Leptin resistance and enhancement of feeding facilitation by melanin-concentrating hormone in mice lacking bombesin receptor subtype-3

Mice lacking either bombesin receptor subtype (BRS)-3 or gastrin-releasing peptide receptor (GRP-R) exhibit feeding abnormalities. However, it is unclear how these receptors are associated with feeding regulation. In BRS-3-deficient mice, we found hyperphagia, subsequent hyperleptinemia, and brain leptin resistance that occurred after the onset of obesity. To explore the cause of this phenomenon, we examined changes in feeding responses to appetite-related neuropeptides in BRS-3-deficient, GRP-R-deficient, and wild-type littermate mice. Among orexigenic neuropeptides, the hyperphagic response to melanin-concentrating hormone (MCH) was significantly enhanced in BRS-3-deficient mice but not in GRP-R-deficient mice. In addition, the levels of MCH-R and prepro-MCH mRNAs in the hypothalamus of BRS-3-deficient mice were significantly more elevated than those of wild-type littermates. There was no significant difference in feeding between BRS-3-deficient and wild-type littermate mice after treatment with bombesin (BN), although the hypophagic response to low-dose BN was significantly suppressed in the GRP-R-deficient mice. These results suggest that upregulation of MCH-R and MCH triggers hyperphagia in BRS-3-deficient mice. From these results, we assume that the BRS-3 gene deletion upsets the mechanism by which leptin decreases the expression of MCH-R and that this effect may be mediated through neural networks independent of BN-related peptides such as GRP-R.     

Anterior fissure of the right liver--the third door of the liver

Background/Purpose Although the anterior segment of the liver has been divided into segments 8 and 5, we have, during surgical or interventional procedures, occasionally encountered patients in whom the right anterior portal vein does not bifurcate into the superior and inferior branches. Thus, the in vivo anatomy of the right liver was reevaluated to clarify the segmental anatomy.Methods We evaluated the hepatic venous and portal ramification patterns, using three-dimensional images reconstructed from computed tomography. In addition, liver volumetry was performed.Results All branches arising from the anterior trunk were divided into two groups: the right ventral portal branches (RVP) and the right dorsal portal branches (RDP), and the anterior fissure vein crossed between the RVP and RDP. The ventral and dorsal regions of the anterior segment were approximately equal from a volumetric point of view.Conclusions The anterior segment seems to be divided into the ventral and dorsal segments by the anterior fissure, and we propose a reclassification of the right liver that divides the right liver into three segments. Dissection of the parenchyma along the anterior fissure makes the third door of the liver open, resulting in the exposing of all Glissonian pedicles of the right liver. The introduction of our segmental anatomy and surgical procedure will allow more systematic and limited liver resections.     

The beneficial effect of effective control of anemia on hyperinsulinemia and hypoxemia in a hemodialysis patient with corrected transposition of the great arteries

We report the beneficial effect of control of anemia on hyperinsulinemia and hypoxemia in a hemodialysis patient with corrected transposition of the great arteries. The patients hemoglobin (Hb) level of 10.3g/dl on admission represents good control for hemodialysis (HD) patients, but it was too low for this patient with secondary polycythemia because of a right-to-left shunt. Control of anemia for a 10-month period was followed by a marked increase in Hb level (from 10.3g/dl to 13.9g/dl) and in aerobic work capacity, while the fasted insulin level decreased from 36.7µU/ml to 8.0µU/ml, without changes in leptin level, body mass index (BMI), fat mass, Kt/V, or protein catabolic rate (PCR). Additionally, hypoxemia was ameliorated, from PO₂ 33.1mmHg to PO₂ 56.2mmHg, and the hyperdynamic cardiac state was improved. The degree of anemia, together with deteriorating tissue oxygenation, may have predisposed this patient to developing insulin resistance and consequent hyperinsulinemia. The most appropriate target Hb concentration should be tailored for the clinical condition of each individual patient, bearing in mind an insulin-resistance state, especially in hemodialysis patients with hypoxemia. A more complete understanding of what regulates insulin resistance and consequent hyperinsulinemia in endstage renal disease (ESRD) awaits the elucidation of carbohydrate and insulin metabolism.     

Secondary nephrotic syndrome due to cardiovascular disease

Cardiovascular diseases ralely evoke nephrotic syndrome. Especially hypertensive renal disease (nephroscrelosis) and renovascular hypertension occasionally may lead to nephrotic syndrome. We reported a case of nephrotic syndrome with renovascular hypertension successfully treated with candesartan. In eldery patients cardiovascular diseases are appeared. It is very important for clinicians to detect the mechanism of nephrotic syndrome caused by cardiovascular diseases.     

