tbuckley/cabot-search huggingface dataset:
Phenotypical and functional characteristics of in vitro expanded bone marrow mesenchymal stem cells from patients with systemic sclerosis
Authors: J Larghero, D Farge, A Braccini, S Lecourt, A Scherberich, E Foïs, F Verrecchia, T Daikeler, E Gluckman, A Tyndall, C Bocelli-Tyndall
Journal: Annals of the Rheumatic Diseases (2007)

Background: Mesenchymal stem cells (MSCs) have a potential immunomodulatory role in autoimmune disease; however, the qualitative properties and haematopoietic support capacity of MSCs derived from patients with autoimmune disease is unclear. Objectives: To further characterise phenotypically and functionally bone marrow (BM)-derived MSCs from patients with systemic sclerosis (SSc). Methods: Key parameters of BM-derived MSC function and phenotype were assessed in 12 patients with SSc and compared with 13 healthy normal controls. The parameters included the ability to: form colony-forming unit fibroblasts (CFU-F), differentiate along the adipogenic and osteogenic lineages, express cell surface antigens defining the MSCs population, support normal haematopoiesis and suppress in vitro lymphocyte proliferation induced by either anti-CD3∊ plus anti-CD28 monoclonal antibodies or the mixed lymphocyte reaction. Results: SSc MSCs were shown to have a similar characteristic phenotype, capacities to form CFU-F and to differentiate along adipogenic and osteogenic lineages as those of healthy donor MSCs. The ability of SSc MSCs to support long-term haematopoiesis was also identical to that of controls. Both healthy donor and SSc BM MSCs reduced the proliferation of autologous and allogeneic peripheral blood mononuclear cells in a cell number dependent fashion. Conclusions: These results show that BM-derived MSCs from patients with SSc under the described culture conditions exhibit the same phenotypic, proliferative, differentiation potential and immunosuppressive properties as their healthy counterparts and could therefore be considered in an autologous setting. Further studies are needed to ensure the quality and safety of large-scale expansion of patient MSCs prior to their potential use in clinical trials.
Emergency department visits by adult asthma patients have been decreasing over the past two decades
Authors: Michiko Hibi, Akira Shiraki, Morihide Ando, Takashi Abe, Harunori Nakashima, Joe Shindo
Journal: European Respiratory Journal (2014)

Background: 

Ogaki municipal hospital is a regional medical center covering population 400,000 in Japan and so many amounts of patients visited to our emergency department (ED) in a year. Asthmatic patients with acute exacerbations often visit an ED and asthma exacerbation is one of the common diseases encountered in ED. For this reason, we devoted effort to reduce ED visits by asthmatic patients through improving disease control by treatment intervention with inhaled corticosteroids (ICS) and patient education. ICS became common in middle of 1990s in Japan.

Aims and objectives: 

The purpose of this study was to examine the incidence of ED visits for asthma and their characteristics.

Methods: 

We reviewed retrospectively adult asthmatic patient visits to the ED of our hospital in 1992, 1999, 2002, 2008 and 2012.

Results: 

The number of whole ED visits has increased from 25,000 in 1992 to 46,000 in 2012. However there are significant changes in rates of ED visits with asthma exacerbations. In 1992, 302 patients visited ED 942 times (2.58 visits a day). In 2012, 123 patients visited ED 174 times (0.48 visits a day). That was 82% reduction from 1992. The number of frequent ED users also decreased from 126(41.7%) to 25(20.3%). On the other hand, the rate of regular ICS utilization of the patients visited to ED increased 61% to 89.5% from 1992 to 2012.

Conclusion: 

Emergency visits of adult asthmatic patients have steadily decreased over the past two decades. However, poor controlled asthma still remains. Additional interventions are needed for them.
Do probiotics prevent childhood illnesses?
Authors: C. A Wanke
Journal: BMJ (2001)

