tbuckley/cabot-search huggingface dataset:
Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model
Authors: R Schwarzer, N Nickel, J Godau, B M Willie, G N Duda, R Schwarzer, B Cirovic, A Leutz, R Manz, B Bogen, B Dörken, F Jundt
Journal: Blood Cancer Journal (2014)

Despite evidence that deregulated Notch signalling is a master regulator of multiple myeloma (MM) pathogenesis, its contribution to myeloma bone disease remains to be resolved. Notch promotes survival of human MM cells and triggers human osteoclast activity in vitro. Here, we show that inhibition of Notch through the γ-secretase inhibitor XII (GSI XII) induces apoptosis of murine MOPC315.BM myeloma cells with high Notch activity. GSI XII impairs murine osteoclast differentiation of receptor activator of NF-κB ligand (RANKL)-stimulated RAW264.7 cells in vitro. In the murine MOPC315.BM myeloma model GSI XII has potent anti-MM activity and reduces osteolytic lesions as evidenced by diminished myeloma-specific monoclonal immunoglobulin (Ig)-A serum levels and quantitative assessment of bone structure changes via high-resolution microcomputed tomography scans. Thus, we suggest that Notch inhibition through GSI XII controls myeloma bone disease mainly by targeting Notch in MM cells and possibly in osteoclasts in their microenvironment. We conclude that Notch inhibition is a valid therapeutic strategy in MM.
Avidity and Bactericidal Activity of Antibody Elicited by Different Haemophilus influenzae Type b Conjugate Vaccines
Authors: Y Schlesinger, D M Granoff
Journal: JAMA (1992)

Antibody avidity is a measure of the functional affinity of serum antibody to bind to antigen. In this study, we compared the avidity of antibodies elicited by vaccination with three Haemophilus influenzae type b (Hib) conjugate vaccines and investigated the relationship between antibody avidity and the ability of antibody to activate complement-mediated bactericidal activity.A convenience sample of 171 postvaccination serum samples with more than 0.5 microgram/mL of anticapsular antibody, the minimum concentration required for measurement of avidity. The serum samples were obtained from infants participating in immunogenicity trials with Hib capsular polysaccharide (PRP) conjugated to meningococcal outer membrane protein complex (PRP-OMPC) or to tetanus toxoid (PRP-T), or PRP oligomers conjugated to a nontoxic mutant diphtheria toxin, CRM197 (Oligo-CRM).Healthy infants recruited in private practices.Avidity of vaccine-induced serum anticapsular antibody and serum bactericidal titers.In infants vaccinated at 2, 4, and 6 months of age, Oligo-CRM evoked antibody of higher avidity than PRP-OMPC (P less than .001). The mean avidity of antibody elicited by PRP-T was intermediate, being lower than Oligo-CRM (P less than .02) but higher than PRP-OMPC (P = .001). Also, after one dose, 18-month-old infants given Oligo-CRM had higher avidity antibodies compared with those given PRP-OMPC (P less than .001). Half of the infants in both age groups who were given Oligo-CRM developed antibody avidity of 2.50 nM-1 or greater, whereas more than two thirds of the infants given PRP-OMPC had avidity values of 1.25 nM-1 or less. Antibodies with avidity of 1.25 nM-1 or less were, on average, 6.6-fold less active in assays of complement-mediated bactericidal activity than antibodies with avidity of 2.50 nM-1 or greater (P less than .001).Oligo-CRM and PRP-T conjugate vaccines elicit higher avidity antibody than PRP-OMPC, and high-avidity antibody is more potent than low-avidity antibody in serum bactericidal assays. Consideration should be given to including measurement of antibody avidity in assessment of new vaccines since avidity may affect the ability of serum antibody to confer protection against disease.
Does tobacco smoking influence the occurrence of hand eczema?
Authors: B. Meding, M. Alderling, M. Albin, J. Brisman, K. Wrangsjö
Journal: British Journal of Dermatology (2008)

