tbuckley/cabot-search huggingface dataset:
Halofuginone Ameliorates Autoimmune Arthritis in Mice by Regulating the Balance Between Th17 and Treg Cells and Inhibiting Osteoclastogenesis
Authors: Mi‐Kyung Park, Jin‐Sil Park, Eun‐Mi Park, Mi‐Ae Lim, Sung‐Min Kim, Dong‐Gun Lee, Seung‐Ye Baek, Eun‐Ji Yang, Jung‐Won Woo, Jennifer Lee, Seung‐Ki Kwok, Ho‐Youn Kim, Mi‐La Cho, Sung‐Hwan Park
Journal: Arthritis & Rheumatology (2013)

Objective The small molecule halofuginone has been shown to inhibit fibrosis, angiogenesis, and tumor progression. This study was undertaken to evaluate the effects of halofuginone in preventing autoimmune arthritis in mice. Methods The effects of halofuginone on joint diseases were assessed by clinical scoring and histologic analysis. Protein expression levels were confirmed by immunohistochemistry, enzyme‐linked immunosorbent assay, flow cytometry, and/or Western blotting. The expression levels of messenger RNA (mRNA) for various molecules were determined by real‐time polymerase chain reaction (PCR). Proliferation of osteoclast precursors was assessed by bromodeoxyuridine uptake. Osteoclast differentiation and activity were determined by quantifying tartrate‐resistant acid phosphatase (TRAP)–positive multinucleated cells and area of resorbed bone. Results Treatment with halofuginone suppressed the development of autoimmune arthritis and reciprocally regulated Th17 cells and FoxP3+ Treg cells. These effects of halofuginone on Th17 differentiation involved increased signaling of ERK and reduction of STAT‐3 and NF‐ATc1 expression. Furthermore, halofuginone induced the expression of indoleamine 2,3‐dioxygenase (IDO) in dendritic cells, leading to reduced production of Th17 cells. In addition, halofuginone prevented the formation and activity of osteoclasts through suppression of transcription factors, such as activator protein 1 and NF‐ATc1, and inhibited cell cycle arrest by the committed osteoclast precursors via expression of Ccnd1 encoding cyclin D1. Conclusion Taken together, our results suggest that halofuginone is a promising therapeutic agent for the treatment of Th17 cell–mediated inflammatory diseases and bone diseases.
Studies on the Mechanism of Ristocetin-Induced Platelet Agglutination
Authors: Barry S. Coller, Harvey R. Gralnick
Journal: Journal of Clinical Investigation (1977)

The mechanism by which ristocetin induces platelet agglutination in the presence of the von Willebrand factor was studied by chemically altering ristocetin and a similar antibiotic, vancomycin, by reaction with a water-soluble carbodiimide in the presence of glycine methyl ester at pH 4.75. Altering ristocetin's phenolic groups (which are thought to be important in its peptide-binding properties) resulted in a loss of both platelet-agglutinating and antibiotic activities. Restoring the phenolic groups with hydroxylamine restored both activities. Vancomycin has antibiotic and peptide-binding properties similar to ristocetin's, but differs structurally in having a free carboxyl group and thus a less positive charge at neutral pH. It does not induce platelet agglutination and actually inhibits ristocetin-induced agglutination. Reacting vancomycin with the water-soluble carbodiimide resulted in alteration of phenolic groups and permanent conversion of the carboxyl to a neutral derivative. Restoring the phenolic groups with hydroxylamine (but leaving the carboxyl neutralized) produced a compound with charge properties similar to ristocetin's which induced platelet agglutination as ristocetin does. These data suggest both a binding requirement (mediated through phenolic groups) and a strong positive charge requirement for ristocetin-induced agglutination. The data are consistent with a model wherein positively charged ristocetin binds, via its phenolic groups, to sites on the platelet surface and reduces the platelet's negative charge. This could reduce the electrostatic repulsion between platelets and/or between platelets and the negatively charged von Willebrand factor, and permit the macromolecular von Willebrand factor to cause agglutination by bridging between platelets.
Over-salting ruins the balance of the immune menu
Authors: Booki Min, Robert L. Fairchild
Journal: Journal of Clinical Investigation (2015)

