Theory-based analysis of anti-inflammatory effect of infliximab on Crohn’s disease and rheumatoid arthritis

In Japan, the recommended dosage regimens of infliximab (IFX) for treatment of rheumatoid arthritis (RA) and Crohn’s disease (CD) are different. However, the differences have not been analyzed theoretically. In a previous study, we constructed a pharmacokinetic–pharmacodynamic model to investigate the effects of IFX for CD and found it useful to establish a rational dosage regimen of IFX for individual patients with CD. In the present study, we investigated whether the theory-based model could be used for cases of RA and also used it to evaluate the validity of the dosage regimen. The results obtained with our model were in good agreement with observed tender joint count (TJC) ratio data, which was considered to show the validity of our analysis. Thus, we concluded that the model could be used for patients with RA. Furthermore, a second administration of IFX given 2 weeks after the first infusion was important to achieve remission in the early stage of RA. We also compared the estimated pharmacodynamic parameters of RA with those of CD. The elimination rate constant of inflammation in RA was greater than that in CD, suggesting that the recovery from inflammation in RA is faster than that in CD, and indicating a reason for the difference in dosage between RA and CD. In conclusion, use of our model in light of the individual quantitative factor of tumor necrosis factor (TNF)-α allows establishment of IFX dosage regimens for individual patients.     

Ribosomal Protein S6 Phosphorylation is Associated with Epithelial Dysplasia and Squamous Cell Carcinoma of the Oral Cavity

Ribosomal protein S6 (RPS6), a downstream effector of the mammalian target of rapamycin pathway (mTOR), is activated in many cancers including oral squamous cell carcinoma (OSCC). However, the role of RPS6 in the progression of potentially malignant disorders (or premalignant lesions) to OSCC is unknown. The purpose of this study was to examine the expression of RPS6 in epithelial dysplasia and OSCC to determine the association of RPS6 in tumor progression. In our study, an immunohistochemical analysis of RPS6 was performed on tissue microarrays containing 30 control samples, 15 epithelial dysplasia cases, and 53 OSCC cases. Correlations between the clinicopathologic features of OSCC and RPS6 expression were analyzed using the Chi-square test. We found RPS6 phosphorylation (p-RPS6) in 15/30 (50 %) control normal oral mucosa samples, 15/15 (100 %) epithelial dysplasia cases, and 47/53 (88.68 %) OSCC cases. The frequency of p-RPS6 in epithelial dysplasia or OSCC showed a statistically significant difference compared to control (P?<?0.001). However, there were no significant correlations between p-RPS6 and the clinicopathologic features of OSCC. Our findings suggest that RPS6 activation is associated with the early events of tumor progression, suggesting p-RPS6 as a potential marker for early detection of oral cancer.     

Neutrophil Phagocytosis of Platelets in the Early Phase of 2,4,6-trinitro-1-chlorobenzene (TNCB)-induced Dermatitis in Mice

Activated platelets form platelet–leukocyte aggregates in the circulation in inflammatory diseases. We investigated whether activated platelets in inflamed skin tissues are phagocytized and removed by neutrophils. To investigate the kinetics of platelets and neutrophils, we immunohistochemically examined the spatiotemporal distribution of them in a murine model of 2,4,6-trinitro-1-chlorobenzene (TNCB)-induced dermatitis by using confocal and structured illumination microscopy. Four hours after elicitation, aggregates of CD41-positive platelets were adhered to CD31-positive endothelial cells within the vessels, and CD62P and PF4, markers of activated platelets, were expressed on platelet aggregates. At 8 hour post-elicitation, fragmented CD41-positive platelets were located both inside and outside vessels. Twenty-four hours after elicitation, the number of Ly-6G-positive neutrophils ingesting fragmented CD41-positive platelets outside vessels was increased, and CD62P and PF4 expression on the phagocytosed platelets was no longer observed. Disc-shaped CD41-positive platelets were not found outside vessels at any time during the experiment. Our data revealed that aggregates of activated platelets inside vessels were ingested and removed by neutrophils in the early stage of TNCB-induced dermatitis, suggesting that the process of removal of activated platelets by neutrophils may play an important role not only in the early phase of skin inflammation but also in other types of acute inflammation.     

Influence of topical steroids on intraocular pressure in patients with atopic dermatitis

Background

Topical corticosteroids (TCS) can induce adverse effects, such as skin atrophy. Although TCS can cause increases in intraocular pressure (IOP), the effects of daily TCS use on IOP have not been fully elucidated. We evaluated the clinical doses of TCS and the change in the IOP during the daily treatment of atopic dermatitis (AD).

