tbuckley/cabot-search huggingface dataset:
Treatment of non-radiographic axial spondyloarthritis: it is only the beginning
Authors: Irene E van der Horst-Bruinsma
Journal: Annals of the Rheumatic Diseases (2013)

The new nomenclature used in spondyloarthritis (SpA), axial versus peripheral, as proposed by the Assessment of SpondyloArthritis international Society (ASAS) and accepted in 2009, has changed the perspective of ankylosing spondylitis (AS) and other types of spondylarthropathies.1 ,2 The axial type of SpA is subdivided in the (early) non-radiographic type (nr-axial SpA) and the radiographic type, which is equivalent to the diagnosis of AS (according to the modified New York criteria3). Instead of debating whether patients with AS do fulfil the grade of radiographic signs of sacroiliitis necessary for the diagnosis AS, the focus of interest has shifted towards the spectre of early detection of inflammation at the MRI of the pelvis and spine. The great advantage of the new nomenclature with an earlier phase of the disease is that the delay in diagnosis of SpA is shortened by years. Now the current research is directed towards the treatment options of this early stage.

The first question to be answered in the near future is whether early anti-tumor necrosis factor (TNF) treatment is effective on clinical symptoms in nr-axial SpA. The second question will be whether treatment in this early phase of the disease will sufficiently suppress inflammation in the long term. Third, and most importantly, the question arises whether this early treatment with anti-TNF has a positive benefit:risk ratio. This early and expensive treatment might diminish symptoms, but it is unclear whether it decreases or even halts the rate of radiographic progression. So far, there is no clear evidence that anti-TNF does delay this process in established AS.

In order to answer the first two questions, two interesting studies are published in Annals of Rheumatic Diseases.4 ,10

The ABILITY trial compares the efficacy of adalimumab versus placebo in nr-axial SpA …
Imaging endpoints to predict response to IGF1R/IR inhibition in CRC models
Authors: Natalie J. Serkova, Erica L. Bradshaw-Pierce, Kendra M. Hasebroock, Andrea L. Merz, Todd M. Pitts, Gail S. Eckhardt
Journal: Clinical Cancer Research (2010)

