tbuckley/cabot-search huggingface dataset:
Adaptive Dosing Approaches to the Individualization of 13-<i>Cis</i>-Retinoic Acid (Isotretinoin) Treatment for Children with High-Risk Neuroblastoma
Authors: Gareth J. Veal, Julie Errington, Sophie E. Rowbotham, Nicola A. Illingworth, Ghada Malik, Michael Cole, Ann K. Daly, Andrew D.J. Pearson, Alan V. Boddy
Journal: Clinical Cancer Research (2012)

Abstract Purpose: To investigate the feasibility of adaptive dosing and the impact of pharmacogenetic variation on 13-cis-retinoic acid (13-cisRA) disposition in high-risk patients with neuroblastoma. Experimental Design: 13-cisRA (160 mg/m2 or 5.33 mg/kg/d) was administered to 103 patients ages 21 years or less and plasma concentrations of 13-cisRA and 4-oxo-13-cisRA quantitated on day 14 of treatment. Seventy-one patients were recruited to a dose adjustment group, targeting a 13-cisRA Cmax of 2 μmol/L, with dose increases of 25% to 50% implemented for patients with Cmax values less than 2 μmol/L. A population pharmacokinetic model was applied and polymorphisms in relevant cytochrome P450 genes analyzed. Results: 13-cisRA Cmax values ranged from 0.42 to 11.2 μmol/L, with 34 of 103 (33%) patients failing to achieve a Cmax more than 2 μmol/L. Dose increases carried out in 20 patients in the dose adjustment study group led to concentrations more than 2 μmol/L in 18 patients (90%). Eight of 11 (73%) patients less than 12 kg, receiving a dose of 5.33 mg/kg, failed to achieve a Cmax of 2 μmol/L or more. Significantly, lower Cmax values were observed for patients treated with 5.33 mg/kg versus 160 mg/m2 (1.9 ± 1.2 vs. 3.1 ± 2.0 μmol/L; mean ± SD; P = 0.023). Cmax was higher in patients who swallowed 13-cisRA capsules as compared with receiving the drug extracted from capsules (4.0 ± 2.2 vs. 2.6 ± 1.8 μmol/L; P = 0.0012). The target Cmax was achieved by 93% (25/27) versus 55% (42/76) of patients in these 2 groups, respectively. No clear relationships were found between genetic variants and 13-cisRA pharmacokinetic parameters. Conclusions: Dosing regimen and method of administration have a marked influence on 13-cisRA plasma concentrations. Body weight–based dosing should not be implemented for children less than 12 kg and pharmacologic data support higher doses for children unable to swallow 13-cisRA capsules. Clin Cancer Res; 19(2); 469–79. ©2012 AACR.
Early infant crying as a behavioral state rather than a signal
Authors: Ronald G. Barr
Journal: Behavioral and Brain Sciences (2004)

I argue that in the first three months, crying is primarily a behavioral state rather than a signal and that its properties include prolonged and unsoothable crying bouts as part of normal development. However, these normal properties trigger Shaken Baby Syndrome, a form of child abuse that does not easily fit an adaptive infanticide analysis.
Summer Wanes, but Dermatologists Caution Threat of Skin Cancer Remains
Authors: Marsha F. Goldsmith
Journal: JAMA (1987)

"STAY OUT OF THE SUN" was the meaning of a bandage on the tip of his nose, President Ronald Reagan said last month. About to undergo the successful excision of his third basal cell epithelioma in two years, the President personalized the statistics and warnings from the American Cancer Society and the Skin Cancer Foundation that increase in number and grow in urgency just as the problem of skin cancer does. Having sensitive "Celtic"-type skin and enjoying the outdoor life in sunny California for many years, both the President and Nancy Reagan (who had a similar cancer removed not long ago) are typical of those at risk of developing skin cancer, says June K. Robinson, MD, associate professor of dermatology and surgery, Northwestern University Medical School, Chicago. Robinson recently reiterated cautions against overexposure to ultraviolet light. "It's necessary to keep reminding people to protect themselves, by covering up and/or using
ANO1: an additional key player in cyst growth
Authors: Tetsuhiro Tanaka, Masaomi Nangaku
Journal: Kidney International (2014)

