Endothelium-dependent vasodilation in type II diabetes mellitus

Endothelial dysfunction is a major feature of atherosclerosis and it can also serve as an early atherosclerotic marker. Evaluation and assessment of the endothelial function is important to prevent serious atherosclerotic disease especially myocardial infarction, cerebrovascular disease and renal failure. To evaluate endothelial function we measured endothelium-dependent vasodilation (flow-mediated dilatation: %FMD) of the brachial artery with ultrasound. This method is non-invasive and can be repeatable in order to follow patients individually. Progressive atherosclerosis is often observed in diabetic patients who are not hypertensive. To evaluate the impairment of the endothelial function in type 2 diabetic patients, we examined %FMD in them and compared with hypertensive patients without diabetes and control subjects. We found that type 2 diabetic patients had the same endothelial dysfunction as hypertensive patients without diabetes. %FMD in both diabetic patients and hypertensive patients was lower than in control subjects. Moreover, %FMD of type 2 diabetic patients with hypertension was lower than %FMD of type 2 diabetic patients without hypertension. These finding suggests that endothelial dysfunction develops under the conditions of hypertension and hyperglycemia. Evaluating endothelial function with ultrasound is useful for assessment of atherosclerosis in diabetes.     

The increase in the intracellular Ca2+ concentration induced by mechanical stimulation is propagated via release of pyrophosphorylated nucleotides in mammary epithelial cells

Mechanical stimulation of one mammary tumor cell in culture induced an increase in its intracellular calcium concentration which spread to surrounding cells. The increase in calcium can also be induced by addition of a solution in which cultured mammary tumor cells were stimulated by repeated pipetting (solution after pipetting cells, SAPC). The activity of the SAPC was completely abolished by treatment with snake venom phosphodiesterase or pyrophosphatase. Uridine triphosphate (UTP), uridine diphosphate (UDP) and ATP (1 M each) were detected in the SAPC, whereas 5-UMP and 5-AMP were produced by phosphodiesterase digestion. A mixture of UTP, UDP and ATP (1 M each) elicited a calcium response which was comparable to that induced by SAPC, while UTP, UDP or ATP alone at 1 M elicited a small increase in calcium concentration in mammary tumor cells. Suramin, a competitive antagonist of P₂ purinoceptors, diminished the spreading of the calcium wave induced by mechanical stimulation. It also blocked the responses to SAPC, UTP, UDP and ATP. These findings suggest that the mechanical stimulation results in the release of UTP, UDP and ATP into the extracellular space which mediates induction of the spreading calcium response via P_2U-type purinoceptors.     

PREGS induces LTP in the hippocampal dentate gyrus of adult rats via the tyrosine phosphorylation of NR2B coupled to ERK/CREB [corrected] signaling

An acute application of neurosteroid pregnenolone sulfate (PREGS) to hippocampal slices from adult rats induced a long-lasting potentiation (LLP PREGS) at the perforant path-granule cell synapse. As a partial mechanism of the LLP PREGS, we previously revealed that PREGS transiently increases the probability of presynaptic glutamate release via a sensitization of alpha7-nicotinic acetylcholine receptor (alpha7nAChR). We herein demonstrate that the LLP PREGS could be separated into two independent processes: the above-mentioned early presynaptic-origin short-term potentiation (STP PREGS) and a delayed postsynaptic N-methyl-d-aspartate receptor (NMDAr)-dependent long-term potentiation termed LTP(PREGS). This study focused on the analysis of the signaling mechanism underlying the LTP PREGS. PREGS increased the tyrosine phosphorylation of NR2B, a subunit of NMDAr, and the NMDAr-mediated Ca2+ influx in the granule cells. The enhanced Ca2+ influx was largely attenuated by the NR2B subunit inhibitor ifenprodil and the Src kinase family inhibitor PP2. PREGS also triggered a persistent phosphorylation of extracellular signal-regulated kinase 2 (ERK2) followed by an ERK-dependent phosphorylation of cAMP-response element-binding protein (CREB), which was crucial for the LTP PREGS induction and was sensitive to ifenprodil. These results suggest that PREGS induces an acute increase in the NR2B tyrosine phosphorylation which enhances the Ca2+ influx through NMDAr, followed by an activation of the ERK/CREB signaling cascade that leads to LTP PREGS.     

Leucoxenols A and B,two new phenolics from Bornean medicinal plant Syzygium leucoxylon

The medicinal plant, Syzygium leucoxylon or commonly known as Obah found in North Borneo was considered as traditional medicine by local committee. Two new phenolics, leucoxenols A (1) and B (2) were isolated and identified as major secondary metabolites from the leaves of S. leucoxylon. Their chemical structures were elucidated based on spectroscopic data such as NMR and HRESIMS. Furthermore, these compounds were active against selected strains of fungi.     

Multiple floppy valves with all cardiac valves prolapsing: Clinical course and treatment

Summary Two cases with prolapse of all four cardiac valves are described and compared with two similar ones previously reported. The severity and progression of regurgitation of each of the valves differed by case, despite having similar echocardiographic findings consistent with the diagnosis of multiple floppy valves. Two of the four patients had their aortic valve replaced because of severe regurgitation: the excised valves revealed myxomatous degeneration. None of the patients had any stigmata of Marfan or Ehlers-Danlos syndrome, except for the presence of hyperextensive joints. There may be an unknown collagen disorder that caused floppiness in all the valves.     