<h3>Abstract</h3> <h3>Background</h3> Tafenoquine is a newly licensed antimalarial drug for the radical cure of <i>Plasmodium vivax</i> malaria. The mechanism of action and the optimal dosing - a balance between haemolytic risk and radical cure efficacy - are uncertain. <h3>Methods</h3> We pooled individual data from 1102 patients with acute vivax malaria and 72 healthy volunteers (all with &gt;70% of the population median whole blood glucose-6-phosphate dehydrogenase [G6PD] activity) who were studied in the pre-registration trials of tafenoquine. Plasma tafenoquine concentrations were analysed under a population pharmacokinetic model. A series of Bayesian logistic and Emax dose-response models were fitted to the primary outcome of any <i>P. vivax</i> recurrence within 4 months. Acute vomiting and haemolysis were secondary outcomes. The key exposure variables were: the mg/kg tafenoquine dose; pharmacokinetic summaries of parent compound exposure (AUC<sub>[0,<i>∞</i>)</sub>, C<sub>max</sub>) and metabolism (terminal elimination half-life); and day 7 methaemoglobin concentration (%) as a measure of oxidative activity. <h3>Results</h3> Tafenoquine dose (mg/kg) was a major determinant of recurrence (odds ratio [OR]: 0.70 per mg/kg increase, 95% credible interval [CI]: 0.65-0.75). After adjustment for dose, the tafenoquine terminal elimination half-life (OR: 1.15 per day increase, 95% CI: 1.06-1.25), and the day 7 methaemoglobin concentration (OR: 0.81 per absolute percentage point increase, 95% CI: 0.65 to 0.99), but not the parent compound exposure, were also associated with recurrence. Under the Emax we estimate that the currently recommended 300mg dose in a 60kg adult (≈5mg/kg) results in approximately 70% of the maximal obtainable hypnozoiticidal effect. Increasing the dose to 7.5mg/kg (i.e. 450mg) would result in 90% reduction in the risk of <i>P. vivax</i> recurrence. Tafenoquine was well tolerated. No patients had severe haemolysis. Acute vomiting was not dose-related. In patients with normal G6PD enzyme concentrations, tafenoquine dose was associated with minor post-treatment haemoglobin reductions on days 2 or 3 (0.02 g/dL per mg/kg increase [95% CI: 0.04 to 0.00]). <h3>Conclusions and interpretation</h3> The currently recommended 300mg adult dose for radical cure of vivax malaria has suboptimal efficacy. Increasing to 450mg is predicted to increase radical cure rates substantially. The production of oxidative metabolites is central to tafenoquine’s hypnozoiticidal efficacy. Clinical trials of higher tafenoquine doses are now needed to characterise efficacy, safety and tolerability.
The National Inquiry into the Causes of our High Maternal Mortality Rate
Authors: T. W. Eden
Journal: BMJ (1929)

WHEN tlle decisioin of the Ministry of Health to set -up a National Coimmiiiittee to inivestigate thle c,auies of imaternlal leaths in Eniglanid and WVales was aii eounced I w-as one of thlose wilo were inclined to think that, excelt in On'e direction, nio v'er-y -definite results could be -anticipated from suchl an inquiry.It was clear that ani inquiry coii- duieted by the medical officers of health in thee districts for whichl they wereC r-esponsible 'miight r lestilt in imiproved organizationi and in a bettel Unde'rstanding oII the part of (loctors and midwvives of the assistance w-hielh tle -public matter.The Aberdeelt records sli0w that until quiito recenttlv in tlmat city praetieally omt5v the cases ivlicil tcirmtiitatedl fatally w-ere niotified, as is shown by time facte that time iuiumber of (leatlis roughlily equal'led the mutimber l3576J
A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients
Authors: Brandon W Higgs, Wei Zhu, Chris Morehouse, Wendy I White, Philip Brohawn, Xiang Guo, Marlon Rebelatto, Chenxiong Le, Anthony Amato, David Fiorentino, Steven A Greenberg, Jorn Drappa, Laura Richman, Warren Greth, Bahija Jallal, Yihong Yao
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure. <h3>Methods</h3> A phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab. <h3>Results</h3> The IFNGS was suppressed by a median of 53–66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle. <h3>Conclusions</h3> Sifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecule9s mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy.
BACTERIOSTATIC EFFECT OF HUMAN SERA ON GROUP A STREPTOCOCCI
Authors: Sidney Rothbard
Journal: The Journal of Experimental Medicine (1945)

