Relationship between serotonin transporter occupancies and analgesic effects of AS1069562, the (+)-isomer of indeloxazine, and duloxetine in reserpine-induced myalgia rats.

Serotonin (5-HT) and norepinephrine (NE) have been implicated in the mediation of endogenous analgesic mechanisms via the descending inhibitory pain pathway in the brain, and dysfunction in both the 5-HT and NE systems has been suggested as an etiology of fibromyalgia (FM). Given that 5-HT reuptake inhibition in the brain appears to be associated with pain reduction, this mechanism might exert an analgesic effect also on pain associated with FM. In this case, it would be of interest to investigate the correlation of 5-HT transporter (SERT) occupancy with in vivo analgesic effect on pain associated with FM. Here, we investigated the relationship between SERT occupancies and the analgesic effects of AS1069562, the (+)-isomer of indeloxazine, and duloxetine, which are both 5-HT and NE reuptake inhibitors (SNRIs), on muscular pain in reserpine-induced myalgia (RIM) rats, an animal model of FM-like chronic pain. We also investigated the SERT occupancy level necessary for AS1069562 and duloxetine to exert analgesic effects on muscular pain. AS1069562 and duloxetine attenuated muscular hyperalgesia in RIM rats, representing the first findings to be reported regarding the analgesic effect of AS1069562 on pain associated with FM. SERT occupancy levels of AS1069562 and duloxetine increased in both dose- and plasma and brain concentration-dependent manners. SERT occupancy levels of AS1069562 and duloxetine were significantly correlated with efficacy on muscular pain thresholds in RIM rats. This finding concerning the precise correlation of SERT occupancy with in vivo analgesic effect on pain associated with FM is reported here for the first time. SERT occupancy level above 70% was necessary for AS1069562 and duloxetine to exert significant analgesic effects on muscular pain. These results suggest that SERT occupancy level is useful in determining appropriate analgesic doses of AS1069562 and duloxetine for treating pain symptoms in FM patients.

The effects of pitch tilt on postrotatory nystagmus in cats.

When the head is tilted away from the upright position immediately after termination of earth-vertical axis (EVA) head rotation at a constant velocity, the rotation axis of postrotatory nystagmus (PRN) is gradually directed toward gravity (spatial reorientation). During roll tilt, the extent of the axis shift varies among species. In cats, the reorientation is limited to about 30-45 degrees of head tilt. In the present study, we examined features of PRN during pitch tilt in cats. The animals were rotated about EVA at a constant velocity of 100 degrees /s for 120 s. Within 2 s after stopping EVA rotation, the animals were tilted toward the pitch plane by as much as +/-90 degrees (nose-down or nose-up) in steps of 15 degrees. Eye movements were measured with 3D magnetic search coils. The angle of the PRN plane and its slow phase eye velocity (SPV) were measured. The duration of PRN decreased as pitch tilt increased regardless of whether the direction was nose-up or nose-down. The mean time constant of SPV was significantly longer for nose-up than for nose-down. PRN maintained its horizontal orientation without any vertical drift during pitch tilt, but there was little reorientation toward gravity. That is, no significant torsional component of SPV emerged to reorient the eyes according to gravity. Our results indicate that spatial reorientation depends on head orientation. For the PRN responses after pitch tilts in cats, the interactions of semicircular canal and otolith inputs in the central vestibular system might be vestigial.

Cerebellar nodulectomy impairs spatial memory of vestibular and optokinetic stimulation in rabbits.

