tbuckley/cabot-search huggingface dataset:
Diabetic gastroparesis: what we have learned and had to unlearn in the past 5 years: Figure 1
Authors: Purna Kashyap, Gianrico Farrugia
Journal: Gut (2010)

<h3>Purpose</h3> To assess the effects of intravitreal bevacizumab (IVB) in the treatment of choroidal neovascularisation (CNV) secondary to serpiginous choroiditis (SC). <h3>Design</h3> Non-randomised, interventional case series. <h3>Participants</h3> Seven patients (seven eyes) affected by juxtafoveal CNV (six eyes) and subfoveal CNV (one eye) associated with SC were recruited. <h3>Methods</h3> Each patient underwent an ophthalmological examination, including measurement of best-corrected visual acuity (BCVA), fluorescein angiography (FA) and optical coherence tomography (OCT). After a first IVB injection (1.25 mg), patients were evaluated monthly over a 12-month follow-up. Further re-treatments were performed on the basis of detection of any type of fluid on OCT and/or presence of leakage on FA. The primary outcome considered was the median change in BCVA, as well as the proportion of eyes gaining at least 5 and 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at the end of the 12-month follow-up. Secondary outcomes included median changes in central macular thickness (CMT) and number of injections over the planned follow-up. <h3>Results</h3> Median BCVA changed from 0.3 to 0.4 LogMAR. A functional improvement of at least 5 and 10 ETDRS letters was obtained in two eyes (28%) and one eye (14%), respectively, at the 12-month examination. Four eyes (57%) had stable BCVA, whereas one eye (14%) experienced a two-line decrease. Median CMT at baseline was 261 μm, decreasing to 196 μm at the 12-month examination. The median number of IVB injections was 1 in 12 months. <h3>Conclusions</h3> IVB can achieve anatomical stabilisation of CNV secondary to SC, avoiding a decline in visual acuity, in almost 90% of cases over a 12-month follow-up.
Long-term treatment of pulmonary hypertension with aerosolized iloprost
Authors: S. Machherndl, M. Kneussl, H. Baumgartner, B. Schneider, V. Petkov, P. Schenk, I.M. Lang
Journal: European Respiratory Journal (2000)

Pulmonary arterial hypertension (PAH), defined as elevated pulmonary arterial pressure and pulmonary vascular resistance, is an end-point of a variety of conditions. The only therapy that has been shown to improve both quality of life and survival is intravenous prostacyclin (prostaglandin I 2 (PGI 2 ), epoprostenol). The effect of long-term aerosolized iloprost (Ilomedin, Schering, Berlin, Germany and Vienna, Austria), a stable prostacyclin analogue and potent vasodilator, on haemodynamics and functional status was investigated in 12 patients with severe pulmonary hypertension. Haemodynamic measurements and vasodilator testing by right heart catheterization were performed prior to and after long-term iloprost inhalation therapy. Haemodynamic improvement or increased exercise tolerance was not observed in any of the patients. After a mean±sd treatment period of 10±5 months, mean±sd pulmonary vascular resistance had increased from 11±3 Wood Units (mmHg·L −1 ·min) to 13±4 Wood Units, with unchanged arterial oxygen saturation (92±4% versus 91±4%). Within the study period, three patients went into right heart failure and had to be placed on intravenous epoprostenol. The authors conclude that inhaled iloprost in addition to conventional therapy in the presently recommended dose of 100 µg·day −1 delivered in 8–10 2 h portions, is not an efficient vasodilator therapy in severe pulmonary hypertension. It remains to be shown whether dose increases and/or combination protocols will be effective, or whether inhalation of iloprost may be safe for selected cases of pulmonary hypertension.
Developing learning organisations in the new NHS
Authors: H. T O Davies
Journal: BMJ (2000)

The government's quality strategy represents a bold blueprint for the new NHS. It embodies the view that managing the organisational culture in tandem with improved learning (albeit overseen by close external monitoring) will deliver substantial gains in performance. The avowed aim is “to create a culture in the NHS which celebrates and encourages success and innovation … a culture which recognises … scope for acknowledging and learning from past mistakes.”1