Abstract Colorectal cancer (CRC) represents a major health burden and accounts for nearly 10% of all cancer-related deaths in the U.S. Among the many new pathways being exploited for cancer treatment is the insulin-like growth factor receptor (IGF1R) signaling pathway, which appears to be a robust target in CRC (e.g., hyperactivated in more than 50% of CRC patients). OSI-906 is a novel selective dual inhibitor IGF-1R and IR kinase activities. Despite advances in molecular predictive markers, a substantial proportion of patients selected for targeted therapy has nonresponsive tumors and require additional combination-based regimens. Unlike cytotoxic chemotherapeutic agents, most novel signal transduction modulators (STMs) induce only modest tumor regression, thus there is significant need for establishing functional pharmacodynamic (e.g., therapy response) endpoints for inhibition of signaling via particular pathways. In the present study we established noninvasive imaging-based endpoints for response to OSI-906 in CRC mouse models. Female nude mice were implanted with either of two human CRC cell lines (one sensitive and one resistant) or individual human surgical CRC explants (with unknown sensitivity). Metabolic changes (decreased glucose uptake and lactate production by FDG-PET and proton MRS, respectively) were apparent in OSI-906-sensitive xenografts as early as 2 days post-treatment when no changes in tumor size were yet detected. A significant decrease in tumor size and membrane choline-containing phospholipids by MRI and MRS, respectively, were seen after 27 days of treatment in OSI-906-sensitive xenografts. No changes in FDG-PET, MRS, or tumor progression were observed in OSI-906 resistant xenografts. Our data indicate that noninvasive functional imaging endpoints can provide early and sensitive markers for cytostatic action of IGF1R/IR inhibitors. This talk is also presented as Poster A14.
Sustained efficacy of the monoclonal anti-interleukin-1 beta antibody canakinumab in a 9-month trial in Schnitzler's syndrome
Authors: Heleen D de Koning, Joost Schalkwijk, Johanna van der Ven-Jongekrijg, Monique Stoffels, Jos W M van der Meer, Anna Simon
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> Schnitzler9s syndrome is a chronic disabling autoinflammatory disorder, characterised by chronic urticaria, paraproteinemia and systemic inflammation. The interleukin (IL) 1 receptor antagonist anakinra is a very effective treatment, but requires daily injection and blocks both IL-1α and IL-1β. Canakinumab is a selective human monoclonal anti-IL-1β antibody with a long half-life. We investigated the long-term efficacy and safety of canakinumab in Schnitzler9s syndrome. <h3>Methods</h3> In an open-label, single-treatment arm trial, eight patients with Schnitzler9s syndrome received monthly injections with 150 mg canakinumab subcutaneously for 6 months, followed by a 3-month observation period. Primary outcome was complete or clinical remission at day 14. Secondary outcome measures included inflammatory markers, quality of life, time to relapse, safety and tolerability. <h3>Results</h3> After stopping anakinra, patients developed moderate to severe clinical symptoms. Canakinumab induced complete or clinical remission at day 14 in all eight patients. Median C-reactive protein concentrations decreased from 169 mg/l at baseline to less than 10 mg/l on day 14 and remained low or undetectable. One patient discontinued participation on day 39 because of return of symptoms while all others remained in complete or clinical remission during the 6-month treatment period. Relapse after last canakinumab dose occurred within 3 months in four patients. For two patients, remission continued several months post-study. Five patients reported at least one adverse event, predominantly mild upper respiratory tract infections. One patient died in a traffic accident. <h3>Conclusions</h3> In this 9-month study, monthly 150 mg canakinumab injection was an effective and well-tolerated treatment for Schnitzler9s syndrome. Our data demonstrate that IL-1β plays a pivotal role in this disease. <h3>ClinicalTrials.gov</h3> NCT01276522.
Thrombolysis Compared With Heparin for the Initial Treatment of Pulmonary Embolism
Authors: Susan Wan, Daniel J. Quinlan, Giancarlo Agnelli, John W. Eikelboom
Journal: Circulation (2004)

Background— Randomized trials and meta-analyses have reached conflicting conclusions about the role of thrombolytic therapy for the treatment of acute pulmonary embolism. Methods and Results— We performed a meta-analysis of all randomized trials comparing thrombolytic therapy with heparin in patients with acute pulmonary embolism. Eleven trials, involving 748 patients, were included. Compared with heparin, thrombolytic therapy was associated with a nonsignificant reduction in recurrent pulmonary embolism or death (6.7% versus 9.6%; OR 0.67, 95% CI 0.40 to 1.12, P for heterogeneity=0.48), a nonsignificant increase in major bleeding (9.1% versus 6.1%; OR 1.42, 95% CI 0.81 to 2.46), and a significant increase in nonmajor bleeding (22.7% versus 10.0%; OR 2.63, 95% CI 1.53 to 4.54; number needed to harm=8). Thrombolytic therapy compared with heparin was associated with a significant reduction in recurrent pulmonary embolism or death in trials that also enrolled patients with major (hemodynamically unstable) pulmonary embolism (9.4% versus 19.0%; OR 0.45, 95% CI 0.22 to 0.92; number needed to treat=10) but not in trials that excluded these patients (5.3% versus 4.8%; OR 1.07, 95% CI 0.50 to 2.30), with significant heterogeneity between these 2 groups of trials ( P =0.10). Conclusions— Currently available data provide no evidence for a benefit of thrombolytic therapy compared with heparin for the initial treatment of unselected patients with acute pulmonary embolism. A benefit is suggested in those at highest risk of recurrence or death. The number of patients enrolled in randomized trials to date is modest, and further evaluation of the efficacy and safety of thrombolytic therapy for the treatment of high-risk patients with acute pulmonary embolism appears warranted.
Pathology, Clinical Presentations, and Outcomes of C1q Nephropathy
Authors: Alenka Vizjak, Dus[Combining Caron] Ferluga, Mojca Roz[Combining Caron]ic[Combining Caron], Anastazija Hvala, Jelka Lindic[Combining Caron], Tanja Kersnik Levart, Vesna Jurc[Combining Caron]ic[Combining Acute Accent], J. Charles Jennette
Journal: Journal of the American Society of Nephrology (2008)

