tbuckley/cabot-search huggingface dataset:
Nationwide Study on Hypertrophic Cardiomyopathy in Iceland
Authors: Berglind Adalsteinsdottir, Polakit Teekakirikul, Barry J. Maron, Michael A. Burke, Daniel F. Gudbjartsson, Hilma Holm, Kari Stefansson, Steven R. DePalma, Erica Mazaika, Barbara McDonough, Ragnar Danielsen, Jonathan G. Seidman, Christine E. Seidman, Gunnar T. Gunnarsson
Journal: Circulation (2014)

The geographic isolation and homogeneous population of Iceland are ideally suited to ascertain clinical and genetic characteristics of hypertrophic cardiomyopathy (HCM) at the population level.Medical records and cardiac imaging studies obtained between 1997 and 2010 were reviewed to identify Icelandic patients with HCM. Surviving patients were recruited for clinical and genetic studies. A previously identified Icelandic mutation, MYBPC3 c.927-2A>G, was genotyped, and mutation-negative samples were sequenced for HCM genes and other hypertrophic genes. Record review identified 180 patients with HCM. Genetic analyses of 151 patients defined pathogenic mutations in 101 (67%), including MYBPC3 c.927-2A>G (88 patients, 58%), 4 other MYBPC3 or MYH7 mutations (5 patients, 3.3%), and 2 GLA mutations (8 patients, 5.3%). Haplotype and genetic genealogical data defined MYBPC3 c.927-2A>G as a founder mutation, introduced into the Icelandic population in the 15th century, with a current population prevalence of 0.36%. MYBPC3 c.927-2A>G mutation carriers exhibited phenotypic diversity but were younger at diagnosis (42 versus 49 years; P=0.001) and sustained more adverse events (15% versus 2%; P=0.02) than mutation-negative patients. All-cause mortality for patients with HCM was similar to that of an age-matched Icelandic population (hazard ratio, 0.98; P=0.9). HCM-related mortality (0.78%/y) occurred at a mean age of 68 compared with 81 years for non-HCM-related mortality (P=0.02).A founder MYBPC3 mutation that arose >550 years ago is the predominant cause of HCM in Iceland. The MYBPC3 c.927-2A>G mutation is associated with low adverse event rates but earlier cardiovascular mortality, illustrating the impact of genotype on outcomes in HCM.
Renal response to environmental toxics
Authors: William F. Finn
Journal: Environmental Health Perspectives (1977)

Several characteristics of normal renal function increase the risk to the kidney of damage by environmental toxins. Due to the magnitude of renal blood flow the total amount of noxious substance delivered may be disproportionately high. Furthermore, the capacity to concentrate substances within the kidney by processes of filtration, reabsorption and secretion has the potential to increase the toxicity of agents which would otherwise not lead to tissue injury. Unfortunately, there are few tests of renal function which are able to detect early functional abnormalities and which, at the same time, are suited for screening purposes by virtue of their simplicity, cost and safety. Furthermore, interpretation of the tests is complicated by adaptive changes in renal function which occur with aging and in response to other disease processes. Environmental agents produce a wide spectrum of renal dysfunction. Acute renal damage follows exposure to glycols, organic solvents, heavy metals, diagnostic and therapeutic agents and a variety of miscellaneous substances. Chronic renal disease may take the form of isolated tubular defects as seen with cadmium, interstitial nephritis due to the ingestion of lead, or vascular damage induced by external radiation. Some forms of glomerulonephritis may also be related to environmental toxins as are certain tumors of the urinary tract. In a somewhat different fashion, patients whose renal function is limited by the presence of pre-existing disease may manifest toxicity from substances ordinarily excreted in the urine. Particular problems exist with the patients on dialysis, as they are at considerable risk to alterations in the environment.
Abstract 2524: Targeting microtubule-associated protein 4 with novel small molecule CH4938056 confers antitumor activity under <i>quasi in vivo</i> conditions and in xenograft models
Authors: Osamu Kondoh, Hidemi Saito, Yoshito Nakanishi, Toshiyuki Tsukaguchi, Kohji Nagano, Noriyuki Inomata, Kiyoaki Sakata, Toshihiko Fujii, Yasuko Satoh, Kazuo Hattori, Satoshi Niizuma, Kohei Koyama, Takehiro Okada, Yukinori Minoshima, Toshiyuki Kawashima, Toshio Kitamura, Takuo Tsukuda, Shimma Nobuo, Mikio Arisawa, Nobuya Ishii, Yuko Aoki
Journal: Cancer Research (2011)

