G‐cell hyperplasia of the stomach induces ECL‐cell proliferation in the pyloric glands in a paracrinal manner

An inhibitory mechanism toward gastrin hypersecretion is significantly different between G‐cell hyperplasia and gastrinoma despite the common clinical manifestations; hypergastrinemia and its related persistent gastric ulcers. We recenlty studied the G‐cell, d ‐cell and ECL‐cell density in a case of G‐cell hyperplasia. The 70‐year‐old patient has been treated for persistent gastric ulcers with a markedly increased plasma gastrin (5600 pg/mL). The stomach was surgically resected because of the obstruction associated with ulcer scars. The number of G‐cells in the pyloric glands was quantified on the surgical specimens and G‐cell hyperplasia was histolopathologically identified. Immunostainig of histidine decarboxylate revealed the presence of ECL‐cell hyperplasia in the pyloric glands and its density was significantly and positively correlated with G‐cell density. Somatostatin immunoreactive cells (d ‐cells) increased in their number in the oxyntic glands. These results all indicated that hypersecretion of gastrin in G‐cell hyperplasia could induce ECL‐cell proliferation in a paracrinal manner. In addition, relatively non‐prominent endocrinological features in the G‐cell hyperplasia compared to gastrinoma could be also related to the paracrinal somatostatin inhibitory effects upon ECL‐cells in the pyloric glands.     

Computational method for estimating progression saturation of analog series

In lead optimization, it is difficult to estimate when an analog series might be saturated and synthesis of additional compounds would be unlikely to yield further progress. Rather than terminating a series, one often continues to generate analogs hoping to reach the final optimization goal, even if obstacles that are faced ultimately prove to be unsurmountable. Clearly, methodologies to better understand series progression and saturation are highly desirable. However, only a few approaches are currently available to monitor series progression and aid in decision making. Herein, we introduce a new computational method to assess progression saturation of an analog series by relating the properties of existing compounds to those of synthetic candidates and comparing their distributions in chemical space. The neighborhoods of analogs are analyzed and the distance relationships between existing and candidate compounds quantified. An intuitive dual scoring scheme makes it possible to characterize analog series and their degree of progression saturation.

Chemical space view of an analog series. Shown are inactive (red) and active (blue) analogs together with virtual candidate compounds (green) available to expand the series. Chemical neighborhoods of analogs are depicted in gray.     

A new manometry device for evaluating the sphincter of Oddi using a fiber-optic pressure sensor

Introduction: Although measuring the pressure of the sphincter of Oddi and the bile duct is considered to be an important examination, called Sphincter of Oddi manometry (SOM), some complications related to the SOM device remain unsolved.

Material and methods: To decrease adverse complications, we developed a 0.46?mm manometry and we performed some in vitro studies.

Results: We successfully developed a 0.46?mm SOM. The diameter is the thinnest size used in endoscopic examinations. The results of in vitro studies show the suitability as SOM.

Conclusion: This device will decrease the risks related to SOM examination. To confirm the safety and feasibility, further studies including in vivo studies will be needed.     

A Randomized Trial Investigating the Pharmacokinetics,Pharmacodynamics, and Safety of Subcutaneous Semaglutide Once-Weekly in Healthy Male Japanese and Caucasian Subjects

Introduction

Semaglutide is a glucagon-like peptide-1 analogue for once-weekly subcutaneous treatment of type 2 diabetes. This trial compared the pharmacokinetics, pharmacodynamics, and safety of semaglutide in Japanese and Caucasian subjects.

Methods

In this single-center, double-blind, parallel-group, 13-week trial, 44 healthy male subjects (22 Japanese, 22 Caucasian) were randomized within each race to semaglutide 0.5 mg (n = 8), 1.0 mg (n = 8), placebo 0.5 mg (n = 3) or 1.0 mg (n = 3). The primary endpoint was semaglutide exposure at steady state [area under the curve (AUC_0–168h)].