Tobacco smoking is known to influence various inflammatory skin diseases and an association between tobacco smoking and hand eczema has been proposed in some studies.To examine a possible association between reported current tobacco smoking and the occurrence of hand eczema.Previously collected questionnaire data on the occurrence of hand eczema in three occupational cohorts and corresponding controls from the general population were studied. The questionnaires used included questions on 1-year prevalence of hand eczema and questions on smoking habits. For one occupational group, hairdressers and their controls, information on amount of smoking was obtained. Information on age, sex and history of atopy was also available.In total, answers regarding smoking and hand eczema were obtained from 13,452 individuals. Out of 3493 smokers, 437 (12.5%) reported hand eczema compared with 1294 out of 9959 nonsmokers (13.0%) (P = 0.51). With regard to the number of cigarettes smoked, 22.6% of the hairdressers smoking more than 10 cigarettes per day reported hand eczema compared with 17.4% of those smoking 0-10 cigarettes per day (P = 0.01). Corresponding figures for the controls were 14.5% and 11.7%, respectively (P = 0.06).No clear association was found between 1-year prevalence of hand eczema and smoking. Heavy smoking, more than 10 cigarettes per day, may give a slightly increased risk of hand eczema. Further studies with information on the amount of tobacco consumption and on possible confounders are needed to evaluate smoking as a risk factor for hand eczema.
The Amazons within: women in the BMA 100 years ago.
Authors: T. Lamont
Journal: BMJ (1992)

above raiding a ward sister's blanket store-with the best of intentions.Always a Bible Christian, Grenfell came to regret his youthful assertiveness and to recognise in others the pre-eminence of character over creed.By selecting for competence he created a health service that would pass amenably into secular control long after his death in 1940.In 1911 work began on the King George V Institute in St John's, a building offering facilities to travellers and safe lodging for girls working as ships' cooks.The king, connected by transatlantic cable, pressed a button in Buckingham Palace to lay the foundation stone on the day of his coronation. (A man was concealed under Grenfell's platform, ready to release the stone if the royal signal failed.)In 1912 the International Grenfell Association was founded and this continues to fund research projects.The climax of Grenfell's career, and his knighthood, came in 1927, with the rebuilding, in brick, of the St Anthony Hospital as a centre of excellence, with 80 beds.When he retired there were six hospitals, seven nursing stations, four hospital ships, two orphanages, two large schools, 14 industrial centres, and a coopera- tive lumbermill in the region he served.And beri-beri had disappeared from Labrador.-~~z 0
Revised Bethesda Guidelines: compliance in identifying HNPCC affected families
Authors: M. Adelson, M. Bielby, P. Dawson, H. Thomas, H. Dorkins, K. Monahan
Journal: Gut (2011)

<h3>Introduction</h3> Hereditary non-polyposis colorectal cancer (HNPCC) causes approximately 3% of colorectal cancer cases in the UK and has significant implications for screening families with multiple affected members. It is usually caused by germ-line mutations in <i>MLH1</i>, <i>MSH2</i> and <i>MSH6</i> mismatch repair genes. The revised Bethesda guidelines are designed to identify colorectal cancer patients who should have immunohistochemistry (IHC) and microsatellite instability (MSI) screening tests for HNPCC. These guidelines are designed to streamline the clinical diagnostic pathways used to identify mutation carriers in patients with colorectal cancer who might or might not fulfil the Amsterdam II criteria, thus increasing diagnostic yield of HNPCC screening. This audit looks at the compliance with revised Bethesda guidelines to identify HNPCC families and their referral for genetic testing. <h3>Methods</h3> Patients were identified from colorectal MDT Imperial College Healthcare NHS Trust from the UK National Bowel Cancer Audit Programme (NBOCAP) data over a period of 18 months up to May 2010. Pathology results were obtained for IHC and MSI testing. Patients who underwent IHC testing at St Mary9s Hospital, London, and referrals to the Kennedy-Galton Clinical Genetics Centre were identified. The number of patients whose tumours were resected was identified and the histology reports reviewed. <h3>Results</h3> 336 patients discussed in colorectal MDT in Hammersmith and Charing Cross Hospitals, London were assessed according to the revised Bethesda guidelines. 18.5% of the reviewed patients satisfied one or more of the revised Bethesda criteria. 5% of these patients were referred to Kennedy-Galton Centre or underwent MSI testing, and none underwent IHC testing. 188 patients of assessed patients had their tumour resected. 7.4% of resected tumours had histology typical of HNPCC (tumour infiltrating lymphocytes, Crohn9s like inflammation, Signet ring cells, medullary growth pattern). <h3>Conclusion</h3> Based on these results, there is a marked incompliance with revised Bethesda guidelines when assessing patients with colorectal cancer. This has a significant impact on clinical pathways for the management of HNPCC families.
Vitamin E for nonalcoholic steatohepatitis: Ready for prime time?
Authors: Jean‐François F. Dufour, Kris Kowdley, Geoffrey McCaughan, Christian Trautwein
Journal: Hepatology (2010)

