tbuckley/cabot-search huggingface dataset:
Sodium-Hydrogen Exchanger Regulatory Factor-1 Interacts with Mouse Urate Transporter 1 to Regulate Renal Proximal Tubule Uric Acid Transport
Authors: Rochelle Cunningham, Marc Brazie, Srilatha Kanumuru, Xiaofei E, Rajat Biswas, Fengying Wang, Deborah Steplock, James B. Wade, Naohiko Anzai, Hitoshi Endou, Shirish Shenolikar, Edward J. Weinman
Journal: Journal of the American Society of Nephrology (2007)

Sodium-hydrogen exchanger regulatory factor-1-deficient (NHERF-1(-/-)) mice demonstrate increases in the urinary excretion of phosphate, calcium, and uric acid associated with interstitial deposition of calcium in the papilla of the kidney. These studies examine the role of NHERF-1 in the tubular reabsorption of uric acid and regulation of mouse urate transporter 1 (mURAT1), a newly described transporter that is responsible for the renal tubular reabsorption of uric acid. In primary cultures of mouse renal proximal tubule cells, uric acid uptake was significantly lower in NHERF-1(-/-) cells compared with wild-type cells over a large range of uric acid concentrations in the media. Western immunoblotting revealed a 56 +/- 6% decrease in the brush border membrane (BBM) expression of mURAT1 in NHERF-1(-/-) compared with wild-type control kidneys (P < 0.05). Confocal microscopy confirmed the reduced apical membrane expression of mURAT1 in NHERF-1(-/-) kidneys and demonstrated mislocalization of mURAT1 to intracellular vesicular structures. Para-aminohippurate significantly inhibited uric acid uptake in wild-type cells (41 +/- 2%) compared with NHERF-1(-/-) cells (8.2 +/- 3%). Infection of NHERF-1(-/-) cells with adenovirus-green fluorescence protein-NHERF-1 resulted in significantly higher rates of uric acid transport (15.4 +/- 1.1 pmol/microg protein per 30 min) compared with null cells that were infected with control adenovirus-green fluorescence protein (7.9 +/- 0.3) and restoration of the inhibitory effect of para-aminohippurate (% inhibition 34 +/- 4%). These findings indicate that NHERF-1 exerts a significant effect on the renal tubular reabsorption of uric acid in the mouse by modulating the BBM abundance of mURAT1 and possibly other BBM uric acid transporters.
NHS may have to charge for some services if spending does not increase, report warns
Authors: Helen Mooney
Journal: BMJ (2015)

The NHS will not be able to react quickly enough to achieve the £22bn (€31.6bn; $34.3bn) in efficiency savings set by the government by the 2020 target, a new report has warned.1

The Chartered Institute of Public Finance and Accountancy (CIPFA), the body for public finance professionals, has issued a stark warning that the NHS is unlikely to achieve such an unprecedented level of savings over the next five years while maintaining the same level of service.

The CIPFA …
High prevalence of asthma in five remote indigenous communities in Australia
Authors: P.C. Valery, A.B. Chang, S. Shibasaki, O. Gibson, D.M. Purdie, C. Shannon, I.B. Masters
Journal: European Respiratory Journal (2001)

Data on the prevalence of asthma in children residing in remote indigenous communities in Australia are sparse, despite the many reports of high prevalence in nonindigenous children of this country. Two previous Australian studies have had poor participation rates, limiting interpretation of their results. A study of children in the Torres Strait and Northern Peninsula Area of Australia was conducted to document the prevalence of asthma symptoms. Five indigenous communities were randomly selected and trained interviewers, who were local indigenous health workers, recruited participants using a house-by-house approach. Information was collected by a structured face-to-face interview based on a standardized questionnaire constructed from the protocol International Study of Asthma and Allergy in Childhood; 1,650 children were included in the study with a 98% response rate. Overall, the prevalence of self-reported ever wheezing was 21%; 12% reported wheezing in the previous year; and 16% reported ever having asthma. There was significant variation in the prevalence of asthma symptoms between communities. It is concluded that there are significant intercommunity variations in the prevalence of asthma symptoms in remote communities and that the prevalence in these communities is as high as in nonindigenous groups.
Experimental non-steroidal anti-inflammatory drug-induced enteropathy in the rat: similarities to inflammatory bowel disease and effect of thromboxane synthetase inhibitors.
Authors: A K Banerjee, T J Peters
Journal: Gut (1990)

