tbuckley/cabot-search huggingface dataset:
Another aspect-oriented approach to diagnosis of cardiac amyloidosis
Authors: Narat Srivali, Supawat Ratanapo, Patompong Ungprasert, Wisit Cheungpasitporn
Journal: Thorax (2013)

Another aspect-oriented approach to diagnosis of cardiac amyloidosisWe read with interest the article by Esterbrook et al 1 on cardiac amyloidosis.Authors demonstrated very excellent clinical presentation and a challenging diagnostic work-up in a patient with cardiac amyloidosis presenting with cough and breathlessness.However, we would like to discuss on another possible straightforward diagnostic approach for this case.A combination of poor R progression on ECG without evidence of coronary artery disease and echocardiographic features of increased ventricular wall thickness in normotensive patients should raise the suspicion of infiltrative heart diseases especially amyloidosis. 2Urine studies including urine protein to creatinine ratio and urine protein electrophoresis are essential from the fact that proteinuria is present in more than 90% of the cases of amyloidosis. 3erum and urine immunofixation can reveal an abnormal monoclonal band in approximately 90% of the cases with primary (AL) amyloidosis as in the case presentation.However, monoclonal protein is present in lower concentration in AL amyloidosis compared with multiple myeloma.So, serum-free light chain assay is a very helpful quantitative test that is abnormal in more than 95% of the cases and should be included in the diagnostic work-up for amyloidosis. 4An excess of lambda or (less common) kappa from serum-free light chain assay can promptly guide us to the diagnosis of AL amyloidosis.
Diagnosis of "Probable" Still's Disease and its Outcome
Authors: B. M. Ansell, E. G. L. Bywaters
Journal: Annals of the Rheumatic Diseases (1962)

To inform ourselves on the prognosis of Still's disease, all referrals to this Unit from 1947 to January, 1959, in whom this diagnosis had been seriously considered were reviewed.Those cases in whom initial examination and investigation revealed some other disorder, such as slipped femoral epiphysis, Thieman's syndrome, or leu- kaemia, or in whom no abnormality could be detected on admission here were excluded.A diagnosis of definite Still's disease was made only if our usual criteria were satisfied: namely, arthritis commencing before the age of 16 years with evidence of at least four joints involved for a minimum of 3 months or, when fewer joints were involved, histological evidence of rheumatoid arthritis.Cases with such other disease as disseminated lupus erythematosus, ankylosing spondylitis, psoriasis, ulcerative colitis, or polyarteritis nodosa were excluded.Of the total of 269 cases reviewed, 219 fulfilled the criteria cited at the time of their discharge from hospital, while psoriasis had been discovered in three and ulcerative colitis in two.The remaining 45 were considered to be suffering from "probable" Still's disease.This label was applied to cases of arthralgia or synovitis with an erythrocyte sedi- 23 7
You think too much
Authors: Liam Farrell
Journal: BMJ (2007)

Having the great thinkers on your practice list is a drag. The last time La Rochefoucauld came in, I happened to be reading a defence society magazine. “There is something, Monsieur, in the misfortune of other doctors which is not entirely unpleasant,” I observed. His eyes narrowing, he took out a little notebook, scribbled furiously for a few seconds, then nodded as if satisfied, before launching into yet another long story about his sinuses and how dry they were (he preferred them pleasantly moist).

When Nietzsche was …
PPARα Activation Can Help Prevent and Treat Non–Small Cell Lung Cancer
Authors: Nataliya Skrypnyk, Xiwu Chen, Wen Hu, Yan Su, Stacey Mont, Shilin Yang, Mahesha Gangadhariah, Shouzuo Wei, John R. Falck, Jawahar Lal Jat, Roy Zent, Jorge H. Capdevila, Ambra Pozzi
Journal: Cancer Research (2013)

