tbuckley/cabot-search huggingface dataset:
The effect of CYP 2D6 genotype and CYP2D6 inhibitors on tamoxife
Authors: V. Stearns, D. F. Hayes, Y. Jin, L. Ullmer, A. Nguyen, A. M. Storniolo, D. Flockhart, Z. Desta
Journal: Journal of Clinical Oncology (2004)

508 Background: We have recently identified and characterized a potent active metabolite of tamoxifen, endoxifen. Co-administration of tamoxifen with the CYP 2D6 inhibitor paroxetine results in a significant reduction in plasma endoxifen concentrations (JNCI 2003;95:1758–64). We report preliminary data from an ongoing prospective study to confirm these findings. Methods: Wild type (Wt) or variant (Vt) genotype of CYP 2D6 (*4 & *6), 2C9 (*2 & *3), or 3A5 (*3) was determined in 80 women who were prescribed tamoxifen 20 mg/day for the adjuvant treatment of breast cancer. Plasma concentrations of tamoxifen and its metabolites N-desmethyl tamoxifen (NDM), 4-hydroxy tamoxifen (4-OH), and endoxifen, were determined 1 and 4 months after initiating tamoxifen. Results: Among subjects who carried CYP 2D6 Wt/Wt, Wt/Vt or Vt/Vt genotype, a statistically significant difference in 4-month plasma endoxifen concentrations was observed, but not in concentrations of tamoxifen or other metabolites (Table). Results were similar after 1 month of tamoxifen. Wt/Wt subjects who were not taking 2D6 inhibitors had significantly higher endoxifen concentrations than those who were Wt/Vt or Vt/Vt (P=0.007). This trend disappeared in subjects who were taking CYP 2D6 inhibitors (P=0.99). The use of CYP 2D6 inhibitors significantly decreased endoxifen concentration in Wt/Wt subjects (P=0.0001) and modestly in Wt/Vt subjects (P=0.07). The CYP 2D6 inhibitors sertraline and paroxetine, but not venlafaxine, were associated with low concentrations of endoxifen. CYP 2C9 genotype and inhibitors, and CYP 3A5 genotype did not effect plasma tamoxifen and metabolite concentrations. Conclusions: CYP 2D6 *4 and *6 genotype and the use of 2D6 inhibitors strongly influence tamoxifen conversion to endoxifen. The clinical implications of these findings are under study. Prescribing practices should not be changed at present. No significant financial relationships to disclose.
Case 18-2001
Authors: William Jerry Durbin, Eugene J. Mark
Journal: New England Journal of Medicine (2001)

Presentation of CaseA 19-month-old boy was admitted to the hospital because of a febrile illness and refusal to walk.The child's immunizations were up to date. His mother was Portuguese, and his father was Brazilian. Two months before admission, during a six-week visit to Brazil, the boy had been treated with penicillin for suspected streptococcal pharyngitis; no culture was performed. Examination of the urine showed minimal protein. Hematologic laboratory tests were performed (Table 1). Forty-eight hours after treatment with penicillin, a rash appeared; another antibiotic was substituted, and the illness resolved. Three weeks before admission, the child was taken . . .
X-Ray Findings in a Child with Candida Esophagitis
Authors: Herbert J. Kaufmann
Journal: New England Journal of Medicine (1958)

INFECTIONS with Candida albicans have become increasingly more frequent in the last decade in adults as well as in the pediatric age group, particularly in the neonatal period. The awareness of this problem is reflected in numerous publications on this subject from all over the world: the United States1 2 3; France4 , 5; Hungary6 , 7; Scandinavia8; Switzerland9; Australia10; and many more.The more severe forms of monilia infection have received considerable attention, particularly the generalized form — that is, sepsis with C. albicans. The need for early recognition of the transition from the carrier state to that of . . .
Anxiety and cerebral blood flow
Authors: R J Mathew, W H Wilson
Journal: American Journal of Psychiatry (1990)

The relationship between anxiety and cerebral blood flow (CBF) is of considerable clinical and research significance. Although a considerable amount of information is available on mechanisms through which anxiety may influence CBF, this topic has not received much attention in psychiatry. Earlier techniques for the measurement of CBF were cumbersome and invasive. With the advent of noninvasive techniques, study of CBF in psychiatric disorders, including anxiety, became easier, and a number of such studies have been conducted. In this article the literature on psychophysiological and clinical aspects of changes in CBF associated with anxiety is reviewed.
PTH-022 The endoscopic management of post-operative bariatric complications: single-centre, single-operator experience in a bariatric unit in the united kingdom
Authors: S Murray, A Mahmoud, K Mannur, R Shidrawi
Journal: Gut (2015)

