tbuckley/cabot-search huggingface dataset:
New Horizons in Cellular Regulation by Inositol Polyphosphates: Insights from the Pancreatic<i>β</i>-Cell
Authors: Christopher J. Barker, Per-Olof Berggren
Journal: Pharmacological Reviews (2013)

Studies of inositol polyphosphates in the pancreatic <i>β</i>-cell have led to an exciting synergism between new discoveries regarding their cellular roles and new insights into <i>β</i>-cell function. Because the loss or malfunction of the <i>β</i>-cell is central to diabetes, these studies open the possibility of new pharmacological interventions in a disease that has reached epidemic proportions worldwide. Using the <i>β</i>-cell as our prime but not exclusive example, we examine the inositol polyphosphates in three main groups: <i>1</i>) inositol 1,4,5-trisphosphate and its influence on Ca<sup>2+</sup> signaling, specifically in a cell in which cytoplasmic-free Ca<sup>2+</sup> concentration is principally increased by plasma membrane standing voltage-gated Ca<sup>2+</sup> channels; <i>2</i>) higher inositol polyphosphates including a novel second messenger inositol 3,4,5,6-tetrakisphosphate and a regulatory role for inositol hexakisphosphate in <i>β</i>-cell Ca<sup>2+</sup> homeostasis and exo- and endocytosis; and <i>3</i>) inositol pyrophosphates and their role in <i>β</i>-cell exocytosis, together with the exciting possibility of being novel targets for therapy in diabetes. We conclude with some of the new perspectives that are likely to become apparent in the next few years.
Paroxetine treatment of premature ejaculation: a double-blind, randomized, placebo-controlled study
Authors: M D Waldinger, M W Hengeveld, A H Zwinderman
Journal: American Journal of Psychiatry (1994)

Seventeen male outpatients with premature ejaculation were randomly assigned to treatment with paroxetine (N = 8) or placebo (N = 9). After a first week dose of 20 mg/day, the paroxetine regimen was increased to 40 mg/day for 5 weeks. Patients and their female partners were interviewed separately. Patients treated with paroxetine had significantly greater clinical improvement than the patients given placebo.
Chronic hypervitaminosis A in an adult
Authors: R. J. Di Benedetto
Journal: JAMA (1967)

Fatigue, musculoskeletal symptoms, skin changes, anorexia, weight loss, and hepatomegaly are the major manifestations of chronic hypervitaminosis A. Withdrawal of vitamin A results in complete recovery. This case is added to the 11 others previously documented in an attempt to stress the importance of earlier diagnosis and increased awareness.
Amphiphilic beads as depots for sustained drug release integrated into fibrillar scaffolds
Authors: Akhilesh K. Gaharwar, Silvia M. Mihaila, Ashish A. Kulkarni, Alpesh Patel, Andrea Di Luca, Rui L. Reis, Manuela E. Gomes, Clemens van Blitterswijk, Lorenzo Moroni, Ali Khademhosseini
Journal: Journal of Controlled Release (2014)
THE INTERACTION BETWEEN <i>TOXOPLASMA GONDII</i> AND MAMMALIAN CELLS
Authors: Thomas C. Jones, Shirley Yeh, James G. Hirsch
Journal: The Journal of Experimental Medicine (1972)

