tbuckley/cabot-search huggingface dataset:
The 6th Annual World Congress on the Insulin Resistance Syndrome
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2009)

the organizer and prime mover of the International Committee for Insulin Resistance, discussed clinical implications of insulin resistance, touching on its relationship to sleep disorders, and the cytokines produced by adipocytes.Reducing adiposity appears to be an optimal approach to treatment of insulin resistance, with excess adipose tissue playing roles in genesis of nonalcoholic steatohepatitis (NASH), hyperuricemia, the polycystic ovary syndrome, atherosclerosis, and diabetes.There are ϳ57 million people in the U.S. and 314 million overall in the world with pre-diabetes, with conversion to diabetes directly related to insulin resistance, particularly in the setting of decreased insulin secretion."Treating diabetes works," he commented, noting the recent UKPDS (United Kingdom Prospective Diabetes Study) follow-up study, and asked whether one should therefore treat pre-diabetes, given the strong similarities in risk for diabetes and cardiovascular disease (CVD), further suggesting that metabolic syndrome should be considered a pre-diabetes equivalent.Treatment of pre-diabetes may benefit from lifestyle intervention, with consideration of pharmacological treatment in high-risk patients, including thiazolidinediones, metformin, and ␣-glucosidase inhibitors; such patients should have aggressive efforts directed to CVD prevention with blood pressure and LDL cholesterol goals of Ͻ130/80 mmHg and Ͻ100 mg/dl, respectively.
An evidence based EULAR meeting?
Authors: P. DIEPPE
Journal: Annals of the Rheumatic Diseases (2000)

Cutaneous leucocytoclastic vasculitis caused by cyclosporin A (Sandimmun)Cutaneous leucocytoclastic vasculitis to cyclosporin A (Sandimmun) has not been previously described.We report the case of a 37 year old man who presented with a 10 day history of a purpuric eruption aVecting both legs.He had been diagnosed as having psoriasis and psoriatic arthropathy 12 years previously, on the basis of joint symptoms, sacroileitis, erosive arthropathy, increased acute phase reactants and positive HLA B27 status.His initial treatments had included oral gold (Auranofin) 3 mg three times per day and salazopyrine 3 g/day.Both were discontinued because of poor control of his joint disease.In July 1997 he was given oral cyclosporin A (Neoral) 50 mg/day, which was increased to 100 mg/day.This was discontinued in January 1998 because of symptoms of fatigue.In April 1998, after further flares of his arthropathy, he was given Sandimmun 50 mg/day by his general practitioner.Within one month of this he developed an acute skin eruption.He was otherwise well and receiving no other medication except indomethacin 150 mg/day, which he had been taking since 1986.On examination, there was a palpable, non-tender, purpuric eruption with necrotising ulceration localised to both lower legs.Routine haematology, biochemistry and urine analysis were normal.Skin biopsy showed a leucocytoclastic vasculitis with heavy dermal neutrophilic infiltrate and few eosinophils (fig 1).Gram stain for organisms was negative.The Sandimmun was discontinued and over a two month period, the purpuric eruption and ulcers healed with residual scarring.
Effect of a high-carbohydrate, low-saturated-fat diet on apolipoprotein B and triglyceride metabolism in Pima Indians.
Authors: W G Abbott, B Swinburn, G Ruotolo, H Hara, L Patti, I Harper, S M Grundy, B V Howard
Journal: Journal of Clinical Investigation (1990)

