tbuckley/cabot-search huggingface dataset:
Clinical and operational value of the extensively drug-resistant tuberculosis definition
Authors: G. B. Migliori, G. Besozzi, E. Girardi, K. Kliiman, C. Lange, O. S. Toungoussova, G. Ferrara, D. M. Cirillo, A. Gori, A. Matteelli, A. Spanevello, L. R. Codecasa, M. C. Raviglione
Journal: European Respiratory Journal (2007)

Currently, no information is available on the effect of resistance/susceptibility to first-line drugs different from isoniazid and rifampicin in determining the outcome of extensively drug-resistant tuberculosis (XDR-TB) patients, and whether being XDR-TB is a more accurate indicator of poor clinical outcome than being resistant to all first-line anti-tuberculosis (TB) drugs. To investigate this issue, a large series of multidrug-resistant TB (MDR-TB) and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation during the period 1999–2006 were analysed. Drug-susceptibility testing for first- and second-line anti-TB drugs, quality assurance and treatment delivery was performed according to World Health Organization recommendations in all study sites. Out of 4,583 culture-positive TB cases analysed, 361 (7.9%) were MDR and 64 (1.4%) were XDR. XDR-TB cases had a relative risk (RR) of 1.58 to have an unfavourable outcome compared with MDR-TB cases resistant to all first-line drugs (isoniazid, rifampicin ethambutol, streptomycin and, when tested, pyrazinamide), and an RR of 2.61 compared with “other” MDR-TB cases (those susceptible to at least one first-line anti-TB drug among ethambutol, pyrazinamide and streptomycin, regardless of resistance to the second-line drugs not defining XDR-TB). The emergence of extensively drug-resistant tuberculosis confirms that problems in tuberculosis management are still present in Europe. While waiting for new tools which will facilitate management of extensively drug-resistant tuberculosis, accessibility to quality diagnostic and treatment services should be urgently ensured and adequate public health policies should be rapidly implemented to prevent further development of drug resistance.
Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function
Authors: Rong Zeng, Rosanne Spolski, Steven E. Finkelstein, SangKon Oh, Panu E. Kovanen, Christian S. Hinrichs, Cynthia A. Pise-Masison, Michael F. Radonovich, John N. Brady, Nicholas P. Restifo, Jay A. Berzofsky, Warren J. Leonard
Journal: The Journal of Experimental Medicine (2005)

Interleukin (IL)-21 is the most recently recognized of the cytokines that share the common cytokine receptor γ chain (γc), which is mutated in humans with X-linked severe combined immunodeficiency. We now report that IL-21 synergistically acts with IL-15 to potently promote the proliferation of both memory (CD44high) and naive (CD44low) phenotype CD8+ T cells and augment interferon-γ production in vitro. IL-21 also cooperated, albeit more weakly, with IL-7, but not with IL-2. Correspondingly, the expansion and cytotoxicity of CD8+ T cells were impaired in IL-21R−/− mice. Moreover, in vivo administration of IL-21 in combination with IL-15 boosted antigen-specific CD8+ T cell numbers and resulted in a cooperative effect on tumor regression, with apparent cures of large, established B16 melanomas. Thus, our studies reveal that IL-21 potently regulates CD8+ T cell expansion and effector function, primarily in a synergistic context with IL-15.
The Effects of Light at Night on Circadian Clocks and Metabolism
Authors: Laura K. Fonken, Randy J. Nelson
Journal: Endocrine Reviews (2014)

Most organisms display endogenously produced ∼24-hour fluctuations in physiology and behavior, termed circadian rhythms. Circadian rhythms are driven by a transcriptional-translational feedback loop that is hierarchically expressed throughout the brain and body, with the suprachiasmatic nucleus of the hypothalamus serving as the master circadian oscillator at the top of the hierarchy. Appropriate circadian regulation is important for many homeostatic functions including energy regulation. Multiple genes involved in nutrient metabolism display rhythmic oscillations, and metabolically related hormones such as glucagon, insulin, ghrelin, leptin, and corticosterone are released in a circadian fashion. Mice harboring mutations in circadian clock genes alter feeding behavior, endocrine signaling, and dietary fat absorption. Moreover, misalignment between behavioral and molecular circadian clocks can result in obesity in both rodents and humans. Importantly, circadian rhythms are most potently synchronized to the external environment by light information and exposure to light at night potentially disrupts circadian system function. Since the advent of electric lights around the turn of the 20th century, exposure to artificial and irregular light schedules has become commonplace. The increase in exposure to light at night parallels the global increase in the prevalence of obesity and metabolic disorders. In this review, we propose that exposure to light at night alters metabolic function through disruption of the circadian system. We first provide an introduction to the circadian system, with a specific emphasis on the effects of light on circadian rhythms. Next we address interactions between the circadian system and metabolism. Finally, we review current experimental and epidemiological work directly associating exposure to light at night and metabolism.
Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin.
Authors: M G Kris, R J Gralla, R A Clark, L B Tyson, J P O'Connell, M S Wertheim, D P Kelsen
Journal: Journal of Clinical Oncology (1985)