C1q nephropathy is an uncommon glomerular disease with characteristic features on immunofluorescence microscopy. In this report, clinicopathologic correlations and outcomes are presented for 72 patients with C1q nephropathy. The study comprised 82 kidney biopsies from 28 children and 54 adults with male preponderance (68%). Immunofluorescence microscopy showed dominant or co-dominant staining for C1q in the mesangium and occasional glomerular capillary walls. Electron-dense deposits were observed in 48 of 53 cases. Light microscopy revealed no lesions (n = 27), focal segmental glomerulosclerosis (FSGS; n = 11), proliferative glomerulonephritis (n = 20), or various other lesions (n = 14). Clinical presentations in the patients who had no lesions histology were normal urine examination (7%), asymptomatic hematuria and/or proteinuria (22%), and nephrotic syndrome (minimal change-like lesion; 63%), which frequently relapsed. All patients with FSGS presented with nephrotic syndrome. Those with proliferative glomerulonephritis usually presented with chronic kidney disease (75%) or asymptomatic urine abnormalities (20%). Of the patients with sufficient follow-up data, complete remission of the nephrotic syndrome occurred in 77% of those with a minimal change-like lesion, progression to end-stage renal disease occurred in 33% of those with FSGS, and renal disease remained stable in 57% of those with proliferative glomerulonephritis. In conclusion, this study identified two predominant clinicopathologic subsets of C1q nephropathy: (1) Podocytopathy with a minimal change-like lesion or FSGS, which typically presents with nephrotic syndrome, and (2) a typical immune complex-mediated glomerular disease that varies from no glomerular lesions to diverse forms of glomerular proliferation, which typically presents as chronic kidney disease. Clinical presentation, histology, outcomes, and presumably pathogenesis of C1q nephropathy are heterogeneous.
Staphylococcal scalded skin syndrome in an HIV-1 seropositive man
Authors: A.M. Farrell, J.S. Ross, S. Umasankar, C.B. Bunker
Journal: British Journal of Dermatology (1996)

The staphylococcal scalded skin syndrome (SSSS) is very rare in adults. Renal impairment and immunocompromise are predisposing causes. We report a 38-year-old HIV-1 seropositive intravenous drug abuser who developed SSSS due to staphylococcal pneumonia. An exfoliating toxin-releasing Staphylococcus aureus, phage type II type 3C, was isolated from the sputum and from blood cultures. This is the third case of adult SSSS to be reported in the context of HIV disease.
Increased Sarcoplasmic Reticulum Calcium Leak but Unaltered Contractility by Acute CaMKII Overexpression in Isolated Rabbit Cardiac Myocytes
Authors: Michael Kohlhaas, Tong Zhang, Tim Seidler, Darya Zibrova, Nataliya Dybkova, Astrid Steen, Stefan Wagner, Lu Chen, Joan Heller Brown, Donald M. Bers, Lars S. Maier
Journal: Circulation Research (2005)

