tbuckley/cabot-search huggingface dataset:
Novel treatments for osteoporosis
Authors: Ernesto Canalis
Journal: Journal of Clinical Investigation (2000)

Osteoporosis is a major health problem that affects 4 to 6 million women and 1 to 2 million men in the US, with an even larger number of individuals having osteopenia or decreased bone mineral density (BMD) (1). The most significant consequence of osteoporosis is osteoporotic fractures, which in 1995 resulted in health care expenditures in the US of $13.8 billion (2). Consequently, the prevention and treatment of osteoporosis are of paramount importance. Currently, all therapeutic agents approved by the Food and Drug Administration for the treatment of osteoporosis are inhibitors of bone resorption. Although these agents are effective in stabilizing or increasing BMD and reducing the risk of fractures, their exact mechanism of action frequently is not known, and they do not increase bone formation. Alternative drug therapies that either block the function of the bone-resorbing osteoclasts or enhance the anabolic function of osteoblasts could prove beneficial to a number of patients with osteoporosis. A recent issue and, now, the current issue of the JCI feature studies on two promising new agents that operate by these complementary strategies and preserve bone mass to a significant extent in rat models of osteoporosis (3, 4). Figure ​Figure11 shows the effect of these agents on the balance between ongoing processes of bone formation and bone resorption, which together determine bone mass.



Figure 1

Two novel approaches to increasing bone mass. Bone mass reflects the relative rates of bone formation, mediated by osteoblasts, and of bone resorption, mediated by osteoclasts. Parathyroid hormone (PTH) has complex effects on bone mass, since it stimulates ...
Dynamic sealing of lung air leaks by the transplantation of tissue engineered cell sheets
Authors: Masato Kanzaki, Masayuki Yamato, Joseph Yang, Hidekazu Sekine, Chinatsu Kohno, Ryo Takagi, Hideyuki Hatakeyama, Tamami Isaka, Teruo Okano, Takamasa Onuki
Journal: Biomaterials (2007)
Allow GPs and consultants to speak to each other again
Authors: A. Smalldridge
Journal: BMJ (2015)

I qualified in 1981 and have been a GP since 1986, spending most of the time in inner city practices in Manchester. Last year I was burnt out and decided to take a gap year, so I left my job and went to work as a GP in Cairns, Queensland. It was a joy to just be a good, old fashioned GP, managing people holistically without the tyranny of the Quality and Outcomes Framework and targets, medicines management, spreadsheets, and referral gateways.

I am now back doing locum shifts in Britain. If …
PTK7 regulates Id1 expression in CD44-high glioma cells
Authors: Qing Liu, Chi Zhang, Jian Yuan, Jun Fu, Minghua Wu, Jun Su, Xiangyu Wang, Xianrui Yuan, Weixi Jiang
Journal: Neuro-Oncology (2014)

CD44 is a molecular marker associated with molecular subtype and treatment resistance in glioma. More effective therapies will result from approaches aimed at targeting the CD44-high gliomas. Protein tyrosine kinase 7 (PTK7) mRNA expression was analyzed based on The Cancer Genome Atlas glioblastoma dataset. PTK7 expression was depleted through lentivirus-mediated short hairpin RNA knockdown. Terminal deoxynucleotidyl transferase dUTP nick-end labeling was used to evaluate cell apoptosis following PTK7 knockdown. Gene expression analysis was performed on Affymetrix microarray. A nude mice orthotopic tumor model was used to evaluate the in vivo effect of PTK7 depletion. PTK7 is highly expressed in CD44-high glioblastoma and predicts unfavorable prognosis. PTK7 knockdown attenuated cell proliferation, impaired tumorigenic potential, and induced apoptosis in CD44-high glioma cell lines. Gene expression analysis identified inhibitor of DNA Binding 1 (Id1) gene as a potential downstream effector for PTK7. Overexpression of Id1 mostly restored the cell proliferation and colony formation attenuated by PTK7 depletion. PTK7 enhanced anchorage-independent growth in normal human astrocytes, which was attenuated by Id1 knockdown. Furthermore, PTK7 regulated Id1 expression through modulating TGF-β/Smad signaling, while pharmacological inhibition on TGF-β/Smad signaling or PTK7/Id1 depletion attenuated TGF-β–stimulated cell proliferation. PTK7 depletion consistently reduced Id1 expression, suppressed tumor growth, and induced apoptosis in a murine orthotopic tumor model, which could be translated into prolonged survival in tumor-bearing mice. PTK7 regulates Id1 expression in CD44-high glioma cell lines. Targeting PTK7 could be an effective strategy for treating glioma with high CD44 expression.
Evaluation of Urine Aquaporin-1 and Perilipin-2 Concentrations as Biomarkers to Screen for Renal Cell Carcinoma
Authors: Jeremiah J. Morrissey, Vincent M. Mellnick, Jingqin Luo, Marilyn J. Siegel, R. Sherburne Figenshau, Sam Bhayani, Evan D. Kharasch
Journal: JAMA Oncology (2015)