1. Type-specific antibodies were demonstrated by the indirect bacteriostatic test in sera from human adults convalescing from group A streptococcal infection of the upper respiratory tract. The time of appearance of the antibodies varied from 3 to 5 weeks; and they persisted in 2 patients for at least 37 weeks after the onset of the infection. 2. The specificity of the antibody response in one serum was tested with strains of 7 heterologous types; in another, with 6; and in the third, with 2; but in no instance were cross-reactions observed. Moreover, each convalescent serum showed approximately equal bacteriostasis for 7 different strains of the same type as that which caused the infection. 3. The antibodies were specifically absorbed from the serum by homologous heat-killed streptococci, but not significantly by strains of heterologous types. 4. The specific M antigen of the streptococcal cell with its respective antibody, and not the T substance, appeared to be concerned in the reaction. 5. In spite of numerous technical difficulties inherent in the method, this bacteriostatic test provides a useful procedure for studying type-specific immunity in streptococcal infections.
Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib
Authors: I. Tamaskar, R. Bukowski, P. Elson, A.G. Ioachimescu, L. Wood, R. Dreicer, T. Mekhail, J. Garcia, B.I. Rini
Journal: Annals of Oncology (2007)
Comparative effects of cholestanol and cholesterol on hepatic sterol and bile acid metabolism in the rat.
Authors: S Shefer, S Hauser, G Salen, F G Zaki, J Bullock, E Salgado, J Shevitz
Journal: Journal of Clinical Investigation (1984)

Large amounts of cholestanol, the 5 alpha-dihydro derivative of cholesterol are found in tissues of patients with the rare inherited sterol storage disease cerebrotendinous xanthomatosis. Although small amounts of cholestanol are present in virtually every tissue of normal man, little is known about its metabolism and effect on cholesterol and bile acid formation. The purpose of this study is to investigate the absorption and metabolism of cholestanol and its early effects on hepatic morphology and on the rate-limiting enzymes of cholesterol and bile acid biosynthesis. After 2 wk on a diet supplemented with 2% cholestanol, total liver sterol content increased by 48% (3.26 vs. 2.20 mg/g), and resulted in a significant rise in hepatic cholestanol concentration to 1.4 mg/g. However, cholestanol was less efficiently absorbed from the intestine than cholesterol and interfered with cholesterol absorption. Furthermore, hepatic hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase activity rose 2.6-fold (from 150.3 to 397.0 pmol/mg per min) during cholestanol feeding, and was associated with a marked proliferation of the smooth endoplasmic reticulum of the centrilobular areas. In addition, significant amounts of allocholic acid (16%) and allochenodeoxycholic acid (5%) were formed from cholestanol and excreted in the bile. These results show that cholestanol is absorbed from the intestine, interferes with cholesterol absorption, and is deposited in the liver. However, in contrast to cholesterol, cholestanol feeding was associated with a marked elevation of HMG-CoA reductase activity. Thus, despite structural similarity between cholesterol and its 5 alpha-saturated derivative, cholestanol does not exert feedback inhibition on hepatic cholesterol biosynthesis.
Carbon Monoxide Induces Heme Oxygenase-1 via Activation of Protein Kinase R–Like Endoplasmic Reticulum Kinase and Inhibits Endothelial Cell Apoptosis Triggered by Endoplasmic Reticulum Stress
Authors: Ki Mo Kim, Hyun-Ock Pae, Min Zheng, Raekil Park, Young-Myeong Kim, Hun-Taeg Chung
Journal: Circulation Research (2007)

Carbon monoxide (CO), a reaction product of the cytoprotective heme oxygenase (HO)-1, is antiapoptotic in a variety of models of cellular injury, but the precise mechanisms remain to be established. In human umbilical vein endothelial cells, exogenous CO activated Nrf2 through the phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK), resulting in HO-1 expression. CO-induced activation of PERK was followed by the phosphorylation of eukaryotic translation initiation factor 2alpha and the expression of activating transcription factor 4. However, CO fails to induce X-box binding protein-1 expression and activating transcription factor 6 cleavage. CO had no significant effect on synthesis of endoplasmic reticulum (ER) chaperone proteins such as the 78-kDa glucose-regulated proteins 78 and 94. Instead, CO prevented X-box binding protein 1 expression and activating transcription factor 6 cleavage induced by ER-stress inducers such as thapsigargin, tunicamycin and homocysteine. CO also prevented endothelial apoptosis triggered by these ER inducers through suppression of C/EBP homologous protein expression, which was associated with its activation of p38 mitogen-activated protein kinase. Similarly, endogenous CO produced from endothelial HO-1 induced by either exogenous CO or a pharmacological inducer was also cytoprotective against ER stress through C/EBP homologous protein suppression. Our findings suggest that CO renders endothelial cells resistant to ER stress not only by downregulating C/EBP homologous protein expression via p38 mitogen-activated protein kinase activation but also by upregulating Nrf2-dependent HO-1 expression via PERK activation. Thus, the HO-1/CO system might be potential therapeutics in vascular diseases associated with ER stress.
Dietary Sodium Content, Mortality, and Risk for Cardiovascular Events in Older Adults
Authors: Andreas P. Kalogeropoulos, Vasiliki V. Georgiopoulou, Rachel A. Murphy, Anne B. Newman, Douglas C. Bauer, Tamara B. Harris, Zhou Yang, William B. Applegate, Stephen B. Kritchevsky
Journal: JAMA Internal Medicine (2015)