Non-small cell lung cancer (NSCLC) not amenable to surgical resection has a high mortality rate, due to the ineffectiveness and toxicity of chemotherapy. Thus, there remains an urgent need of efficacious drugs that can combat this disease. In this study, we show that targeting the formation of proangiogenic epoxyeicosatrienoic acids (EET) by the cytochrome P450 arachidonic acid epoxygenases (Cyp2c) represents a new and safe mechanism to treat NSCLC growth and progression. In the transgenic murine K-Ras model and human orthotopic models of NSCLC, we found that Cyp2c44 could be downregulated by activating the transcription factor PPARα with the ligands bezafibrate and Wyeth-14,643. Notably, both treatments reduced primary and metastatic NSCLC growth, tumor angiogenesis, endothelial Cyp2c44 expression, and circulating EET levels. These beneficial effects were independent of the time of administration, whether before or after the onset of primary NSCLC, and they persisted after drug withdrawal, suggesting the benefits were durable. Our findings suggest that strategies to downregulate Cyp2c expression and/or its enzymatic activity may provide a safer and effective strategy to treat NSCLC. Moreover, as bezafibrate is a well-tolerated clinically approved drug used for managing lipidemia, our findings provide an immediate cue for clinical studies to evaluate the utility of PPARα ligands as safe agents for the treatment of lung cancer in humans.
A Phase Ib Study of AMG 102 in Combination with Bevacizumab or Motesanib in Patients with Advanced Solid Tumors
Authors: Peter J. Rosen, Christopher J. Sweeney, Dorothy J. Park, Darrin M. Beaupre, Hongjie Deng, Ian M. Leitch, Poornima Shubhakar, Min Zhu, Kelly S. Oliner, Abraham Anderson, Lorrin K. Yee
Journal: Clinical Cancer Research (2010)

This phase Ib study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 102, a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in combination with bevacizumab or motesanib in patients with advanced solid tumors.Patients with treatment-refractory advanced solid tumors were sequentially enrolled into four cohorts (3, 10, or 20 mg/kg AMG 102 plus 10 mg/kg bevacizumab i.v. every 2 weeks, or 3 mg/kg AMG 102 i.v. every 2 weeks plus 75 mg motesanib orally once daily).Fourteen patients were enrolled and received AMG 102. The combination of AMG 102 with bevacizumab (n = 12) seemed to have acceptable toxicity. The number of patients (n = 2) who received AMG 102 plus motesanib was insufficient to adequately assess safety. No dose-limiting toxicities were reported. Enrollment in the motesanib cohort was suspended because of reports of cholecystitis in other motesanib studies. Treatment-emergent adverse events among patients receiving AMG 102 plus bevacizumab were generally mild and included fatigue (75%), nausea (58%), constipation (42%), and peripheral edema (42%). No anti-AMG 102 antibodies were detected. Bevacizumab did not seem to affect AMG 102 pharmacokinetics. Circulating total HGF/SF increased from baseline throughout the study. Eight of 10 evaluable patients had reductions in tumor dimensions, and stable disease at > or =8, > or =16, and > or =24 weeks occurred in 9, 7, and 4 patients, respectively. Progression-free survival ranged from 7.9 to 121.9 weeks.AMG 102 in combination with bevacizumab was well tolerated. Further evaluation of AMG 102 in combination with antiangiogenic agents is warranted.
Prion Diseases of Humans and Animals: Their Causes and Molecular Basis
Authors: John Collinge
Journal: Annual Review of Neuroscience (2001)

Prion diseases are transmissible neurodegenerative conditions that include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals. Prions appear to be composed principally or entirely of abnormal isoforms of a host-encoded glycoprotein, prion protein. Prion propagation involves recruitment of host cellular prion protein, composed primarily of alpha-helical structure, into a disease specific isoform rich in beta-sheet structure. The existence of multiple prion strains has been difficult to explain in terms of a protein-only infections agent, but recent studies suggest that strain specific phenotypes can be encoded by different prion protein conformations and glycosylation patterns. The ability of a protein to encode phenotypic information has important biological implications. The appearance of a novel human prion disease, variant CJD, and the clear experimental evidence that it is caused by exposure to BSE has highlighted the need to understand the molecular basis of prion propagation, pathogenesis, and the barriers limiting intermammalian transmission. It is unclear if a large epidemic of variant CJD will occur in the years ahead.
Bone Marrow Aspiration and Biopsy
Authors: Suman Malempati, Sarita Joshi, Susanna Lai, Dana A V Braner, Ken Tegtmeyer
Journal: New England Journal of Medicine (2009)

