Evaluation of in vivo genotoxicity induced by N‐ethyl‐N‐nitrosourea,benzo[a]pyrene,and 4‐nitroquinoline‐1‐oxide in the Pig‐a and gpt assays

The recently developed Pig‐a mutation assay is based on flow cytometric enumeration of glycosylphosphatidylinositol (GPI) anchor‐deficient red blood cells caused by a forward mutation in the Pig‐a gene. Because the assay can be conducted in nontransgenic animals and the mutations accumulate with repeat dosing, we believe that the Pig‐a assay could be integrated into repeat‐dose toxicology studies and provides an alternative to transgenic rodent (TGR) mutation assays. The capacity and characteristics of the Pig‐a assay relative to TGR mutation assays, however, are unclear. Here, using transgenic gpt delta mice, we compared the in vivo genotoxicity of single oral doses of N‐ethyl‐N‐nitrosourea (ENU, 40 mg/kg), benzo[a]pyrene (BP, 100 and 200 mg/kg), and 4‐nitroquinoline‐1‐oxide (4NQO, 50 mg/kg) in the Pig‐a (peripheral blood) and gpt (bone marrow and liver) gene mutation assays. Pig‐a assays were conducted at 2, 4, and 7 weeks after the treatment, while gpt assays were conducted on tissues collected at the 7‐week terminal sacrifice. ENU increased both Pig‐a and gpt mutant frequencies (MFs) at all sampling times, and BP increased MFs in both assays but the Pig‐a MFs peaked at 2 weeks and then decreased. Although 4NQO increased gpt MFs in the liver, only weak, nonsignificant increases (two‐ or threefold above control) were detected in the bone marrow in both the Pig‐a and the gpt assay. These findings suggest that further studies are needed to elucidate the kinetics of the Pig‐a mutation assay in order to use it as an alternative to the TGR mutation assay. Environ. Mol. Mutagen. 54:747–754, 2013. © 2013 Wiley Periodicals, Inc.     

Lymphoid hyperplasia of the colon and its association with underlying allergic airway diseases

Purpose

The purpose of this study was to determine the prevalence of lymphoid hyperplasia in the lower gastrointestinal tract and its role in patients undergoing colonoscopic examinations, particularly focusing on any allergic predisposition.

Methods

A database search performed at the Department of Gastroenterology at Onomichi Municipal Hospital identified seven patients with lymphoid hyperplasia in the large intestine (i.e., cecum, colon, and/or rectum). Data regarding the endoscopic, biological, and pathological examinations performed and the allergic histories for each patient were retrospectively reviewed from the clinical records.

Results

Median age of the patients (four males, three females) was 50 years. Lymphoid hyperplasia was seen in the cecum (n?=?5), ascending colon (n?=?2), and transverse colon (n?=?1). Six patients (85.7 %) had one of the allergic airway diseases: allergic rhinoconjunctivitis for pollen (n?=?3), bronchial asthma (n?=?1), infantile asthma (n?=?1), or allergic bronchitis (n?=?1). Drug allergy (n?=?3) and urticaria (n?=?2) were also found. All seven patients had one or more allergic diseases; however, none had a history of food allergy. Blood tests for allergens revealed that six patients (85.7 %) had positive reactions to inherent allergens, whereas only one patient had a positive reaction to food allergens.

Conclusions

Our results indicate that lymphoid hyperplasia in the large intestine may be associated with allergic airway diseases rather than with food allergies; thus, its presence may be useful to detect patients with underlying airway hyperreactivity.

     

Multicenter,Randomized, Controlled Study Comparing Tafluprost/Timolol Fixed Combination with Latanoprost/Timolol Fixed Combination in Primary Open-Angle Glaucoma and Ocular Hypertension

Introduction

This was the first exploratory randomized controlled study to compare the efficacy and safety of a preserved tafluprost/timolol fixed combination (TAF/TIM) with a preserved latanoprost/timolol fixed combination (LAT/TIM).

