tbuckley/cabot-search huggingface dataset:
Dose-dependent onset and cessation of action of inhaled budesonide on exhaled nitric oxide and symptoms in mild asthma
Authors: S A Kharitonov
Journal: Thorax (2002)

<b>Background:</b> Dose dependent anti-inflammatory effects of inhaled corticosteroids in asthma are difficult to demonstrate in clinical practice. The anti-inflammatory effect of low dose inhaled budesonide on non-invasive exhaled markers of inflammation and oxidative stress were assessed in patients with mild asthma. <b>Methods:</b> 28 patients entered a double blind, placebo controlled, parallel group study and were randomly given either 100 or 400 μg budesonide or placebo once daily, inhaled from a dry powder inhaler (Turbohaler), for 3 weeks followed by 1 week without treatment. Exhaled nitric oxide (NO), exhaled carbon monoxide (CO), nitrite/nitrate, S-nitrosothiols, and 8-isoprostanes in exhaled breath condensate were measured four times during weeks 1 and 4, and once a week during weeks 2 and 3. <b>Results:</b> A dose-dependent speed of onset and cessation of action of budesonide was seen on exhaled NO and asthma symptoms. Treatment with 400 μg/day reduced exhaled NO faster (–2.06 (0.37) ppb/day) than 100 μg/day (–0.51 (0.35) ppb/day; p&lt;0.01). The mean difference between the effect of 100 and 400 μg budesonide was –1.55 ppb/day (95% CI –2.50 to –0.60). Pretreatment NO levels were positively related to the subsequent speed of reduction during the first 3–5 days of treatment. Faster recovery of exhaled NO was seen after stopping treatment with budesonide 400 μg/day (1.89 (1.43) ppb/day) than 100 μg/day (0.49 (0.34) ppb/day, p&lt;0.01). The mean difference between the effect of 100 and 400 μg budesonide was 1.40 ppb/day (95% CI –0.49 to 2.31). Symptom improvement was dose-dependent, although symptoms returned faster in patients treated with 400 μg/day. A significant reduction in exhaled nitrite/nitrate and S-nitrosothiols after budesonide treatment was not dose-dependent. There were no significant changes in exhaled CO or 8-isoprostanes in breath condensate. <b>Conclusion:</b> Measurement of exhaled NO levels can indicate a dose-dependent onset and cessation of anti-inflammatory action of inhaled corticosteroids in patients with mild asthma.
A Novel ex Vivo Angiogenesis Assay Based on Electroporation-Mediated Delivery of Naked Plasmid DNA to Skeletal Muscle
Authors: Hyung-Suk Jang, Hyun-Joong Kim, Jeong-Min Kim, Young-Sam Lee, Koung Li Kim, Jeong-A Kim, Jae-Young Lee, Wonhee Suh, Jin-Ho Choi, Eun-Seok Jeon, Jonghoe Byun, Duk-Kyung Kim
Journal: Molecular Therapy (2004)

