tbuckley/cabot-search huggingface dataset:
Role of miR-146a in regulation of the acute inflammatory response to monosodium urate crystals
Authors: Nicola Dalbeth, Bregina Pool, Odette M Shaw, Jacquie L Harper, Paul Tan, Christopher Franklin, Meaghan E House, Jillian Cornish, Dorit Naot
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> MicroRNAs (miRNA) are small non-coding RNAs that function as post-transcriptional repressors of gene expression. We hypothesised that miRNA regulate gene expression of proinflammatory cytokines in response to monosodium urate (MSU) crystals. <h3>Methods</h3> We stimulated human monocytic THP-1 cells with MSU crystals and examined miRNA and proinflammatory cytokine gene expression. The effects of miR-146a overexpression were examined by transfecting THP-1 cells with miR-146a precursor. miR-146a expression was examined in the urate peritonitis model, in peripheral blood mononuclear cells from people with gout and control participants, and in gouty tophus samples. <h3>Results</h3> MSU crystals increased miR-146a expression in THP-1 cells, but not other miRNA implicated in interleukin (IL)-1β regulation. Overexpression of miR-146a expression reduced MSU crystal-induced IL-1β, tumour necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and IL-8 gene expression. In the urate peritonitis model, reduced miR-146a expression was observed during the acute inflammatory response to MSU crystal injection. In people with intercritical gout, peripheral blood mononuclear cells expressed significantly higher levels of miR-146a, compared with normouricaemic and hyperuricaemic control participants and those with acute gout flares. Expression of miR-146a was also observed in all tophus samples. <h3>Conclusions</h3> Collectively, these data suggest that miR-146a is a transcriptional brake that is lost during the acute inflammatory response to MSU crystals.
Matrix metalloproteinases and their inhibitors in pulmonary hypertension
Authors: Prakash Chelladurai, Werner Seeger, Soni Savai Pullamsetti
Journal: European Respiratory Journal (2012)

Pulmonary hypertension (PH) is a severe and progressive disease characterised by high pulmonary artery pressure, usually culminating in right heart failure. Current therapeutic approaches in PH largely provide symptomatic relief while the prognosis rate is lower due to the lack of specific molecular targets and the involvement of several factors in the development of PH. Numerous studies have suggested a crucial role of matrix metalloproteinase (MMP) axis during development and disease states, specifically with regard to extracellular matrix remodelling and vascular homeostasis. Increased MMP activity has been demonstrated in experimental animal models of PH, and MMP inhibition has been shown to either attenuate or enhance vascular remodelling. Moreover, several studies emphasise that restoration of deregulated MMPs to physiological MMP/tissue inhibitor of MMPs ratios would potentiate reverse remodelling in PH. This article will highlight the pathophysiological role of MMPs in vascular remodelling and the establishment of PH. In particular, we will focus on the MMP expression and regulation in pulmonary vasculature and pulmonary vascular remodelling. We will also provide an overview of recent clinical and experimental findings and their impact on achieving maximum reversal of PH, as well as current issues and future perspectives.
Isometric exercise induces analgesia and reduces inhibition in patellar tendinopathy
Authors: Ebonie Rio, Dawson Kidgell, Craig Purdam, Jamie Gaida, G Lorimer Moseley, Alan J Pearce, Jill Cook
Journal: British Journal of Sports Medicine (2015)

