tbuckley/cabot-search huggingface dataset:
Airway Delivery of Low-Dose Miglustat Normalizes Nasal Potential Difference in F508del Cystic Fibrosis Mice
Authors: Bob Lubamba, Jean Lebacq, Patrick Lebecque, Rita Vanbever, Anissa Leonard, Pierre Wallemacq, Teresinha Leal
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

N-butyldeoxynojyrimicin (NB-DNJ, miglustat [Zavesca]) an approved drug for treating Gaucher disease, was reported to be able to correct the defective trafficking of the F508del-CFTR protein.To evaluate the efficacy of in vivo airway delivery of miglustat for restoring ion transport in cystic fibrosis (CF).We used nasal transepithelial potential difference (PD) as a measure of sodium and chloride transport. The effect of nasal instillation of a single dose of miglustat was investigated in F508del, cftr knockout and normal homozygous mice. The galactose iminosugar analog N-butyldeoxygalactonojirimycin (NB-DGJ) was used as a placebo.In F508del mice, sodium conductance (evaluated by basal hyperpolarization) and chloride conductance (evaluated by perfusing the nasal mucosa with chloride-free solution in the presence of amiloride and forskolin) were normalized 1 hour after an intranasal dose of 50 picomoles of miglustat. Chloride conductance in the presence of 200 microM 4-4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS), an inhibitor of alternative chloride channels, was much higher after miglustat than after placebo. In cftr knockout mice, a normalizing effect was observed on sodium but not on chloride conductance.Our results provide clear evidence that nasal delivery of miglustat, at picomolar doses, normalizes sodium and Cftr-dependent chloride transport in F508del transgenic mice; they highlight the potential of topical miglustat as a therapy for CF.
Absence of T Cells Confers Increased Pulmonary Arterial Hypertension and Vascular Remodeling
Authors: Laimute Taraseviciene-Stewart, Mark R. Nicolls, Donatas Kraskauskas, Robertas Scerbavicius, Nana Burns, Carlyne Cool, Kathy Wood, Jane E. Parr, Susan A. Boackle, Norbert F. Voelkel
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Severe pulmonary arterial hypertension (SPH) is a frequently lethal condition characterized by pulmonary vascular remodeling and right heart strain or failure. SPH is also often associated with autoimmune and collagen vascular disorders.Objectives: To study the effects of T cells on the development of experimental SPH.Methods: Athymic nude rats lacking T cells were treated with a single subcutaneous injection of vascular endothelial growth factor (VEGF) receptor blocker SU5416 (20 mg/kg) to induce pulmonary vascular endothelial cell apoptosis. Immunohistochemical analysis and IL-4 levels of the lung tissue were performed. Cell death and proliferation were assessed by Western blot and immunohistochemistry.Measurements and Main Results: In contrast to SU5416-treated euthymic rats that develop SPH only in combination with chronic hypoxia, athymic nude rats developed SPH and vascular remodeling (similar to clinical SPH) at normoxic conditions as demonstrated by measurements of pulmonary artery pressure and right ventricle hypertrophy. Pulmonary arterioles became occluded with proliferating endothelial cells and were surrounded by mast cells, B cells, and macrophages. IL-4, proliferating cell nuclear antigen, and collagen type I levels were markedly increased in SU5416-treated athymic rat lungs. Antibody deposition was noted along the vascular endothelium in rats with SPH. Finally, protection from SPH was conferred by immune challenge with spleen cells from euthymic nude rats.Conclusions: These studies demonstrate the importance of a complete, intact immune system in protecting against pulmonary angioproliferation in this new model of SPH as well as the importance of intact VEGF receptor signaling for lung endothelial cell homeostasis.
Negligible clearance of ultrafine particles retained in healthy and affected human lungs
Authors: P. Wiebert, A. Sanchez-Crespo, J. Seitz, R. Falk, K. Philipson, W. G. Kreyling, W. Möller, K. Sommerer, S. Larsson, M. Svartengren
Journal: European Respiratory Journal (2006)

