tbuckley/cabot-search huggingface dataset:
Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families
Authors: W Friedl
Journal: Gut (2001)

<h3>BACKGROUND AND AIMS</h3> In familial adenomatous polyposis (FAP), correlations between site of mutation in the adenomatous polyposis coli (<i>APC</i>) gene and severity of colonic polyposis or extracolonic manifestations are well known. While mutation analysis is important for predictive diagnosis in persons at risk, its relevance for clinical management of individual patients is open to question. <h3>METHODS</h3> We examined 680 unrelated FAP families for germline mutations in the<i>APC</i> gene. Clinical information was obtained from 1256 patients. <h3>RESULTS</h3> APC mutations were detected in 48% (327/680) of families. Age at diagnosis of FAP based on bowel symptoms and age at diagnosis of colorectal cancer in untreated patients were used as indicators of the severity of the natural course of the disease. A germline mutation was detected in 230 of 404 patients who were diagnosed after onset of bowel symptoms (rectal bleeding, abdominal pain, diarrhoea). When these patients were grouped according to the different sites of mutations, mean values for age at onset of disease differed significantly: patients carrying<i>APC</i> mutations at codon 1309 showed a disease onset 10 years earlier (mean age 20 years) compared with patients with mutations between codons 168 and 1580 (except codon 1309) (mean age 30 years), whereas patients with mutations at the 5′ end of codon 168 or the 3′ end of codon 1580 were diagnosed at a mean age of 52 years. Within each group of patients however large phenotypic variation was observed, even among patients with identical germline mutations. A higher incidence of desmoids was found in patients with mutations between codons 1445 and 1580 compared with mutations at other sites, while no correlation between site of mutation and presence of duodenal adenomas was observed. <h3>CONCLUSIONS</h3> As age at manifestation and course of the disease may be rather variable, even in carriers of identical germline mutations, therapeutic decisions should be based on colonoscopic findings in individual patients rather than on the site of mutation. However, in patients with mutations within codons 1445–1580, it may be advisable to postpone elective colectomy because desmoids may arise through surgical intervention.
Relations Between Subclinical Disease Markers and Type 2 Diabetes, Metabolic Syndrome, and Incident Cardiovascular Disease: The Jackson Heart Study
Authors: Vanessa Xanthakis, Jung Hye Sung, Tandaw E. Samdarshi, Alethea N. Hill, Solomon K. Musani, Mario Sims, Kamel A. Ghraibeh, Philip R. Liebson, Herman A. Taylor, Ramachandran S. Vasan, Ervin R. Fox
Journal: Diabetes Care (2015)

OBJECTIVE The presence of subclinical disease measures has been directly associated with the development of cardiovascular disease (CVD) in whites. African Americans (AAs) in the U.S. are at higher risk of CVD compared with non-Hispanic whites; however, data on the prevalence of subclinical disease measures in AAs and their association to CVD remain unclear and may explain the higher CVD risk in this group. RESEARCH DESIGN AND METHODS We evaluated 4,416 participants attending the first examination of the Jackson Heart Study (mean age 54 years; 64% women) with available subclinical disease measures. RESULTS There were 1,155 participants (26%) with subclinical disease, defined as the presence of one or more of the following: peripheral arterial disease, left ventricular hypertrophy, microalbuminuria, high coronary artery calcium (CAC) score, and low left ventricular ejection fraction. In cross-sectional analyses using multivariable-adjusted logistic regression, participants with metabolic syndrome (MetS) or diabetes (DM) had higher odds of subclinical disease compared with those without MetS and DM (odds ratios 1.55 [95% CI 1.30–1.85] and 2.86 [95% CI 2.32–3.53], respectively). Furthermore, the presence of a high CAC score and left ventricular hypertrophy were directly associated with the incidence of CVD (265 events) in multivariable-adjusted Cox proportional hazards regression models (P &amp;lt; 0.05). In prospective analyses, having MetS or DM significantly increased the hazard of incident CVD, independent of the presence of subclinical disease (P &amp;lt; 0.001). CONCLUSIONS In our community-based sample of AAs, we observed a moderately high prevalence of subclinical disease, which in turn translated into a greater risk of CVD, especially in people with MetS and DM.
Modifying the first minute of reperfusion: potential for myocardial salvage
Authors: R Diaz
Journal: Cardiovascular Research (2004)

See article by Kin et al. [1] (pages 74–85) in this issue .