Background Few interventions reduce patellar tendinopathy (PT) pain in the short term. Eccentric exercises are painful and have limited effectiveness during the competitive season. Isometric and isotonic muscle contractions may have an immediate effect on PT pain. Methods This single-blinded, randomised cross-over study compared immediate and 45 min effects following a bout of isometric and isotonic muscle contractions. Outcome measures were PT pain during the single-leg decline squat (SLDS, 0–10), quadriceps strength on maximal voluntary isometric contraction (MVIC), and measures of corticospinal excitability and inhibition. Data were analysed using a split-plot in time-repeated measures analysis of variance (ANOVA). Results 6 volleyball players with PT participated. Condition effects were detected with greater pain relief immediately from isometric contractions: isometric contractions reduced SLDS (mean±SD) from 7.0±2.04 to 0.17±0.41, and isotonic contractions reduced SLDS (mean±SD) from 6.33±2.80 to 3.75±3.28 (p&lt;0.001). Isometric contractions released cortical inhibition (ratio mean±SD) from 27.53%±8.30 to 54.95%±5.47, but isotonic contractions had no significant effect on inhibition (pre 30.26±3.89, post 31.92±4.67; p=0.004). Condition by time analysis showed pain reduction was sustained at 45 min postisometric but not isotonic condition (p&lt;0.001). The mean reduction in pain scores postisometric was 6.8/10 compared with 2.6/10 postisotonic. MVIC increased significantly following the isometric condition by 18.7±7.8%, and was significantly higher than baseline (p&lt;0.001) and isotonic condition (p&lt;0.001), and at 45 min (p&lt;0.001). Conclusions A single resistance training bout of isometric contractions reduced tendon pain immediately for at least 45 min postintervention and increased MVIC. The reduction in pain was paralleled by a reduction in cortical inhibition, providing insight into potential mechanisms. Isometric contractions can be completed without pain for people with PT. The clinical implications are that isometric muscle contractions may be used to reduce pain in people with PT without a reduction in muscle strength.
Matrix Metalloproteinase 12 Overexpression in Lung Epithelial Cells Plays a Key Role in Emphysema to Lung Bronchioalveolar Adenocarcinoma Transition
Authors: Peng Qu, Hong Du, Xi Wang, Cong Yan
Journal: Cancer Research (2009)

Chronic obstructive pulmonary disease (COPD) and lung cancer are two diseases that are related to smoking in humans. The molecular mechanism linking these two diseases is poorly understood. Matrix metalloproteinase 12 (MMP12) is a member of the MMP family, which can be induced by smoking. Because MMP12 overexpression in epithelial cells has been reported in inflammation-triggered lung remodeling, a murine CCSP-rtTA/(tetO)(7)-MMP12 bitransgenic model was created. In this model, MMP12-Flag fusion protein overexpression and its increased enzymatic activity were observed in the lung in an inducible manner, which led to inflammatory cell infiltration and increased epithelial growth. In sequential events, spontaneous emphysema and bronchioalveolar adenocarcinoma were developed as a result of MMP12 overexpression. During this process, the concentration of interleukin-6 was steadily increased in bronchioalveolar lavage fluid, which activated the oncogenic signal transducer and activator of transcription 3 (Stat3) in alveolar type II epithelial cells. Expression of Stat3 downstream genes that are known to stimulate inflammation and tumor formation was significantly increased in the lung. When tested in humans, MMP12 up-regulation was highly associated with COPD and lung cancer in patients. Together, these studies support that MMP12 is a potent proinflammatory and oncogenic molecule. MMP12 up-regulation plays a critical role in emphysema to lung cancer transition that is facilitated by inflammation.
Psychogenic Rheumatism: The Musculoskeletal Expression of Psychoneurosis
Authors: E. W. Boland
Journal: Annals of the Rheumatic Diseases (1947)

A patient with systemic lupus erythematosus who developed reactive amyloidosis associated with high levels of serum amyloid-A protein (SAA) is reported. The possible relevance of elevated SAA levels in the aetiology of amyloidosis is discussed.
Challenges in pulmonary fibrosis {middle dot} 5: The NSIP/UIP debate
Authors: R. du Bois, T. E King
Journal: Thorax (2007)

Among the idiopathic interstitial pneumonias, the two entities—idiopathic pulmonary fibrosis (IPF) characterised by the presence of the usual interstitial pneumonia pattern of histopathology (IPF/UIP) and non-specific interstitial pneumonia (NSIP; same nomenclature for the histopathological pattern and idiopathic disease)—have provoked considerable debate. IPF/UIP and NSIP closely mimic each other clinically but NSIP has a far better outcome. However, it remains unclear if NSIP is a truly separate and distinct entity. The histopathological pattern of NSIP can be found in a wide variety of clinical and radiological contexts. This review addresses these and other uncertainties regarding NSIP and UIP.
One-Year Glycemic Control With a Sulfonylurea Plus Pioglitazone Versus a Sulfonylurea Plus Metformin in Patients With Type 2 Diabetes
Authors: Markolf Hanefeld, Paolo Brunetti, Guntram H. Schernthaner, David R. Matthews, Bernard H. Charbonnel
Journal: Diabetes Care (2004)

