tbuckley/cabot-search huggingface dataset:
Glycemic Variability: Can We Bridge the Divide Between Controversies?
Authors: Louis Monnier, Claude Colette
Journal: Diabetes Care (2011)

What does it take to put glucose variability into or out the heart of glycemic disorders in type 2 diabetes? By analyzing the database of the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) HEART2D trial, a premonitory acronym, Siegelaar et al. (1) have reported in this issue of Diabetes Care that glycemic variability cannot be placed at the heart of the risk factors implicated in the progression of cardiovascular diseases in people with type 2 diabetes. The HEART2D trial (2) was initially designed to know whether control of basal hyperglycemia or postprandial hyperglycemia is best for reducing cardiovascular outcomes in patients with type 2 diabetes who had a history of myocardial infarction. In order to answer this question, the investigators of the HEART2D trial have enrolled poorly controlled type 2 diabetic patients who had experienced acute myocardial infarction. Patients were further assigned to either a basal insulin strategy that targeted fasting and interprandial glycemia or an insulin regimen with three daily injections of a rapid insulin analog at premeal times in order to target postprandial glucose excursions. A similar lowering effect on ambient (sustained chronic) hyperglycemia assessed by HbA1c levels was observed with the two insulin regimens. No difference in the incidence of cardiovascular events was detected between the two regimens despite that the prandial group had lower postprandial glycemia compared with the basal group at interim analysis, when the study was halted after a mean follow-up of 2.7 years. Even though the authors of the HEART2D trial did not perform any specific assessment of glycemic variability, a rapid glance at the 7-point glycemic profile seems to indicate that the range of glycemic variability was different between the prandial and basal insulin regimens at study end. The analysis …
Erythropoietin-directed erythropoiesis depends on serpin inhibition of erythroblast lysosomal cathepsins
Authors: Arvind Dev, Susan M. Byrne, Rakesh Verma, Philip G. Ashton-Rickardt, Don M. Wojchowski
Journal: The Journal of Experimental Medicine (2013)

Erythropoietin (EPO) and its cell surface receptor (EPOR) are essential for red blood cell production and exert important cytoprotective effects on select vascular, immune, and cancer cells. To discover novel EPO action modes, we profiled the transcriptome of primary erythroid progenitors. We report Serpina3g/Spi2A as a major new EPO/EPOR target for the survival of erythroid progenitors. In knockout mice, loss of Spi2A worsened anemia caused by hemolysis, radiation, or transplantation. EPO-induced erythropoiesis also was compromised. In particular, maturing erythroblasts required Spi2A for cytoprotection, with iron and reactive oxygen species as cytotoxic agents. Spi2A defects were ameliorated by cathepsin-B/L inhibition, and by genetic co-deletion of lysosomal cathepsin B. Pharmacological inhibition of cathepsin B/L enhanced EPO-induced red cell formation in normal mice. Overall, we define an unexpected EPO action mode via an EPOR–Spi2A serpin–cathepsin axis in maturing erythroblasts, with lysosomal cathepsins as novel therapeutic targets.
Oxidative stress and intracellular infections: more iron to the fire
Authors: Norma W. Andrews
Journal: Journal of Clinical Investigation (2012)

The immune system’s battle against pathogens includes the “respiratory burst,” a rapid release of ROS from leukocytes, thought to play a role in destroying the invading species. In this issue of the JCI, Paiva et al. demonstrate that oxidative stress actually enhances infection with the protozoan Trypanosoma cruzi, by a mechanism that may involve facilitating parasite access to iron. Their findings suggest a novel direction for the development of drugs against intracellular parasites.
Oxygen free radicals in ischemic acute renal failure in the rat.
Authors: M S Paller, J R Hoidal, T F Ferris
Journal: Journal of Clinical Investigation (1984)

