Tofacitinib, a Janus Kinase Inhibitor Demonstrates Efficacy in an IL-15 Transgenic Mouse Model that Recapitulates Pathologic Manifestations of Celiac Disease

Celiac disease (CD) is an immune-mediated, inflammatory disorder of the small intestines with a defined genetic etiological component associated with the expression of HLA-DQ2 and/or HLA-DQ8 haplotypes. The dietary consumption of gluten-rich cereals triggers a gluten-specific immune response in genetically susceptible individuals leading to a spectrum of clinical manifestations ranging from an inapparent subclinical disease, to overt enteropathy that can in some individuals progress to enteropathy-associated T cell lymphoma (EATL). The tissue-destructive pathologic process of CD is driven by activated NK-like intraepithelial CD8⁺ lymphocytes and the proinflammatory cytokine IL-15 has emerged to be pivotal in orchestrating this perpetual tissue destruction and inflammation. Moreover, transgenic mice that over-express human IL-15 from an enterocyte-specific promoter (T3^b-hIL-15 Tg) recapitulate many of the disease-defining T and B cell-mediated pathologic features of CD, further supporting the evolving consensus that IL-15 represents a valuable target in devising therapeutic interventions against the form of the disease that is especially refractory to gluten-free diet. In the present study, we evaluated the potential efficacy of tofacitinib, a pan-JAK inhibitor that abrogates IL-15 signaling, as a therapeutic modality against CD using T3^b-hIL-15 Tg mice. We demonstrate that tofacitinib therapy leads to a lasting reversal of pathologic manifestations in the treated mice, thereby highlighting the potential value of tofacitininb as a therapeutic modality against refractory CD for which no effective therapy exists currently. Additionally, the visceral adiposity observed in the tofacitinib-treated mice underscores the importance of continued evaluation of the drug’s impact on the lipid metabolism.     

The cross-sectional head circumference growth curves for Japanese from birth to 18 years of age: the 1990 and 1992-1994 national survey data

Objective : The purpose of this study is to construct the cross-sectional head circumference growth curves, intended for clinical use, for the Japanese from birth to 18 years of age. Subjects and methods : Two sets of the national survey data on head circumference and height were utilized for the study: (1) The 1990 data collected by the Japanese Ministry of Health and Welfare on children below 7 years of age ( n = 16 621, 8511 males, 8110 females). (2) The 1992-1994 data collected by the Research Institute of Human Engineering for Quality Life on children from 7 to 18 years of age ( n = 10 183, 5610 males, 4573 females). We used the LMS method to obtain the 3rd, 10th, 25th, 50th, 75th, 90th and 97th percentile values for each age and gender. Results and conclusions : The results showed a persistent positive secular trend in head circumference in Japanese children of both genders. Comparison of these data with those of recent Caucasian studies revealed ethnic difference in head circumference, with Japanese having relatively larger head circumference for height as compared with Caucasians.     

Gastric undifferentiated carcinoma with diffuse c-kit overexpression and focal neuroendocrine differentiation

A case of gastric undifferentiated carcinoma with diffuse c-kit overexpression and focal neuroendocrine differentiation is described. A 76-year-old man presented appetite loss for 1 month. Gastric endoscopy showed an exophytic huge nodular mass with central ulceration at the gastric prepylorus. Distal gastrectomy was performed with lymph node dissection. Histology indicated anaplastic medium- to large-sized round tumor cells in discohesive sheets. Adenocarcinomatous areas forming tubular glands or with intracytoplasmic mucin on PAS and Alcian-blue staining were not found in any sections. Immunohistochemistry showed that the tumor cells were diffusely positive for cytokeratin, vimentin, c-kit and focally positive for chromogranin A and synaptophysin.     

Self-assembly of photoresponsive azo-containing phospholipids with a polar group as the tail

Vesicles or micelles prepared from amphiphiles with azobenzene (Az) moieties and long alkyl chains have attracted much attention in drug delivery systems. To induce release behavior from smart carriers via trans–cis photoisomerization of the Az groups, UV light exposure is typically used, but it can damage DNA and hardly penetrates cells. In this paper, Az-containing phospholipids without long alkyl tails were designed and synthesized; in these compounds, the end group of the Az moiety was substituted with a –NO₂ and –OCH₃ group (abbreviated N6 and M6, respectively). N6 self-assembled into H-aggregates with an interdigitated bilayered structure in water through the antiparallel orientation due to π–π interactions of the Az group, the attractive van der Waals forces, and the interactions and bending behavior of the phosphocholine groups. Vesicles showing visible light stimuli-responsive behavior were obtained by mixing N6 and M6, and the release of encapsulated calcein was triggered by visible light.

A mixture of a nitro- and methoxy-substituted azo-containing phospholipids without long alkyl tails formed vesicles showing visible light stimuli-responsive behavior. Release of encapsulated calcein from the vesicles was triggered by visible light.     

Diagnosing infection of extracardiac conduit in children

Summary Between August 1985 and July 1992, at our center, 142 Japanese children had an extracardiac conduit operation to reconstruct the right ventricular outflow tract. The study group consisted of 22 of these 142 children who had a persistent fever and whose serum was positive for acute-phase reactants after the operation. We present the diagnostic findings for 10 children with infection of an extracardiac conduit that had been placed to restore the continuity of the right ventricle-pulmonary artery. They were part of the group of 22 children who were followed over the past 7 years with blood cultures, echocardiography, and⁶⁷Ga imaging. All 10 developed a persistent fever and were seropositive for acute-phase reactants. Conduit infection was diagnosed in only 2 patients by the detection of vegetation on echocardiography and was diagnosed in 9 of the 10 patients by an abnormal⁶⁷Ga uptake in the area of the artificial vessels used to reconstruct the pulmonary artery. The present study compared the use of blood cultures, echocardiography, and⁶⁷Ga imaging in diagnosing an infection of the extracardiac conduit. The sensitivity of blood cultures in diagnosing an extracardiac conduit infection was 70% (7/10), and the specificity was 92% (1/12).⁶⁷Ga imaging showed a higher sensitivity than echocardiography in diagnosing infection of an extracardiac conduit.