Although learning is something undertaken and developed by individuals, organisational arrangements can foster or inhibit the process. The organisational culture within which individuals work shapes their engagement with the learning process. More than this, there are serious questions about whether and how the organisation can harness the learning achieved by its individual members. Thus, although continuing professional development has long been a part of the NHS, evidence from other sectors suggests that learning needs to take a more central role. Organisations that position learning as a core characteristic have been termed “learning organisations,”2–4 and this concept is an important one in the context of organisational development.5

This paper explores organisational learning and the characteristics of the organisational cultures needed to underpin this learning. We have drawn on existing publications in this area and have used informal synthesis to summarise the key elements of learning organisations and relate these to recent developments in the NHS. Our aim is to encourage the transference of some of these ideas to the NHS.

#### Summary points

The national quality strategy for the new NHS highlights lifelong learning as a way of improving health care

Learning is something achieved by individuals, but “learning organisations” can configure themselves to maximise, mobilise, and retain this learning potential

Learning occurs at different levels—single loop learning is about incremental improvements to existing practice; double loop learning occurs …
Clinician-friendly lower extremity physical performance measures in athletes: a systematic review of measurement properties and correlation with injury, part 1. The tests for knee function including the hop tests
Authors: Eric J Hegedus, Suzanne McDonough, Chris Bleakley, Chad E Cook, G David Baxter
Journal: British Journal of Sports Medicine (2014)

To review the measurement properties of physical performance tests (PPTs) of the knee as each pertain to athletes, and to determine the relationship between PPTs and injury in athletes age 12 years to adult.A search strategy was constructed by combining the terms 'lower extremity' and synonyms for 'performance test', and names of performance tests with variants of the term 'athlete'. In this, part 1, we report on findings in the knee. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were followed and the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist was used to critique the methodological quality of each paper. A second measure was used to analyse the quality of the measurement properties of each test.In the final analysis, we found 29 articles pertinent to the knee detailing 19 PPTs, of which six were compiled in a best evidence synthesis. The six tests were: one leg hop for distance (single and triple hop), 6 m timed hop, crossover hop for distance, triple jump and single leg vertical jump. The one leg hop for distance is the most often studied PPT. There is conflicting evidence regarding the validity of the hop and moderate evidence that the hop test is responsive to changes during rehabilitation. No test has established reliability or measurement error as assessed by the minimal important change or smallest detectable change. No test predicts knee injury in athletes.Despite numerous published articles addressing PPTs at the knee, there is predominantly limited and conflicting evidence regarding the reliability, agreement, construct validity, criterion validity and responsiveness of commonly used PPTs. There is a great opportunity for further study of these tests and the measurement properties of each in athletes.
The Role of Reverse Transcriptase in Intron Gain and Loss Mechanisms
Authors: Noa E. Cohen, Roy Shen, Liran Carmel
Journal: Molecular Biology and Evolution (2011)