BACKGROUND: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. METHODS: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. RESULTS: Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. CONCLUSIONS: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.) 2010 Massachusetts Medical Society
Antenatal screening for syphilis Is not justified
Authors: N Snowise, J Sweeney, G A Forster, B T Goh
Journal: BMJ (1994)

EDITOR, - In these heady days of cost effective health care, priority setting, and market forces, I felt as though I was back in the 1970s while reading Angus Nicoll and Clare Moisley's editorial on antenatal screening for syphilis.1 They describe a routine test that is extensively carried out to prevent a condition whose true incidence is unknown. It is all very well applauding new surveillance initiatives, but isn't it surprising that these were not started some years go? There is no mention at all of the costs of the tests in Britain, let alone whether the tests are cost effective. Screening for some conditions - for …
New Japanese Rubella Vaccine: Comparative Trials
Authors: J. M. Best, J. E. Banatvala, J. M. Bowen
Journal: BMJ (1974)

A total of 142 seronegative volunteers were given one of the following rubella vaccines: Cendehill, HPV77. DE-5, RA27/3, or a new Japanese vaccine, To-336. To-336 vaccine produced a slightly higher geometric mean antibody titre (G.M.T.) (65·7) than did the HPV77. DE-5 (63·1) or RA27/3 vaccine (61·9) but the G.M.T. induced by Cendehill vaccine was much lower (39·3). Reactions, particularly joint symptoms, occurred least commonly after vaccination with To-336 vaccine. Joint symptoms occurred within seven days of menstruation in 30 out of 37 (81%) vaccines (P &lt;0·01); their incidence was not related to oral contraception. Though there is evidence to suggest that Japanese virus strains may be non-teratogenic further data on the incidence of congenitally acquired infection in Japan must be collected before this conclusion can be supported on epidemiological grounds.
Focal In-Stent Restenosis Near Step-Up
Authors: Attila Thury, Jolanda J. Wentzel, Ruud V.H. Vinke, Frank J.H. Gijsen, Johan C.H. Schuurbiers, Rob Krams, Pim J. de Feyter, Patrick W. Serruys, Cornelis J. Slager
Journal: Circulation (2002)
Attention-Deficit Hyperactivity Disorder: Physicians Helping Parents Pay More Heed
Authors: Virginia S. Cowart
Journal: JAMA (1988)

A FEW YEARS ago, Dennis Cantwell, MD, was giving a lecture on attention-deficit hyperactivity disorder to his colleagues in the Department of Psychiatry at the University of California at Los Angeles (UCLA). As Cantwell, the Joseph Campbell professor of child psychiatry, finished, a fellow physician exclaimed, "Now I understand what's wrong with my son." "How old is the boy?," Cantwell inquired. "Thirty-four" was the reply. <h3>Long Time to Diagnosis</h3> Sometimes it can take a long time to arrive at a diagnosis of attention-deficit hyperactivity disorder, a condition that may affect as many as one in five school-age children and which does not, as had been assumed, disappear after puberty. Attention-deficit hyperactivity disorder is the single most prevalent disability reported by elementary schools and one of the most common referral problems to child psychiatry outpatient clinics. It is probably the most researched problem in child psychiatry. Adults with a history of
Incremental payments for consultants
Authors: N. Jones, P J Booth, J. Chawner, N G Cockman, G Crompton, R H Davies, H A Edwards, T J B Harris, N G Hodges, H E T Korn, R T Maxwell, H K Mehta, D P W Roberts, E. Richards, D. M Wayte, J G Williams, J P Williams, V L. Woolley
Journal: BMJ (1976)
Artifact ulcers and bone lesions produced by elastic bands.
Authors: I. D. Kitchin, C. McGibbon, R. H. Seville
Journal: BMJ (1967)