During renal ischemia, ATP is degraded to hypoxanthine. When xanthine oxidase converts hypoxanthine to xanthine in the presence of molecular oxygen, superoxide radical (O-2) is generated. We studied the role of O-2 and its reduction product OH X in mediating renal injury after ischemia. Male Sprague-Dawley rats underwent right nephrectomy followed by 60 min of occlusion of the left renal artery. The O-2 scavenger superoxide dismutase (SOD) was given 8 min before clamping and before release of the renal artery clamp. Control rats received 5% dextrose instead. Plasma creatinine was lower in SOD treated rats: 1.5, 1.0, and 0.8 mg/dl vs. 2.5, 2.5, and 2.1 mg/dl at 24, 48, and 72 h postischemia. 24 h after ischemia inulin clearance was higher in SOD treated rats than in controls (399 vs. 185 microliter/min). Renal blood flow, measured after ischemia plus 15 min of reflow, was also greater in SOD treated than in control rats. Furthermore, tubular injury, judged histologically in perfusion fixed specimens, was less in SOD treated rats. Rats given SOD inactivated by prior incubation with diethyldithiocarbamate had plasma creatinine values no different from those of control rats. The OH X scavenger dimethylthiourea (DMTU) was given before renal artery occlusion. DMTU treated rats had lower plasma creatinine than did controls: 1.7, 1.7, and 1.3 mg/dl vs. 3.2, 2.2, and 2.4 mg/dl at 24, 48, and 72 h postischemia. Neither SOD nor DMTU caused an increase in renal blood flow, urine flow rate, or solute excretion in normal rats. The xanthine oxidase inhibitor allopurinol was given before ischemia to prevent the generation of oxygen free radicals. Plasma creatinine was lower in allopurinol treated rats: 2.7, 2.2, and 1.4 mg/dl vs. 3.6, 3.5, and 2.3 mg/dl at 24, 48, and 72 h postischemia. Catalase treatment did not protect against renal ischemia, perhaps because its large size limits glomerular filtration and access to the tubular lumen. Superoxide-mediated lipid peroxidation was studied after renal ischemia. 60 min of ischemia did not increase the renal content of the lipid peroxide malondialdehyde, whereas ischemia plus 15 min reflow resulted in a large increase in kidney lipid peroxides. Treatment with SOD before renal ischemia prevented the reflow-induced increase in lipid peroxidation in renal cortical mitochondria but not in crude cortical homogenates. In summary, the oxygen free radical scavengers SOD and DMTU, and allopurinol, which inhibits free radical generation, protected renal function after ischemia. Reperfusion after ischemia resulted in lipid peroxidation; SOD decreased lipid peroxidation in cortical mitochondria after renal ischemia and reflow. We concluded that restoration of oxygen supply to ischemic kidney results in the production of oxygen free radicals, which causes renal injury by lipid peroxidation.
Anti-Plasminogen Antibodies Compromise Fibrinolysis and Associate with Renal Histology in ANCA-Associated Vasculitis
Authors: Annelies E. Berden, Sarah L. Nolan, Hannah L. Morris, Rogier M. Bertina, Dianhdra D. Erasmus, E. Christiaan Hagen, Donal P. Hayes, Nico H. van Tilburg, Jan A. Bruijn, Caroline O.S. Savage, Ingeborg M. Bajema, Peter Hewins
Journal: Journal of the American Society of Nephrology (2010)

Antibodies recognizing plasminogen, a key component of the fibrinolytic system, associate with venous thrombotic events in PR3-ANCA vasculitis. Here, we investigated the prevalence and function of anti-plasminogen antibodies in independent UK and Dutch cohorts of patients with ANCA-associated vasculitis (AAV). We screened Ig isolated from patients (AAV-IgG) and healthy controls by ELISA. Eighteen of 74 (24%) UK and 10/38 (26%) Dutch patients with AAV had anti-plasminogen antibodies compared with 0/50 and 1/61 (2%) of controls. We detected anti-plasminogen antibodies in both PR3-ANCA– and MPO-ANCA–positive patients. In addition, we identified anti-tissue plasminogen activator (tPA) antibodies in 13/74 (18%) patients, and these antibodies were more common among patients with anti-plasminogen antibodies (P = 0.011). Eighteen of 74 AAV-IgG (but no control IgG) retarded fibrinolysis in vitro, and this associated with anti-plasminogen and/or anti-tPA antibody positivity. Only 4/18 AAV-IgG retarded fibrinolysis without harboring these antibodies; dual-positive samples retarded fibrinolysis to the greatest extent. Patients with anti-plasminogen antibodies had significantly higher percentages of glomeruli with fibrinoid necrosis (P < 0.05) and cellular crescents (P < 0.001) and had more severely reduced renal function than patients without these antibodies. In conclusion, anti-plasminogen and anti-tPA antibodies occur in AAV and associate with functional inhibition of fibrinolysis in vitro. Seropositivity for anti-plasminogen antibodies correlates with hallmark renal histologic lesions and reduced renal function. Conceivably, therapies that enhance fibrinolysis might benefit a subset of AAV patients.
Whole of community physical activity interventions: easier said than done
Authors: W K Mummery, W J Brown
Journal: British Journal of Sports Medicine (2008)

