Augmentation of intrarenal angiotensin II levels in uninephrectomized aldosterone/salt-treated hypertensive rats; renoprotective effects of an ultrahigh dose of olmesartan.

Recent studies have suggested that aldosterone plays a role in the pathogenesis of renal injury. In this study, we investigated whether local angiotensin II (Ang II) activity contributes to the progression of renal injury in aldosterone/salt-induced hypertensive rats. Uninephrectomized rats were treated with 1% NaCl in a drinking solution and one of the following combinations for 6 weeks: vehicle (2% ethanol, s.c.; n=9), aldosterone (0.75 mug/h, s.c.; n=8), aldosterone+Ang II type 1 receptor blocker olmesartan (10 mg/kg/day, p.o.; n=8), or aldosterone+olmesartan (100 mg/kg/day, p.o.; n=9). Aldosterone/salt-treated hypertensive rats exhibited severe proteinuria and renal injury characterized by glomerular sclerosis and tubulointerstitial fibrosis. Aldosterone/salt-induced renal injury was associated with augmented expression of angiotensin converting enzyme and Ang II levels in the renal cortex and medullary tissues. Renal cortical and medullary mRNA expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) as well as the collagen contents were increased in aldosterone/salt-treated hypertensive rats. Treatment with olmesartan (10 or 100 mg/kg/day) had no effect on blood pressure but attenuated proteinuria in a dose-dependent manner. Olmesartan at 10 mg/kg/day tended to decrease renal cortical and medullary Ang II levels, TGF-beta and CTGF expression, and collagen contents; however, these changes were not significant. On the other hand, an ultrahigh dose of olmesartan (100 mg/kg/day) significantly decreased these values and ameliorated renal injury. These data suggest that augmented local Ang II activity contributes, at least partially, to the progression of aldosterone/salt-dependent renal injury.     

Superovulation-induced transient hyperprolactinemia in human in vitro fertilization and embryo transfer

To examine the effects of transient hyperprolactinemia on in vitro fertilization and embryo transfer, 61 cycles in 50 euprolactinemic ovulatory women with irreparable tubal diseases were stimulated with clomiphene (CC) alone or CC and human menopausal gonadotropin followed by human chorionic gonadotropin (hCG). Serum prolactin (PRL) increased after hCG administration with peak values of 45.4 +/- 4.2 ng/ml on the day of laparoscopic oocyte aspiration. The highest serum estradiol (E2) concentration was found on the day before PRL peak and serum progesterone (P) began to increase after hCG injection concomitant with the PRL rise. The group having 50 ng/ml or more of PRL (34 cycles) had significantly higher levels of E2 during preovulatory and early luteal phase compared to those of the group having less than 50 ng/ml of PRL (27 cycles) but there was no significant difference between the P levels in the two groups. In the higher PRL group 72 (62.1%) of 116 collected oocytes were fertilized and 6 (20.0%) conceived. In the lower PRL group 45 oocytes (58.4%) of 77 were fertilized and 3 (12.5%) became pregnant. These data suggest that elevated serum PRL concentrations may have no effect on fertilization of oocytes in vitro or embryonic development.     

ENDOSCOPIC SUBMUCOSAL DISSECTION FOR RECURRENT GASTRIC TUMORS

Endoscopic resection has been accepted as the standard treatment for intramucosal gastric tumors of differentiated type. However, the indication was limited to small tumors to achieve en bloc resection and prevent local recurrence in cases of conventional endoscopic mucosal resection (EMR) such as the strip biopsy and the cap technique. To avoid multi‐fragmental resection, we have developed endoscopic submucosal dissection (ESD) as a new endoscopic resection technique. ESD is a remarkable technique, because we make it possible to remove the lesions en bloc regardless of size, shape, coexisting ulcer, and location. However, it is difficult or impossible to resect recurrent tumors en bloc in conventional EMR owing to hard fibrosis, and some patients need laparotomy. Using ESD, we can dissect the submucosal layer as we directly look at the submucosa, and remove the lesion safely and reliably even in cases of hard fibrosis. The key to treatment of recurrent tumors in ESD are as follows: (i) using enough submucosal injection solution (we use a mixture of Glyceol and 1% 1900 kDa hyaluronic acid preparation); (ii) incising the mucosa without fibrosis; (iii) understanding characteristics of various cutting devices, and changing other devices in difficult situations. In these ways we can remove the majority of the recurrent tumors en bloc. Hence, we consider that ESD is a very effective treatment which achieves excellent en bloc and complete resection rates and enables patients with intramucosal gastric tumors to a recurrent‐free survival even in recurrent tumors.     