Macrophage, fibroblast, and HeLa cell cultures have been infected with Toxoplasma gondii, and observations have been made on parasite entry and fate. A special procedure was devised for studying the entry of toxoplasmas by electron microscopy. Toxoplasmas were centrifuged onto the cells in the cold; fixation 1-3 min after warming yielded specimens showing numerous examples of parasites in the process of entering cells. The mechanism of entry into macrophages, fibroblasts, and HeLa cells was in all cases by phagocytosis. Micropseudopods were extended by the cells to envelop the attached parasites in a typical phagocytic vacuole. Apparently the toxoplasmas stimulated this response of HeLa cells and fibroblasts, cell types not usually phagocytic. No instance was seen of penetration of toxoplasmas through the cell membrane, or of parasites located free in the cytoplasm. Essentially all of the toxoplasmas that entered HeLa cells divided with a generation time of 9 hr; the parasites formed large rosettes situated in vacuoles, eventually leading to host cell rupture. Macrophages took in larger numbers of toxoplasmas than did HeLa cells, but approximately half of the parasites inside of macrophages degenerated within a few hours. The surviving toxoplasmas in macrophages divided every 8 hr, forming rosettes and eventually rupturing the cells.
Transcription Enhancer Factor-1-Related Factor-Transgenic Mice Develop Cardiac Conduction Defects Associated With Altered Connexin Phosphorylation
Authors: Hsiao-Huei Chen, Catherine J. Baty, Tomoji Maeda, Steven Brooks, Linda C. Baker, Takahisa Ueyama, Erdal Gursoy, Samir Saba, Guy Salama, Barry London, Alexandre F.R. Stewart
Journal: Circulation (2004)

Background— Conduction system defects and slowed ventricular conduction are common in patients with systolic dysfunction and contribute to arrhythmias and sudden death. In animal models of heart failure, cardiac α 1 -adrenergic signaling is constitutively activated. Here, we report the effects of constitutive activation of α 1 -adrenergic signaling on connexin phosphorylation and cardiac conduction. Methods and Results— Transgenic mice were generated with cardiac-specific overexpression of the transcription factor RTEF-1 (transcription enhancer factor-1-related factor), which mediates α 1 -adrenergic signaling in cardiac myocytes. Surface and intracardiac ECGs revealed prolongation of the PR, QRS, and AH intervals and the appearance of progressive atrial arrhythmias in RTEF-1 mice. Optical mapping using voltage-sensitive dye revealed slower conduction velocities across the atrial and ventricular myocardium. Intercellular dye transfer between RTEF-1 transgenic cardiac myocytes confirmed impaired conduction at the cellular level. Conduction defects were correlated with dephosphorylation of connexin40 and connexin43 and upregulation of protein phosphatase 1β (PP1β). Overexpression of PP1β in HeLa cells dephosphorylated cardiac connexin. Confocal microscopy revealed increased levels of dephosphorylated connexin43 at the cardiac gap junctions in RTEF-1 mice, suggesting that defective conduction is a result of impaired gap-junction conductance rather than assembly. Conclusion— Constitutive activation of α 1 -adrenergic signaling through the RTEF-1 transcription factor results in chronic elevation of PP1β expression and connexin dephosphorylation. This mechanism may underlie some defects in cardiac conduction.
Lack of effect of inhaled morphine on exercise-induced breathlessness in chronic obstructive pulmonary disease.
Authors: A R Masood, J W Reed, S H Thomas
Journal: Thorax (1995)

BACKGROUND--Inhaled nebulised morphine may reduce breathlessness in patients with lung disease, although the results of controlled trials are conflicting. A direct action of morphine on the lung has been postulated. This study aimed to investigate whether nebulised morphine reduced exercise-induced breathlessness in patients with chronic obstructive pulmonary disease (COPD) and to determine if this was a local pulmonary effect or occurred after systemic morphine absorption. METHODS--A double blind, randomised, crossover study was performed in 12 men with COPD to compare the effects of nebulised morphine (10 and 25 mg), equivalent intravenous doses (1 and 2.5 mg), and placebo. Breathlessness (visual analogue scale), ventilation, gas exchange, and exercise endurance were measured during graded bicycle exercise. RESULTS--None of the treatments altered breathlessness, ventilation, or gas exchange at rest or at any time during exercise, and exercise endurance was unaffected. At peak exercise mean (95% CI) changes from placebo in ventilation were -0.8 (-0.57 to 1.1) l/min and -0.4 (-2.8 to 2.0) l/min for the highest intravenous and nebulised doses, respectively. For breathlessness equivalent values were +2 (-5 to 9) and +1 (-9 to 11) mm. The study was of sufficient power that it is unlikely that a clinically important effect was missed. CONCLUSIONS--Nebulised morphine in these doses has no effect on exercise-induced breathlessness. These findings do not support the hypothesis that intrapulmonary opiates modulate the sensation of breathlessness in patients with COPD.
Allergic Reactions to Penicillin
Authors: Paul P. VanArsdel
Journal: JAMA (1965)

