunting nutrients to the distal gut, where it increases activation of nutrient receptors and mediator release, but cellular mechanisms of activation are largely unknown. We determined which nutrient receptors are expressed in which gut regions and in which cells in mouse and human, how they are associated with different types of EEC, how they are activated leading to hormone and 5-HT release. <h3>Design and results</h3> mRNA expression of 17 nutrient receptors and EEC mediators was assessed by quantitative PCR and found throughout mouse and human gut epithelium. Many species similarities emerged, in particular the dense expression of several receptors in the distal gut. Immunolabelling showed specific colocalisation of receptors with EEC mediators PYY and GLP-1 (L-cells) or 5-HT (enterochromaffin cells). We exposed isolated proximal colonic mucosa to specific nutrients, which recruited signalling pathways within specific EEC extracellular receptor-regulated kinase (p-ERK) and calmodulin kinase II (pCAMKII), as shown by subsequent immunolabelling, and activated release of these mediators. Aromatic amino acids activated both pathways in mouse, but in humans they induced only pCAMKII, which was colocalised mainly with 5-HT expression. Activation was pertussis toxin-sensitive. Fatty acid (C12) potently activated p-ERK in human in all EEC types and evoked potent release of all three mediators. <h3>Conclusions</h3> Specific nutrient receptors associate with distinct activation pathways within EEC. These may provide discrete, complementary pharmacological targets for intervention in obesity and type II diabetes.
Anticoagulation in cirrhosis: Ready … set … wait!
Authors: Susana Seijo, Juan Carlos Garcia-Pagan
Journal: Hepatology (2013)

Background & Aims: We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a lowmolecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis.Methods: In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n 5 34) or no treatment (controls, n 5 36).Ultrasonography (every 3 months) and computed tomography (every 6 months) were performed to check the portal vein axis.The primary outcome was prevention of PVT.Radiologists and hepatologists that assessed outcomes were blinded to group assignments.Analysis was by intention to treat.Results: At 48 weeks, none of the patients in the enoxaparin group had developed PVT, compared with 6 of 36 (16.6%) controls (P 5 0.025).At 96 weeks, no patient developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P 5 0.001).At the end of the follow-up period, 8.8% of patients in the enoxaparin group and 27.7% of controls developed PVT (P 5 0.048).The actuarial probability of PVT was lower in the enoxaparin group (P 5 0.006).Liver decompensation was less frequent among patients given enoxaparin (11.7%) than controls (59.4%)(P 5 0.0001); overall values were 38.2% vs 83.0%, respectively (P 5 0.0001).The actuarial probability of liver decompensation was lower in the enoxaparin group (P 5 0.0001).Eight patients in the enoxaparin group and 13 controls died.The actuarial probability of survival was higher in the enoxaparin group (P 5 0.020).No relevant side effects or hemorrhagic events were reported.Conclusions: In a small randomized controlled trial, a 12-month course of enoxaparin was safe and effective in preventing PVT in patients with cirrhosis and a Child-Pugh score of 7-10.Enoxaparin appeared to delay the occurrence of hepatic decompensation and to improve survival.