Regulatory components of the immune system are critical for preventing unintended activation of immune cells. Failure to prevent this unintended activation raises the risk of developing exaggerated inflammation and autoimmunity. In this issue of the JCI, Binger et al. and Hernandez et al. report that salt can play an important role in undermining regulatory mechanisms of the innate and adaptive immune systems. High salt levels interfere with alternative activation of macrophages (M2), which function in attenuating tissue inflammation and promoting wound healing. High salt also impairs Treg function by inducing IFNγ production in these cells. Together, these results provide evidence that environmental signals in the presence of high dietary salt enhance proinflammatory responses by interfering with both innate and adaptive regulatory mechanisms.
Patiromer induces rapid and sustained potassium lowering in patients with chronic kidney disease and hyperkalemia
Authors: David A. Bushinsky, Gordon H. Williams, Bertram Pitt, Matthew R. Weir, Mason W. Freeman, Dahlia Garza, Yuri Stasiv, Elizabeth Li, Lance Berman, George L. Bakris
Journal: Kidney International (2015)

Patients with chronic kidney disease (CKD) have a high risk of hyperkalemia, which increases mortality and can lead to renin-angiotensin-aldosterone system inhibitor (RAASi) dose reduction or discontinuation. Patiromer, a nonabsorbed potassium binder, has been shown to normalize serum potassium in patients with CKD and hyperkalemia on RAASi. Here, patiromer's onset of action was determined in patients with CKD and hyperkalemia taking at least one RAASi. After a 3-day potassium- and sodium-restricted diet in an inpatient research unit, those with sustained hyperkalemia (serum potassium 5.5 - under 6.5 mEq/l) received patiromer 8.4 g/dose with morning and evening meals for a total of four doses. Serum potassium was assessed at baseline (0 h), 4 h postdose, then every 2-4 h to 48 h, at 58 h, and during outpatient follow-up. Mean baseline serum potassium was 5.93 mEq/l and was significantly reduced by 7 h after the first dose and at all subsequent times through 48 h. Significantly, mean serum potassium under 5.5 mEq/l was achieved within 20 h. At 48 h (14 h after last dose), there was a significant mean reduction of 0.75 mEq/l. Serum potassium did not increase before the next dose or for 24 h after the last dose. Patiromer was well tolerated, without serious adverse events and no withdrawals. The most common gastrointestinal adverse event was mild constipation in two patients. No hypokalemia (serum potassium under 3.5 mEq/l) was observed. Thus, patiromer induced an early and sustained reduction in serum potassium and was well tolerated in patients with CKD and sustained hyperkalemia on RAASis.
Bacterial colonisation/infection and airway inflammation in preschool children with recurrent wheeze
Authors: Kim D.G. van de Kant, Ester M.M. Klaassen, Koen van Aerde, Cathrien Bruggeman, Foekje Stelma, Ellen Stobberingh, Ger T. Rijkers, Jean W.M. Muris, Quirijn Jobsis, Onno C.P. van Schayck, Edward Dompeling
Journal: European Respiratory Journal (2011)

Background: Wheeze is a common symptom in preschool children. The role of bacteria in preschool wheeze and their possible association with airway inflammation is largely unknown.

Aims: 

Methods: We recruited 252 children (aged 2-4 years) with (n=202) and without (n=50) recurrent wheeze. Nasal and throat swabs were analysed for the presence of Streptococcus (S.) pneumoniae and Haemophilus (H.) influenzae . Serology for Chlamydia (C.) and Mycoplasma (M.) pneumoniae was assessed. EBC was collected using a closed-glass condenser. Inflammatory markers ((Interleukin (IL)-4, IL-8, IL-13) in EBC were measured using multiplex immunoassay.

Results: Only positive serology for M. pneumonia was slightly higher in children with recurrent wheeze compared with healthy controls (11% vs. 2%, p=0.09). Wheezing children colonised with H. influenzae (N=61) had higher levels of all interleukins compared with colonised children without recurrent wheeze (N=15) (p<0.05).

Conclusion: We found no convincing evidence for an association between bacterial colonisation/infection and preschool recurrent wheeze. Airway colonisation with H. influenzae leads to elevated pro-inflammatory markers in recurrent wheezers, indicating augmented airway inflammation in these children.
Crizotinib as Salvage and Maintenance With Allogeneic Stem Cell Transplantation for Refractory Anaplastic Large Cell Lymphoma
Authors: James M. Cleary, Scott Rodig, Paul M. Barr, Atul B. Shinagare, Jeffrey W. Clark, Geoffrey I. Shapiro, Philippe Armand
Journal: Journal of the National Comprehensive Cancer Network (2014)