An angiogenesis assay based on gene transfer would be extremely useful for angiogenic gene therapy. A simple, reproducible, and quantitative assay to test angiogenic genes would provide more accurate predictions than conventional peptide-based assays. Here, we have developed a semiquantitative angiogenesis assay utilizing gene transfer into skeletal muscle, which is a target tissue for ischemic limb diseases. To facilitate quick and clean analysis, a naked plasmid DNA vector combined with an electroporation procedure was used for gene transfer. When the plasmid vector encoding vascular endothelial growth factor cDNA (pJDK-VEGF165) was injected into the tibialis anterior muscle of BALB/c mice, followed by in vivo electroporation and explant culture in growth factor-reduced Matrigel, the outward migration of sprouting cells was observed as early as day 2. The cells soon formed capillary networks, which peaked at day 7 and persisted until day 14. The capillary-like structures were positive for von Willebrand factor, platelet endothelial cell adhesion molecule, and vimentin, suggesting they were endothelial cells. There was little, if any, sprouting or formation of capillaries from the control vector (pJDK)-injected group. Consistent with the region of sprouting and network formation, the amount of secreted VEGF increased in the conditioned medium of explant cultures. The angiogenic potential of connective tissue growth factor (CTGF) was examined using the new assay. Whereas the CTGF gene alone induced weak sprouting activity, it appeared to inhibit the angiogenic activity of the VEGF165 gene during cotreatment. This attenuating activity of CTGF on VEGF was reproduced in vivo in a murine model of hindlimb ischemia. In a group of mice treated with both pJDK-CTGF and pJDK-VEGF165, the blood flow measured by laser Doppler imaging was significantly lower than that of the pJDK-VEGF165-treated group 10 days after femoral artery excision. These results are consistent with recent reports that suggest that CTGF inhibits VEGF. This confirms the usefulness of this novel ex vivo assay in assessing the angiogenic capacity of genes of interest. In summary, this new gene-based angiogenesis assay should be widely applicable in the study of angiogenic or antiangiogenic genes because it can readily predict the angiogenic potential of specific genes and their combinations.
Na+/H+ Exchanger Regulatory Factor 3 Is Critical for Multidrug Resistance Protein 4–Mediated Drug Efflux in the Kidney
Authors: Joonhee Park, Jin-Oh Kwak, Brigitte Riederer, Ursula Seidler, Susan P.C. Cole, Hwa Jeong Lee, Min Goo Lee
Journal: Journal of the American Society of Nephrology (2014)

Na+/H+ exchanger regulatory factor 3 (NHERF3) is a PSD-95/discs large/ZO-1 (PDZ)-based adaptor protein that regulates several membrane-transporting proteins in epithelia. However, the in vivo physiologic role of NHERF3 in transepithelial transport remains poorly understood. Multidrug resistance protein 4 (MRP4) is an ATP binding cassette transporter that mediates the efflux of organic molecules, such as nucleoside analogs, in the gastrointestinal and renal epithelia. Here, we report that Nherf3 knockout (Nherf3−/−) mice exhibit profound reductions in Mrp4 expression and Mrp4-mediated drug transport in the kidney. A search for the binding partners of the COOH-terminal PDZ binding motif of MRP4 among several epithelial PDZ proteins indicated that MRP4 associated most strongly with NHERF3. When expressed in HEK293 cells, NHERF3 increased membrane expression of MRP4 by reducing internalization of cell surface MRP4 and consequently, augmented MRP4-mediated efflux of adefovir, a nucleoside-based antiviral agent and well known substrate of MRP4. Examination of wild-type and Nherf3−/− mice revealed that Nherf3 is most abundantly expressed in the kidney and has a prominent role in modulating Mrp4 levels. Deletion of Nherf3 in mice caused a profound reduction in Mrp4 expression at the apical membrane of renal proximal tubules and evoked a significant increase in the plasma and kidney concentrations of adefovir, with a corresponding decrease in the systemic clearance of this drug. These results suggest that NHERF3 is a key regulator of organic transport in the kidney, particularly MRP4-mediated clearance of drug molecules.
A plasmatic factor may cause platelet activation in acute ischemic stroke.
Authors: R Joseph, K M Welch, S B Oster, S Grunfeld, G D'Andrea
Journal: Circulation Research (1989)

To study the pathogenesis of platelet activation in ischemic stroke, ionized calcium ([Cai2+]) was measured in aequorin-loaded gel-filtered platelets in the basal and stimulated state. Basal [Cai2+] was increased in stroke patients maximally 36-72 hours after onset. The increase in [Cai2+] after stimulation with thrombin, collagen, and platelet-activating factor were also greater in stroke patients, but the profiles of these [Cai2+] changes were parallel to control. Cross incubation of control platelets with plasma from stroke patients resulted in raised basal [Cai2+] and caused the release of serotonin from platelets. These results indicate that the higher platelet basal [Cai2+] in stroke patients represents a lowered threshold for activation and that this may be due to a plasmatic factor rather than a primary platelet defect.
White Count, Ph and Lactate in Ascites in the Diagnosis of Spontaneous Bacterial Peritonitis
Authors: Chaur-Young Yang, Yun-Fan Liaw, Chia-Ming Chu, I-Shyan Sheen
Journal: Hepatology (1985)