Objectives: To reflect on whole community intervention approaches to promoting physical activity, using experiences from the 10,000 Steps Rockhampton project. Design: Many studies are quasi-experimental with single site intervention and comparison communities. Setting and participants: Whole communities. Intervention: Coordinated multiple strategies designed to address individual, interpersonal and environmental determinants of physical activity. Main outcome measure: Physical activity Results: There are many challenges to conducting whole community interventions. Developing community partnerships and coalitions, reaching socially disadvantaged groups, and developing effective evaluation methods are identified as specific concerns. Conclusions: Despite the challenges, the whole community approach still offers tremendous potential for developing the social and cultural change which will be required for sustained improvements in population physical activity
Joint and tendon involvement predict disease progression in systemic sclerosis: a EUSTAR prospective study
Authors: Jérôme Avouac, Ulrich A Walker, Eric Hachulla, Gabriela Riemekasten, Giovanna Cuomo, Patricia E Carreira, Paola Caramaschi, Lidia P Ananieva, Marco Matucci-Cerinic, Laszlo Czirjak, Christopher Denton, Ulf Müller Ladner, Yannick Allanore
Journal: Annals of the Rheumatic Diseases (2014)

To determine whether joint synovitis and tendon friction rubs (TFRs) can predict the progression of systemic sclerosis (SSc) over time.We performed a prospective cohort study that included 1301 patients with SSc from the EUSTAR database with disease duration ≤3 years at inclusion and with a follow-up of at least 2 years. Presence or absence at clinical examination of synovitis and TFRs was extracted at baseline. Outcomes were skin, cardiovascular, renal and lung progression. Overall disease progression was defined according to the occurrence of at least one organ progression.Joint synovitis (HR: 1.26, 95% CI 1.01 to 1.59) and TFRs (HR: 1.32, 95% CI 1.03 to 1.70) were independently predictive of overall disease progression, as were also the diffuse cutaneous subset (HR: 1.30, 95% CI 1.05 to 1.61) and positive antitopoisomerase-I antibodies (HR: 1.25, 95% CI 1.02 to 1.53). Regarding skin progression, joint synovitis (HR: 1.67, 95% CI 1.06 to 2.64) and TFRs (HR: 1.69, 95% CI 1.02 to 2.77) were also independently predictive of worsening of the modified Rodnan skin score. For cardiovascular progression, joint synovitis was predictive of the occurrence of new digital ulcer(s) (HR: 1.45, 95% CI 1.08 to 1.96) and decreased left ventricular ejection fraction (HR: 2.20, 95% CI 1.06 to 4.57); TFRs were confirmed to be an independent predictor of scleroderma renal crisis (HR: 2.33, 95% CI 1.03 to 6.19).Joint synovitis and TFRs are independent predictive factors for disease progression in patients with early SSc. These easily detected clinical markers may be useful for the risk stratification of patients with SSc.
Glomerular Filtration Rate and Albuminuria
Authors: Ian H. de Boer, Michael W. Steffes
Journal: Journal of the American Society of Nephrology (2007)

In the past three decades, urinary albumin excretion has assumed a central role in the diagnosis and management of kidney disease among people with diabetes, both type 1 and type 2. Microalbuminuria was initially found to predict subsequent overt albuminuria (dipstick positive, or ≥300 mg/24 h),
Double-Blind, Randomized Trial Comparing the Efficacy and Tolerability of Fulvestrant Versus Anastrozole in Postmenopausal Women With Advanced Breast Cancer Progressing on Prior Endocrine Therapy: Results of a North American Trial
Authors: C.K. Osborne, J. Pippen, S.E. Jones, L.M. Parker, M. Ellis, S. Come, S.Z. Gertler, J.T. May, G. Burton, I. Dimery, A. Webster, C. Morris, R. Elledge, A. Buzdar
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) with anastrozole in the treatment of advanced breast cancer in patients whose disease progresses on prior endocrine treatment. PATIENTS AND METHODS: In this double-blind, double-dummy, parallel-group study, postmenopausal patients were randomized to receive either an intramuscular injection of fulvestrant 250 mg once monthly or a daily oral dose of anastrozole 1 mg. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rate, duration of response (DOR), and tolerability. RESULTS: Patients (n = 400) were followed for a median period of 16.8 months. Fulvestrant was as effective as anastrozole in terms of TTP (hazard ratio, 0.92; 95.14% confidence interval [CI], 0.74 to 1.14; P = .43); median TTP was 5.4 months with fulvestrant and 3.4 months with anastrozole. OR rates were 17.5% with both treatments. Clinical benefit rates (complete response + partial response + stable disease ≥ 24 weeks) were 42.2% for fulvestrant and 36.1% for anastrozole (95% CI, −4.00% to 16.41%; P = .26). In responding patients, median DOR (from randomization to progression) was 19.0 months for fulvestrant and 10.8 months for anastrozole. Using all patients, DOR was significantly greater for fulvestrant compared with anastrozole; the ratio of average response durations was 1.35 (95% CI, 1.10 to 1.67; P &lt; 0.01). Both treatments were well tolerated. CONCLUSION: Fulvestrant was at least as effective as anastrozole, with efficacy end points slightly favoring fulvestrant. Fulvestrant represents an additional treatment option for postmenopausal women with advanced breast cancer whose disease progresses on tamoxifen therapy.
Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth disease
Authors: Luan-Yin Chang, Tzou-Yien Lin, Kuang-Hung Hsu, Yhu-Chering Huang, Kuang-Lin Lin, Chuen Hsueh, Shin-Ru Shih, Hsiao-Chen Ning, Mao-Sheng Hwang, Huei-Shyoung Wang, Chin-Yun Lee
Journal: The Lancet (1999)
Failure of dideoxynucleosides to inhibit human immunodeficiency virus replication in cultured human macrophages.
Authors: D D Richman, R S Kornbluth, D A Carson
Journal: The Journal of Experimental Medicine (1987)