This video will demonstrate the procedure for bone marrow aspiration and bone marrow biopsy from the posterior iliac crest. Obtaining a bone marrow aspirate and core biopsy is often necessary when evaluating a patient who has a hematologic abnormality. Examining bone marrow is also useful in the diagnosis of metastatic spread of nonhematologic malignancies and to diagnose metabolic disorders. Gather the necessary equipment prior to performing the procedure. You will require equipment for sterile skin preparation and a sterile field, 1 percent lidocaine buffered with sterile sodium bicarbonate, a 25-gauge needle and 5-ml syringe, a bone marrow aspiration needle, . . .
Release of guanosine triphosphate binding protein subunits from mouse myocardial membranes: Basic properties and their alterations in acute murine Chagas disease
Authors: H. Huan, M. Wittner, H. Tanowitz, J. P Bilezikian, S. A Morris
Journal: Cardiovascular Research (1995)

The aim was to investigate the arrangement of heterotrimeric alpha beta gamma G proteins in myocardial membranes using GTP gamma S dependent release characteristics of their alpha subunits in acute murine Chagas disease.The properties of GTP gamma S dependent alpha subunit release were monitored immunochemically as well as by cholera toxin and pertussis toxin catalysed [32P]ADP ribosylation.GTP gamma S, as opposed to other nucleotides, caused optimal and virtually instantaneous release of soluble 40 kDa [32P]ADP ribosylated protein in pertussis toxin treated membranes. When determined immunochemically, infection decreased both the sensitivity to GTP gamma S dependent release of alpha i subunits and appeared to facilitate the appearance of GTP gamma S dependent release of alpha i3. GTP gamma S also caused the release of soluble 45 and 40 kDa proteins as detected by cholera toxin-[32P]ADP ribosylated membranes and immunochemical analysis. With regard to cholera toxin-[32P]ADP ribosylated Gs substrates sensitive to GTP gamma S dependent release, infection (1) decreased the amount of 45 kDa alpha s protein, (2) increased the amount of 40 kDa protein, and (3) enhanced sensitivity to GTP gamma S. In contrast, there was no effect of infection on the magnitude or sensitivity to GTP gamma S dependent release of immunochemical alpha s.The diverse characteristics of GTP gamma S dependent release of the very similar alpha subunits from myocardial membranes and their unique sensitivity to infection with T cruzi suggest that these very similar proteins are arranged within the plasma membrane in such a manner as to modify their biochemical behaviour.
Selective activation of adenosine A3 receptors with N6-(3-chlorobenzyl)-5′-N-methylcarboxamidoadenosine (CB-MECA) provides cardioprotection via KATP channel activation
Authors: W Tracey
Journal: Cardiovascular Research (1998)