Almost every type of adverse reaction from drugs, L including fatal arteritis, has been attributed to penicillin. Only approximate estimates of the relative frequency of these reactions can be made, for the more serious and explosive types of reactions are obviously more likely to be reported and, conversely, many cutaneous reactions, especially in children, may be manifestations of the primary disease rather than being induced by the drug. It is not surprising, then, that estimates of the frequency of allergic reactions to penicillin range from 1% to over 10%. The lower figure is probably closer to the actual incidence in a general, ambulatory population, and the higher figure is probably applicable to select groups, such as the chronically ill who have been exposed repeatedly to penicillin, and hospitalized patients with serious acute bacterial infections.<sup>1</sup>The incidence of allergic reactions in patients receiving continuous prophylactic treatment is very low; indeed,
986 CHRONIC ETHANOL CONSUMPTION MODULATE THE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) IN C57BL/6J ANIMAL MODEL
Authors: J.E. Yeon, Jeong H. Kim, Y.K. Jung, M.K. Joo, Ji H. Kim, J.J. Park, J.S. Kim, Y.T. Bak, K.S. Byun
Journal: Journal of Hepatology (2008)
Lung tumor-associated derepressed alloantigen coded for by the K region of the H-2 major histocompatibility complex
Authors: TG Gipson, M Imamura, MA Conliffe, WJ Martin
Journal: The Journal of Experimental Medicine (1978)

Transplacental induction of lung tumors in C3HfeB/HeN (C3Hf) strain mice can be readily achieved with the carcinogen 1-ethyl-1-nitrosourea. Several of these tumors express, as a tumor-associated transplantation antigen (TATA), a normal tissue alloantigen present in strain A and C3H/HeN (C3H) mice. In the present study it was shown that the tumor-associated alloantigen on the C3Hf-derived lung tumor 85 was present in all mice of H-2(a) and H-2(k) haplotypes tested and in CBA (532) strain mice (H-2(ka) haplotype). Studies using congenic-resistant and recombinant strains of mice indicated that the genetic locus controlling the expression of this antigen was either within or to the left of the H-2K region of the major histocompatibility complex (MHC). Thus the antigen was expressed in B10.A (4R) mice (kkbbbb MHC haplotype) but not in B10 (bbbbbb) or B10.AQR mice (qkkddd). The antigen was expressed in all tissues tested of C3H and A strain mice. It was not detected on any tissue tested including embryo tissue of C3Hf mice or mice of MHC haplotype other than H-2(k) or H-2(a). Because C3Hf strain mice were originally derived from C3H strain mice (H-2(k)), the MHC haplotype of C3Hf mice has been provisionally designated H-2(kb). The finding of a tumor-associated change in the expression of a H-2K region-coded antigen is consistent with the concept that MHC-coded antigens may act as targets for immunological surveillance of tumors.
Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease
Authors: Marcello D'Amelio, Virve Cavallucci, Silvia Middei, Cristina Marchetti, Simone Pacioni, Alberto Ferri, Adamo Diamantini, Daniela De Zio, Paolo Carrara, Luca Battistini, Sandra Moreno, Alberto Bacci, Martine Ammassari-Teule, Hélène Marie, Francesco Cecconi
Journal: Nature Neuroscience (2010)
Persistence of Hypertriglyceridemic Effect of Low-Fat High-Carbohydrate Diets in NIDDM Patients
Authors: Ann M Coulston, Clarie B Hollenbeck, Arthur L M Swislocki, Gerald M Reaven
Journal: Diabetes Care (1989)