The mechanisms by which high-carbohydrate, low-saturated-fat diets lower LDL cholesterol (LDLC) concentrations are unknown. In this study, kinetics of VLDL, intermediate density lipoprotein (IDL), and LDL apoprotein B and VLDL triglyceride were determined in seven nondiabetic (ND) and seven non-insulin-dependent diabetic (NIDDM) Pima Indian subjects on high-fat and high-carbohydrate (HICHO) diets. Metabolic changes were similar in ND and NIDDM. On the HICHO diet, LDLC decreased (131 +/- 8 vs. 110 +/- 7 mg/dl, P less than 0.0001) in all subjects. Mean fasting and 24-h triglyceride (TG) concentrations were unchanged, as were mean production rates and fractional clearance rates (FCR) of VLDL apoB and VLDL TG. The mean VLDL apoB pool size (303 +/- 20 vs. 371 +/- 38 mg, P = 0.01) increased owing to a decrease in the mean transport rate (10.7 +/- 1.1 vs. 8.4 +/- 0.9 mg/kg fat-free mass (ffm) per day, P less than 0.0001) and the mean rate constant (2.3 +/- 0.2 vs. 1.5 +/- 0.2, P less than 0.001) for the VLDL apoB to IDL apoB conversion pathway. The mean transport rate of VLDL apoB to LDL apoB via IDL (10.2 +/- 0.9 vs. 8.0 +/- 0.8 mg/kg ffm per day, P less than 0.001) decreased. Mean LDL apoB concentrations decreased (70 +/- 5 vs. 61 +/- 5 mg/dl, P less than 0.001) on the HICHO diet. Means for total LDL apoB transport rate, LDL apoB FCR, and LDLC/apoB ratios were unchanged. In summary, the HICHO diet decreased the activity of mechanisms that convert VLDL to LDL, which contributed to the decrease in LDLC in all subjects. There was also evidence in some subjects for increased activity of LDL apoB clearance mechanisms, and a decrease in the LDLC to apoB ratio.
Interleukin-21 Has Activity in Patients With Metastatic Melanoma: A Phase II Study
Authors: Teresa M. Petrella, Richard Tozer, Karl Belanger, Kerry J. Savage, Ralph Wong, Michael Smylie, Suzanne Kamel-Reid, Victor Tron, Bingshu E. Chen, Naomi N. Hunder, Linda Hagerman, Wendy Walsh, Elizabeth A. Eisenhauer
Journal: Journal of Clinical Oncology (2012)

Purpose We report a multicenter phase II study of patients with metastatic melanoma (MM), evaluating the efficacy, toxicity, progression-free survival (PFS), immunogenicity, and biomarker profile of interleukin-21 (IL-21). Patients and Methods Patients with no prior systemic therapy and with limited-disease MM were treated with IL-21 by using three different dosing regimens. Cohort 1 received 50 μg/kg per day by outpatient intravenous bolus injection for 5 days of each week during weeks 1, 3, and 5 of an 8-week cycle. Cohort 2 received 30 μg/kg per day on the same schedule, and cohort 3 received 50 μg/kg per day for 5 days of each week during weeks 1 and 3 of a 6-week cycle. Results Forty patients were enrolled: three in cohort 1, 30 in cohort 2, and seven in cohort 3. Two patients in cohort 1 and four in cohort 3 had dose-limiting toxicities; all other patients were treated with a dose of 30 μg/kg per day. Common adverse events were fatigue, rash, diarrhea, nausea, and myalgia. Overall response rate (ORR) was 22.5%, with nine confirmed partial responses (median response duration, 5.3 months); 16 had stable disease (median response duration, 5.3 months). ORR did not appear to depended on IL-21 receptor expression or BRAF mutation status. The median PFS was 4.3 months and median overall survival (OS) was 12.4 months (95% CI, 10.09 to 17.81 months). Conclusion The ORR to IL-21 is 22.5% for first-line MM and warrants further investigation. The favorable PFS and OS suggest that this is an active agent in comparison to both historical NCIC Clinical Trials Group data and data from meta-analysis of Cooperative Group phase II trials.
Treatment of Ductal Carcinoma In Situ After Excision: Would a Prophylactic Paradigm Be More Appropriate?
Authors: R. S. Punglia, S. J. Schnitt, J. C. Weeks
Journal: JNCI Journal of the National Cancer Institute (2013)

