Haplotype analysis reveals founder effects of thyroglobulin gene mutations C1058R and C1977S in Japan

CONTEXT: Thyroglobulin (Tg) mutations were previously believed to be rare, resulting in congenital goitrous hypothyroidism. However, an increasing number of patients with Tg mutations, who are euthyroid to mildly hypothyroid, have been identified in Japan. OBJECTIVES: The purpose of this study was to investigate whether the three frequently found Tg mutations, namely C1058R, C1245R, and C1977S, were caused by a founder effect. RESULTS: We found 26 different mutations within the Tg gene in 52 patients from 41 families. Thirty-five patients were homozygous for the mutations, whereas the others were compound heterozygous. The occurrence of Tg mutation within the general Japanese population is one in 67,000. Patients with the C1245R mutation were found throughout Japan, whereas those with the C1058R mutation were confined to a small village on a southern island, and those with the C1977S mutation were restricted to a city. The eight patients with the C1058R mutation and the seven patients with the C1977S mutation all showed the same combinations of 18 single-nucleotide polymorphisms in the coding region of the Tg gene, which would appear in one in 810 million and one in 37 billion, respectively, control subjects. CONCLUSIONS: The frequently found mutations, C1058R and C1977S, were caused by founder effects. This result suggests that Tg mutations may provide a genetic basis for the cause of familial euthyroid goiter.     

Imidafenacin has no influence on learning in nucleus basalis of Meynert-lesioned rats

The prevalence of overactive bladder (OAB) and Alzheimer’s disease (AD) increases with age, and much attention has been paid to the risk of cognitive impairment which may be induced by antimuscarinics used for OAB in patients with AD. Imidafenacin, an antimuscarinic agent for OAB treatment, has been reported not to affect learning in normal animals. However, under the condition in which sensitivity to learning impairment by antimuscarinics is increased, it remains unclear whether imidafenacin still does not impair the learning. Therefore, the influences of imidafenacin on passive avoidance response were investigated in sham-operated and nucleus basalis of Meynert (nbM)-lesioned rats and compared with oxybutynin hydrochloride and tolterodine tartrate. The learning-inhibitory doses of intravenous oxybutynin hydrochloride and tolterodine tartrate were 0.3 and 3 mg/kg in sham-operated rats and 0.1 and 1 mg/kg in nbM-lesioned rats, respectively. Thus, the learning impairments by those antimuscarinics were more sensitive in nbM-lesioned rats than in sham-operated rats. On the other hand, intravenous administration of imidafenacin had no influence on learning in either case of the rats. In normal rats, however, intracerebroventricular administration of imidafenacin impaired learning to the same degree as that of oxybutynin hydrochloride. Thus, the present study suggests that imidafenacin, unlike the other antimuscarinics used, has no significant risk of enhancing learning impairment even in models whose sensitivity to learning impairment by antimuscarinics is commonly increased, probably because of its low brain penetration.     

Increased lymphocyte subpopulations and macrophages in the ovaries and oviducts of laying hens infected with Salmonella enterica serovar Enteritidis

Salmonella enterica serovar Enteritidis (SE) is a causative agent for human food poisoning cases throughout the world. The ovaries and the oviducts of the laying hens are the major sites of SE colonization from which vertical transmission to eggs occurs. In this study, Salmonella-induced changes in T lymphocytes, B lymphocytes and macrophages in the ovaries and oviducts were assessed after primary and secondary experimental inoculations of laying hen with SE. Statistically significant increases in the numbers of T cells (both CD4⁺ and CD8⁺) and macrophages were observed 7 to 14 days after primary inoculation, followed by a peak in B-cell numbers from the 14th day post-primary inoculation onwards in the secretory areas of the oviducts. The peak in lymphocyte numbers immediately preceded a decline in the rate of SE recovery from the reproductive tract beginning at day 14. The correlation of decreased Salmonella recovery with elevated lymphocyte and macrophage numbers strongly suggests that local cell-mediated immunity is involved in controlling SE injection in the ovaries and oviducts.     

Electron Microscopic Study on Normal Rat Peritoneal Mesothelium and its Changes in Absorption of Particulate Iron Dextran Complex

Fine structures of peritoneal mesothelium of normal rat omentum and its changes in absorption of iron dextran complex were studied by means of electron microscope. Peritoneal mesothelium resembles endothelial sheet of blood- and lymph-vessels without specific pores, and also has abundant pinocytic vesicles throughout the cytoplasm. In the mesothelium of both normal and experimental cases, there are no free openings comparable to "Stomata or Stigmata", on the existence of which many observers have discussed from the findings in photo- microscopic studies. Iron dextran particles injected intraperitoneally seem to be able to pass through the cytoplasm of the cell and can enter the interstitial space by "Transmembranation (T anaka ) or Diffusion" as well as "Pinocytosis".
A part of them are gathered within membrane closed round vesicles (Segresomes, T anaka ) by a phagocyte-like action of the mesothelial cells.     