Historically, early detection of small asymptomatic kidney tumors presages better patient outcome. Screening for asymptomatic renal tumors by abdominal imaging is not cost-effective and cannot reliably distinguish benign from malignant tumors.This investigation evaluated the clinical utility, sensitivity, and specificity of urine aquaporin-1 (AQP1) and perilipin-2 (PLIN2) concentrations as unique, noninvasive biomarkers to diagnose malignant clear cell or papillary renal cell carcinoma (RCC) in a screening paradigm.From February through December 2012, urine samples were obtained from 720 patients undergoing routine abdominal computed tomography (CT) (screening population), 80 healthy controls, and 19 patients with pathologically confirmed RCC.Urine AQP1 and PLIN2 concentrations were measured by sensitive and specific enzyme-linked immunosorbent assay and Western blot procedures, respectively, in all groups. In the otherwise asymptomatic screening population, the absence or presence of a renal mass and RCC were verified by abdominal CT and by postnephrectomy pathologic diagnosis, respectively.Urine AQP1 and PLIN2 concentrations were significantly higher (all P < .001) in the 19 patients with known RCC (AQP1 median [95% CI], 225.0 [121.0-450.0] ng/mg urine creatinine; and PLIN2 median [95% CI], 37.8 [22.8-83.7] absorbance units/mg creatinine) than in the 80 healthy controls (AQP1 median [95% CI], 1.1 [0.9-1.3] ng/mg urine creatinine; and PLIN2 median [95% CI], 3.1 [2.4-3.7] absorbance units/mg creatinine) and the 720 patient screening population (AQP1 median [95% CI], 0.5 [0.0-1.0] ng/mg urine creatinine; and PLIN2 median [95% CI], 0 [0-0] absorbance units/mg creatinine). The area under the receiver operating characteristic curve for urine AQP1 and PLIN2 concentrations individually or in combination was 0.990 or greater, with 95% or greater sensitivity and 91% or greater specificity compared with controls or the screening population. Of the 720 screened patients, 3 had biomarker concentrations suggestive of RCC and were found to have an imaged renal mass by CT. Two of the patients had pathologically confirmed RCC in further evaluation.These results demonstrate the clinical utility, specificity, and sensitivity of urine AQP1 and PLIN2 to diagnose RCC. These tumor-specific proteins have high clinical validity and substantial potential as specific diagnostic and screening biomarkers for clear cell or papillary RCC and in the differential diagnosis of imaged renal masses.
The cardiac cocaine connection
Authors: C GROHE
Journal: Cardiovascular Research (2003)

See article by Moritz et al. \[9\] (pages 834–843) in this issue. 

Cocaine (benzoylmethylecgonine) is increasingly used as an illegal stimulatory and hallucinogenic drug. This abuse is associated with a large array of clinically relevant cardiovascular side effects that after long-term use may lead from myocardial hypertrophy and necrosis to progressive left ventricular dysfunction [1]. To further dissect the underlying mechanisms, two pathophysiological entities have to be taken into account and deserve further attention: the acute effects and the biochemical and cellular changes in the myocardium after chronic abuse.

Cocaine was introduced as the first local anaesthetic agent at the end of the 19th century. Its local anaesthetic effect originates in from a blockade of voltage-gated Na+ channels. This is accompanied by a sympathomimetic influence of the drug due to central stimulation of sympathetic outflow and inhibition of norepinephrine reuptake into sympathetic nerve terminals. The sympathomimetic property supports the local anaesthetic influence by inducing local vasoconstriction and thus preventing fast dilution of the drug.