Results

Steady-state exposure of semaglutide was similar for both populations: AUC_0–168h estimated race ratio (ERR), Japanese/Caucasian: 0.5 mg, 1.06; 1.0 mg, 0.99; maximum concentration (C_max) ERR: 0.5 mg, 1.06; 1.0 mg, 1.02. Exposure after the first dose (0.25 mg) was slightly higher in Japanese versus Caucasian subjects (AUC_0–168h ERR 1.11; C_max ERR 1.14). Dose-dependent increases in AUC_0–168h and C_max occurred in both populations. Accumulation was as expected, based on the half-life (t_1/2, ~ 1 week) and dosing interval of semaglutide. Significant body weight reductions were observed with semaglutide 0.5 mg and 1.0 mg in Japanese (both p ≤ 0.05) and Caucasian (both p ≤ 0.05) subjects versus placebo. No new safety issues were identified.

Conclusions

The pharmacokinetic, pharmacodynamic, and safety profiles of semaglutide were similar in Japanese and Caucasian subjects, suggesting that no dose adjustment is required for the clinical use of semaglutide in Japanese subjects.

Funding

Novo Nordisk A/S, Denmark.

Trial registration

ClinicalTrials.gov identifier NCT02146079. Japanese trial registration number JapicCTI-142550.

     

The Development of Foveolar-type Gastric Adenocarcinoma during Maintenance Therapy of Vonoprazan for Reflux Esophagitis

We herein report the first case of foveolar-type gastric adenocarcinoma that developed after the initiation of vonoprazan (VPZ). A 51-year-old man had heartburn at the first visit and reflux esophagitis endoscopically, so he started taking VPZ. An approximately 5-mm-sized reddish polyp with a raspberry-like morphology was detected at the anterior wall of the upper body of the stomach 156 weeks after starting maintenance therapy with VPZ 10 mg/day. It was diagnosed as foveolar-type gastric adenocarcinoma based on a biopsy. Another approximately 4-mm-sized foveolar-type gastric adenocarcinoma was also detected at the posterior wall of the middle body of the stomach.     

Exacerbation of Ulcerative Colitis with Tocilizumab: A Report of Two Cases,One with Takayasu Arteritis and the Other with Relapsing Polychondritis

Tocilizumab (TCZ), a biologic that blocks the signal transduction of interleukin-6, has been used for the treatment of various autoimmune diseases. Many of these cases are sometimes complicated by ulcerative colitis (UC). However, the effect of TCZ on UC is unclear. We experienced two cases with concomitant UC that were treated with TCZ, one for Takayasu arteritis (TAK) and the other for relapsing polychondritis (RP). TCZ did not improve UC in either of these cases. TCZ might have adverse effects on the intestinal tract, since interleukin-6 signaling plays an important role in intestinal epithelium maintenance. Treatment with TCZ should therefore be carefully provided in patients complicated with UC.     

Unilateral active adrenal tuberculosis featuring persistent intermittent fever

The adrenal gland is one of the organs which tuberculosis infects. In most clinical settings bilateral adrenal tuberculosis has been clarified after adrenal insufficiency is overt. On the contrary, active adrenal tuberculosis is rarely detected during the survey of infectious disease. A 68-year-old man was admitted because of intermittent fever. The fever had continued for the last 3 months. The intermittent fever was accompanied with leukocytosis and elevation of C-reactive protein. Serum soluble interleukin-2 receptor was 1920 U/ml, and beta2-microglobulin was 4.0 mg/l. Bacterial cultures of blood, sputa, urine, bone marrow and cerebrospinal fluid did not show any particular bacteria. Mycobacterium tuberculosis was negative in culture of sputa, and there was no tuberculin reaction. Plasma ACTH and serum cortisol were 18.5 pmol/l and 527.0 nmol/l, respectively. Abdominal CT scan showed right adrenal mass with a size of 28 x 20 mm, which was low density and had a well-encapsulated homogenous appearance. After the adrenalectomy, histology verified active adrenal tuberculosis. The intermittent fever disappeared, and white blood cells and C-reactive protein normalized. These findings indicate an atypical, rare case of unilateral, active adrenal tuberculosis closely linked to intermittent fever, and without any other organ involvement.