Pharmacodynamic Actions of a Long‐Acting PTH Analog (LA‐PTH) in Thyroparathyroidectomized (TPTX) Rats and Normal Monkeys

Hypoparathyroidism is a disease of chronic hypocalcemia and hyperphosphatemia due to a deficiency of parathyroid hormone (PTH). PTH and analogs of the hormone are of interest as potential therapies. Accordingly, we examined the pharmacological properties of a long‐acting PTH analog, [Ala^1,3,12,18,22, Gln¹⁰,Arg¹¹,Trp¹⁴,Lys²⁶]‐PTH(1‐14)/PTHrP(15‐36) (LA–PTH) in thyroparathyroidectomized (TPTX) rats, a model of HP, as well as in normal monkeys. In TPTX rats, a single intravenous administration of LA‐PTH at a dose of 0.9 nmol/kg increased serum calcium (sCa) and decreased serum phosphate (sPi) to near‐normal levels for longer than 48 hours, whereas PTH(1‐34) and PTH(1‐84), each injected at a dose 80‐fold higher than that used for LA‐PTH, increased sCa and decreased sPi only modestly and transiently (<6 hours). LA‐PTH also exhibited enhanced and prolonged efficacy versus PTH(1‐34) and PTH(1‐84) for elevating sCa when administered subcutaneously (s.c.) into monkeys. Daily s.c. administration of LA‐PTH (1.8 nmol/kg) into TPTX rats for 28 days elevated sCa to near normal levels without causing hypercalciuria or increasing bone resorption markers, a desirable goal in the treatment of hypoparathyroidism. The results are supportive of further study of long‐acting PTH analogs as potential therapies for patients with hypoparathyroidism. © 2016 American Society for Bone and Mineral Research.     

Correlation of amino-acid uptake using methionine PET and histological classifications in various gliomas

OBJECTIVE: The uptake of L-methyl-11C-methionine (MET) by gliomas is greater than that by intact tissue, making methionine very useful for evaluation of tumor extent. If the degree of malignancy of brain tumors can be evaluated by MET-PET, the usefulness of MET-PET as a means of diagnosing brain tumors will increase. METHODS: We performed this study on 67 glioma patients between 3 and 69 years of age (36 males and 31 females). Tumors included diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, ependymoma, oligodendroglioma, medulloblastoma, dysembryoplastic neuroepithelial tumor, choroid plexus papilloma, central neurocytoma, optic glioma, gliomatosis cerebri, pleomorphic xanthoastrocytoma, and ganglioglioma. Tumor activity and degree of malignancy were evaluated using Ki-67LI (LI: labeling index) and Kaplan-Meier survival curves. The correlations between methionine uptake and tumor proliferation (tumor versus contralateral gray matter ratio (T/N) and Ki-67LI) were determined for the group of all subjects. The existence of significant correlations between T/N and Ki-67LI and between SUV and Ki-67LI was determined for astrocytic tumors. Receiver operating characteristics (ROC) analysis of T/N and standardized uptake value (SUV) was performed for the group of astrocytic tumors. We also determined the ROC cut-off levels to ensure high accuracy of the analysis. RESULTS: For the 67 cases of glioma, the degree of accumulation was variable. Ki-67LI differed significantly between the high-grade group and low-grade group at T/N levels between 1.5 and 1.8 on analysis using tumor proliferative potential (p = 0.019-0.031). The prognosis differed significantly between the high-grade and low-grade groups when T/N was in the range of 1.6-1.8 (p = 0.028-0.032). The accuracy thus calculated was highest (85.7%) when T/N was 1.5 as determined by ROC analysis. CONCLUSIONS: When analysis was confined to cases of astrocytic tumor, a correlation was noted between methionine accumulation and Ki-67LI. For the astrocytic tumors, T/N ratio seemed to be more useful as a diagnostic indicator than SUV. The cut-off level of T/N ratio for distinction between high-grade and low-grade astrocytoma appears to lie between 1.5 and 1.6.     

Evaluation of 18F-FDG PET with bladder irrigation in patients with uterine and ovarian tumors.

