tbuckley/cabot-search huggingface dataset:
Antiribosomal-P autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosis
Authors: Soledad Matus, Patricia V. Burgos, Marcela Bravo-Zehnder, Regine Kraft, Omar H. Porras, Paula Farías, L. Felipe Barros, Fernando Torrealba, Loreto Massardo, Sergio Jacobelli, Alfonso González
Journal: The Journal of Experimental Medicine (2007)

The interesting observation was made 20 years ago that psychotic manifestations in patients with systemic lupus erythematosus are associated with the production of antiribosomal-P protein (anti-P) autoantibodies. Since then, the pathogenic role of anti-P antibodies has attracted considerable attention, giving rise to long-term controversies as evidence has either contradicted or confirmed their clinical association with lupus psychosis. Furthermore, a plausible mechanism supporting an anti-P–mediated neuronal dysfunction is still lacking. We show that anti-P antibodies recognize a new integral membrane protein of the neuronal cell surface. In the brain, this neuronal surface P antigen (NSPA) is preferentially distributed in areas involved in memory, cognition, and emotion. When added to brain cellular cultures, anti-P antibodies caused a rapid and sustained increase in calcium influx in neurons, resulting in apoptotic cell death. In contrast, astrocytes, which do not express NSPA, were not affected. Injection of anti-P antibodies into the brain of living rats also triggered neuronal death by apoptosis. These results demonstrate a neuropathogenic potential of anti-P antibodies and contribute a mechanistic basis for psychiatric lupus. They also provide a molecular target for future exploration of this and other psychiatric diseases.
mTOR Complex 2 Is Involved in Regulation of Cbl-Dependent c-FLIP Degradation and Sensitivity of TRAIL-Induced Apoptosis
Authors: Liqun Zhao, Ping Yue, Fadlo R. Khuri, Shi-Yong Sun
Journal: Cancer Research (2013)

The mTOR positively regulates cell proliferation and survival through forming 2 complexes with raptor (mTOR complex 1; mTORC1) or rictor (mTOR complex 2; mTORC2). Compared with the mTORC1, relatively little is known about the biologic functions of mTORC2. This study focuses on addressing whether mTORC2 regulates apoptosis, particularly induced by TRAIL (TNFSF10). Using the mTOR kinase inhibitor, PP242, as a research tool, we found that it synergized with TRAIL to augment apoptosis of cancer cells. PP242 reduced the abundance of the short form of c-FLIP (FLIP(S), CFLAR(S)) and survivin (BIRC5). Enforced expression of ectopic FLIP(S), but not survivin, attenuated augmented apoptosis induced by PP242 plus TRAIL. Thus, it is FLIP(S) downregulation that contributes to synergistic induction of apoptosis by PP242 plus TRAIL. PP242 decreased FLIP(S) stability, increased FLIP(S) ubiquitination, and facilitated FLIP(S) degradation. Moreover, knockdown of the E3 ligase Cbl (CBL) abolished PP242-induced FLIP(S) reduction. Thus, PP242 induces Cbl-dependent degradation of FLIP(S), leading to FLIP(S) downregulation. Consistently, knockdown of rictor or mTOR, but not raptor, mimicked PP242 in decreasing FLIP(S) levels and sensitizing cells to TRAIL. Rictor knockdown decreased FLIP(S) stability, whereas enforced expression of rictor stabilized FLIP(S). Moreover, silencing of Cbl abrogated FLIP(S) reduction induced by rictor knockdown. Collectively we conclude that it is mTORC2 inhibition that results in FLIP(S) downregulation and subsequent sensitization of TRAIL-induced apoptosis. Our findings provide the first evidence showing that mTORC2 stabilizes FLIP(S), hence connecting mTORC2 signaling to the regulation of death receptor-mediated apoptosis.
PEDro systematic review update: the effectiveness of physiotherapy exercises in subacromical impingement syndrome
Authors: Zoe A Michaleff, Steven J Kamper
Journal: British Journal of Sports Medicine (2013)

▸  Hanratty CE, McVeigh JG, Kerr DP, et al . The effectiveness of physiotherapy exercises in subacromical impingement syndrome: a systematic review and meta-analysis. Semin Arthritis Rheum 2012; 42 :297–316.

