tbuckley/cabot-search huggingface dataset:
Pax2 and Pax8 Proteins Regulate Urea Transporters and Aquaporins to Control Urine Concentration in the Adult Kidney
Authors: Ann M. Laszczyk, Atsuko Y. Higashi, Sanjeevkumar R. Patel, Craig N. Johnson, Abdul Soofi, Saji Abraham, Gregory R. Dressler
Journal: Journal of the American Society of Nephrology (2020)

As the glomerular filtrate passes through the nephron and into the renal medulla, electrolytes, water, and urea are reabsorbed through the concerted actions of solute carrier channels and aquaporins at various positions along the nephron and in the outer and inner medulla. Proliferating stem cells expressing the nuclear transcription factor Pax2 give rise to renal epithelial cells. Pax2 expression ends once the epithelial cells differentiate into mature proximal and distal tubules, whereas expression of the related Pax8 protein continues. The collecting tubules and renal medulla are derived from Pax2-positive ureteric bud epithelia that continue to express Pax2 and Pax8 in adult kidneys. Despite the crucial role of Pax2 in renal development, functions for Pax2 or Pax8 in adult renal epithelia have not been established.To examine the roles of Pax2 and Pax8 in the adult mouse kidney, we deleted either Pax2, Pax8, or both genes in adult mice and examined the resulting phenotypes and changes in gene expression patterns. We also explored the mechanism of Pax8-mediated activation of potential target genes in inner medullary collecting duct cells.Mice with induced deletions of both Pax2 and Pax8 exhibit severe polyuria that can be attributed to significant changes in the expression of solute carriers, such as the urea transporters encoded by Slc14a2, as well as aquaporins within the inner and outer medulla. Furthermore, Pax8 expression is induced by high-salt levels in collecting duct cells and activates the Slc14a2 gene by recruiting a histone methyltransferase complex to the promoter.These data reveal novel functions for Pax proteins in adult renal epithelia that are essential for retaining water and concentrating urine.
Covid-19: Allow pharmacists to dispense controlled drugs without prescription, urge specialists
Authors: Gareth Iacobucci
Journal: BMJ (2020)

Revised legislation allowing pharmacists to supply some controlled drugs without prescription must be enacted “without delay” to protect patients and to support clinicians, experts have said.

Last week (28 April) the UK home secretary, Priti Patel, laid legislation before parliament that allows for a relaxation of the regulations for prescribing controlled drugs, to ensure access is not delayed during the covid-19 pandemic.1 The relaxation would allow pharmacists, in a pandemic situation, to supply some drugs that were previously only supplied to a patient by doctors on prescription. It would also allow pharmacists, in cases of shortages, to alter …
PTH-065 Single centre experience of simtomax, a point-of-care test for coeliac disease, to avoid duodenal biopsies
Authors: Pranav Vyas, Victoria Appleby, Carol Firth, Sulleman Moreea
Journal: Endoscopy (2018)

