This study aimed to construct a widely applicable method for quantitative analyses of drug–drug interactions (DDIs) caused by the inhibition of hepatic organic anion transporting polypeptides (OATPs) ...using physiologically based pharmacokinetic (PBPK) modeling. Models were constructed for pitavastatin, fluvastatin, and pravastatin as substrates and cyclosporin A (CsA) and rifampicin (RIF) as inhibitors, where enterohepatic circulations (EHC) of statins were incorporated. By fitting to clinical data, parameters that described absorption, hepatic elimination, and EHC processes were optimized, and the extent of these DDIs was explained satisfactorily. Similar in vivo inhibition constant (Ki) values of each inhibitor against OATPs were obtained, regardless of the substrates. Estimated Ki values of CsA were comparable to reported in vitro values with the preincubation of CsA, while those of RIF were smaller than reported in vitro values (coincubation). In conclusion, this study proposes a method to optimize in vivo PBPK parameters in hepatic uptake transporter‐mediated DDIs.
Matrix metalloproteinases (MMPs) are endopeptidases that play pivotal roles in promoting tumor disease progression, including tumor angiogenesis. In many solid tumors, MMP expression could be ...attributed to tumor stromal cells and is partially regulated by tumor-stroma interactions via tumor cell-associated extracellular matrix metalloproteinase inducer (EMMPRIN). The role of EMMPRIN during tumor angiogenesis and growth was explored by modulating EMMPRIN expression and activity using recombinant DNA engineering and neutralizing antibodies. In human breast cancer cells, changes in EMMPRIN expression influenced vascular endothelial growth factor (VEGF) production at both RNA and protein levels. In coculture of tumor cells and fibroblasts mimicking tumor-stroma interactions, VEGF expression was induced in an EMMPRIN- and MMP-dependent fashion, and was further enhanced by overexpressing EMMPRIN. Conversely, VEGF expression was inhibited by suppressing EMMPRIN expression in tumor cells, by neutralizing EMMPRIN activity, or by inhibiting MMPs. In vivo, EMMPRIN overexpression stimulated tumor angiogenesis and growth; both were significantly inhibited by antisense suppression of EMMPRIN. Expression of both human and mouse VEGF and MMP, derived from tumor and host cells, respectively, was regulated by EMMPRIN. These results suggest a novel tumor angiogenesis mechanism in which tumor-associated EMMPRIN functionally mediates tumor-stroma interactions and directly contributes to tumor angiogenesis and growth by stimulating VEGF and MMP expression.
Background and Objective
Factors such as vascularization of the periodontium, inflammatory reactions and immune response affect the oral environment and ecology, decreasing host resistance and ...promoting the development of symptoms and the advancement of periodontal disease. Fatigue also influences the hypothalamic–pituitary–adrenal axis and reports relate it to systemic resistance. The aim of this study was to evaluate whether fatigue is a modifying factor for periodontal disease in rats.
Material and Methods
We divided 24 3‐wk‐old male Sprague–Dawley rats randomly into the following four groups: control; fatigue (deep sleep deprivation for 7 d); infection (rats inoculated with carboxymethyl cellulose containing periodontopathic bacteria); and compound (combined fatigue and infection conditions). Weight, serum corticosterone levels, serum albumin levels, interleukin‐1β and tumor necrosis factor‐α expression levels and distance from the cement–enamel junction to the alveolar bone crest were measured at baseline, and on the 36th (before sleep deprivation), 43rd (immediately after sleep deprivation) and 57th d (end of experiment).
Results
Immediately after sleep deprivation and at the end of the experiment, weight gain in the fatigue and compound groups was significantly lower than in controls (p < 0.05). Immediately after sleep deprivation, serum corticosterone levels were significantly higher in the fatigue and compound groups than in controls (p < 0.05). Moreover, serum albumin levels were significantly lower in the fatigue and compound groups than in controls (p < 0.05). Immediately after sleep deprivation, gene expression of interleukin‐1β was significantly higher in the infection and compound groups than in controls (p < 0.05). Moreover, gene expression of tumor necrosis factor‐α was significantly higher in the compound group than in controls (p < 0.05). At the end of the experiment, the distance from the cement–enamel junction to the alveolar bone crest was significantly higher in the infection and compound groups than in controls (p < 0.05). Moreover, the distance was significantly higher in the compound group than in the infection group.
Conclusions
Fatigue worsened systemic health in rats and increased gingival inflammation and alveolar bone loss in experimental periodontitis. In conclusion, our results suggest that fatigue is a modifying factor for periodontal disease in rats.
Matrix metalloproteinases (MMPs) are metal-dependent endopeptidases that play pivotal roles in tumor disease progression. In many solid tumors, MMPs are indeed produced by tumor stromal cells, rather ...than by tumor cells. This expression pattern is, at least in part, regulated by tumor-stroma interaction via tumor cell-associated extracellular matrix metalloproteinase inducer (EMMPRIN). In vitro, recombinant EMMPRIN dose-dependently stimulated MMP-1 production by primary human fibroblast cells. Interestingly, in addition to stimulating MMP expression, EMMPRIN also induced its own gene expression. To further explore this potential positive feedback regulatory mechanism, we generated human breast cancer cells expressing different levels of EMMPRIN. Coculture of EMMPRIN-positive tumor cells with fibroblast cells resulted in a concomitant stimulation of MMP-2, MMP-9, and EMMPRIN production. This induction was EMMPRIN dependent, was further enhanced by overexpression, and was reduced by antisense suppression of EMMPRIN expression in tumor cells. Increased expression of membrane-associated EMMPRIN was accompanied by an MMP-dependent generation of a soluble form of EMMPRIN representing a proteolytic cleavage product lacking the carboxyl terminus. On the basis of these findings, we propose a model in which tumor cell-associated EMMPRIN stimulates MMPs, as well as EMMPRIN expression in tumor stroma. Increased MMP activity in tumor local environment results in proteolytic cleavage of membrane-associated EMMPRIN, releasing soluble EMMPRIN. Soluble EMMPRIN in turn acts in a paracrine fashion on stroma cells that are both adjacent and distant to tumor sites to further stimulate the production of MMPs and additional EMMPRIN, which consequently contributes to tumor angiogenesis, tumor growth, and metastasis.