Subacromial impingement syndrome (SAIS) is thought to be the final pathological pathway for numerous pathologies of the shoulder and is used to describe a broad spectrum of symptoms rather than a single diagnosis.1 ,2 Physiotherapy management of SAIS most commonly involves exercise (eg, strengthening, stretching and scapular stability exercises). The goal of a physiotherapy shoulder exercise programme is to relieve pain, restore range of motion, improve strength and muscle coordination. While the use of exercise in the management of SAIS is common and widespread, little high-quality evidence supports the administration of exercise alone.3–5 The current review aimed to provide up to date evidence relevant to this question while avoiding some of the methodological limitations apparent in previous reviews.

The authors synthesised the best available evidence to determine the effectiveness of exercise in management of SAIS. A secondary aim was to provide guidelines for therapists as to the most effective mode, exercise …
A new class of lipid mediators: cytochrome P450 arachidonate metabolites
Authors: M. A Carroll
Journal: Thorax (2000)

Cranial visceral afferents innervate second-order nucleus tractus solitarius (NTS) neurons via myelinated (A-type) and unmyelinated (C-type) axons in the solitary tract (ST). A- and C-type afferents often evoke reflexes with distinct performance differences, especially with regard to their frequency-dependent properties. In horizontal brainstem slices, we used the vanilloid receptor 1 agonist capsaicin (CAP; 100 nm) to identify CAP-sensitive and CAP-resistant ST afferent pathways to second-order NTS neurons and tested whether these two groups of neurons had similar intrinsic potassium currents. ST stimulation evoked monosynaptic EPSCs identified by minimal synaptic jitter (&lt;150 μsec) and divided into two groups: CAP-sensitive (<i>n</i> = 37) and CAP-resistant (<i>n</i> = 22). EPSCs in CAP-sensitive neurons had longer latencies (5.1 ± 0.3 vs 3.6 ± 0.3 msec;<i>p</i> = 0.001) but similar jitter (<i>p</i> = 0.57) compared with CAP-resistant neurons, respectively. Transient outward currents (TOCs) were significantly greater in CAP-sensitive than in CAP-resistant neurons. Steady-state currents were similar in both groups. 4-Aminopyridine or depolarized conditioning blocked the TOC, but tetraethylammonium had no effect. Voltage-dependent activation and inactivation of TOC were consistent with an A-type K<sup>+</sup> current, <i>I</i><sub>KA</sub>. In current clamp, the activation of <i>I</i><sub>KA</sub> reduced neuronal excitability and action potential responses to ST transmission. Our results suggest that the potassium-channel differences of second-order NTS neurons contribute to the differential processing of A- and C-type cranial visceral afferents beginning as early as this first central neuron. <i>I</i><sub>KA</sub> can act as a frequency transmission filter and may represent a key target for the modulation of temporal processing of reflex responsiveness such as within the baroreflex arc.
2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis
Authors: J Braun, R van den Berg, X Baraliakos, H Boehm, R Burgos-Vargas, E Collantes-Estevez, H Dagfinrud, B Dijkmans, M Dougados, P Emery, P Geher, M Hammoudeh, RD Inman, M Jongkees, MA Khan, U Kiltz, TK Kvien, M Leirisalo-Repo, WP Maksymowych, I Olivieri, K Pavelka, J Sieper, E Stanislawska-Biernat, D Wendling, S Özgocmen, C van Drogen, BJ van Royen, D van der Heijde
Journal: Annals of the Rheumatic Diseases (2011)

This first update of the ASAS/EULAR recommendations on the management of ankylosing spondylitis (AS) is based on the original paper, a systematic review of existing recommendations and the literature since 2005 and the discussion and agreement among 21 international experts, 2 patients and 2 physiotherapists in a meeting in February 2010. Each original bullet point was discussed in detail and reworded if necessary. Decisions on new recommendations were made - if necessary after voting. The strength of the recommendations (SOR) was scored on an 11-point numerical rating scale after the meeting by email. These recommendations apply to patients of all ages that fulfill the modified NY criteria for AS, independent of extra-articular manifestations, and they take into account all drug and non-drug interventions related to AS. Four overarching principles were introduced, implying that one bullet has been moved to this section. There are now 11 bullet points including 2 new ones, one related to extra-articular manifestations and one to changes in the disease course. With a mean score of 9.1 (range 8-10) the SOR was generally very good.
Complexity Made Simple in Diffuse Large B-Cell Lymphoma
Authors: Jon Aster, Jeffery Kutok
Journal: Clinical Cancer Research (2009)