Ambient particles are believed to be a specific health hazard, although the underlying mechanisms are not fully understood. There are data in the literature indicating fast and substantial systemic uptake of particles from the lung. The present authors have developed an improved method to produce ultrafine particles with more stable radiolabelling and defined particle size range. Fifteen subjects inhaled technetium 99m ( 99m Tc)-labelled carbonaceous particles of 100 nm in size. Radioactivity over the lung was followed for 70 h. The clearance of these ultrafine particles from the lungs and specifically translocation to the circulation was tested. Lung retention for all subjects at 46 h was mean± sd 99±4.6%. Cumulative leaching of 99m Tc activity from the particles was 2.6±0.96% at 70 h. The 24-h activity leaching in urine was 1.0±0.55%. No evidence of a quantitatively important translocation of 100-nm particles to the systemic circulation from the lungs was found. More research is needed to establish if the ∼1% cleared activity originates from leached activity or insoluble translocated particles, and whether a few per cent of translocated particles is sufficient to cause harmful effects.
Neural Correlates of Emotional Distractibility in Bipolar Disorder Patients, Unaffected Relatives, and Individuals With Hypomanic Personality
Authors: Philipp Kanske, Janine Heissler, Sandra Schönfelder, Johanna Forneck, Michèle Wessa
Journal: American Journal of Psychiatry (2013)

Neuropsychological deficits and emotion dysregulation are present in symptomatic and euthymic patients with bipolar disorder. However, there is little evidence on how cognitive functioning is influenced by emotion, what the neural correlates of emotional distraction effects are, and whether such deficits are a consequence or a precursor of the disorder. The authors used functional MRI (fMRI) to investigate these questions.fMRI was used first to localize the neural network specific to a certain cognitive task (mental arithmetic) and then to test the effect of emotional distractors on this network. Euthymic patients with bipolar I disorder (N=22), two populations at high risk for developing the disorder (unaffected first-degree relatives of individuals with bipolar disorder [N=17]), and healthy participants with hypomanic personality traits [N=22]) were tested, along with three age-, gender-, and education-matched healthy comparison groups (N=22, N=17, N=24, respectively).There were no differences in performance or activation in the task network for mental arithmetic. However, while all participants exhibited slower responses when emotional distractors were present, this response slowing was greatly enlarged in bipolar patients. Similarly, task-related activation was generally increased under emotional distraction; however, bipolar patients exhibited a further increase in right parietal activation that correlated positively with the response slowing effect.The results suggest that emotional dysregulation leads to exacerbated neuropsychological deficits in bipolar patients, as evidenced by behavioral slowing and task-related hyperactivation. The lack of such a deficit in high-risk populations suggests that it occurs only after disease onset, rather than representing a vulnerability marker.
Metronomic oral topotecan prolongs survival and reduces liver metastasis in improved preclinical orthotopic and adjuvant therapy colon cancer models
Authors: Christina Hackl, Shan Man, Giulio Francia, Chloe Milsom, Ping Xu, Robert S Kerbel
Journal: Gut (2012)