<h3>Introduction</h3> The British Society of Gastroenterology (BSG) guidelines recommend screening for coeliac disease in patients with iron deficiency anaemia (IDA) with coeliac serology; but states that if it hasn't been carried out or if the result is unavailable, duodenal biopsies should be taken if the patient is undergoing a gastroscopy. As the prevalence of coeliac disease in the UK is around 1% and 5% in IDA, majority of duodenal biopsies are negative. As biopsies are costly we have been investigating ways to avoid doing them without missing the diagnosis of coeliac disease. Simtomax is a finger prick test for coeliac disease that provides immediate results, hence shown to be valuable as a negative predictive test.<sup>1</sup> The aim was to evaluate the value of Simtomax pre-endoscopy to reduce the number of duodenal biopsies without missing the diagnosis of coeliac disease in our local population. <h3>Methods</h3> Between May-December 2016 we obtained informed consent and performed 106 Simtomax tests on patients attending for a gastroscopy (OGD) with an indication of anaemia/weight loss prior to their endoscopy. Using our databases, we collected the following: patient demographics, coeliac serology (anti tTG/EMA) if done, OGD findings and duodenal biopsy histology. <h3>Results</h3> 106 patients (M=38, mean age 62, age range 34–91; F=68, mean age 62, age range 18–95) had both a Simtomax test and an OGD. 101/106 had duodenal biopsies (endoscopist's discretion) and 52 (49%) had coeliac serology (anti tTG). With histology as the gold standard for the diagnosis of coeliac disease, prevalence of the disease in these patients with IDA/weight loss was 3%. The negative predictive value (NPV) of a negative Simtomax test was 96% and the NPV of a negative Simtomax AND negative coeliac serology was 97%. The positive predictive values were 11% and 33% respectively for these 2 tests. The sensitivity and specificity of Simtomax were 33% and 96%. <h3>Conclusions</h3> In the current NHS climate every saving is welcome as long as patient care isn't compromised. Our study shows that around 50% of patients attending for an OGD for IDA/weight loss didn't have coeliac serology available at the time of the procedure, therefore requiring duodenal biopsies as per BSG guidelines. Using a point of care test with a high negative predictive value would save more patients from having biopsies, save money<sup>1</sup> and valuable time of endoscopists, nurses and histopathologists. Our study confirms the high NPV of the point of care test Simtomax and would save biopsies in 96% of patients who haven't had coeliac serology prior to endoscopy (a saving of around £100 per set of duodenal biopsies). <h3>Reference</h3> 1. BMC Gastroenterol. doi:10.1186/s12876–016–0521537
Human-induced pluripotent stem cells for modelling metabolic perturbations and impaired bioenergetics underlying cardiomyopathies
Authors: Chrishan J A Ramachandra, Jasper Chua, Shuo Cong, Myu Mai Ja Kp, Winston Shim, Joseph C Wu, Derek J Hausenloy
Journal: Cardiovascular Research (2020)

Abstract Normal cardiac contractile and relaxation functions are critically dependent on a continuous energy supply. Accordingly, metabolic perturbations and impaired mitochondrial bioenergetics with subsequent disruption of ATP production underpin a wide variety of cardiac diseases, including diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, anthracycline cardiomyopathy, peripartum cardiomyopathy, and mitochondrial cardiomyopathies. Crucially, there are no specific treatments for preventing the onset or progression of these cardiomyopathies to heart failure, one of the leading causes of death and disability worldwide. Therefore, new treatments are needed to target the metabolic disturbances and impaired mitochondrial bioenergetics underlying these cardiomyopathies in order to improve health outcomes in these patients. However, investigation of the underlying mechanisms and the identification of novel therapeutic targets have been hampered by the lack of appropriate animal disease models. Furthermore, interspecies variation precludes the use of animal models for studying certain disorders, whereas patient-derived primary cell lines have limited lifespan and availability. Fortunately, the discovery of human-induced pluripotent stem cells has provided a promising tool for modelling cardiomyopathies via human heart tissue in a dish. In this review article, we highlight the use of patient-derived iPSCs for studying the pathogenesis underlying cardiomyopathies associated with metabolic perturbations and impaired mitochondrial bioenergetics, as the ability of iPSCs for self-renewal and differentiation makes them an ideal platform for investigating disease pathogenesis in a controlled in vitro environment. Continuing progress will help elucidate novel mechanistic pathways, and discover novel therapies for preventing the onset and progression of heart failure, thereby advancing a new era of personalized therapeutics for improving health outcomes in patients with cardiomyopathy.
Pituitary Adenomas
Authors: Mumtaz A. Siddiqui
Journal: Annals of Internal Medicine (1995)