Although low-fat high-carbohydrate diets are recommended for patients with non-insulin-dependent diabetes mellitus (NIDDM) in an effort to reduce the risk of coronary artery disease (CAD), the results of short-term studies have shown that these diets can lead to changes in carbohydrate and lipid metabolism associated with an increased risk of CAD. This study has extended these earlier observations by determining the metabolic effects of such diets over a longer period in these patients. The comparison diets contained either 40 or 60% of the total calories as carbohydrates, with reciprocal changes in fat content from 40 to 20% consumed in random order for 6 wk in a crossover experimental design. The ratio of polyunsaturated to saturated fat and the total cholesterol intake were held constant in the two diets. Plasma glucose and insulin concentrations were significantly (P &amp;lt; .001) elevated throughout the day when patients consumed the 60% carbohydrate diet, and 24-h urinary glucose excretion more than doubled (0.8 vs. 1.8 mol/24 h). Fasting plasma total and very-low-density lipoprotein (VLDL) triglyceride (TG) concentrations increased by 30% (P &amp;lt; .001) after 1 wk on the 60% carbohydrate diet, and the magnitude of carbohydrate-induced hypertriglyceridemia persisted unchanged throughout the 6-wk study period. Total plasma cholesterol concentrations were similar after both diets. However, VLDL cholesterol (VLDL-chol) was significantly increased, whereas both low-density lipoprotein (LDL-) and high-density lipoprotein (HDL-) chol concentrations were significantly decreasedafter consumption of the 60% carbohydrate diet. Consequently, neither total-chol-to-HDL-chol nor LDL-chol-to-HDL-chol ratios changed. The results of this study indicate that high-carbohydrate diets lead to several changes in carbohydrate and lipid metabolism in patients with NIDDM that could lead to an increased risk of CAD, and these effects persist for &amp;gt;6 wk. Given these results, it seems reasonable to suggest that the routine recommendation of low-fat high-carbohydrate diets for patients with NIDDM be reconsidered.
Convergence between Wnt-β-catenin and EGFR signaling in cancer
Authors: Tianhui Hu, Cunxi Li
Journal: Molecular Cancer (2010)

Wnt and EGFR signaling play key roles in embryonic development and cell proliferation. It is well documented that dysregulation of these two pathways often leads to tumorigenesis with poor prognosis. However, the possible crosstalk between the two pathways in cancer development is largely unknown. Although some reports show that EGFR might antagonize Wnt signaling during development in Drosophila, an increasing body of evidence indicates that Wnt and EGFR signaling crosstalk and transactivate one another in development and cancer. This review summarizes recent studies on the crosstalk between Wnt and EGFR signaling in cancers and points out several possible convergence points. Wnt ligands can activate EGFR signaling through their 7-transmembrane domain receptor Frizzled while EGFR can activate β-catenin via receptor tyrosine kinase-PI3K/Akt pathway; EGFR has been shown to form a complex with β-catenin and increase the invasion and metastasis of cancer cells. NKD2, a Wnt antagonist by interacting with Dishevelled, also escorts TGFα-containing exocytic vesicles to the basolateral membrane of polarized epithelial cells. Down-regulation of NKD2 causes Wnt activation and TGFα misdelivery, suggesting its functions in cell homeostasis and prevention of tumorigenesis.
Composition of weight lost during short-term weight reduction. Metabolic responses of obese subjects to starvation and low-calorie ketogenic and nonketogenic diets.
Authors: M U Yang, T B Van Itallie
Journal: Journal of Clinical Investigation (1976)