The purpose of this study was to evaluate PET using (18)F-FDG for gynecologic lesions with continuous bladder irrigation to eliminate artifacts from the (18)F-FDG activity in the bladder. METHODS: Forty-one patients were studied. They had 23 cervical uterine lesions (15 cases of cancer, 5 recurrences, 3 nonrecurrences); 8 cases of uterine corpus cancer, including 2 recurrences; and 10 ovarian masses (6 malignant, 4 nonmalignant). All cases of cancer were histologically proven; however, 2 cases of nonrecurrent uterine cervical carcinomas were diagnosed by clinical course. Continuous bladder irrigation was performed 35-55 min after intravenous administration of 185-370 MBq (18)F-FDG, and an emission scan was obtained 40-55 min after intravenous administration. Standardized uptake value (SUV) was used to estimate the degree of (18)F-FDG uptake quantitatively. RESULTS: After bladder irrigation, the (18)F-FDG activity in the urinary tract was eliminated in 33 patients, so that detection of tumor (18)F-FDG accumulation was easy. Two patients showed residual activity in the urinary bladder, and 6 patients showed activity in the ureter. An artifact was seen in 1 patient with residual activity in the urinary bladder caused by insufficient irrigation. However, these residual activities had no influence on detecting (18)F-FDG accumulation in tumor. The mean (+/-SD) of SUVs of malignant lesions was 6.04 +/- 3.22, that of nonmalignant lesions was 1.71 +/- 1.12, and the difference was significant (P = 0.0002). SUVs of all malignant lesions were greater than 2.0, and SUVs of all nonmalignant lesions, except the 1 case of ovarian fibroma, were less than 2.0. CONCLUSION: (18)F-FDG PET with continuous bladder irrigation is useful for eliminating (18)F-FDG activity in the bladder and for differentiating between malignant and nonmalignant uterine or ovarian masses.     

Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain

Insomnia, depression, and anxiety disorder are common problems for people with neuropathic pain. In this study, mild noxious heat stimuli increased the duration and number of spontaneous pain‐like behaviors in sciatic nerve‐ligated mice. We used functional magnetic resonance imaging to visualize the increased blood oxygenation level‐dependent signal intensity in the anterior cingulate cortex (ACC) of mice with sciatic nerve ligation under mild noxious stimuli. Such stimuli significantly increased the release of glutamate in the ACC of nerve‐ligated mice. In addition, sciatic nerve ligation and mild noxious stimuli changed the morphology of astrocytes in the ACC. Treatment of cortical astrocytes with glutamate caused astrocytic activation, as detected by a stellate morphology. Furthermore, glutamate induced the translocation of GAT‐3 to astrocyte cell membranes using primary cultured glial cells from the mouse cortex. Moreover, the GABA level at the synaptic cleft in the ACC of nerve‐ligated mice was significantly decreased exposure to mild noxious stimuli. Finally, we investigated whether astrocytic activation in the ACC could directly mediate sleep disorder. With the optogenetic tool channel rhodopsin‐2 (ChR2), we demonstrated that selective photostimulation of these astrocytes in vivo triggered sleep disturbance. Taken together, these results suggest that neuropathic pain‐like stimuli activated astrocytes in the ACC and decreased the extracellular concentration of GABA via an increase in the release of glutamate. Furthermore, these findings provide novel evidence that astrocytic activation in the ACC can mimic sleep disturbance in mice. Synapse 68:235–247, 2014 . © 2014 Wiley Periodicals, Inc.     

Synchrotron radiation microtomography of brain hemisphere and spinal cord of a mouse model of multiple sclerosis revealed a correlation between capillary dilation and clinical score