Abstract Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease and response to therapy is difficult to predict. An algorithm to sort DLBCL cases using a series of five immunohistochemical markers (GCET1, CD10, BCL6, MUM1, FOXP1) accurately predicts survival in patients treated with current chemotherapeutic regimens. (Clin Cancer Res 2009;15(17):5291–3)
Albumin and stellate cell activation: wonders will never cease!
Authors: M. Pinzani
Journal: Gut (2009)

In addition to the liver, stellate cells are present in extrahepatic organs such as the pancreas, lung, kidney, intestine, spleen, adrenal gland, ductus deferens and vocal cords. Hepatic and extrahepatic stellate cells form what has been defined “the stellate cell system”. Besides clear morphological similarities, two main features are peculiar to this type of cells in the liver as well as in other organs: (1) a perivascular location and a distribution typical of a pericyte, particularly when associated with a sinusoidal type of endothelium; and (2) the capability of storing retinoids.1 Although stellate cells, and in particular hepatic stellate cells (HSC), were described more than a century ago, their real physiological and pathophysiological relevance has emerged only in the last 20 years. In these years the knowledge on their profibrogenic role has grown exponentially and the elucidation of the cellular and molecular basis of fibrogenesis has brought important advances in the knowledge of chronic fibrogenic disorders of the liver and pancreas. In this context, understanding the biology of stellate cells, either HSCs or pancreatic stellate cells (PSCs), has been a great adventure for many researchers around the world.

Research on PSCs gradually started in the 1990s following the successful flourish of HSC research. The entrance of PSC into the fibrogenesis research community was highly welcomed, as witnessed by a commentary that I wrote for Gut in 1999.2 Initially, research on PSCs was mainly focused on the demonstration of their potential profibrogenic role and, accordingly, the large majority of …
Use of steroid receptor related STIP1 gene analysis as an asthma marker
Authors: Helly Einisman, María Loreto Reyes, Jenniffer Angulo, Marcelo López-Lastra, Jaime Cerda, José Antonio Castro-Rodríguez
Journal: European Respiratory Journal (2012)

Introduction: Inhaled steroids are first choice for asthma treatment. However, some patients do not respond, needing higher doses or combined therapies. This difference in responsiveness might be associated to genetic makeup. We evaluated the possible association between variations in treatment requirement and single nucleotide polymorphism (SNP) in importin-13 and STIP1 (steroid receptor related genes).

Aims: Study SNP in importin-13 and STIP1, in healthy and asthmatic children.

Methods: Healthy children were enrolled by a public call. Asthmatics treated with ≥3 months of inhaled steroids were enrolled in outpatient clinics. A clinical questionnaire was applied. SNP were analyzed by PCR-RFLP assay.

Results: 125 children between 2 and 18 years of age were included, 227 healthy and 75 with asthma. Analysis of STIP1 SNP (rs2236647) was obtained in all healthy children and in 63 of the 75 asthmatics. The C allele (minor allele) was present in all asthmatic patients, 46 were heterozygous and 17 homozygous. In contrast, in healthy children, none were homozygous for this allele, 43/50 were heterozygous and 7/50 did not have the C allele (p<0.0001). When considered as a diagnostic test, STIP1 SNP analysis showed to have a sensibility of 100% with the presence of al least one C allele, and a specificity of 100% considering being homozygous. We did not find differences regarding asthma control and treatment requirement. No association could be established with importin-13 SNP (rs6671164 and rs2301993).

Conclusions: Analysis of STIP1 genetic variant rs2236647 serves as an asthma marker. Further investigation with a bigger N is needed to fully validate this study and establish other possible applications of these findings.
Diabetes and the Labor Market
Authors: H. Shelton Brown, Joselita K. Estrada, Gautam Hazarika, Elena Bastida
Journal: Diabetes Care (2005)