The NPM-ALK fusion protein is found in ALK+ anaplastic large cell lymphomas harboring the t(2;5) chromosomal translocation. Patients harboring ALK translocations typically have an excellent prognosis with conventional chemotherapy and a reported 5-year survival rate of 70%. Although most patients with ALK+ anaplastic large cell lymphoma have a good prognosis, some patients do not respond to standard therapies. In patients with refractory anaplastic large cell lymphoma who can achieve remission, allogeneic stem cell transplant is a potentially curative option. This article describes a patient with refractory ALK+ anaplastic large cell lymphoma who experienced a complete response to the ALK inhibitor crizotinib and then underwent an allogeneic stem cell transplant followed by crizotinib maintenance therapy.
Cardiac Energetics in Congestive Heart Failure
Authors: Houman Ashrafian
Journal: Circulation (2002)

failure rats were undoubtedly in decompensated failure because, as a consequence of reduced velocity of shortening of the left ventricle and high end diastolic pressure, they had severe lung congestion.However, it remains to be seen whether MCT1 upregulation is a general feature of end stage heart failure irrespective of cause.
Quantification of sleep disordered breathing by computerized analysis of oximetry, heart rate and snoring
Authors: H Rauscher, W Popp, H Zwick
Journal: European Respiratory Journal (1991)

Intermittent snoring and cyclic oscillations of heart rate and oxyhaemoglobin saturation (Sao2) are characteristic features of the obstructive sleep apnoea syndrome (OSAS). Thus, overnight recordings of laryngeal sounds and heart rate by a portable device (MESAM) and of Sao2 by oximetry are applicable to screen outpatients for the presence of OSAS. Computerized analysis for time intervals of constant heart rate and intervals between snoring sounds is used by MESAM to quantify respiratory disturbances during sleep. Rapid increases in Sao2 during the postapnoeic hyperventilation period together with the number of desaturations are used by a new software for quantitative analysis of oximetry. To elucidate reliability of results from automatically scored MESAM and oximetry recordings, we compared the four computer calculated respiratory disturbance indices from heart rate (RDIH), snoring (RDIS), resaturations (RDIR) and desaturations (RDID) with the apnoea plus hypopnoea index (AHI) from simultaneously performed polysomnography. The study population consisted of 53 snorers with an AHI of 19.0 +/- 2.6 (median +/- SEM; range 0.7-87.8). Whereas both RDI's from MESAM correlated rather weakly with the AHI from polysomnography (RDIH: r = 0.32, p less than 0.05; RDIS: r = 0.33, p less than 0.05), this correlation was much better for the RDI's from oximetry (RDIR: r = 0.951, RDID: r = 0.93; p much less than 0.0001). Accepting a plus/minus 30 percent difference from the AHI, the RDIR classified 77% of patients correctly, the RDID 62%, the RDIS 32% and the RDIH 23%. In conclusion, results from computerized analysis of oximetry for desaturations and rapid resaturations correlate more closely with polysomnography than those from automatic scoring of MESAM recordings.
Usefulness of serum anti-glycopeptidolipid core IgA antibody assay for the diagnosis of pulmonary infection of mycobacterium avium complex
Authors: Sayaka Arakawa, Akira Yokoyama, Yuki Shinno, Kota Itahashi, Asae Kamiyama, Masaki Kawakami, Masaru Suzuki, Yoshio Sakamoto
Journal: European Respiratory Journal (2014)

Background: The number of patients with mycobacterium avium complex(MAC)-pulmonary disease is increasing world-widely. As it is sometimes difficult to detect the organism in specimens obtained from respiratory tract, not a few patients remain suspicious MAC-pulmonary disease in spite of typical radiographycal findings on chest X-ray and CT. Serum IgA class antibody(Ab) raised against MAChas been developed for an alternative method to diagnose MAC infection, but it still needs to be validated.  Purpose: We measured anti-GPL core Abs in patients who had been followed in the outpatient clinic of Kanto Central Hospital with diagnosis of definite or suspicious MAC-pulmonary disease and its usefulness was evaluated.  Methods: Anti-GPL core IgA Abs were assayed by ELISA kits. The cut-off value was set at 0.5 U/ml. Serum levels were measured in 92 patients(definite 45, and suspicious 47; 82(89%) females, and aged from 32 to 87 years). Anti-MAC therapy was administered in 21(47%) out or 45 definite cases.  Results: Serum Ab levels were elevated in 72(78%) of 92 patients; 42(93%) out of 45 definite cases, and 32(68%) out of 47 suspicious cases. The Ab levels were elevated in 19(91%) out of 21 patients who received anti-MAC therapy.  Conclusion: Measurement of serum anti-GPL core IgA Abs seems useful for the diagnosis of MAC-pulmonary disease in patients in whom the detection of the organism was unsuccessful or difficult. It may also provide information for the decision making of administration of anti-MAC microbial therapy.
Octreotide for cirrhosis after variceal bleeding
Authors: D Patch, A. Burroughs, R. Sutton
Journal: BMJ (1998)