<h3>Introduction</h3> The obesity epidemic has seen a corresponding rise in bariatric surgery, resulting in an increased prevalence of patients with post-operative complications from bariatric surgery. Endoscopists need to be aware of the symptoms and common findings seen at endoscopy, and the various endoscopic treatments available. <h3>Method</h3> A total 150 out of 1947 (7.7%) patients who underwent bariatric surgery for obesity were referred to the Endoscopy service between March 2011 and July 2014. We retrospectively reviewed the patient characteristics, type and interval following bariatric surgery, indications, findings and endoscopic intervention of these patients using our endoscopy database. <h3>Results</h3> 129 women (86%) and 21 men were referred to our service with a mean age of 47.2 years (range 22–74) following laparoscopic gastric bypass (59.7%), laparoscopic sleeve gastrectomy (28.4%) and laparoscopic band gastroplasty (11.9%). Presenting complaints 2–126 months post bariatric surgery included abdominal pain (49.3%), nausea and vomiting (20.6%), dysphagia (20.6%), profound weight loss and malabsorption (8.6%) and failure to lose weight (0.6%). Findings at endoscopy included anastomotic stenosis (23.8%), anastomotic ulceration (7.9%), visceral fistulation (4.6%), combined anastomotic ulceration with stenosis (3.3%) and band erosion (1.3%). A significant proportion of patients had macroscopically normal findings at endoscopy (58%). CLO tests for Helicobacter pylori were positive in 48% compared with 42% of unmatched historical controls within our department (p &gt; 0.05). Endoscopic intervention either as a single procedure or on multiple occasions included 34 dilatations of anastomotic stricture by bougienage (22.5%), eighteen wire-guided balloon dilatations of anastomotic strictures (11.9%), eighteen naso-jejunal tube insertions for nutritional support (11.9%), six Ovesco clip applications (4.0%), and the repeated application of histoacryl glue to a visceral fistula in one case (0.7%). <h3>Conclusion</h3> The incidence of post-operative bariatric complications is not insignificant. These patients present with specific problems which are amenable to endoscopic therapy, and with which the endoscopy community will have to become more familiar as the prevalence of patients undergoing bariatric surgery continues to rise globally. <h3>Disclosure of interest</h3> None Declared.
Modification of Parkinsonism — Chronic Treatment with L-Dopa
Authors: George C. Cotzias, Paul S. Papavasiliou, Rosemary Gellene
Journal: New England Journal of Medicine (1969)

Slowly increasing oral doses of L-3,4-dihydroxyphenylalanine (L-dopa) induced at least partial improvement of some manifestations in a series of 28 patients with Parkinsonism. Improvement of performance was graded as modest in four, moderate in four, marked in 10 and dramatic in 10. This was usually sustained for periods up to two years. Evidence of toxicity was signaled by few of the variables monitored. Mental effects included enhanced interest, improved memory, transitory sleeplessness and nervousness. Nausea and vomiting were largely circumvented by slowing of the increases of the daily dose. A peripheral dopadecarboxylase inhibitor diminished the therapeutic dose of L-dopa required and eliminated anorexia and nausea in one case. Neurologic side effects consisted of involuntary movements ranging from fleeting to severe.
Lorenzo's Oil and Thrombocytopenia in Patients with Adrenoleukodystrophy
Authors: William H. Zinkham, Thomas Kickler, Janet Borel, Hugo W. Moser
Journal: New England Journal of Medicine (1993)

To the Editor: Adrenoleukodystrophy is a sex-linked disorder in which very-long-chain fatty acids accumulate in all body tissues1. For this reason, a variety of diets have been formulated to lower the levels of these acids. One diet includes Lorenzo's Oil, a product that contains 20 percent erucic acid (22:1) and 80 percent oleic acid (18:1). During the past two years, 40 male and 6 female patients have received Lorenzo's Oil according to a protocol calculated to provide 20 percent of daily caloric intake. In 19 of these patients the platelet count has decreased significantly (Table 1). The degree of . . .
Far Upstream Element-Binding Protein 1 Binds the 3′ Untranslated Region of PKD2 and Suppresses Its Translation
Authors: Wang Zheng, Fan Shen, Ruikun Hu, Birbickram Roy, JungWoo Yang, Qian Wang, Fan Zhang, Jennifer C. King, Consolato Sergi, Song-Mei Liu, Emmanuelle Cordat, Jingfeng Tang, Ying Cao, Declan Ali, Xing-Zhen Chen
Journal: Journal of the American Society of Nephrology (2016)

