tbuckley/cabot-search huggingface dataset:
Paradoxical resistance to diet-induced obesity in UCP1-deficient mice
Authors: Xiaotuan Liu, Martin Rossmeisl, Jennifer McClaine, Leslie P. Kozak
Journal: Journal of Clinical Investigation (2003)

The availability of mice lacking the mitochondrial uncoupling protein UCP1, has provided an opportunity to analyze the relationship between the capacity for energy expenditure and the development of obesity in response to a high-fat, high-sucrose diet. Congenic UCP1-deficient mice on a C57BL/6J genetic background show a temperature-dependent resistance to diet-induced obesity when compared with wild-type mice. This resistance, which occurs at 20°C, is quickly reversed when the ambient temperature is increased to 27°C. At 20°C, total oxygen consumption and physical activity of mutant and wild-type mice are indistinguishable; however, body temperature is higher in UCP1-deficient mice by 0.1–0.3°C, and respiratory quotient is slightly reduced. A reduced respiratory quotient, together with elevated β-hydroxybutyrate and reduced plasma fatty acid levels, suggests that the mutants oxidize a greater proportion of fat than wild-type mice, and that this possibly accounts for the resistance to diet-induced obesity. Although shivering is one alternative mechanism of thermogenesis that is probably used in UCP1-deficient mice, whether there are others remains to be determined. Nevertheless, our study underscores the paradox that elimination of the major thermogenic mechanism in the animal reduces rather than increases metabolic efficiency. We propose that in the absence of nonshivering thermogenesis, alternative, calorically more costly pathways of metabolism must be used to maintain body temperature.
Rapid mixed lymphocyte culture testing by analysis of the insulin receptor on alloactivated T lymphocytes: implications for human tissue typing.
Authors: J H Helderman, T B Strom, M R Garovoy
Journal: Journal of Clinical Investigation (1981)

Responses in the mixed lymphocyte culture (MLC) are traditionally evaluated by measurement of DNA synthesis or blast transformation. However, these events occur too late in the MLC to permit prospective matching for cadaveric renal transplantation. Presentation of allogeneic cells to the T lymphocyte within the MLC results in the emergence of an insulin receptor pharmacokinetically similar to that on other tissues such as fat, liver, and muscle. Intrafamilial MLC were studied by simultaneous assessment of DNA synthesis and insulin receptor binding. In 68 studies from seven families that provide examples of two haplotype identical matches, haplo-identical matches and total haplo mismatches, the presence of an insulin receptor correlated in every case with a positive MLC as estimated by [3H]thymidine incorporation. A quantitative relationship existed between the strength of the MLC and the amount of receptor binding. Based on analysis of cells from several families in which crossover events were known to have occurred, the appearance of an insulin receptor always corresponded with a mismatch at the portion of histocompatibility leukocyte antigen (HLA) chromosome bearing the D region. Finally, it was demonstrated in each of 30 cultures that insulin receptor emergence occurred significantly before detectable DNA synthesis, as early as 24 h after the initiation of the MLC, well within the time-constraint limitations for renal preservation. Appearance of the insulin receptor on activated lymphocytes may be a more rapid measure of mixed lymphocyte responses, and should permit prospective matching for cadaveric renal transplantation.
The anticipatory regulation of performance: the physiological basis for pacing strategies and the development of a perception-based model for exercise performance
Authors: R Tucker
Journal: British Journal of Sports Medicine (2009)

During self-paced exercise, the exercise work rate is regulated by the brain based on the integration of numerous signals from various physiological systems. It has been proposed that the brain regulates the degree of muscle activation and thus exercise intensity specifically to prevent harmful physiological disturbances. It is presently proposed how the rating of perceived exertion (RPE) is generated as a result of the numerous afferent signals during exercise and serves as a mediator of any subsequent alterations in skeletal muscle activation levels and exercise intensity. A conceptual model for how the RPE mediates feedforward, anticipatory regulation of exercise performance is proposed, and this model is applied to previously described research studies of exercise in various conditions, including heat, hypoxia and reduced energy substrate availability. Finally, the application of this model to recent novel studies that altered pacing strategies and performance is described utilising an RPE clamp design, central nervous system drugs and the provision of inaccurate duration or distance feedback to exercising athletes.
Study design biases in pancreatic inflammatory diseases
Authors: Giulia Martina Cavestro, Alberto Mariani, Satish K Singh, Paolo Giorgio Arcidiacono, Pier Alberto Testoni
Journal: Gut (2012)

The recent report by Sadr-Azodi et al entitled ‘Cigarette smoking, smoking cessation and acute pancreatitis: a prospective population-based study,’1 suggests that smoking is an important risk factor for non-gallstone-related acute pancreatitis.