The effects of starvation, an 800-kcal mixed diet and an 800-kcal ketogenic (low carbohydrate-high fat) diet on the composition of weight lost were determined in each of six obese subjects during three 10-day periods.The energy-nitrogen balance method was used to quantify the three measurable components of weight loss; protein, fat, and water. On the 800-kcal ketogenic diet, subjects lost (mean +/- SE) 466.6 +/-51.3 g/day; on the isocaloric mixed diet, which provided carbohydrate and fat in conventional proportions, they lost 277.9+/- 32.1 g/day. Composition of weight lost (percentage) during the ketogenic diet was water 61.2, fat 35.0, protein 3.8. During the mixed diet, composition of loss was water 37.1, fat 59.5, protein 3.4...
Obesity and risk of subsequent hospitalisation with pneumonia
Authors: J.B. Kornum, M. Nørgaard, C. Dethlefsen, K.M. Due, R.W. Thomsen, A. Tjønneland, H.T. Sørensen, K. Overvad
Journal: European Respiratory Journal (2010)

Obesity may be associated with increased risk of pneumonia, but available data on this relationship are sparse and inconsistent. We followed a prospective cohort of 22,578 males and 25,973 females from the Danish Diet, Cancer and Health Study, aged 50–64 yrs and free from major chronic diseases at baseline (1993–1997), for first-time hospitalisation with pneumonia (median follow-up 12 yrs). Compared with males of normal weight, adjusted hazard ratios (HRs) for pneumonia were 1.4 (95% CI 1.2–1.7) for males with moderate obesity (body mass index (BMI) 30.0–34.9 kg·m −2 ), and 2.0 (95% CI 1.4–2.8) for males with severe obesity (BMI ≥35.0 kg·m −2 ), controlling for lifestyle and educational variables. Among females the associations were weaker, with adjusted HRs of 0.8 (95% CI 0.6–1.0) for moderate obesity, and 1.2 (95% CI 0.8–1.6) for severe obesity. Adjustment for major chronic diseases diagnosed during follow-up eliminated the associations between obesity and pneumonia risk. Obesity is associated with higher risk of hospitalisation with pneumonia among males but not among females, which is apparently explained by occurrence of other chronic diseases.
A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis
Authors: Javier Corral, Rocio González-Conejero, Jose Manuel Soria, Jose Ramón González-Porras, Elena Pérez-Ceballos, Ramón Lecumberri, Vanessa Roldán, Juan Carlos Souto, Antonia Miñano, David Hernández-Espinosa, Ignacio Alberca, Jordi Fontcuberta, Vicente Vicente
Journal: Blood (2006)
Evidence for Selective Transformation of Autoreactive Immature Plasma Cells in Mice Deficient in <i>Fasl </i>
Authors: Jian Qiao Zhang, Cheryl Okumura, Thomas McCarty, Min Sun Shin, Partha Mukhopadhyay, Mitsuo Hori, Ted A. Torrey, Zohreh Naghashfar, Jeff X. Zhou, Chang Hoon Lee, Derry C. Roopenian, Herbert C. Morse, Wendy F. Davidson
Journal: The Journal of Experimental Medicine (2004)

Germline mutations in Fas and Fasl induce nonmalignant T cell hyperplasia and systemic autoimmunity and also greatly increase the risk of B cell neoplasms. B lymphomas occurring in Fasl mutant (gld) mice usually are immunoglobulin (Ig) isotype switched, secrete Ig, and are plasmacytoid in appearance but lack Myc translocations characteristic of other plasma cell (PC) neoplasms. Here, we explore the relationship between B cell autoreactivity and transformation and use gene expression profiling to further classify gld plasmacytoid lymphomas (PLs) and to identify genes of potential importance in transformation. We found that the majority of PLs derive from antigen-experienced autoreactive B cells producing antinuclear antibody or rheumatoid factor and exhibit the skewed Ig V gene repertoire and Ig gene rearrangement patterns associated with these specificities. Gene expression profiling revealed that both primary and transplanted PLs share a transcriptional profile that places them at an early stage in PC differentiation and distinguishes them from other B cell neoplasms. In addition, genes were identified whose altered expression might be relevant in lymphomagenesis. Our findings provide a strong case for targeted transformation of autoreactive B cells in gld mice and establish a valuable model for understanding the relationship between systemic autoimmunity and B cell neoplasia.
RMP — As I Knew Him: The Rise and Fall of an Idea
Authors: E. Grey Dimond
Journal: New England Journal of Medicine (1974)