Subcellular localization of glucose transporter 4 in the hypothalamic arcuate nucleus of ob/ob mice under basal conditions

Glucose transporter (GLUT) 4 plays an important role in insulin-induced glucose uptake in skeletal muscle and white adipose tissue. Although GLUT4 is abundant in the hypothalamus as well as in these peripheral tissues, little is known about the role of GLUT4 in the hypothalamus. In this study, we examined the subcellular localization of GLUT4 and the activation of insulin signaling pathways in the hypothalamic arcuate nucleus of ob/ob mice under basal conditions. The expression of GLUT4 in the arcuate nucleus of ob/ob mice was higher than that in lean mice. Interestingly, GLUT4 on the plasma membrane increased significantly in neurons of the arcuate nucleus of ob/ob mice when compared to that in lean mice. Because serum insulin levels of ob/ob mice were very high, we hypothesized that insulin strongly stimulates GLUT4 translocation in the arcuate nucleus of ob/ob mice. Unexpectedly, tyrosine phosphorylation of IR and insulin receptor substrate-1 (IRS-1) was faint in the hypothalamus of lean and ob/ob mice. In addition, phosphorylation of IRS-1 at Ser307 in the hypothalamus of ob/ob mice was higher when compared to that in lean mice, suggesting that insulin signaling is impaired by phosphorylation of IRS-1 at Ser307 in the hypothalamus of ob/ob mice. However, serine phosphorylation of Akt in the arcuate nucleus of ob/ob mice increased significantly when compared to that in lean mice. Furthermore, the expression of brain-derived neurotrophic factor, an activator of PI3K-Akt pathway in neurons, increased significantly in the ventromedial hypothalamus of ob/ob mice. We discuss the possibility of novel pathways which induce the translocation of GLUT4 in the arcuate nucleus of ob/ob mice.     

A Fast Placement Technique for Covered Tracheobronchial Stents in Patients with Complicated Esophagorespiratory Fistulas

Purpose To test an endotracheal placement procedure for malignant esophagorespiratory fistula when endoesophageal placement is inapplicable.Methods We report on patients with malignant esophagorespiratory fistula to which endoesophageal approaches were complicated with a complete obstruction of the hypopharynx, a collapsible tracheobronchus, or a previously placed endoesophageal stents. Gore-Tex membrane-covered Z-stents were deployed in the trachea using a coaxial introducer system in three patients. A Dumon tube was deployed in the bronchus over the bronchofiberscope in one patient.Results All fistula were completely sealed by the endotracheal or endobronchial stenting. Symptomatic and clinical improvements were immediate obtained.Conclusion Endotracheal or endobronchial covered stent placement is thought to be an effective alternative method for sealing esophagorespiratory fistula.     

Extracellular ATP mediated mechano-signaling in mammary glands

ATP, an important and ubiquitous extracellular signaling molecule, is often released by mechanical stimuli and plays an essential role in mechano-signaling. In lactating mammary glands, secretory epithelial (SE) cells form alveoli in which milk is held, and myoepithelial (ME) cells surrounding the alveoli contract in response to oxytocin to expel milk. Previously we found that the contraction of ME cells worked as a mechanical stress to SE cells and caused ATP-release in cultured mammary epithelial cells. The released ATP activated P2Y2 in surrounding SE cells and P2Y1 in ME cells. We already reported that ATP synergistically enhanced oxytocin response in ME cells. These findings mean that ME and SE cells interact mutually via released ATP to enhance the milk ejection. Recently, we found that cell-stretch also induced Ca(2+)-increases and ATP-release. The stretching of alveoli should occur by milk filling. So, only the milk-filled alveoli (but not empty alveoli) are surrounded by ATP. The ATP lowers the threshold of the oxytocin receptors and enables the milk-filled alveoli to contract in response to oxytocin at a concentration in the blood. Slight but apparent constitutive-ATP-release was observed in non-stimulated cells and the release was enhanced in Ca(2+)-free solution. The pathway of ATP-release is not yet clear, but pharmacologically, there seems to be two or more pathways.     

Neurosarcoidosis with spinal root pain as the first symptom

We report a 60-year-old woman with neurosarcoidosis. She was referred to our hospital for examination of the cause of pain in left Th4-6 dermatome. Chest X-ray and computed tomography (CT) revealed bilateral hilar and mediastinal lymphadenopathy, and her serum angiotensin converting enzyme (ACE) level was elevated. Histological finding of mediastinal lymph nodes consisted with sarcoidosis. Therefore, her pain was thought to be spinal root pain caused by neurosarcoidosis. With the administration of prednisolone, her symptom and bilateral hilar lymphadenopathy disappeared, and serum ACE level became normal. It is important to pay attention to neurosarcoidosis when patients show unknown spinal root symptom, although it is rare.     

Impaired delay but normal trace eyeblink conditioning in PLCbeta4 mutant mice

To elucidate the functional role of phospholipase Cbeta4 (PLCbeta4), which is highly expressed in the Purkinje cells of the rostral cerebellum, cerebellar long-term depression (LTD) and delay and trace eyeblink conditioning were investigated in PLCbeta4-deficient mice. Rostral cerebellar LTD and delay eyeblink conditioning were severely impaired, whereas trace eyeblink conditioning was not. These results indicate that PLCbeta4 is essential for LTD in the rostral cerebellum and delay conditioning, but not trace conditioning. Rostral cerebellar LTD may be required as a neural substrate for delay conditioning, but is not required for trace conditioning.