Methods

This prospective, randomized, open-label study was conducted in Japanese patients with primary open-angle glaucoma, including normal-tension glaucoma or ocular hypertension. Following a 4-week LAT/TIM run-in period, eligible patients entered a 12-week treatment period, during which they received either LAT/TIM or TAF/TIM. The efficacy endpoint was the change in intraocular pressure (IOP) from baseline to week 12 and the safety endpoints included the changes from baseline to week 12 in superficial punctate keratopathy (SPK) score, tear breakup time (TBUT), and hyperemia score, as well as adverse events (AEs). At week 6, ocular symptoms were evaluated using a questionnaire.

Results

In total, 131 patients provided informed consent. Of these, 115 completed the run-in period and were assigned to receive TAF/TIM (n?=?60) or LAT/TIM (n?=?55). At week 12, there were no significant differences between the TAF/TIM and LAT/TIM groups in the change from baseline in trough IOP and IOP at 4–6 h after instillation. There were no significant differences between the two groups in the change from baseline to week 12 in SPK score, TBUT, and hyperemia score. However, only in the TAF/TIM group, the total SPK score and the inferior cornea SPK score were significantly lower at week 12 compared with baseline. Eye irritation and eye pain were significantly decreased in the TAF/TIM group compared with the LAT/TIM group. Two treatment-related AEs were reported in the TAF/TIM group (3.3%) and none in the LAT/TIM group, while no serious AEs were reported in either group.

Conclusion

TAF/TIM is as effective as LAT/TIM in terms of IOP-reducing effect, with fewer ocular symptoms. TAF/TIM was associated with a significant improvement in SPK scores.

Trial Registration

UMIN Clinical Trials Registry Identifier, UMIN000023862.

Funding

Santen Pharmaceutical Co., Ltd., Osaka, Japan.

     

Leucine-rich alpha-2 glycoprotein is a potential biomarker to monitor disease activity in inflammatory bowel disease receiving adalimumab: PLANET study

Journal of Gastroenterology - This multicenter prospective study (UMIN000019958) aimed to evaluate the usefulness of serum leucin-rich alpha-2 glycoprotein (LRG) levels in monitoring disease...     

An esophageal cancer case unresectable due to tuberculous fibrosing mediastinitis: report of a case

We present a case of esophageal carcinoma in which esophagectomy was not possible because of tuberculous fibrosing mediastinitis. A 77-year-old man was diagnosed with carcinoma of the thoracic esophagus and admitted to our hospital. Chest radiography on admission revealed no abnormality except pleural thickening of the pulmonary apices, suggesting a history of subclinical infection of tuberculous pleurisy. The patient underwent surgery with a curative intent. Thoracotomy revealed that the mediastinum had been replaced with dense fibrous tissues and was widely encased with laminar calcification. Esophagectomy was not performed because it was considered impossible to do so safely. Although diagnosis of fibrous mediastinitis was not made preoperatively, review of the preoperative computed tomographic scans revealed proliferation of mediastinal soft tissues that were associated with patchy and laminar calcifications. Tuberculous fibrosing mediastinitis is an uncommon but clinically important disease for physicians who are involved in the diagnosis and treatment of esophageal cancer.     

Case Report: Determination of Primary Foci of Metastatic Tumors by p53 Mutational Analysis in Intraesophageal Multiple Carcinomas

It is well known that squamous carcinomasfrequently develop multifocally, either synchronously ormetachronously, in the upper aerodigestive tract (1).Such phenomena were first reported by Slaughter et al in 1953, and they were named fieldcancerization (2). Using recent molecular biologytechniques, these multiple carcinomas have been revealedto arise from independent origins (3). Esophagealcarcinomas have been reported to frequently metastasize tothe lymph nodes even at the early stage of tumorextension (4). Furthermore, simultaneous multifocalcancer development is not rare in the esophagus (5). In cases of intraesophageal multiple carcinomaswith lymph node metastases, the primary focus of themetastatic tumors cannot be identified by conventionalhistologic examination. Here we report a case of intraesophageal multiple carcinomas in whichthe attributed foci of lymph nodal metastases could beclearly identified by analyzing the p53 gene mutationalstatus used as a clonal marker.