Natural vestibular and optokinetic stimulation were used to investigate the possible role of the cerebellar nodulus in the regulation and modification of reflexive eye movements in rabbits. The nodulus and folium 9d of the uvula were destroyed by surgical aspiration. Before and after nodulectomy the vertical and horizontal vestibuloocular reflexes (VVOR, HVOR) were measured during sinusoidal vestibular stimulation about the longitudinal (roll) and vertical (yaw) axes. Although the gain of the HVOR (G(HVOR) = peak eye movement velocity/peak head velocity) was not affected by the nodulectomy, the gain of the VVOR (G(VVOR)) was reduced. The gains of the vertical and horizontal optokinetic reflexes (G(VOKR), G(HOKR)) were measured during monocular, sinusoidal optokinetic stimulation (OKS) about the longitudinal and vertical axes. Following nodulectomy, there was no reduction in G(VOKR) or G(HOKR). Long-term binocular OKS was used to generate optokinetic afternystagmus, OKAN II, that lasts for hours. After OKAN II was induced, rabbits were subjected to static pitch and roll, to determine how the plane and velocity of OKAN II is influenced by a changing vestibular environment. During static pitch, OKAN II slow phase remained aligned with earth-horizontal. This was true for normal and nodulectomized rabbits. During static roll, OKAN II remained aligned with earth-horizontal in normal rabbits. During static roll in nodulectomized rabbits, OKAN II slow phase developed a centripetal vertical drift. We examined the suppression and recovery of G(VVOR) following exposure to conflicting vertical OKS for 10-30 min. This vestibular-optokinetic conflict reduced G(VVOR) in both normal and nodulectomized rabbits. The time course of recovery of G(VVOR) after conflicting OKS was the same before and after nodulectomy. In normal rabbits, the head pitch angle, at which peak OKAN II velocity occurred, corresponded to the head pitch angle maintained during long-term OKS. If the head was maintained in a "pitched-up" or "pitched-down" orientation during long-term OKS, the subsequently measured OKAN II peak velocity occurred at the same orientation. This was not true for nodulectomized rabbits, who had OKAN II peak velocities at head pitch angles independent of those maintained during long-term OKS. We conclude that the nodulus participates in the regulation of compensatory reflexive movements. The nodulus also influences "remembered" head position in space derived from previous optokinetic and vestibular stimulation.

Influence of fixation on circular vection.

The contribution of fixation to latency of circular vection (CV) was examined in twenty-five normal adults aged 18-30 years. For induction of self-motion a random dot pattern was projected onto a hemispherical dome. The pattern was rotated either about the subject's vertical axis or about their interaural axis at a constant acceleration of 1 deg/s2. For the group tested, the perceived CV latencies were significantly shorter with fixation than without fixation in both horizontal and vertical CV. The effect of fixation was pronounced in subjects with longer latencies. The mean CV latencies for two different fixation points between the subject's eyes and the moving pattern did not differ significantly. Our results suggest that the potential influence of fixation must be carefully controlled in studies of visually induced self-motion. Possible explanations for the effect of fixation on the generation of CV will also be discussed.

Directional preponderance in pitch circular vection.

We used optokinetic stimulation (OKS) in eighteen normal adults aged 18-30 years to investigate vertical self-motion perception. In order to induce self-rotation, either a stripe pattern or a random dot pattern was projected onto the inner wall of a hemispherical dome with a diameter of 150 cm. The pattern was rotated either about the subject's vertical axis (yaw) or about the subject's interaural axis (pitch) for 80 s at a constant acceleration of 1 deg/s2. Stimuli were randomly repeated three to four times in each direction. The latency of onset as well as the perceived intensity of circular vection (CV) was measured for each stimulus presentation. CV latencies for upward rotational stimulation were significantly longer than those for downward rotational stimulation under both types of stimulus conditions. There was no significant difference in CV latency between rightward and leftward rotational stimulation. For most subjects, the magnitudes of the perceived CV for rightward rotational stimulation were equal to those for leftward rotational stimulation, whereas the magnitudes of the perceived CV for vertical stimulation showed large intersubject variability. These results provide additional evidence that fundamental differences exist between different types of self-motion. Possible explanations for the directional asymmetry in vertical perception of self-motion will also be discussed.

Cervical adenocarcinoma, a novel combination chemotherapy with mitomycin C, etoposide, and cisplatin for advanced or recurrent disease.

We review the cases of 31 patients with stage IVb or recurrent cervical adenocarcinoma who were treated with combination chemotherapy utilizing mitomycin C, etoposide, and cisplatin (MEP). The total response rate was 16.1% (95% confidence intervals (CIs), 5. 5 to 33.7%) with 4 patients having a complete response (CR) and 1 having a partial response. In patients with no prior chemotherapy, the response rate was 26.7% (95% CIs, 7.8 to 55.1%) with 2 of these CR patients surviving over 3 years, 1 a disease-free survival. A marked response was found in distant recurrent lesions. The major toxicity was myelosuppression. Forty-five percent of patients had leukocytopenia above grade 3; thrombocytopenia and anemia were not common. In patients with cervical adenocarcinoma and no prior chemotherapy, there was a moderate response to MEP therapy.