In the cardiovascular system, acute cocaine application prolongs QRS duration, increases heart rate and myocardial contractility, and elicits intense vasoconstriction in coronary and peripheral vascular beds [1]. Inhibition of cardiac Na+ current by cocaine is voltage- and frequency-dependent. Reduced Na+ current leads to a depression of V max in the action potential (AP) that reduces AP propagation in the heart, consistent with the finding of a prolonged QRS complex. The reduction … 

c.grohe{at}uni-bonn.de
Scaffolding emotions and evolving language
Authors: Eva Jablonka, Simona Ginsburg
Journal: Behavioral and Brain Sciences (2012)

Abstract We suggest that, in animals, the core-affect system is linked to partially assimilated behavioral dispositions that act as developmental scaffolds for the ontogenetic construction of emotions. We also propose that in humans the evolution of language altered the control of emotions, leading to categories that can be adequately captured only by emotion-words.
The Seat of Pain in Biliary Colic
Authors: J. H. Keay
Journal: BMJ (1900)

DISEASE COMPLICATED WITH GANGRENE.LMDTICL JBao:sflL go has been known to exist for several years may throw light upon the nature of the ailment, but until it has been proved that the prognosis is serious I should wish to look upon the occasional appearance of albumen in the urine, and the swell- ing of the eyelids associated with it, as evidence of some vasomotor instability or defective metabolism.NOTES AND REFERBNCES.1 Cold nitric acid is mentioned as the test used2 but where a ring with nitric acid was obtained there was also a precipitate on boiling in every instance. 2A fourth case of swelling of the eyelids with intermittent al- buminuria occurring in a boy, aged Io, is at present under my care at the Bristol Children's Hospital.3M1edical Week, I895, p. 25. 4 Lancet,
Patients with prostate cancer should be enrolled in a national, controlled trial
Authors: R G Willis
Journal: BMJ (1999)

EDITOR—I endorse the views of Mulley and Barry on treating prostate cancer.1 British urologists are deluged with data from the United States which encourages radical prostatectomy, yet there is no good evidence from randomised controlled trials to validate their policy.

If the editorial had been written by an American urologist the conclusion would have been entirely different. Mulley and Barry failed to emphasise the powerful financial motives behind much of what is published about prostate cancer in the …
Sclerodermoid graft-versus-host disease-like lesions occurring after drug-induced hypersensitivity syndrome
Authors: Y. Kano, K. Sakuma, T. Shiohara
Journal: British Journal of Dermatology (2007)

Journal Article Sclerodermoid graft‐versus‐host disease‐like lesions occurring after drug‐induced hypersensitivity syndrome Get access Y. Kano, Y. Kano Department of Dermatology, Kyorin University School of Medicine, 6‐20‐2 Shinkawa Mitaka, Tokyo 181‐8611, Japan E‐mail: kano@kyorin‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar K. Sakuma, K. Sakuma Department of Dermatology, Kyorin University School of Medicine, 6‐20‐2 Shinkawa Mitaka, Tokyo 181‐8611, Japan E‐mail: kano@kyorin‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar T. Shiohara T. Shiohara Department of Dermatology, Kyorin University School of Medicine, 6‐20‐2 Shinkawa Mitaka, Tokyo 181‐8611, Japan E‐mail: kano@kyorin‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 156, Issue 5, 1 May 2007, Pages 1061–1063, https://doi.org/10.1111/j.1365-2133.2007.07784.x Published: 01 May 2007
THE ROENTGEN RADIATION OF PAPILLOMA VIRUS (SHOPE)
Authors: J. T. Syverton, R. A. Harvey, G. P. Berry, S. L. Warren
Journal: The Journal of Experimental Medicine (1941)

Virus-induced papillomas (Shope) on domestic rabbits are susceptible to Roentgen rays. The dosage which uniformly brings about their complete and permanent disappearance has been found to be 3600 r (200 kilovolts), whether this dose be administered at one time or fractionally. 60 per cent of the tumors are cured when irradiated with 3000 r.
865 MITOCHONDRIAL DYSFUNCTION AND MUSCLE PH ABNORMALITY POST-EXERCISE: A TWO-HIT MECHANISM FOR FATIGUE PATHOGENESIS IN PRIMARY BILIARY CIRRHOSIS
Authors: J.L. Newton, K.G. Hollingsworth, J.M. Palmer, C.M. McDonald, R. Taylor, A.M. Blamire, D.E. Jones
Journal: Journal of Hepatology (2008)
The Joseph Garland Librarian — Richard J. Wolfe
Authors: F.J. Ingelfinger
Journal: New England Journal of Medicine (1976)