Although many trials have evaluated the severity and treatment of nausea and vomiting immediately after cisplatin administration, no studies have focused on vomiting occurring more than 24 hours after chemotherapy--delayed emesis. Two consecutive trials were undertaken to evaluate the incidence, course (trial 1), and severity (trial 2) of delayed nausea and emesis and to develop methods to study these conditions. Eighty-six patients receiving cisplatin (120 mg/m2) for the first time were entered. On the day of cisplatin treatment, all received intravenous (IV) metoclopramide (3 mg/kg X 2 doses) plus dexamethasone (20 mg IV X 1 dose) with either diphenhydramine (50 mg IV) or lorazepam (1.0 to 1.5 mg/m2). Sixty-two percent of patients experienced no vomiting during the 24 hours immediately after administration of cisplatin. Overall, 93% of studied patients experienced some degree of delayed nausea or vomiting from 24 to 120 hours after cisplatin. In trial 1, the incidence of delayed vomiting ranged from 21% to 61% and delayed nausea from 24% to 78% in 58 patients. The highest incidence of both delayed nausea and emesis occurred during the period from 48 to 72 hours after administration of cisplatin. Patients who had no emesis during the initial 24 hours after cisplatin were less likely to experience delayed emesis. The severity of delayed nausea and vomiting was evaluated in 28 patients in trial 2. The amount of delayed nausea and vomiting was assessed daily by patients using a visual analogue scale and by an observer rating. The highest nausea and vomiting scores were seen during the period from 48 to 72 hours after administration of cisplatin, with acceptable correlation between patient scores and observer ratings. Although the nausea and vomiting occurring 24 or more hours after cisplatin administration is not as severe as that seen during the initial 24 hours after administration of cisplatin in patients not receiving antiemetics, it is a common condition that merits both further study and specific treatment.
Structural and Functional Alterations of FLT3 in Acute Myeloid Leukemia
Authors: Soheil Meshinchi, Frederick R. Appelbaum
Journal: Clinical Cancer Research (2009)

Hematopoiesis is highly regulated through cytokine-induced stimulation of multiple signal transduction pathways in order to mediate appropriate differentiation and proliferation of specific progenitor populations. Ligand-induced stimulation of the FMS-like tyrosine kinase 3 (FLT3) leads to activation of multiple downstream effector pathways resulting in differentiation and proliferation of specific progenitor cell populations. Genomic alterations of the FLT3 gene, including FLT3 internal tandem duplication (FLT3/ITD) and FLT3 activation loop mutation (FLT3/ALM) lead to autonomous receptor activation, dysregulation of FLT3 signal transduction pathways, contribute to myeloid pathogenesis, and have been linked to response to therapy and clinical outcome. Exploring the mechanisms by which these FLT3 alterations lead to dysregulated proliferation should provide a better understanding of the molecular pathogenesis of acute myeloid leukemia (AML) and may provide insights into potential therapeutic interventions. FLT3 inhibitors are under evaluation for their efficacy in AML patients with FLT3 mutations.
Evolution of Functionally Diverse Alleles Associated with PTC Bitter Taste Sensitivity in Africa
Authors: M. C. Campbell, A. Ranciaro, A. Froment, J. Hirbo, S. Omar, J.-M. Bodo, T. Nyambo, G. Lema, D. Zinshteyn, D. Drayna, P. A. S. Breslin, S. A. Tishkoff
Journal: Molecular Biology and Evolution (2011)