The predominant cardiac Ca2+/calmodulin-dependent protein kinase (CaMK) is CaMKIIdelta. Here we acutely overexpress CaMKIIdeltaC using adenovirus-mediated gene transfer in adult rabbit ventricular myocytes. This circumvents confounding adaptive effects in CaMKIIdeltaC transgenic mice. CaMKIIdeltaC protein expression and activation state (autophosphorylation) were increased 5- to 6-fold. Basal twitch contraction amplitude and kinetics (1 Hz) were not changed in CaMKIIdeltaC versus LacZ expressing myocytes. However, the contraction-frequency relationship was more negative, frequency-dependent acceleration of relaxation was enhanced (tau(0.5Hz)/tau(3Hz)=2.14+/-0.10 versus 1.87+/-0.10), and peak Ca2+ current (ICa) was increased by 31% (-7.1+/-0.5 versus -5.4+/-0.5 pA/pF, P<0.05). Ca2+ transient amplitude was not significantly reduced (-27%, P=0.22), despite dramatically reduced sarcoplasmic reticulum (SR) Ca2+ content (41%; P<0.05). Thus fractional SR Ca2+ release was increased by 60% (P<0.05). Diastolic SR Ca2+ leak assessed by Ca2+ spark frequency (normalized to SR Ca2+ load) was increased by 88% in CaMKIIdeltaC versus LacZ myocytes (P<0.05; in an multiplicity-of-infection-dependent manner), an effect blocked by CaMKII inhibitors KN-93 and autocamtide-2-related inhibitory peptide. This enhanced SR Ca2+ leak may explain reduced SR Ca2+ content, despite measured levels of SR Ca2+-ATPase and Na+/Ca2+ exchange expression and function being unaltered. Ryanodine receptor (RyR) phosphorylation in CaMKIIdeltaC myocytes was increased at both Ser2809 and Ser2815, but FKBP12.6 coimmunoprecipitation with RyR was unaltered. This shows for the first time that acute CaMKIIdeltaC overexpression alters RyR function, leading to enhanced SR Ca2+ leak and reduced SR Ca2+ content but without reducing twitch contraction and Ca2+ transients. We conclude that this is attributable to concomitant enhancement of fractional SR Ca2+ release in CaMKIIdeltaC myocytes (ie, CaMKII-dependent enhancement of RyR Ca2+ sensitivity during diastole and systole) and increased ICa.
Unusual Neurotoxicity of Kanamycin
Authors: Frank R. Freemon
Journal: JAMA (1967)

THE ANTIBIOTIC kanamycin sulfate, when administered parenterally, often has a toxic effect on the sensory hair cells of the organ of Corti of the inner ear. Autopsy of the temporal bone in three cases of kanamycin deafness demonstrated degeneration of these hair cells.<sup>1</sup>Studies have shown a similar propensity for the sensory hair cells of animals to degenerate, leaving relatively unscathed the nerve fibers of the eighth cranial nerve.<sup>2</sup>Kanamycin deafness is directly related to the dose administered per day<sup>3</sup>and to the age of the patient.<sup>4</sup> Less frequent neurotoxicity caused by kanamycin includes blurring of vision, paresthesia, and curare-like neuromuscular blockade. In an early series of cases in which 23 of 81 patients receiving parenterally administered kanamycin experienced tinnitus or deafness or both, an additional four patients experienced other neurotoxicity. Two suffered transient blurring of vision; another, numbness and burning pain along the posterior aspect
AN INVESTIGATION OF TRENCH NEPHRITIS BY MEANS OF PHENOLSULPHONEPHTHALEIN
Authors: A. G. Auld
Journal: BMJ (1917)

