The role of mineralocorticoid receptor expression in brain remodeling after cerebral ischemia

Mineralocorticoid receptors (MRs) are classically known to be expressed in the distal collecting duct of the kidney. Recently it was reported that MR is identified in the heart and vasculature. Although MR expression is also found in the brain, it is restricted to the hippocampus and cerebral cortex under normal condition, and the role played by MRs in brain remodeling after cerebral ischemia remains unclear. In the present study, we used the mouse 20-min middle cerebral artery occlusion model to examine the time course of MR expression and activity in the ischemic brain. We found that MR-positive cells remarkably increased in the ischemic striatum, in which MR expression is not observed under normal conditions, during the acute and, especially, subacute phases after stroke and that the majority of MR-expressing cells were astrocytes that migrated to the ischemic core. Treatment with the MR antagonist spironolactone markedly suppressed superoxide production within the infarct area during this period. Quantitative real-time RT-PCR revealed that spironolactone stimulated the expression of neuroprotective or angiogenic factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), whereas immunohistochemical analysis showed astrocytes to be cells expressing bFGF and VEGF. Thereby the incidence of apoptosis was reduced. The up-regulated bFGF and VEGF expression also appeared to promote endogenous angiogenesis and blood flow within the infarct area and to increase the number of neuroblasts migrating toward the ischemic striatum. By these beneficial effects, the infarct volume was significantly reduced in spironolactone-treated mice. Spironolactone may thus provide therapeutic neuroprotective effects in the ischemic brain after stroke.     

Expression of sex steroid hormone-related genes in the embryo of the leopard gecko

Sex steroid hormones are known to play a central role in vertebrate sex determination and differentiation. However, the tissues in which they are produced or received during development, especially around the period of sex determination of the gonads, have rarely been investigated. In this study, we identified the cDNA sequence, including the full-length of the coding region of cholesterol side-chain cleavage enzyme (P450scc), from the leopard gecko; a lizard with temperature-dependent sex determination. Embryonic expression analysis of two steroidogenic enzymes, P450scc and P450 aromatase (P450arom), and four sex steroid hormone receptors, androgen receptor, estrogen receptor alpha and beta, and progesterone receptor, was subsequently conducted. mRNA expression of both steroidogenic enzymes was observed in the brain and gonads prior to the temperature-sensitive period of sex determination. The mRNAs of the four sex steroid hormone receptors were also detected in the brain and gonads at all stages examined. These results suggest the existence of a gonad-independent sex steroid hormone signaling system in the developing leopard gecko brain.     

A case of primary small cell carcinoma arising from the common bile duct]

Small cell carcinoma is usually seen in the lung, but rarely involves the gastrointestinal tract including biliary tract. A 65 year-old man was admitted because of obstructive jaundice. A smooth-surfaced round intraluminal mass with proximal bile duct dilatation was seen in the proximal common bile duct on endoscopic retrograde cholangiogram. Under the diagnosis of bile duct cancer, pylorus-preserving pancreatoduodenectomy was done. Pathology revealed a 2 cm sized small cell carcinoma in the proximal common bile duct and distal common hepatic duct. On immunohistochemical stain, the tumor cells were positive for neuroendocrine markers CD56 and synaptophysin. After surgery, the patient received 5 cycles of adjuvant chemotherapy with VIP (etoposide, ifosfamide, and cisplatin) regimen. However, the patient died of liver metastasis 12 months after the diagnosis. We report a case of extrapulmonary small cell carcinoma arising from the common bile duct.     

Microscopic polyangiitis associated with diffuse panbronchiolitis

There are several case reports of systemic vasculitis associated with chronic suppurative lung diseases. We describe a 46-year-old female, previously diagnosed as having diffuse panbronchiolitis (DPB), presenting with hemosputum and dyspnea. Her serum titer of MPO-ANCA was positive together with a high titer of BPI-ANCA. Chest X-ray and chest CT scan showed pulmonary hemorrhage, and the renal biopsy specimen revealed necrotizing, crescentic glomerulonephritis. She was diagnosed as having ANCA-associated vasculitis, and more specifically, microscopic polyangiitis accompanied by DPB. She was treated with methylprednisolone pulse therapy, followed by intravenous cyclophosphamide. This case suggested a possible association with chronic bacterial infection, which may play a role in the pathogenesis of ANCA-associated vasculitis.     

Influence of ventricular pacing on myocardial oxygen tension

INTRODUCTION: The influence of heart rate on cardiac output, oxygen consumption, and myocardial activity has been widely investigated. However, the influence of heart rate on myocardial oxygen tension (pO2) remains unclear. Since the introduction of flexible pO2 micro catheters to measure partial oxygen tension in a working muscle, it is possible to investigate the influence of heart rate on myocardial oxygen tension. METHODS: Intraoperatively, a flexible pO2 micro catheter was positioned in the mid-myocardium of 8 male farm pigs. The heart rate was varied via an external pacer from base rate up to fibrillation and the corresponding myocardial pO2 was measured. RESULTS: Within 2 min, the myocardial pO2 adjusted to a change in heart rate. In this animal model, an optimal myocardial pO2 was observed at 109 bpm. A further increase in heart rate led to a decrease in myocardial pO2. When the heart rate was reaching the level of a fibrillation, pO2 dropped to zero. CONCLUSION: In young healthy pigs--with a normal blood vessel regulation and the pharmacologic and experimental conditions used in this study--a significant relation between myocardial pO2 and heart rate was observed. Myocardial oxygen tension increased during cardiac pacing until a heart rate of 109 bpm. Thereafter a decline of pO2 occurred. Each change in heart rate resulted in a corresponding change of pO2 within roughly 2 min.     