Although human bitter taste perception is hypothesized to be a dietary adaptation, little is known about genetic signatures of selection and patterns of bitter taste perception variability in ethnically diverse populations with different diets, particularly from Africa. To better understand the genetic basis and evolutionary history of bitter taste sensitivity, we sequenced a 2,975 bp region encompassing TAS2R38, a bitter taste receptor gene, in 611 Africans from 57 populations in West Central and East Africa with diverse subsistence patterns, as well as in a comparative sample of 132 non-Africans. We also examined the association between genetic variability at this locus and threshold levels of phenylthiocarbamide (PTC) bitterness in 463 Africans from the above populations to determine how variation influences bitter taste perception. Here, we report striking patterns of variation at TAS2R38, including a significant excess of novel rare nonsynonymous polymorphisms that recently arose only in Africa, high frequencies of haplotypes in Africa associated with intermediate bitter taste sensitivity, a remarkably similar frequency of common haplotypes across genetically and culturally distinct Africans, and an ancient coalescence time of common variation in global populations. Additionally, several of the rare nonsynonymous substitutions significantly modified levels of PTC bitter taste sensitivity in diverse Africans. While ancient balancing selection likely maintained common haplotype variation across global populations, we suggest that recent selection pressures may have also resulted in the unusually high level of rare nonsynonymous variants in Africa, implying a complex model of selection at the TAS2R38 locus in African populations. Furthermore, the distribution of common haplotypes in Africa is not correlated with diet, raising the possibility that common variation may be under selection due to their role in nondietary biological processes. In addition, our data indicate that novel rare mutations contribute to the phenotypic variance of PTC sensitivity, illustrating the influence of rare variation on a common trait, as well as the relatively recent evolution of functionally diverse alleles at this locus.
Megaloblastic hematopoiesis in vitro. Interaction of anti-folate receptor antibodies with hematopoietic progenitor cells leads to a proliferative response independent of megaloblastic changes.
Authors: A C Antony, R A Briddell, J E Brandt, J E Straneva, R S Verma, M E Miller, L A Kalasinski, R Hoffman
Journal: Journal of Clinical Investigation (1991)

We tested the hypothesis that anti-placental folate receptor (PFR) antiserum-mediated effects on hematopoietic progenitor cells in vitro of increased cell proliferation and megaloblastic morphology were independent responses. We determined that (a) purified IgG from anti-PFR antiserum reacted with purified apo- and holo-PFR and specifically immunoprecipitated a single (44-kD) iodinated moiety on cell surfaces of low density mononuclear cells (LDMNC); (b) when retained in culture during in vitro hematopoiesis, anti-PFR IgG (in contrast to PFR-neutralized anti-PFR IgG and nonimmune IgG) consistently led to increased cloning efficiency of colony forming unit-erythroid (CFU-E), burst forming unit-E (BFU-E), CFU-granulocyte macrophage (CFU-GM), and CFU-GEM megakaryocyte (CFU-GEMM), and objectively defined megaloblastic changes in orthochromatic normoblasts from CFU-E- and BFU-E-derived colonies; (c) when anti-PFR antiserum was removed after initial (less than 1 h) incubation with LDMNC, a cell proliferation response was induced, but megaloblastic changes were not evident. (d) Conversely, delay at 4 degrees C for 24 h before long-term plating with antiserum resulted in megaloblastosis without increased cell proliferation; (e) however, 500-fold molar excess extracellular folate concentrations completely abrogated the expected anti-PFR antiserum-induced megaloblastic changes, without altering cell proliferative responses. Thus, although cell proliferative and megaloblastic changes are induced after short-term and prolonged interaction of antibody with folate receptors on hematopoietic progenitors, respectively, they are independent effects.
Bone marrow necrosis in acute leukemia: Clinical characteristic and outcome
Authors: Talha Badar, Aditya Shetty, Carlos Bueso‐Ramos, Jorge Cortes, Marina Konopleva, Gautam Borthakur, Sherry Pierce, Xuelin Huang, Hsiang‐Chun Chen, Tapan Kadia, Naval Daver, Courtney Dinardo, Susan O'Brien, Guillermo Garcia‐Manero, Hagop Kantarjian, Farhad Ravandi
Journal: American Journal of Hematology (2015)