Abstract Tumor microenvironment is a major factor influencing treatment resistance to conventional anticancer therapies. Indeed, under “quasi in vivo” conditions, with low oxygen (1%), low pH (6.5) and low glucose concentration (0.01%) to mimic the environments in grafted tumors in mice or in clinical tumors, anti-proliferative activities of some conventional anticancer agents were diminished. Here, we describe the small molecule CH4938056, which has a novel chemical structure and was identified through cell-based screening under the “quasi in vivo” conditions followed by chemical modification. Our initial phenotypic profiling revealed that CH4938056 specifically arrests cells at the M phase and that it overcomes multiple resistance mechanisms to conventional anticancer agents including over-expression of MDR1 and BCRP. Then, after designing and identifying a water-soluble phosphate prodrug which successfully converts to CH4938056 after injection, we demonstrated antitumor efficacy of CH4938056 in a HCT116 xenograft model and a MDR1-overexpressing cancer model. Chemo-proteomic studies and consequent biochemical analysis revealed that CH4938056 binds to microtubule-associated protein 4 (MAP4). Moreover, CH4938056 inhibited MAP4-dependent microtubule assembly in a cell free system. siRNA-mediated knockdown of MAP4 induced chromosomal misalignment in metaphase cells, which closely resembles the primary phenotype of the CH4938056-treated cells. Under the “quasi in vivo” conditions, MAP4 expression turned out to be down-regulated (since MAP4 transcription is known to be negatively regulated by p53 which is up-regulated under these conditions) and when we knocked down MAP4 with siRNA, cancer cells became sensitive to CH4938056, which altogether is consistent with the fact that CH4935056 has antitumor activity even under the “quasi in vivo” conditions. From these observations, we conclude that CH4938056 inhibits proliferation of cancer cells by targeting MAP4. Targeting MAP4 with CH4938056 offers a novel approach for the treatment of cancer, especially for patients resistant to conventional anticancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2524. doi:10.1158/1538-7445.AM2011-2524
Release and bioactivity of bone morphogenetic protein-2 are affected by scaffold binding techniques in vitro and in vivo
Authors: Salwa Suliman, Zhe Xing, Xujun Wu, Ying Xue, Torbjorn O. Pedersen, Yang Sun, Anne P. Døskeland, Joachim Nickel, Thilo Waag, Henning Lygre, Anna Finne-Wistrand, Doris Steinmüller-Nethl, Anke Krueger, Kamal Mustafa
Journal: Journal of Controlled Release (2014)

A low dose of 1μg rhBMP-2 was immobilised by four different functionalising techniques on recently developed poly(l-lactide)-co-(ε-caprolactone) [(poly(LLA-co-CL)] scaffolds. It was either (i) physisorbed on unmodified scaffolds [PHY], (ii) physisorbed onto scaffolds modified with nanodiamond particles [nDP-PHY], (iii) covalently linked onto nDPs that were used to modify the scaffolds [nDP-COV] or (iv) encapsulated in microspheres distributed on the scaffolds [MICS]. Release kinetics of BMP-2 from the different scaffolds was quantified using targeted mass spectrometry for up to 70days. PHY scaffolds had an initial burst of release while MICS showed a gradual and sustained increase in release. In contrast, NDP-PHY and nDP-COV scaffolds showed no significant release, although nDP-PHY scaffolds maintained bioactivity of BMP-2. Human mesenchymal stem cells cultured in vitro showed upregulated BMP-2 and osteocalcin gene expression at both week 1 and week 3 in the MICS and nDP-PHY scaffold groups. These groups also demonstrated the highest BMP-2 extracellular protein levels as assessed by ELISA, and mineralization confirmed by Alizarin red. Cells grown on the PHY scaffolds in vitro expressed collagen type 1 alpha 2 early but the scaffold could not sustain rhBMP-2 release to express mineralization. After 4weeks post-implantation using a rat mandible critical-sized defect model, micro-CT and Masson trichrome results showed accelerated bone regeneration in the PHY, nDP-PHY and MICS groups. The results demonstrate that PHY scaffolds may not be desirable for clinical use, since similar osteogenic potential was not seen under both in vitro and in vivo conditions, in contrast to nDP-PHY and MICS groups, where continuous low doses of BMP-2 induced satisfactory bone regeneration in both conditions. The nDP-PHY scaffolds used here in critical-sized bone defects for the first time appear to have promise compared to growth factors adsorbed onto a polymer alone and the short distance effect prevents adverse systemic side effects.
Impact Of School Peanut-Free Guidelines On Epinephrine Administration
Authors: Lisa M. Bartnikas, Michelle F. Huffaker, William J. Sheehan, Watcharoot Kanchongkittiphon, Carter Petty, Anne Sheetz, Robert Leibowitz, Michael C. Young, Wanda Phipatanakul
Journal: Journal of Allergy and Clinical Immunology (2014)
Guide-wire Perforation during Bougienage and Tube Positioning. Report on Three Cases and Technical Improvement
Authors: H. Kowalewski, W. Roesch
Journal: Endoscopy (1988)