Banter, F. C, Lotz, M., Thier, S., Rosenberg, L. E., and Potts, J. T. (1965). Ann. intern. Med.t 62, 796. Boulding, J. E. (1961). In Wilson's Disease : Some Current Concepts, edited by J. M. Walshe and J. N. Cumings. Oxford. Brand, E.. Cahill, G. F., and Harris, M. M. (1935). J. biol. Chem., 109, 69. Crawhall, J. C, Saunders, E. P., Thompson, C. J. (1964). First Meeting of Federation of European Biochemical Societies. Abstract A 117. -(1966). Ann. hum. Genet., 29, 257. Scowen, E. F.. and Watts, R. W. E. (1963). Brit. med. J., 1, 588. -(1964). Ibid., 1, 1411. and Thompson, C. I. (1965). Science, 147, 1459. Dent, C. E., Friedman, M., Green, H., and Watson, L. A. C. (1965). Brit. med. J., 1, 403. and ?senior, B. (1955). Brit. J. Urol, 27, 317. King, J. S. and Boyce, W. H (1965). Invest. Urol, 2, 595. Lewis, H. B. (1933) Ann. intern. Med., 6, 183. Lotz, M., and Bartter, F. C. (1965). Brit. med. J., 1, 855. and Potts, J. T (1964). J. clin. Invest., 43, 1293. McDonald, J. E., and Henneman, P. H. (1965). New Engl. J. Med., 273, 578. Sherwin, A. L., Beck, I. T., and McKenna, R. D. (1960). Canad. med. Ass. J., 83, 160.
Psoas abscess: unusual complication of effective chemotherapy for teratoma.
Authors: J Maguire, S B Kaye
Journal: BMJ (1985)

We recommend that starter regimens can therefore be abandoned when elemental as well as polymeric diets are administered naso- gastrically over 24 hours.1 Jones BJM, Lees R, Andrews J, Frost P, Silk DBA.Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function.
Haute cuisine and the colon
Authors: R C SPILLER
Journal: Gut (2000)

<h3>Abstract</h3> Post-translationally modified peptides are involved in many aspects of plant growth and development. The maturation of these peptides from their larger precursors is still poorly understood. We show here that the biogenesis of CLEL6 and CLEL9 peptides in <i>Arabidopsis thaliana</i> requires a series of processing events in consecutive compartments of the secretory pathway. Following cleavage of the signal peptide upon entry into the endoplasmic reticulum (ER), the peptide precursors are processed in the cis-Golgi by the subtilase SBT6.1. SBT6.1-mediated cleavage within the variable domain allows for continued passage of the partially processed precursors through the secretory pathway, and is a prerequisite for subsequent post-translational modifications including tyrosine sulfation and proline hydroxylation within, and proteolytic maturation after exit from the Golgi. Activation by subtilase SBT3.8 in post-Golgi compartments depends on the N-terminal aspartate of the mature peptides. Our work highlights the complexity of post-translational precursor maturation allowing for stringent control of peptide biogenesis.
Painless Chronic Sigmoid Volvulus
Authors: Charles N. Verheyden
Journal: JAMA (1978)