In this study, the examined populations consisted of participants from the Swedish Mammography Cohort (SMC) established between 1987 and 1990. A questionnaire pertaining to diet, body size and education was mailed to 90 303 women born between 1914 and 1948; 66 651 women (74%) returned the questionnaire. In 1997, all surviving participants (56 030) received a new expanded questionnaire regarding anthropometric and lifestyle factors, including smoking status: 38 988 women returned a completed questionnaire. In addition in 1997, a questionnaire identical to the one …
Temperature Differentials and Metabolic Acidosis in Profound Hypothermia
Authors: Sidney K. Wolfson, Erdogan H. Yalav, Saul Eisenstat
Journal: JAMA (1963)

METABOLIC ACIDOSIS following profound hypothermia has been attributed to hypoxia due to inadequate perfusion. This condition is most severe when complete circulatory arrest is effected. Evidence has been presented suggesting that temp differentials within the body may be a major contributor to this hypoxia.<sup>1-3</sup>Lactic acid concentrations have been observed to be higher in femoral vein blood than in mixed venous blood. Temp differentials could result in hypoxia of peripheral tissues, since with blood heat exchanger techniques their circulation would be curtailed early in accordance with the decreased "core" temp before the average body temp is reduced adequately. The major muscle mass lies within these peripheral areas. Under normothermic or moderately hypothermic conditions, it is possible to maintain a rate of perfusion which will minimize this effect. However, when central temp are below 20 C (68 F), it is difficult to have higher flow rates because of the
Small intestinal nodular lymphoid hyperplasia in patients with giardiasis and normal serum immunoglobulins.
Authors: H Ward, K N Jalan, T K Maitra, S K Agarwal, D Mahalanabis
Journal: Gut (1983)

Nodular lymphoid hyperplasia of the upper small intestine was demonstrated in 25 patients with giardiasis. All had normal serum immunoglobulin levels and seven patients initially presented with clinical findings suggestive of an abdominal lymphoma. In only two, however, was the diagnosis of primary jejunal lymphoma confirmed. It is possible that an aetiological relationship exists between recurrent parasitic infestation and nodular lymphoid hyperplasia of the upper small intestine.
S101 Src/bcr-abl Inhibition With Dasatinib In Sterile And Non-sterile Acute Lung Inflammation
Authors: J. Macfarlane, D. Dorward, C. Lucas, J. Scott, M. Ruchaud-Sparagano, C. Khan, A. Rossi, A. Simpson
Journal: Thorax (2014)

