tbuckley/cabot-search huggingface dataset:
Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction
Authors: A. Cogolludo, L. Moreno, G. Frazziano, J. Moral-Sanz, C. Menendez, J. Castaneda, C. Gonzalez, E. Villamor, F. Perez-Vizcaino
Journal: Cardiovascular Research (2008)

The mechanisms involved in hypoxic pulmonary vasoconstriction (HPV) are not yet fully defined. The aim of the study was to determine the role of protein kinase C ζ (PKCζ) and neutral sphingomyelinase (nSMase) in HPV. Ceramide content was measured by immunocytochemistry and voltage-gated potassium channel (KV) currents were recorded by the patch clamp technique in isolated rat pulmonary artery smooth muscle cells (PASMC). Contractile responses were analysed in rat pulmonary arteries mounted in a wire myograph. Pulmonary pressure was recorded in anesthetized open-chest rats. Protein and mRNA expression were measured by western blot and RT–PCR, respectively. We found that hypoxia increased ceramide content in PASMC which was abrogated by inhibition of nSMase, but not acid sphingomyelinase (aSMase). The hypoxia-induced vasoconstrictor response in isolated pulmonary arteries and the inhibition of KV currents were strongly reduced by inhibition of PKCζ or nSMase but not aSMase. The nSMase inhibitor GW4869 prevented HPV in vivo. The vasoconstrictor response to hypoxia was mimicked by exogenous addition of bacterial Smase and ceramide. nSMase2 mRNA expression was ∼10-fold higher in pulmonary compared with mesenteric arteries. In mesenteric arteries, hypoxia failed to increase ceramide but exogenous SMase induced a contractile response. nSMase-derived ceramide production and the activation of PKCζ are early and necessary events in the signalling cascade of acute HPV.
FRI0295 Rituximab Retention Rate in Clinical Practice: A Large Multicentre Italian Cohort of Rheumatoid Arthritis Patients
Authors: A. Batticciotto, M. Covelli, L. Dinoia, A. Rinaldi, S. Giacuzzo, M. Govoni, D. Biasi, I. Dal Forno, M. Benucci, F. Li Gobbi, R. Caporali, M. Todoerti, M.A. Cimmino, G. Zampogna, A. Marchesoni, P. Gibertini, R. Pellerito, R. Vitetta, S. De Vita, L. Quartuccio, G. Paolazzi, P. Sarzi-Puttini
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Rituximab (RTX), a chimeric monoclonal antibody targeting CD20 B cell antigens, is a safe and effective treatment for rheumatoid arthritis (RA) [1]. It has been approved for RA patients who have inadequately responded to one or more anti-TNF agent and has recently been demonstrated to be significantly more effective after a first anti-TNF than switching to a second [2]. Long-term extensions of randomised controlled trials have demonstrated that prolonged RTX exposure of up to 9.5 years does not affect its safety, but there are no data concerning real-life clinical experience. <h3>Objectives</h3> The aim of this multicentre clinical study was to evaluate the retention of RTX treatment in patients with RA. <h3>Methods</h3> The clinical records of 472 RA patients treated with RTX from August 2006 to December 2013 in ten Italian rheumatology centres were reviewed, and treatment survival and the impact of selected variables were evaluated using Kaplan-Meier and Cox survival analyses. <h3>Results</h3> Four hundred and seventy-two patients with a diagnosis of RA based on the 1987 ACR classification criteria (81.6% female; mean age 56.2±12.8 years; mean disease duration 10.5±8 years; 76.3% RF positive; 75% anti-CCP positive) were treated with RTX for a mean of 40.1±26.37 months (range 0-122). Seventy-six percent were co-treated with MTX, and 24% had previously received two or more anti-TNF agents. Their median DAS28 score at baseline was 5.07±1.3. For patients completing at least 12, 24, 36, 48 and 60 months of follow-up, the retention rates were respectively 87.9%, 78.8%, 72.5%, 67.6% and 63.8% (Fig. I) Treatment discontinuations because of adverse events and inefficacy had a similar temporal trend. Multivariate analysis (Cox regression) showed that none of the considered predictive variables was significantly associated with treatment survival: gender p=0.399; age p=0.486; disease duration p=0.999, baseline DAS28 p=0.412; number of previous anti-TNFα failures p=0.975; the presence of RF p=0.513; MTX treatment p=0.340. <h3>Conclusions</h3> Our findings show that 63.8% of RA patients continued treatment with RTX for 60 months. <h3>References</h3> Chi Chiu Mok. Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des Devel Ther. 2013;8:87-100 Emery P, et al. Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study. Ann Rheum Dis. 2014. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3994
Post-traumatic swelling
Authors: A. O'Keeffe, J. Terris
Journal: BMJ (2012)