The aim of this study was to characterize the adenosine A3 receptor agonist, N6-(3-chlorobenzyl)-5'-N-methylcarboxamidoadenosine (CB-MECA), evaluate its ability to reduce myocardial ischemia/reperfusion injury and determine the role of KATP-channel activation in A3 receptor-mediated cardioprotection.Binding affinities and adenylate cyclase inhibition were examined in CHO cells expressing rabbit recombinant adenosine A1 or A3 receptors. Infarct size (normalized for area-at-risk; % IA/AAR) was measured in buffer-perfused rabbit hearts exposed to 30-min regional ischemia and 120 min of reperfusion.CB-MECA was 100-fold selective for A3 vs. A1 receptors (A3 Ki: 1 nM; A1 Ki: 105 nM). Five-min perfusion with CB-MECA before ischemia/reperfusion elicited a concentration-dependent reduction in infarct size (EC50: 0.3 nM). The CB-MECA-dependent cardioprotection (control: 58 +/- 2; CB-MECA: 21 +/- 3% IA/AAR) was unchanged by an A1-selective concentration of the antagonist, BWA1433, but was completely prevented (P < 0.05) by a nonselective (A1/A3) concentration (55 +/- 6% IA/AAR). The KATP channel inhibitors, glibenclamide and 5-HD, had no effect on control infarct size, yet significantly (P < 0.05) blunted the CB-MECA-dependent cardioprotection (glibenclamide: 49 +/- 6; 5-HD: 58 +/- 4% IA/AAR).CB-MECA is a novel 100-fold A3 receptor-selective agonist which should prove useful for elucidating A3-dependent mechanisms in the rabbit heart. Selective stimulation of adenosine A3 receptors with CB-MECA reduces myocardial ischemia/reperfusion injury via a mechanism which involves activation of KATP channels.
Clinical trial of a new carbenoxolone analogue (BX24), zinc sulphate, and vitamin A in the treatment of gastric ulcer
Authors: P. M. Fraser, R. Doll, M. J. S. Langman, J. J. Misiewicz, H. H. Shawdon
Journal: Gut (1972)

The effects of a new carbenoxolone analogue (BX24), zinc sulphate, and vitamin A on the healing of gastric ulcer have been assessed in a multifactorial clinical trial conducted in out-patients treated for four weeks. Forty-eight patients completed the trial. Three groups of eight patients were given respectively 300, 600, and 1 200 mg of BX24 daily and were compared with 24 patients who were given 300 mg of carbenoxolone sodium daily. The size of the ulcer niche was reduced on average by 14·6% in the eight patients given BX24 300 mg daily, by 47·6% in the patients given 600 mg daily, and by 51·0% in the patients given 1 200 mg daily. In the patients given carbenoxolone the size of the niche was reduced by 68·9%. These results were compared with those obtained previously with carbenoxolone and inert tablets and it was concluded that BX24 is without clinically useful effect in the doses used. Eleven of the 24 patients (46%) treated with carbenoxolone sodium developed side effects due to fluid retention and electrolyte disturbances. None of the patients given BX24 experienced such effects. In addition to carbenoxolone or BX24, 24 patients were given zinc sulphate, 660 mg daily, and in 24 patients these tablets were withheld. Among the patients given carbenoxolone the reduction in the size of the niche was much the same irrespective of whether or not the patients received zinc sulphate. Among the 12 patients given BX24 with zinc sulphate the ulcer healed completely in four and, on average, the size of the niche was reduced by 53·5%, compared with 21·9% in the 12 patients given BX24 alone. This difference is not statistically significant but the possibility of a beneficial effect from zinc is not excluded. No side effects attributable to zinc were observed. Twenty-four patients were also given vitamin A, 50 000 units daily, and in 24 patients the vitamin was withheld. No evidence was obtained to suggest that vitamin A had any beneficial effect on the healing of gastric ulcer.
Interleukin-10 Inhibits Macrophage-Induced Glomerular Injury
Authors: XIOU RU HUANG, A. RICHARD KITCHING, PETER G. TIPPING, STEPHEN R. HOLDSWORTH
Journal: Journal of the American Society of Nephrology (2000)