Corresponding to the increased use of mammography, the incidence of ductal carcinoma in situ (DCIS) has risen dramatically in the past 30 years. Despite its growing incidence, the treatment of DCIS remains highly variable and controversial. Although DCIS itself does not metastasize and is never lethal, it may be a precursor of invasive breast cancer and is a marker of increased breast cancer risk. Confusing a precursor lesion with cancer, many clinicians apply an invasive breast cancer treatment paradigm to DCIS patients, offering adjuvant radiation therapy and tamoxifen after diagnosis. In this commentary, we outline the issues associated with DCIS management—is DCIS a cancer, a precursor of cancer, or a marker of invasive carcinoma risk? Specifically, we argue that consideration be given to removing the term "carcinoma" from DCIS, using cancer "occurrence" to mean the diagnosis of invasive cancer after DCIS instead of "recurrence," and make the argument that a prophylactic paradigm of treatment after excision may be more appropriate.
Nitric oxide is not involved in hepatocyte killing by neutrophils activated byN-formyl-methionyl-leucyl-phenylalanine or phorbol myristate acetatein vitro
Authors: J G Wagner, P E Ganey, R A Roth
Journal: Hepatology (1996)

Polymorphonuclear leukocytes (PMNS) have been implicated as cellular mediators of hepatic injury in models of inflammation in vivo. In vitro, hepatocyte killing by activated PMNs is mediated in part by proteases, but the role of nitric oxide is unknown. NO is produced by PMNs and hepatocytes and can act either to damage or protect in various models of toxicity. Therefore, we tested the hypothesis that NO is important in PMN-mediated hepatocyte killing in vitro. Freshly isolated hepatocytes from rat liver and PMNs elicited from rat peritoneum were cultured together or alone for 16 hours. Both cell types spontaneously released NO, estimated as its stable breakdown product, nitrite. Accumulation of nitrite in medium from hepatocyte cultures was augmented threefold by incubation with L-arginine and was completely inhibited by treatment with the nitric oxide synthase (NOS) inhibitor NG-methyl-L-arginine (NMA). Nitrite release in PMN cultures was unaffected by L-arginine addition and only partially inhibited by NMA. In PMN: hepatocyte cocultures (10:1), accumulation of nitrite was additive relative to cells cultured separately. Incubation with NMA blocked nitrite production completely in cocultures, whereas L-arginine caused a two-fold increase in nitrite. Addition of PMN stimulants, N-formyl-methionyl-leucyl-phenylalanine (FMLP), or phorbol myristate acetate (PMA), caused increased release of alanine aminotransferase (ALT) activity into medium from hepatocytes cultured with PMNs but not from hepatocytes cultured alone; this indicated that injury to hepatocytes was due to activated PMNS. However, neither FMLP nor PMA significantly altered nitrite release from cocultures. Despite the alterations in NO production induced by addition of NMA or L-arginine, neither agent altered the release of ALT from hepatocytes in coculture with activated PMNs. Thus, PMNs and hepatocytes provided NO in vitro, but neither suppression nor elevation of NO production affected PMN-mediated hepatocyte killing. Accordingly, NO is not involved in the mechanisms by which FMLP-or PMA-stimulated PMNs mediate hepatocyte injury in vitro.
Altered peptide ligands regulate muscarinic acetylcholine receptor reactive T cells of patients with Sjogren's syndrome
Authors: Y Naito
Journal: Annals of the Rheumatic Diseases (2006)

In the generation of Sjogren’s syndrome (SS), CD4 positive αβ T cells have a crucial role. Previous studies have provided evidence about the T cell receptor (TCR) Vβ and Vα genes on these T cells, and sequence analysis of the CDR3 region indicates the presence of some conserved amino acid motifs, supporting the notion that infiltrating T cells recognise relatively few epitopes on autoantigens.1

Candidate autoantigens recognised by T cells that infiltrate the labial salivary glands of patients with SS have been analysed, and Ro/SSA 52 kDa,2 α-amylase, heat shock protein, and TCR BV6 have been identified, although Ro/SSA 52 kDa reactive T cells were not increased in peripheral blood.3 Gordon et al indicated that anti-M3R autoantibodies occurred in SS and were associated with the sicca symptoms.4 Recently, we provided evidence for the presence of autoantibodies against the second extracellular domain of muscarinic acetylcholine receptor (M3R) in a subgroup of patients with SS.5 The M3R is an interesting molecule, because this portion has an important role in intracellular signalling,5 although the function of anti-M3R autoantibodies remains unknown.