In order to evaluate the diagnostic accuracy of ascitic pH and lactate for early confirmation of spontaneous bacterial peritonitis (SBP), 109 consecutive patients with ascites were studied. The mean ascitic leukocyte [white blood cell (WBC)] and polymorphonuclear cell (PMN) counts, pH and lactate levels in 42 patients with sterile "normal" ascites were 124 +/- 157 per mm3, 41 +/- 77 per mm3, 7.502 +/- 0.097 and 11.1 +/- 7.9 mg per dl, respectively. Mean ascitic WBC and PMN counts were significantly increased in 10 patients with SBP (10,452 +/- 8,091 and 9,522 +/- 7,470 per mm3), in 10 patients with bloody ascites (2,591 +/- 4,284 and 1,057 +/- 1,494 per mm3) and in 11 patients with cytology positive malignant ascites (1,529 +/- 2,071 and 868 +/- 1,601 per mm3) (p less than 0.001). Mean ascitic pH was significantly reduced in SBP (7.335 +/- 0.048), in bloody ascites (7.384 +/- 0.037) and in cytology positive malignant ascites (7.355 +/- 0.167) (p less than 0.001). Mean ascitic lactate was also significantly elevated in these three groups of patients (36.8 +/- 17.0, 42.8 +/- 35.8 and 24.0 +/- 17.5 mg per dl, respectively; p less than 0.001) as well as in patients with bacteremia (51.6 +/- 78.0 mg per dl, p less than 0.005). However, ascitic pH less than 7.31, ascitic lactate greater than 33 mg per dl were observed only in three of the patients with SBP.(ABSTRACT TRUNCATED AT 250 WORDS)
Clinical Factors And Laboratory Correlates Of Milk Allergy Resolution In A Cohort Of Infants With Milk Allergy (CoFAR)
Authors: R. Wood, S. Jones, B. Vickery, A. Liu, W. Burks, D. Fleischer, D. Stablein, A. Henning, L. Mayer, H. Sampson
Journal: Journal of Allergy and Clinical Immunology (2011)
Severe linear form of granuloma annulare along Blaschko’s lines preceding the onset of a classical form of granuloma annulare in a child
Authors: F. Morice-Picard, F. Boralevi, S. Lepreux, C. Labrèze, D. Lacombe, A. Taïeb
Journal: British Journal of Dermatology (2007)