In this issue of Cardiovascular Research, Kin et al. [1] have demonstrated in vivo in rats that following a 30-min index regional myocardial ischemia, protection against reperfusion injury assessed 3 h later through necrosis quantification by tetrazolium staining was achieved by a 1-min duration reperfusion modification protocol that consisted of three cycles of 10 s each of unrestricted reperfusion followed by 10 s of re-occlusion of the same coronary artery subjected to the occlusion causing the index ischemia. This protection, while evident, was substantially less than that achieved by one cycle of preconditioning (5 min of ischemia followed by 10 min of reperfusion immediately preceding the index ischemia). Importantly, delaying the three-cycle (10-s ‘on’/10-s ‘off’) reperfusion modification protocol by 1 min (its duration) failed to protect the myocardium at risk against infarction. Furthermore, doubling the reperfusion modification protocol to six cycles (10-s ‘on’/10-s ‘off’) produced no measurable improvement in protection compared to three cycles. These findings focusing on events in the first minute of reperfusion are, in our view, the novel and potentially important contribution of this paper.

The same group, led by Dr. Vinten-Johansen, has previously reported in the dog a substantial reduction in infarct size as a percentage of region at risk, producing about the same amount of protection as single-cycle ischemic preconditioning (same duration as in the rats [1]), with a three-cycle, 30-s unrestricted reperfusion/30-s re-occlusion protocol immediately upon reperfusion after a 60-min index regional ischemia [2]. However, when this reperfusion modification protocol was delayed by 5 min, the protection was lost. The present paper by Kin et al. [1], as described above, refines the temporal focus to the first minute of reperfusion.

The Vinten-Johansen group has called the reperfusion modification protocols … 

* Corresponding author. Division of Cardiovascular Research, Research Institute, The Hospital for Sick Children, McMaster Building, Rm. 7019C, 555 University Avenue, Toronto, ON, Canada M5G 1X8. Tel.: +1-416-813-8720; fax: +1-416-813-7480. Email address: diazport{at}sickkids.ca
Survey of Physician Practice Behaviors Related to Diabetes Mellitus in the U.S.: I. Design and Methods
Authors: Carolyn Siebert, Lois F Lipsett, Janet Greenblatt, Robert E Silverman
Journal: Diabetes Care (1993)

To conduct a survey among a representative sample of primary care physicians in the U.S. to assess practice behaviors, treatment goals, and beliefs related to management of diabetes mellitus and prevention of its complications.A mail survey with telephone follow-up was conducted among 3481 primary care physicians in active practice in the continental U.S. A stratified probability sample was selected using the files of the American Medical Association and American Osteopathic Association. Four specialties were selected to be included in the study: family physician, general practitioner, internist, and pediatrician. Two versions of a questionnaire were constructed: one for pediatricians containing questions about IDDM only and one for the other three specialties containing questions about both IDDM and NIDDM. Physicians who were not actively engaged in practice or did not see patients with diabetes were excluded.Completed questionnaires were received from 1502 of 3481 sampled physicians. Based on various assumptions of eligibility among nonresponders, an overall response rate to the survey was estimated to be between 65.7 and 86.5%. Discrepancies between specialty identifications as noted on the American Medical Association/American Osteopathic Association files and as self-designated were noted.This report describes the methodology used in the design and conduct of the survey, and data are provided to document the technical success of survey execution. This report provides the methodological basis for a series of separate reports on demographic characteristics of the physicians, their practices and their patients, and on specific attitudes, beliefs, and practice behaviors of primary care physicians in the U.S. with regard to diabetes mellitus.
A new perspective on concepts of asthma severity, control and optimum treatment
Authors: F. Madsen
Journal: European Respiratory Journal (2009)

