Serotonergic neurons in the brainstem modulate animal hypnosis

We previously found that the center of animal hypnosis production in the rabbit is located around the locus ceruleus and brachium conjunctivum (LC-BC) of the brainstem. The involvement of serotonergic neurons in this area of animal hypnosis was investigated by microinjection of serotonin into these regions. The duration of animal hypnosis (DAH) induced by inversion was diminished to about 65% of the controls by serotonin microinjection into the LC-BC and microinjection of methysergide prolonged the DAH to 3.2 times that of the controls. Flexor muscle contraction (CFM) of the upper extremities induced by electrical stimulation of the motor cortex was enhanced by serotonin. In normal rabbits, hard pressure on the ear base or the lumbar paravertebral area reduced CFM and this effect was partially antagonized by serotonin microinjected into the LC-BC. The results suggest that serotonergic neurons in the LC-BC modulate animal hypnosis.     

The microvasculature of the cerebral white matter: arteries of the subcortical white matter

The microvascular architecture of the human cerebral subcortical white matter was studied. Most of the subcortical arteries ran straight through the cortex, but upon entering the white matter, they began to coil, loop, and spiral. Vascular stains showed wide spaces between the adventitial sheaths and blood vessels. The blood vessels coiled, looped, and spiraled within these wide adventitial spaces. This phenomenon was observed in the brains from persons ranging from the first to ninth decades of life and there were no statistically significant age-related correlations. Furthermore, there was no evidence of a reduction in the volume of white matter after fixation. Therefore, the observed tortuosity does not appear to be the result of shrinkage of brain tissue following fixation. While the mechanisms responsible for the subcortical arteries circuitry remain undetermined, this coiling architecture may serve as a trap for tumor cells and microorganisms passing through the blood stream, suggesting that these coiling arterial blood vessels may play a significant role in the pathogenesis of tumor metastasis and the brain abscess that frequently occurs in the gray-white matter junction.     

Comparison of dose-volume analysis between standard Manchester plan and magnetic resonance image-based plan of intracavitary brachytherapy for uterine cervical cancer

To investigate the feasibility of image-based intracavitary brachytherapy (IBICBT) for uterine cervical cancer, we evaluated the dose–volume histograms (DVHs) for the tumor and organs at risk (OARs) and compared results from the IBICBT plan and the standard Manchester system (Manchester plan) in eight patients as a simulation experiment. We performed magnetic resonance imaging (MRI) and computed tomography (CT) following MRI-adapted applicator insertion, then superimposed MR images on the planning CT images to describe the contours of high-risk clinical target volume (HR CTV) and OARs. The median volume of HR CTV was 29 cm³ (range, 21–61 cm³). Median D90 (HR CTV) and V100 (HR CTV) were 116.1% prescribed doses (PD) (90.0–150.8%) and 96.7% (84.2–100%), respectively, for the Manchester plan. In comparison, we confirmed that the median D90 (HR CTV) was 100% PD in the IBICBT plan for all patients. Mean D_2cc (bladder) was 101.8% PD for the Manchester plan and 83.2% PD for the IBICBT plan. Mean D_2cc (rectum) was 80.1% PD for the Manchester plan and 64.2% PD for the IBICBT plan. Mean D_2cc (sigmoid) was 75% PD for the Manchester plan and 57.5% PD for the IBICBT plan. One patient with a large tumor (HR CTV, 61 cm³) showed lower D90 (HR CTV) with the Manchester plan than with the IBICBT plan. The Manchester plan may represent overtreatment for small tumors but insufficient dose distribution for larger tumors. The IBICBT plan could reduce OAR dosage while maintaining adequate tumor coverage.Key words: Image-based intracavitary brachytherapy, MRI-adapted applicator, uterine cervical cancer, dose–volume histogram     

Ameliorating effect of FK614, a novel nonthiazolidinedione peroxisome proliferator-activated receptor gamma agonist, on insulin resistance in Zucker fatty rat