The mechanism through which a peptide is recognised by a TCR is flexible. If the amino acid residue of the peptide ligands for TCR is substituted by a different amino acid and can still …
The Social World of the Ants Compared With That of Man
Authors: D. O'Neill
Journal: BMJ (2010)

Imagine a world where there are weavers, butchers, cattle rearers, masons, road makers, harvesters, bakers, mushroom farmers, excellent nurses of various kinds, gardeners, warriors, pacificists, slave makers, thieves, brigands, and parasites, but where we find no professors, orators, governors, bureaucrats, or generals, nor even corporals; nor do we find capitalists, speculators, or mere swindlers. This idyllic world was described almost 10 years before the great depression, and 80 years before our current recession, by one of the great medical polymaths of the last century, Auguste Forel (1848-1931).

That the world described in this exquisite two volume book belongs to ants should come as no surprise, since Forel was one of the world’s greatest authorities on ants at …
Age-specific Relationship between CD14 and Atopy in a Cohort Assessed from Age 8 to 25 Years
Authors: Anne R. O'Donnell, Brett G. Toelle, Guy B. Marks, Catherine M. Hayden, Ingrid A. Laing, Jennifer K. Peat, Jack Goldblatt, Peter N. Le Souëf
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

CD14 influences postnatal switching of T helper cell responses. CD14 C-159T has been associated with altered CD14 and IgE levels in cross-sectional studies. Identifying whether associations vary with age requires data from children of the same age followed longitudinally over many years. In this study, an unselected population with extensive longitudinal data was used to test the hypothesis that CD14 C-159T was associated with early-onset atopy. A total of 305 subjects were assessed on up to seven occasions between ages 8 and 25 years by questionnaire, histamine challenge, and skin prick test. For atopy, airway hyperresponsiveness (AHR), and wheeze, each subject was classified as having early onset, late onset, or no disease onset during follow-up. Compared with subjects with -159CT and -159TT, subjects with -159CC had an odds ratio of 2.2 (p = 0.018) for early-onset atopy and an odds ratio of 2.6 (p = 0.019) for early-onset AHR. Cross-sectional analysis showed increased prevalence of -159CC in subjects with atopy and AHR in childhood but not adulthood. These data suggest that the influence of CD14 -159C on the atopic phenotype may be age specific, exerting an effect during midchildhood, which is no longer apparent by early adulthood.
<sup>18</sup>Fluorodeoxyglucose Positron Emission Tomography to Detect Mediastinal or Internal Mammary Metastases in Breast Cancer
Authors: W. B. Eubank, D. A. Mankoff, J. Takasugi, H. Vesselle, J. F. Eary, T. J. Shanley, J. R. Gralow, A. Charlop, G. K. Ellis, K. L. Lindsley, M. M. Austin-Seymour, C. P. Funkhouser, R. B. Livingston
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To determine the prevalence of suspected disease in the mediastinum and internal mammary (IM) node chain by 18 fluorodeoxyglucose (FDG) positron emission tomography (PET), compared with conventional staging by computed tomography (CT) in patients with recurrent or metastatic breast cancer. PATIENTS AND METHODS: We retrospectively evaluated intrathoracic lymph nodes using FDG PET and CT data in 73 consecutive patients with recurrent or metastatic breast cancer who had both CT and FDG PET within 30 days of each other. In reviews of CT scans, mediastinal nodes measuring 1 cm or greater in the short axis were considered positive. PET was considered positive when there were one or more mediastinal foci of FDG uptake greater than the mediastinal blood pool. RESULTS: Overall, 40% of patients had abnormal mediastinal or IM FDG uptake consistent with metastases, compared with 23% of patients who had suspiciously enlarged mediastinal or IM nodes by CT. Both FDG PET and CT were positive in 22%. In the subset of 33 patients with assessable follow-up by CT or biopsy, the sensitivity, specificity, and accuracy for nodal disease was 85% , 90%, and 88%, respectively, by FDG PET; 54% , 85%, and 73%, respectively, by prospective interpretation of CT; and 50%, 83%, and 70%, respectively, by blinded observer interpretation of CT. Among patients suspected of having only locoregional disease recurrence (n = 33), 10 had unsuspected mediastinal or IM disease by FDG PET. CONCLUSION: FDG PET may uncover disease in these nodal regions not recognized by conventional staging methods. Future prospective studies using histopathology for confirmation are needed to validate the preliminary findings of this retrospective study.
Correspondence Anti–Tumor Necrosis Factor-α in Asthma
Authors: Frans H. Krouwels
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