Central sympathoinhibitory action of a direct-acting vasodilator, budralazine, in anesthetized rats

Previous data on budralazine, 1-[2-(1,3-dimethyl-2-butenylidene)-hydrazino]-phthalazine, has indicated that it is a direct-acting vasodilating agent that does not produce marked tachycardia. The present study was undertaken to elucidate what effects may be seen on the central sympathetic nerve activity when budralazine is given systemically to rats. Budralazine (0.5, 1.0 and 5.0 mg/kg, i.v.) produced a dose-dependent reduction of mean arterial pressure. At doses of 0.5 and 1.0 mg/kg, budralazine induced bradycardia accompanied with a decrease in cardiac sympathetic nerve activity. Preganglionic adrenal sympathetic nerve activity was also reduced by budralazine (1.0 mg/kg, i.v.). A dose of 0.5 mg/kg of budralazine neither influenced carotid sinus nerve activity nor augmented aortic depressor nerve activity. On the contrary, a high dose of budralazine (5.0 mg/kg) produced simultaneous increases in the heart rate and cardiac sympathetic nerve activity along with a marked suppression of aortic depressor nerve activity. Plasma norepinephrine and epinephrine concentrations were also increased at a dose of 5.0 mg/kg. These findings suggest that budralazine doses of 0.5 and 1.0 mg/kg may reduce the sympathetic outflow that is mediated via central sympathoinhibitory action. Baroreceptor-mediated tachycardia occurred after high dose budralazine (5.0 mg/kg) administration in anesthetized rats.     

Modulation of a motor evoked response to transcranial magnetic stimulation by the activity level of the first dorsal interosseous muscle in humans when grasping a stationary object with different grip widths

A relation between corticospinal excitability and background voluntary muscular activity was investigated at low and high transcranial magnetic stimulation (TMS) intensities while grasping a stationary object with different widths (2 and 8 cm) using a precision grip. The muscle activity was recorded from the first dorsal interosseous muscle. Regression analysis revealed that there was a linear relation between the motor evoked potential (MEP) and background muscular activity for both grip widths at each of the TMS intensities. At the low TMS intensity, the slope of the regression lines was similar for the 2 and 8 cm grip widths. It was, however, different when the TMS intensity was high. The results suggested that sensitivity modulation of bias level (input) facilitation occurred with wider grip width. The results of this study would reflect to quantitative aspects of the relation between the synaptic drive to the motoneuron pool and the resulting efferent activity characterized, i.e. input-output relations of the human corticospinal pathway dependent on the occasion demand.     

Evolution of interleukin-18 binding proteins and interleukin-1 receptor, type II proteins

Interleukin-18 (IL-18) is one of the pivotal cytokines controlling the defense mechanism called inflammation. As a first step to develop proteins for controlling the IL-18 level, we initiated a study of IL-18-binding proteins (IL-18BPs). Twenty-four IL-18BP family members, 11 from vertebrates and 13 from chordopoxviruses, were picked from the NCBI database. Eight of these vertebrate IL-18BPs and two of the chordopoxvirus IL18-BPs were identified here and characterized as new members of the IL-18BP family. Their IL-18 binding domains were aligned and the distribution of highly conserved critical amino acid residues was analyzed and used to construct a phylogenetic tree. From this tree it was inferred that at least two independent events created two different ancestral viral IL-18BP genes by retroposition of IL-18BP genes from the vertebrate lineage. These two events are estimated to have occurred after an ancient mammalian IL-18BP gene diverged from birds, and before the mammalian IL-18BP gene diverged into human, ungulate and rodent IL-18BP genes. Moreover, our results suggest that IL-18BP and interleukin-1 receptor, type II (IL-1R2) had a common ancestral gene and diverged from the ancestral gene into IL-18BP and IL-1R2 genes in the fish period.     

Further insight into the task-dependent excitability of motor evoked potentials in first dorsal interosseous muscle in humans

We have reexamined the contradictory evidence in which task-dependent excitation of motor evoked potentials (MEPs) in the first dorsal interosseous (FDI) muscle was stronger with increasingly more complex finger tasks than with individual finger movement tasks. In the first step of the experiment, based on previous findings, we investigated remarkable functional differences between intrinsic and extrinsic hand muscles during complex finger tasks (precision and power grip). During the performance of the tasks, the optimal stimulus intensity of the transcranial magnetic stimulation (TMS) was applied to the contralateral motor cortex. MEPs of the FDI, extensor carpi radialis (ECR), and flexor carpi radialis (FCR) muscles were recorded simultaneously with increased background EMG activity step by step in both tasks. The intensity threshold of TMS was lower in the precision grip. Furthermore, the MEP amplitudes of FDI muscle dependent on the background EMG activity were different between these two tasks, i.e., MEP amplitudes and regression coefficients in a precision grip were larger than those in a power grip. Although our results for MEP amplitude and threshold in the FDI muscle were similar to previous reported evidence, the different contributions of a synergistic muscle (in particular, the ECR muscle) during performance in these tasks was new evidence. Since there were no differences in cutaneous afferent effects on both tasks, corticomotoneuronal (CM) cells connected to FDI motoneurons seemed generally to be more active during precision than power gripping, and there were different contributions from synergistic muscles during the performance of these tasks. In the second part of the experiment, the results obtained from the complex tasks were compared with those from a simple task (isolated index finger flexion). MEP amplitudes, dependent on the background EMG activity during isolated index finger flexion, varied among subjects, i.e., the relationship between the MEP amplitude and the background EMG of the FDI muscle showed individual, strategy-dependent modulation. There were several kinds of individual motor strategies for performing the isolated finger movement. The present results may explain the previous contradictory evidence related to the contribution of the CM system during coordinated finger movement.