<h3>Introduction and objectives</h3> Adult respiratory distress syndrome (ARDS) is a commonly fatal complication of lung infection and inflammation, with no effective treatment. It is characterised by excessive neutrophil influx and degranulation into the lungs, with alveolar leak and severe hypoxia. <i>Src</i> family tyrosine kinases are critical in integrin-dependent neutrophil degranulation. Dasatinib is a <i>Src/Bcr-abl </i>inhibitor used in chronic myeloid leukaemia. We investigated our hypothesis that extracellular neutrophil degranulation could be inhibited by dasatinib <i>in vitro</i> and would modulate the inflammatory response <i>in vivo</i> in models of infective and sterile lung injury. <h3>Methods</h3> Whole blood and isolated blood neutrophils from healthy volunteers were pre-treated with dasatinib and treated with neutrophil stimuli or live bacteria. Degranulation was measured by granule receptor expression and presence of extracellular granule products. Other neutrophil functions were assessed, including adhesion, L-selectin shedding, chemotaxis, phagocytosis, oxidative burst, bacterial killing and apoptosis. Neutrophilic lung inflammation was induced in mice using intratracheal <i>E. coli</i> or hydrochloric acid. <h3>Results</h3> <i>In vitro</i>, dasatinib inhibited neutrophil degranulation in response to lipopolysaccharide derived from <i>E. Coli</i> 026:B6, fMLF and <i>Staphylococcus aureus</i> at concentrations above 100 nM, with no effect on neutrophil viability or apoptosis. Integrin-dependent functions including adhesion, chemotaxis and phagocytosis in adherent conditions were impaired, but phagocytosis was unaffected in whole blood. Intracellular oxidative burst was maintained, with normal bacterial killing, but extracellular superoxide anion release was impaired. <i>In vivo,</i> dasatinib had modest effects on the pro-inflammatory response to <i>E. coli</i>, reducing%interstitial neutrophils, alveolar myeloperoxidase and TNFα at 1 mg/kg and alveolar lactoferrin at 10 mg/kg. Bacterial killing was impaired in a dose dependent fashion, with associated alveolar leak and systemic toxicity at 10 mg/kg. In sterile acid injury, 5 mg/kg dasatinib reduced%neutrophils, degranulation (interstitial CD11b/alveolar lactoferrin) and monocyte-chemotactic protein-1 (MCP-1) in the alveolar space, but induced detrimental effects at 10 mg/kg. <h3>Conclusions</h3> The pan-<i>Src</i> kinase inhibitor dasatinib modifies multiple pro-inflammatory neutrophil functions <i>in vitro</i> and <i>in vivo</i> with an impairment in bacterial killing observed in infective lung injury. In the context of sterile inflammation, manipulation of neutrophil degranulation also alters the inflammatory environment and this approach warrants further study as a therapeutic strategy in ARDS.
Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study
Authors: Huining Kang, Carla S. Wilson, Richard C. Harvey, I.-Ming Chen, Maurice H. Murphy, Susan R. Atlas, Edward J. Bedrick, Meenakshi Devidas, Andrew J. Carroll, Blaine W. Robinson, Ronald W. Stam, Maria G. Valsecchi, Rob Pieters, Nyla A. Heerema, Joanne M. Hilden, Carolyn A. Felix, Gregory H. Reaman, Bruce Camitta, Naomi Winick, William L. Carroll, ZoAnn E. Dreyer, Stephen P. Hunger, Cheryl L. Willman
Journal: Blood (2011)
Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling
Authors: Xiwu Chen, Hongtao Wang, Hong-Jun Liao, Wen Hu, Leslie Gewin, Glenda Mernaugh, Sheng Zhang, Zhong-Yin Zhang, Lorenzo Vega-Montoto, Roberto M. Vanacore, Reinhard Fässler, Roy Zent, Ambra Pozzi
Journal: Journal of Clinical Investigation (2014)

Tubulointerstitial fibrosis underlies all forms of end-stage kidney disease. TGF-β mediates both the development and the progression of kidney fibrosis through binding and activation of the serine/threonine kinase type II TGF-β receptor (TβRII), which in turn promotes a TβRI-mediated SMAD-dependent fibrotic signaling cascade. Autophosphorylation of serine residues within TβRII is considered the principal regulatory mechanism of TβRII-induced signaling; however, there are 5 tyrosine residues within the cytoplasmic tail that could potentially mediate TβRII-dependent SMAD activation. Here, we determined that phosphorylation of tyrosines within the TβRII tail was essential for SMAD-dependent fibrotic signaling within cells of the kidney collecting duct. Conversely, the T cell protein tyrosine phosphatase (TCPTP) dephosphorylated TβRII tail tyrosine residues, resulting in inhibition of TβR-dependent fibrotic signaling. The collagen-binding receptor integrin α1β1 was required for recruitment of TCPTP to the TβRII tail, as mice lacking this integrin exhibited impaired TCPTP-mediated tyrosine dephosphorylation of TβRII that led to severe fibrosis in a unilateral ureteral obstruction model of renal fibrosis. Together, these findings uncover a crosstalk between integrin α1β1 and TβRII that is essential for TβRII-mediated SMAD activation and fibrotic signaling pathways.
THE EFFECT OF ACTH AND PATHOLOGICAL INCREASES IN ADRENAL CORTICAL FUNCTION ON URINARY ALPHAKETOLIC STEROID METABOLITES 1
Authors: F. C. Dohan, J. C. Touchstone, E. M. Richardson, Helen Bulaschenko, Irmgard Landolt, Walter Applin
Journal: Journal of Clinical Investigation (1955)

