Influence of the selective ORL1 receptor agonist, Ro64-6198, on rodent neurological function.

Identification of synthetic agonists and antagonists at orphan receptors represents an important step for understanding their physiological function and therapeutic potential. Accordingly, we have recently described a non-peptide agonist at the opioid receptor like (ORL1) receptor (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro64-6198; Jenck et al., PNAS 94 (2000) 4938; Wichmann et al., Eur. J. Med. Chem. 35 (2000) 839). We have investigated the effects of this compound in various tests of rodent neurological function, utilising ORL1 knockout mice to examine the pharmacological specificity of Ro64-6198. In male C57BL/6J mice, effects on balance and motor co-ordination were detected following low doses (0.3-1mg/kg IP) of Ro64-6198. At higher doses (1-3mg/kg IP), effects on swim behaviour and hypothermia was observed. At 10mg/kg, each effect became more profound and a severe neurological disturbance appeared, including loss of righting reflex. These effects of Ro64-6198 (10mg/kg IP) were absent in ORL1 receptor knockout mice. In male, hooded Lister rats, Ro64-6198 (6-10mg/kg IP), produced some disturbance of neurological function, including hypoactivity, rotarod performance, grip strength and mild hypothermia. An impairment of food responding under a variable interval (VI) 20s schedule of reinforcement was noted at 3mg/kg. These results confirm Ro64-6198 to be a highly selective pharmacological tool to investigate ORL1 receptor function in vivo and, furthermore, that activation of this receptor is accompanied by a variety of effects on neurological function.     

Transrectal ultrasound-guided 10-core biopsy of the prostate for Japanese patients

To determine the utility of transrectal ultrasound (TRUS)-guided 10-core prostate biopsy (sextant plus 4 far lateral cores) for Japanese patients, we compared it with the standard sextant for detection of prostate cancer. The study patients were 564 consecutive Japanese men (median age 71 years) who underwent 10-core biopsy because of PSA values of > or = 2.0 ng/ml at Hiroshima University Hospital between March 2000 and December 2004. The overall cancer detection rate for the 10-core biopsy was 42.6% (240/564), which was significantly higher than the 36.3% (205/564) for the standard sextant biopsy (P=0.0330), with a 14.6% (35/240) improvement. The 10-core biopsy also detected a significant number of additional cancers in the sub-groups of patients with PSA values of 2 to approximately 10 ng/ml (P=0.0275), a prostate volume of > 20 cc (P=0.0440), or normal findings of digital rectal examination (P=0.0304). The 10-core biopsy scheme detected 9.6% and 2.1 to approximately 8.3% more cancers than the lateral sextant (apex, lateral mid portion, and lateral base) and the probable different combinations of 8-core biopsy designs, respectively. Compared to the standard sextant biopsy, the 10-core biopsy did not detect an increased proportion of clinically insignificant cancers. There was no severe morbidity, and only 2 patients (0.4%) were briefly hospitalized due to high fever. These results show that the TRUS-guided 10-core biopsy yields a better prostate cancer detection rate than the 6-core or 8-core protocol without severe complications. Therefore, it seems to be practicable for Japanese patients.     

Treatment of squamous cell carcinoma of the uterine cervix with radiation therapy alone: long-term survival, late complications, and incidence of second cancers

The objective of this retrospective study was to determine the survival rate, incidence of late complications, and incidence of second cancers when radiation therapy alone is used for carcinoma of the uterine cervix. Between 1971 and 1995, 1495 patients with squamous cell carcinoma of the uterine cervix (stages I-IV) were treated with radiation therapy alone in our hospital. Radiation therapy consisted of a combination of high-dose-rate intracavitary brachytherapy and external beam radiotherapy. The cumulative 5-year survival rates for stages Ib, II, and III/IVa carcinoma were 93.5, 77.0, and 60.3%, respectively, and the 10-year survival rates were 90.9, 74.5, and 56.1%, respectively. Local control rates for stages Ib, II, and III/IVa carcinoma were 92.0, 79.4 and 64.2%, respectively. Eighty-two (5.5%) patients suffered grade III/IV or V (fatal) complications. A second cancer developed in 13 (0.87%) patients. Second cancers were observed most frequently in the rectum (five cases), colon (three cases), and uterine body (two cases). Long-term follow-up data revealed that our method of radiation therapy alone for locally advanced carcinoma of the uterine cervix is effective, with low incidences of late complications and second cancers.     

Anesthetic management of combined kidney and pancreas transplantation

Combined kidney and pancreas transplantation was performed for the first time in Japan in a 29-year-old diabetic male with end stage renal nephropathy. He previously required injections of 44 IU insulin daily, and the fasting plasma glucose concentration before the transplant was 722 mg/dl. Anesthesia was maintained with fentanyl, nitrous oxide (70%) and halothane (0 approximately 1.0%). A continuous infusion of intravenous regular insulin (2 approximately 8 IU/hr) was started after induction of anesthesia. After revascularization of the pancreatic graft, his plasma glucose concentration fell from 350 mg/dl to 130 mg/dl in one hour and a half. Blood glucose level was maintained between 200 to 300 mg/dl without insulin during anesthesia and thereafter. The grafted kidney and pancreas showed good function during this period. In this report, anesthetic problems in combined kidney and pancreas transplantation were discussed.     

Circulatory responses to baroreflexes, Valsalva maneuver, coughing, swallowing, and nasal stimulation during acute cardiac sympathectomy by epidural blockade in awake humans

Reflex circulatory responses are chiefly governed by the integrated functions of both sympathetic and parasympathetic nervous systems at any moment. To examine how sympathetic denervation of the important effector organ, the heart, modifies such reflex responses, the authors compared circulatory responses to arterial baroreflexes, the Valsalva maneuver (VM), coughing (C), swallowing (S), and nasal stimulation (NS) before and after cervical epidural blockade using 10 ml of 1.5% lidocaine in awake, healthy humans. The cervico-thoracic sympathetic denervation (sensory block of C4-T7) caused a slight suppression of the baroreflex sensitivity assessed by increases in RR intervals to increased systolic blood pressure with a pressor test (phenylephrine) in all eight subjects studied; the mean slopes of the regression lines were 29.1 +/- 9.8 ms X mmHg-1 before the blockade and 17.2 +/- 6.3 ms X mmHg-1 after the blockade (P less than 0.05). However, the baroreflex sensitivity to a depressor test (nitroglycerin) remained unchanged following the blockade. Furthermore, the responses in heart rate and blood pressure to VM (Phases II and IV) and the responses in heart rate to C, S, and NS were partially suppressed after the blockade (P less than 0.05). Despite these suppressions, the overall responses to VM, C, S, and NS remained unchanged after the blockade. No predominant parasympathetic responses such as profound hypotension and bradycardia were observed during any maneuver after the blockade.(ABSTRACT TRUNCATED AT 250 WORDS)