Letters15 March 1995Pituitary AdenomasMumtaz A. SiddiquiMumtaz A. SiddiquiSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-122-6-199503150-00019 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:The article by Kupersmith and colleagues [1] does not mention the findings from magnetic resonance imaging and computed tomography scans in their patients with macroadenoma of the pituitary gland and visual field defects. A hemorrhagic pituitary adenoma during pregnancy may cause an acute increase in the size of the macroadenoma and may cause visual field defects. On the basis of magnetic resonance imaging scans, such pituitary “apoplexy” has been classified as classical, subacute, and asymptomatic [2]. Further, the density of the pituitary adenoma may give an idea of the acuteness of the apoplexy and help distinguish a ...References1. Kupersmith MJ, Rosenberg C, Kleinberg D. Visual loss in pregnant women with pituitary adenomas. Ann Intern Med. 1994; 121:473-7. Google Scholar2. Kannuki S, Bando K, Sirakawa N, Matsumoto K, Bando H, Saito S, et al. MRI findings and endocrinological dysfunction in hemorrhagic pituitary adenoma. Neurological Surgery. 1993; 21:1005-12. Google Scholar3. Hua F, Asato R, Miki Y, Okumura R, Hashimota N, Kikuchi H, et al. Differentiation of suprasellar nonneoplastic cysts from cystic neoplasms by Gd-DTPA MRI. J Comput Assist Tomogr. 1992; 16:744-9. Google Scholar4. Coyne TJ, Atkinson RL, Prins JB. Adrenocorticotropic hormone-secreting pituitary tumor associated with pregnancy: case report. Neurosurgery. 1992; 31:953-5. Google Scholar5. Ohtsubo T, Asakura T, Kadota K, Takasaki K, Uchimura K, Makiuchi T, et al. A report of a trans-sphenoidal operation during pregnancy for a pituitary adenoma. Neurological Surgery. 1991; 19:867-70. Google Scholar Author, Article, and Disclosure InformationAuthors: Mumtaz A. SiddiquiAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 March 1995Volume 122, Issue 6Page: 476KeywordsComputed axial tomographyMagnetic resonance imagingPituitary glandPituitary tumorsPregnancyStrokeSurgical resection ePublished: 15 August 2000 Issue Published: 15 March 1995 Copyright & PermissionsCopyright © 1995 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Boy is set to receive millions in damages after NHS missed deliberate injuries
Authors: Clare Dyer
Journal: BMJ (2020)

A 7 year old boy is set to win millions of pounds in damages from the NHS because doctors missed deliberate injuries when he was brought to hospital within weeks of his birth and allowed him to go home with his parents.1

Chest radiography showed healing rib fractures, but these were missed by hospital staff, and further investigations that would have led to the involvement of social services were not carried out. An anonymity order is in place, and neither boy nor trust can be identified.

Within months he had sustained devastating …
A phase I dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma.
Authors: S. Choo, B. Chowbay, Q. Ng, C. Thng, H. Li, H. Huynh, D. Poon, M. Ang, S. Chang, H. Toh
Journal: Journal of Clinical Oncology (2010)

4097 Background: Rapamycin combined with bevacizumab can inhibit tumor growth and downstream targets of the mTOR pathway in hepatocellular cancer xenografts. Methods: We performed a phase I study to determine the MTD and clinical activity of rapamycin with bevacizumab in patients with unresectable hepatocellular carcinoma. Patients with prior treatment, ECOG 0-2 and Child-Pugh A or B were included. Intravenous bevacizumab was given at 5 mg/kg every 2 weeks with daily oral dose-escalated rapamycin (levels 1 to 5: 1 to 5mg, respectively). An expanded cohort of 6 was recruited at MTD. Each cycle was 28 days. Rapamycin PK was determined at steady-state on day 8 of the first cycle. Pharmacodynamic analysis using DCE-CT to assess antiangiogenic effects were performed at baseline and on day 8. Results: Eighteen patients (M/F: 13/5; median age: 63; Child-Pugh A/B: 15/3; prior chemotherapy: 6) were treated. DLTs in the first cycle were grade 3 mucositis in 1 patient and grade 3 thrombocytopenia in another patient at dose level 5. Thus the MTD of rapamycin was 4mg with bevacizumab 5 mg/kg. Other common treatment-related toxicities included fatigue (50%), hyperlipidemia (50%), anorexia (50%) and diarrhea (39%). Rapamycin PK exhibited dose linearity for Cmax and AUC0-inf from dose levels 1-5. Trough levels increased 3-fold between dose levels 2 and 3-5. Rapamycin clearance was highest at dose level 1 but similar between dose levels 2 to 5. Blood flow reduction correlated linearly with AUC0-inf (r = 0.63, p = 0.039), and Cmax (r = 0.79, p = 0.004), and reduction in permeability correlated with Cmax (r = 0.72, p = 0.013) of rapamycin. One patient achieved complete response (5.6%), 9 stable disease (50%), 6 progressive disease (33.3%) and 2 dropped out of study before evaluation. Median OS was 17.5 months (Childs-Pugh A) and 3.1 months (Childs-Pugh B) (p = 0.0005). Median PFS was 6.6 months. Conclusions: The MTD for rapamycin was 4 mg daily when administered with bevacizumab 5 mg/kg fortnightly. Clinical activity was also seen at lower doses of rapamycin. No significant financial relationships to disclose.
In vitro sequence-dependent interaction between paclitaxel and gefitinib in human lung cancer cell lines
Authors: H. Cheng, Y. Wu, S. An, S. Dong, H. Chen, X. Zhang, A. Guo
Journal: Journal of Clinical Oncology (2009)