Economic analyses of diabetes and diabetes treatment and prevention are increasingly common (1–11). The cost of illness studies divide costs into direct and indirect components (12,13). Indirect costs are typically those associated with limited employment-related productivity (14–18). Direct costs usually include hospital and other medical costs (19–25). While these approaches have merit at the national level, they are less applicable at the community level for two reasons. First, lost income due to diabetes translates into substantially reduced local spending for everyone in communities where the prevalence of diabetes is high. For example, in a community with high diabetes-related unemployment, income reductions related to diabetes translate into less local spending, leading to layoffs and reduced expenditures. Second, the economy of the local community partially benefits from medical expenditures, which are largely inflows from outside the community but spent locally. In this study, we use an alternative method to assess the local economic impact of diabetes: input-output analysis. We focus on a largely Mexican-American community with a 25% type 2 diabetes prevalence rate, the Lower Rio Grande Valley (LRGV) of South Texas (26). We intend to show that the standard practice of including local medical care costs is not necessary to highlight …
Copper, Zinc, Manganese, and Magnesium Status and Complications of Diabetes Mellitus
Authors: Rober M Walter, Janet Y Uriu-Hare, Katherine Lewis Olin, Michelle H Oster, Bradley D Anawalt, James W Critchfield, Carl L Keen
Journal: Diabetes Care (1991)

Objective To evaluate copper, zinc, manganese, magnesium, and other indices of peroxidative status in diabetic and nondiabetic human subjects. Research Design and Methods Convenience sample of 57 insulin-dependent or non-insulin-dependent diabetic subjects recruited from the diabetes clinic of the University of California, Davis, Medical Center and 28 nondiabetic subjects recruited from the staffs of the Departments of Internal Medicine and Nutrition. Individuals conducting laboratory analyses were blind to subject group. A fasting blood sample was collected from all subjects and appropriately processed for future analyses. A 24-h urine collection was obtained in a subset of subjects. Results Hyperzincuria and hypermagnesuria were evident in diabetic subjects compared with control subjects. There were no differences in plasma magnesium or whole-blood manganese between groups. Plasma copper was higher and plasma zinc was lower in diabetic than in control subjects. When data were viewed with respect to specific diabetes-associated complications, diabetic subjects with retinopathy, hypertension, or microvascular disease had higher plasma copper concentrations compared with both diabetic subjects without complications and with control subjects. There were no significant differences between control and diabetic subjects in erythrocyte copper-zinc superoxide dismutase activity or whole-blood glutathione peroxidase or glutathione reductase activities. Plasma peroxide concentrations were higher in diabetic than control subjects. Conclusions Diabetes can alter copper, zinc, magnesium, and lipid peroxidation status. Perturbations in mineral metabolism are more pronounced in diabetic populations with specific complications. It is not known whether differences in trace element status are a consequence of diabetes, or alternatively, whether they contribute to the expression of the disease.
Haemodynamic, renal sodium handling, and neurohormonal effects of acute administration of low dose losartan, an angiotensin II receptor antagonist, in preascitic cirrhosis
Authors: N Girgrah
Journal: Gut (2000)

<h3>BACKGROUND</h3> The renin-angiotensin system may be implicated in the subtle sodium handling abnormality in preascitic cirrhosis. <h3>AIMS</h3> To assess the role of angiotensin II in sodium homoeostasis in preascitic cirrhosis, using losartan, its receptor antagonist. <h3>PATIENTS</h3> Nine male, preascitic cirrhotic patients, and six age matched, healthy male controls. <h3>METHODS</h3> A dose response study using 2.5, 5, 7.5, and 10 mg of losartan was performed on a daily 200 mmol sodium intake, followed by repeat studies with the optimal dose, 7.5 mg of losartan, to determine its effects on systemic and renal haemodynamics, renal sodium handling, and neurohumoral factors. <h3>RESULTS</h3> Preascitic cirrhotic patients had significantly reduced baseline urinary sodium excretion compared with controls (154 (8) versus 191 (12) mmol/day, p&lt;0.05), associated with significantly reduced systemic angiotensin II levels (6.0 (1.7) versus 39.5 (10.0) pmol/l, p=0.002). Losartan 7.5 mg normalised renal sodium handling in the preascitic cirrhotic patients (202 (12) mmol/day, p=0.05 versus baseline), without any change in systemic or renal haemodynamics, but with significantly increased systemic angiotensin II levels (7.8 (2.3) pmol/l, p=0.05 versus baseline). Losartan had no effect on renal sodium handling in controls. <h3>CONCLUSIONS</h3> In preascitic cirrhotic patients, the subtle renal sodium retention, paradoxically associated with low systemic neurohumoral factor levels, is improved with low dose losartan, suggesting the involvement of angiotensin II via its direct action on the renal tubule.
Response to ‘Are steroids required for induction therapy and relapses in lupus nephritis?’ by Abud-Mendoza <i>et al</i>
Authors: Marie Condon
Journal: Annals of the Rheumatic Diseases (2013)