Most men and women in private medical practice enjoy an innocent belief that they are in "private" practice and are not politically involved in medicine. This innocence probably stems from the passive role of the majority of physicians. They are not involved with the mechanics of legislation and, in fact, would be unable to describe how federal legislation in the health field comes about. A few brief paragraphs appear in the local newspaper on in a medical journal indicating hearings, or voting, or lambasting about some aspect of medical care. The doctor is busy and does not have the time . . .
Risk of depression and self-harm in teenagers identifying with goth subculture: a longitudinal cohort study
Authors: Lucy Bowes, Rebecca Carnegie, Rebecca Pearson, Becky Mars, Lucy Biddle, Barbara Maughan, Glyn Lewis, Charles Fernyhough, Jon Heron
Journal: The Lancet Psychiatry (2015)

BackgroundPrevious research has suggested that deliberate self-harm is associated with contemporary goth subculture in young people; however, whether this association is confounded by characteristics of young people, their families, and their circumstances is unclear. We aimed to test whether self-identification as a goth is prospectively associated with emergence of clinical depression and self-harm in early adulthood.MethodsWe used data from the Avon Longitudinal Study of Parents and Children, a UK community-based birth cohort of 14 541 pregnant women with expected delivery between April 1, 1991, and Dec 31, 1992. All children in the study were invited to attend yearly follow-up visits at the research clinic from age 7 years. At 15 years of age, participants reported the extent to which they self-identified as a goth. We assessed depressive mood and self-harm at 15 years with the Development and Wellbeing Assessment (DAWBA) questionnaire, and depression and self-harm at 18 years using the Clinical Interview Schedule-Revised. We calculated the prospective association between goth identification at 15 years and depression and self-harm at 18 years using logistic regression analyses.FindingsOf 5357 participants who had data available for goth self-identification, 3694 individuals also had data for depression and self-harm outcomes at 18 years. 105 (6%) of 1841 adolescents who did not self-identify as goths met criteria for depression compared with 28 (18%) of 154 who identified as goths very much; for self-harm, the figures were 189 (10%) of 1841 versus 57 (37%) of 154. We noted a dose–response association with goth self-identification both for depression and for self-harm. Compared with young people who did not identify as a goth, those who somewhat identified as being a goth were 1·6 times more likely (unadjusted odds ratio [OR] 1·63, 95% CI 1·14–2·34, p<0·001), and those who very much identified as being a goth were more than three times more likely (unadjusted OR 3·67, 2·33–4·79, p<0·001) to have scores in the clinical range for depression at 18 years; findings were similar for self-harm. Associations were not attenuated after adjustment for a range of individual, family, and social confounders.InterpretationOur findings suggest that young people identifying with goth subculture might be at an increased risk for depression and self-harm. Although our results suggest that some peer contagion operates within the goth community, our observational findings cannot be used to claim that becoming a goth increases risk of self-harm or depression. Working with young people in the goth community to identify those at increased risk of depression and self-harm and provide support might be effective.FundingWellcome Trust, Medical Research Council Programme.
Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling
Authors: Marc S. Raab, Iris Breitkreutz, Giovanni Tonon, Jing Zhang, Patrick J. Hayden, Thu Nguyen, Johannes H. Fruehauf, Boris K. Lin, Dharminder Chauhan, Teru Hideshima, Nikhil C. Munshi, Kenneth C. Anderson, Klaus Podar
Journal: Blood (2008)