Circular vection in patients with age-related macular degeneration.

We have used optokinetic stimulation in patients with unilateral age-related macular degeneration (AMD) and central scotoma to investigate the possible contribution of the central visual field to circular vection (CV). Six patients aged 42-73 years with unilateral AMD and an aged-matched control group of nine elderly adults aged 47-75 years were examined. Monocular visual field defects were verified with the Goldmann perimeter by kinetic perimetry. The device used to induce CV was a random dot pattern projected onto a hemispherical dome with a radius of 75 cm. The pattern was rotated horizontally at a constant acceleration of 1 deg/s2. Monocular stimuli were randomly repeated two to three times in both temporal-nasal (T-N) and nasal-temporal (N-T) directions. The latency of onset of CV was measured for each stimulus presentation. In the age-matched control group the CV latencies varied from 4.2 to 72.0 s. In each case, however, the CV latencies were stable. No significant differences in CV latencies were found between right and left eyes in both stimulus directions (p > 0.05). In patients with AMD, no statistically significant difference in CV latency was found between the affected and unaffected eyes (p > 0.05). Marked central visual field loss in AMD does not significantly impair peripherally induced CV. Our results are compatible with the hypothesis that the peripheral retina dominates CV.

[Evaluation of a new anti-cancer drug regimen for surface epithelial-stromal ovarian cancer].

BACKGROUND: The purpose of this study was to describe a new anti-cancer drug regimen for epithelial ovarian cancer. METHODS: The cytotoxicities of some anti-cancer drugs regimens against human epithelial ovarian cancer xenografted into nude mice (TOM, TOH, TON) have been studied. The activities of CDDP, CPT-11, TXL, CDDP + CPM, CDDP + CPT-11, CDDP + TXL, CPT-11 + CPM, CPT-11 + TXL, and TXL + CPM were evaluated comparing with a control group using saline. Three mice were used for each group, and when the xenografted tumor reached 6 mm in diameter, 1/5 LD50 of these drugs was administered into the peritoneal cavity of mice once a week for three weeks. RESULTS: The three most effective regimens were CPT-11 + TXL, CDDP + CPM, and CDDP + CPT-11 for epithelial ovarian cancer.

[Evaluation of a new anti-cancer drug regimen for endometrial cancer].

BACKGROUND: The purpose of this study was to describe a new anti-cancer drug regimen for endometrial cancer. METHODS: The cytotoxicities of some anti-cancer drugs regimens against human endometrial cancer xenografted into nude mice (TEI, TET, TEU, TEN) have been studied. The activities of ADM, CDDP, CPM, CPT-11, TXL, CDDP + ADM, CDDP + CPM, CDDP + CPT-11, CDDP + TXL, CPT-11 + TXL were evaluated in comparison with a control group using saline. Three mice were used for each group, and when xenografted tumor reached 6 mm of its diameter, 1/5 LD50 of these drugs was administered into the periotoneal cavity mice once a week for three weeks. RESULTS: The effective regimens were CPT-11 + TXL, CDDP + CPT-11, CDDP + CPM, CDDP + TXL for the endometrial cancer. CONCLUSIONS: It is suggested that these new drugs regimens should be tested in clinical studies.

[Evaluation of a new anti-cancer drug regimen against uterine cervical cancer in nude mice].

The purpose of this study was to describe a new anti-cancer drug regimen for uterine cervical cancer. The cytotoxicities of some anti-cancer drugs regimens against the human uterine cervical cancer xenografted into nude mice have been studied. The activities of CDDP, CPT-11, TXL, CDDP + BLM, CDDP + MMC, CPT-11 + BLM, CPT-11 + CDDP, CDDP + 5-FU, CPT-11 + MMC, CPT-11 + TXL and CDDP + TXL for squamous cell carcinoma (TCR, TCK, TCG), and CDDP, MMC, TXL, CDDP + TXL, CDDP + MMC and MMC + TXL for adenocarcinoma (TCO, TCM, TCY), were evaluated comparing with a control group using saline. Five mice were used for each groups. When the xenografted tumor reached 6 mm in diameter, 1/5 LD50 of these drugs were administered into the peritoneal cavity of the mice once a week for three weeks. The effective regimens were CDDP + MMC, CDDP + BLM, CDDP + CPT-11 and CPT-11 + MMC for squamous cell carcinoma of the uterine cervix. CDDP + MMC, CDDP + TXL, MMC + TXL and CDDP were effective for endocervical adenocarcinoma. It was suggested that these new drug regimens should be used in clinical studies.