Bone marrow necrosis (BMN) is characterized by infarction of the medullary stroma, leading to marrow necrosis with preserved cortical bone. In reported small series, BMN in hematological malignancies is associated with poor prognosis. We sought to find the impact of BMN on clinical outcome in a relatively larger cohort of patients with acute leukemias. Overall we evaluated 1,691 patients; 1,051 with acute myeloid leukemia (AML) and 640 with acute lymphocytic leukemia referred to our institution between 2002 and 2013. Patients with AML and acute lymphoblastic leukemia (ALL) were evaluated separately to determine the incidence of BMN, associated clinical features and its prognostic significance. At initial diagnosis, BMN was observed in 25 (2.4%) patients with AML and 20 (3.2%) patients with ALL. In AML, BMN was significantly associated with French-American-British AML M5 morphology (32% vs. 10%, P = 0.002). The complete remission (CR) rate in AML with and without BMN was 32% and 59% respectively (P = 0.008). Likewise, CR rate in ALL with BMN was also inferior, 70% vs. 92% (P = 0.005). The median overall survival (OS) in AML with BMN was significantly poorer, 3.7 months compared to 14 months without BMN (P = 0.003). Similarly, the median OS in ALL with and without BMN was 61.7 and 72 months respectively (P = 0.33). BMN is not a rare entity in AML and ALL, but is infrequent. BMN in AML and in ALL is suggestive of inferior response and poor prognosis.
Regulation of Aquaporin mRNA Expression in Rat Kidney by Water Intake
Authors: MARIA I. MURILLO-CARRETERO, ANUNCIACIÓN A. ILUNDÁIN, MIRIAM ECHEVARRIA
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Three aquaporins (AQP) are present in the membrane of the principal collecting duct cells. On the apical side, the levels of AQP2 protein are increased in response to both arginine vasopressin and water deprivation. However, whether this change parallels changes in the abundance of AQP3 and AQP4 in the basolateral membrane is less well known. This study evaluates the effect of either dehydration or water loading on the rat kidney mRNA expression of AQP2, AQP3, and AQP4. Poly(A + )RNA was prepared from renal cortex and medulla of control, water-deprived, well hydrated, and water-deprived rats treated with OPC31260, a V2 receptor antagonist. Northern blots were done and mRNA levels were quantified using a PhosphorImager system. Relative to control, water deprivation increased the expression of cortical AQP2, -3, and -4, whereas water loading decreased the cortical and medullar expression of AQP2, -3, and -4. Therefore, in addition to AQP2 and -3, AQP4 expression is also regulated by water intake. Treatment with OPC31260 (40 mg/kg of weight per d) inhibited up to 20 to 30% the upregulation of AQP-mRNA induced by water deprivation. Blood values of arginine vasopressin and aldosterone were significantly increased by water deprivation, whereas they were unchanged by water overloading. Taken together, these results indicate that renal AQP2, -3, and -4 expression is regulated in a coordinated manner. Simultaneous up- or downregulation of the three transcripts occurred upon either water deprivation or water loading of animals, respectively. However, the signaling mechanism for the two longterm adaptive processes may be different, and, in addition to arginine vasopressin, other factors may be involved in the transcriptional regulatory processes.
Probiotics prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological stress
Authors: M Zareie, K Johnson-Henry, J Jury, P-C Yang, B-Y Ngan, D M McKay, J D Soderholm, M H Perdue, P M Sherman
Journal: Gut (2006)

<b>Background and aim:</b> Chronic psychological stress, including water avoidance stress (WAS), induces intestinal mucosal barrier dysfunction and impairs mucosal defences against luminal bacteria. The aim of this study was to determine the ability of a defined probiotic regimen to prevent WAS induced intestinal pathophysiology. <b>Methods:</b> Male rats were subjected to either WAS or sham stress for one hour per day for 10 consecutive days. Additional animals received seven days of <i>Lactobacillus helveticus</i> and <i>L rhamnosus</i> in the drinking water prior to stress and remained on these probiotics for the duration of the study. Rats were then sacrificed, intestinal segments assessed in Ussing chambers, and mesenteric lymph nodes cultured to determine bacterial translocation. <b>Results:</b> All animals remained healthy for the duration of the study. Chronic WAS induced excess ion secretion (elevated baseline short circuit current) and barrier dysfunction (increased conductance) in both the ileum and colon, associated with increased bacterial adhesion and penetration into surface epithelial cells. Approximately 70% of rats subjected to WAS had bacterial translocation to mesenteric lymph nodes while there was no bacterial translocation in controls. Probiotic pretreatment alone had no effect on intestinal barrier function. However, WAS induced increased ileal short circuit current was reduced with probiotics whereas there was no impact on altered conductance. Pretreatment of animals with probiotics also completely abrogated WAS induced bacterial adhesion and prevented translocation of bacteria to mesenteric lymph nodes. <b>Conclusion:</b> These findings indicate that probiotics can prevent chronic stress induced intestinal abnormalities and, thereby, exert beneficial effects in the intestinal tract.
Genetic Analysis of the Interleukin-18 System Highlights the Role of the Interleukin-18 Gene in Cardiovascular Disease
Authors: Laurence Tiret, Tiphaine Godefroy, Edith Lubos, Viviane Nicaud, David-Alexandre Tregouet, Sandrine Barbaux, Renate Schnabel, Christoph Bickel, Christine Espinola-Klein, Odette Poirier, Claire Perret, Thomas Münzel, Hans-Jurgen Rupprecht, Karl Lackner, François Cambien, Stefan Blankenberg
Journal: Circulation (2005)