Editor—The conclusion drawn by Jenkins et al is that octreotide improves liver function, lowers portal pressure, and protects against variceal rebleeding.1 The paper, however, does not justify this conclusion. 

Firstly, the number of patients is too small. The authors state that as long term octreotide had not been used previously in patients with cirrhosis there were no data from which to perform a power calculation. This is incorrect. Primignani et al showed no difference when subcutaneous octreotide or placebo was added for 29 days to sclerotherapy in the prevention of variceal rebleeding in 58 patients.2 In addition, there is a wealth of data that suggest that sclerotherapy reduces the incidence of variceal rebleeding to 50% at one year. The authors could have expected, at best, an additional reduction of 20% with octreotide. Using a β of 20% and an α of 5%, a trial of 193 patients with 77 events would be required, assuming no withdrawals and a two tailed analysis.3 Jenkins et al’s trial is open to a type 2 error. 

Secondly, in a trial predominantly of patients with cirrhosis of an alcoholic aetiology (23/32), no information is given on the number of patients who became abstinent. Patients who are motivated to inject themselves twice a day with octreotide are also likely to be the type of patients who stop drinking. Abstinence is the single most predictive factor for a long term fall in wedge hepatic venous pressure (a marker of portal pressure) and protection against further variceal bleeding.4,5

On the basis of these points alone, the paper by Jenkins et al does not provide any evidence for a change in clinical practice.
Decreased expression of neuropilin-1 as a novel key factor contributing to peripheral microvasculopathy and defective angiogenesis in systemic sclerosis
Authors: Eloisa Romano, Inês Chora, Mirko Manetti, Celestina Mazzotta, Irene Rosa, Silvia Bellando-Randone, Jelena Blagojevic, Raquel Soares, Jerôme Avouac, Yannick Allanore, Lidia Ibba-Manneschi, Marco Matucci-Cerinic, Serena Guiducci
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> In systemic sclerosis (SSc), vascular involvement is characterised by vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR) system disturbances. Neuropilin-1 (NRP1), a receptor for both class-3 semaphorins (Sema3s) and VEGF-A, is required for optimal VEGF-A/VEGFR-2 signalling. Here, we investigated the possible involvement of Sema3A/NRP1 axis in SSc. <h3>Methods</h3> Circulating Sema3A and soluble NRP1 (sNRP1) were measured in patients with SSc and controls. NRP1 and Sema3A expression in skin biopsies was evaluated by immunofluorescence and western blotting. NRP1 expression was assessed in SSc and healthy dermal microvascular endothelial cells (SSc-MVECs and H-MVECs), and in SSc and control endothelial progenitor cell (EPC)-derived endothelial cells (ECs). The possible impact of transcription factor Friend leukaemia integration 1 (Fli1) deficiency on endothelial NRP1 expression was investigated by gene silencing. The binding of Fli1 to NRP1 gene promoter was evaluated using chromatin immunoprecipitation. Capillary morphogenesis was performed on Matrigel. <h3>Results</h3> Decreased sNRP1 levels in SSc were associated with active and late nailfold videocapillaroscopy patterns and digital ulcers. No difference in Sema3A was found between patients and controls. NRP1 was significantly decreased in SSc-MVECs both ex vivo and in vitro. NRP1 and Fli1 significantly decreased in H-MVECs challenged with SSc sera, while they were not different in SSc and control EPC-derived ECs. Fli1 occupied the NRP1 gene promoter and Fli1 gene silencing reduced NRP1 expression in H-MVECs. NRP1 gene silencing in H-MVECs resulted in a significantly impaired angiogenic capacity comparable to that of cells treated with SSc sera. <h3>Conclusion</h3> In SSc, NRP1 deficiency may be an additional factor in the perturbed VEGF-A/VEGFR-2 system contributing to peripheral microvasculopathy and defective angiogenesis.
Comparative study of respiratory symptoms, lung function, BMI and exercise capacity in patients with COPD associated with tobacco smoke (TS) and biomass smoke (BS) exposure
Authors: Lalita Fernandes, Anthony Mesquita
Journal: European Respiratory Journal (2012)