CHRONIC painless sigmoid volvulus apparently has not been described previously. We recently encountered a patient who complained of chronic constipation without recurrent episodes of pain or bowel obstruction. Barium enema examination together with surgical exploration confirmed the presence of chronic sigmoid volvulus associated with megacolon and chronic constipation. We present this case to broaden the spectrum of symptoms that can occur in patients with sigmoid volvulus.  Report of a Case  A 59-year-old man was referred to the Mayo Clinic for evaluation of possible Hirschsprung's disease. He recalled having been constipated since childhood. The problem had been controlled with enemas, initially one each month but gradually progressing to two or three weekly. In the past five years, he had also taken cathartics with increasing frequency. At the time of his admission he was having one bowel movement each week with the aid of enemas and large doses of milk of magnesia.
Phase I and Pharmacokinetic Studies of Erlotinib Administered Concurrently with Radiotherapy for Children, Adolescents, and Young Adults with High-Grade Glioma
Authors: Alberto Broniscer, Suzanne J. Baker, Clinton F. Stewart, Thomas E. Merchant, Fred H. Laningham, Paula Schaiquevich, Mehmet Kocak, E. Brannon Morris, Raelene Endersby, David W. Ellison, Amar Gajjar
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To estimate the maximum-tolerated dose (MTD) of erlotinib administered during and after radiotherapy, and to describe the pharmacokinetics of erlotinib and its metabolite OSI-420 in patients between 3 and 25 years with newly diagnosed high-grade glioma who did not require enzyme-inducing anticonvulsants. Experimental Design: Five dosage levels (70, 90, 120, 160, and 200 mg/m2 per day) were planned in this phase I study. Dose-limiting toxicities (DLT) were evaluated during first 8 weeks of therapy. Local radiotherapy (dose between 54 and 59.4 Gy) and erlotinib started preferentially on the same day. Erlotinib was administered once daily for a maximum of 3 years. Pharmacokinetic studies were obtained after first dose and on day 8 of therapy. Mutational analysis of EGFR kinase domain, PIK3CA, and PTEN was done in tumor tissue. Results: Median age at diagnosis of 23 patients was 10.7 years (range, 3.7-22.5 years). MTD of erlotinib was 120 mg/m2 per day. Skin rash and diarrhea were generally well controlled with supportive care. Dose-limiting toxicities were diarrhea (n = 1), increase in serum lipase (n = 1), and rash with pruritus (n = 1). The pharmacokinetic variables of erlotinib and OSI-420 in children were similar to those described in adults. However, there was no relationship between erlotinib dosage and drug exposure. No EGFR kinase domain mutations were observed. Two patients with glioblastoma harbored mutations in PIK3CA (n = 1) or PTEN (n = 1). Conclusions: Although the MTD of erlotinib in children with newly diagnosed high-grade glioma was 120 mg/m2 per day, pharmacokinetic studies showed wide interpatient variability in drug exposure.
Erratum: Corrigendum: miR-92a regulates expression of synaptic GluA1-containing AMPA receptors during homeostatic scaling
Authors: Mathieu Letellier, Sara Elramah, Magali Mondin, Anaïs Soula, Andrew Penn, Daniel Choquet, Marc Landry, Olivier Thoumine, Alexandre Favereaux
Journal: Nature Neuroscience (2014)
Darwin as a Dermatologist
Authors: Markus Reinholz, Thomas Ruzicka
Journal: JAMA Dermatology (2014)

TheBritish scientist Charles RobertDarwin (1809-1882), famous for his contributions to the theory of evolution, was without question one of themostoutstanding scientists inhistory.Onlya fewpeopleknow,however, that he also showed interest in the field of dermatology and described the anhidrotic ectodermal dysplasia as one of the first Xchromosomal, recessively inherited skin diseases. In 1875, Charles Darwin reported in his work The Variation of Animals and Plants under Domestication a Hindu family that developed in the course of 4 generations “only four small andweak incisor teeth and [...] eight posterior molars.” In addition, “themen thus affected have very little hair on the body, andbecomebald early in life. They also suffermuchduringhotweather fromexcessive dryness of the skin. It is remarkable that no instancehas occurredof adaughterbeing thusaffected; and this fact remindsushow much more liable men are in England to become bald than women. Though thedaughters in theabove family areneveraffected, they transmit the tendency to their sons; and no case has occurred of a son transmitting it to his sons.” These observations of hypodontia, hypotrichosis, and hypohidrosis are the symptoms of anhidrotic ectodermal dysplasia. Later, in thebeginningof the20thcentury,whensimilar reportswere publishedbyChrist,Siemens,andTouraine, thesynonymChrist-SiemensTouraine syndromewas introduced. Darwin’s report is evenmore relevant and extraordinary because it appeared just 9 years after Gregor JohannMendel (1822-1884), the famous naturalist, published his ground-breaking laws of Mendelian inheritance and the results of his experiments on plant hybridization. WhatDarwindescribed,mostprobablyunknowingly,waswhat is todayknownasclassicalX-chromosomal recessive inheritance.Onceagain, Darwin, with his astute observations and deductions, was ahead of his time and also should be honored in the field of dermatology as the descriptor of one of the first genodermatoses.