See also: "Guide-wire Perforation during Bougienage and Tube Positioning. Report on Three Cases and Technical Improvement"Endoscopy 1989; 21(03): 157-157DOI: 10.1055/s-2007-1012930
Sildenafil for Treatment of Erectile Dysfunction in Men With Diabetes
Authors: Marc S. Rendell, Jacob Rajfer, Pierre A. Wicker, Michael D. Smith, None for the Sildenafil Diabetes Study Group
Journal: JAMA (1999)

IABETES MELLITUS AFFECTS AN estimated 15.7 million people in the United States, including 7.5 million men, with type 2, non-insulin-dependent, diabetes accounting for 90% to 95% of the diagnosed cases and type 1, insulindependent, diabetes accounting for 5% to 10%. 1 A common complication of diabetes in men is erectile dysfunction (ED), defined by the National Institutes of Health Consensus Panel on Impotence as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual activity. 2he prevalence of ED of any degree in men aged 40 to 70 years was estimated to be 52% in the Massachusetts Male Aging Study (MMAS), with a prevalence of 25% for moderate ED and 10% for complete ED (ie, no erections). 3The prevalence of ED is age dependent, with the rate of complete ED increasing from 5% among men aged 40 years to 15% among those aged 70 years. 3rectile dysfunction in men with diabetes is often associated with diabetic neuropathy and peripheral vascular disease. 4,5It occurs at an earlier age in men with diabetes than in men
Abstract 1235: Induction of a p21 mediated senescence program by p53 impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer
Authors: James G. Jackson, Leslie L. Chang, Alfonso Quintás-Cardama, Adel K. El-Naggar, Guillermina Lozano
Journal: Cancer Research (2011)

Abstract How p53 mediates response to DNA damage induced by chemotherapy treatment of breast cancer is not well understood with few mechanistic studies addressing the conflicting reports in the literature. We have used the MMTV-Wnt1 mouse model of breast cancer to examine the role of the p53 pathway in the biochemical, cellular and clinical response to doxorubicin. We found that treatment of p53 wild type breast tumors, or heterozygous tumors that retained the wild type allele, resulted in an initial mean tumor regression of only 35%, followed by stable disease (∼1 to 2 weeks) and relapse by 11 days. Surprisingly, we found that breast tumors with mutant p53 responded better to treatment, with regression of 70% and 24 days to relapse (p&amp;lt;0.001). Investigating the mechanism of these responses, we found that p53 mutant tumors harvested 24 hours after final treatment did not induce p53 targets after treatment when compared to untreated tumors, did not enter proliferative arrest, but did undergo p53-independent apoptosis, consistent with tumor regression data. Conversely, treated p53 wild type tumors induced p53 targets such as p21 and Puma, were negative for the proliferation marker Ki67, and did not induce apoptosis. Further characterization of the partial response in p53 wild type tumors revealed that tumors harvested in the stable arrest phase (7-14 days after treatment) had elevated markers of senescence, including p21, Dec1, Dcr2, p15, p16 and PML, compared to relapsed or resistant tumors. To more precisely address which of the myriad p53 functions was responsible for the poor response in p53 wild type tumors, we bred the MMTV-Wnt1 mice into a p21 null background and treated and monitored mice that formed tumors. We found that genetic loss of p21 in the tumors was sufficient to achieve the dramatic response observed in p53 null tumors. These data show that p53 mediated activation of a senescence program via p21 is the primary outcome in treated MMTV-Wnt1tumors, resulting in an incomplete response, stable disease and eventual early relapse, while treated p53 mutant or p21 null tumors undergo cell death and tumor regression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1235. doi:10.1158/1538-7445.AM2011-1235
THE BEHAVIOR OF THE PYLORUS
Authors: Robert A. Arens
Journal: JAMA (1926)