F.J. Ingelfinger: We here at the Journal office are tickled pink to hear that you, Dick Wolfe, have been given an appointment named in honor of the Journal's former editor, Dr. Joseph Garland. Richard J. Wolfe: Yes — the Boston Medical Library has just established the position of Joseph Garland Librarian — and remember Dr. Garland, in addition to his editorial achievements, was President of that Library for three years. FJI: But you are also Curator of Rare Books and Manuscripts in the Francis A. Countway Library of Medicine. How is that? RJW: Well, one should . . .
Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome
Authors: Walter HA Kahr, Jesse Hinckley, Ling Li, Hansjörg Schwertz, Hilary Christensen, Jesse W Rowley, Fred G Pluthero, Denisa Urban, Shay Fabbro, Brie Nixon, Rick Gadzinski, Mike Storck, Kai Wang, Gi-Yung Ryu, Shawn M Jobe, Brian C Schutte, Jack Moseley, Noeleen B Loughran, John Parkinson, Andrew S Weyrich, Jorge Di Paola
Journal: Nature Genetics (2011)
Formation of a PKCζ/β-catenin complex in endothelial cells promotes angiopoietin-1–induced collective directional migration and angiogenic sprouting
Authors: Malika Oubaha, Michelle I. Lin, Yoran Margaron, Dominic Filion, Emily N. Price, Leonard I. Zon, Jean-François Côté, Jean-Philippe Gratton
Journal: Blood (2012)
Incorporation of TGF‐Beta 3 within Collagen–Hyaluronic Acid Scaffolds Improves their Chondrogenic Potential
Authors: Amos Matsiko, Tanya J. Levingstone, John P. Gleeson, Fergal J. O'Brien
Journal: Advanced Healthcare Materials (2015)

Incorporation of therapeutics in the form of growth factors within biomaterials can enhance their biofunctionality. Two methods of incorporating transforming growth factor-beta 3 within collagen–hyaluronic acid scaffolds are described, markedly improving mesenchymal stem cell-mediated chondrogenic differentiation and matrix production. Such scaffolds offer control over the release of therapeutics, demonstrating their potential for repair of complex chondral defects requiring additional stimuli.
Facts on New Growths
Authors: R. A. M. Case
Journal: BMJ (1967)

<h3>Abstract</h3> <h3>Objective</h3> To determine the willingness of Canadians to accept treatment from physician assistants (PAs). <h3>Design</h3> Respondents were asked to be surrogate patients or parents under 1 of 3 conditions selected at random. Two scenarios involved injury to themselves, with the third involving injury to their children. The wait time for a physician was assumed to be 4 hours, whereas to explore the sensitivity of patients’ preferences for a range of times, PA wait times were 30 minutes, 1 hour, and 2 hours. <h3>Setting</h3> Vancouver, BC. <h3>Participants</h3> Two hundred twenty-nine mothers attending a hospital with their children. <h3>Main outcome measures</h3> The main outcome measure was the proportion of individuals in each scenario who were willing to be treated by PAs for at least one of the time trade-off options offered. A secondary outcome was the proportion of individuals who changed their answers when the waiting time to see the PA varied. <h3>Results</h3> Regardless of the scenarios, 99% of participants opted for PAs under the personal circumstances; 96% opted for PAs when the issue involved their children. The choice favouring the PA persisted, albeit at slightly lower proportions, as the difference in wait time between PAs and physicians decreased (85% and 67% for a difference in PA and physician wait time of 3 and 2 hours, respectively). <h3>Conclusion</h3> These findings suggest that British Columbians are willing to be treated by PAs under most circumstances, whether this includes themselves or their children. The high level of willingness to be treated by PAs demonstrates public confidence in PA care, and suggests that the use of PAs in Canadian emergency departments or clinics is a viable policy response to decreasing primary care capacity.
Superior Transduction of Mouse Hematopoietic Stem Cells with 10A1 and VSV-G Pseudotyped Retrovirus Vectors
Authors: Stephane Barrette, Janet Douglas, Donald Orlic, Stacie M. Anderson, Nancy E. Seidel, A. Dusty Miller, David M. Bodine
Journal: Molecular Therapy (2000)

