Anatomical variations of the ten triangles around the cavernous sinus.

The dimensions of the 10 triangles around the cavernous sinus were measured to define the anatomical characteristics of the triangles and to compare their consistency in shape and area. Twelve tissue blocks containing the bilateral cavernous sinuses and medial two-thirds of the middle cranial fossae were obtained from Japanese adults at autopsy, fixed to a stereotactic frame, and examined with an operative microscope. The dimensions of each triangle were measured with calipers and compared, based on the same point and border. The anteromedial triangle and the superolateral (Parkinson's) triangle were more consistent in shape than the paramedial and oculomotor triangles, but the oculomotor triangle was larger in area than these other triangles. The posteromedial (Kawase's) triangle was more consistent in shape and larger than the anterolateral, lateral, and the posterolateral (Glasscock's) triangles. The anteromedial and superolateral (Parkinson's) triangles are important for the combined epi- and subdural approach to cavernous sinus lesions. The posteromedial (Kawase's) triangle is important for gaining access to the posterior cranial fossa from the middle cranial fossa.

A new ultrasensitive assay for quantitation of HIV-1 RNA in plasma.

Nucleic acid-based diagnostic assays for the quantitation of plasma HIV-1 RNA levels are used to monitor disease progression and the response of patients to antiretroviral drug therapy. The LCx HIV RNA Quantitative Assay (Abbott Laboratories, North Chicago, IL) is an assay for the quantitation of HIV type 1 RNA in plasma that uses competitive reverse transcription PCR (RT-PCR) followed by Microparticle Enzyme Immunoassay, and includes an internal control for inhibition and RNA recovery, that is taken through the entire sample preparation procedure. The performance of the assay was assessed for 1 and 0.2 ml sample volumes. For a 1 ml sample volume, the lower limit of detection was found to be 50 copies/ml with a linear range from 50 to 1 million copies/ml. For a 0.2 ml sample volume, the lower limit of detection was found to be 178 copies/ml with a linear range from 178 to 5 million copies/ml. The assay is able to detect and quantitate HIV subtypes A-G and group O. LCx HIV RNA assay quantitation results are highly correlated to the standard and ultrasensitive Amplicor HIV-1 Monitor assay (Roche Molecular Systems) quantitation results. Assay performance is consistent with the use of this test for routine quantitation of HIV-1 RNA in plasma.

A dose-escalation and pharmacokinetic study of subcutaneously administered recombinant human interleukin 12 and its biological effects in Japanese patients with advanced malignancies.

A pilot dose-escalation study of recombinant human interleukin 12 (rhIL-12) was conducted in Japanese patients with advanced malignancies. Cohorts of three patients received escalating doses of rhIL-12 that increased from 50 to 300 ng/kg/day s.c. three times a week for 2 weeks followed by 1-week rest. The same dosage and schedule was repeated for two additional courses. Sixteen previously treated patients were registered, and 15 were evaluated. Common toxicities were fever and leukopenia; the abnormality of laboratory tests included elevations in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, C-reactive protein, and beta2-microglobin. Dose-limiting toxicity was the grade 3 elevation of aminotransferases, and was observed in two of six patients at the 300-ng/kg dose level after the first course in one patient and after the third course in the other. Leukopenia was observed at all of the dose levels; two of six patients at 300 ng/kg experienced grade 3 leukopenia. Thus, 300 ng/kg was determined to be the maximum acceptable dose. Peak plasma levels of rhIL-12 decreased in the second courses, but the areas under the curve were almost the same in the first and second courses. Biological effects included increases of plasma levels of IFN-gamma, tumor necrosis factor-alpha, IL-6, IL-10, and neopterin. In two patients with renal cell carcinoma, complete response and partial response of metastatic tumors were observed with 50 and 300 ng/kg; the responses lasted for 5 and 3.5 months, respectively. Although immunological response to rhIL-12 varies depending on administration route and schedule and on patients' physiological conditions, the recommended dose for Phase II studies is 300 ng/kg s.c. three times a week for 2 weeks followed by 1-week rest.

Postoperative oblique sagittal MR imaging of microvascular decompression for hemifacial spasm.

Pre-operative and postoperative oblique sagittal gradient-echo magnetic resonance (MR) imaging was used to evaluate micro-vascular decompression of the facial nerves in 26 patients with hemifacial spasm. The pre-operative MR images were divided into two groups as follows: 22 images in Group I, clear imaging of a high-intensity line and/or spot at the root exit zone (REZ) of the facial nerve; and 4 in Group II, and unreliable image around the REZ. Surgery found that the causative vessel was the vertebral artery (VA) in 9 cases and the anterior inferior cerebellar artery (AICA) or the posterior inferior cerebellar artery (PICA) in 13 cases in Group I, and the AICA or the PICA in the 4 cases in Group II. Postoperative MR imaging showed clear decompression as the high-intensity line and/or spot completely separated from the REZ by a low- and/or iso- intensity area in 9 cases of VA compression repositioned to the petrous dura matter, in 11 cases of PICA or AICA compression treated by shredded Teflon pledgets in Group I and in 3 cases in Group II. Postoperative MR imaging showed an incomplete separation of any high-intensity line and/or spot in the REZ in 2 cases of PICA or AICA compression in Group I and in one in Group II. The outcome was excellent in 22 of 23 cases with clear decompression, and in 1 of 3 cases of unclear decompression. Hemifacial spasm persisted in 3 cases. Oblique sagittal gradient-echo MR imaging is a useful method for postoperative follow-up which can demonstrate changes around the REZ of the facial nerve if hemifacial spasm recurs.