<h3>To the Editor:</h3> —The editorial on "The Behavior of the Pylorus" (The Journal, July 31) states that "it is currently concluded from roentgen-ray evidence in animals and in man, and from experimental evidence in animals, that the pylorus is normally open at the height of antral contraction and that every antral contraction is normally followed by the discharge of chyme through the pylorus." My experience in a large number of cases is directly contrary to this statement. There is no question about the fact that the pylorus apparently is open at the height of antral contraction, yet it does not follow that the pylorus is open at the height of every antral contraction. It is a common occurrence to see four or five peristaltic waves in succession complete their cycle at the pylorus without any opaque medium passing through.
Circulating interleukin-1 and tumor necrosis factor antagonists in liver disease
Authors: Herbert Tilg, Wolfgang Vogel, Christian J. Wiedermann, Leland Shapiro, Manfred Herold, Gert Judmaier, Charles A. Dinarello
Journal: Hepatology (1993)

The proinflammatory cytokines interleukin-1 and tumor necrosis factor-alpha are thought to play important roles in the pathophysiology of liver disease. Specific antagonists of these cytokines have been found in recent years. Interleukin-1 receptor antagonist is a specific interleukin-1 antagonist. The soluble receptor derived from the cell-surface p55 tumor necrosis factor receptor p55 is a naturally occurring substance that inhibits the biological effects of tumor necrosis factor. We used specific radioimmunoassays to detect circulating interleukin-1 receptor antagonist and tumor necrosis factor soluble receptor p55 levels in 14 patients with acute viral hepatitis and in 160 patients with various chronic liver diseases. Levels of interleukin-1 receptor antagonist and, especially, tumor necrosis factor soluble receptor were markedly increased in most patients with chronic liver disease regardless of pathogenesis and in viral hepatitis. Patients with chronic liver disease and cirrhosis showed significantly higher levels of both cytokine antagonists than did noncirrhotic patients. Correlations between interleukin-1 receptor antagonist and tumor necrosis factor soluble receptor were more significant than those of either antagonist with C-reactive protein or blood sedimentation rate. Interleukin-1 receptor antagonist and tumor necrosis factor soluble receptor levels were also positively correlated with bilirubin and AST levels. We conclude that circulating levels of interleukin-1 receptor antagonist and tumor necrosis factor soluble receptor may reflect ongoing disease activity and probably modulate some effects of endogenous interleukin-1 and tumor necrosis factor.
The Appropriateness of Carotid Endarterectomy
Authors: David W. Smith, William Stiers
Journal: JAMA (1987)

<h3>To the Editor.—</h3> The growth in frequency of carotid endarterectomies in the United States during the 1970s and through 1984 has been documented by Dyken and Pokras.<sup>1</sup>Updated information from Veterans Administration (VA) medical centers shows that the number of carotid endarterectomies was stable from 1983 (fiscal year, starting Oct 1, 1982) through 1985, after growing at about 12% a year (compounded) for three years, or a total of about 50%, from 1980 to 1983 (Figure). In 1984 the number of procedures fell 0.2% (seven procedures) and in 1985 rose 2.2% (68 procedures). Carotid endarterectomies were done in 117 VA medical centers (172 institutions total); the 102 VA medical centers affiliated with academic medical centers performed 96% of the carotid endarterectomies. Recent professional concern<sup>2-4</sup>about complications and benefits of carotid endarterectomies could have already influenced medical decision making sufficiently to curtail the frequency of carotid endarterectomies in VA
Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells
Authors: Rachael A. Clark, Susan J. Huang, George F. Murphy, Ilse G. Mollet, Dirkjan Hijnen, Manoj Muthukuru, Carl F. Schanbacher, Vonetta Edwards, Danielle M. Miller, Jenny E. Kim, Jo Lambert, Thomas S. Kupper
Journal: The Journal of Experimental Medicine (2008)