Chloride secretion driven by calcium-dependent chloride channels has a major impact on cyst enlargement in polycystic kidney disease. Buchholz et al. studied the functional role of anoctamin 1 (ANO1), a recently identified calcium-activated chloride channel, in kidney cyst growth, using principal-like cells forming cysts within a collagen matrix and an embryonic kidney cyst model. Their results support a potential role for this chloride channel in cyst generation.
From the authors
Authors: B. Schaaf, K. Dalhoff
Journal: European Respiratory Journal (2008)

Given its rich history and tradition as well as its incredible complexity, wine has been the subject of a considerable amount of research. Grape and wine phenolics, because of their complexity and importance in wine quality, serves as a good example of how tradition and science have coevolved. This review summarizes early research on grape and wine phenolics and provides justification for continued research.
Role of spin echo and cine magnetic resonance imaging in presurgical planning of heterotaxy syndrome. Comparison with echocardiography and catheterization.
Authors: T Geva, G W Vick, R E Wendt, R Rokey
Journal: Circulation (1994)

BACKGROUND Patients with heterotaxy syndrome frequently have complex congenital cardiac and noncardiac malformations requiring detailed diagnostic evaluation by noninvasive as well as invasive imaging modalities for management planning. Recent advances in magnetic resonance imaging (MRI) techniques allow detailed delineation of cardiovascular anatomy and blood flow in young infants with rapid heart rates. The present study was undertaken to prospectively evaluate the role of MRI in the presurgical evaluation of patients with heterotaxy syndrome. METHODS AND RESULTS Between January 1 and December 31, 1992, 14 consecutive patients with heterotaxy syndrome and complex congenital heart disease were enrolled in a prospective protocol. After evaluation by echocardiography and cardiac catheterization, a tentative management plan was recorded. Subsequently, a MRI study was performed and surgical planning was reevaluated. MRI was found to be comparable to echocardiography in terms of length of examination and sedation requirements. Surgical planning was altered in four patients because MRI provided additional data not evident on echocardiography and catheterization. Comparison of diagnostic yield between echocardiography, catheterization, and MRI showed that MRI is superior to echocardiography and often to catheterization in delineation of systemic and pulmonary venous anatomy and their relation to mediastinal structures. When the anatomic and hemodynamic data obtained by echocardiography and MRI were considered together, cardiac catheterization data were necessary only to determination of pulmonary vascular resistance before Fontan operation. CONCLUSIONS MRI provides excellent anatomic and functional information that in some patients was not available by echocardiography or catheterization. Combined with echocardiography, MRI provides the high-quality diagnostic information necessary for management planning in most patients with heterotaxy syndrome. Cardiac catheterization is indicated when determination of pulmonary vascular resistance is necessary for decision making or when an interventional procedures is indicated.
Methotrexate treatment of squamous-cell head and neck cancers: dose-response evaluation.
Authors: R L Woods, R M Fox, M H Tattersall
Journal: BMJ (1981)

Seventy-two patients with advanced squamous-cell carcinomas of the head and neck were randomised to receive weekly intravenous methotrexate at doses of either 50 mg/m2 (low dose), 500 mg/m2 (medium dose), or 5 g/m2 (high dose). Patients who failed to respond after four treatments at their initial dose were given four further treatments at the next higher dose. There were two complete responses and 21 partial responses to the initial dose--in 10 out of 22 patients given the high dose, seven out of 27 given the medium dose, six out of 23 given the low dose. A further five out of 16 patients responded after crossing over to a higher dose. Toxicity was more severe with the high-dose regimen. Responders survived significantly longer than non-responders (p less than 0.05), but there was no significant difference in durations of survival among the three treatment groups. Analysis of patients who completed the first four treatments indicated an improved response rate and duration of survival for the high-dose group. Because of toxicity associated with high-dose methotrexate this treatment produces no overall greater benefit than low-dose regimens.
Small-molecule inhibitors prevent the genotoxic and protumoural effects induced by colibactin-producing bacteria
Authors: Antony Cougnoux, Julien Delmas, Lucie Gibold, Tiphanie Faïs, Chiara Romagnoli, Frederic Robin, Gabriel Cuevas-Ramos, Eric Oswald, Arlette Darfeuille-Michaud, Fabio Prati, Guillaume Dalmasso, Richard Bonnet
Journal: Gut (2015)