OBJECTIVE—The goal was to assess the 1-year efficacy and safety of the addition of pioglitazone or metformin to existing sulfonylurea (SU) therapy in patients with inadequately controlled type 2 diabetes. RESEARCH DESIGN AND METHODS—In this multicenter, double-blind study, patients were randomized to receive either pioglitazone 15 mg (n = 319) or metformin 850 mg (n = 320) and up to 45 mg/day and 2,550 mg/day, respectively. The primary efficacy endpoint was HbA1c at week 52. Fasting plasma glucose, insulin, and lipid profiles were also measured. RESULTS—HbA1c was reduced by 1.20% in the SU plus pioglitazone group and 1.36% in the SU plus metformin group, and fasting plasma glucose was reduced by 2.2 and 2.3 mmol/l in the respective groups. Fasting insulin levels were also reduced (pioglitazone arm −1.3 μIU/ml; metformin arm −0.8 μIU/ml). There were no significant between-treatment differences in these three parameters. Pioglitazone addition to SU significantly reduced triglycerides (−16 vs. −9%; P = 0.008) and increased HDL cholesterol (14 vs. 8%; P &amp;lt; 0.001) compared with metformin addition. LDL cholesterol was increased 2% by the addition of pioglitazone and decreased 5% by the addition of metformin to SU (P &amp;lt; 0.001). Urinary albumin-to-creatinine ratio was reduced by 15% in the SU plus pioglitazone group and increased 2% in the SU plus metformin group (P = 0.017). Both combinations were well tolerated with no evidence of hepatic or cardiac toxicity in either group. CONCLUSIONS—Clinically equivalent improvements in glycemic control were observed for both combinations. Compared with metformin plus SU, addition of pioglitazone to SU resulted in a reduction of the urinary albumin-to-creatinine ratio, a small but significant rise in LDL cholesterol, and significantly greater improvements in triglyceride levels and HDL cholesterol levels. Metformin plus SU was associated with a significant reduction in LDL cholesterol. SU plus pioglitazone is an effective and well-tolerated combination regimen that may provide additional beneficial effects for patients with type 2 diabetes.
Amino acids at the site of V kappa-J kappa recombination not encoded by germline sequences.
Authors: M Heller, J D Owens, J F Mushinski, S Rudikoff
Journal: The Journal of Experimental Medicine (1987)

Murine V kappa-J kappa recombination is characterized by a maintenance of size at the site of recombination and the use of nucleic acids found only in germline sequences. This is in contrast to heavy chain VH-D-JH assembly where random nucleotides are added at the recombination sites to produce considerable size variation, even though the heptamer/nonomer recombination sequences are identical in both kappa and heavy chain genes. We have examined the origin of an unusual amino acid, Ile, found at the site of V kappa-J kappa recombination in antigalactan antibodies, by sequence analysis of the corresponding rearranged and germline genes. Results indicate that the Ile codon can be generated by use of a single nucleotide 3' of the V kappa segment in combination with the second and third nucleotides of the first codon of J kappa 5 or J kappa 4. However, several antigalactan antibodies express Ile in combination with J kappa 2. An Ile codon cannot be generated by recombination in any reading frame between germline V kappa and J kappa 2 segments. These results suggest that the origin of the Ile codon in lines using J kappa 2 may represent a novel even in murine light chain assembly, possibly similar to the de novo addition of nucleotides observed in heavy chain gene recombination.
A non-invasive screen for infectivity in transmissible spongiform encephalopathies
Authors: D G Glover, B J Pollard, L Gonzalez, S Siso, D Kennedy, M Jeffrey
Journal: Gut (2007)

The risk of transmissible spongiform encephalopathy (TSE) infection from endoscopic procedures has been discussed recently in this journal.1,2 Subclinical carriers of variant Creutzfeldt–Jakob disease (vCJD), the numbers of whom are unknown, may present a risk of iatrogenic infection to susceptible patients participating in endoscopy. We report a pilot study, undertaken here on sheep, describing a non-invasive assessment of autonomic function based on heart rate variability (HRV) which may provide a useful screening method for subclinical carriers of certain TSE diseases.