<h3>Background</h3> Research reveals consistently higher injury rates amongst Aboriginal Australian children (AIHW: Pointer 2014). Intervention strategies for this population must be culturally appropriate and take into account a broad range of social, historical and cultural factors impacting on Aboriginal health and safety, however few culturally acceptable interventions have been developed or evaluated. We conducted an evaluation of a home visiting model of early intervention developed by the Illawarra Aboriginal Medical Service as an injury prevention program targeting disadvantaged Aboriginal families with young children aged 0–5 and their families living in an urban region of NSW. <h3>Methods</h3> The evaluation conducted between January 2014 and June 2015 included process, impact and outcomes components. Data collection included: routinely collected program data; semi-structured interviews with 35 individuals; and a family worker survey. All data was coded thematically and a framework analysis applied using NVivo software. Capacity building activities were conducted throughout the period. <h3>Results</h3> The Program addressed the need for a culturally appropriate safety program delivered by Aboriginal family workers to vulnerable families. Clients expressed a high degree of satisfaction with the family workers’ delivery of the program and the holistic model of service provision offered. Key results included: increased engagement in safety programs; improved child safety knowledge and skills; increased accessibility for parents/carers, children and families to services; improved attitudes to home and community safety; changes in the home safety environment. The evaluation provided opportunities for collaboration between researchers and the Aboriginal medical service and capacity building for the Aboriginal family workers. <h3>Conclusions</h3> The ‘Safe Homes Safe Kids’ program offers a promising program for addressing unintentional injury to vulnerable Aboriginal children in urban areas.
Movement dynamics in speed/accuracy trade-off
Authors: P. Morasso, V. Sanguineti
Journal: Behavioral and Brain Sciences (1997)

Fitts' law and the ΔΛ model are “weak” theories of motor control because they are limited to the kinematic aspects of movement and do not capture its essential dynamic nature. The internal source of “noise” that determines the speed/ accuracy trade-off can be associated with the partial compensation of movement-generated “parasitic” forces.
Acetylcholinesterase-positive nerves of the rhesus monkey bronchial tree.
Authors: A W El-Bermani, M Grant
Journal: Thorax (1975)

The rhesus monkey lung was stained both by histological methods and histochemically for specific acetylcholinesterase (AChE). AChE-containing nerves in bundles were demonstrated in connective tissue of the hilum and in association with clusters of ganglion cells. These bundles become associated with the bronchial tree as they enter the lung parenchyma, and their numbers of myelinated fibres diminish as they pass scattered ganglion cells along the bronchial system. Extrachondral and subchondral plexuses of nerves were found to be interconnected and to contribute to the perimuscular varicose nerve plexus of the bronchi and bronchioles. These nerve plexuses were found to extend as far as the respiratory bronchioles. In the bronchial submucosa there are AChE-positive nerve plexuses which arise from three sources: (1) the adventitial plexus in bronchioles, or the subchondral plexus in bronchi, (2) the perimuscular nerve plexus, and (3) AChe-containing nerves associated with the bronchial artery. The submucosal plexus appears to innervate the acinar submucosal glands in bronchi as well as continuing as central nerves in the mucosal folds. In the bronchioles the nerves in the mucosal fold are in close relationship with the mucosa.
Automated alerts for acute kidney injury warrant caution
Authors: S. Sawhney
Journal: BMJ (2015)

<h3>Abstract</h3> Hyperinsulinemia is commonly viewed as a compensatory response to insulin resistance, yet studies have suggested that chronically elevated insulin may also drive insulin resistance. The molecular mechanisms underpinning this potentially cyclic process remain poorly defined, especially on a transcriptome-wide level. To study the direct effects of prolonged exposure to excess insulin in muscle cells, we incubated C2C12 myotubes with elevated insulin for 16 hours, followed by 6 hours of serum starvation, and established that acute AKT and ERK signaling were attenuated in this model of <i>in vitro</i> hyperinsulinemia. Global RNA-sequencing of cells both before and after nutrient withdrawal highlighted genes in the insulin signaling, FOXO signaling, and glucose metabolism pathways indicative of ‘hyperinsulinemia’ and ‘starvation’ programs. We observed that hyperinsulinemia led to a substantial reduction in insulin receptor (<i>Insr)</i> gene expression, and subsequently a reduced surface INSR and total INSR protein, both <i>in vitro</i> and <i>in vivo</i>. Transcriptomic meta-analysis in &gt;450 human samples demonstrated that fasting insulin reliably and negatively correlated with insulin receptor (<i>INSR</i>) mRNA in skeletal muscle. Bioinformatic modeling combined with RNAi, identified SIN3A as a negative regulator of <i>Insr</i> mRNA (and JUND, MAX, and MXI as positive regulators of <i>Irs2</i> mRNA). Together, our analysis identifies novel mechanisms which may explain the cyclic processes underlying hyperinsulinemia-induced insulin resistance in muscle, a process directly relevant to the etiology and disease progression of type 2 diabetes.
Genome-wide analysis of plant nat-siRNAs reveals insights into their distribution, biogenesis and function
Authors: Xiaoming Zhang, Jing Xia, Yifan E Lii, Blanca E Barrera-Figueroa, Xuefeng Zhou, Shang Gao, Lu Lu, Dongdong Niu, Zheng Chen, Christy Leung, Timothy Wong, Huiming Zhang, Jianhua Guo, Yi Li, Renyi Liu, Wanqi Liang, Jian-Kang Zhu, Weixiong Zhang, Hailing Jin
Journal: Genome biology (2012)

