tbuckley/cabot-search huggingface dataset:
Radio: The Real Frasiers
Authors: Sabina Dosani
Journal: BMJ (2005)

In a bossy voice that would better suit a dominatrix than a radio psychologist, Dr Joy Browne asks, “Are you having sex?” Browne is doling out no-nonsense marital advice to a timid sounding woman who is worried that her husband is taking drugs. Although she inflicts irritating catchphrases such as “Better to be curious than furious” and “What's your question?” on her listeners, five to eight million of them tune into her daily programme, making her the fourth most listened to broadcaster in the United States.

Browne is just one of the psychologists and psychiatrists who host radio phone-in shows around the world. She and four others from India, Argentina, South Africa, and Kenya are interviewed by the UK media personality and psychiatrist Raj Persaud in the course of this five part series.

When Persaud asks Browne how she compares to the eponymous Frasier Crane of the US sitcom, she jokes that she has better hair and legs. They talk about some of her calls, including one from a mafia hitman who didn't know whether to tell his fiancee the truth about his day job. This is armchair anthropology at its finest but hardly the stuff of psychiatric outpatient clinics.

Which is a pity, as Persaud asserts that talking publicly about emotional or psychological problems can help destigmatise psychiatric ailments. Stigma is often a barrier to seeking and accepting treatment for mental illness. Many people associate mental illness with self indulgence, weakness, and malingering. Countless others are embarrassed by mentally ill people. Discrimination may bring on loss of job, home, or friendship, precipitating a depressive episode or relapses of schizophrenia. Almost half of all people with severe and enduring mental illness report abuse. Over a quarter move home because of harassment. Around a third have been sacked or made to resign from work.

Shame and low self esteem among callers are common themes in a couple of the programmes. Radio Mirchi's Dr Sanjay Chung explains that in India the stigma of mental illness is so severe that his callers' voices are almost never heard. In Kenya Dr Frank Njengaare diagnoses depression in his callers. Most were not aware that such an illness existed. These programmes may be going some way to encourage listeners to overcome their preconceptions.​preconceptions.




Figure 1



A comic hit...psychiatrist Frasier Crane

Credit: NBC/EVERETT/REX




High profile psychiatrists and psychologists have many opportunities to lay bare the myths surrounding mental illness through their radio surgeries. Part of the reason Frasier Crane is such a comic hit is his narcissism, self importance, and ego. Some of the real Frasiers are still trapped in his mould. Their audiences may become voyeurs of the worried well but are unlikely to come away with a more positive attitude towards manic depression or paranoid schizophrenia.
Acquired Vitamin K-Dependent Carboxylation Deficiency in Liver Disease
Authors: Rita A. Blanchard, Barbara C. Furie, Maria Jorgensen, Steven F. Kruger, Bruce Furie
Journal: New England Journal of Medicine (1981)

gamma-Carboxyglutamic acid residues on prothrombin are synthesized from glutamic acid on a prothrombin precursor in the liver through a vitamin K-dependent carboxylase. In the absence of vitamin K or in the presence of vitamin K antagonists, an inert form of prothrombin - abnormal prothrombin - circulates in the blood. We have developed specific immunoassays for native and abnormal human prothrombin. The prothrombin concentration in our normal subjects was 108 +/- 19 microgram per milliliter. The abnormal-prothrombin concentration varied over four orders of magnitude between the limits of detection in normal plasma and the level in patients with cirrhosis (0 to 5 microgram per milliliter), acute hepatitis (0 to 33 microgram per milliliter), or vitamin K deficiency (32 to 100 microgram per milliliter) and in those treated with sodium warfarin (12 to 65 microgram per milliliter). These studies indicate that abnormal prothrombin is not a component of normal plasma but appears in a variety of hepatic and nutritional disorders characterized by impaired hepatic vitamin-K-dependent carboxylation.
EPIG-02DYNAMIC EPIGENETIC MODULATION OF GLIOBLASTOMA TUMORIGENICITY BY INHIBITION OF LYSINE-SPECIFIC DEMETHYLASE 1 (LSD1)
Authors: David Kozono, Jie Li, Oltea Sampetrean, David Gonda, Deepa Kushwaha, Dmitry Merzon, Masayuki Nitta, Valya Ramakrishnan, Shan Zhu, Kaya Zhu, Hiroko Matsui, Olivier Harismendy, Wei Hua, Ying Mao, Chang-Hyuk Kwon, HIdeyuki Saya, Ichiro Nakano, Donald Pizzo, Scott Vandenberg, Clark Chen
Journal: Neuro-Oncology (2015)