Previous studies ( 1 ) have shown that the specific alpha-ketolic steroid metabolites found in the urine after administration of a known alpha- ketolic steroid reflect, to a limited extent, the na- ture of the precursor.With this study as a base- line, we have determined the major urinary alpha- ketolic steroid metabolites found after intravenous infusion of human subjects with ACTH, and some of those found in the urine of a man with Cush- ing's syndrome, and in that of a woman with meta- static adrenocortical carcinoma.The results of this study and some speculations concerning the possible nature and rate of alpha-ketolic steroid secretion are presented in this paper. METHODSMethods employed and their limitations have been pre- sented previously (1).Terminology has been previously discussed (1).The abbreviations employed are indicated in Table I.The commonly employed letter designations (Kendall's compounds F, E, B, and A; Reichstein's S and DOC) have been used with the addition that HI indicates the tetrahydro compound (Pregnane-3a-ol) and H, in- dicates the "dihydro compound" (Pregnane-3-one).Glu- curonidase, 100 units per ml. of urine, was employed for hydrolysis.(It is now recognized that this is insufficient for maximum hydrolysis and hence for maximum yield.)After glucuronidase hydrolysis, the urine was extracted at pH 1 with CHC1, for one hour on an os- cillating shaker.Paper chromatographic separation was accomplished primarily by using the toluene-propylene glycol system of Burton, Zaffaroni, and Keutmann (2).After development of the chromatogram, the absorption of ultra-violet light of the paper strip at 245 mn was de- termined directly in a Beckman DU spectrophotometer
Human suction blister interstitial fluid prevents metal ion-dependent oxidation of low density lipoprotein by macrophages and in cell-free systems.
Authors: A J Dabbagh, B Frei
Journal: Journal of Clinical Investigation (1995)

LDL in the circulation is well protected against oxidation by the highly efficient antioxidant defense mechanisms of human plasma. LDL oxidation contributing to atherosclerosis, therefore, has been hypothesized to take place in the interstitial fluid of the arterial wall. We investigated the antioxidant composition and the capacity to inhibit LDL oxidation of human suction blister interstitial fluid (SBIF), a suitable representative of interstitial fluid. We found that the concentrations in SBIF of the aqueous small-molecule antioxidants ascorbate and urate were, respectively, significantly higher (P < 0.05) and identical to plasma concentrations. In contrast, lipoprotein-associated lipids and lipid-soluble antioxidants (alpha-tocopherol, ubiquinol-10, lycopene, and beta-carotene) were present at only 8-23% of the concentrations in plasma. No lipid hydroperoxides could be detected ( < 5 nM) in either fluid. The capacity of serum and SBIF to protect LDL from oxidation was investigated in three metal ion-dependent systems: copper, iron, and murine macrophages in Ham's F-10 medium. In all three systems, addition of > or = 6% (vol/vol) of either serum or SBIF inhibited LDL oxidation by > 90%. The concentration that inhibited macrophage-mediated LDL oxidation by 50% was as low as 0.3% serum and 0.7% SBIF. The enzymatic or physical removal of ascorbate or urate and other low molecular weight components did not affect the ability of either fluid to prevent LDL oxidation, and the high molecular weight fraction was as protective as whole serum or SBIF. These data demonstrate that both serum and SBIF very effectively protect LDL from metal ion-dependent oxidation, most probably because of a cumulative metal-binding effect of several proteins. Our data suggest that LDL in the interstitial fluid of the arterial wall is very unlikely to get modified by metal ion-mediated oxidation.
Methane excretion in man.
Authors: Y Peled
Journal: Gut (1985)