Intron density is highly variable across eukaryotic species. It seems that different lineages have experienced considerably different levels of intron gain and loss events, but the reasons for this are not well known. A large number of mechanisms for intron loss and gain have been suggested, and most of them have at least some level of indirect support. We therefore figured out that the variability in intron density can be a reflection of the fact that different mechanisms are active in different lineages. Quite a number of these putative mechanisms, both for intron loss and for intron gain, postulate that the enzyme reverse transcriptase (RT) has a key role in the process. In this paper, we lay out three predictions whose approval or falsification gives indication for the involvement of RT in intron gain and loss processes. Testing these predictions requires data on the intron gain and loss rates of individual genes along different branches of the eukaryotic phylogenetic tree. So far, such rates could not be computed, and hence, these predictions could not be rigorously evaluated. Here, we use a maximum likelihood algorithm that we have devised in the past, Evolutionary Reconstruction by Expectation Maximization, which allows the estimation of such rates. Using this algorithm, we computed the intron loss and gain rates of more than 300 genes in each branch of the phylogenetic tree of 19 eukaryotic species. Based on that we found only little support for RT activity in intron gain. In contrast, we suggest that RT-mediated intron loss is a mechanism that is very efficient in removing introns, and thus, its levels of activity may be a major determinant of intron number. Moreover, we found that intron gain and loss rates are negatively correlated in intron-poor species but are positively correlated for intron-rich species. One explanation to this is that intron gain and loss mechanisms in intron-rich species (like metazoans) share a common mechanistic component, albeit not a RT.
Human leukocyte antigens class II and tumor necrosis factor genetic polymorphisms are independent predictors of non-Hodgkin lymphoma outcome
Authors: Przemyslaw Juszczynski, Ewa Kalinka, Jacques Bienvenu, Grzegorz Woszczek, Maciej Borowiec, Tadeusz Robak, Marek Kowalski, Ewa Lech-Maranda, Lucile Baseggio, Bertrand Coiffier, Gilles Salles, Krzysztof Warzocha
Journal: Blood (2002)
Inhibition of TGF-β3 restores the invasive capability of extravillous trophoblasts in preeclamptic pregnancies
Authors: Isabella Caniggia, Sorina Grisaru-Gravnosky, Maciej Kuliszewsky, Martin Post, Stephen J. Lye
Journal: Journal of Clinical Investigation (1999)

Preeclampsia, the major cause of maternal morbidity and mortality in developed countries, is associated with abnormalities of placenta function due to shallow invasion of the maternal decidua by trophoblasts. Data suggest that TGF-beta may play a role in inhibiting trophoblast outgrowth or invasion, or both. We report that placental TGF-beta 3 expression is high in early pregnancy but falls at around 9 weeks' gestation. This pattern is inversely correlated with trophoblast outgrowth and fibronectin synthesis, markers of early trophoblast differentiation toward an invasive phenotype. We demonstrate that TGF-beta 3 is overexpressed in preeclamptic placentae. In contrast to control placentae, explants from preeclamptic pregnancies fail to exhibit spontaneous invasion in vitro. Significantly, antisense-induced inhibition of TGF-beta 3 expression, and inhibition of TGF-beta 3 activity with antibodies, induces the formation of columns of trophoblast cells, which migrate out of the explant into the underlying Matrigel. To our knowledge, this is the first demonstration that the hypoinvasive placental phenotype characteristic of preeclampsia can be essentially normalized in vitro by biochemical manipulation. We speculate that a failure to downregulate expression of TGF-beta 3 at around 9 weeks' gestation results in shallow trophoblast invasion and predisposes the pregnancy to preeclampsia.
Ritonavir blocks AKT signaling, activates apoptosis and inhibits migration and invasion in ovarian cancer cells
Authors: Sanjeev Kumar, Christopher S Bryant, Sreedhar Chamala, Aamer Qazi, Shelly Seward, Jagannath Pal, Christopher P Steffes, Donald W Weaver, Robert Morris, John M Malone, Masood A Shammas, Madhu Prasad, Ramesh B Batchu
Journal: Molecular Cancer (2009)