Glioblastoma is one of the most devastating of human cancers, with near-uniform fatality within two years of diagnosis. Therapeutic failure is thought to be related to small subpopulation of cells that exhibit the properties of self-renewal and tumorigenicity. It remains unclear whether tumorigenicity exists as a static property of a few cells (“elite” model) or as a dynamically acquired property (“stochastic” model). We used tumor-sphere and xenograft formation as assays for tumorigenicity and examined subclones isolated from established and primary patient-derived glioblastoma (PDX) lines. In multiple PDX lines, glioblastoma subclones that are isogenic (within the limits of the current DNA sequencing technology) nevertheless display varying tumorigenicity. Moreover, the property can be gained or lost at low frequencies. The results indicated that while glioblastoma tumorigenicity largely conforms to the “elite” model, there is dynamic interplay between tumorgenic and non-tumorgenic cell states. Using independent Genetically Engineered Murine Models (GEMMs) of glioblastoma, PDX glioblastoma models, and single cell analysis of clinical glioblastoma specimens, we demonstrate that these dynamic transitions are governed by epigenetic reprogramming through the lysine-specific demethylase 1 (LSD1). LSD1 depletion increases H3K4me3 accumulation at the MYC locus, which elevates MYC expression. MYC, in turn, regulates OLIG2, SOX2 and POU3F2, a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Altered tumorgenic potential was not accompanied by a change in the molecular subtype (as defined by the TCGA) and was therefore not related to subtype plasticity. Importantly, complete inhibition or silencing of LSD1 led to suppression of MYC expression and glioblastoma tumorigenicity in vitro and in vivo. However, partial inhibition of LSD1 lead to epigenetic reprogramming resulting in heritable increase MYC expression and glioblastoma tumorigenicity. Our model suggests epigenetic regulation of key transcription factors governs transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development.
Case 35-2005
Authors: Nancy E. Davidson, Monica Morrow, Daniel B. Kopans, Frederick C. Koerner
Journal: New England Journal of Medicine (2005)

A 56-year-old woman with a 1-cm invasive ductal carcinoma of the breast came to a multidisciplinary breast clinic for advice on management. A lumpectomy and axillary dissection disclosed a small focus of metastatic tumor in a sentinel lymph node. The staging and management of breast cancer with sentinel lymph-node involvement are discussed.
Impact of rolapitant on quality of life (QoL) in patients (pts) receiving highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC).
Authors: Martin Chasen, Laszlo Urban, Ian Schnadig, Bernardo Leon Rapoport, Allen Poma, Sujata Arora, Rudolph M. Navari, Lee Steven Schwartzberg, Cesare Gridelli
Journal: Journal of Clinical Oncology (2015)