adequate overall left ventricular filling, thus, resulting in LV diastolic dysfunction [6,7].The elegant experiments by SANTAMORE et al. [8] demonstrated that the diastolic properties of the left ventricle can be modified by changes in RV pressure and compliance even without a change in RV volume.Ventricular interdependence is defined as the forces that are transmitted from one ventricle to the other ventricle through the myocardium and pericardium, independent of neural, humoral, or circulatory effects [9].This phenomenon is a consequence of the close anatomic association between the ventricles, the key role of the interventricular septum and the pericardial constraint and can explain the diastolic impairment of one ventricle in the presence of systolic impairment of the adjacent ventricle [10].In conclusion, patients with idiopathic pulmonary fibrosis exhibit predominantly left ventricular diastolic dysfunction in addition to the expected impairment of right ventricular systolic and diastolic function.The presence of severe left ventricular systolic dysfunction should guide the clinician to search for other causes of left ventricular impairment.
Development of Resistance to MOPC-315 Plasmacytoma After Intralesional and Intraperitoneal Melphalan Therapy of Tumor-Bearing BALB/c Mice. I. Enhancement of In Vivo Rejection Responses by Combined Chemotherapy-Immunotherapy&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: A Adler, I Altbaum
Journal: JNCI Journal of the National Cancer Institute (1982)

Experimental and clinical evidence indicates that some chemotherapeutic agents may enhance tumor cell immunogenicity. This study was undertaken to test the possibility that melphalan [L-phenylalanine mustard (L-PAM)]--a clinically useful drug--can modulate tumor cells in vivo and in vitro in a syngeneic experimental system of MOPC-315 plasmacytoma in BALB/c mice and that this modulation can be expressed in vivo by enhanced tumor resistance. Tumor-bearing mice were treated with L-PAM intralesionally and ip by a split-course chemotherapy to avoid excessive toxicity of the drug. As a result of this treatment, about 60% of the mice had complete tumor regression; of these, 40-60% were resistant to viable tumor cell challenge and were designated as "cured-immune." Immunogenicity of irradiated MOPC-315 was tested in BALB/c mice; significant protection against tumor cell challenge was not achieved. In vitro L-PAM-treated MOPC-315 cells induced a measurable but weak antitumor response. Combination of both therapeutic approaches, i.e., chemotherapy and active immunization by L-PAM-treated tumor cells, was attempted with the use of various schedules. Immunotherapy given after L-PAM-induced tumor regression significantly enhanced in vivo antitumor response to challenge by 10(4) and 10(5) viable MOPC-315 tumor cells. When immunotherapy was attempted before chemotherapy in the presence of actively growing though still occult tumor, it reduced the chemotherapy cure rate and resulted in a low rate of tumor resistance. Addition of BCG did not remarkably affect the results. The findings point to the importance of timing of active immunization relative to tumor load and chemotherapy. The implication is that chemotherapy-induced regression is mediated by host immune mechanisms in this experimental model.
William Close (1775-1813): medicine, music, ink and engines in the Lake District
Authors: D. Gardner-Thorpe, C. Gardner-Thorpe, J. Pearn
Journal: Journal of the Royal Society of Medicine (2004)

Within the chronology of medicine there are occasional figures—for example, Leonardo da Vinci on a broader canvas—whose inventiveness has bequeathed valuable legacies in diverse fields of human endeavour. Erasmus Darwin (1731-1802)1 was one such, Ferdinand von Helmholtz (1821-1894) another.2 We believe that to this company should be added the little-known Lakeland surgeon and apothecary, William Close (1775-1813). In his brief life of 38 years, in addition to 'diligent attention to the duties of his profession'3 he contributed to the broader betterment of humankind with an extraordinary array of inventions4—notably in mine safety, brass musical instruments and hydraulics. Two hundred years have elapsed since this kind and respected village doctor invented his 'Engine for raising water by the lateral Communication of Motion'. We believe that this is an appropriate time to record a short biography.
Characterization of the metabolic and physiologic response to chromium supplementation in subjects with type 2 diabetes mellitus
Authors: William T. Cefalu, Jennifer Rood, Patricia Pinsonat, Jianhua Qin, Olga Sereda, Lilian Levitan, Richard A. Anderson, Xian H. Zhang, Julie M. Martin, Corby K. Martin, Zhong Q. Wang, Bradley Newcomer
Journal: Metabolism (2009)
Lipoprotein-Associated Phospholipase A <sub>2</sub> and Its Association With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction) Trial
Authors: Michelle O’Donoghue, David A. Morrow, Marc S. Sabatine, Sabina A. Murphy, Carolyn H. McCabe, Christopher P. Cannon, Eugene Braunwald
Journal: Circulation (2006)