We have validated an established animal model of acute inflammatory bowel disease in indomethacin-treated rats. Studies in both in vitro and in vivo 51chromium-labelled ethylenediamine tetra-acetate (51Cr-EDTA) permeability and tissue myeloperoxidase activity, a marker of inflammatory cell invasion, showed increased permeability and enzyme levels, respectively, in treated animals compared to controls (in vitro 51Cr-EDTA permeability: (mean (SE] control 0.10 (0.02) microliter/mg per tissue, experimental 0.17 (0.02) (p &lt; 0.01, 2 way analysis of variance); in vivo 51Cr-EDTA permeability: control 3.9 (1.3) (% dose recovered), experimental 12.1 (1.5) (p &lt; 0.01); tissue myeloperoxidase: control 10.8 (0.4) mU/mg, experimental 17.2 (0.5) p less than 0.01). Pretreatment or simultaneous treatment of indomethacin-treated animals with glucocorticoids, sulphasalazine, or tetracycline reduced the permeability changes and the tissue inflammatory response (in vitro 51Cr-EDTA permeability: (mean (SE] sulphasalazine + indomethacin 0.11 (0.2) microliter/mg tissue (p &lt; 0.01), prednisolone +/- indomethacin 0.12 (0.02) (p &lt; 0.01), tetracycline + indomethacin 0.12 (0.02) (p &lt; 0.01]. Glucocorticoids and sulphasalazine, but not tetracycline, administered after the indomethacin also partially corrected the permeability and inflammatory changes induced by indomethacin (in vitro 51Cr-EDTA permeability: sulphasalazine 0.15 (0.02) microliter/mg, p &lt; 0.02; prednisolone 0.12 (0.02) microliter/mg, p &lt; 0.01). This approach was used to investigate the effects of two different thromboxane synthetase inhibitors in indomethacin-treated animals. Simultaneous treatment with thromboxane synthetase inhibitors and indomethacin prevented the 51Cr-EDTA permeability and tissue myeloperoxidase increases induced by indomethacin alone (in vitro 51Cr-EDTA permeability: thromboxane synthetase inhibitors + indomethacin 0.11 (0.01) microliter/mg (p0.01); tissue myeloperoxidase: 11 (0.4) mU/mg, (p &lt; 0.01). Thromboxane synthetase inhibitors administered after the indomethacin also partially corrected the permeability and inflammatory changes induced by indomethacin (in vitro 51Cr-EDTA permeability: thromboxane synthetase inhibitors 0.12 (0.02) mU/mg (p &lt; 0.01); tissue myeloperoxidase 13.8 (0.5) (p &lt; 0.01). These studies indicate that thromboxane synthetase inhibitors partially correct the intestinal lesion non-steroidal anti-inflammatory drug enteropathy and may therefore be of use in inflammatory bowel diseases in humans.
Ventricular intramural and epicardial potential distributions during ventricular activation and repolarization in the intact dog.
Authors: M S Spach, R C Barr
Journal: Circulation Research (1975)

Ventricular intramural and epicardial potential distributions were measured during normal excitation and repolarization in intact dogs. Potential distributions were chosen because they can be unambiguously measured, are useful in understanding the shapes of wave forms at many specific sites, and provide a direct measure of repolarization. Unipolar wave forms were recorded from intramural and epicardial electrodes and converted into potential distributions. Well-known shapes of wave forms recorded at the inner and outer layers of the ventricles as well as peak-to-peak voltages were shown by the potential distributions to be determined primarily by superposition effects of distant excitation waves. These effects were most prominent before epicardial breakthrough and then receded during the last half of the QRS complex. However, the potential distributions became more complex as excitation waves merged, collided, and terminated. During terminal depolarization, there were scattered positive repolarization potentials intramurally. Normal repolarization was characterized by positive potentials over the ventricular epicardium while there were changes intramurally and on the atrium. Throughout the T wave, there was a predominant transmural unidirectional gradient with the inner wall being more negative than the outer wall. This finding confirms that the sequence of repolarization is from the epicardium to the endocardium with the middle layers having an intermediate time.
Markers of Inflammation and Cardiovascular Disease
Authors: Thomas A. Pearson, George A. Mensah, R. Wayne Alexander, Jeffrey L. Anderson, Richard O. Cannon, Michael Criqui, Yazid Y. Fadl, Stephen P. Fortmann, Yuling Hong, Gary L. Myers, Nader Rifai, Sidney C. Smith, Kathryn Taubert, Russell P. Tracy, Frank Vinicor
Journal: Circulation (2003)