Additional information is needed about the role of dietary sodium on health outcomes in older adults.To examine the association between dietary sodium intake and mortality, incident cardiovascular disease (CVD), and incident heart failure (HF) in older adults.We analyzed 10-year follow-up data from 2642 older adults (age range, 71-80 years) participating in a community-based, prospective cohort study (inception between April 1, 1997, and July 31, 1998).Dietary sodium intake at baseline was assessed by a food frequency questionnaire. We examined sodium intake as a continuous variable and as a categorical variable at the following levels: less than 1500 mg/d (291 participants [11.0%]), 1500 to 2300 mg/d (779 participants [29.5%]), and greater than 2300 mg/d (1572 participants [59.5%]).Adjudicated death, incident CVD, and incident HF during 10 follow-up years. Analysis of incident CVD was restricted to 1981 participants without prevalent CVD at baseline.The mean (SD) age of participants was 73.6 (2.9) years, 51.2% were female, 61.7% were of white race, and 38.3% were black. After 10 years, 881 participants had died, 572 had developed CVD, and 398 had developed HF. In adjusted Cox proportional hazards regression models, sodium intake was not associated with mortality (hazard ratio [HR] per 1 g, 1.03; 95% CI, 0.98-1.09; P = .27). Ten-year mortality was nonsignificantly lower in the group receiving 1500 to 2300 mg/d (30.7%) than in the group receiving less than 1500 mg/d (33.8%) and the group receiving greater than 2300 mg/d (35.2%) (P = .07). Sodium intake of greater than 2300 mg/d was associated with nonsignificantly higher mortality in adjusted models (HR vs 1500-2300 mg/d, 1.15; 95% CI, 0.99-1.35; P = .07). Indexing sodium intake for caloric intake and body mass index did not materially affect the results. Adjusted HRs for mortality were 1.20 (95% CI, 0.93-1.54; P = .16) per milligram per kilocalorie and 1.11 (95% CI, 0.96-1.28; P = .17) per 100 mg/kg/m2 of daily sodium intake. In adjusted models accounting for the competing risk for death, sodium intake was not associated with risk for CVD (subHR per 1 g, 1.03; 95% CI, 0.95-1.11; P = .47) or HF (subHR per 1 g, 1.00; 95% CI, 0.92-1.08; P = .92). No consistent interactions with sex, race, or hypertensive status were observed for any outcome.In older adults, food frequency questionnaire-assessed sodium intake was not associated with 10-year mortality, incident CVD, or incident HF, and consuming greater than 2300 mg/d of sodium was associated with nonsignificantly higher mortality in adjusted models.
Hip Fracture
Authors: Fred C. Ko, R. Sean Morrison
Journal: JAMA Internal Medicine (2014)

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Activity of the Kinesin Spindle Protein Inhibitor Ispinesib (SB-715992) in Models of Breast Cancer
Authors: James W. Purcell, Jefferson Davis, Mamatha Reddy, Shamra Martin, Kimberly Samayoa, Hung Vo, Karen Thomsen, Peter Bean, Wen Lin Kuo, Safiyyah Ziyad, Jessica Billig, Heidi S. Feiler, Joe W. Gray, Kenneth W. Wood, Sylvaine Cases
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein, a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have shown a 9% response rate in patients with locally advanced or metastatic breast cancer and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities, or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer, we explored the activity of ispinesib alone and in combination with several therapies approved for the treatment of breast cancer. Experimental Design: We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo and tested the ability of ispinesib to enhance the antitumor activity of approved therapies. Results: In vitro, ispinesib displayed broad antiproliferative activity against a panel of 53 breast cell lines. In vivo, ispinesib produced regressions in each of five breast cancer models and tumor-free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the antitumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine and exhibited activity comparable with paclitaxel and ixabepilone. Conclusions: These findings support further clinical exploration of kinesin spindle protein inhibitors for the treatment of breast cancer. Clin Cancer Res; 16(2); 566–76