Abnormal asymmetries in subcortical brain volume in schizophrenia.

Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.

Clinical pilot studies on pre-operative hyperthermic tumour ablation for advanced breast carcinoma using an 8 MHz radiofrequency heating device.

The multimodality treatment approach for advanced breast cancer provides survival advantages with decreased locoregional and distant recurrences, but these intensive anti-tumour treatments cause severe myelosuppression. Thus, in this study, the usefulness of pre-operative anti-tumour treatment without myelosuppression was investigated. Nine patients with advanced breast carcinoma underwent pre-operative hyperthermic tumour ablation (HTA) using an 8 MHz radiofrequency (RF) heating device (Thermotron RF-8) combined with a grounded needle electrode. The patients had a mean age of 58.3+/-13.9 years and included four patients with stage IIIA, two with stage IIIB and three with stage IV cancer. The target temperature was over 50 degrees C. They tolerated pre-operative HTA therapy well with no early or late complications. The initial mean tumour size was 122.1+/-71.5 cm3 and the post-HTA tumour size was 82.2+/-63.4 cm3; the reduction rate was significant (p = 0.000 293). After the pre-operative HTA, all patients underwent surgery with Level III nodal extirpation. Post-operatively, no locoregional recurrence was observed. Microscopic examination of the primary focus showed complete coagulation necrosis expanding for a diameter of 3.5-5.0 cm. Taken together, the pre-operative HTA was a safe, well-tolerated and effective treatment, achieving tumour reduction as well as complete coagulation necrosis that resulted in a large volume of destruction in breast cancer tissue.

Green tea polyphenols as potent enhancers of glucocorticoid-induced mouse mammary tumor virus gene expression.

The effect of natural and synthetic galloyl esters on glucocorticoid-induced gene expression was evaluated by using rat fibroblast 3Y1 cells stably transfected with a luciferase reporter gene under the transcriptional regulation of the mouse mammary tumor virus promoter. The glucocorticoid-induced gene transcription was strongly suppressed by synthetic alkyl esters; n-dodecyl gallate showed the most potent inhibition (66% inhibition at 10 microM), which was far more potent than that of crude tannic acid. n-Octyl and n-cetyl gallate also showed good inhibition, while gallic acid itself was not so active, suggesting that the presence of hydrophobic side chain is important for the suppressive effect. On the other hand, surprisingly, green tea gallocatechins, (-)-epigallocatechin-3-O-gallate and theasinensin A, potently enhanced the promoter activity (182 and 247% activity at 1 microM, respectively). The regulation of the level of the glucocorticoid-induced gene expression by the antioxidative gallates is of great interest from a therapeutic point of view.

Effect of surface roughness and calcium phosphate coating on the implant/bone response.

The influence of surface roughness and calcium phosphate (Ca-P) coating on the bone response of titanium implants was investigated. Four types of titanium implants, i.e. as-machined, grit blasted, as-machined with Ca-P sputter coating, and grit blasted with Ca-P sputter coating, were prepared. The Ca-P sputter-coating, produced by using the RF magnetron sputter technique, was rapid heat-treated with infrared radiation at 600 degrees C. These implants were inserted into the left and right femoral condyles and the left and right tibial diaphyses of the rabbits. After implantation periods of 2 and 12 weeks, the bone-implant interface was evaluated histologically and histomorphometrically. Histological evaluation revealed no new bone formation around different implant materials after 2 weeks of implantation. After 12 weeks, bone healing was almost completed. For both tibial and femoral implants, Ca-P coated implants always showed a higher amount of bone contact than either of the non-coated implants. On the other hand, surface roughness improved only the response to implants inserted into the tibial diaphysis. On the basis of these findings, we concluded that 1) deposition of a sputtered Ca-P coating on an implant has a beneficial effect on the bone response to this implant during the healing phase, and 2) besides implant surface conditions the bone response is also determined by local implant site conditions.

Suppressive activity of the chloroform extract of Tripterygium wilfordii Hook f on effector T cell activation during Hymenolepis nana infection in mice.