Abstract Background Many eukaryotic genomes encode cis -natural antisense transcripts ( cis -NATs). Sense and antisense transcripts may form double-stranded RNAs that are processed by the RNA interference machinery into small interfering RNAs (siRNAs). A few so-called nat-siRNAs have been reported in plants, mammals, Drosophila , and yeasts. However, many questions remain regarding the features and biogenesis of nat-siRNAs. Results Through deep sequencing, we identified more than 17,000 unique siRNAs corresponding to cis -NATs from biotic and abiotic stress-challenged Arabidopsis thaliana and 56,000 from abiotic stress-treated rice. These siRNAs were enriched in the overlapping regions of NATs and exhibited either site-specific or distributed patterns, often with strand bias. Out of 1,439 and 767 cis -NAT pairs identified in Arabidopsis and rice, respectively, 84 and 119 could generate at least 10 siRNAs per million reads from the overlapping regions. Among them, 16 cis -NAT pairs from Arabidopsis and 34 from rice gave rise to nat-siRNAs exclusively in the overlap regions. Genetic analysis showed that the overlapping double-stranded RNAs could be processed by Dicer-like 1 (DCL1) and/or DCL3. The DCL3-dependent nat-siRNAs were also dependent on RNA-dependent RNA polymerase 2 (RDR2) and plant-specific RNA polymerase IV (PolIV), whereas only a fraction of DCL1-dependent nat-siRNAs was RDR- and PolIV-dependent. Furthermore, the levels of some nat-siRNAs were regulated by specific biotic or abiotic stress conditions in Arabidopsis and rice. Conclusions Our results suggest that nat-siRNAs display distinct distribution patterns and are generated by DCL1 and/or DCL3. Our analysis further supported the existence of nat-siRNAs in plants and advanced our understanding of their characteristics.
Effects of potassium ion on the microcirculation of the hamster.
Authors: B R Duling
Journal: Circulation Research (1975)

The vasoactive properties of potassium were assessed in the microcirculation of the hamster cremaster muscle and the muscular and epithelial portions of the hamster cheek pouch. Tissues were transilluminated and suffused with a physiological salt solution whose potassium concentration varied from 0 to 20 mM. Vessel diameters were measured and normalized as a percent of the control diameter (+/- SE) observed during exposure to 4.7 mM K+. Altering the potassium concentration in the suffusion solution caused a transient vascular response. The peak changes in the vascular diameter of the arterioles supplying striated muscle varied directly with the suffusion solution potassium concentration from a minimum of 78 +/- 3% in 0 mM K+ to 155 +/- 15% in 15 mM K+. Vascular diameter increases were sustained for the full 5-minute test period only in 15 mM K+. In the epithelial portions of the cheek pouch, only the constrictor component of the potassium response was observed. The data indicate that potassium is sufficiently potent to participate in initiating functional hyperemia in striated muscle and might cause as much as a 6.3-fold increase in flow. Functional hyperemias exceeding approximately 3 minutes cannot be due to potassium ion, since the dilation induced by this agent is transient.