Background— Interleukin (IL)-18 plays a key role in atherosclerosis and its complications. The present study investigated the genetic variability of 4 genes of the IL-18 system— IL18 , IL18R1 , IL18RAP , and IL18BP —in relation to circulating IL-18 levels and cardiovascular mortality. Methods and Results— Twenty-two polymorphisms were genotyped in 1288 patients with coronary artery disease prospectively followed up during a median period of 5.9 years. The end point was death from cardiovascular causes (n=142). Baseline IL-18 levels were predictive of cardiovascular deaths occurring during ≤4 years of follow-up (HR=2.96, 95% CI 1.54 to 5.70, P =0.001 for the top compared with the bottom quartile) but not of later deaths. Haplotypes of the IL18 gene were associated with IL-18 levels ( P =0.002) and cardiovascular mortality ( P =0.006) after adjustment for cardiovascular risk factors. The same haplotype was associated with both a 9% lowering effect on IL-18 levels and a protective effect on risk (HR=0.57, 95% CI 0.36 to 0.92). IL18 haplotypes explained only 2% of IL-18 variability. Adjustment for baseline IL-18 levels abolished the association of haplotypes with cardiovascular risk. The haplotype associated with phenotypes was the only one carrying the minor allele of the IL18 /A+183G polymorphism located in the 3′untranslated region and potentially affecting mRNA stability. The other genes of the system were not related to IL-18 levels or cardiovascular outcome. Conclusion— Variations of the IL18 gene consistently influence circulating levels of IL-18 and clinical outcome in patients with coronary artery disease, which supports the hypothesis of a causal role of IL-18 in atherosclerosis and its complications.
Neglecting the posterior parietal cortex: The role of higher-order perceptual memories for working-memory retention
Authors: Axel Mecklinger, Bertram Opitz
Journal: Behavioral and Brain Sciences (2003)

The view that posterior brain systems engaged in lower-order perceptual functions are activated during sustained retention is challenged by fMRI data, which show consistent retention-related activation of higher-order memory representations for a variety of working-memory materials. Sustained retention entails the dynamic link of these higher-order memories with schemata for goal-oriented action housed by the frontal lobes.
INHIBITION OF PROTEIN SYNTHESIS IN MAMMALIAN CELL-FREE SYSTEMS BY CHLORAMPHENICOL
Authors: Austin S. Weisberger, Sidney Wolfe, Steven Armentrout
Journal: The Journal of Experimental Medicine (1964)

Chloramphenicol can inhibit protein synthesis in mammalian cell-free systems as effectively as it inhibits protein synthesis in analogous microbial systems. Significant inhibition in mammalian systems was obtained only when protein synthesis was stimulated by the addition of template RNA to the system, there being comparatively little inhibition of protein synthesis by ribosomes in the absence of stimulatory RNA. It is postulated that chloramphenicol may inhibit the function of messenger or template RNA by successfully competing for ribosomal binding sites, thereby preventing the attachment of RNA to ribosomes. The apparent discrepancy in the sensitivity of mammalian and microbial cells to chloramphenicol may be related to differences in turnover or stability of ribosomal template RNA rather than to intrinsic differences in mechanism of protein synthesis. These observations are in accord with the suggestion that protein synthesis in intact mammalian cells may be susceptible to chloramphenicol inhibition only at the time that new messenger or template RNA is being deposited on ribosomes and that more mature cells may be resistant because informative RNA already deposited on ribosomes is not accessible to chloramphenicol inhibition. The inhibitory effect of chloramphenicol on protein synthesis in proliferating cells may be an important factor in hematologic toxicity attributable to chloramphenicol.