In 1998, the American Heart Association convened Prevention Conference V to examine strategies for the identification of high-risk patients who need primary prevention. Among the strategies discussed was the measurement of markers of inflammation.1 The Conference concluded that “many of these markers (including inflammatory markers) are not yet considered applicable for routine risk assessment because of: (1) lack of measurement standardization, (2) lack of consistency in epidemiological findings from prospective studies with endpoints, and (3) lack of evidence that the novel marker adds to risk prediction over and above that already achievable through the use of established risk factors.” The National Cholesterol Education Program Adult Treatment Panel III Guidelines identified these markers as emerging risk factors,1a which could be used as an optional risk factor measurement to adjust estimates of absolute risk obtained using standard risk factors. Since these publications, a large number of peer-reviewed scientific reports have been published relating inflammatory markers to cardiovascular disease (CVD). Several commercial assays for inflammatory markers have become available. As a consequence of the expanding research base and availability of assays, the number of inflammatory marker tests ordered by clinicians for CVD risk prediction has grown rapidly. Despite this, there has been no consensus from professional societies or governmental agencies as to how these assays of markers of inflammation should be used in clinical practice.

On March 14 and 15, 2002, a workshop titled “CDC/AHA Workshop on Inflammatory Markers and Cardiovascular Disease: Applications to Clinical and Public Health Practice” was convened in Atlanta, Ga, to address these issues. The goals of this workshop were to determine which of the currently available tests should be used; what results should be used to define high risk; which patients should be tested; and the indications for which the tests would be most useful. These …
Interleukin 1-Dependent and -Independent Mouse Melanoma Metastases
Authors: M. J. Anasagasti, E. Olaso, F. Calvo, L. Mendoza, J. J. Martin, J. Bidaurrazagav, F. Vidal-Vanaclocha
Journal: JNCI Journal of the National Cancer Institute (1997)

The adhesion of cancer cells to the endothelial lining of blood vessels, which is important for metastasis, is promoted by the action of interleukin 1 (IL-1) and other cytokines.IL-1-producing melanoma cells were used to induce metastases in mice to test whether melanoma metastasis--wherever it occurs--depends on the action of IL-1.We used the following experimental designs in this study: 1) Male C57BL/6J mice were inoculated in the left cardiac ventricle with 5 x 10(4) murine B16 melanoma cells, and no treatment was given (control animals). 2) Mice received an intraperitoneal injection of either saline (control animals) or recombinant human IL-1 receptor antagonist (rHuIL-1Ra) 2 hours before the injection of cancer cells; thereafter, they received an additional injection of saline or rHuIL-1Ra daily for 20 days. 3) Mice received an intravenous injection of either saline or rHuIL-1Ra; 15 minutes later, mice that received saline were given either a second injection of saline (control animals) or an injection of bacterial lipopolysaccharide (LPS) to stimulate host IL-1 production and endothelial cell activation. The mice that received rHuIL-1Ra were also given an injection of LPS at this time. Six hours later, all mice were inoculated with cancer cells, followed by no further treatment. In all experiments, the mice were killed 20 days after the injection of cancer cells, and metastases were counted in multiple organs and bones. Metastasis incidence values (relating to the frequency that a given site was positive for metastasis) and metastasis development index values (relating to the extent of metastasis at a given site) were calculated. A hierarchical cluster analysis was performed to determine whether groups of organs exhibited characteristic changes in their metastasis development index values in response to the three treatments given (i.e., rHuIL-1Ra, LPS, or rHuIL-1Ra plus LPS). Reported P values are two-sided.Treatment with rHuIL-1Ra alone significantly (P<.05) reduced the occurrence of metastasis in the bone marrow, spleen, liver, lung, pancreas, skeletal muscle, adrenal gland, and heart, indicating that host- and/or melanoma-derived IL-1 promoted metastasis in these organs; treatment with rHuIL-1Ra had no effect on metastasis in the kidney, testis, brain, skin, and gastrointestinal tract, suggesting that metastasis in these latter organs was IL-1 independent. Treatment with LPS alone significantly (P<.05) enhanced metastasis in the same organs for which rHuIL-1Ra treatment reduced metastasis, except for the heart and the adrenal gland. Treatment with rHuIL-1Ra 15 minutes before LPS treatment abrogated the LPS-mediated enhancement of metastasis. Two independent organ groups for which IL-1 promoted melanoma metastasis were identified in the cluster analysis.
Serological diagnosis of hepatitis B and delta virus (HBV/HDV) coinfection
Authors: B. Salassa, Enrica Daziano, F. Bonino, Carla Lavarini, Antonina Smedile, Elisabetta Chiaberge, F. Rosina, Maurizia Rossana Brunetto, Enrica Pessione, C. Spezia, C. Bramato, Maria Luisa Soranzo
Journal: Journal of Hepatology (1991)
Effects of Antenatal Depression and Antidepressant Treatment on Gestational Age at Birth and Risk of Preterm Birth
Authors: Rita Suri, Lori Altshuler, Gerhard Hellemann, Vivien K. Burt, Ana Aquino, Jim Mintz
Journal: American Journal of Psychiatry (2007)