A 49 year old woman presented to the emergency department with facial swelling (fig 1⇓). She had fallen four days previously, striking her back on a large piece of concrete. After picking herself up she proceeded with her normal activities. The morning after the fall she awoke with swelling of the ankles. The swelling gradually spread throughout her body and four days later it began to compromise her vision. On admission to the emergency department she was generally fit and well, despite the swelling, although she was slightly short of breath on exertion.



Fig 1 Patient’s appearance at presentation



On examination she had gross swelling of the chest wall and abdomen extending to the ankles and wrists in the periphery. Breath sounds could be auscultated with a small amount of continuous pressure to the chest wall with the stethoscope. There was a hyper-resonant percussion note and reduced breath sounds on the left side of the thorax, with mild tenderness to percussion on the left posterior thorax over the eighth, ninth, and tenth ribs. Her vision was reduced owing to restricted eye opening, but when her eyelids were opened manually her pupils were equal and reactive to light and accommodation bilaterally. Visual acuity and eye movements were normal in both eyes. All other systems examinations were normal and oxygen saturations on room air were 96%. She underwent computed tomography of the thorax (fig 2⇓)



Fig 2 Computed tomography of the thorax





### 1 What is the differential diagnosis for widespread soft tissue swelling?

#### Short answer

The causes of generalised swelling can …
CCR2, CCR5, their ligands and chemokine receptor-interacting protein FROUNT have impressive effects on pulmonary adenocarcinoma
Authors: Meiji Itakura, Masato Shingyoji, Toshihiko Iizasa, Yasushi Yoshida, Hironori Ashinuma, Yasumitsu Miriya, Hajime Tamura
Journal: European Respiratory Journal (2013)

CC chemokine receptor 2 (CCR2), CC chemokine receptor 5 (CCR5) and their ligands, CCL2, CCL5 acts as a potent chemoattractant for inflammatory cells to promote migration from the peripheral circulation to sites of inflammation. FROUNT interacts with CCR2 and CCR5 C-terminal and react to CCR2 and CCR5 signals. 120 patients with pulmonary adenocarcinoma were included in this retrospective analysis. The expression of FROUNT, its’ related receptors and ligands mRNA expression in pulmonary adenocarcinoma were examined and evaluated the relation to the clinical data, prognosis, the effect of EGFR, p53 and KRAS genetical mutations. Immunohistochemical staining was performed about the resected cancer specimens.  FOUNT and their related-receptors CCR2 and CCR5 mRNA and protein were expressed in clinically resected lung cancer. The differentiation of pathological diagnosis was related with the CCR2, CCR5, CCL2 and CCL5 expression in tumor specimens. High mRNA expression of FROUNT, CCR2, CCR5, and CCL2 are related with smaller tumor size of surgical resected specimens. The mRNA expression of FROUNT in pulmonary adenocarcinoma specimens was influenced by the mutation of EGFR or the combination of p53 and EGFR mutation in lung cancer specimens. High mRNA expression of CCR2, CCR5, CCL2 and CCL5 in lung cancer patients indicated significantly good prognosis than the groups of low expressions. Wild type of p53 and high expression of CCR2, CCR5 and their ligands improved the prognosis. In conclusion, we propose CCR2, CCR5, CCL2, CCL5 and their related molecule, FROUNT as clinical good prognostic factors in pulmonary adenocarcinoma.
Ultraviolet (UV) A- and UVB-induced redox alterations and activation of nuclear factor-κB in human melanocytes-protective effects of<i>α</i>-tocopherol
Authors: P. Larsson, K. Öllinger, I. Rosdahl
Journal: British Journal of Dermatology (2006)

