Hirokazu Okazaki

Plasma brain-derived neurotrophic factor and reverse dipping pattern of nocturnal blood pressure in patients with cardiovascular risk factors.

Context Basic studies have shown that brain-derived neurotrophic factor (BDNF) has critical roles in the survival, growth, maintenance, and death of central and peripheral neurons, while it is also involved in regulation of the autonomic nervous system. Furthermore, recent clinical studies have suggested potential role of plasma BDNF in the circulatory system. Objective We investigated the mutual relationships among plasma BDNF, patterns of nocturnal blood pressure changes (dippers, non-dippers, extra-dippers, and reverse-dippers), and cardiac autonomic function as determined by heart rate variability (HRV). Design This was a cross-sectional study of patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) Study from October 2010 to November 2012. Patients Two-hundred fifty patients with 1 or more cardiovascular risk factor(s) (obesity, smoking, presence of cardiovascular event history, hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease) were enrolled. Results Plasma BDNF levels (natural logarithm transformed) were significantly (p = 0.001) lower in reverse-dipper patients (7.18±0.69 pg/ml, mean ± SD, n = 36) as compared to dippers (7.86±0.86 pg/ml, n = 100). Multiple logistic regression analysis showed that BDNF (odds ratios: 0.417, 95% confidence interval: 0.228–0.762, P = 0.004) was the sole factor significantly and independently associated with the reverse-dippers as compared with dippers. Furthermore, plasma BDNF level was significantly and positively correlated with the time-domain (SDNN, SDANN5, CVRR) and frequency-domain (LF) of HRV parameters. Finally, multiple logistic regression analyses showed that the relationship between plasma BDNF and the reverse-dippers was weakened, yet remained significant or borderline significant even after adjusting for HRV parameters. Conclusions Low plasma BDNF was independently associated with patients showing a reverse-dipper pattern of nocturnal blood pressure, in which an imbalance of cardiac autonomic function may be partly involved.

Partial HPRT Deficiency with a Novel Mutation of the HPRT Gene in Combination with Four Previously Reported Variants Associated with Hyperuricemia

A 15-year-old boy was referred to our department due to gout. The laboratory findings showed hyperuricemia with a decreased erythrocyte hypoxanthine phosphoribosyl transferase (HPRT) activity. The HPRT cDNA sequence was revealed to be 206A>T, which has not been previously reported. In addition, direct sequencing of genomic DNA showed the patient to possess four variants reported to be associated with hyperuricemia. This is the first case report of partial HPRT deficiency due to a novel HPRT mutation accompanied by variants associated with hyperuricemia. Combination treatment consisting of benzbromarone and febuxostat had a significant effect in reducing the urate level in our patient.

Oncostatin M Promotes Osteoblastic Differentiation of Human Vascular Smooth Muscle Cells Through JAK3‐STAT3 Pathway

Vascular calcification is a clinically significant component of atherosclerosis and arises from chronic vascular inflammation. Oncostatin M (OSM) derived from plaque macrophages may contribute to the development of atherosclerotic calcification. Here, we investigated the stimulatory effects of OSM on osteoblastic differentiation of human vascular smooth muscle cells (HVSMC) derived from various arteries including umbilical artery, aorta, and coronary artery and its signaling pathway. Osteoblastic differentiation was induced by exposure of HVSMC to osteogenic differentiation medium (ODM) (10% fetal bovine serum, 0.1 μM dexamethasone, 10 mM β‐glycerophosphate and 50 μg/ml ascorbic acid 2‐phosphate in Dulbeccos modified Eagles medium [DMEM]). OSM significantly increased alkaline phosphate (ALP) activity and matrix mineralization in HVSMC from all sources. Osteoblast marker genes such as ALP and Runx2 were also up‐regulated by OSM in these cells. OSM treatment induced activation of STAT3 in HVSMC from umbilical artery as evidenced by immunoblot. Moreover, not only a JAK3 inhibitor, WHI‐P154, but also knockdown of JAK3 by siRNA prevented the OSM‐induced ALP activity and matrix mineralization in umbilical artery HVSMC. On the other hand, silencing of STAT3 almost completely suppressed OSM‐induced ALP expression and matrix mineralization in HVSMC from all sources. These data suggest that OSM promotes osteoblastic differentiation of vascular smooth muscle cells through JAK3/STAT3 pathway and may contribute to the development of atherosclerotic calcification. J. Cell. Biochem. 116: 1325–1333, 2015.

Nonpharmacological Management of Gout and Hyperuricemia: Hints for Better Lifestyle

We reviewed lifestyle factors that influence serum uric acid levels and risk of gout flare, and how to improve their deleterious effects. Since obesity increases uric acid and weight gain increases gout risk, weight reduction by daily exercise and limiting intake of excess calories is recommended. However, strenuous exercise, which causes adenine nucleotide degradation; starvation, which decreases uric acid excretion; and dehydration may raise the level of uric acid in serum and trigger gout. Increased intake of purine-rich foods, such as meat and seafood, raise the level of uric acid in serum and is associated with increased risk of gout, whereas dairy products, especially low-fat types, are associated with a lower risk of gout. Also, heavy alcohol drinking raises the uric acid level and increases the risk of gout through adenine nucleotide degradation and lactate production. Sweet fruits and soft drinks containing fructose should be moderated, since fructose may raise uric acid and increase gout risk through uric acid production and/or decreased excretion. On the other hand, the Mediterranean diet is recommended for gout patients, since it may also help prevent hyperuricemia. Furthermore, coffee and vitamin C supplementation could be considered as preventive measures, as those can lower serum uric acid levels as well as the risk of gout.

Anaplastic thyroid carcinoma accompanied by uncontrollable eosinophilia.

Anaplastic thyroid carcinoma is a rare disease, and cases associated with eosinophilia are even rarer. We herein report a case of anaplastic thyroid carcinoma accompanied by remarkable and uncontrollable eosinophilia. A 71-year-old man was diagnosed with end-stage anaplastic thyroid carcinoma. Throughout the aggressive clinical course of the cancer, eosinophilia dramatically progressed and became extremely refractory to steroid treatment. We measured the serum levels of hematopoietic cytokines potentially involved in eosinophilia, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3 and IL-5. Although the GM-CSF level was moderately elevated, both the IL-3 and IL-5 levels were within the normal ranges. In this case, the patients eosinophilia may have been related to his severe dyspnea and was likely responsible for the allergic reaction to the anticancer drug. Therefore, it is essential to elucidate the etiology of eosinophilia in patients with thyroid cancer in order to improve the treatment for patients with anaplastic thyroid carcinoma.

Concomitant Cushing's Disease and Marked Hyperprolactinemia: Response to a Dopamine Receptor Agonist

A 38-year-old woman was admitted to our hospital because of amenorrhea, multiple bone fractures, and a Cushingoid appearance. Endocrinological investigations revealed that she had co-existing Cushings disease and prolactinoma, with a serum level of prolactin (PRL) at 1,480 ng/mL, corticotropin (ACTH) at 81.3 pg/mL, and cortisol at 16.6 μg/dL. Due to the lack of indication for transsphenoidal surgery, cabergoline monotherapy was initiated. A 6-month course of treatment resulted in only subtle amelioration of hypercortisolism, while hyperprolactinemia was dramatically improved. In 5 cases of bihormonal (ACTH/PRL) pituitary macroadenoma reported in the English literature, 2 were initially treated with dopaminergic agonists with substantial effectiveness for both PRL and ACTH. We herein report an extremely rare case of bihormonal macroadenoma in which only PRL was responsive to treatment.