In their recent article on the effects of anti–tumor necrosis factor (TNF)in asthma, Erin and colleagues report that infliximab reduces the number of asthma exacerbations in symptomatic patients with moderate asthma who are taking inhaled corticosteroids (1). Although I recognize the need for new asthma treatment modalities, I have serious problems with the use of anti–TNFin this patient group as the drug can induce severe side effects. The dose of inhaled corticosteroids used was not high (in placebo and infliximab groups, respectively, 605 and 753 g/d of beclomethasone dipropionate equivalent). This can be considered a moderate dose, and increasing this dose or adding a longacting -agonist has been shown to result in a markedly better control of asthma (2) without a significant change in side effects. In addition, the study reports a decrease in exacerbations during a 12-wk period. Exacerbations were considered either moderate (two or more consecutive days with more symptoms or a decrease in morning PEF of more than 20%) or severe (requiring oral corticosteroids). In the placebo group, as many as 72% of the patients experienced an exacerbation, but it is not stated whether these were moderate or severe exacerbations. This is a rather high percentage, which suggests that all may have been moderate exacerbations. As severe exacerbations have a clearly higher impact on the patient, this information should be provided to judge the additional effect of infliximab. Anti–TNFis now used for patients with severe and invalidating complaints of Crohn’s disease or rheumatoid arthritis. Pulmonologists became familiar with this treatment when severe cases of tuberculosis were found in these patients. The incidence of anti–TNFinduced tuberculosis can be as high as 224/100,000 treated patients. Manifestations are often extrapulmonary, and in 24% of the cases there is disseminated disease (3, 4) with a significant risk of death. Physicians are now more aware of this problem, and when mycobacterial infections are suspected antituberculosis treatment is now advised. But there is still an increased risk as the protective effect of such treatment is estimated not to be higher than 60%. Therefore, in my opinion, anti–TNFshould be used with much care, and studies on the therapeutic value in asthma should be focused on patients with severe debilitating disease. In such cases, the effects of anti–TNFshould be studied in addition to the best current modalities, which are high doses of inhaled corticosteroids in combination with a long-acting -agonist.
Suppurative polyarthritis following a rat bite
Authors: B Y.-H. Thong
Journal: Annals of the Rheumatic Diseases (2003)

A 62 year old healthy Chinese man was admitted to hospital three weeks after a rat bit his left foot. Four days after the bite he developed pain over his left foot followed by pain and swelling in both knees, elbows, wrists, the small joints of both hands, and the left ankle. He had no fever or constitutional symptoms.

On admission he was febrile and jaundiced. His blood pressure was 110/70 mm Hg. No cardiac murmurs were heard. There was no right hypochondrial tenderness or hepatomegaly. There was synovitis affecting his wrists, interphalangeal and metacarpophalangeal joints of the hands, effusions in his right knee, right ankle, and left midtarsal joint (fig 1).