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with the risk of cardiovascular (CV) events in population-based studies. The prognostic value of Lp-PLA2 in patients with acute coronary syndromes (ACS) has not been established.Plasma levels of Lp-PLA2 activity were measured at baseline (n=3648) and 30 days (n=3265) in patients randomized to atorvastatin 80 mg/d or pravastatin 40 mg/d after ACS in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) trial. The primary end point was death, myocardial infarction, unstable angina, revascularization, or stroke (mean follow-up 24 months). At baseline after ACS, the risk of recurrent CV events was similar across all quintiles of Lp-PLA2 activity (Ptrend=0.88). Overall, mean levels of Lp-PLA2 were lower at 30 days of follow-up than at baseline (35.7 versus 40.9 nmol.min(-1).mL(-1), P<0.001). In particular, treatment with atorvastatin 80 mg/d was associated with a 20% reduction in Lp-PLA2 activity (P<0.001), whereas Lp-PLA2 rose 3.6% with pravastatin 40 mg/d (P<0.001). Patients with 30-day Lp-PLA2 activity in the highest quintile were at significantly increased risk of recurrent CV events compared with those in the lowest quintile (26.4% versus 17.6%, Ptrend=0.002). After adjustment for cardiac risk factors, treatments, achieved low-density lipoprotein (LDL), and C-reactive protein, Lp-PLA2 activity in the highest quintile remained independently associated with a higher risk of recurrent CV events (adjusted hazard ratio 1.33, 95% confidence interval [CI] 1.01 to 1.74).Lp-PLA2 is not useful for risk stratification when measured early after ACS. At 30 days, Lp-PLA2 activity is significantly lowered with high-dose statin therapy and is associated with an increased risk of CV events independent of C-reactive protein and LDL cholesterol levels.
Female Sexual Dysfunction Associated With Antidepressant Administration: A Randomized, Placebo-Controlled Study of Pharmacologic Intervention
Authors: D Michelson, J Bancroft, S Targum, Y Kim, R Tepner
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Few controlled trials of pharmacologic intervention in women with antidepressant-associated sexual dysfunction have been reported, and there is uncertainty about the usefulness of putative treatments and the assessment methodologies. The authors evaluated the efficacy of buspirone and amantadine in the treatment of sexual dysfunction associated with fluoxetine administration. METHOD: Women who had been successfully treated with fluoxetine for at least 8 weeks and who had reported a deterioration in sexual function not present before the initiation of fluoxetine entered a 4-week assessment period. After assessment they were randomly assigned to an 8-week treatment trial with buspirone (N=19), amantadine (N=18), or placebo (N=20). Outcomes were assessed by using a patient-rated daily diary and a clinician-rated structured interview. RESULTS: While the amantadine-treated women did report significantly greater improvements in energy levels than women in the placebo group, all treatment groups experienced improvement in overall sexual function as well as in most individual measures. There were no statistically significant differences among the three groups. CONCLUSIONS: Neither buspirone nor amantadine was more effective than placebo in ameliorating antidepressant-associated sexual dysfunction. All groups experienced marked nonspecific improvement during treatment, which suggests the importance of placebo-controlled trials for this condition.
Phylogenetic position of phylum Nemertini, inferred from 18S rRNA sequences: molecular data as a test of morphological character homology.
Authors: J M Turbeville, K G Field, R A Raff
Journal: Molecular Biology and Evolution (1992)