Journal Article Ultraviolet (UV) A‐ and UVB‐induced redox alterations and activation of nuclear factor‐κB in human melanocytes—protective effects of α‐tocopherol Get access P. Larsson, P. Larsson Department of Biomedicine and Surgery Division of Dermatology, and Department of Neuroscience and Locomotion, Division of Pathology II, Faculty of Health Sciences, Linköping University, S‐581 85 Linköping, Sweden Petra Larsson. E‐mail: petla@ibk.liu.se Search for other works by this author on: Oxford Academic Google Scholar K. Öllinger, K. Öllinger Department of Biomedicine and Surgery Division of Dermatology, and Department of Neuroscience and Locomotion, Division of Pathology II, Faculty of Health Sciences, Linköping University, S‐581 85 Linköping, Sweden Search for other works by this author on: Oxford Academic Google Scholar I. Rosdahl I. Rosdahl Department of Biomedicine and Surgery Division of Dermatology, and Department of Neuroscience and Locomotion, Division of Pathology II, Faculty of Health Sciences, Linköping University, S‐581 85 Linköping, Sweden Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 155, Issue 2, 1 August 2006, Pages 292–300, https://doi.org/10.1111/j.1365-2133.2006.07347.x Published: 01 August 2006 Article history Accepted: 09 February 2006 Published: 01 August 2006
Determination of high energy phosphates and glycogen in cardiac and skeletal muscle biopsies, with special reference to influence of biopsy technique and delayed freezing
Authors: H. E. Botker, P. Helligso, H. H. Kimose, A. R. Thomassen, T. T. Nielsen
Journal: Cardiovascular Research (1994)

The aim was to clarify the influence of biopsy technique and the effects of temporal delay between sampling and freezing on tissue contents of labile metabolites.Cardiac and skeletal muscle concentrations of adenine nucleotides, phosphocreatine, creatine, and glycogen in pigs were determined in endomyocardial and transmural myocardial biopsies and in skeletal muscle biopsies obtained with either endomyocardial bioptome or Tru-cut needle. The influence of the temporal delay between biopsy sampling and freezing was evaluated by keeping the biopsies at room temperature for varying intervals up to 300 s before freezing.Skeletal muscle showed higher concentrations of creatine compounds and lower contents of ADP and AMP than cardiac muscle, whereas ATP, total adenine nucleotide pool, and glycogen were similar. Lower phosphocreatine contents were found both in endomyocardial biopsies and in skeletal muscle biopsies obtained with bioptome compared to transmural myocardial biopsies and skeletal muscle biopsies obtained with Tru-cut needle, respectively. Other metabolites were unaffected by the biopsy technique. With extended delays between biopsy sampling and freezing, an increase in skeletal muscle phosphocreatine averaging 26% after 5 min was observed. In the heart, a decrease in glycogen content averaging 42% after 5 min was found. These changes were not related to the biopsy procedure and were not observed within the period usually required to freeze biopsies in experimental as well as clinical settings.There are essential metabolic differences between cardiac and skeletal muscle. Low endomyocardial phosphocreatine levels are influenced by the biopsy technique, compromising the use of endomyocardial biopsies for establishing myocardial phosphocreatine content. Reliable measurements of adenine nucleotides and glycogen can be obtained with endomyocardial biopsies.
Initiation and Gradual Intensification of Premixed Insulin Lispro Therapy Versus Basal ± Mealtime Insulin in Patients With Type 2 Diabetes Eating Light Breakfasts
Authors: Dario Giugliano, Mariusz Tracz, Sanjiv Shah, Alfonso Calle-Pascual, Cristina Mistodie, Rui Duarte, Ramazan Sari, Vincent Woo, Alina O. Jiletcovici, Jürgen Deinhard, Simone A. Wille, Jacek Kiljański
Journal: Diabetes Care (2013)