Autosomal dominant polycystic kidney disease pathogenesis can be recapitulated in animal models by gene mutations in or dosage alterations of polycystic kidney disease 1 (PKD1) or PKD2, demonstrating that too much and too little PKD1/PKD2 are both pathogenic. Gene dosage manipulation has become an appealing approach by which to compensate for loss or gain of gene function, but the mechanisms controlling PKD2 expression remain incompletely characterized. In this study, using cultured mammalian cells and dual-luciferase assays, we found that the 3' untranslated region (3'UTR) of PKD2 mRNA inhibits luciferase protein expression. We then identified nucleotides 691-1044, which we called 3FI, as the 3'UTR fragment necessary for repressing the expression of luciferase or PKD2 in this system. Using a pull-down assay and mass spectrometry we identified far upstream element-binding protein 1 (FUBP1) as a 3FI-binding protein. In vitro overexpression of FUBP1 inhibited the expression of PKD2 protein but not mRNA. In embryonic zebrafish, FUBP1 knockdown (KD) by morpholino injection increased PKD2 expression and alleviated fish tail curling caused by morpholino-mediated KD of PKD2. Conversely, FUBP1 overexpression by mRNA injection significantly increased pronephric cyst occurrence and tail curling in zebrafish embryos. Furthermore, FUBP1 binds directly to eukaryotic translation initiation factor 4E-binding protein 1, indicating a link to the translation initiation complex. These results show that FUBP1 binds 3FI in the PKD2 3'UTR to inhibit PKD2 translation, regulating zebrafish disease phenotypes associated with PKD2 KD.
Carcinoembryonic antigen (CEA) surge in patients with metastatic colorectal cancer receiving systemic chemotherapy
Authors: A. Y. Sunga, S. Ailawadhi, G. Y. Yang, A. Rajput, J. L. Smith, M. G. Fakih
Journal: Journal of Clinical Oncology (2005)

3615 Background: We noted a surge in CEA lasting > 3 months associated with a clinical response in a patient treated with 5-FU, oxaliplatin, and leucovorin (FOLFOX). This brought to question the utility of CEA progression, as defined by ASCO (CEA testing every 2 months, with 2 sequential CEA levels above baseline), in the era of new chemotherapeutic agents. Thus, we investigated the prevalence of CEA surge in patients with metastatic colorectal cancer (MCRC) and its implication on clinical outcome. Methods: Retrospective chart review of patients with MCRC treated with chemotherapy at Roswell Park Cancer Institute from January 2000 to May 2004 was conducted. A CEA surge was defined as an increase of > 20% from baseline followed by a ≥ 20% drop in subsequent CEA(s) compared to baseline. The prevalence of CEA surge in this population and its association with clinical outcome was investigated. Results: Charts of 170 patients were screened and 89 met the inclusion criteria. Mean age was 61 years with equal gender distribution. Moderately differentiated pathology was seen in 59% of the cases. A CEA surge was seen in 10 patients. Amongst them the median baseline CEA was 377ng/ml [39–843]. Median peak of surge was 557ng/ml [47.5–1927] and this occurred at a median of 4 weeks [2–10 weeks] from start of chemotherapy. The surge lasted 4–18 weeks, exceeding 11 weeks in 7/10 patients. CEA level was above baseline after 12 weeks from initiation of treatment in 2/10 patients. CEA surge was significantly associated with peritoneal metastasis (O.R.- 6.9, CI = 1.3–35.8). None of the patients had CEA elevations above baseline beyond 4 months from start of treatment. All 10 patients (9 FOLFOX; 1 Irinotecan) benefited from chemotherapy (3 Partial Response, 7 Stable Disease). Conclusions: CEA surges are not infrequently observed in patients receiving FOLFOX and are often associated with a clinical benefit. A significant correlation was noted between CEA surge and the presence of peritoneal metastasis. None of the CEA surges satisfied the definition of CEA progression as per ASCO criteria. These findings suggest that a rise in CEA after initiation of chemotherapy, unless lasting > 4 months, cannot be used as an indicator of progressive disease. No significant financial relationships to disclose.
Activity of cediranib, a highly potent and selective VEGF signaling inhibitor, in alveolar soft part sarcoma
Authors: K. Gardner, I. Judson, M. Leahy, E. Barquin, M. Marotti, B. Collins, H. Young, M. Scurr
Journal: Journal of Clinical Oncology (2009)