Ovarian cancer is the leading cause of mortality from gynecological malignancies, often undetectable in early stages. The difficulty of detecting the disease in its early stages and the propensity of ovarian cancer cells to develop resistance to known chemotherapeutic treatments dramatically decreases the 5-year survival rate. Chemotherapy with paclitaxel after surgery increases median survival only by 2 to 3 years in stage IV disease highlights the need for more effective drugs. The human immunodeficiency virus (HIV) infection is characterized by increased risk of several solid tumors due to its inherent nature of weakening of immune system. Recent observations point to a lower incidence of some cancers in patients treated with protease inhibitor (PI) cocktail treatment known as HAART (Highly Active Anti-Retroviral Therapy).Here we show that ritonavir, a HIV protease inhibitor effectively induced cell cycle arrest and apoptosis in ovarian cell lines MDH-2774 and SKOV-3 in a dose dependent manner. Over a 3 day period with 20 muM ritonavir resulted in the cell death of over 60% for MDAH-2774 compared with 55% in case of SKOV-3 cell line. Ritonavir caused G1 cell cycle arrest of the ovarian cancer cells, mediated by down modulating levels of RB phosphorylation and depleting the G1 cyclins, cyclin-dependent kinase and increasing their inhibitors as determined by gene profile analysis. Interestingly, the treatment of ritonavir decreased the amount of phosphorylated AKT in a dose-dependent manner. Furthermore, inhibition of AKT by specific siRNA synergistically increased the efficacy of the ritonavir-induced apoptosis. These results indicate that the addition of the AKT inhibitor may increase the therapeutic efficacy of ritonavir.Our results demonstrate a potential use of ritonavir for ovarian cancer with additive effects in conjunction with conventional chemotherapeutic regimens. Since ritonavir is clinically approved for human use for HIV, drug repositioning for ovarian cancer could accelerate the process of traditional drug development. This would reduce risks, limit the costs and decrease the time needed to bring the drug from bench to bedside.
The Central Autonomic Nervous System: Conscious Visceral Perception and Autonomic Pattern Generation
Authors: Clifford B. Saper
Journal: Annual Review of Neuroscience (2002)

▪ Abstract The overall organization of the peripheral autonomic nervous system has been known for many decades, but the mechanisms by which it is controlled by the central nervous system are just now coming to light. In particular, two major issues have seen considerable progress in the past decade. First, the pathways that provide visceral sensation to conscious perception at a cortical level have been elucidated in both animals and humans. The nociceptive system runs in parallel to the pathways carrying visceral sensation from the cranial nerves and may be considered in itself a component of visceral sensation. Second, structures in the central nervous system that generate patterns of autonomic response have been identified. These pattern generators are located at multiple levels of the central nervous system, and they can be combined in temporal and spatial patterns to subserve a wide range of behavioral needs.
Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06)
Authors: C. Rochlitz, T. Ruhstaller, S. Lerch, C. Spirig, J. Huober, T. Suter, M. Bühlmann, M. Fehr, A. Schönenberger, R. von Moos, R. Winterhalder, D. Rauch, A. Müller, M. Mannhart-Harms, R. Herrmann, B. Cliffe, M. Mayer, K. Zaman
Journal: Annals of Oncology (2010)
Thrombin-activatable fibrinolysis inhibitor (TAFI) deficiency is compatible with murine life
Authors: Mariko Nagashima, Zheng-Feng Yin, Lei Zhao, Kathy White, Yanhong Zhu, Nina Lasky, Meredith Halks-Miller, George J. Broze, William P. Fay, John Morser
Journal: Journal of Clinical Investigation (2002)