9615 Background: Rolapitant is a novel NK-1 receptor antagonist with a half-life of 180h, and does not inhibit CYP3A4 as other drugs do in the class, and therefore requires no dose modifications of concomitant steroids. Rolapitant demonstrated efficacy for prevention of CINV in phase 3 trials (HEC1, HEC2, and MEC). This pooled analysis examined the effect of rolapitant on QoL. Methods: In 3 double-blind, active-controlled studies, pts were randomized to oral rolapitant 200 mg or placebo 1–2 h before chemotherapy. All pts received active control: granisetron 2 mg oral or 10 mcg/kg IV and oral dexamethasone 20 mg. In the MEC study, granisetron was continued on Days 2 and 3. QoLwas assessed on Day 6 using the Functional Living Index-Emesis (FLIE) Questionnaire, and reported as a total score and by nausea and vomiting domains. Pts with a valid questionnaire from the MITT population (all randomized pts who received at least 1 dose of study drug) in the 2 pooled HEC studies and one MEC study were analyzed. Results: Baseline characteristics were comparable across treatment groups. Most common cancers were breast for MEC and lung for HEC studies. At Day 6, significant improvements (P < 0.05) were observed with rolapitant vs. active control for FLIE total, nausea, and vomiting domain scores (Table). Conclusions: Rolapitant improved QoLin pts receiving both HEC and MEC compared with active control, in addition to providing significant protection from CINV. Clinical trial information: NCT01500213; NCT01499849; NCT01500226. HEC MEC Rolapitant Active Control Rolapitant Active Control Total Score, n 491 479 605 607 Mean (SD) 114.5 (17.3) 109.3 (24.5) 112.7 (19.7) 108.6 (23.5) Mean difference (95% CI) 5.2 (2.6, 7.9) 4.1 (1.7, 6.5) p-value* < 0.001 < 0.001 Nausea Domain, n 493 480 606 608 Mean (SD) 55.3 (11.3) 53.5 (13.5) 54.1 (12.4) 52.3 (13.8) Mean difference (95% CI) 1.8 (0.2, 3.4) 1.8 (0.3, 3.3) p-value* 0.020 0.019 Vomiting Domain, n 491 479 605 607 Mean (SD) 59.2 (8.1) 55.8 (12.3) 58.6 (9.2) 56.3 (11.3) Mean difference (95% CI) 3.4 (2.1, 4.7) 2.3 (1.1, 3.4) p-value* < 0.001 < 0.001 No impact on daily life** n/N (%) 371/491 (75.6) 339/479 (70.8) 443/605 (73.2) 409/607 (67.4) p-value 0.082 0.027 *ANCOVA with study and gender as covariates; **FLIE total score >108
Methylazoxymethanol: Effect on the Immune Response of Rats to Human Serum Albumin&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: A F Habeeb, A M Preston, P Sanabria, N Escobales
Journal: JNCI Journal of the National Cancer Institute (1982)

Inbred male F344 rats treated with 20 mg methylazoxymethanol (MAM)/kg body weight showed minimal damage to DNA in bone marrow, spleen, and thymus and no suppression of the humoral immune response to human serum albumin (HSA). At high doses of MAM (40, 60, and 80 mg/kg), damage to DNA of bone marrow, spleen, and thymus was noted. The effect on the humoral immune responses was nonuniform. Some rats responded normally by eliciting precipitating antibodies, whereas others responded by synthesizing nonprecipitating antibodies at low levels. The production of nonprecipitating antibodies may indicate a restriction of the recognition of HSA antigenic determinants in rats given injections of MAM prior to immunization. The restriction may be a consequence of suppression or elimination of certain clones of lymphocytes responsible for recognition of certain antigenic determinants. This interference in some clones of lymphocytes would result in the synthesis of antibodies against one or two antigenic sites on the HSA and the concomitant inability of the produced antibodies to form complete lattice structure with antigen.
Valvular Heart Disease Associated with Dexfenfluramine
Authors: Lauralyn B. Cannistra, Steven M. Davis, Anne G. Bauman
Journal: New England Journal of Medicine (1997)

To the Editor: The appetite-suppressant drugs fenfluramine, dexfenfluramine (the purified d isomer of fenfluramine), and phentermine have each been associated with an increased risk of pulmonary hypertension when used alone.1–3 In this issue of the Journal, an unusual form of valvular heart disease is reported to be associated with use of the combination drug fenfluramine–phentermine,4 but whether valvular disease is also associated with use of the single agent dexfenfluramine is unknown. We wish to report a case of unusual valvular heart disease involving primarily the mitral valve in a young woman taking dexfenfluramine. A 32-year-old woman was referred for . . .
Abstract B46: MYCN regulates nuclear hormone receptors and impairs differentiation and survival in neuroblastoma
Authors: Diogo Ribeiro, Ulrica Westermark, Marcus Klarqvist, Jakob Lovén, Marie Arsenian Henriksson
Journal: Cancer Research (2016)