<h3>Objective</h3> Advanced and recurrent diseases are the major causes of death in colon cancer. No standard preclinical model addresses advanced disease and spontaneous metastasis after orthotopic tumour growth. In this study, the authors report the establishment of such standardised orthotopic mouse models of colon cancer and their use in evaluating metronomic topotecan alone or in combination with standard chemotherapy. <h3>Design</h3> Human colon cancer cell lines, transfected with human chorionic gonadotropin and luciferase, were injected orthotopically into the caecal wall of severe combined immunodeficient mice, intrasplenically or subcutaneously. For adjuvant therapy, caecal resections were performed 3–5 weeks after tumour cell injection. Chemotherapy drugs tested included uracil/tegafur, folinic acid, oxaliplatin, topotecan, pazopanib and various combinations. <h3>Results</h3> Subcutaneous tumours showed exaggerated sensitivity to treatment by delayed tumour growth (p<i>=</i>0.002) and increased survival (p<i>=</i>0.0064), but no metastatic spread. Intrasplenic cell injection resulted in rapid and extensive but artefactual metastasis without treatment effect. Intracaecal cell injection with tumour take rates of 87.5–100% showed spontaneous metastases at clinically relevant rates. Metronomic topotecan significantly polonged survival and reduced metastasis. In the adjuvant setting, metronomic maintenance therapy (after FOLFOX-like induction) prolonged survival compared with vehicle controls (p=0.0003), control followed by topotecan (p=0.0161) or FOLFOX-like therapy (p=0.0003). <h3>Conclusion</h3> The refined orthotopic implantation technique proved to be a clinically relevant model for metastasis and therapy studies. Furthermore, metronomic therapy with oral topotecan may be promising to consider for clinical trials of metastatic colon cancer and long-term adjuvant maintenance therapy of colon cancer.
Differential expression of syndecans and glypicans in chronically inflamed synovium
Authors: A M Patterson, A Cartwright, G David, O Fitzgerald, B Bresnihan, B A Ashton, J Middleton
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Background:</h3> Membrane-bound heparan sulphate proteoglycans (HSPGs) act as co-receptors and presenters of cytokines and are involved in cell–matrix and cell–cell adhesion. <h3>Aim:</h3> To investigate which HSPGs are expressed in knee joint synovia from patients with different forms of arthritis and normal individuals. <h3>Methods:</h3> Synovial samples were obtained from patients with early rheumatoid arthritis (n = 8), longstanding rheumatoid arthritis (n = 13), psoriatic arthritis (n = 7), osteoarthritis (n = 6) and normal joints (n = 12). Expression of syndecan-1, -2, -3 and -4 and glypican-1, -3 and -4 was analysed by immunohistochemistry and dual label immunofluorescence. <h3>Results:</h3> The expression of HSPGs in chronically inflamed synovium exhibited a differential distribution. Syndecan-1 was present in the mononuclear infiltrates of synovia from patients with rheumatoid and psoriatic arthritis where it was expressed by plasma cells. Syndecan-2 was present mainly in blood vessels where it occurred on endothelial cells, pericytes and smooth muscle cells. Syndecan-3 stained intensely in endothelial cells but also occurred in sublining macrophages and the lining layer. Glypican-4 occurred in the lining layer and blood vessels. Increased expression of these HSPGs was apparent in rheumatoid and psoriatic compared to osteoarthritic and normal synovia. Little or no staining for syndecan-4, glypican-1 and glypican-3 was seen in all samples. <h3>Discussion:</h3> Selected HSPGs, such as syndecan-1, -2 and -3 and glypican-4, could play a part in the pathophysiology of arthritis, such as the migration and retention of leukocytes and angiogenesis in the chronically inflamed synovium.
Scintigraphic measurement of tracheal mucus velocity in vivo
Authors: L. Morgan, M. Pearson, R. de Iongh, D. Mackey, H. van der Wall, M. Peters, J. Rutland
Journal: European Respiratory Journal (2004)

Mucociliary clearance (MCC) is an important mechanism for removing inhaled particles, secretions and cellular debris from the respiratory tract. Here, a direct measurement of tracheal mucus velocity (TMV) for assessment of MCC, suitable for clinical and research use, is reported, and a comparison is made of TMV in normal subjects and patients with chronic obstructive pulmonary disease (COPD). A 0.1‐mL bolus of radiolabelled (2–5 MBq), technetium-labelled macroaggregated human albumin ( 99m Tc MAA) was injected through the cricothyroid membrane into the trachea of 20 young (&lt;50 yrs) and 12 older (&gt;50 yrs) normal subjects and 34 patients with COPD. Repeat studies were carried out in 13 normal subjects and 16 COPD patients. Movement of the bolus in the trachea was recorded (15 min) using a gamma camera interfaced to a computer. Data were analysed using specifically designed software. The test was well tolerated by subjects and patients, and no significant adverse events were reported. No significant differences were observed between data recorded from different regions of the bolus (leading edge, peak, trailing edge) by analysis of variance (ANOVA). Bland-Altman plots of the repeat studies indicated that data were more variable in normal subjects (coefficient of repeatability (COR) 10.3 mm·min −1 ) than in COPD patients (COR 5.5 mm·min −1 ). TMV (mean±sd) in young normal subjects (n=20) was 10.7±3.5 mm·min −1 . TMV was reduced in older normal subjects (n=12; 6.5±2.6 mm·min −1 ) and further reduced in COPD (n=34; 2.1±2.7 mm·min −1 ). In conclusion, this technique can be used to measure tracheal mucus velocity rapidly and safely in healthy subjects and patients with respiratory tract disease. This study has confirmed that tracheal mucus velocity declines with age and is further impaired in patients with chronic obstructive pulmonary disease.
Pathophysiology of Preeclampsia
Authors: M D Lindheimer, A I Katz
Journal: Annual Review of Medicine (1981)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Visualizing translocation dynamics and nascent transcript errors in paused RNA polymerases in vivo
Authors: Masahiko Imashimizu, Hiroki Takahashi, Taku Oshima, Carl McIntosh, Mikhail Bubunenko, Donald L. Court, Mikhail Kashlev
Journal: Genome biology (2015)