The ability of interleukin-10 (IL-10) to inhibit macrophage recruitment, activation, and proliferation in vivo was studied in a macrophage-mediated, but T cell-independent, passive anti-glomerular basement membrane antibody-induced model of glomerulonephritis (GN) in rats. Treatment with recombinant murine IL-10 resulted in dose-dependent reductions in proteinuria (high dose: 16 ± 1 mg/24 h; low dose: 30 ± 2 mg/24 h; control treatment: 69 ± 6 mg/24 h; normal: 7 ± 1 mg/24 h) and glomerular macrophage recruitment (high dose: 1.8 ± 0.1 macrophages per glomerular cross section [c/gcs]; low dose: 5.5 ± 0.2 c/gcs; control treatment: 12.1 ± 0.6 c/gcs). Macrophage and intrinsic glomerular cell proliferation were reduced at both doses of IL-10, as was glomerular expression of P-selectin and monocyte chemoattractant protein-1. IL-10 treatment also resulted in a dose-dependent reduction of macrophage activation as indicated by MHC class II and IL-1β expression. Glomerular nitrite production by isolated cultured glomeruli was reduced after IL-10 treatment in vivo (high dose: 2.3 ± 2.3 nmol/104 glomeruli per 72 h; low dose: 28 ± 5 nmol/104 glomeruli per 72 h; control treatment: 82 ± 11 nmol/104 glomeruli per 72 h). Tumor necrosis factor-α production was abolished by high-dose treatment and reduced by the lower dose (3.8 ± 3.8 pg/104 glomeruli per 72 h; control treatment: 249 ± 23 pg/104 glomeruli per 72 h). These studies demonstrate that IL-10 directly attenuates glomerular macrophage recruitment, activation, and proliferation in vivo and can significantly attenuate macrophage-mediated GN independent of any effects on T cells.
Psoriasis and melanocytic naevi: does the first confer a protective role against melanocyte progression to naevi?
Authors: N. Balato, L. Di Costanzo, A. Balato, C. Patruno, M. Scalvenzi, F. Ayala
Journal: British Journal of Dermatology (2011)

Some of the cytokines that have effects on melanogenesis are also reported to be involved in psoriasis.We therefore studied the relationship between psoriasis and melanocytic naevi. In particular, the aim of our study was to investigate the number of melanocytic naevi in patients with psoriasis vs. controls.We performed a prospective case-control study, analysing 93 adult patients with psoriasis and 174 adult aged-matched controls. For each participant a questionnaire was completed to establish personal data, personal medical history, and personal and familial history of skin cancer and psoriasis. We analysed interleukin (IL)-1α, IL-6 and tumour necrosis factor (TNF)-α gene expression at the peripheral blood mononuclear cell level in patients with psoriasis and in controls.In our study, patients with psoriasis presented a lower number of areas with naevi in comparison with controls (P < 0·0001). Nobody had ever had squamous cell carcinoma or melanoma in the psoriatic group; moreover, there was a significant difference in familial history of melanoma between the two groups (none in the psoriatic group vs. 8% in the control group; P < 0·05). IL-1α, IL-6 and TNF-α expression levels were higher in patients with psoriasis.People with psoriasis had fewer melanocytic naevi. This suggests that the proinflammatory cytokine network in psoriasis skin might inhibit melanogenesis, melanocyte growth and/or progression to naevi.
Secretory component production by human bronchial epithelial cells is upregulated by interferon gamma
Authors: V Godding, Y Sibille, PP Massion, M Delos, C Sibille, P Thurion, D Giffroy, A Langendries, JP Vaerman
Journal: European Respiratory Journal (1998)

Secretory immunoglobulin A (S-IgA) participates in the first noninflammatory line of defence of the respiratory tract. S-IgA consists of dimeric IgA (dIgA) produced by plasma cells and secretory component (SC) produced by epithelial cells. This study compared SC production by primary cultures of human bronchial epithelial cells (HBEC) and by respiratory epithelial cell lines. Among the cell lines, A549 did not produce detectable SC, 16HBE produced very low levels of SC, while CALU-3 produced significant levels of SC. HBEC produced SC in nonpolarized and polarized primary cultures, where it was secreted apically. Polarized HBEC transcytosed radiolabelled and cold dIgA, resulting in the presence of S-IgA in their apical media. SC production and IgA transcytosis by polarized HBEC were upregulated by interferon-gamma (IFN-gamma) after 48 h. By reverse transcription-polymerase chain reaction, no SC messenger ribonucleic acid (mRNA) was detected in A549 and 16HBE, while SC mRNA in CALU-3 was comparable to that of HBEC incubated for 48 h with IFN-gamma. By immunocytochemistry, HBEC expressed SC immunostaining and its intensity increased after 48 h with IFN-gamma. It is concluded that human bronchial epithelial cells produce secretory component and transcytose dimeric immunoglobulin A in vitro. These processes were apically polarized and upregulated by interferon-gamma. Among the cell lines studied, only CALU-3 expressed secretory component-messenger ribonucleic acid and produced detectable secretory component.
Dipeptidyl Peptidase-4 Inhibition by Vildagliptin and the Effect on Insulin Secretion and Action in Response to Meal Ingestion in Type 2 Diabetes
Authors: Chiara Dalla Man, Gerlies Bock, Paula D. Giesler, Denise B. Serra, Monica Ligueros Saylan, James E. Foley, Michael Camilleri, Gianna Toffolo, Claudio Cobelli, Robert A. Rizza, Adrian Vella
Journal: Diabetes Care (2008)