Rizatriptan (Maxalt), a new entity of triptan for migraine: pharmacology and therapeutic relevance

Rizatriptan is a highly potent, selective serotonin 5-HT(1B/1D)-receptor agonist. Current theories on the mechanism of migraine suggest the central role of vasodilation of intracranial, extracerebral blood vessels and activation of perivascular trigeminal sensory nerves. There abundantly exist 5-HT(1B) receptors in meningeal blood vessels and 5-HT(1D) receptors in the trigeminal ganglia. The therapeutic activity of rizatriptan in migraine can most likely be attributed to agonist effects at 5-HT(1B/1D) receptors on these target sites. Two types of the 10 mg formulation, a tablet (Maxalt) tablet) and an orally disintegrating tablet (Maxalt)RPD tablet), are available. The latter may have a clinical relevance for patients who administer it without liquid. Pharmacokinetic study demonstrated the approximate T(max) of 1.0 or 1.1 h in tablets and 1.3 h in RPD tablets, resulting in early onset for headache relief and also pain free. Bioavailability was estimated to be about 45%. The efficacy and good tolerability and underlying profiles of pharmacokinetics of rizatriptan are almost similar between Japanese and other races, and a reduction in headache response up to 2 h can be attained in a large majority of patients. Several reports have described the favorable clinical profile of rizatriptan in comparison to other triptans. Rizatriptan is thus effective and provides migraine sufferers with an appropriate quality of life.     

Synergy between anti-endoglin (CD105) monoclonal antibodies and TGF-beta in suppression of growth of human endothelial cells

Endoglin (CD105) is a proliferation-associated cell membrane antigen of endothelial cells and strongly expressed in the angiogenic vasculature of solid tumors. Endoglin is essential for angiogenesis/vascular development and an ancillary transforming growth factor beta (TGF-beta) receptor. Certain anti-endoglin monoclonal antibodies (mAbs), termed SN6 series mAbs, inhibited angiogenesis, tumor growth and metastasis in mice. We investigated the mechanisms by which anti-endoglin mAbs suppress growth of proliferating endothelial cells. We found that 4 SN6 series mAbs suppressed growth of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner in the absence of any effector cells or complement. Significant differences in the growth suppression between the 4 anti-endoglin mAbs defining different epitopes were observed. These differences were not determined by antigen-binding avidities of the mAbs. Combination of TGF-beta1 and each of the 4 anti-endoglin mAbs exerted synergistic growth suppression of HUVECs. Binding of anti-endoglin mAbs to endoglin-expressing cells did not block the subsequent binding of TGF-beta1. Conversely, preincubation of HUVECs with TGF-beta1 did not change cell surface expression of endoglin. The present results suggest that direct suppression of the endothelial cell growth by SN6 series mAbs is one of the underlying mechanisms by which anti-endoglin mAbs exert antiangiogenic and tumor-suppressive activity in vivo. The results further suggest that TGF-beta1 plays an important role in the in vivo antiangiogenic efficacy of anti-endoglin mAbs by synergistically enhancing the activity of these mAbs. Further studies of the present novel findings may provide valuable information about the functional roles of endoglin and anti-endoglin mAbs in the TGF-beta-mediated cell regulation.     

Intraventricular transplantation of embryonic stem cell-derived neural stem cells in intracerebral hemorrhage rats

In the present study, we attempted to explore cell transplantation therapy for intracerebral hemorrhage (ICH) using embryonic stem (ES) cells. Collagenase-induced ICH rats were used as model animals. Mouse ES cells were differentiated into nestin-positive neural stem cells in vitro by alltrans retinoic acid (ATRA). ATRA-treated ES cells (10(5)) were transplanted into the lateral ventricle in the hemisphere contralateral to the hemorrhage 7 days after collagenase infusion. Twenty-eight days after transplantation, ES-derived neurons and astrocytes were observed around the hematoma cavities of the brain in all of the ten rats receiving grafts. Graft-derived neurons were found in the subependymal area of the lateral ventricle as cellular nodules. Although one of the ten rats receiving grafts showed uncontrolled growth of astroglia derived from the ES cells, intraventricular transplantation of ATRA-treated ES cells is an effective delivery system of neuronal lineage-committed progenitor cells toward the site of ICH.     

Age-related changes in growth hormone (GH)-releasing hormone and somatostatin neurons in the hypothalamus and in GH cells in the anterior pituitary of female mice

We have observed growth hormone-releasing hormone (GHRH)-immunoreactive (ir) neurons in the arcuate nucleus (ARC), somatostatin (SS)-ir neurons in the periventricular nucleus (PeN), and pituitary growth hormone (GH)-ir cells in female C57BL/6J mice at 2 months old (2 M), 4, 12 and 23 M, using immunocytochemical and morphometric methods. The number of GHRH-ir neurons decreased with age. The number of SS-ir neurons increased from 2 to 4 M, but decreased after 4 M. The volume of the anterior pituitary and the number of adenohypophysial parenchymal cells fell from 12 to 23 M. The proportion of GH-ir cells decreased significantly from 2 to 4 M and decreased in number from 12 to 23 M as well as in size from 2 to 4 M and from 12 to 23 M. Our results show that both GHRH-ir neurons and SS-ir neurons are fewer in old female mice, but the ratio of the number of SS-ir neurons to GHRH-ir neurons increases in old females. We suggest that the fall in the number and size of GH-ir cells in the pituitary gland with age may be involved in the increase in the ratio of the number of SS-ir neurons to GHRH-ir neurons in the hypothalamus in female mice, as well as in males.