Abstract Background Transcription elongation is frequently interrupted by pausing signals in DNA, with downstream effects on gene expression. Transcription errors also induce prolonged pausing, which can lead to a destabilized genome by interfering with DNA replication. Mechanisms of pausing associated with translocation blocks and misincorporation have been characterized in vitro , but not in vivo . Results We investigate the pausing pattern of RNA polymerase (RNAP) in Escherichia coli by a novel approach, combining native elongating transcript sequencing (NET-seq) with RNase footprinting of the transcripts (RNET-seq). We reveal that the G-dC base pair at the 5′ end of the RNA-DNA hybrid interferes with RNAP translocation. The distance between the 5′ G-dC base pair and the 3′ end of RNA fluctuates over a three-nucleotide width. Thus, the G-dC base pair can induce pausing in post-translocated, pre-translocated, and backtracked states of RNAP. Additionally, a CpG sequence of the template DNA strand spanning the active site of RNAP inhibits elongation and induces G-to-A errors, which leads to backtracking of RNAP. Gre factors efficiently proofread the errors and rescue the backtracked complexes. We also find that pausing events are enriched in the 5′ untranslated region and antisense transcription of mRNA genes and are reduced in rRNA genes. Conclusions In E. coli , robust transcriptional pausing involves RNAP interaction with G-dC at the upstream end of the RNA-DNA hybrid, which interferes with translocation. CpG DNA sequences induce transcriptional pausing and G-to-A errors.
Improved Postprandial Glycemic Control With Biphasic Insulin Aspart Relative to Biphasic Insulin Lispro and Biphasic Human Insulin in Patients With Type 2 Diabetes
Authors: Kjeld Hermansen, Michele Colombo, Heidi Storgaard, Anette Østergaard, Klaus Kølendorf, Sten Madsbad
Journal: Diabetes Care (2002)

The rapid-acting insulin analogs aspart and lispro have now been developed in biphasic formulations. This trial compared the postprandial serum glucose control of biphasic insulin aspart 30 (BIAsp 30: 30% aspart, 70% protaminated aspart) with that of biphasic insulin lispro 25 (Mix25: 25% lispro, 75% protaminated lispro) and biphasic human insulin 30 (BHI 30: 30% regular insulin, 70% NPH insulin) in insulin-treated subjects with type 2 diabetes.This was an open-labeled, randomized, single-dose, three-way crossover trial of 61 insulin-treated subjects with type 2 diabetes who had no significant late diabetic complications. BIAsp 30 and Mix25 were injected subcutaneously immediately before a test meal, and BHI 30 was injected 15 min before a test meal. The primary target of analysis was serum glucose excursion 0-5 h after a meal.The postprandial glycemic control with BIAsp 30, as assessed by the 5-h postmeal serum glucose excursion, was superior to that with both BHI 30 and Mix25 (16.6 +/- 4.5 vs. 20.1 +/- 4.9 and 18.9 +/- 6.1 mmol/l per hour, respectively; P < 0.001 and P < 0.05). For BIAsp 30 versus BHI 30, this was supported by a reduced maximum glucose concentration [C(max(SG))] (-5%; P < 0.05) occurring earlier (-13 min; P < 0.01). Furthermore, BIAsp 30 displayed a higher maximum serum insulin concentration (+101%; P < 0.001) occurring earlier (-55 min; P < 0.001) compared with BHI 30. Compared with Mix25, there was a shorter time to C(max(SG)) (-11 min; P < 0.05) after treatment with BIAsp 30.This trial demonstrates that BIAsp 30 improves postprandial glycemic control compared with both Mix25 and BHI 30 in subjects with type 2 diabetes.
Clinical Effectiveness of Statin Therapy After Ischemic Stroke: Primary Results From the Statin Therapeutic Area of the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) Study
Authors: Emily C. O’Brien, Melissa A. Greiner, Ying Xian, Gregg C. Fonarow, DaiWai M. Olson, Lee H. Schwamm, Deepak L. Bhatt, Eric E. Smith, Lesley Maisch, Deidre Hannah, Brianna Lindholm, Eric D. Peterson, Michael J. Pencina, Adrian F. Hernandez
Journal: Circulation (2015)