Colorectal cancers (CRCs) are frequently colonised by colibactin toxin-producing Escherichia coli bacteria that induce DNA damage in host cells and exhibit protumoural activities. Our objective was to identify small molecules inhibiting the toxic effects induced by these colibactin-producing bacteria.A structural approach was adopted for the identification of a putative ligand for the ClbP enzyme involved in the synthesis of colibactin. Intestinal epithelial cells and a CRC mouse model were used to assess the activity of the selected compounds in vitro and in vivo.Docking experiments identified two boron-based compounds with computed ligand efficiency values (-0.8 and -0.9 kcal/mol/atom) consistent with data expected for medicinal chemistry leads. The crystalline structure of ClbP in complex with the compounds confirmed that the compounds were binding to the active site of ClbP. The two compounds (2 mM) suppressed the genotoxic activity of colibactin-producing E coli both in vitro and in vivo. The mean degree of suppression of DNA damage for the most efficient compound was 98±2% (95% CI). This compound also prevented cell proliferation and colibactin-producing E coli-induced tumourigenesis in mice. In a CRC murine model colonised by colibactin-producing E coli, the number of tumours decreased by 3.5-fold in animals receiving the compound in drinking water (p<0.01).These results demonstrate that targeting colibactin production controls the genotoxic and protumoural effects induced by this toxin.
Negative regulators of sodium transport in the kidney: Key factors in understanding salt-sensitive hypertension?
Authors: Bernard C. Rossier
Journal: Journal of Clinical Investigation (2003)

Miner. Res. 16:s427. 11. Pi, M., Garner, S.C., Flannery, P., Spurney, R.F., and Quarles, L.D. 2000. Sensing of extracellular cations in CasR-deficient osteoblasts. Evidence for a novel cation-sensing mechanism. J. Biol. Chem. 275:3256–3263. 12. Kanatani, M., Sugimoto, T., Kanzawa, M., Yano, S., and Chihara, K. 1999. High extracellular calcium inhibits osteoclast-like cell formation by directly acting on the calcium-sensing receptor existing in osteoclast precursor cells. Biochem. Biophys. Res. Commun. 261:144–148. 13. Zaidi, M., Adebanjo, O.A., Moonga, B.S., Sun, L., and Huang, C.L. 1999. Emerging insights into the role of calcium ions in osteoclast regulation. J. Bone Miner. Res. 14:669–674. 14. Kos, C.H., et al. 2003. The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone. J. Clin. Invest. 111:1021–1028. doi:10.1172/JCI200317416. 15. Tu, Q., et al. 2003. Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. J. Clin. Invest. 111:1029–1037. doi:10.1172/JCI200317054. 16. Gunther, T., et al. 2000. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature. 406:199–203. 17. Imanishi, Y., et al. 2001. Primary hyperparathyroidism caused by parathyroid-targeted d overexpression of cyclin D1 in transgenic mice. J. Clin. Invest. 107:1093–1102. 18. Skerry, T.M. 1999. Identification of novel signaling pathways during functional adaptation of the skeleton to mechanical loading: the role of glutamate as a paracrine signaling agent in the skeleton. J. Bone Miner. Metab. 17:66–70. 19. Kubo, Y., Miyashita, T., and Murata, Y. 1998. Structural basis for a Ca2+-sensing function of the metabotropic glutamate receptors. Science. 279:1722–1725. 20. Neuman, W., and Neuman, M.W. 1958. The chemical dynamics of bone mineral. University of Chicago Press. Chicago, Illinois, USA. 209 pp.
New law spells out rights of `exceptional children'
Authors: Beverly J. Montgomery
Journal: JAMA (1978)

Pediatricians, psychiatrists, orthopedic surgeons, and otolaryngologists are among those physicians who will be consulted more often by educators and parents under the mandates of a new law (effective since Sept 1) delineating the rights of "exceptional children." Known as Public Law (PL) 94-142, the act stipulates that all "exceptional" (previously called handicapped or gifted) children between the ages of 3 and 18 years shall be offered, without charge, certain services that will help them reach their educational potential. (Beginning Sept 1, 1980, provisions of the law will extend to the age of 20 years.) These children include the mentally retarded, the hard of hearing, the deaf, the speech impaired, the emotionally disturbed, and the orthopedically impaired, as well as children with certain chronic illnesses or specific learning disabilities. As much as possible, the children will be kept in regular school programs. One type of service covered by the law, for
Epidemiology of Amebiasis in the US
Authors: M. M. Brooke
Journal: JAMA (1964)