The inefficient transduction of human hematopoietic stem cells (HSC) with amphotropic retroviral vectors has been an obstacle to gene therapy for hematopoietic diseases. We have previously reported low levels of amphotropic retrovirus receptor (Pit-2) mRNA and higher levels of gibbon ape leukemia virus (GALV) or 10A1 retrovirus receptor (Pit-1) mRNA in mouse and human HSC. The vesicular stomatitis virus (VSV-G) uses an abundant membrane phospholipid as a receptor. We hypothesized that transduction of HSC requires relatively high levels of retrovirus receptor molecules. Because mouse HSC can be efficiently transduced by ecotropic virus through the abundant ecotropic receptor, the mouse is an ideal model to compare receptor levels and transduction. We have developed a cotransduction assay where ecotropic retrovirus transduction is a positive internal control for downstream steps in retrovirus transduction. A comparison of mouse HSC transduction with amphotropic, 10A1, and VSV-G envelopes showed that the level of amphotropic and 10A1 receptor mRNA in HSC correlated with the frequency of transduction. Transduction with VSV-G vectors was similar to that with 10A1 vectors. We conclude that the level of retrovirus receptor on HSC is critical for HSC transduction and that GALV or VSV-G vectors would be better for human HSC transduction. The inefficient transduction of human hematopoietic stem cells (HSC) with amphotropic retroviral vectors has been an obstacle to gene therapy for hematopoietic diseases. We have previously reported low levels of amphotropic retrovirus receptor (Pit-2) mRNA and higher levels of gibbon ape leukemia virus (GALV) or 10A1 retrovirus receptor (Pit-1) mRNA in mouse and human HSC. The vesicular stomatitis virus (VSV-G) uses an abundant membrane phospholipid as a receptor. We hypothesized that transduction of HSC requires relatively high levels of retrovirus receptor molecules. Because mouse HSC can be efficiently transduced by ecotropic virus through the abundant ecotropic receptor, the mouse is an ideal model to compare receptor levels and transduction. We have developed a cotransduction assay where ecotropic retrovirus transduction is a positive internal control for downstream steps in retrovirus transduction. A comparison of mouse HSC transduction with amphotropic, 10A1, and VSV-G envelopes showed that the level of amphotropic and 10A1 receptor mRNA in HSC correlated with the frequency of transduction. Transduction with VSV-G vectors was similar to that with 10A1 vectors. We conclude that the level of retrovirus receptor on HSC is critical for HSC transduction and that GALV or VSV-G vectors would be better for human HSC transduction.
Constitutive phosphorylation of the active Notch1 intracellular domain in chronic lymphocytic leukemia cells with NOTCH1 mutation
Authors: F De Falco, R Sabatini, F Falzetti, M Di Ianni, P Sportoletti, S Baldoni, B Del Papa, I Screpanti, P Marconi, E Rosati
Journal: Leukemia (2014)
Pooled Analysis of Antidepressant Levels in Lactating Mothers, Breast Milk, and Nursing Infants
Authors: Alicia M. Weissman, Barcey T. Levy, Arthur J. Hartz, Suzanne Bentler, Micca Donohue, Vicki L. Ellingrod, Katherine L. Wisner
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: The available data on antidepressant levels in nursing infants were analyzed in order to calculate average infant drug levels and determine what factors influence plasma drug levels in breast-feeding infants of mothers treated with antidepressants. METHOD: Electronic searches of MEDLINE, PreMEDLINE, Current Contents, Biological Abstracts, and PsycINFO from 1966 through July 2002 followed by bibliographic searches identified 67 relevant studies (two unpublished). By consensus the authors identified 57 studies of maternal plasma, breast milk, and/or infant plasma antidepressant levels from nursing mother-infant pairs, measured by liquid chromatography. RESULTS: Infants with recent prenatal exposure and symptomatic infants included in case reports were analyzed separately. Infant plasma levels were standardized against the average maternal level for each drug. The average infant-maternal plasma ratio was calculated for each drug, and correlations of infant plasma level to maternal dose, maternal plasma level, and breast milk level were calculated. Nortriptyline, paroxetine, and sertraline usually produce undetectable infant levels. Of drugs currently used, fluoxetine produces the highest proportion (22%) of infant levels that are elevated above 10% of the average maternal level. Based on smaller numbers, the data on citalopram indicate that it produces elevated levels in 17% of infants. The milk-to-plasma ratios for 11 antidepressants had a statistically significant negative association with the percentage of the drug bound to protein. CONCLUSIONS: Nortriptyline, paroxetine, and sertraline may be preferred choices in breast-feeding women. Minimizing the maternal dose may be helpful with citalopram. Current data do not support monitoring breast milk levels in individual patients. Future researchers should report maternal, breast milk, and infant antidepressant levels along with other appropriate variables.
Macromolecular prodrugs for use in targeted cancer chemotherapy: melphalan covalently coupled to N- (2-hydroxypropyl) methacrylamide copolymers
Authors: Ruth Duncan, Isabella C. Hume, Harold J. Yardley, Pauline A. Flanagan, Karel Ulbrich, Vladimir Subr, Jiri Strohalm
Journal: Journal of Controlled Release (1991)