The chloroform extract of Tripterygium wilfordii Hook f (TWH extract) administered into mice daily at doses of 80.0 to 200.0 micrograms/kg (but not 40.0 micrograms/kg) caused suppression of protective immunity to Hymenolepis nana when the extract was injected subcutaneously during the induction phase of protective immunity. Daily administration of 200.0 micrograms/kg TWH extract, during the course of larval development from challenge, also suppressed protective immunity. Inhibition of protective immunity was only observed in mice that received TWH extract for 6 days at a daily dose of 200.0 micrograms/kg and were challenged 24 h after the final injection. TWH extract did not inhibit formation of effector cells that mediate delayed type hypersensitivity (DTH) to H. nana egg antigen when the extract was administered subcutaneously at a dose of 200.0 micrograms/kg/day for 5 days before cell preparation. However, TWH extract did inhibit DTH effector cell activation when cells prepared from infected, PBS-injected mice were transferred into 200.0 micrograms/kg TWH extract-treated recipient mice. These results strongly indicate that TWH extract cannot inhibit the generation of effector cells but will suppress their function in vivo.

Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts.

Osteoclasts are multinucleate giant cells playing key roles in bone resorption. These cells solubilize mineralized bone matrix by means of acid and protease action; however, the precise mechanism of this process is not well known. Recently, we succeeded in the isolation of pure osteoclasts from rabbit bones and constructed a cDNA library. Using a differential screening procedure, two genes expressed predominantly in osteoclasts compared with spleen cells were isolated (Tezuka, K., Sato, T., Kamioka, H., Nijweide, P. J., Tanaka, K., Matsuo, T., Ohta, M., Kurihara, N., Hakeda, Y., and Kumegawa, M. (1992) Biochem. Biophys. Res. Commun. 186, 911-917). One of them, OC-2, was found to encode a possible cysteine proteinase structurally related to cathepsins L and S. By in situ hybridization, OC-2 was confirmed to be expressed in osteoclasts in vivo. By Northern blot analysis, OC-2 was highly and preferentially expressed in osteoclasts compared with other tissues such as kidney, liver, spleen, and lung. The predominant expression of OC-2 in osteoclasts may suggest that OC-2 encodes a protein, possibly a cysteine proteinase, that plays an important role in osteoclastic bone resorption.

Intraoperative radiation therapy combined with hyperthermia against pancreatic carcinoma.

Fourteen patients with pancreatic carcinoma were treated by intraoperative radiation therapy (IORT) combined with hyperthermia (hyperthermia group). Their treatment results were compared with those of fifty five patients treated by IORT without hyperthermia (control group). Most of patients underwent some kind of chemotherapy for the carcinoma and some of them received post-operative irradiation. Although there was no significant difference in pain relief between hyperthermia group and control group, the local tumor control rate of the former group was a little better. The survival rate of all patients was 14.5% at one year, 2.9% at two years, 2.9% at three years and 0% at four years after surgery. The survival rate of the hyperthermia group was 21.4% at one year and 7.1% at two years and that of the control group was 12.7% at one year and 1.8% at two years. The survival of the hyperthermia group was a little better than that of control group, but the difference was not significant. Only 36% of patients of hyperthermia group were successfully heated, and if hyperthermia were given successfully to all patients, their prognoses would be possibly improved.

[Influences of menopause and oophorectomy on bone metabolism and spinal bone mineral content].

The present study was performed on bone metabolism and spinal bone mineral content (BMC) in 3 groups of age- and body size-matched subjects: Thirty-three postmenopausal subjects, 37 oophorectomized (OPX) subjects and 22 premenopausal subjects. Serum levels of Alp and osteocalcin (OC) as indices of bone formation, U-Ca/cr and U-hydroxyproline (Hpr)/cr as indices of bone resorption, and Ca-regulating hormones, M-PTH, calcitonin (CT) and 1,25(OH)2D; were measured and spinal BMC was determined by QCT. Alp and OC levels were slightly higher in the postmenopausal group than in the OPX group and, in contrast, U-Ca/cr and U-Hpr/cr were slightly higher in the latter. The M-PTH level was slightly higher in the latter, and the CT level in the former. There was no difference in the 1,25(OH)2D level between two groups. For BMC, there was no difference between the two groups. The above results corresponded to the previously reported significant reductions in sex steroids. OPX seemed to affect bone metabolism more than menopause, there was no specific influence of OPX on spinal BMC as compared with QCT findings in postmenopausal subjects. Our previous study and the present study demonstrated that, at an interval of about 3 years after menopause or OPX, the endocrine system and bone metabolism tended to be more affected by OPX. However, BMC did not reflect any influence of OPX, or of menopause. There was no clear clinical difference between postmenopausal subjects and the OPX subjects with regard to the osteoporotic condition.

[Low-dose-rate teletherapy combined with hyperthermia as a boost therapy].