Topography and reciprocal activity of cerebellar Purkinje cells in the uvula-nodulus modulated by vestibular stimulation.

In the rabbit uvula-nodulus, vestibular and optokinetic information is mapped onto parasagittal zones by climbing fibers. These zones are related functionally to different pairs of vertical semicircular canals, otolithic inputs and horizontal optokinetic inputs. Vestibular stimulation restricted to one of these zones modulates climbing fiber responses (CFRs). Within each of these zones, simple spikes (SSs) are modulated reciprocally with CFRs. In rabbits anesthetized with chloralose-urethan, we have used vestibular and optokinetic stimulation to evoke CFRs within a parasagittal zone while recording from Purkinje cells in adjacent zones. We have examined whether the CFRs evoked by vestibular stimulation in one zone influence the SSs of an adjacent zone. CFRs and SSs were recorded during roll vestibular stimulation. The orientation of the head of the rabbit with respect to the axis of rotation was varied systematically so that a climbing fiber null plane could be determined. This null plane was the orientation of the head about the vertical axis at which no modulation of the CFR was observed during rotation about the longitudinal axis of the vestibular rate table. In the left uvula-nodulus, a medial sagittal strip extending through all the folia contained Purkinje cells with CFRs that had optimal planes of stimulation coplanar with the left posterior-right anterior semicircular canals (LPC-RAC). Lateral to this strip was a strip of Purkinje cells with CFRs that were characterized by optimal planes corresponding to stimulation of the left anterior-right posterior semicircular canals (LAC-RPC). SSs in Purkinje cells were modulated out of phase with CFRs from the same Purkinje cell. The depth of modulation of both CFRs and SSs was reduced during rotation in the climbing fiber "null plane". The depth of modulation of SSs was greatest when recorded from Purkinje cells located at the center of semicircular canal-related strip. We observed that 1) all folia of the uvula-nodulus receive vestibular climbing fiber inputs; 2) these climbing fiber inputs convey information from the vertical semicircular canals and otoliths but not the horizontal semicircular canals; 3) CFRs evoked in a particular sagittal zone do not influence SSs in adjacent zones; 4) modulation of a CFRs in a particular Purkinje cell can occur without modulation of SSs in the same Purkinje cell, although modulation of SSs was not observed in the absence of CFR modulation; and 5) modulation of SSs sometimes preceded that of CFRs in the same cell, implying that interneuronal pathways may contribute to SS modulation. Climbing fiber-driven Golgi cells, the inhibitory axon terminals of which end on granule cell dendrites in the classic glomerular synapse, may provide this interneuronal mechanism.

Characterization of a newly established human tumor cell line (TEN) from a patient with clear cell carcinoma of the uterine body and its sensitivity to anti-cancer agents.

A cell line derived from human endometrial clear cell adenocarcinoma was newly established and named TEN. The tumor cells were obtained from uterine body of a 74-year-old who had been undergone an abdominal simple hysterectomy. The histologic features of the tumor cells showed abundant clear cytoplasm with diastase digested glycogen granule growing in solid nest and tubular pattern. The TEN cells were continuously propagated in vitro during the past 45 months and they were at 75th passage. They grew in a monolayered sheet with a doubling time of about 53 hours. The TEN cells resembled the structure of the original tumor and had abundant glycogen granules, lipid droplets in the cytoplasm. The histopathology of the transplanted tumor in SCID mice resembled that of the original tumors. The TEN cells secreted a high content of CA125. Immunohistochemically, the TEN cells had c-erbB-2 and Cathepsin D immunoreactivity in some parts of the cell population. But they did not have estrogen, progesterone and EGF receptor. Sensitivities of the TEN cells to a variety of anti-cancer drugs were examined. In in-vitro tests, MTT assays employed. The results suggested that the TEN cells were not sensitive to any of 13 agents. On the other hand, in-vivo sensitivity test of transplanted tumor in SCID mice, the tumors were sensitive to CPT-11 and paclitaxel. We conclude that the TEN cell line will be effective material for chemosensitivities against the endometrial clear cell adenocarcinoma.