Objective: The authors evaluated the effects of prenatal antidepressant exposure and maternal depression on infant gestational age at birth and risk of preterm birth. Method: Ninety women were followed in a prospective, naturalistic design through pregnancy with monthly assessments of symptoms of depression and anxiety using the Structured Clinical Interview for DSM-IV mood module for depression, the Hamilton Depression Rating Scale, the Beck Depression Inventory, and the Perceived Stress Scale. Participants included 49 women with major depressive disorder who were treated with antidepressants during pregnancy (group 1), 22 women with major depressive disorder who were either not treated with antidepressants or had limited exposure to them during pregnancy (group 2), and 19 healthy comparison subjects (group 3). The primary outcome variables were the infants' gestational age at birth, birth weight, 1- and 5-minute Apgar scores, and admission to the special care nursery. Results: Groups 1, 2, and 3 differed significantly in gestational age at birth (38.5 weeks, 39.4 weeks, 39.7 weeks, respectively), rates of preterm birth (14.3%, 0%, 5.3%, respectively), and rates of admission to the special care nursery (21%, 9%, 0%, respectively). Birth weight and Apgar scores did not differ significantly between groups. Mild to moderate depression during pregnancy did not affect outcome measures. Conclusions: Prenatal antidepressant use was associated with lower gestational age at birth and an increased risk of preterm birth. Presence of depressive symptoms was not associated with this risk. These results suggest that medication status, rather than depression, is a predictor of gestational age at birth.
The American Psychiatric Publishing Textbook of Psychiatry, Sixth Editionedited by Robert E. Hales, M.D., M.B.A., Stuart C. Yudofsky, M.D., and Laura Weiss Roberts, M.D., M.A., foreword by David J. Kupfer, M.D. Washington, DC, American Psychiatric Publishing, 2014, 1,511 pp., $249.00.
Authors: Molly McVoy
Journal: American Journal of Psychiatry (2014)
Orexins in the Brain-Gut Axis
Authors: Annette L. Kirchgessner
Journal: Endocrine Reviews (2002)

Orexins (hypocretins) are a novel pair of neuropeptides implicated in the regulation of energy balances and arousal. Previous reports have indicated that orexins are produced only in the lateral hypothalamic area, although orexin-containing nerve fibers were observed throughout the neuroaxis. Recent evidence shows that orexins and functional orexin receptors are found in the periphery. Vagal and spinal primary afferent neurons, enteric neurons, and endocrine cells in both the gut and pancreas display orexin- and orexin receptor-like immunoreactivity. Orexins excite secretomotor neurons in the guinea pig gut and modulate gastric and intestinal motility and secretion. In addition, orexins modulate hormone release from pancreatic endocrine cells. Moreover, fasting up-regulates the phosphorylated form of cAMP response element binding protein in orexin-immunoreactive enteric neurons, indicating a functional response to food status in these cells. The purpose of this article is to summarize evidence for the existence of a brain-gut network of orexin-containing cells that appears to play a role in the acute regulation of energy homeostasis.
Decreased Nitric Oxide Bioavailability in a Mouse Model of Fabry Disease
Authors: Liming Shu, James L. Park, Jaeman Byun, Subramaniam Pennathur, Jessica Kollmeyer, James A. Shayman
Journal: Journal of the American Society of Nephrology (2009)