Detection of disease associated prion protein (PrPd) in the brain stem is used in confirmatory postmortem tests for bovine spongiform encephalopathy (BSE) and sheep scrapie; this protein is also present in humans with vCJD.3–5 In scrapie, the timing of PrPd accumulation in the dorsal motor nucleus of the vagus nerve (DMNX) indicates that this is a likely site of initial neuroinvasion.4 Non-myelinated vagal fibres from the DMNX and faster myelinated vagal fibres from the nucleus ambiguus are involved in the control of HRV, which is the millisecond beat to beat change that is …
Listeria monocytogenes mutants lacking phosphatidylinositol-specific phospholipase C are avirulent.
Authors: A Camilli, H Goldfine, D A Portnoy
Journal: The Journal of Experimental Medicine (1991)

A number of bacterial species secrete phosphatidylinositol-specific phospholipase C (PI-PLC). In this report, we show that the facultative intracellular bacterial pathogen, Listeria monocytogenes, contains a gene, plcA, predicting a polypeptide with 31% amino acid identity to a Bacillus thuringiensis PI-PLC. Accordingly, L. monocytogenes secretes PI-PLC activity, while a mutant with a transposon insertion in plcA lacks detectable PI-PLC activity. In addition, expression of plcA in B. subtilis resulted in secretion of PI-PLC activity. The L. monocytogenes PI-PLC-defective mutant was three logs less virulent for mice and failed to grow in host tissues. The mutant was also defective for in vitro growth in mouse peritoneal macrophages. These results strongly suggest that PI-PLC is an essential determinant of L. monocytogenes pathogenesis. Whether the PI-PLC acts on a bacterial or host substrate remains to be determined.
Bortezomib Sensitizes Pancreatic Cancer Cells to Endoplasmic Reticulum Stress-Mediated Apoptosis
Authors: Steffan T. Nawrocki, Jennifer S. Carew, Maria S. Pino, Ralph A. Highshaw, Kenneth Dunner, Peng Huang, James L. Abbruzzese, David J. McConkey
Journal: Cancer Research (2005)

Bortezomib (PS-341, Velcade) is a potent and selective inhibitor of the proteasome that is currently under investigation for the treatment of solid malignancies. We have shown previously that bortezomib has activity in pancreatic cancer models and that the drug induces endoplasmic reticulum (ER) stress but also suppresses the unfolded protein response (UPR). Because the UPR is an important cytoprotective mechanism, we hypothesized that bortezomib would sensitize pancreatic cancer cells to ER stress-mediated apoptosis. Here, we show that bortezomib promotes apoptosis triggered by classic ER stress inducers (tunicamycin and thapsigargin) via a c-Jun NH(2)-terminal kinase (JNK)-dependent mechanism. We also show that cisplatin stimulates ER stress and interacts with bortezomib to increase ER dilation, intracellular Ca(2+) levels, and cell death. Importantly, combined therapy with bortezomib plus cisplatin induced JNK activation and apoptosis in orthotopic pancreatic tumors resulting in a reduction in tumor burden. Taken together, our data establish that bortezomib sensitizes pancreatic cancer cells to ER stress-induced apoptosis and show that bortezomib strongly enhances the anticancer activity of cisplatin.
Ventilatory mechanics in patients with bronchiectasis starting in childhood
Authors: L. I. Landau, P. D. Phelan, H. E. Williams
Journal: Thorax (1974)

<b>Landau, L. I., Phelan, P. D., and Williams, H. E. (1974).</b><i>Thorax</i>, <b>29</b>, 304-312. <b>Ventilatory mechanics in patients with bronchiectasis starting in childhood.</b> The mechanics of ventilation have been studied in 69 children and young adults with bronchiectasis since childhood. Many were well with little disability and although symptoms had ameliorated in the second decade cough and sputum still persisted. This study suggests that many patients had generalized small airway disease, as demonstrated by abnormal maximum expiratory flow volume curves together with increased lung volumes and frequency dependence of dynamic compliance. A group of patients was found in whom compliant airways in the bronchiectatic segment may have been contributing to `slow space9 emptying and air trapping. Postoperative function in those treated surgically related to the extent of persisting disease rather than to the resection itself. In the absence of persisting disease there were no significant changes in lung volumes or elastic recoil after resection of one or two lobes in childhood.
Congenital Heart Defects in Chick Embryos Subjected to Temperature Variations
Authors: María V. de la Cruz, Carlos Campillo-Sainz, Simón Muñoz-Armas, Guillermina Pallares, Rafaela Zamudio Bandera
Journal: Circulation Research (1966)

The effect of incubator temperature on mortality rates and on appearance of congenital malformations in white leghorn chicks and embryos was studied. The elevation of incubation temperature to 39.44°C led to a high mortality and to malformations in the eyes and the nervous system, as well as to abnormal torsion of the body axis. It did not produce any cardiac abnormalities, which would have been detected easily because the mortality peak occurred after the development of the heart was complete. Decreasing temperature of incubation to 35.83°C produced a high mortality rate and, very frequently, interventricular septal defects. These results and the possible mechanisms by which changes of temperature exert teratogenic effects are discussed.
SEBUM EXCRETION RATE AND BIOCHEMISTRY IN PATIENTS WITH ACNE VULGARIS TREATED BY ORAL FENFLURAMINE
Authors: J. A. COTTERILL, W. J. CUNLIFFE, B. WILLIAMSON
Journal: British Journal of Dermatology (1971)