Background— In patients with ischemic stroke, data on the real-world effectiveness of statin therapy for clinical and patient-centered outcomes are needed to better inform shared decision making. Methods and Results— Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) is a Patient-Centered Outcomes Research Institute–funded research program designed with stroke survivors to evaluate the effectiveness of poststroke therapies. We linked data on patients ≥ 65 years of age enrolled in the Get With The Guidelines–Stroke Registry to Medicare claims. Two-year to postdischarge outcomes of those discharged on a statin versus not on a statin were adjusted through inverse probability weighting. Our coprimary outcomes were major adverse cardiovascular events and home time (days alive and out of a hospital or skilled nursing facility). Secondary outcomes included all-cause mortality, all-cause readmission, cardiovascular readmission, and hemorrhagic stroke. From 2007 to 2011, 77 468 patients who were not taking statins at the time of admission were hospitalized with ischemic stroke; of these, 71% were discharged on statin therapy. After adjustment, statin therapy at discharge was associated with a lower hazard of major adverse cardiovascular events (hazard ratio, 0.91; 95% confidence interval, 0.87–0.94), 28 more home-time days after discharge ( P &lt;0.001), and lower all-cause mortality and readmission. Statin therapy at discharge was not associated with increased risk of hemorrhagic stroke (hazard ratio, 0.94; 95% confidence interval, 0.72–1.23). Among statin-treated patients, 31% received a high-intensity dose; after risk adjustment, these patients had outcomes similar to those of recipients of moderate-intensity statin. Conclusion— In older ischemic stroke patients who were not taking statins at the time of admission, discharge statin therapy was associated with lower risk of major adverse cardiovascular events and nearly 1 month more home time during the 2-year period after hospitalization.
Enablers and Barriers to Large-Scale Uptake of Improved Solid Fuel Stoves: A Systematic Review
Authors: Eva A. Rehfuess, Elisa Puzzolo, Debbi Stanistreet, Daniel Pope, Nigel G. Bruce
Journal: Environmental Health Perspectives (2013)

Globally, 2.8 billion people rely on household solid fuels. Reducing the resulting adverse health, environmental, and development consequences will involve transitioning through a mix of clean fuels and improved solid fuel stoves (IS) of demonstrable effectiveness. To date, achieving uptake of IS has presented significant challenges.We performed a systematic review of factors that enable or limit large-scale uptake of IS in low- and middle-income countries.We conducted systematic searches through multidisciplinary databases, specialist websites, and consulting experts. The review drew on qualitative, quantitative, and case studies and used standardized methods for screening, data extraction, critical appraisal, and synthesis. We summarized our findings as "factors" relating to one of seven domains-fuel and technology characteristics; household and setting characteristics; knowledge and perceptions; finance, tax, and subsidy aspects; market development; regulation, legislation, and standards; programmatic and policy mechanisms-and also recorded issues that impacted equity.We identified 31 factors influencing uptake from 57 studies conducted in Asia, Africa, and Latin America. All domains matter. Although factors such as offering technologies that meet household needs and save fuel, user training and support, effective financing, and facilitative government action appear to be critical, none guarantee success: All factors can be influential, depending on context. The nature of available evidence did not permit further prioritization.Achieving adoption and sustained use of IS at a large scale requires that all factors, spanning household/community and program/societal levels, be assessed and supported by policy. We propose a planning tool that would aid this process and suggest further research to incorporate an evaluation of effectiveness.
Spirometric reference values in a large Middle Eastern population
Authors: M. Golshan, M. Nematbakhsh, B. Amra, R.O. Crapo
Journal: European Respiratory Journal (2003)

Ethnic differences in pulmonary function have been frequently reported. The purposes of this study were to derive equations for the prediction of normative spirometry values for a large population of Persians in Isfahan and compare them to reference values from a White Euro-USA population. Spirometry measurements were obtained from 4,341 randomly selected healthy nonsmoker subjects in Isfahan, Iran, utilising American Thoracic Society guidelines and a vigorous quality assurance program. Measured data from 3,213 subjects were analysed using multiple regression techniques to derive prediction equations for spirometric variables; the remaining 1,128 subjects were used as a control group to test the validity of the derived equations. In addition, predicted values were compared with values derived from recently published equations for the USA. Derived prediction equations showed good performance for most spirometric parameters. Compared with USA Whites, adult Persians have minimally lower forced vital capacities, while the values for children are close to USA Whites. In comparison with reference equations based on European or USA populations, local reference values are more biologically and technically suitable for the interpretation of spirometric data from Iranian populations.