[Familial ovarian cancer, uterine cancer].

Familial ovarian cancer is described as a familial aggregation of ovarian cancer. The disease is heterogeneous, with at least three genotypes prodisposing to distinctive hereditary syndrome, site-specific ovarian cancer, wherein familial cancer risk is restricted to ovarian carcinoma; breast/ovary carcinoma syndrome, that is ovarian carcinoma in association with carcinoma of the breast; and Lynch syndrome II, characterized by hereditary nonpolyposis colorectal cancer with proximal colonic cancer predominance, endometrial carcinoma, and ovarian carcinoma. When a familial aggregation of ovarian cancer is observed, unaffected women in the family should have periodic gynecologic examinations, including cytologic and ultrasonographic, radiologic studies and magnetic resonance imaging, in an effort to detect preinvasive ovarian cancer. Until more reliable diagnostic methods are developed, however, the physician should consider the advisability of prophylactic oophorectomy and oral contraceptives when counseling women who have several close relatives with ovarian cancer.

Alterations of visual climbing fiber response properties in cat cerebellar flocculus after cerebral cortical lesions.

1. In the anesthetized decorticate cat, we recorded complex spike (CS) activity together with concomitant simple spike (SS) activity of the cerebellar flocculus (FL) Purkinje cells that responded to large-field visual pattern movement. The cerebral cortical contributions to the visual response characteristics were investigated by comparing the present results with the previous results of the anesthetized normal cat. 2. The direction-selective characteristics of the CS responses at a low (2 degrees/s) stimulus velocity are well preserved after the decortication. As in the normal cat, the cells are divided into two major types: the horizontal type that prefers horizontal stimuli and the vertical type that prefers vertical stimuli. The CS rate of the former increases during stimuli directed contralaterally to the recording site and decreases during ipsiversive stimuli, whereas that of the latter increases during upward stimuli and decreases during downward stimuli. Reciprocal properties of the CS and SS responses also are preserved: when the CS rate increases, the SS rate decreases and vice versa. 3. For both types, the CS modulation at high stimulus velocities is reduced after the decortication. The half-reduction of the average modulation occurs at approximately 100 degrees/s stimulus velocity compared with the modulation at 2 degrees/s in the normal cat, whereas it occurs at a lower velocity approximately 50 degrees/s in the decorticate cat. 4. For both types, the CS responses usually are driven through either eye in the normal cat. After the decortication, the CS modulation through the contralateral eye is reduced. 5. For both types, the receptive field of the ipsilateral eye extends into both visual hemifields in the normal cat. The CS responses through the contralateral visual hemifield are abolished, whereas those through the ipsilateral visual hemifield are preserved after the decortication. The CS modulation during stimuli restricted within a small central visual field (15 degrees x 15 degrees) projecting to the area centralis is prominent (approximately 70% of the full-screen response) in the normal cat and is sharply reduced (30%) after the decortication.(ABSTRACT TRUNCATED AT 400 WORDS)

Climbing fiber responses of Purkinje cells to retinal image movement in cat cerebellar flocculus.