Primary human monocyte-derived macrophages (MDM) were shown to have diminished deoxynucleoside kinase activities compared to T lymphoblasts, and a reduced ability to phosphorylate dideoxynucleosides with anti-human immunodeficiency virus (HIV) activity. These drugs, azidothymidine (AZT), dideoxycytidine (ddC), and dideoxyadenosine (ddA), which are potent anti-HIV agents in CD4 lymphocytes, did not inhibit HIV replication in MDM, even at concentrations of 100 microM. This drug concentration of AZT is approximately 100-fold higher than the levels attained in the serum of treated patients and the levels required to inhibit HIV replication in lymphocytes. These observations may explain the failure of AZT therapy to clear viremia, consistent with the presence of a drug-resistant reservoir of infected cells in vivo. New therapeutic approaches to inhibit the replication of HIV in MDM may be needed.
Measuring total plasma amino acid concentrations as a test of exocrine pancreatic function.
Authors: A M Allen, P S Oates
Journal: Gut (1992)

Endogenous and exogenous stimulation of the pancreas was studied to determine whether changes in protein output could be linked to decreased total plasma amino acid concentrations. In fasted rats, diversion of pancreatic juice resulted in a transient increase in protein output and a linked fall in total plasma amino acid. In fed animals, however, diversion of juice did not result in any change in protein output or total plasma amino acid concentrations, although protein output was two-fold greater than in fasted animals. Similarly, after atropine treatment, diversion of juice failed to result in any change in protein output or total plasma amino acid in either fed or fasted animals. Stimulation of the gland with increasing doses of cholecystokinin ranging from 1.25 to 10.00 Crick Harper Raper Units, resulted in dose response increases in protein output and corresponding dose response falls in total plasma amino acid concentrations. Maximum decrease in total plasma amino acid concentrations was seen at 50% from the baseline with 5.00 Crick Harper Raper Units of cholecystokinin. These results show that with exogenous and endogenous stimulation in fasted animals, a highly significant, inverse relationship exists between protein output and total plasma amino acid. This relationship is the basis for a reliable, non-invasive test of pancreatic function that allows free mobility, although a period of fasting is required in order to increase the sensitivity of the test.
Sex‐dependent regulation of fibrosis and inflammation in human left ventricular remodelling under pressure overload
Authors: Georgios Kararigas, Elke Dworatzek, George Petrov, Holger Summer, Tabea Marie Schulze, Istvan Baczko, Christoph Knosalla, Stefan Golz, Roland Hetzer, Vera Regitz‐Zagrosek
Journal: European Journal of Heart Failure (2014)
Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: Analysis of instances of therapeutic misadventure
Authors: Hyman J. Zimmerman, Willis C. Maddrey
Journal: Hepatology (1995)