Age-related changes of NGF, BDNF, parvalbumin and neuronal nitric oxide synthase immunoreactivity in the mouse hippocampal CA1 sector

We investigated the age-related alterations in nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), parvalbumin and neuronal nitric oxide synthase (nNOS) immunoreactivity of the mouse hippocampal CA1 sector. NGF and BDNF immunoreactivity was unchanged in the hippocampal CA1 pyramidal neurons from 2 to 50-59 weeks of birth. In contrast, a significant increase in the NGF and BDNF immunoreactivity was observed in glial cells of the hippocampal CA1 sector from 40-42 to 50-59 weeks of birth. On the other hand, the number of parvalbumin- and nNOS-positive interneurons was unchanged in the hippocampal CA1 sector during aging processes, except for a significant decrease of nNOS-positive interneurons 2 weeks of birth. Our results indicate that NGF and BDNF immunoreactivity was unaltered in the hippocampal CA1 pyramidal neurons during aging processes. In contrast, a significant increase in the NGF and BDNF immunoreactivity was observed in glial cells of the hippocampal CA1 sector during aging processes. The present study also shows that the number of parvalbumin- and nNOS-positive interneurons was unchanged in the hippocampal CA1 sector during aging processes, except for a significant decrease of nNOS-positive interneurons 2 weeks of birth. These results demonstrate that the expression of glial NGF and BDNF may play a key role for helping survival and maintenance of pyramidal neurons and neuronal functions in the hippocampal CA1 sector during aging processes. Furthermore, our findings suggest that parvalbumin- and nNOS-positive interneurons in the hippocampal CA1 sector are resistant to aging processes. Moreover, our findings suggest that nitric oxide synthesized by the nNOS may play some role for neuronal growth during postnatal development.     

Primary high-grade myofibroblastic sarcoma arising from the pericardium.

Primary pericardial sarcomas are very rare. A 62-year-old Japanese man presented with cardiac tamponade. Echocardiography, computed tomography and magnetic resonance imaging revealed massive pericardial effusion and a large tumor in the pericardial cavity, attached to the pericardium of the left ventricular posterolateral free wall. Surgical excision of the tumor was performed and histopathological and immunohistochemical examinations identified high-grade myofibroblastic sarcoma. Because of local recurrence soon after surgery, the patient received adjuvant chemotherapy, including doxorubicin and ifosfamide, and subsequent radiotherapy. As of 6 months after completing radiotherapy, the patient was alive and no disease progression or distant metastases were evident. This may be the first report of primary high-grade myofibroblastic sarcoma arising from the pericardium.     

Pupillary reflex dilation in response to incremental nociceptive stimuli in patients receiving intravenous ketamine

Pupillometry is a non-invasive monitoring technique, which allows dynamic pupillary diameter measurement by an infrared camera. Pupillary diameter increases in response to nociceptive stimuli. In patients anesthetized with propofol or volatile agents, the magnitude of this pupillary dilation is related to the intensity of the stimulus. Pupillary response to nociceptive stimuli has never been studied under ketamine anesthesia. Our objective was to describe pupillary reflex dilation after calibrated tetanic stimulations in patients receiving intravenous ketamine. After written consent, 24 patients of our pediatric burn care unit were included. They received an oral morphine premedication (0.3 mg kg^?1) 1 h before their scheduled daily dressing change. Just before the procedure, they received 1 mg kg^?1 of intravenous ketamine. Two minutes after this bolus, tetanic stimulations of incremental intensities were performed on the arm of each patient (5–10–20–30–40–60 mA, 60 s interval between stimulations). Pupillary diameter, heart rate and movements were recorded before and after each stimulation. Tetanic stimulations were associated with changes in pupillary diameter and heart rate. The magnitude of these changes was significantly influenced by the intensity of stimulation (ANOVA for repeated measures, p?<?0.001). Movement was associated with a 32% increase in diameter (ROC curves, AUC 0.758) with 65% sensitivity and 77% specificity. In children, pupillary reflex dilation to nociceptive stimuli persists under deep sedation obtained with 1 mg kg^?1 of intravenous ketamine combined with a 0.3 mg kg^?1 oral morphine premedication, and its magnitude depends on the intensity of the stimulation. Our results confirm that pupillometry could be a relevant way to monitor nociception in anaesthetised subjects, including those receiving ketamine. Trial registration clinicaltrials.gov, NCT 02648412