e22025 Background: Cytotoxicity chemotherapy has been standard first line treatment for advanced NSCLC. Clinical trials comparing first line EGFR TKI therapy over cytotoxicity chemotherapy are under investigation in phase III trials. The aim of this study is to test the hypothesis that paclitaxel followed by gefitinib would be superior to the opposite order in EGFR TKI resistant cell lines because of cell signaling pathway and cell cycle interaction. Methods: we have used EGFR-TKI resistant human lung cancer cell lines A549, H1975 and H1650 as an in vitro model for defining the differential effects of opposite sequence of combination of cytotoxic drug and anti- EGFR agents on cell growth, signaling pathway, cell cycle distribution and induction of apoptosis. Results: Paclitaxel 24 hours followed by gefitinib 72 hours in A549, H1975 and H1650 cells produced synergistic effects, while the reverse sequence produced antagonistic effects. Exposure to paclitaxel resulted in an increased pEGFR and pAKT level, this increase of phosphorylation can be inhibited by the following gefitinib exposure, while the reverse sequence resulted in no change in EGFR and AKT phosphorylation. We confirmed that gefitinib arrested the cells in G1, paclitaxel arrested cells in S phase. The sequence of paclitaxel followed by gefitinib cause cells arrested in G1, while the reverse sequence cause cells arrested in S and G2 phase. Conclusions: These findings suggest that the sequence of paclitaxel followed by gefitinib may be superior to the reverse sequence in gefitinib resistant NSCLC, and support the investigation of these sequential treatment in the clinical setting. This work was supported by the grants from the National Natural Science Foundation of China (No. 30772531). No significant financial relationships to disclose.
Translating evidence into practice: eligibility criteria fail to eliminate clinically significant differences between real-world and study populations
Authors: Amelia J. Averitt, Chunhua Weng, Patrick Ryan, Adler Perotte
Journal: npj Digital Medicine (2020)

Randomized controlled trials (RCTs) are regarded as the most reputable source of evidence. In some studies, factors beyond the intervention itself may contribute to the measured effect, an occurrence known as heterogeneity of treatment effect (HTE). If the RCT population differs from the real-world population on factors that induce HTE, the trials effect will not replicate. The RCTs eligibility criteria should identify the sub-population in which its evidence will replicate. However, the extent to which the eligibility criteria identify the appropriate population is unknown, which raises concerns for generalizability. We compared reported data from RCTs with real-world data from the electronic health records of a large, academic medical center that was curated according to RCT eligibility criteria. Our results show fundamental differences between the RCT population and our observational cohorts, which suggests that eligibility criteria may be insufficient for identifying the applicable real-world population in which RCT evidence will replicate.
A digital embrace to blunt the curve of COVID19 pandemic
Authors: Lee H. Schwamm, Alistair Erskine, Adam Licurse
Journal: npj Digital Medicine (2020)

Abstract Digital health, virtual care, telehealth, and telemedicine are all terms often used interchangeably to refer to the practice of care delivered from a distance. Because virtual care collapses the barriers of time and distance, it is ideal for providing care that is patient-centered, lower cost, more convenient and at greater productivity. All these factors make virtual care tools indispensable elements in the COVID19 response. In this perspective, we offer implementation guidance and policy insights relevant to the use of virtual care tools to meet the challenges of the COVID19 pandemic.
Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation
Authors: Jamie Bates, Archana Vijayakumar, Sarani Ghoshal, Bruno Marchand, Saili Yi, Dmytro Kornyeyev, Anna Zagorska, David Hollenback, Katie Walker, Kathy Liu, Swetha Pendem, David Newstrom, Robert Brockett, Igor Mikaelian, Saritha Kusam, Ricardo Ramirez, David Lopez, Li Li, Bryan C. Fuchs, David G. Breckenridge
Journal: Journal of Hepatology (2020)