IN A COUNTRY as large as the US, with so many different geographical areas and socioeconomic groups, it is probably unwise to give a prevalence figure of Entamoeba histolytica for the general population. However, since the prevalence rate has been frequently cited to be 10 to 20%, it is well to state that it is more likely around 5%. Although it is possible that the incidence of E histolytica is declining in the US, this lower appraisal of the prevalence results from accepting the so-called small race E histolytica as a separate species ( Entamoeba hartmanni ) and from considering primarily survey results of the general public.<sup>1</sup> E histolytica has been found throughout the US wherever careful examinations have been performed, but the rates vary from place to place and even from group to group within the same general locality. For example, on Indian reservations in five different states the prevalence rate was found to range from 1.5% to 33%<sup>2</sup>and in the vicinity of Little Rock, Ark, it ranged from 1% to 6% in four separate yet fairly close communities.<sup>3</sup>Therefore, for a given community or population group, it is not satisfactory to assume a particular prevalence rate until a careful survey has been performed.
928-81 Importance of Holter Monitoring, as Compared to Exercise Testing, in Revealing ST-segment Changes in Patients with Syndrome X
Authors: Gaetano A. Lanza, Alessandro Manzoli, Giuseppe Colonna, Vincenzo Pasceri, Giuseppe M.C. Rosano, Filippo Crea, Attilio Maseri
Journal: Journal of the American College of Cardiology (1995)
Chlorine exposure and the upper respiratory tract
Authors: D. Shusterman, C. Solomon, J. Balmes, P. Blanc
Journal: European Respiratory Journal (2002)

To the Editor: 

We read with great interest the report of Schins et al. 1 on their controlled human-exposure study of chlorine inhalation. The air pollutant studied, gaseous chlorine, is one of substantial relevance in terms of total industrial usage and involvement in emergency release scenarios.

The authors referred to “…a paucity of human data on the effect …
Transient Blindness following Blood Transfusion
Authors: D. Lehane
Journal: BMJ (1941)

MEDICAL JOURtNAL injecting into the sac 4 c.cm. of lithocaine (lithium salicylate 30% and tutocain 1%), followed by 2 c.cm. of quinine-urethane.The parts are thoroughly massaged after the injection, and the patient is ordered to wear a testicular support.A week later the fluid which accumulates in the tunica vaginalis as the result of chemical irritation of the delicafe endothelial lining is cautiously aspirated.
Exposure to antipsychotics and risk of stroke: self controlled case series study
Authors: I. J Douglas, L. Smeeth
Journal: BMJ (2008)

<b>Objectives</b> To investigate the association between use of typical and atypical antipsychotic drugs and incidence of stroke in patients with and without dementia. <b>Design</b> Self controlled case series. <b>Setting</b> UK based electronic primary care records in the general practice research database (GPRD). <b>Participants</b> All patients registered in the database with a recorded incident stroke and at least one prescription for any antipsychotic drug before the end of 2002: 6790 eligible participants were identified and included in the final analysis. <b>Main outcome measures</b> Rate ratio for stroke in periods of time exposed to antipsychotics compared with unexposed periods. <b>Results</b> Use of any antipsychotic drug was associated with a rate ratio for stroke of 1.73 (95% confidence interval 1.60 to 1.87): 1.69 (1.55 to 1.84) for typical antipsychotics and 2.32 (1.73 to 3.10) for atypical antipsychotics. In patients receiving any antipsychotic drug, the rate ratios were 3.50 (2.97 to 4.12) for those with dementia and 1.41 (1.29 to 1.55) for those without dementia. <b>Conclusions</b> All antipsychotics are associated with an increased risk of stroke, and the risk might be higher in patients receiving atypical antipsychotics than those receiving typical antipsychotics. People with dementia seem to be at a higher risk of an associated stroke than people without dementia and use of antipsychotics should, when possible, be avoided in these patients.
The Ecology of R Factors
Authors: David H. Smith, Pierce Gardner
Journal: New England Journal of Medicine (1970)

THE ability of many gram-negative bacilli to resist certain commonly used antibiotics has been shown to be mediated in large part by R factors. Since the incidence of infections caused by gram-negative bacilli has been increasing, and since R factors can mediate multiple-drug resistance, and can be transferred between bacteria, these extrachromosomal genetic elements have concerned public-health workers and interested microbiologists.In this issue of the Journal, Davis and Anandan report the recovery of Escherichia coli with R factors from an "antibiotic virgin" community in Borneo. Their findings confirm and extend those of other studies1 , 2 indicating that resistant, and . . .
Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Moderate or Severe Renal Impairment: Observations From the SAVOR-TIMI 53 Trial
Authors: Jacob A. Udell, Deepak L. Bhatt, Eugene Braunwald, Matthew A. Cavender, Ofri Mosenzon, Ph. Gabriel Steg, Jaime A. Davidson, Jose C. Nicolau, Ramon Corbalan, Boaz Hirshberg, Robert Frederich, KyungAh Im, Amarachi A. Umez-Eronini, Ping He, Darren K. McGuire, Lawrence A. Leiter, Itamar Raz, Benjamin M. Scirica
Journal: Diabetes Care (2014)