Fabry disease is a lysosomal storage disorder that results in an accumulation of globotriaosylceramide in vascular tissue secondary to a deficiency in alpha-galactosidase A. The glycolipid-associated vasculopathy results in strokes and cardiac disease, but the basis for these complications is poorly understood. Recent studies in the alpha-galactosidase A-knockout mouse suggested that a decrease in nitric oxide (NO) bioavailability may play a role in the abnormal thrombosis, atherogenesis, and vasorelaxation that are characteristic of these mice. To understand better the association between impaired NO bioavailability and glycolipid accumulation, we studied alpha-galactosidase A-knockout mice or primary cultures of their aortic endothelial cells. Treatment of knockout mice with a potent inhibitor of glucosylceramide synthase reversed accumulation of globotriaosylceramide but failed to normalize the defect in vasorelaxation. Basal and insulin-stimulated endothelial NO synthase (eNOS) activities in endothelial cells derived from knockout mice were lower than those observed from wild-type mice; normalization of glycolipid only partially reversed this reduction in eNOS activity. The loss of eNOS activity associated with a decrease in high molecular weight caveolin oligomers in endothelial cells and isolated caveolae, suggesting a role for glycolipids in caveolin assembly. Finally, concentrations of ortho-tyrosine and nitrotyrosine in knockout endothelial cells were markedly elevated compared with wild-type endothelial cells. These findings are consistent with a loss of NO bioavailability, associated with eNOS uncoupling, in the alpha-galactosidase A-knockout mouse.
Immune Chaperone gp96 Drives the Contributions of Macrophages to Inflammatory Colon Tumorigenesis
Authors: Crystal Morales, Saleh Rachidi, Feng Hong, Shaoli Sun, Xinshou Ouyang, Caroline Wallace, Yongliang Zhang, Elizabeth Garret-Mayer, Jennifer Wu, Bei Liu, Zihai Li
Journal: Cancer Research (2013)

Macrophages are important drivers in the development of inflammation-associated colon cancers, but the mechanistic underpinnings for their contributions are not fully understood. Furthermore, Toll-like receptors have been implicated in colon cancer, but their relevant cellular sites of action are obscure. In this study, we show that the endoplasmic reticulum chaperone gp96 is essential in tumor-associated macrophages (TAM) to license their contributions to inflammatory colon tumorigenesis. Mice where gp96 was genetically deleted in a macrophage-specific manner exhibited reduced colitis and inflammation-associated colon tumorigenesis. Attenuation of colon cancer in these mice correlated strikingly with reduced mutation rates of β-catenin, increased efficiency of the DNA repair machinery, and reduced expression of proinflammatory cytokines, including interleukin (IL)-17 and IL-23 in the tumor microenvironment. The genotoxic nature of TAM-associated inflammation was evident by increased expression of genes in the DNA repair pathway. Our work deepens understanding of how TAM promote oncogenesis by altering the molecular oncogenic program within epithelial cells, and it identifies gp96 as a lynchpin chaperone needed in TAM to license their function and impact on expression of critical inflammatory cytokines in colon tumorigenesis.
Temozolomide as salvage treatment for recurrent intracranial ependymomas of the adult: a retrospective study
Authors: Roberta Rudà, Chiara Bosa, Michela Magistrello, Federica Franchino, Alessia Pellerino, Valentina Fiano, Morena Trevisan, Paola Cassoni, Riccardo Soffietti
Journal: Neuro-Oncology (2015)

Few data are available on temozolomide (TMZ) in ependymomas. We investigated the response, survival, and correlation with MGMT promoter methylation in a cohort of patients with adult intracranial ependymoma receiving TMZ as salvage therapy after failure of surgery and radiotherapy. We retrieved clinical information from the institutional database and follow-up visits, and response to TMZ on MRI was evaluated according to the MacDonald criteria. Eighteen patients (median age, 42 y), with either WHO grade III (10) or grade II (8) ependymoma were evaluable. Tumor location at diagnosis was supratentorial in 11 patients and infratentorial in 7. Progression before TMZ was local in 11 patients, local and spinal in 6 patients, and spinal only in one patient. A median of 8 cycles of TMZ (1–24) was administered. Response to TMZ consisted of complete response (CR) in one (5%) patient, partial response (PR) in 3 (17%) patients, stable disease (SD) in 7 (39%) patients, and progressive disease (PD) in 7 (39%) patients. Maximum response occurred after 3, 10, 14, and 15 cycles, respectively, with neurological improvement in 2 patients. All 4 responding patients were chemotherapy naïve. Both anaplastic (2) and grade II (2) tumors responded. Median progression-free survival and overall survival were 9.69 months (95% CI, 3.22–30.98) and 30.55 months (95% CI, 12.85–52.17), respectively. MGMT methylation was available in 11 patients and was not correlated with response or outcome. TMZ has a role in recurrent chemo-naïve adult patients with intracranial ependymoma, regardless of tumor grade and MGMT methylation. We suggest that, after failure of surgery and radiotherapy, TMZ should be considered as a possible first-line treatment for recurrent ependymoma.