SUMMARY.— Six patients with acne vulgaris were given oral fenfluramine. There was no clinical improvement in the acne vulgaris. The sebum excretion rate and skin surface lipid composition were also investigated. There were no significant changes in either the sebum excretion rate or sebum biochemistry after 1, 2 and 3 months of therapy.
A Phase 1 Open-Label, Accelerated Dose-Escalation Study of the Hypoxia-Activated Prodrug AQ4N in Patients with Advanced Malignancies
Authors: Kyriakos P. Papadopoulos, Sanjay Goel, Murali Beeram, Alvin Wong, Kavita Desai, Missak Haigentz, María L. Milián, Sridhar Mani, Anthony Tolcher, Alshad S. Lalani, John Sarantopoulos
Journal: Clinical Cancer Research (2008)

Abstract Purpose: AQ4N is a novel prodrug that is selectively bioreduced to AQ4, a topoisomerase II inhibitor, in hypoxic tumor. This study assessed the maximum tolerated dose and pharmacokinetics of AQ4N when administered weekly in patients with advanced cancers. Experimental Design: AQ4N was administered as a 30-minute i.v. infusion on days 1, 8, and 15 of a 28-day cycle in eight dose cohorts ranging from 12 to 1,200 mg/m2. Accelerated titration design was used and the maximum tolerated dose was defined as the highest dose at which fewer than two of six patients had a dose-limiting toxicity. Results: Sixteen patients were treated with cumulative doses of AQ4N ranging from 61.6 through 9,099.1 mg/m2. A single patient per cohort was treated up to 384 mg/m2 without toxicities. At 1,200 mg/m2, two of five patients experienced a dose-limiting toxicity (grade 5 respiratory failure and grade 3 fatigue). Five cohort assigned patients were treated without toxicity at 768 mg/m2, establishing this dose as the maximum tolerated dose. Among the most common adverse events observed were fatigue (38%), diarrhea (31%), nausea (25%), vomiting (25%), and anorexia (13%). Anticipated blue coloration of body fluids or skin was observed in all patients. The pharmacokinetics of AQ4N were dose proportional over all doses studied. Three patients experienced stable disease, including a patient with collecting duct renal cancer stable for 25 months. Conclusion: AQ4N is well tolerated when administered weekly on a 3-of-4-week schedule at 768 mg/m2. Further combination studies investigating the safety and efficacy of AQ4N are ongoing.
Effects of Testosterone and Castration on Cholesteremia and Atherogenesis in Chicks on High Fat, High Cholesterol Diets
Authors: R. PICK, J. STAMLER, S. RODBARD, L. N. KATZ
Journal: Circulation Research (1959)

Testosterone in large doses in intact cholesterol-fed cockerels partially inhibited hypercholesteremia, without effecting aorta or coronary atherosclerosis. Castration, with and without testosterone administration in young male and female chicks, was without influence on hypercholesteremia and atherogenesis.
Remarks ON THE SURGERY OF THE PITUITARY GLAND
Authors: A. J. Walton
Journal: BMJ (1922)

INSULIN AND DIABETES.[ T1! B3xa 3 'NOV-4, lg221-I~~~~~~~~~~*MZwIJMc 3OuuwZ 8 can be no doubt that when insulin comes to be more available its exhibition along with intelligent control of diet will have the same beneticial results in all the serious forms of the disease.In cases of threatened coma its value is undoubted, and this is also the case when it is used as a precautionary measure against post-operative risk in surgical practice.Until the clinical effects have been more thoroughly investigated it would be out of place here to discuss in further detail the therapeutic value of insulin.Whenever it is certain that a thorouglhly reliable large scale riiethod for a product of constant potency has been workedout the special agreement between thle University and the collaborating firm will terminate, and the University will issue licences to other approved firms.Realizing that it could not exercise proper supervision over the production of insulin in more countries than Canada and the United States, the University has offered to the Medical Research Council the assignment of the patents applied for in Great Britain for tie purpose of safeguarding the production and standardization of insulin in that country.