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic lipid accumulation, inflammation, and progressive fibrosis. Acetyl-CoA carboxylase (ACC) catalyzes the rate-limiting step of de novo lipogenesis and regulates fatty acid β-oxidation in hepatocytes. ACC inhibition reduces hepatic fat content and markers of liver injury in patients with NASH; however, the effect of ACC inhibition on liver fibrosis has not been reported.A direct role for ACC in fibrosis was evaluated by measuring de novo lipogenesis, procollagen production, gene expression, glycolysis, and mitochondrial respiration in hepatic stellate cells (HSCs) in the absence or presence of small molecule inhibitors of ACC. ACC inhibitors were evaluated in rodent models of liver fibrosis induced by diet or the hepatotoxin, diethylnitrosamine. Fibrosis and hepatic steatosis were evaluated by histological and biochemical assessments.Inhibition of ACC reduced the activation of TGF-β-stimulated HSCs, as measured by both α-SMA expression and collagen production. ACC inhibition prevented a metabolic switch necessary for induction of glycolysis and oxidative phosphorylation during HSC activation. While the molecular mechanism by which inhibition of de novo lipogenesis blocks glycolysis and oxidative phosphorylation is unknown, we definitively show that HSCs require de novo lipogenesis for activation. Consistent with this direct antifibrotic mechanism in HSCs, ACC inhibition reduced liver fibrosis in a rat choline-deficient, high-fat diet model and in response to chronic diethylnitrosamine-induced liver injury (in the absence of hepatic lipid accumulation).In addition to reducing lipid accumulation in hepatocytes, ACC inhibition also directly impairs the profibrogenic activity of HSCs. Thus, small molecule inhibitors of ACC may lessen fibrosis by reducing lipotoxicity in hepatocytes and by preventing HSC activation, providing a mechanistic rationale for the treatment of patients with advanced liver fibrosis due to NASH.Hepatic fibrosis is the most important predictor of liver-related outcomes in patients with non-alcoholic steatohepatitis (NASH). Small molecule inhibitors of acetyl-CoA carboxylase (ACC) reduce hepatic fat content and markers of liver injury in patients with NASH. Herein, we report that inhibition of ACC and de novo lipogenesis also directly suppress the activation of hepatic stellate cells - the primary cell responsible for generating fibrotic scar in the liver - and thus fibrosis. These data provide further evidence for the use of ACC inhibitors to treat patients with NASH and advanced fibrosis.
Treatment of angina pectoris.
Authors: J. D. Proctor, A. J. Wasserman, E. Gamble
Journal: BMJ (1968)

MDICBJOu 515 once to call in the family doctor to see a sick infant, particularly late at night, at the week-end, or on his day off.No fewer than 80% of the families concerned had serious problems, such as marital disharmony, Inadequate or erratic income, poor housing, niot solely overcrowding, or chronic physical or mental illness.This prevalence was significantly greater than in a control group.Another finding, the importance of which is as yet obscure, was that in 55% of the families the mother was unable to communi- cate with the father during the night when the child died.You do not suggest what incipient symp- toms (and signs ?) should be looked for, pre- sumably in the first place by parents.In cmy series the mothers of about a quarter of the infants had noted the signs mentioned in the Liverpool study-lack of response, stupor, pallor, and cyanosis-together with failure to feed, for a day or two before death without obtaining medical attention.This was not the result of indifference or lack of intelligence.It is to be hoped that future studies of large groups of infants of this kind will include an examination of the social circumstances in which the death took place, covering not so much such items as the bedding, feeding, and housing dealt with in a recent study,2 as the attitudes and general patterns of behaviour of the family as a group.It may be that preventive action based on such knowledge would do more to reduce the number of deaths from this con- dition than the present possibilities of specific therapy.-Iam, etc.,
Abstract 12346: Aortic Valve Imaging in Aortic Stenosis - A Network and Pairwise Meta-analysis
Authors: Lisa Q Rong, Irbaz Hameed, Antonino Di Franco, Mohamed Rahouma, Faiza Khan, Richard B Devereux, Mario Gaudino
Journal: Circulation (2019)

Background: Accurate grading of aortic stenosis by aortic valve area (AVA) is crucial for timing of treatment and intervention. AVA is commonly determined from 2D transthoracic echo (TTE) by means ...