Squamous cell carcinomas (SCCs) of the skin are sun-induced skin cancers that are particularly numerous in patients on T cell immunosuppression. We found that blood vessels in SCCs did not express E-selectin, and tumors contained few cutaneous lymphocyte antigen (CLA)+ T cells, the cell type thought to provide cutaneous immunosurveillance. Tumors treated with the Toll-like receptor (TLR)7 agonist imiquimod before excision showed induction of E-selectin on tumor vessels, recruitment of CLA+ CD8+ T cells, and histological evidence of tumor regression. SCCs treated in vitro with imiquimod also expressed vascular E-selectin. Approximately 50% of the T cells infiltrating untreated SCCs were FOXP3+ regulatory T (T reg) cells. Imiquimod-treated tumors contained a decreased percentage of T reg cells, and these cells produced less FOXP3, interleukin (IL)-10, and transforming growth factor (TGF)-β. Treatment of T reg cells in vitro with imiquimod inhibited their suppressive activity and reduced FOXP3, CD39, CD73, IL-10, and TGF-β by indirect mechanisms. In vivo and in vitro treatment with imiquimod also induced IL-6 production by effector T cells. In summary, we find that SCCs evade the immune response at least in part by down-regulating vascular E-selectin and recruiting T reg cells. TLR7 agonists neutralized both of these strategies, supporting their use in SCCs and other tumors with similar immune defects.
Scottish physicians withdraw their support for health bill in England
Authors: B. Christie
Journal: BMJ (2012)

The list of leading medical organisations opposing the government’s Health and Social Care Bill has increased with the decision of the Royal College of Physicians of Edinburgh to withdraw its support.

The college stopped short of calling for the full withdrawal of the bill as has been demanded by other organisations, including the BMA, but says it cannot support the legislation in its current form.

The college, which has more than 2500 members in England, asked all its fellows and members in the UK for their views …
Both unilateral naevus achromicus and congenital agminated Spitz naevi in a checkerboard mosaic pattern
Authors: S. Menni, R. Betti, D. Boccardi, L. Gualandri
Journal: British Journal of Dermatology (2001)

Sir, Spitz naevus is considered to be a type of melanocytic naevus. The solitary form is the most frequent, while multiple disseminated and multiple agminated types are considered rare. Multiple Spitz naevi disseminated over the entire surface, grouped and arizing on normal skin, hypopigmented or hyperpigmented area have been described.1–2 The only case in which Spitz naevi arose on a depigmented patch of naevus achromicus was described by Korting et al.3 Naevus achromicus (NA) is a congenital, non‐progressive, hypopigmented macule or patch that may be localized, segmental or, more rarely, systematized when it follows Blaschko’s lines.4 Very rarely, it has been described in association with other skin lesions or with lesions located within it.5 Here we describe a patient in whom multiple agminated congenital Spitz naevi arose on a large unilateral achromic patch disposed in a particular distribution, similar to that which Happle defined as a checkerboard mosaic pattern. A 4‐year‐old female child had a congenital pink papule (4‐mm in diameter) located on her left forearm and present from birth. From the fourth month of life several similar papular lesions, 1–4 mm in diameter, erupted. The lesions were pink and light or dark brown in colour, and smooth or slightly rough on the surface. All these lesions were confined within the distribution of a large unilateral congenital achromic area covering the back from midline at the level of T5–T6 extending laterally onto the right shoulder and arm down to the hand (Fig. 1a). In the thorax area, the achromic lesion involved a wide region from the midline at the level of T5–T6 extending on the flexural aspect of the right arm, forearm and hand (Fig. 1b). Some older papular lesions had become modified in their colour and flattened. Physical examination at the age of 4 years revealed about 200 brown and reddish papular lesions. Three biopsies were performed. In every case, histological examination showed the features of Spitz naevus. The young patient was in good health and had no family history of similar lesions. Routine blood count and bone radiography of the upper extremities were normal.
F-18 FDG PET/CT Study Showing Cervical Extension of Thymic Tissue
Authors: Ka Kit Wong, Elisa Foster, Morand Piert
Journal: Clinical Nuclear Medicine (2008)

Thymic hyperplasia with increased F-18 fluoro-deoxyglucose (FDG) uptake on PET imaging is a common finding in young children and adolescents after chemotherapy. A variant where thymic tissue extends into the superior mediastinum and lower neck likely represents an embryologic remnant along the track of descent. We report a case of a 4-year-old boy with intracranial sarcoma treated with surgical resection and chemotherapy. An F-18 FDG PET/CT study performed 3 months later revealed anterior mediastinal FDG uptake typical for thymic hyperplasia. Additionally, mild focal uptake in the left lower neck localized to a 1.2-cm soft tissue mass was initially thought to be a lymph node. Review of a head and neck MRI from 10 days earlier demonstrated this mass to be a lobulated extension of thymic tissue into the left medial supraclavicular region. For suspected cases of aberrant cervical thymic tissue, if an anterior neck mass is directly contiguous with and follows the same signal characteristics as the main body of the thymus on MRI, the diagnosis can be confidently made and unnecessary biopsy avoided.