Conflicts of interest: none declared. Sir, Happle postulated that cutaneous lesions following Blaschko's lines are manifestations of somatic mosaicism, abnormal skin being distributed along a linear pattern surrounded by normal skin.1 When a mutation occurs in a heterozygous embryo, loss of heterozygosity (LOH) in a cellular clone gives rise to an association of severe linear cutaneous lesions and a classical generalized phenotype (corresponding to Happle's type 2 mosaicism).2, 3 In a recent study, Poblete‐Gutierrez et al. provided a molecular basis for this type 2 segmental mosaicism in Hailey–Hailey disease, an autosomal dominant disorder characterized by abnormal keratinocyte differentiation.4 In the patient with both the linear and the generalized form of Hailey–Hailey disease, the proven subsequent LOH in the linear lesion could have resulted from a postzygotic event at an early stage in the heterozygote embryo. Thus, homozygosity for the disease‐causing gene could explain a dose‐dependent effect and the more severe linearly localized lesions of the skin disease. Here, we report a patient with a 5‐year history of granuloma annulare (GA) showing a predominantly unilateral distribution of linear lesions following Blaschko's lines associated with a classical symmetrical presentation of the disease, and discuss the applicability of the concept of type 2 mosaicism to polygenic skin disorders.
Renal Cysts of inv/inv Mice Resemble Early Infantile Nephronophthisis
Authors: Carrie L. Phillips, Karen J. Miller, Adele J. Filson, Jens Nürnberger, Jeffrey L. Clendenon, Gregory W. Cook, Kenneth W. Dunn, Paul A. Overbeek, Vincent H. Gattone, Robert L. Bacallao
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Cystic kidney disease has been linked to mutations in the Invs gene in mice with inversion of embryonic turning (inv/inv) and the INVS (NPHP2) gene in infants with nephronophthisis type 2 (NPHP2). The inv mouse model features multiorgan defects including renal cysts, altered left-right laterality, and hepatobiliary duct malformations transmitted in an autosomal recessive manner. Affected mice usually die of renal and liver failure by postnatal day 7. Although cardiopulmonary and liver anomalies have been carefully detailed, renal cysts have yet to be fully characterized in inv/inv. By use of three-dimensional visualization by two-photon microscopy, this study provides the first comprehensive analysis of in situ cyst formation and progression in inv/inv kidneys. At embryonic day 15, there is dilatation of Bowman's capsule followed temporally by corticomedullary cysts involving collecting ducts, proximal tubules, and thick ascending limbs. Collecting ducts of newborn inv/inv mice are uniformly and diffusely cystic from medulla to cortex, with normal diameters found only at their most proximal tips. Proximal tubules form fusiform cysts that alternate with segments of normal or narrowed caliber along torturous convolutions. Because defective cilia have been linked to situs inversus and cystogenesis, we examined inv/inv cilia by scanning and transmission electron microscopy. The former detected monocilia of expected length in cystic collecting ducts and proximal tubules; the latter demonstrated the usual 9 + 2 pattern in respiratory cilia. The inv mutant mouse has renal cysts resembling infantile NPHP2 and will provide broader insight into the role cilia play in renal cystogenesis.
Phase III Study of Docetaxel Compared With Vinorelbine in Elderly Patients With Advanced Non–Small-Cell Lung Cancer: Results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904)
Authors: Shinzoh Kudoh, Koji Takeda, Kazuhiko Nakagawa, Minoru Takada, Nobuyuki Katakami, Kaoru Matsui, Tetsu Shinkai, Toshiyuki Sawa, Isao Goto, Hiroshi Semba, Takashi Seto, Masahiko Ando, Taroh Satoh, Naruo Yoshimura, Shunichi Negoro, Masahiro Fukuoka
Journal: Journal of Clinical Oncology (2006)

Docetaxel has shown activity in elderly patients with advanced non-small-cell lung cancer (NSCLC). This randomized phase III trial evaluated the efficacy and safety of docetaxel versus vinorelbine (the current standard treatment) in elderly patients.Chemotherapy-naïve patients age 70 years or older with stage IIIB/IV NSCLC and performance status 2 or lower were eligible. Patients randomly received docetaxel 60 mg/m2 (day 1) or vinorelbine 25 mg/m2 (days 1 and 8) every 21 days for four cycles. The primary end point was overall survival. Overall disease-related symptom improvement was assessed using an eight-item questionnaire.In total, 182 patients were enrolled. Median age was 76 years (range, 70 years to 86 years). There was no statistical difference in median overall survival with docetaxel versus vinorelbine (14.3 months v 9.9 months; hazard ratio, 0.780; 95% CI, 0.561 to 1.085; P = .138). There was a significant difference in median progression-free survival (5.5 months v 3.1 months; P < .001). Response rates were also significantly improved with docetaxel versus vinorelbine (22.7% v 9.9%; P = .019). The most common grade 3 to 4 toxicities were neutropenia (82.9% for docetaxel; 69.2% for vinorelbine; P = .031) and leukopenia (58.0% for docetaxel; 51.7% for vinorelbine). Other toxicities were mild and generally well tolerated. Docetaxel improved overall disease-related symptoms over vinorelbine (odds ratio, 1.86; 95% CI, 1.09 to 3.20).Docetaxel improved progression-free survival, response rate, and disease-related symptoms versus vinorelbine. Overall survival was not statistically significantly improved at this time. Docetaxel monotherapy may be considered as an option in the standard treatment of elderly patients with advanced NSCLC.
Hyperinsulinemia. A link between hypertension obesity and glucose intolerance.
Authors: M Modan, H Halkin, S Almog, A Lusky, A Eshkol, M Shefi, A Shitrit, Z Fuchs
Journal: Journal of Clinical Investigation (1985)