Alpha-toxin facilitates the generation of CXC chemokine gradients and stimulates neutrophil homing in Staphylococcus aureus pneumonia

BACKGROUND: Staphylococcus aureus alpha-toxin is a major virulence factor, but its mechanism of action in vivo is incompletely understood. METHODS: We examined the role of alpha-toxin in S. aureus pneumonia using the mouse model of intranasal lung infection with S. aureus strain 8325-4 (hla(+) S. aureus) and an alpha-toxin-deficient mutant strain made on the 8325-4 background (hla(-) S. aureus). RESULTS: Intranasal infection of mice with hla(-) S. aureus resulted in substantially less lung injury and inflammation, pulmonary edema, and tissue bacterial burden than did infection with hla(+) S. aureus. Furthermore, fewer mice infected with hla(-) S. aureus died of the infection, compared with those infected with hla(+) S. aureus. Levels of the CXC chemokines keratinocyte-derived chemokine and macrophage inflammatory protein-2 were significantly lower in the airways of mice infected with hla(-) S. aureus, and this difference was the result of reduced secretion of newly synthesized chemokines into the airway. Consistent with these data, significantly fewer neutrophils were present in the airways and lungs of mice infected with hla(-) S. aureus, compared with those infected with hla(+) S. aureus. CONCLUSIONS: These data suggest that alpha-toxin enhances virulence by facilitating the generation of CXC chemokine gradients and stimulating chemokine-induced neutrophil influx in S. aureus pneumonia.     

Family history of diabetes and risk of atherosclerotic cardiovascular disease in Korean men and women

The importance of family history of type 2 diabetes (FHD) as a risk factor for atherosclerotic cardiovascular disease (ASCVD) remains controversial. A report of diabetes in parents and siblings was used to establish FHD in a cohort of 1,005,230 Koreans aged 30-95 years insured by the National Health Insurance Corporation who had a biennial medical evaluation during 1992-1995. ASCVD morbidity and mortality from 1993 to 2005 were examined in relation to FHD and other ASCVD risk factors. The risk of ischemic heart disease (IHD) increased significantly (19%) in men with FHD but not in women. A strong interaction was observed between FHD and personal history of diabetes for the occurrence of ASCVD; men with both diabetes and FHD were at significantly increased risk of developing IHD, cerebrovascular disease and ASCVD with hazard ratios (HR) of 2.28, 2.07, and 2.12, respectively, compared to those who had neither FHD nor type 2 diabetes. Corresponding risks were 2.64, 2.03, and 2.10 in women, respectively. This study demonstrates that risk of ASCVD is increased among those with diabetes and a family history of diabetes; suggesting that genetic factors associated with occurrence of familial diabetes may increase risk of ASCVD beyond the risk among people without FHD.     

Association of abdominal fat distribution and cardiometabolic risk factors among obese Korean adolescents

The association between abdominal fat distribution and cardiometabolic risk factors using direct measures of abdominal fat in adolescents has not been extensively researched. This study was designed to investigate the association between visceral and subcutaneous fat and cardiometabolic risk factors, in obese Korean adolescents. The study enrolled 175 adolescents (72 boys, 103 girls), from ages nine to 19 years, who were referred to the Obesity Clinic of Asan Medical Center. Body mass index (BMI) and waist circumference (WC) were measured for each study participant. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were calculated by computed tomography. Blood pressure, fasting plasma glucose, total cholesterol, triglycerides, HDL cholesterol, insulin and homeostasis model assessment (HOMA) score were measured. Systolic blood pressure, HDL cholesterol, fasting insulin and the HOMA score were significantly correlated with BMI, WC, VAT and SAT. In addition, VAT was significantly correlated with diastolic blood pressure and triglyceride levels. On multiple regression analysis, VAT was independently correlated with blood pressure, triglycerides, HDL cholesterol, fasting insulin and the HOMA score, while SAT was independently correlated with systolic blood pressure, fasting insulin and the HOMA score. This study determined that cardiovascular risk factors are closely associated with VAT, while insulin resistance is closely associated with both VAT and SAT among obese Korean adolescents.     

Ligands for peroxisome proliferator-activated receptorγ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice

Induction of differentiation and apoptosis in cancer cells through ligands of nuclear hormone receptors (NHRs) is a novel and promising approach to cancer therapy. All-trans-retinoic acid (ATRA), an RA receptor-specific NHR ligand, is now used for selective cancers. The NHR, peroxisome proliferator-activated receptor γ (PPARγ) is expressed in breast cancer cells. Activation of PPARγ through a synthetic ligand, troglitazone (TGZ), and other PPARγ-activators cause inhibition of proliferation and lipid accumulation in cultured breast cancer cells. TGZ (10⁻⁵ M, 4 days) reversibly inhibits clonal growth of MCF7 breast cancer cells and the combination of TGZ (10⁻⁵ M) and ATRA (10⁻⁶ M, 4 days) synergistically and irreversibly inhibits growth and induces apoptosis of MCF7 cells, associated with a dramatic decrease of their bcl-2 protein levels. Similar effects are noted with in vitro cultured breast cancer tissues from patients, but not with normal breast epithelial cells. The observed apoptosis mediated by TGZ and ATRA may be related to the striking down-regulation of bcl-2, because forced over-expression of bcl-2 in MCF7 cells cultured with TGZ and ATRA blocks their cell death. TGZ significantly inhibits MCF7 tumor growth in triple immunodeficient mice. Combined administration of TGZ and ATRA causes prominent apoptosis and fibrosis of these tumors without toxic effects on the mice. Taken together, this combination may provide a novel, nontoxic and selective therapy for human breast cancers.