Effect of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide (FK614), a novel nonthiazolidinedione peroxisome proliferator-activated receptor (PPAR) gamma agonist, on glucose tolerance and insulin resistance in peripheral tissues and in liver using Zucker fatty rats (genetically obese and insulin-resistant) was evaluated and compared to other insulin sensitizers. FK614 (0.32, 1 and 3.2 mg/kg), two thiazolidinedione PPAR gamma agonists, rosiglitazone (0.1, 0.32, 1 and 3.2 mg/kg) and pioglitazone (1, 3.2 and 10 mg/kg), and a biguanide, metformin (320 and 1000 mg/kg), were orally administered to Zucker fatty rats once a day for 14 days. Zucker fatty rats treated with FK614 and rosiglitazone were subjected to evaluation by oral glucose tolerance test. Ameliorating effect of each compound on peripheral and hepatic insulin resistance was evaluated using a euglycemic-hyperinsulineamic clamp procedure. FK614 and rosiglitazone dose-dependently improved impaired glucose tolerance in Zucker fatty rats. In addition, FK614 dose-dependently ameliorated peripheral and hepatic insulin resistance in Zucker fatty rats, with the degree of its effect in peripheral tissues almost equivalent to that in liver when compared at each dose tested. Similar data indicating ameliorating effects on insulin resistance was obtained for rosiglitazone and pioglitazone. Metformin showed less potent effects than other insulin sensitizers and its effect in liver tended to be greater than that in peripheral tissues. These findings suggest clinical potential for FK614 as a treatment of type 2 diabetes, acting by ameliorating insulin resistance both in peripheral tissues and liver.     

Anti-tumor angiogenesis therapy using soluble receptors: enhanced inhibition of tumor growth when soluble fibroblast growth factor receptor-1 is used with soluble vascular endothelial growth factor receptor

We have shown that a soluble receptor for vascular endothelial growth factor (sVEGFR), which adsorbs VEGF and may function as a dominant-negative receptor, suppresses tumor angiogenesis and enhances apoptosis of cancer cells, thereby inhibiting tumor growth [Cancer Res 60 (2000) 2169-2177]. In the present study, using as many as 11 cancer cell lines, we tested two hypotheses: (a) that a soluble fibroblast growth factor receptor-1 (sFGFR1) might inhibit tumor angiogenesis and growth in sVEGFR-resistant cancers, and (b) that combining sFGFR1 with sVEGFR might produce an enhanced inhibitory effect. In two cell lines derived from human lung cancer, H460 and A549, both of which produce a considerable amount of FGF-2, sVEGFR and a soluble receptor for angiopoietin-1 were both ineffective; however, sFGFR1 inhibited tumor angiogenesis and growth, demonstrating the critical role that FGFs play in some cancers. In three cell lines (QG56 from lung cancer, T3M4 and Panc1 from pancreatic cancer), which produced both VEGF and FGF-2 at detectable levels, combined sVEGFR and sFGFR1 produced an enhanced inhibitory effect compared to their individual effects. The combined usage of sVEGFR plus sFGFR1 suppressed tumor growth in all cancer cell lines tested, suggesting possible effectiveness of this strategy against a wide range of cancers.     

Crosstalk between high-molecular-weight adiponectin and T-cadherin during liver fibrosis development in rats

Adiponectin, a circulating adipocyte-derived secretory protein, reportedly plays an important role in liver fibrosis development, although the biological role of adiponectin in liver fibrogenesis is still controversial. Adiponectin is present in the serum as three oligometric complexes; namely, high-, middle-, and low-molecular weight (HMW, MMW, and LMW, respectively). Adiponectin exerts different biological activities in an oligomerization-dependent manner. The aim of our current study was to examine the alteration of each isoform of adiponectin and its receptors (AdipoR1, AdipoR2, and T-cadherin) during the choline-deficient L-amino acid-defined (CDAA) diet-induced rat liver fibrosis development. We also elucidated the methylation status of all receptors. The serum level of total adiponectin significantly increased during the liver fibrosis development. Among the three isoforms, only HMW adiponectin was significantly up-regulated whereas MMW and LMW were not. The expression of T-cadherin, which exclusively binds with HMW adiponectin, was significantly augmented as well. The AdipoR2 expression was markedly decreased and showed no marked difference from that of AdipoR1. No obvious methylation change was observed in all three receptors, suggesting that another mechanism is involved in the alteration of receptor gene expression. Collectively, since the specific ligand and receptor were augmented together, crosstalk between HMW adiponectin and T-cadherin may play an important role during liver fibrosis development in rats.