We compared two strategies initiating and intensifying insulin treatment and tested for noninferiority of premixed insulin to basal ± mealtime insulin analog in patients eating light breakfasts.This randomized, open-label, 48-week study compared two algorithms. Up to three injections of insulin lispro mix 25 and/or insulin lispro mix 50 (premix; premixed insulin lispro) or basal insulin glargine plus up to three injections of insulin lispro (basal+; glargine + insulin lispro) were used in type 2 diabetic patients uncontrolled with oral antihyperglycemic medication and consuming <15% daily calories at breakfast. The hypothesis was to test noninferiority of premix to basal+ for glycemic control measured by HbA1c after 48 weeks, assessed using ANCOVA with a 0.4% margin.Patients (n = 344; 176 [51%] females; mean [SD] age 54.3 [8.8] years; BMI 29.4 [4.6] kg/m(2); baseline HbA1c 9.02 [0.97]%) were randomized to premix (n = 171) or basal+ (n = 173). In the per-protocol analysis (n = 230), least squares means (95% CI) end point HbA1c were 7.40% (7.15-7.65) and 7.55% (7.27-7.82) in respective arms. Between-treatment difference was -0.14% (-0.42 to 0.13), with noninferiority met. Significantly more patients in premix achieved HbA1c targets of <7.0% compared with basal+ (48.2 vs. 36.2%; P = 0.024). Self-monitored blood glucose profiles, body weight changes, total insulin doses, and overall hypoglycemia (65 vs. 60%) were similar in premix and basal+ (P = 0.494), except nocturnal episodes (34.3 vs. 23.7%; P = 0.018) were more common in premix.Both intensive insulin strategies improved glycemic control; however, final HbA1c levels were seen above those achieved in previous treat-to-target trials, likely due to the inadequate insulin titrations and probably due to the complexity of tested insulin regimens. A higher percentage of patients achieved target HbA1c <7% with multiple premixed insulins, but this treatment resulted in more nocturnal hypoglycemia than a basal-bolus regimen.
Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint
Authors: Matthew D Hellmann, Jamie E Chaft, William N William, Valerie Rusch, Katherine M W Pisters, Neda Kalhor, Apar Pataer, William D Travis, Stephen G Swisher, Mark G Kris
Journal: The Lancet Oncology (2014)
All-cause and disease-specific mortality among male, former elite athletes: an average 50-year follow-up
Authors: Jyrki A Kettunen, Urho M Kujala, Jaakko Kaprio, Heli Bäckmand, Markku Peltonen, Johan G Eriksson, Seppo Sarna
Journal: British Journal of Sports Medicine (2014)

Aim To investigate life expectancy and mortality among former elite athletes and controls. Methods HR analysis of cause-specific deaths sourced from the national death registry for former Finnish male endurance, team and power sports athletes (N=2363) and controls (N=1657). The median follow-up time was 50 years. Results Median life expectancy was higher in the endurance (79.1 years, 95% CI 76.6 to 80.6) and team (78.8, 78.1 to 79.8) sports athletes than in controls (72.9, 71.8 to 74.3). Compared to controls, risk for total mortality adjusted for socioeconomic status and birth cohort was lower in the endurance ((HR 0.70, 95% CI 0.61 to 0.79)) and team (0.80, 0.72 to 0.89) sports athletes, and slightly lower in the power sports athletes (0.93, 0.85 to 1.03). HR for ischaemic heart disease mortality was lower in the endurance (0.68, 0.54 to 0.86) and team sports (0.73, 0.60 to 0.89) athletes. HR for stroke mortality was 0.52 (0.33 to 0.83) in the endurance and 0.59 (0.40 to 0.88) in the team sports athletes. Compared to controls, the risk for smoking-related cancer mortality was lower in the endurance (HR 0.20, 0.08 to 0.47) and power sports (0.40, 0.25 to 0.66) athletes. For dementia mortality, the power sports athletes, particularly boxers, had increased risk (HR 4.20, 2.30 to 7.81). Conclusions Elite athletes have 5–6 years additional life expectancy when compared to men who were healthy as young adults. Lower mortality for cardiovascular disease was in part due to lower rates of smoking, as tobacco-related cancer mortality was especially low.
Predicting CAP-related mortality with CRB-65
Authors: P. G. P. Charles
Journal: Thorax (2010)

We welcome the letter from Dr Iles and the opportunity to make additional comments on the subject of our recent editorial. 1 It is correct that the mortality rate in normotensive patients with acute pulmonary embolus (PE) reported in the recent study by Boca et al 2 refers to all-cause mortality at 3 months and not inpatient mortality, and we are pleased to have the opportunity to clarify this.A wide range of mortality rates in acute PE have been reported in published studies, depending on whether hypotensive and normotensive patients are included together or reported separately and whether inpatient, 30-day or 3-month mortality is quoted as an end point.Furthermore, identifying the exact cause of death in studies of PE is very difficult and few if any have been able to provide accurate data on this, therefore most report all-cause mortality.In the recent European Society of Cardiology guidelines on acute PE 3 it states that the risk of early mortality in normotensive patients with acute PE is dependent on the presence of right ventricular dysfunction (RVD) on transthoracic echocardiography, with studies reporting rates of 3e15% in those who are normotensive with RVD and <3% in those without RVD.Indeed, in the ICOPER study, 4 50% of normotensive patients with acute PE had RVD and the mortality in that group was 10%, much higher than in those who were normotensive but without evidence of RVD.These observations imply that, even in normotensive patients, clot burden as implied by the presence of RVD contributes to the risk of early death.This suggests that death after PE in those normotensive at presentation is not simply down to other diagnoses such as cancer but that cardiorespiratory comorbidities are likely to contribute to the risk in an additive way.In a recent study by Ibrahim and colleagues which included >15 000 patients with acute PE, the 30-day mortality rate in normotensive patients not receiving thrombolysis was 7.7% and the in-hospital mortality rate for normotensive patients who did not receive thrombolysis was 7.2 per 1000 person days. 5We therefore believe that it would be wrong to underestimate the early acute PE-associated mortality risk, even in normotensive patients.We believe this is significant in those with objective evidence on echocardiography or on cardiac biomarkers of RVD.It is this association which is eloquently described in the original article on which our editorial was based, stressing its importance to the literature.
Maximal HIV-1 Replication in Alveolar Macrophages during Tuberculosis Requires both Lymphocyte Contact and Cytokines
Authors: Yoshihiko Hoshino, Koh Nakata, Satomi Hoshino, Yoshihiro Honda, Doris B. Tse, Tatsuo Shioda, William N. Rom, Michael Weiden
Journal: The Journal of Experimental Medicine (2002)