Background : COPD is the 4th leading cause of death and is expected to be 3rd by 2030. Tobacco smoke and indoor air pollution are the major risk factors for COPD. While there are large number of studies on tobacco smoke and COPD, there is paucity of data on biomass smoke and COPD. It is not clear whether this phenotype of COPD is different or similar to COPD caused by tobacco smoke.   Aim : To compare the clinical symptoms, lung function, BMI and 6MWD (exercise capacity) in TS-COPD and BS-COPD.   Methods : We prospectively evaluated 103 stable COPD patients from the outpatient clinic. COPD was diagnosed by GOLD guidelines (post bronchodilator FEV1/FVC    Results :   There were 75(TS-COPD) and 28(BS-COPD) patients with mean age of 63.39(8.87) and 60.04(7.57) respectively. Females (92.85%) dominated the biomass group while 97.3% males were in the tobacco smoking group.TS-COPD presented with wheeze(24%) as compared to 3.6% in BS COPD(p=0.017). There was no difference in clinical symptoms of cough and dyspnea in both groups. Severity of disease, BMI and exercise capacity showed no statistical difference in both groups.   Conclusions : Our results confirmed that BS-COPD and TS-COPD have similar clinical characteristics.
Strategy and implementation documents were published to improve outcomes in COPD and asthma in England
Authors: Sue Hill, Joanna Clarke, Kevin Holton, Robert Winter, Anne Moger, Matt Kearney
Journal: European Respiratory Journal (2012)

Rationale   Despite three million people estimated to have COPD in the UK, only 900,000 currently have a diagnosis. Variation in care and outcomes is significant. Action was required to move from a reactionary service, treating those with moderate to severe disease, to prevention, earlier diagnosis and pro-active management.   Methods   A systematic evidence review was undertaken with the engagement of a range of healthcare professionals from primary and secondary care. Following wide consultation, consensus was reached on six high-level objectives to improve outcomes for patients which would require a collaborative approach involving public health, health and social care services.   Results   An Outcomes Strategy for COPD and Asthma was published in July 2011. This was accompanied by an implementation document specifically for the health service, which set out in more detail the actions to help meet the objectives.  A baseline dataset of indicators for measuring and monitoring outcomes for improvements in the respiratory care have been established and benchmarking data produced to assess variation in models of service provision across England. This dataset is responsive to change at all levels of the provider system from local through to national and helps to identify areas and particular aspects of care for local action.   Conclusion   Through the Outcomes Strategy for COPD and Asthma, the NHS implementation document that accompanies it, and the regional clinical leadership, care and outcomes for COPD are improving through a shift in the burden of the disease to prevention, diagnosis and proactive management.
A phase I clinical, plasma, and cellular pharmacology study of gemcitabine.
Authors: J L Abbruzzese, R Grunewald, E A Weeks, D Gravel, T Adams, B Nowak, S Mineishi, P Tarassoff, W Satterlee, M N Raber
Journal: Journal of Clinical Oncology (1991)

A novel deoxycytidine analog, gemcitabine (2',2'-difluorodeoxycytidine [dFdC]), has been studied in a phase I clinical and pharmacology trial. Doses ranging from 10 to 1,000 mg/m2 were administered over 30 minutes weekly times 3 weeks every 4 weeks. The maximum-tolerated dose (MTD) was 790 mg/m2. The dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocytopenia. Nonhematologic toxicity was minimal. Two responses in patients with adenocarcinomas of the colon and lung were documented. The maximum dFdC plasma concentration, reached after 15 minutes of infusion, was proportional to the total dose administered. Elimination, due mainly to deamination, was rapid (terminal half-life [t1/2], 8.0 minutes) and dose independent. The deamination product 2',2'-difluorodeoxyuridine (dFdU) was eliminated with biphasic kinetics characterized by a long terminal phase (t1/2, 14 hours); it was the sole metabolite detected in urine. The concentration of dFdC 5'-triphosphate in circulating mononuclear cells increased in proportion to the dFdC dose at infusions between 35 and 250 mg/m2. No further increment in dFdC 5'-triphosphate (dFdCTP) was observed at higher doses, which resulted in plasma dFdC concentrations greater than 20 mumol/L (350 to 1,000 mg/m2), suggesting saturation of dFdC 5'-phosphate accumulation. The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk.