Multiple ulcers in the small and large intestines occurred during tocilizumab therapy for rheumatoid arthritis.

Tocilizumab is a monoclonal antibody against human interleukin-6 receptor which blocks the binding of interleukin-6 to its receptor. Tocilizumab is effective for the treatment of inflammatory disorders including rheumatoid arthritis. We report a case of multiple ulcers in the small and large intestines, which occurred during tocilizumab therapy. A 57-year-old woman started to use tocilizumab for rheumatoid arthritis. Three months later, she complained of hematochezia. Double-balloon endoscopy revealed multiple small aphthoid ulcers in the small and large intestines. One month after the woman had recovered, she was given tocilizumab again. The woman had hematochezia and abdominal pain again 2 weeks later. Colonoscopy revealed multiple round, discrete punched-out ulcers in the terminal ileum, and vast deep ulcers from the cecum to the descending colon. Bioptic histopathology and cultivation showed non-specific findings. Six weeks after discontinuation of tocilizumab, ulcers in the small and large intestine dramatically improved, leaving ulcer scars. This disease course and the results of examination made us strongly suspect that tocilizumab induced multiple ulcers in the small and large intestines. Interleukin-6 is a pleiotropic cytokine and involved in intestinal mucosal wound healing as well as in inflammatory processes. It is possible that tocilizumab inhibited tissue repair of the intestine and caused intestinal ulcers.

Persistent gut motor dysfunction in a murine model of T-cell-induced enteropathy.

BACKGROUND: Inflammatory bowel disease (IBD) patients in remission often experience irritable bowel syndrome (IBS)-like symptoms. We investigated the mechanism for intestinal muscle hypercontractility seen in T-cell-induced enteropathy in recovery phase. METHODS: BALB/c mice were treated with an anti-CD3 antibody (100 microg per mouse) and euthanized at varying days post-treatment to investigate the histological changes, longitudinal smooth muscle cell contraction, cytokines (Th1, Th2 cytokines, TNF-alpha) and serotonin (5-HT)-expressing enterochromaffin cell numbers in the small intestine. The role of 5-HT in anti-CD3 antibody-induced intestinal muscle function in recovery phase was assessed by inhibiting 5-HT synthesis using 4-chloro-DL-phenylalanine (PCPA). KEY RESULTS: Small intestinal tissue damage was observed from 24 h after the anti-CD3 antibody injection, but had resolved by day 5. Carbachol-induced smooth muscle cell contractility was significantly increased from 4 h after injection, and this muscle hypercontractility was evident in recovery phase (at day 7). Th2 cytokines (IL-4, IL-13) were significantly increased from 4 h to day 7. 5-HT-expressing cells in the intestine were increased from day 1 to day 7. The 5-HT synthesis inhibitor PCPA decreased the anti-CD3 antibody-induced muscle hypercontractility in recovery phase. CONCLUSIONS & INFERENCES: Intestinal muscle hypercontractility in remission is maintained at the smooth muscle cell level. Th2 cytokines and 5-HT in the small intestine contribute to the maintenance of the altered muscle function in recovery phase.

Impact of double-balloon endoscopy on the diagnosis of jejunoileal involvement in primary intestinal follicular lymphomas: a case series.

In recent years, primary gastrointestinal follicular lymphoma has been increasingly detected in the duodenum on esophagogastroduodenoscopy (EGD). Primary gastrointestinal follicular lymphomas are frequently distributed to multiple sites in the gastrointestinal tract. Therefore, investigation into the spread of follicular lymphomas in the small bowel is important in order to determine the most appropriate treatment strategy. The performance of double-balloon endoscopy (DBE) in the diagnosis of jejunoileal follicular lymphoma lesions has not been fully evaluated. We aimed to investigate the value of DBE in addition to computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) in the diagnosis of jejunoileal follicular lymphoma. DBE with biopsy was performed in seven patients with primary duodenal follicular lymphoma diagnosed by EGD, in order to investigate jejunoileal involvement. Jejunoileal follicular lymphoma lesions were detected by DBE in six out of the seven patients (three in the jejunum and three in the jejunum and ileum), whereas CT and (18)F-FDG-PET failed to detect the existence of these lesions. Endoscopic findings of the jejunoileal lesions revealed multiple white nodules and white villi, which were similar to those of duodenal lesions. DBE was more useful for the diagnosis of jejunoileal involvement in primary intestinal follicular lymphoma than CT and (18)F-FDG-PET. The use of DBE will become important for determining the most appropriate treatment for gastrointestinal follicular lymphoma.

Colonic muco-submucosal elongated polyp: diagnosis with endoscopic ultrasound.

Colonic muco-submucosal elongated polyp is a new clinical entity first reported in 1998. The purpose of this report is to determine the value of endoscopic ultrasound in the diagnosis of this condition. We reviewed the endosonographic and histological findings of seven colonic muco-submucosal elongated polyps that were removed completely by endoscopic resection or surgery. The lesions appeared as pedunculated submucosal tumours, measuring 1-4 cm in maximal diameter. Endosonographically, all lesions consisted of mucosal and submucosal layers, and microcystic components were found in the submucosal layer. There were no echogenic masses or muscularis propria within the polyps. These endosonographic features corresponded to histological findings of this type of polyp which was covered with normal mucosa and composed of submucosal layer alone. The submucosal layer consisted of oedematous, loose, connective tissue and/or fibrous tissue, accompanied by dilated blood vessels and lymphatics. Endoscopic ultrasound enabled differentiation of colonic muco-submucosal elongated polyp from other submucosal lesions.

Sodium fluoride increases intracellular calcium in rat renal epithelial cell line NRK-52E.

In our previous experiment using rats, fluoride was reported to cause renal calcification, whose mechanism was deduced to be due to an increase in parathyroid hormone (PTH) secretion. However fluoride-induced renal calcification that was independent of PTH has not been understood well in the nephron of fluoride-treated animals. Thus, we examined the effect of sodium fluoride on intracellular calcium mobilization in a normal rat kidney epithelial cell line (NRK-52E cells). The calcium accumulation was found to be remarkably increased by the addition of sodium fluoride (NaF). The elevation of [Ca2+]i was demonstrated to be due to calcium entry through nifedipine-sensitive calcium channels. In addition, fluoride activates phospholipase C, but inositol 1,4,5-triphosphate (IP3) didn't induce Ca2+ release from the endoplasmic reticulum (ER). Moreover, fluoride alone was deduced to enhance the activity of ER-type Ca2+-ATPase. Finally, on the mechanism of fluoride-induced calcium accumulation in NRK-52E cells, fluoride may activate phospholipase C to generate IP3 and diacylglycerol, and these increases can be elucidated to induce calcium entry through dihydropiridine-sensitive calcium channels. Moreover, fluoride was found to stimulate calcium accumulation through ER-type Ca2+-ATPase into the endoplasmic reticulum. The elevation of ER-type Ca2+-ATPase activity by fluoride was elucidated to operate as a regulatory system to protect against abnormally higher increases in cytosolic calcium concentration via an increase of calcium influx into the endoplasmic reticulum.

High incidence of silent myocardial ischemia in elderly patients with non insulin-dependent diabetes mellitus.

The present study was designed to reveal the incidence of silent myocardial ischemia in asymptomatic elderly non-insulin-dependent diabetic (NIDDM) patients (aged over 60 years). As a first step screening, maximal treadmill exercise test was performed. Of 140 patients studied, 54 (38.6%) were unable or not expected to achieve diagnostic levels of exercise during treadmill testing. A positive exercise test was noted in 39 of 86 (45.3%) subjects. As a second step examination, dipyridamole thallium scintigraphy was performed for 93 subjects who exhibited a positive exercise test and could not perform a maximal exercise test. Abnormal perfusion pattern was found in 39 of 93 (41.9%), who were finally considered to have a silent myocardial ischemia. Coronary angiography was performed in 18 subjects with diagnosis of silent myocardial ischemia, who gave their consent. Significant coronary artery stenosis was in fact found in 17 of 18 (94.4%) subjects studied, confirming a very high positive predictive value of this diagnostic procedure. In conclusion, elderly NIDDM patients (aged over 60 years) had an extremely high prevalence (estimated 26.3%) of silent myocardial ischemia. This evidence suggests that early and intensive detection may be needed as a part of routine care for this group.

Magnetic resonance imaging of anterior cruciate ligament (ACL) tears: diagnostic value of ACL-tibial plateau angle.

Tears of the anterior cruciate ligament (ACL) are often difficult to diagnose on magnetic resonance imaging (MRI), as it is often difficult to interpret the images. We developed a quantitative method for diagnosing ACL tears on MRI; the method involves measuring the angle formed by the intersection between a straight line drawn along the anterior border of the ACL and a straight line drawn along the medial tibial plateau (AT angle) on MRI. The AT angle was measured by two orthopedic surgeons approved by the Japanese Orthopedic Association and one orthopedic resident, none of whom had any prior knowledge of the physical and arthroscopic findings of the patients. Measurements were performed in 30 knees with ACL tears and 57 knees without tears. There was no significant difference between the AT angles measured by the three examiners in either the group with ACL tears or that without ACL tears. The mean value of the AT angle in the torn ACL group (33.9 +/- 1.1 degrees) was significantly smaller than that in the intact ACL group (52.3 +/- 1.0 degrees; mean +/- SE). When 45 degrees or less was set as the criterion defining a tear of the ACL, the diagnostic accuracy of our method was 87.4%; sensitivity was 93.3%, and specificity, 84.2%.

[Outcome of long-term nasal intermittent positive pressure ventilation in 41 patients with hypercapnic respiratory failure].

Nasal intermittent positive pressure ventilation (NIPPV) is widely used in domiciliary treatment of chronic ventilatory disorders. The outcomes of long-term NIPPV were analyzed in 41 patients with hypercapnic respiratory failure due to pulmonary tuberculosis sequelae (PTS; n = 17), neuromuscular disease (NMD; n = 8), kyphoscoliosis (KS; n = 7), chronic obstructive pulmonary disease (COPD; n = 6), and miscellaneous diseases (n = 3). Twenty-seven patients with chronic conditions but without acute exacerbations began receiving NIPPV, and fourteen patients began receiving NIPPV after an acute exacerbation. Outcome measures included the probability of continuing NIPPV, survival after starting NIPPV, survival after starting home oxygen therapy (HOT), arterial blood gases, nocturnal oxygen saturation, pulmonary function, and the number of hospital days. Two patients with PTS died, 7 and 40 months after starting NIPPV. Two patients (one with PTS and one with COPD) switched from NIPPV to intermittent positive pressure ventilation via a tracheostomy. The condition of one patient with NMD improved and NIPPV was discontinued. The three-year and five-year probabilities of continuing NIPPV in all patients were 82%, and 71%, respectively. The survival rates three and five years after starting NIPPV were 97% and 85%, respectively. The survival rates one to nine years, and ten to eleven years after starting HOT were 98% and 65%, respectively. The arterial PO2 and PCO2, nocturnal oxygen saturation, vital capacity, and forced expiratory volume, in one second all improved after NIPPV was begun. NIPPV also reduced the number of hospital days, particularly in patients with KS. In conclusion, the long-term outcome of NIPPV in patients with hypercapnic respiratory failure is encouraging.

Ventilatory effects on pulmonary vascular inflow and outflow patterns.

Ventilation of an isolated lung lobe modifies the rate of inflow into its pulmonary artery (Murao and Rodbard, 1971). The present studies show that ventilation also influences the rate of outflow from the pulmonary vein in a manner which differs significantly from the effects on the rate of inflow into the pulmonary artery. Since this difference between instantaneous inflow and outflow rates affects the calculation of vascular conductance (resistance) and its interpretation we have compared and analysed the effects of ventilation on simultaneous flow patterns in the pulmonary artery and vein.

Mathematical formulation of post-occlusion hyperaemia and autoregulation of blood flow in the capillaron model.

A mathematical formulation of the blood flow behaviour through a capillaron model is described. The formulation is applied to the analysis of post-occlusion (reactive) hyperaemia and autoregulation.