1. The complex spike (CS) of the floccular Purkinje cell has been reported to be driven by retinal image movement in the rabbit, the rat, and the monkey, but not yet in the cat, in which the floccular neuronal network is well known. We recorded the CS activity together with concomitant simple spike (SS) activity of the floccular Purkinje cells that responded to large-field visual pattern movement in the anesthetized cat. 2. On the basis of the direction selectivity we divided the cells into two major types: the horizontal type that preferred horizontal stimuli and the vertical type that preferred vertical stimuli. The CS activity of the horizontal-type cell increased during stimuli directed contralaterally to the recording site and decreased during ipsilaterally directed stimuli, whereas that of the vertical-type cell increased during upward stimuli and decreased during downward stimuli. 3. In both types the CS response was larger at lower-velocity stimuli and the response was well maintained at higher-velocity stimuli < or = 180 degrees/s tested. The mean response decline was only 50% at stimulus velocities 90-150 degrees/s compared with the response amplitude at 2 degrees/s stimulus velocity. 4. The majority of the horizontal-type cells were modulated by the stimuli presented to either eye and the dominant eye was ipsilateral to the recording site. The majority of the vertical-type cells were also modulated by the stimuli presented to either eye without obvious differences between two eyes. 5. In both types the receptive field of the ipsilateral eye always included the area centralis and extended widely on both visual hemifields. The receptive field of the contralateral eye also included the area centralis and was usually restricted within the ipsilateral visual hemifield. The stimuli of small visual field (15 degrees x 15 degrees) projecting to the area centralis evoked especially large responses (70% of the full-screen response). 6. The CS and SS responses were reciprocal to each other, that is, when the CS firing increased the SS firing decreased and vice versa. 7. These CS responses are well suited for the direction detection of large-field retinal image motion at a wide velocity range. In light of the present unitary spike data together with the anatomic and eye movement data reported previously, we conclude that the cat flocculus is responsible for reduction of the large-field retinal image motion by producing eye movement in the same direction with the visual motion.

Barbiturate depresses simple spike activity of cerebellar Purkinje cells after climbing fiber input.

1. Some scientists reported that the simple spike (SS) activity was transiently depressed after climbing fiber input, but others reported that predominant population of Purkinje cells increased their SS activity after the complex spike (CS). In the present study, SS activity after spontaneous CS was compared before and after the administration of pentobarbital sodium and of ketamine in high decerebrate cats. 2. Frequencies of spontaneous CS and SS firing were reduced (P < 0.001, t test) after pentobarbital administration of a total dose of 20-30 mg/kg. 3. In the peri-CS time histogram, the SS activity during a post-CS period of 10-110 ms with respect to that during a pre-CS period of -100-0 ms was reduced (P < 0.001) after the pentobarbital administration from, on average, 132.4 to 81.9%. In contrast, the SS activity during a post-CS period of 110-210 ms remained unchanged (P > 0.2). 4. In the pre-CS time histogram constructed after the pentobarbital administration, there were no significant differences (P > 0.01) between the SS activity during a pre-CS period of -600 to -500 ms and that during each of other pre-CS periods, suggesting that the barbiturate had little effect on the SS activity preceding the CS. 5. Analysis of raster diagrams revealed the variability of individual SS activity after the CS.(ABSTRACT TRUNCATED AT 250 WORDS)

Complex spike responses of cerebellar Purkinje cells to constant velocity optokinetic stimuli in the cat flocculus.

In the cat cerebellar flocculus without cerebrum but with intact accessory optic tract, complex spike (CS) responses to horizontal optokinetic stimuli (velocity-step at 2 degrees/s) were investigated. The directionally selective CS responses were present only during the short-duration stimuli but not during the continuous unidirectional stimuli. Following the end of the stimuli during the stationary surround phase, the CS activity was modulated in a manner opposite to the preceding CS response during the stimulation. These CS responses cannot simply be interpreted as sensory responses to the retinal slip input; they may in fact be deeply associated with the motor control command of the eye movement which would be elicited by the retinal slip.

Direction selective climbing fiber responses to horizontal and vertical optokinetic stimuli in the cat cerebellar flocculus.

In ketamine anesthetized cats, complex spike (CS) responses to movement of a large-field visual surround (optokinetic stimulus) were recorded in the cerebellar flocculus. Two types of Purkinje cells were found. One type showed increased CS activity to optokinetic stimuli directed contralaterally to the recording site and decreased activity to stimuli directed ipsilaterally. The modulation occurred in both monocular (responses to the stimuli for only the ipsilateral eye) and binocular forms (dominant eye, ipsilateral). The other type of cell showed increased CS activity during upward optokinetic stimuli and decreased activity during downward stimuli. The responses occurred only in the binocular form. The dominant eye was either ipsilateral or contralateral with respect to the recording site. Thus, there are two types of Purkinje cells in the cat flocculus: horizontal type cell showing CS modulation during horizontal optokinetic stimuli, and vertical type cell showing CS modulation during vertical optokinetic stimuli.