OBJECTIVE The glycemic management of patients with type 2 diabetes mellitus (T2DM) and renal impairment is challenging, with few treatment options. We investigated the effect of saxagliptin in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial according to baseline renal function. RESEARCH DESIGN AND METHODS Patients with T2DM at risk for cardiovascular events were stratified as having normal or mildly impaired renal function (estimated glomerular filtration rate [eGFR] &amp;gt;50 mL/min/1.73 m2; n = 13,916), moderate renal impairment (eGFR 30–50 mL/min/1.73 m2; n = 2,240), or severe renal impairment (eGFR &amp;lt;30 mL/min/1.73 m2; n = 336) and randomized to receive saxagliptin or placebo. The primary end point was cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS After a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions ≥0.19). Overall, the risk of hospitalization for heart failure among the three eGFR groups of patients was 2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95–2.91], P &amp;lt; 0.001), and 13.0% (adjusted HR 4.59 [95% CI 3.28–6.28], P &amp;lt; 0.001), respectively. The relative risk of hospitalization for heart failure with saxagliptin was similar (P for interaction = 0.43) in patients with eGFR &amp;gt;50 mL/min/1.73 m2 (HR 1.23 [95% CI 0.99–1.55]), eGFR 30–50 mL/min/1.73 m2 (HR 1.46 [95% CI 1.07–2.00]), and in patients with eGFR &amp;lt;30 (HR 0.94 [95% CI 0.52–1.71]). Patients with renal impairment achieved reductions in microalbuminuria with saxagliptin (P = 0.041) that were similar to those of the overall trial population. CONCLUSIONS Saxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk of heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function.
Review: Rapid-response teams do not reduce mortality in hospital patients
Authors: Steven M. Belknap
Journal: Annals of Internal Medicine (2010)

ACP Journal Club15 June 2010Review: Rapid-response teams do not reduce mortality in hospital patientsSteven M. Belknap, MDSteven M. Belknap, MDNorthwestern University Feinberg School of Medicine, Chicago, Illinois, USA (S.M.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-152-12-201006150-02003 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationChan PS, Jain R, Nallmothu BK, Berg RA, Sasson C. Rapid response teams: a systematic review and meta-analysis. Arch Intern Med. 2010;170:18-26. https://pubmed.ncbi.nlm.nih.gov/20065195Clinical Impact RatingsEmergency Med: Hospitalists: Cardiology: References1 Priestley G, Watson W, Rashidian A, et al. Introducing Critical Care Outreach: a ward-randomised trial of phased introduction in a general hospital. Intensive Care Med. 2004;30:1398-404. [PMID: 15112033] Google Scholar2 Hillman K, Chen J, Cretikos M, et al; MERIT study investigators. Introduction of the medical emergency team (MET) system: a cluster-randomised controlled trial. Lancet. 2005;365:2091-7. [PMID: 15964445] Google Scholar3 “Clinical triggers” program cuts cardio arrest rate. Healthcare Benchmarks Qual Improv. 2009;16:52-3. [PMID: 19432380] Google Scholar4 Akre M, Finkelstein M, Erickson M, et al. Sensitivity of the Pediatric Early Warning Score to identify patient deterioration. Pediatrics. 2010 Mar 22. [Epub ahead of print.] [PMID: 20308222] Google Scholar Author, Article, and Disclosure InformationAuthors: Steven M. Belknap, MDAffiliations: Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA (S.M.B.)This article was published at Annals.org on 1 June 2010. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byRapid Response Systems in the Netherlands 15 June 2010Volume 152, Issue 12Page: JC6-3KeywordsChildrenHeartIntensive care unitsMortalityResearch designResearch quality assessmentResuscitationSystematic reviewsTriage ePublished: 15 June 2010 Issue Published: 15 June 2010 Copyright & PermissionsCopyright © 2010 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...