HIV-1 replication is markedly upregulated in alveolar macrophages (AM) during pulmonary tuberculosis (TB). This is associated with loss of an inhibitory CCAAT enhancer binding protein β (C/EBPβ) transcription factor and activation of nuclear factor (NF)-κB. Since the cellular immune response in pulmonary TB requires lymphocyte–macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBPβ, activated NF-κB, and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBPβ expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-κB was activated. Antibodies that cross-linked macrophage expressed B-7, and vascular cell adhesion molecule and CD40 were used to mimic lymphocyte contact. All three cross-linking antibodies were required to abolish inhibitory C/EBPβ expression. However, the HIV-1 LTR was not maximally stimulated and NF-κB was not activated. Maximal HIV-1–LTR stimulation required both lymphocyte-derived soluble factors, and cross-linking of macrophage expressed costimulatory molecules. High level HIV-1–LTR stimulation was also achieved when IL-1β, IL-6, and TNF-β were added to macrophages with cross-linked costimulatory molecules. Contact between activated lymphocytes and macrophages is necessary to down-regulate inhibitory C/EBPβ, thereby derepressing the HIV-1 LTR. Lymphocyte-derived cytokines activate NF-κB, further enhancing the HIV-1 LTR.
Effective Photoimmunotherapy of Murine Colon Carcinoma Induced by the Combination of Photodynamic Therapy and Dendritic Cells
Authors: Ahmad Jalili, Marcin Makowski, Tomasz Świtaj, Dominika Nowis, Grzegorz M. Wilczyński, Ewa Wilczek, Magdalena Chorąży-Massalska, Anna Radzikowska, Włodzimierz Maśliński, Łukasz Biały, Jacek Sieńko, Aleksander Sieroń, Mariusz Adamek, Grzegorz Basak, Paweł Mróz, Ireneusz W. Krasnodębski, Marek Jakóbisiak, Jakub Gołąb
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The unique mechanism of tumor destruction by photodynamic therapy (PDT), resulting from apoptotic and necrotic killing of tumor cells accompanied by local inflammatory reaction and induction of heat shock proteins (HSPs), prompted us to investigate the antitumor effectiveness of the combination of PDT with administration of immature dendritic cells (DCs). Experimental Design: Confocal microscopy and Western blotting were used to investigate the influence of PDT on the induction of apoptosis and expression of HSP expression in C-26 cells. Confocal microscopy and flow cytometry studies were used to examine phagocytosis of PDT-treated C-26 cells by DCs. Secretion of interleukin (IL)-12 was measured with ELISA. Cytotoxic activity of lymph node cells was evaluated in a standard 51Cr-release assay. The antitumor effectiveness of PDT in combination with administration of DCs was investigated in in vivo model. Results: PDT treatment resulted in the induction of apoptotic and necrotic cell death and expression of HSP27, HSP60, HSP72/73, HSP90, HO-1, and GRP78 in C-26 cells. Immature DCs cocultured with PDT-treated C-26 cells efficiently engulfed killed tumor cells, acquired functional features of maturation, and produced substantial amounts of IL-12. Inoculation of immature DCs into the PDT-treated tumors resulted in effective homing to regional and peripheral lymph nodes and stimulation of cytotoxic activity of T and natural killer cells. The combination treatment with PDT and administration of DCs produced effective antitumor response. Conclusions: The feasibility and antitumor effectiveness demonstrated in these studies suggest that treatment protocols involving the administration of immature DCs in combination with PDT may have clinical potential.