OBJECTIVE—The purpose of this study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS—We measured insulin secretion and action as well as glucose effectiveness in 14 subjects with type 2 diabetes who received vildagliptin (50 mg b.i.d.) or placebo for 10 days in random order separated by a 3-week washout. On day 9 of each period, subjects ate a mixed meal. Insulin sensitivity (SI), glucose effectiveness, and β-cell responsivity indexes were estimated using the oral glucose and C-peptide minimal models. At 300 min 0.02 unit/kg insulin was administered intravenously. RESULTS—Vildagliptin reduced postprandial glucose concentrations (905 ± 94 vs. 1,008 ± 104 mmol/6 h, P = 0.02). Vildagliptin did not alter net SI (7.71 ± 1.28 vs. 6.41 ± 0.84 10−4 dl · kg−1 · min−1 · μU−1 · ml−1, P = 0.13) or glucose effectiveness (0.019 ± 0.002 vs. 0.018 ± 0.002 dl · kg−1 · min−1, P = 0.65). However, the net β-cell responsivity index was increased (35.7 ± 5.2 vs. 28.9 ± 5.2 10−9 min−1, P = 0.03) as was total disposition index (381 ± 48 vs. 261 ± 35 10−14 dl · kg−1 · min−2 · pmol−1 · l−1, P = 0.006). Vildagliptin lowered postprandial glucagon concentrations (27.0 ± 1.1 vs. 29.7 ± 1.5 μg · l−1 · 6 h−1, P = 0.03), especially after administration of exogenous insulin (81.5 ± 6.4 vs. 99.3 ± 5.6 ng/l, P = 0.02). CONCLUSIONS—Vildagliptin lowers postprandial glucose concentrations by stimulating insulin secretion and suppressing glucagon secretion but not by altered insulin action or glucose effectiveness. A novel observation is that vildagliptin alters α-cell responsiveness to insulin administration, but the significance of this action is as yet unclear.
Epstein-Barr Virus Infections in Males with the X-Linked Lymphoproliterative Syndrome
Authors: HELEN GRIERSON
Journal: Annals of Internal Medicine (1987)

A registry of persons with the X-linked lymphoproliferative syndrome, which is characterized by marked susceptibility to diseases induced by the Epstein-Barr virus, has enrolled 161 patients within 44 kindreds. Fifty-seven percent of the males died of infectious mononucleosis, 29% developed acquired hypogammaglobulinemia, and 24% had malignant lymphoma. The mortality rate was 80%; 70% died by 10 years of age and 100% by 40 years. Thirty-two boys survive, most with malignant lymphoma, acquired hypogammaglobulinemia, or both. We hypothesized that the defective lymphoproliferative control locus on the X chromosome results in unregulated cytotoxic lymphocytic responses to the Epstein-Barr virus; hence, severe hepatitis and virus-associated hemophagocytic syndrome occur with the infectious mononucleosis phenotype. T-cell suppression of immunoglobulin secretion by B cells is responsible for acquired hypogammaglobulinemia. A sustained polyclonal B-cell proliferation probably converts to a monoclonal B-cell malignancy as a result of molecular alterations.