Background Vertigo or dizziness is a common occurrence, but it remains a challenging symptom when encountered in the emergency department (ED). A diagnostic score for stroke with high accuracy is ...therefore required. Methods A single-center observational study (498 patients) was conducted. The predictor variables were derived from a multivariate logistic regression analysis with Akaike information criterion. The outcome was the occurrence of stroke. We evaluated the utility of a new diagnostic score (TriAGe+) and compared it with the ABCD2 score. Results The cohorts included 498 patients (147 with stroke 29.4%). Eight variables were included: triggers, atrial fibrillation, male gender, blood pressure ≥140/90 mm Hg, brainstem or cerebellar dysfunction, focal weakness or speech impairment, dizziness, and no history of vertigo or dizziness or labyrinth or vestibular disease. We derived the TriAGe+ score from these variables. In the cohort, the prevalence of stroke increased significantly using the diagnostic score: 5.9% for a score of 0-4; 9.1% for 5-7; 24.7% for 8-9; and 57.3% for 10-17. At a cutoff value of 10 points, the sensitivity of the score was 77.5%, the specificity was 72.1%, and the positive likelihood ratio was 3.2. When the cutoff was defined as 5 points, the score obtained a high sensitivity (96.6%) with a good negative likelihood ratio (.15). The new score outperformed the ABCD2 score for the occurrence of stroke (C statistic, .818 versus .726; P < .001). Conclusions The TriAGe+ score can identify the occurrence of stroke in patients with vertigo or dizziness presenting to the ED.
A new paradigm is becoming widely accepted, that chronic inflammation, driven in part by chemokines and cytokines at the site of a tumour, may facilitate tumour progression instead of promoting ...anti-tumour immunity. Tumours and activated stromal cells secrete pro-inflammatory chemokines and cytokines that act either directly or indirectly through stimulation of the vascular endothelium to recruit leukocytes to the tumour. After activation, these tumour-associated leukocytes release angiogenic factors, mitogens, proteolytic enzymes, and chemotactic factors, recruiting more inflammatory cells and stimulating angiogenesis to sustain tumour growth and facilitate tumour metastasis. Breaking this cycle by inhibiting targets such as cytokines, chemokines and other inflammatory mediators, either alone, or more realistically, in combination with other therapies, such as anti-angiogenic or cytotoxic agents, may provide highly efficacious therapeutic regimens for the treatment of malignancies. This article reviews anti-cytokine and anti-chemokine therapies being pursued in cancer, and discusses in more detail anti-tumour necrosis factor-α (TNF) approaches.
A middle-sensitivity scintillating fiber detector (hereafter middle Sci-Fi detector) that works at a deuterium-tritium neutron flux of ~10
5
-10
7
cm
−2
s
−1
was utilized to measure secondary ...deuterium-tritium neutron emission rates with high temporal resolution at a total neutron emission rate of 10
13
to 10
15
n/s, where strong magnetohydrodynamic (MHD) instabilities were observed in the large helical device deuterium plasma experiments. The gain and angular characteristics of the middle Sci-Fi detector were evaluated in an accelerator-based deuterium-tritium neutron source in the intense 14 MeV neutron source facility at Osaka University. Observation of 1 MeV triton transport due to MHD instability was performed by a middle Sci-Fi detector whose deuterium-tritium neutron counting rate was approximately 20 times higher than that of the conventional Sci-Fi detector. Fusion-born triton transport due to energetic-particle-driven MHD instability was observed using the middle Sci-Fi detector due to its high detection efficiency and high discrimination ability of deuterium-tritium neutrons from the sea of deuterium-deuterium neutrons.
Summary
Background
Patch testing is less dangerous than oral provocation testing for identification of the causative drug for patients with drug eruption; however, its usefulness for such ...identification is controversial.
Aim
To clarify the rates of positive patch testing for patients with drug eruption, classified by causative drugs and clinical features.
Methods
We analysed results during the period 1990–2010 for 444 patients (151 men, 293 women; mean ± SD age 49.9 ± 18.6 years) who were tested for drug eruption. In the patient group, there were 309 people (69.1%) with maculopapular eruption and 31 (6.9%) with severe drug eruption. The test materials were applied to the back and left for 2 days under occlusion, then results were assessed by the International Contact Dermatitis Research Group (ICDRG) scoring system 3 days after application. Reactions of + to +++ were regarded as positive.
Results
Of the 444 patients, 100 (22.4%) had a positive patch test result to a suspected drug. Positive rates were 23.6% and 20.0% for maculopapular eruption and fixed drug eruption, respectively. The class of materials to which most patients reacted positively was contrast medium (n = 53; 41.1%), followed by drugs acting on the central nervous system (n = 18; 28.6%). In the latter group, 16 of the 18 patients were positive to antiepileptics.
Conclusions
Positive rates depend on the causative drug rather than the clinical features of the drug eruption. Patch testing is useful when contrast medium or antiepileptics are suspected to be the causative drugs. However, standardization of patch test materials and method of reading is needed, as well as guidelines regarding when testing should be performed. Although patch testing for drug eruption has significant potential, it requires further validation.
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