To investigate the consequence of deficiency in thrombin-activatable fibrinolysis inhibitor (TAFI), we generated homozygous TAFI-deficient mice by targeted gene disruption. Intercrossing of heterozygous TAFI mice produced offspring in the expected Mendelian ratio, indicating that transmission of the mutant TAFI allele did not lead to embryonic lethality. TAFI-deficient mice developed normally, reached adulthood, and were fertile. No gross physical abnormalities were observed up to 24 months of age. Hematological analysis of TAFI-deficient mice did not show any major differences including plasma fibrinogen level, prothrombin time, and activated partial thromboplastin time. TAFI-deficient mice did not suffer from excess bleeding as determined by blood loss following tail transection, although their plasma failed to prolong clot lysis time in vitro. In vivo, TAFI deficiency did not influence occlusion time in either an arterial or a venous injury model. TAFI deficiency did not improve survival rate compared with the wild-type in thrombin-induced thromboembolism, factor X coagulant protein-induced thrombosis, and endotoxin-induced disseminated intravascular coagulation. Furthermore, TAFI deficiency did not alter kaolin-induced writhing response, implying that TAFI does not play a major role in bradykinin catabolism. The current study demonstrates that TAFI deficiency does not change normal responses to acute challenges.
Lung Tissue Engineering Technique with Adipose Stromal Cells Improves Surgical Outcome for Pulmonary Emphysema
Authors: Norihisa Shigemura, Meinoshin Okumura, Shinya Mizuno, Yukiko Imanishi, Akifumi Matsuyama, Hiroyuki Shiono, Toshikazu Nakamura, Yoshiki Sawa
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Hepatocyte growth factor (HGF) is a potent regenerative factor generated after a lung injury, and HGF supplementation after surgical reduction has been shown to enhance compensatory growth in remnant lungs and improve pathophysiologic conditions in a rat model of emphysema. Adipose tissue-derived stromal cells (ASCs) produce a large amount of angiogenic factors, including HGF. After lung volume reduction surgery (LVRS), we treated rats by implanting HGF-secreting ASCs with a scaffold onto the remnant lung tissue to determine the usefulness of this technique for treating respiratory dysfunction.Cells were isolated from rat inguinal adipose tissue and characterized by flow cytometry. ASCs were cultured on a polyglycolic acid felt sheet as a sealant material, and were shown to secrete significantly greater amounts of HGF than other angiogenic factors. Next, ASCs on polyglycolic acid felt sheets were used to cover the cut edge of the remaining lungs after LVRS for emphysema in rats. One week after implantation of the ASCs, both alveolar and vascular regeneration were significantly accelerated as compared with the rats that underwent LVRS alone. Consequently, gas exchange and exercise tolerance were also significantly restored, with these good results persisting for more than 1 mo.The present findings demonstrate the therapeutic potential of cell therapy using ASCs with a scaffold for selective delivery of HGF to remnant lungs, which resulted in enhancement of compensatory growth, after surgical resection. This approach may provide a new strategy for lung tissue engineering to improve LVRS outcome.
Abstract IA10: Interrogating gene regulatory networks to explore the boundary between chemistry and biology in cancer
Authors: Andrea Califano
Journal: Cancer Research (2012)

Abstract In this presentation we will discuss new methods for the computational assembly and experimental validation of gene regulatory network based approaches to study the activity of small-molecules in mouse and human cells. Specifically, we will address the interrogation of context specific models of regulation, inferred from primary data, to elucidate effector genes mediating compound mechanism of action in vitro and in vivo. The analysis can be specifically directed to the identification of biomarkers of drug activity, candidate targets to abrogate resistance, as well as candidate target for combination therapy. Furthermore, we will discuss various mechanisms supporting synergistic compound activity in cancer cells and discuss a systems biology approach that allows the identification of such synergistic combinations on a computational, predictive basis. Specific examples in high-grade glioma and non-small cancer adenocarcinoma will be discussed. Citation Format: Andrea Califano. Interrogating gene regulatory networks to explore the boundary between chemistry and biology in cancer [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr IA10.
Anti–<i>N-</i>Methyl-<scp>d</scp>-Aspartate Receptor Encephalitis
Authors: Alissa Thomas, Paula Rauschkolb, Núria Gresa-Arribas, Alan Schned, Josep O. Dalmau, Camilo E. Fadul
Journal: JAMA Neurology (2013)

IMPORTANCE-N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is an autoimmune encephalitis that can be paraneoplastic and usually responds to treatment.It is quickly becoming the most common paraneoplastic encephalitis.OBSERVATIONS-We present a case of a woman in her late 30s who developed psychiatric symptoms that progressed to encephalopathy, seizures, autonomic instability, and hyperkinetic movements.The patient was found to have an ovarian teratoma and serum and cerebrospinal fluid NMDAR antibodies.Despite resection of the teratoma and treatment with immunosuppressive therapy, the patient progressed to a minimally conscious state.She was supported medically in our institution for 25 months.During her hospitalization, she was treated with multiple immunosuppressive agents.With each treatment, we analyzed the serum and cerebrospinal fluid for NMDAR antibodies.While there was some initial reduction in the serum antibodies, the spinal fluid antibodies remained persistently elevated.The patient did not have any clinical improvement and eventually died after the family decided to withdraw care. CONCLUSIONS AND RELEVANCE-As far as we know, this case represents the longest active treatment without improvement of a patient with anti-NMDAR encephalitis.The patient had persistently high cerebrospinal fluid and serum antibody titers, which may be of prognostic significance.