Familial hypobetalipoproteinemia caused by homozygous loss-of-function mutations in PCSK9: A case report.

Here, we present the first case of a Japanese patient with familial hypobetalipoproteinemia (HBL) that is caused by homozygous loss-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). A 46-year-old female patient who was born in a consanguineous marriage of parents who were second cousins was referred to our hospital due to decreased low-density lipoprotein (LDL)-cholesterolemia (22 mg/dL). She did not have any secondary HBL causes. Novel homozygous mutations were identified in PCSK9 (c.1133G>A [p.Cys378Tyr]) using panel sequencing. The serum levels of heterodimer PCSK9 and furin-cleaved PCSK9 were extremely low (<32 and 15 ng/mL, respectively), leading to the diagnosis of familial HBL diagnosis caused by loss-of-function mutations in PCSK9. The patient did not exhibit any complications associated with low LDL cholesterol, except for mild fatty liver and reduced serum 25-OH vitamin D level (15.7 ng/mL). Here, we provide a detailed molecular and functional characterization of a novel loss-of-function mutation in PCSK9.

Effect of disclosing the relation between effort and unit reliability on system reliability: An economic experiment.

The purpose is to experimentally examine the effect of disclosing the risk probability of each unit in a production system on human behavior and the resulting system reliability. We used an economic experiment based on the theoretical model of Hausken (2002) to evaluate the effect of disclosing the relation between effort and unit reliability. We conducted first the non-disclosed-risk experiment and then the disclosed-risk experiment within subjects in both series and parallel systems. Our experimental results show that disclosing the relation between effort and unit reliability has two positive effects. First, subjects succeeded in improving the system reliability while cutting back on efforts to reduce the risk of their units when the risk probability was disclosed. In each system, the disclosed-risk condition achieves significantly higher system reliability on average than does the non-disclosed-risk condition, although the average level of effort is significantly lower under the disclosed-risk condition than under the non-disclosed-risk condition. Second, disclosing the risk probability simplified the subjects' decision-making process and reduced its cost because subjects made their decisions on the amount of effort to exert based only on the risk probability information without considering other factors, such as the number of accidents.

Two Cases of Hypopituitarism Caused by Intrasellar Aneurysm.

Giant internal carotid artery aneurysms sometimes extend into the sellar region, which rarely but occasionally results in hypopituitarism due to the compression of the normal pituitary gland or hypothalamus. Hyponatremia is a known complication of hypopituitarism. We herein report two cases of hypopituitarism caused by intrasellar aneurysm of different origins, resulting in hyponatremia. Untreated hypopituitarism may lead to lethargy, coma, cardiac arrhythmia, and death. Therefore, we must be alert for the occurrence of giant intrasellar aneurysm, as it causes hypopituitarism. The prompt diagnosis and treatment of hypopituitarism are necessary to prevent this fatal outcome.

Acute Adrenal Insufficiency Associated with Rathke's Cleft Cyst.

Rathke's cleft cysts are known to cause hormone-related abnormalities. However, the natural history of this disorder is obscure, so it is rarely associated with acute adrenal insufficiency. We herein describe a case of Rathke's cleft cyst associated with acute adrenal insufficiency in a 27-year-old man. The patient experienced severe headaches due to acute adrenal insufficiency without changes in the size of the cyst. Glucocorticoid administration improved these symptoms, and the cyst spontaneously shrank before operation. This case led us to conclude that Rathke's cleft cysts should be considered in the differential diagnosis of patients who present with adrenal insufficiency, and that the cysts can be reduced by glucocorticoids.

Novel mechanism of chronic exposure of oleic acid-induced insulin release impairment in rat pancreatic beta-cells.

A sustained, high circulating level of free fatty acids (FFAs) is an important risk factor for the development of insulin resistance, islet beta-cell dysfunction, and pathogenesis of type 2 diabetes. Here, we report a novel mechanism of chronic exposure of oleic acid (OA)-induced rat insulin release impairment. Following a 4-day exposure to 0.1 mM OA, there was no significant difference in basal insulin release when comparing OA-treated and untreated islets in the presence of 2.8 mM glucose, whereas 16.7 mM glucose-stimulated insulin release increased 2-fold in control, but not in OA-treated, islets. Perforated patch-clamp recordings showed that untreated beta-cells exhibited a resting potential of -62.1 +/- 0.9 mV and were electrically silent, whereas OA-treated beta-cells showed more positive resting potentials and spontaneous action potential firing. Cell-attached single-channel recordings revealed spontaneous opening of ATP-sensitive potassium (K(ATP)) channels in control, but not in OA-treated, beta-cells. Inside-out excised patch recordings showed similar activity in both OA-treated and untreated beta-cells in the absence of ATP on the inside of the cellular membrane, whereas in the presence of ATP, K(ATP) channel activity was significantly reduced in OA-treated beta-cells. Electron microscopy demonstrated that chronic exposure to OA resulted in the accumulation of triglycerides in beta-cell cytoplasm and reduced both the number of insulin-containing granules and insulin content. Collectively, chronic exposure to OA closed K(ATP) channels by increasing the sensitivity of K(ATP) channels to ATP, which in turn led to the continuous excitation of beta-cells, depletion of insulin storage, and impairment of glucose-stimulated insulin release.