<h3>Abstract</h3> The extent to which genomic convergence shapes locally adapted phenotypes in different species remains a fundamental question in evolutionary biology. To bring new insights to this debate we set up a framework which aimed to compare the adaptive trajectories of two domesticated mammal species co-distributed in diversified landscapes. We sequenced the genomes of 160 sheep and 161 goats extensively managed along environmental gradients, including temperature, rainfall, seasonality and altitude, to identify genes and biological processes shaping local adaptation. Allele frequencies at adaptive loci were rarely found to vary gradually along environmental gradients, but rather displayed a discontinuous shift at the extremities of environmental clines. Of the more than 430 adaptive genes identified, only 6 were orthologous between sheep and goats and those responded differently to environmental pressures, suggesting different adaptive mechanisms in these two closely related species. Such diversity of adaptive pathways may result from a high number of biological functions involved in adaptation to multiple eco-climatic gradients, and provides more arguments for the role of contingency and stochasticity in adaptation rather than repeatability.
P18.10 * ASSESSMENT OF CLINICAL SIGNS AND SYMPTOMS AS WELL AS TREATMENT IN THE END OF LIFE OF GLIOBLASTOMA PATIENTS
Authors: K. Thier, B. Calabek, A. Tinchon, W. Grisold, S. Oberndorfer
Journal: Neuro-Oncology (2014)

INTRODUCTION: High grade gliomas are the most frequent primary brain tumours. Despite improvement of novel targeted therapies survival is still poor. In the last years the importance of quality of life came to the fore. It is well known that patients who suffer from a primary malignant brain tumour differ in the end of life phase from other oncological patients. The aim of this study is to survey sign and symptoms as well as therapeutic strategies in patients with malignant gliomas in an end of life hospital setting. METHODS: The end of life of 57 consecutive patients, who died due to a malignant glioma in a hospital setting, was analysed prospectively using a standardized protocol. Clinical signs and symptoms and supportive therapy were analysed within the last 10 days before death. RESULTS: Sixty-eight percent of patients (n = 39/57) were male, 32% (n= 18/57) were female with a mean age of 59 years (Standard deviation [SD] ±11) and an overall survival of 48 weeks (SD ±47). Most frequent symptoms were decrease of vigilance (95%, n = 54/57), fever (88%, n = 50/54), dysphagia (65%, n = 37/54), seizures (65%, n = 37/57) and headache (33%, n = 19/57). Eighteen patients (32%) sustained pneumonia. In 13 patients (23%) a urinary tract infection was diagnosed. With respect to treatment, 95% (n = 54/57) needed opioids. In 77% (n = 44/57) NSAIDs were administered additively. 86% (n = 49/57) received gastric protection, 88% (n = 50/57) LMWH and 91% (n= 52/57) intravenous fluids. In 75% (n = 43/57) anticonvulsant medication was needed. Steroids were administered in 56% (n = 32/57) of patients and only 26% (n = 15/57) received antibiotics. DISCUSSION: Due to a decrease of vigilance and cognitive impairment, assessment of clinical signs and symptoms such as pain in the end of life is often difficult. As reported signs and symptoms such as headache, dysphagia, seizures and fever are the most common ones, interventions and treatment strategies should be focused on these symptoms. Our study emphasizes the importance of standardized guidelines for end of life care in patients with malignant gliomas.
<i>Bartonella</i> Adhesin A Mediates a Proangiogenic Host Cell Response
Authors: Tanja Riess, Siv G.E. Andersson, Andrei Lupas, Martin Schaller, Andrea Schäfer, Pierre Kyme, Jörg Martin, Joo-Hee Wälzlein, Urs Ehehalt, Hillevi Lindroos, Markus Schirle, Alfred Nordheim, Ingo B. Autenrieth, Volkhard A.J. Kempf
Journal: The Journal of Experimental Medicine (2004)

Bartonella henselae causes vasculoproliferative disorders in humans. We identified a nonfimbrial adhesin of B. henselae designated as Bartonella adhesin A (BadA). BadA is a 340-kD outer membrane protein encoded by the 9.3-kb badA gene. It has a modular structure and contains domains homologous to the Yersinia enterocolitica nonfimbrial adhesin (Yersinia adhesin A). Expression of BadA was restored in a BadA-deficient transposon mutant by complementation in trans. BadA mediates the binding of B. henselae to extracellular matrix proteins and to endothelial cells, possibly via β1 integrins, but prevents phagocytosis. Expression of BadA is crucial for activation of hypoxia-inducible factor 1 in host cells by B. henselae and secretion of proangiogenic cytokines (e.g., vascular endothelial growth factor). BadA is immunodominant in B. henselae–infected patients and rodents, indicating that it is expressed during Bartonella infections. Our results suggest that BadA, the largest characterized bacterial protein thus far, is a major pathogenicity factor of B. henselae with a potential role in the induction of vasculoproliferative disorders.