Abstract Neuroblastoma is the most common extra-cranial solid tumor in children and arises from neural crest cells involved in the development of sympathetic nervous tissue. This childhood tumor is characterized by heterogeneity and amplification of the MYCN oncogene is highly associated with aggressive tumors and poor outcome. The aim of this study was to investigate the role of the MYCN-driven miR-17-92 cluster in neuroblastoma pathogenesis. In order to identify putative targets of miR-17-92 we performed in silico prediction analysis and found that miR-17-92 target sites are significantly enriched in the nuclear hormone receptor (NHR) super family, indicating a role for hormonal regulation in neuroblastoma tumorigenesis. Importantly, high expression of several of the NHRs correlated with increased event-free survival of neuroblastoma patients. By using non-MYCN amplified neuroblastoma cells with a tet-regulatable miR-17~92 we could verify a differentially expressed NHR profile in induced compared to uninduced cells. Interestingly, one of the most significantly dowregulated NHRs was the glucocorticoid receptor (GR). Moreover, luciferase reporter assays containing the wildtype or mutated 3'UTR from the gene encoding GR demonstrate that it is a direct target of miR-17~92. Importantly, both MYCN and miR17~92 are able to downregulate GR. We further show that activation of GR signaling by dexamethasone induces differentiation markers and contributes to neural differentiation. Inhibition of MYCN activity and activation of GR signaling induced a significant reduction in tumor growth in a xenograft model of neuroblastoma. Taken together, our findings indicate an important role for miR-17-92 cluster in regulation of NHRs in neuroblastoma biology, with important implications for future therapeutic approaches in patients with MYCN-amplification. Citation Format: Diogo Ribeiro, Ulrica Westermark, Marcus Klarqvist, Jakob Lovén, Marie Arsenian Henriksson. MYCN regulates nuclear hormone receptors and impairs differentiation and survival in neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B46.
Case 40-2010
Authors: Michael H. Picard, Kenneth Rosenfield, Subba Digumarthy, R. Neal Smith
Journal: New England Journal of Medicine (2010)

A 68-year-old woman was transferred to this hospital because of substernal chest pain. An ECG showed evidence of MI. Coronary angiography was performed, with stenting of an occluded coronary artery. On the fourth hospital day, hypotension, bradycardia, and cardiac arrest occurred, and the patient died.
Sentinel lymph node micrometastasis detection using immunohistochemistry and reverse transcription-polymerase chain reaction for cytokeratin 19 in breast cancer
Authors: Q. Cao, S. Wang, X. Liu, L. Lin, J. Zhao
Journal: Journal of Clinical Oncology (2007)

11074 Background: In breast cancer, the sentinel lymph node (SLN) can be used to assess the axillary nodal status to guide the axillary surgery, tumor staging and adjuvant systematic therapy. Histology and immunohistochemistry (IHC) are currently the routine methods of SLN assay. The facts that about 30% of node-negative breast cancer patients relapse within five years and that micrometastasis were found in 9%∼30% negative lymph nodes when they were re-examined using serial sectioning suggest that current histological detection methods are inadequate for identifying metastatic tumor cells in lymph nodes. The primary objective of this study was to develop an assay by using a combination of reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry for cytokeratin 19 (KT19) expression in SLN. Methods:139 SLN samples were collected from 139 breast cancer patients undergoing SLN biopsy using Isosulfan Blue dye during modified mastectomy between June 2002 and June 2005. The SLNs were dissected into two parts, half were frozen in liquid nitrogen during sugery for RT-PCR detection and another half were kept in liquor formaldehyde for routine hematoxylin-eosin (H&amp;E) examination and IHC detection. In 62 tumor-negative SLNs at routine H&amp;E examination (pN0), we performed IHC and RT-PCR for KT19. Results: Of the 62 tumor-negative SLNs at routine H&amp;E examination, 11% (7/62) were positive on extensive IHC analyses for KT-19, which were all positively identified by RT-PCR assay. Six SLNs (10%) were negative for micrometastases (with H&amp;E and IHC for KT-19) but RT-PCR positive. There was asignificant difference in detective rate between these two methods statistically (χ2 = 4.1667 , P = 0.0412) and the coincidence were high ( kappa = 0.6483) Conclusions: As IHC analysis resulted in a 11% detection rate in H&amp;E negative SLNs, IHC is essential to avoid false- negative SLN micrometastases. Molecular analysis with KT19 allows detection of breast cancer micrometastases with an additional 10% detection rate in H&amp;E negative SLNs and resulted in a high coincidence with IHC analysis. However, the clinical value of these histologically negative but RT-PCR positive SLNs can only be determined with long term follow up. No significant financial relationships to disclose.
OC-046 5 years on: development of leicester’s out of hours bleeder service
Authors: RD Ramiah, D Lim, P Wurm
Journal: Gut (2015)