Hypertension and glucose intolerance, determined in a random population sample (n = 2,475), showed a highly significant (P less than 0.001) association from the mildest levels of both conditions, independent of the confounding effects of age, sex, obesity, and antihypertensive medications. Summary rate ratios for hypertension were 1.48 (1.18-1.87) in abnormal tolerance and 2.26 (1.69-2.84) in diabetes compared with normal tolerance. Altogether, 83.4% of the hypertensives were either glucose-intolerant or obese--both established insulin-resistant conditions. Fasting and post-load insulin levels in a representative subgroup (n = 1,241) were significantly elevated in hypertension independent of obesity, glucose intolerance, age, and antihypertensive medications. The mean increment in summed 1- and 2-h insulin levels (milliunits per liter) compared with nonobese normotensives with normal tolerance was 12 for hypertension alone, 47 for obesity alone, 52 for abnormal tolerance alone, and 124 when all three conditions were present. The prevalence of concentrations (milliequivalents per liter) of erythrocyte Na+ greater than or equal to 7.0, K+ less than 92.5, and plasma K+ greater than or equal to 4.5 in a subsample of 59 individuals with all combinations of abnormal tolerance obesity and hypertension was compared with those in 30 individuals free of these conditions. Altogether, 88.1% of the former vs. 40.0% of the latter group presented at least one of these three markers of internal cation imbalance (P less than 0.001). We conclude that insulin resistance and/or hyperinsulinemia (a) are present in the majority of hypertensives, (b) constitute a common pathophysiologic feature of obesity, glucose intolerance, and hypertension, possibly explaining their ubiquitous association, and (c) may be linked to the increased peripheral vascular resistance of hypertension, which is putatively related to elevated intracellular sodium concentration.
Plasma IGFBP-2 levels predict clinical outcomes of patients with high-grade gliomas
Authors: Yi Lin, Tao Jiang, Kaijia Zhou, Li Xu, Baoshi Chen, Guilin Li, Xiaoguang Qiu, Tianzi Jiang, Wei Zhang, Sonya W. Song
Journal: Neuro-Oncology (2009)