 Figure 1  
Synovitis of the right ankle and left midtarsal joint with the site of the rat bite (circled), which has healed.



His haemoglobin was 125 g/l, white cell count 29.3×109/l with 90% polymorphs, platelet count 621×109/l. The C reactive protein was 197 mg/l. Renal function was normal. Liver function tests showed a cholestatic hepatitis with serum bilirubin 55 μmol/l, alkaline phosphatase 399 U/l, alanine aminotransferase 230 U/l, and aspartate aminotransferase 63 U/l. Hepatitis B and C serology findings were negative.

Pus, aspirated from the right knee, contained 90 000 white cells/μl with 98% polymorphs. The Gram stain showed regular Gram negative intracellular bacilli. With the history and the Gram stain finding, both the microbiologist and rheumatologist were alerted to the possibility of streptobacillary septic arthritis.

Oral ciprofloxacin and doxycycline were empirically started as the patient had …
SD-208, a Novel Transforming Growth Factor β Receptor I Kinase Inhibitor, Inhibits Growth and Invasiveness and Enhances Immunogenicity of Murine and Human Glioma Cells<b><i>In vitro</i></b>and<b><i>In vivo</i></b>
Authors: Martin Uhl, Steffen Aulwurm, Jörg Wischhusen, Markus Weiler, Jing Ying Ma, Ramona Almirez, Ruban Mangadu, Yu-Wang Liu, Michael Platten, Ulrich Herrlinger, Alison Murphy, Darren H. Wong, Wolfgang Wick, Linda S. Higgins, Michael Weller
Journal: Cancer Research (2004)

Abstract The cytokine transforming growth factor (TGF)-β, by virtue of its immunosuppressive and promigratory properties, has become a major target for the experimental treatment of human malignant gliomas. Here we characterize the effects of a novel TGF-β receptor (TGF-βR) I kinase inhibitor, SD-208, on the growth and immunogenicity of murine SMA-560 and human LN-308 glioma cells in vitro and the growth of and immune response to intracranial SMA-560 gliomas in syngeneic VM/Dk mice in vivo. SD-208 inhibits the growth inhibition of TGF-β–sensitive CCL64 cells mediated by recombinant TGF-β1 or TGF-β2 or of TGF-β–containing glioma cell supernatant at an EC50 of 0.1 μmol/L. SD-208 blocks autocrine and paracrine TGF-β signaling in glioma cells as detected by the phosphorylation of Smad2 or TGF-β reporter assays and strongly inhibits constitutive and TGF-β–evoked migration and invasion, but not viability or proliferation. Peripheral blood lymphocytes or purified T cells, cocultured with TGF-β–releasing LN-308 glioma cells in the presence of SD-208, exhibit enhanced lytic activity against LN-308 targets. The release of interferon γ and tumor necrosis factor α by these immune effector cells is enhanced by SD-208, whereas the release of interleukin 10 is reduced. SD-208 restores the lytic activity of polyclonal natural killer cells against glioma cells in the presence of recombinant TGF-β or of TGF-β–containing glioma cell supernatant. The oral bioavailability of SD-208 was verified by demonstrating the inhibition of TGF-β–induced Smad phosphorylation in spleen and brain. Systemic SD-208 treatment initiated 3 days after the implantation of SMA-560 cells into the brains of syngeneic VM/Dk mice prolongs their median survival from 18.6 to 25.1 days. Histologic analysis revealed no difference in blood vessel formation, proliferation, or apoptosis. However, animals responding to SD-208 showed an increased tumor infiltration by natural killer cells, CD8 T cells, and macrophages. These data define TGF-β receptor I kinase inhibitors such as SD-208 as promising novel agents for the treatment of human malignant glioma and other conditions associated with pathological TGF-β activity.