<h3>Introduction</h3> University Hospitals of Leicester (UHL) NHS Trust has been offering a comprehensive out of hour (OOH) endoscopy service for almost 10 years. In the wake of rising demands on in-patient endoscopy services we introduced a Consultant led and Gastro-intestinal registrar supported weekday in-reach service in July 2013, with a morning visit to the acute receiving medical units and a daily in-patient emergency list. Our study looked at the effect of this on OOH endoscopy volume, call outs and therapeutic interventions. <h3>Method</h3> To compare our data with our previous data set we analysed 6 month periods of OOH data from August to January of each year [2011–15]. Activity was collated by reviewing endoscopy reports [Unisoft reporting tool), separate OOH record books and daily spreadsheet activity returns. We looked at indication and timing of procedures, endoscopic findings, interventions and outcomes. <h3>Results</h3> 640 procedures were performed during the study period. The introduction of an in-reach service initially resulted in reduced daytime weekend activity but one-year later weekend activity was back to baseline. Although there was an apparent increase in ‘true OOH calls’, i.e. 5 pm until 9 am over our 5 year period the absolute numbers remain small and are in fact not different from our previous study, with approximately one emergency procedure per week. There was a 15.9% rise in appropriate referrals as per UHL criteria. Endoscopic findings of varices and variceal bleeding increased by approximately 3.5-fold. There was also a 3.5-fold increase in the proportion of endoscopies employing combination therapy and the use of injection mono-therapy halved, a reflection of recent NICE guidance.<sup>1</sup>The number of patients requiring emergency laparotomy or arterial embolisation remained very small [2–4 cases per 6 month interval]. <h3>Conclusion</h3> The total number of procedures has reduced compared to 2006–2010.<sup>2</sup>This is likely to be the result of better education, change in referral pathways and working patterns. The increase of patients presenting with variceal bleeding reflects a nationwide trend. We observed a decrease in the use of adrenaline mon-otherapy and concurrent increase in combination therapy for non-variceal upper gastrointestinal bleeds. Gastroenterology units need to review and re-invent their in-patient and OOH work pattern on a regular basis to address the increasing demands on inpatient endoscopy services. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Acute upper gastrointestinal bleeding:management. NICE Guidance (CG141) June 2012 Ramiah R, Wurm P. Provision of an out-of-hours emergency endoscopy service: the Leicester experience. Frontline Gastroenterol. 2013;4:288–295
Soundings: Uncompassionate care
Authors: George Dunea
Journal: BMJ (2005)

Two days after returning from a tropical country, a woman doctor awoke in the middle of the night with shaking chills and diarrhoea.

She calls for an ambulance. She waits in the emergency room of a prestigious teaching hospital for six hours and is admitted to the ward. They find Escherichia coli in the blood and administer a wide spectrum antibiotic (piperacillin-tazobactam). But the fever and diarrhoea continue unabated for the next three days. The patient and her spouse are becoming anxious. They have seen the attending physician only once, briefly, on the day of admission. The residents work in shifts, are constantly rushing around, and nobody can shed light on the problem.

A computed tomograph is now ordered. It shows a complex mass in the left iliac fossa. Is it an abscess or cancer? The patient, a surgeon herself, thinks it is abscess and should be explored and drained. The internist in charge is nowhere to be seen.

She is next transferred to a surgical ward. New doctors, new history, and exams—all the previous doctors have vanished. It is Friday. A taciturn young surgeon visits but says little. Antibiotics are continued. The family is becoming desperate.

Comes the weekend. Everything slows to a standstill—that is until Sunday night, when the patient has severe abdominal pain and undergoes emergency surgery at 2 am. A benign small bowel tumour is removed; because of peritonitis she is left for three months with a colostomy, also an iliostomy that is highly awkward to manage. Eventually everything is restored to normal.

It is unfair to second guess the management of this case without at least seeing the x rays. Some seasoned surgeons have suggested that they might have intervened earlier; have wondered why both a colostomy and iliostomy were necessary; and implied that academia does not lend itself to surgeons becoming highly experienced. And yet nobody's reputation would have been harmed if the doctors of that prestigious institution had spared a few minutes of their valuable time to talk to the patient and her family, listen, explain, and assuage their anxieties.