Selective binding of bladder muscarinic receptors in relation to the pharmacokinetics of a novel antimuscarinic agent, imidafenacin, to treat overactive bladder

The binding of orally administered imidafenacin, used to treat overactive bladders, to muscarinic receptors in rat tissue was characterized based on pharmacokinetics. The binding in six tissues including bladder tissue was measured using [N-methyl-(3)H] scopolamine methyl chloride ([(3)H]NMS). Pharmacokinetic parameters were estimated from measurements of the concentration of imidafenacin in serum, the bladder, and the submaxillary gland by liquid chromatography-mass spectrometry/mass spectrometry. The receptor binding affinity of imidafenacin in vitro was significantly lower in the bladder than submaxillary gland or colon. The oral administration of imidafenacin (0.79, 1.57, and 6.26 μmol/kg) was characterized by a more selective and longer-lasting binding to muscarinic receptors in the bladder than other tissues. Imidafenacin showed little binding to brain muscarinic receptors, consistent with its minor effect on the central nervous system. Pharmacokinetic data showed that orally administered imidafenacin was distributed at a higher concentration in the bladder than the serum or submaxillary gland of rats. After the intravesical instillation of imidafenacin, there was significant binding of muscarinic receptors in the bladder. Furthermore, a significant level of imidafenacin was detected in the urine of rats given a 1.57 μmol/kg concentration of this agent. The present study demonstrated that imidafenacin administered orally distributes predominantly to the bladder and exerts more selective and longer-lasting effect on the bladder than other tissues, such as the submaxillary gland, colon, and brain. Furthermore, the imidafenacin excreted in urine may play an important role in pharmacokinetic and pharmacological selectivity.     

Astrocyte‐mediated infantile‐onset leukoencephalopathy mouse model

Astrocytes have recently been shown to provide physiological support for various brain functions, although little is known about their involvement in white matter integrity. Several inherited infantile‐onset leukoencephalopathies, such as Alexander disease and megalencephalic leukoencephalopathy with subcortical cysts (MLC), implicate astrocytic involvement in the formation of white matter. Several mouse models of MLC had been generated by knocking out the Mlc1 gene; however, none of those models was reported to show myelin abnormalities prior to formation of the myelin sheath. Here we generated a new Mlc1 knockout mouse and a Mlc1 overexpressing mouse, and demonstrate that astrocyte‐specific Mlc1 overexpression causes infantile‐onset abnormalities of the white matter in which astrocytic swelling followed by myelin membrane splitting are present, whereas knocking out Mlc1 does not, and only shows myelin abnormalities after 12 months of age. Biochemical analyses demonstrated that MLC1 interacts with the Na⁺/K⁺ ATPase and that overexpression of Mlc1 results in decreased activity of the astrocytic Na⁺/K⁺ pump. In contrast, no changes in Na⁺/K⁺ pump activity were observed in Mlc1 KO mice, suggesting that the reduction in Na⁺/K⁺ pump activity resulting from Mlc1 overexpression causes astrocytic swelling. Our infantile‐onset leukoencephalopathy model based on Mlc1 overexpression may provide an opportunity to further explore the roles of astrocytes in white matter development and structural integrity. We established a novel mouse model for infantile‐onset leukoencephalopathy by the overexpression of Mlc1. Mlc1 overexpression reduced activity of the astrocytic sodium pump, which may underlie white matter edema followed by myelin membrane splitting. GLIA 2016 GLIA 2017;65:150–168     

A case of leiomyosarcoma of the small intestine with perforative peritonitis

On April 15th, 1986, the patient, a 58-year-old man, felt ill because of a stomachache. On April 15, he was referred to our hospital and admitted after having been diagnosed as having pan peritonitis. During surgery, an extraintestinal growth, a small fist-size tumor, was detected in the jejunum. The tumor was partly perforated, and a partial resection of the small intestine was carried out. A histopathological examination led to the diagnosis of a leiomyosarcoma of the small intestine. On June 12, 1987, the patient again returned to our hospital, complaining of a stomachache. A reoperation was performed for perforative peritonitis due to its recurrence but only palliative treatment could be provided.