10523 Background: Alveolar soft part sarcoma (ASPS) is a rare entity making up &lt;1% of soft tissue sarcomas (STS). It is typically indolent but with a high incidence of metastatic disease, usually to lungs, but also to sites such as the brain. Response to conventional chemotherapy is poor (overall response rates are approximately 7% [Reichardt P et al,Eur J Cancer.2003;39:1511–1516]). This is a preliminary report of the activity of cediranib, a highly potent and selective VEGF signaling inhibitor, in this disease. Methods: Efficacy and tolerability data were collected for seven patients with ASPS. One patient was treated in a phase II randomized trial of cediranib ± prophylactic antihypertensive therapy and six were treated in a Phase II study in patients with imatinib-refractory gastrointestinal stromal tumors or other STS. Cediranib was administered orally, once daily at an initial dose of 45 mg. Response was assessed using RECIST (Response Evaluation Criteria in Solid Tumors). Results: Median age at diagnosis was 39 years (range: 26–49). All patients had pulmonary metastases and two had additional sites of disease (brain, bone, intra-abdominal) at study entry. Adverse events were generally CTC grade 1–2 and manageable. The most common adverse events were fatigue (n = 6), diarrhea (n = 5), stomatitis (n = 4), headache (n = 3), and hypertension (n = 3). Four patients had a best response of partial response, two patients had a confirmed reduction in maximum tumor diameter of ≥10% and &lt;30% and one patient experienced stable disease. As of November 2008, three patients remain on treatment with a median (range) time on study of 61 weeks (49–74). Time to progression and progression-free survival will be calculated and available at the time of presentation. Conclusions: These data demonstrate the promising preliminary activity and safety of chronic administration of cediranib in this disease. Further investigation is warranted, particularly as there is no effective systemic treatment for patients with advanced ASPS. [Table: see text]
Effectiveness and Toxicity of Vinblastine, Cisplatin, Cyclophosphamide, Bleomycin, Doxorubicin and Etoposide (Vpcbae) in the Management of Patients with Small Cell Carcinoma of the Ovary-Hypercalcemic Type (Sccoht)
Authors: D. Callegaro-Filho, P.T. Ramirez, A.M. Nick, J.J. Kavanagh, E.D. Euscher, A.S. Dickens, D.K. Patel, K.M. Schmeler
Journal: Annals of Oncology (2014)
Website of the Week: Passive smoking
Authors: Adrian Gonzalez
Journal: BMJ (2003)

While the connection between active smoking and disease has been widely documented, the jury is still out on the dangers of passive smoking, which is the subject of a paper and an editorial in this week's BMJ (p 1048 and p 1057).

The internet has much to say about the dangers of passive smoking. For a general review on the topic visit the website of Action on Smoking and Health (www.ash.org.uk/html/passive/html/passive.html), which presents a summary of the evidence. The site discusses links between passive smoking and pulmonary and cardiovascular diseases, and visitors can also find information about the impact of passive smoking on children and about local policies.

The US Centers for Disease Control and Prevention (CDC) has launched a web page (www.cdc.gov/tobacco/ets.htm) full of information and links about environmental tobacco smoke. Here you can find information about the prevention of exposure and links to papers and reports.

The effects of passive smoking on children is a recurring concern (www.ash.org.uk/html/passive/html/who-ets.html). Those looking for brief information for their patients might want to recommend a short review from the American Academy of Paediatrics (www.medem.com/MedLB/article_detaillb.cfm?article_ID=ZZZ1UBHWQ7C&sub_cat=29).

The CDC can also help in giving advice: its page “Taking Action on Second Hand Smoking. An Online Toolkit” is a well done, interactive educational resource with much information and many links (www.cdc.gov/tobacco/ETS_Toolkit/index.htm).
PWE-369 Increasing uptake in the bowel cancer screening programme with gp participation: the pearl project
Authors: SC Benton, P Butler, K Reed, S Rickard, S Stanley, M Chesters, R Roope, SP Halloran
Journal: Gut (2015)