Many thanks for the very interesting letter from Abud-Mendoza and Gonzalez-Amaro,1 highlighting their work in Mexico where they have successfully used rituximab in the treatment of both lupus nephritis …
Reticulin Accumulation in Essential Thrombocythemia: Prognostic Significance and Relationship to Therapy
Authors: Peter J. Campbell, David Bareford, Wendy N. Erber, Bridget S. Wilkins, Penny Wright, Georgina Buck, Keith Wheatley, Claire N. Harrison, Anthony R. Green
Journal: Journal of Clinical Oncology (2009)

Purpose Essential thrombocythemia (ET) manifests substantial interpatient heterogeneity in rates of thrombosis, hemorrhage, and disease transformation. Bone marrow histology reflects underlying disease activity in ET but many morphological features show poor reproducibility. Patients and Methods We evaluated the clinical significance of bone marrow reticulin, a measure previously shown to have relatively high interobserver reliability, in a large, prospectively-studied cohort of ET patients. Results Reticulin grade positively correlated with white blood cell (P = .05) and platelet counts (P = .0001) at diagnosis. Elevated reticulin levels at presentation predicted higher rates of arterial thrombosis (hazard ratio [HR], 1.8; 95% CI, 1.1 to 2.9; P = .01), major hemorrhage (HR, 2.0; 95% CI, 1.0 to 3.9; P = .05), and myelofibrotic transformation (HR, 5.5; 95% CI, 1.7 to 18.4; P = .0007) independently of known risk factors. Higher reticulin levels at diagnosis were associated with greater subsequent falls in hemoglobin levels in patients treated with anagrelide (P &lt; .0001), but not in those receiving hydroxyurea (P = .9). Moreover, serial trephine specimens in patients randomly assigned to anagrelide showed significantly greater increases in reticulin grade compared with those allocated to hydroxyurea (P = .0003), and four patients who developed increased bone marrow reticulin on anagrelide showed regression of fibrosis when switched to hydroxyurea. These data suggest that patients receiving anagrelide therapy should undergo surveillance bone marrow biopsy every 2 to 3 years and that those who show substantially increasing reticulin levels are at risk of myelofibrotic transformation and may benefit from changing therapy before adverse clinical features develop. Conclusion Our results demonstrate that bone marrow reticulin grade at diagnosis represents an independent prognostic marker in ET, reflecting activity and/or duration of disease, with implications for the monitoring of patients receiving anagrelide.
Lower Prepulse Inhibition in Children With the 22q11 Deletion Syndrome
Authors: Christina Sobin, Karen Kiley-Brabeck, Maria Karayiorgou
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: The 22q11 deletion syndrome is associated with a range of possible physical anomalies, probable ongoing learning disabilities, and a specific constellation of neuropsychological deficits, including impairments in selective and executive visual attention, working memory, and sensorimotor functioning. It has been estimated that 25% of the children with 22q11 deletion syndrome go on to develop schizophrenia in late adolescence or adulthood. This is of urgent concern. Specification of early brain network vulnerabilities may provide a basis for early intervention while indicating critical links between genes and severe psychiatric illness. Neuropsychological studies of children with 22q11 deletion syndrome have implicated an array of potentially aberrant brain pathways. This study was conducted to determine whether preattentive processing ("sensorimotor gating") deficits are present in this population. METHOD: The authors administered a test of prepulse inhibition to 25 children with 22q11 deletion syndrome and their 23 sibling comparison subjects, ages 6–13. It was predicted that the children with 22q11 deletion syndrome would have lower prepulse inhibition than the comparison subjects. RESULTS: Prepulse inhibition in the children with 22q11 deletion syndrome (26.06%) was significantly less than that of the sibling comparison subjects (46.41%). Secondary analyses suggested that this decrement did not reflect developmental delay, and lower prepulse inhibition was associated with particular subsyndromal symptoms in some children. CONCLUSIONS: Sensorimotor gating is lower in children with 22q11 deletion syndrome. These findings may indicate specific brain circuits that are anomalous in 22q11 deletion syndrome.