The efficacy of the low dose rate teletherapy (LDRT; 1 Gy/hr, 4 Gy/day, 2-3 times/week) combined with hyperthermia as a boost therapy (H (+) group) against far advanced carcinomas was examined. The treatment results in H (+) group (17 esophageal carcinomas, 3 pancreatic and bile duct carcinomas and 5 other carcinomas) were compared with the ones in H (-) group (38 esophageal carcinomas, 5 pancreatic and bile duct carcinomas and 13 other carcinomas) which were treated with the LDRT (1 Gy/hr, 7 Gy/day, every day) as a boost. A total dose of 14-24 Gy by the LDRT was followed after the irradiation of 50-60 Gy by conventionally fractionated method (1.5-2 Gy/day). H (+) cases were treated with 42.5 degrees C, 1 hour hyperthermia immediately before the LDRT and 19 cases (76%) were successfully heated. There were no significant differences between H (+) group and H (-) group in local control, late severe complication and survival rates, even when they were corrected by primary sites and stages. The incidence of metastases was higher in H (+) group. It was considered that the gain of the combination of the LDRT and the hyperthermia as a boost therapy was a little.

[Mechanism of the decrease in metacarpal bone mineral content due to oophorectomy].

In order to determine the pathogenesis and pathophysiology of post-oophorectomized osteopenia, we have investigated the bone mineral status and the serum levels of calcium regulating hormones in 250 females. The bone mineral status was measured in 250 [173 pre-menopausal females (controls) and 77 who received oophorectomy] females by microdensitometry in the metacarpal bone. Among these subjects, in some cases who were selected randomly, the serum levels of Alp, Ca, Pi, M-PTH, calcitonin (CT), bone gla protein (BGP), estrone, estradiol and delta 4-androstenedione, and the urinary excretion of Ca and hydroxyproline (OH-pro) as a function of the creatinine ratio were measured. The mineralization indices of bone such as GSmax, GSmin, and sigma GS/D in oophorectomized patients were significantly less than those in controls at ages up to 45 years. On the other hand, the index of periosteal bone resorption (MCI) in the oophorectomized group was less than that in controls at ages up to 50 years. Serum levels of Alp, Ca, Pi and BGP were higher in oophorectomized subjects than in controls. Despite these facts, the serum levels of calcium regulating hormones such as M-PTH and CT in these two groups were significantly different. Urinary Ca/cr and OH-pro/cr ratios were significantly higher in oophorectomized subjects at ages 40-44 than those in age matched controls. These data clearly indicate that oophorectomy causes high turn-over osteopenia.

Biological activities of deoxyspergualin in autoimmune disease mice.

An assessment of the prophylactic and ameliorative effects of deoxyspergualin (NKT-01), an immunosuppressive agent, was carried out in male MRL/MpJ-lpr/lpr (MRL/1) mice which spontaneously develop lupus-like lesions. When NKT-01 was administered ip daily from the age of either 8 or 19 weeks, diseases such as massive lymphadenopathy, circulating anti-DNA antibody and lupus nephritis were markedly suppressed. The primary response to lipopolysaccharide was significantly reduced in MRL/1 mice administered NKT-01 but the response to sheep red blood cells was not affected. The ability of spleen cells to release interleukins 2 and 3 with or without mitogen was significantly enhanced in mice receiving NKT-01. These findings demonstrate that NKT-01 has therapeutic activity against the development of spontaneous disease in MRL/1 mice.

The effects of electrical stimulation on denervated muscle using implantable electrodes.

This experimental study investigated the effects of continuous electrical stimulation on denervated muscle. The canine peroneal nerve was severed and repaired microsurgically, and the denervated extensor muscle group of the leg was stimulated continuously with an implantable electrode and pulse generator. EMG study, muscle force measurement, muscle weight measurement, histology, and histochemistry were performed to study the effect at eight weeks after the operation. Continuous electrical stimulation (pulse frequency 130 pps, burst rate approximately 1 train/min) was effective in decreasing muscle atrophy and in improving muscle force. These findings may have broader clinical applications.

Constituents of cultivated mulberry tree.

From the ethyl acetate extract of the cultivated mulberry tree (Morus alba L.), two new flavonoid derivatives with a fused dihydrochalcone partial moiety were isolated, and named kuwanons K and L. The structures of kuwanons K and L were shown to be 1 and 2 respectively, on the basis of chemical and spectral data. Kuwanons K ( 1) and L ( 2) are regarded biogenetically as Diels-Alder adducts of a chalcone derivative and a dehydroprenylflavonoid derivative, and are the first example of a flavonoid derivative possessing a cyclohexene ring at a B ring of a flavonoid derivative.