Multiple sclerosis is a neurological disorder in which the myelin sheaths of axons are damaged by the immune response. We report here a three-dimensional structural analysis of brain and spinal cord tissues of a mouse model of multiple sclerosis, known as experimental autoimmune encephalomyelitis (EAE). EAE-induced mice were raised with or without administration of fingolimod, which is used in the treatment of multiple sclerosis. Brains and spinal cords dissected from the EAE mice were lyophilized so as to reconstitute the intrinsic contrast of tissue elements, such as axons, in X-ray images. Three-dimensional structures of the brain hemispheres and spinal cords of the EAE mice were visualized with synchrotron radiation microtomography. Microtomographic cross sections reconstructed from the X-ray images revealed dilation of capillary vessels and vacuolation in the spinal cord of the EAE mice. Vacuolation was also observed in the cerebellum, suggesting that the neuroinflammatory response progressed in the brain. The vessel networks and vacuolation lesions in the spinal cords were modelled by automatically tracing the three-dimensional image in order to analyze the tissue structures quantitatively. The results of the analysis indicated that the distribution of vacuolations was not uniform but three-dimensionally localized. The mean vessel diameter showed a linear correlation with the clinical score, indicating that vasodilation is relevant to paralysis severity in the disease model. We suggest that vasodilation and vacuolation are related with neurological symptoms of multiple sclerosis.     

Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice

Background

Epithelial sodium channel (ENaC, Scnn1) hyperactivity in the lung leads to airway surface dehydration and mucus accumulation in cystic fibrosis (CF) patients and in mice with CF-like lung disease.

Audiovisual temporal capture underlies flash fusion

When sequential visual flashes are accompanied by a lower number of sequential auditory pulses, the perceived number of visual flashes is lower than the actual number, an illusion termed ‘flash fusion’. We examined whether temporal capture of flashes by pulses underlay flash fusion. One of the visual flashes was given a luminance increment, and observers reported which flash had the luminance increment. Results showed that the pulse strongly captured the flashes in its temporal vicinity, resulting in flash fusion. Moreover, when one of the successive pulses was given a higher frequency than others, the luminance increment was perceptually paired with the pulse with the higher frequency. The pairing of audiovisual features disappeared when the temporal pattern of the pulse frequency was difficult for the observer to anticipate. These data indicate that flash fusion is caused by temporal capture of flashes by the pulse, and that feature matching between auditory and visual signals also contributes to the modulation of perceived temporal structure of flashes during flash fusion.     

Habitual intake of lactic acid bacteria and risk reduction of bladder cancer

INTRODUCTION: A kind of lactic acid bacteria, Lactobacillus casei strain Shirota, shows antitumor activity in experimental animals. One clinical trial using L. casei showed a significant decrease in the recurrence of superficial bladder cancer. So, to assess the preventive effect of the intake of L. casei, widely taken as fermented milk products in Japan, against bladder cancer, we conducted a case-control study. METHODS: A total of 180 cases (mean age: 67 years, SD 10) were selected from 7 hospitals, and 445 population-based controls matched by gender and age were also selected. Interviewers asked them 81 items. The conditional logistic regression was used to estimate adjusted odds ratios (OR). RESULTS: The OR of smoking was 1.61 (95% confidence interval: 1.10-2.36). Those of previous (10-15 years ago) intake of fermented milk products were 0.46 (0.27-0.79) for 1-2 times/week and 0.61 (0.38-0.99) for 3-4 or more times/week, respectively. CONCLUSION: It was strongly suggested that the habitual intake of lactic acid bacteria reduces the risk of bladder cancer.     

Effect of phenylephrine injected into the nucleus tractus solitarius of Sprague-Dawley rats and spontaneously hypertensive rats

In alpha-chloralose-anesthetized Sprague-Dawley (SD) rats with unilateral nucleus tractus solitarius (NTS) lesions, injection of the alpha(1)-adrenergic receptor agonist phenylephrine into the contralateral NTS dose-dependently increased arterial pressure (AP). Bunazosin (0.1 nmol) or prazosin (0.36 nmol), an alpha(1)-adrenergic receptor antagonist, also increased AP. When injected into the NTS, pre-treatment with phenylephrine (10 nmol) or both antagonists abolished the cardiovascular effects of glutamate and acetylcholine. In contrast, pre-treatment with prazosin or methylatropine did not alter the effect of phenylephrine. Phenylephrine (30 nmol) injected into the NTS abolished aortic depressor nerve (ADN) evoked-responses. The pressor effect of phenylephrine in the NTS was exaggerated in spontaneously hypertensive rats (SHR). These results suggest that when injected into the NTS, the effect of phenylephrine may be due to a baroreflex blockade resulting from direct modulatory actions or non-specific neuronal alterations rather than stimulating the alpha(1)-adrenergic receptor. Additionally, this effect is enhanced in SHR.