<h3>Introduction</h3> There is wide variation in uptake of bowel cancer screening in England. Areas with a high index of multiple deprivation (IMD) score (more deprived) have lower uptake than areas with low IMD (less deprived). Initiatives to raise awareness of bowel cancer and screening have been sporadic and have not been sustained. Previous studies have demonstrated endorsement by a general practitioner (GP) can increase uptake of bowel cancer screening. The Bowel Cancer Screening Programme (BCSP) Southern Hub is piloting a sustainable intervention to engage subjects in bowel cancer screening by exploiting GP patient knowledge and the Hub’s established procedures for communication - the PEARL (Practice Endorsed Additional Reminder Letter) project. <h3>Method</h3> Practices participating in the project supplied the Hub with a letterhead and GP signature. A computer program was developed to interrogate the BCSP database and identify subjects in those practices who had not participated in screening within 30 days after the standard reminder letter. The list of non-participants was e-mailed to each practice for GPs to identify subjects not suitable for the GP reminder letter (<i>e.g.</i>subjects in receipt of end-of-life-care, unable to have colonoscopy). The list was returned to the Hub and checked again to exclude recent responders and any subjects who had died. Subjects on the final list received an approved GP-endorsed reminder letter on headed and signed stationery. Practices returning three lists received a financial reward. <h3>Results</h3> Forty-six practices with uptake &lt;55% were invited to participate and 25 accepted. Between September 2014–January 2015, 2,370 subjects were identified as non-responders and 1,433 received a GP-endorsed reminder letter. Seventy-seven subjects were excluded by their GP, 853 subjects were on lists not returned to the Hub and three practices failed to return any lists. <h3>Conclusion</h3> We have developed a robust and sustainable system to send GP-endorsed reminder letters to non-responders. The pilot will now be extended to assess the impact on screening uptake and explore factors that will improve GP engagement. The pilot will assess the viability of national adoption within the BCSP. <h3>Disclosure of interest</h3> None Declared.
A Decision Analysis of Streptokinase plus Heparin as Compared with Heparin Alone for Deep-Vein Thrombosis
Authors: James J. O'Meara, Robert A. McNutt, Arthur T. Evans, Stacy W. Moore, Stephen M. Downs
Journal: New England Journal of Medicine (1994)

It is uncertain whether patients with proximal deep-vein thrombosis should be treated with streptokinase followed by intravenous heparin or with intravenous heparin alone. Published reports indicate that streptokinase plus heparin increases the risk of bleeding, including central nervous system bleeding and death, but decreases the risk of postphlebitic syndrome. Previous recommendations regarding these treatments have not considered patients' preferences or the values they attach to the possible outcomes of therapy.
Clinical value of on-treatment HCV RNA levels during different sofosbuvir-based antiviral regimens
Authors: Benjamin Maasoumy, Johannes Vermehren, Martin-Walter Welker, Birgit Bremer, Dany Perner, Christoph Höner zu Siederdissen, Katja Deterding, Patrick Lehmann, Gavin Cloherty, Birgit Reinhardt, Jean-Michel Pawlotsky, Michael P. Manns, Stefan Zeuzem, Markus Cornberg, Heiner Wedemeyer, Christoph Sarrazin
Journal: Journal of Hepatology (2016)
Reply:
Authors: Isabelle Colle, Christophe Van Steenkiste
Journal: Hepatology (2011)

We read with great interest the Letter to the Editor sent by Coriat et al. as well as their article published in PLoS One.1 In this article, they showed a significant reduction of 54% in portal venous flow 1 month after sorafenib treatment and they concluded that it was consistent with a decrease in portal pressure. However, they did not measure the hepatic venous pressure gradient, which is the most appropriate way to assess portal pressure. Because portal pressure depends not only on splanchnic blood flow, but also on intrahepatic vascular resistance, it is difficult to state that portal pressure decreased in the study by Coriat et al. The reason why we suggest that anti-PLGF (placental growth factor) is probably safer than sorafenib is that PLGF is not necessary for normal physiological angiogenesis and is only involved in pathological angiogenesis.2 Targeting PLGF may, therefore, lead to less collateral damage and side effects. We completely agree that further clinical studies with anti-PLGF and sorafenib should be conducted to evaluate the hemodynamic effects and safety in patients with cirrhosis. Isabelle Colle M.D., Ph.D.*, Christophe Van Steenkiste M.D., Ph.D.*, * Department of Hepatology and Gastroenterology Ghent University Hospital Medical School Ghent, Belgium.
Low Levels of LPS Promotes a Th2 Sensitization to Pru p 3 Generating Anaphylactic Mice
Authors: María J. Rodriguez, Ana Aranda Guerrero, Tahia D. Fernandez, Nuria Cubells, Ana Molina, Maria J. Torres, Francisca Gómez, Francisca Palomares, Javier Rojo, Miguel Blanca, Araceli Diaz-Perales, Cristobalina Mayorga
Journal: Journal of Allergy and Clinical Immunology (2016)