Insulin-like growth factor binding protein 2 (IGFBP-2) is a malignancy-associated protein measurable in tumors and blood. Increased IGFBP-2 is associated with shortened survival of advanced glioma patients. Thus, we examined plasma IGFBP-2 levels in glioma patients and healthy controls to evaluate its value as a plasma biomarker for glioma. Plasma IGFBP-2 levels in 196 patients with newly diagnosed glioma and 55 healthy controls were analyzed using an IGFBP-2 ELISA kit. Blood was collected before surgery, after two-cycle adjuvant chemotherapy, and at recurrence. Plasma IGFBP-2 levels were correlated with disease-free survival (DFS) using Cox regression analyses. We found that preoperative plasma IGFBP-2 levels were significantly higher in high-grade glioma patients (n = 43 for grade III glioma; n = 72 for glioblastoma multiforme [GBM]) than in healthy controls (n = 55; p < 0.001) and low-grade (grade II) glioma patients (n = 81; p < 0.001). No significant differences in preoperative plasma IGFBP-2 levels were observed between grade III glioma and GBM patients or between grade II glioma patients and healthy controls. After recurrence, plasma IGFBP-2 levels were significantly increased in GBM patients (n = 26; p < 0.001). Preoperative plasma IGFBP-2 levels were significantly correlated with DFS in GBM patients (hazard ratio, 1.404; 95% confidence interval, 1.078-1.828; p = 0.012). We conclude that preoperative plasma IGFBP-2 levels are significantly higher in high-grade glioma patients than in low-grade glioma patients and healthy subjects, and are significantly correlated with recurrence and DFS in patients with GBM. Longitudinal studies with a larger study population are needed to confirm these findings.
Baseline quantitative hepatitis B core antibody titre alone strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated with peginterferon or nucleos(t)ide analogues
Authors: Rong Fan, Jian Sun, Quan Yuan, Qing Xie, Xuefan Bai, Qin Ning, Jun Cheng, Yanyan Yu, Junqi Niu, Guangfeng Shi, Hao Wang, Deming Tan, Mobin Wan, Shijun Chen, Min Xu, Xinyue Chen, Hong Tang, Jifang Sheng, Fengmin Lu, Jidong Jia, Hui Zhuang, Ningshao Xia, Jinlin Hou
Journal: Gut (2015)

<h3>Objective</h3> The investigation regarding the clinical significance of quantitative hepatitis B core antibody (anti-HBc) during chronic hepatitis B (CHB) treatment is limited. The aim of this study was to determine the performance of anti-HBc as a predictor for hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive CHB patients treated with peginterferon (Peg-IFN) or nucleos(t)ide analogues (NUCs), respectively. <h3>Design</h3> This was a retrospective cohort study consisting of 231 and 560 patients enrolled in two phase IV, multicentre, randomised, controlled trials treated with Peg-IFN or NUC-based therapy for up to 2 years, respectively. Quantitative anti-HBc evaluation was conducted for all the available samples in the two trials by using a newly developed double-sandwich anti-HBc immunoassay. <h3>Results</h3> At the end of trials, 99 (42.9%) and 137 (24.5%) patients achieved HBeAg seroconversion in the Peg-IFN and NUC cohorts, respectively. We defined 4.4 log<sub>10</sub> IU/mL, with a maximum sum of sensitivity and specificity, as the optimal cut-off value of baseline anti-HBc level to predict HBeAg seroconversion for both Peg-IFN and NUC. Patients with baseline anti-HBc ≥4.4 log<sub>10</sub> IU/mL and baseline HBV DNA &lt;9 log<sub>10</sub> copies/mL had 65.8% (50/76) and 37.1% (52/140) rates of HBeAg seroconversion in the Peg-IFN and NUC cohorts, respectively. In pooled analysis, other than treatment strategy, the baseline anti-HBc level was the best independent predictor for HBeAg seroconversion (OR 2.178; 95% CI 1.577 to 3.009; p&lt;0.001). <h3>Conclusions</h3> Baseline anti-HBc titre is a useful predictor of Peg-IFN and NUC therapy efficacy in HBeAg-positive CHB patients, which could be used for optimising the antiviral therapy of CHB.
Reply to P.J. van Diest et al
Authors: Naoki Niikura, Yutaka Tokuda, Gabriel N. Hortobagyi, Naoto T. Ueno
Journal: Journal of Clinical Oncology (2012)

cancers.I would fully concur that an attempt to biopsy a metastatic lesion(s) would be appropriate, should the results be the basis for clinical management decisions.In standard clinical practice, however, the oncologist is unlikely to reassess the primary tumor simultaneously with the metastatic lesion to control for analytic variables.Thus the commentary was meant to remind readers that multiple factors exist besides clonal heterogeneity, which can account for receptor discordance, and that in instances of a reported discordance, clinicians should take some caution and remind themselves of the impact of preanalytic and analytic variables that could also contribute to this process.