Partial 18S rRNA sequence of the nemertine Cerebratulus lacteus was obtained and compared with those of coelomate metazoans and acoelomate platyhelminths to test whether nemertines share a most recent common ancestor with the platyhelminths, as traditionally has been implied, or whether nemertines lie within a protostome coelomate clade, as suggested by more recent morphological analyses. Maximum-parsimony analysis supports the inclusion of the nemertine within a protostome-coelomate clade that falls within a more inclusive coelomate clade. Bootstrap analysis indicates strong support for a monophyletic Coelomata composed of a deuterostome and protostome-coelomate clade. Support for a monophyletic protostome Coelomata is weak. Inference by distance analysis is consistent with that of maximum parsimony. Analysis of down-weighted paired sites by maximum parsimony reveals variation in topology only within the protostome-coelomate clade. The relationships among the protostome coelomates cannot be reliably inferred from the partial sequences, suggesting that coelomate protostomes diversified rapidly. Results with evolutionary parsimony are consistent with the inclusion of the nemertine in a coelomate clade. The molecular inference corroborates recent morphological character analyses that reveal no synapomorphies of nemertines and flatworms but instead suggest that the circulatory system and rhynchocoel of nemertines are homologous to coelomic cavities of protostome coelomates, thus supporting the corresponding hypothesis that nemertines belong within a protostome-coelomate clade. The sequence data provide an independent test of morphological character homology.
Evidence of a common mechanism of disassembly of adherens junctions through Gα13 targeting of VE-cadherin
Authors: Haixia Gong, Xiaopei Gao, Shaoting Feng, M. Rizwan Siddiqui, Alexander Garcia, Marcelo G. Bonini, Yulia Komarova, Stephen M. Vogel, Dolly Mehta, Asrar B. Malik
Journal: The Journal of Experimental Medicine (2014)

The heterotrimeric G protein Gα13 transduces signals from G protein–coupled receptors (GPCRs) to induce cell spreading, differentiation, migration, and cell polarity. Here, we describe a novel GPCR-independent function of Gα13 in regulating the stability of endothelial cell adherens junctions (AJs). We observed that the oxidant H2O2, which is released in response to multiple proinflammatory mediators, induced the interaction of Gα13 with VE-cadherin. Gα13 binding to VE-cadherin in turn induced Src activation and VE-cadherin phosphorylation at Tyr 658, the p120-catenin binding site thought to be responsible for VE-cadherin internalization. Inhibition of Gα13–VE-cadherin interaction using an interfering peptide derived from the Gα13 binding motif on VE-cadherin abrogated the disruption of AJs in response to inflammatory mediators. These studies identify a unique role of Gα13 binding to VE-cadherin in mediating VE-cadherin internalization and endothelial barrier disruption and inflammation.
Circulating miR-29a, Among Other Up-Regulated MicroRNAs, Is the Only Biomarker for Both Hypertrophy and Fibrosis in Patients With Hypertrophic Cardiomyopathy
Authors: Roberta Roncarati, Chiara Viviani Anselmi, Maria Angela Losi, Laura Papa, Elena Cavarretta, Paula Da Costa Martins, Carla Contaldi, Gloria Saccani Jotti, Anna Franzone, Laura Galastri, Michael V.G. Latronico, Massimo Imbriaco, Giovanni Esposito, Leon De Windt, Sandro Betocchi, Gianluigi Condorelli
Journal: Journal of the American College of Cardiology (2013)
Objective tumor response to denosumab in patients with giant cell tumor of bone: a multicenter phase II trial
Authors: T. Ueda, H. Morioka, Y. Nishida, S. Kakunaga, H. Tsuchiya, Y. Matsumoto, Y. Asami, T. Inoue, T. Yoneda
Journal: Annals of Oncology (2015)

BackgroundGiant cell tumor of bone (GCTB) is a rare primary bone tumor, characterized by osteoclast-like giant cells that express receptor activator of nuclear factor-kappa B (RANK), and stromal cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. A RANKL-specific inhibitor, denosumab, was predicted to reduce osteolysis and control disease progression in patients with GCTB.Patients and methodsSeventeen patients with GCTB were enrolled. Patients were treated with denosumab at 120 mg every 4 weeks, with a loading dose of 120 mg on days 8 and 15. To evaluate efficacy, objective tumor response was evaluated prospectively by an independent imaging facility on the basis of prespecified criteria.ResultsThe proportion of patients with an objective tumor response was 88% based on best response using any tumor response criteria. The proportion of patients with an objective tumor response using individual response criteria was 35% based on the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 82% based on the modified European Organization for Research and Treatment of Cancer (EORTC) criteria, and 71% based on inverse Choi criteria. The median time of study treatment was 13.1 months.ConclusionThe findings demonstrate that denosumab has robust clinical efficacy in the treatment of GCTB.