Hepatic injury in alcoholics due to intake of acetaminophen (APAP or acetylparaaminophenol) with therapeutic intent has been reported, but the extent of the phenomenon is not clear, pertinent details of the association remain insufficiently clarified, and the importance of the phenomenon is not widely appreciated. The present report describes 67 patients who developed hepatic injury after ingestion of APAP with therapeutic intent. All were regular users of alcohol. Sixty-four percent of the patients were considered to be “alcoholic” or reported intakes greater than 80 g/d, 35% took 60 g/d or less, and the remainder were vague in their reporting. Doses of APAP were in the “nontoxic” range (&lt;6 g/d) in 60% of the group, within the recommended range (&lt;4 g/d) in 40%, and at 4.1 to 6 g/d in 20%. Characteristic feature was the towering level reached by aspartate transaminase (AST) with figures ranging from 3,000 to 48,000 IU in more than 90% of cases. Almost 20% of the patients died. The data on these patients were similar to 94 cases of injury from APAP taken with therapeutic intent reported in the literature. This study provides further evidence of hepatic injury in regular users of alcohol, especially chronic alcoholics, who take APAP with therapeutic intent. Susceptibility is presumably caused by induction of cytochrome P-4502EI by ethanol and by depletion of glutathione (GSH) because of the effects of alcohol, the malnutrition often associated with alcoholism, and the depletion associated with chronic use of APAP and impaired glucuronidation caused by fasting perhaps as well. The syndrome of liver injury is distinctive, marked by uniquely elevated levels of AST, and poses a significant threat. A greater awareness of the phenomenon by the medical and lay community is essential. (Hepatology 1995;22:767-773.)
Why Is This Effective HSP90 Inhibitor Not Being Developed in HER2+ Breast Cancer?
Authors: Carlos L. Arteaga
Journal: Clinical Cancer Research (2011)

Inhibition of the HSP90 chaperone leads to degradation of the HER2 receptor. The HSP90 inhibitor tanespimycin in combination with trastuzumab is active in patients with HER2-overexpressing metastatic breast cancer. This combination is one of several HER2-targeted therapies that will significantly improve the outcome of patients with this subtype of breast cancer.
Virtues of "Brown" Bread
Authors: M. G. Eggleton
Journal: BMJ (1939)

<h3>Background</h3> Low socioeconomic status (SES) has been linked to increased risk of hypertension, a known risk factor for cardiovascular disease. How the risk is altered by intergenerational social mobility is not well known. The aim of this study is to investigate parental SES, adult SES and the intergenerational social mobility in relation to hypertension risk. <h3>Methods</h3> By using data from the Swedish Twin Registry, the authors obtained information about both parental and adult SES and hypertension in 12 030 individuals born from 1926 to 1958. Generalised estimating equations were used to estimate ORs with 95% CIs. <h3>Results</h3> Low parental SES was associated with increased odds of hypertension (OR 1.42, 95% CI 1.14 to 1.76). Low SES in adulthood was associated with increased odds for women but not for men (OR 1.40, 95% CI 1.15 to 1.70 and OR 1.01, 95% CI 0.83 to 1.24, respectively). Compared with the stable low social status group, the upward mobile group had lower odds of hypertension (OR 0.82, 95% CI 0.70 to 0.97). Compared with the stable high social status group, the results for the downward mobile group indicated an increased risk. A co-twin case-control analysis indicated that the results were independent of familial factors. <h3>Conclusions</h3> These findings suggest that the risk of hypertension associated with low parental social status can be modified by social status later in life. Possibly, this could be targeted by public health or political interventions. As parental social status has an impact on later health, such interventions should be introduced early.
Ultrasound Prevents Renal Ischemia-Reperfusion Injury by Stimulating the Splenic Cholinergic Anti-Inflammatory Pathway
Authors: Joseph C. Gigliotti, Liping Huang, Hong Ye, Amandeep Bajwa, Kryt Chattrabhuti, Sangju Lee, Alexander L. Klibanov, Kambiz Kalantari, Diane L. Rosin, Mark D. Okusa
Journal: Journal of the American Society of Nephrology (2013)

AKI affects both quality of life and health care costs and is an independent risk factor for mortality. At present, there are few effective treatment options for AKI. Here, we describe a nonpharmacologic, noninvasive, ultrasound-based method to prevent renal ischemia-reperfusion injury in mice, which is a model for human AKI. We exposed anesthetized mice to an ultrasound protocol 24 hours before renal ischemia. After 24 hours of reperfusion, ultrasound-treated mice exhibited preserved kidney morphology and function compared with sham-treated mice. Ultrasound exposure before renal ischemia reduced the accumulation of CD11b+Ly6Ghigh neutrophils and CD11b+F4/80high myeloid cells in kidney tissue. Furthermore, splenectomy and adoptive transfer studies revealed that the spleen and CD4+ T cells mediated the protective effects of ultrasound. Last, blockade or genetic deficiency of the α7 nicotinic acetylcholine receptor abrogated the protective effect of ultrasound, suggesting the involvement of the cholinergic anti-inflammatory pathway. Taken together, these results suggest that an ultrasound-based treatment could have therapeutic potential for the prevention of AKI, possibly by stimulating a splenic anti-inflammatory pathway.