[Phase I study of gemcitabine hydrochloride (LY 188011) combination therapy with cisplatin in the patients with non-small cell lung cancer].

The combination Phase I study of gemcitabine hydrochloride with cisplatin was conducted in the patients with non-small cell lung cancer (NSCLC) at 5 investigation sites. Gemcitabine was administrated on day 1, 8 and 15 and cisplatin on day 1 of each 28-day cycle. The dosage of cisplatin was fixed to 80 mg/m2 and the dosage of Gemcitabine was gradually escalated in 3 dosing level from 600, 800 to 1,000 mg/m2. The maximum tolerated dose (MTD) and the recommended dose was determined with Continual Reassessment Method. For each dose level, 6 cases, 3 cases and 6 cases were registered respectively and all 15 cases were evaluable. In the dose level 3 with 1,000 mg/m2 of gemcitabine and 80 mg/m2 of cisplatin, grade 4 neutropenia was observed as DLT in 3 out of 6 cases, thus dose level 3 was considered as MTD and the recommended dose. Major adverse events were leukopenia, neutropenia, nausea/vomiting and anorexia. The incidence of such adverse events seemed to be dose-dependent and especially the grade of neutropenia seemed to be more serious as the dose increased. Also, the grade of liver function tests abnormal seemed to be more serious as the dose increased but the incidence as well as the grade did not have tendency of dose-dependent in another events including renal function tests abnormal. On the other hand, as to the efficacy PR was observed in 4 out of 15 cases. Based upon the results, it is necessary to discuss further the efficacy in the recommended dose in the combination therapy of gemcitabine and cisplatin.

Prediction of vertebral artery compression in patients with hemifacial spasm using oblique sagittal MR imaging.

To discriminate between the various compressing vessels of the facial nerves in patients with hemifacial spasm, pre-operative oblique sagittal gradient-echo MR imaging was performed. Forty-two patients underwent pre-operative MR imaging and microvascular decompression. The MR images were divided according to findings into three groups as follows: Group A, a thick and/or long high-intensity line along the root exit zone (REZ) of the facial nerve; Group B, a thin and/or short high-intensity line along the REZ; and Group C, an unreliable image around the REZ. Fifteen images were classified as Group A, 19 as Group B, and 8 as Group C. In Group A, vertebral artery (VA) compression was confirmed intra-operatively in 12 cases and posterior inferior cerebellar artery (PICA) or anterior inferior cerebellar artery (AICA) compression in 3. In Group B, PICA or AICA compression was confirmed intra-operatively in all cases. In Group C, PICA or AICA compression was confirmed intra-operatively in 7 cases and no compression in one. In all cases of VA compression of the facial nerve, the oblique sagittal gradient-echo images demonstrated a thick and/or long high intensity line along the REZ. Oblique sagittal gradient-echo MR imaging is a useful preoperative planning aid, which can predict the possibility of VA compression prior to microvascular decompression for hemifacial spasm.

Evaluation of ligase chain reaction for use with urine for identification of Neisseria gonorrhoeae in females attending a sexually transmitted disease clinic.

The high sensitivity of nucleic acid amplification tests such as ligase chain reaction (LCR) has the potential to simplify specimen collection for the microbiologic diagnosis of gonorrhea. We screened first-void urine specimens from 283 women attending a Birmingham, Ala., sexually transmitted disease (STD) clinic by using LCR and compared the results to those of cervical and urethral cultures for gonorrhea diagnosis. Fifty-three (18.7%) women had positive cervical cultures for gonorrhea, and 41 of the 53 (77%) also had positive urethral cultures. One additional patient had only a positive urethral culture (the cervical gonorrhea culture was negative). LCR testing of urine specimens for gonorrhea yielded positive results for 51 of 54 (94.4%) women with positive cervical or urethral cultures. Of 229 women with both urethral and cervical cultures negative for gonorrhea, 2 (0.8%) had positive urine LCR results as well. To resolve the discrepancies between urine LCR and culture results, LCR tests of simultaneously collected urethral and cervical swab specimens and LCR tests of the same urine specimens using different nucleotide primers were conducted. After evaluation of five discrepant results, the sensitivity, specificity, positive predictive value, and negative predictive value of LCR for the detection of gonorrhea in urine specimens were 94.6%, 100%, 100%, and 98.7%, respectively. We conclude that urine LCR testing for Neisseria gonorrhoeae is a practical alternative to culture for the detection of gonorrhea in women. Urine testing for STD diagnosis has the potential to simplify and expand the opportunities for STD screening and surveillance of women.

[A late phase II comparative study of idarubicin + cytarabine and daunorubicin + cytarabine in adult patients with acute non-lymphocytic leukemia. Idarubicin Study Group].

In adult patients with acute non-lymphocytic leukemia (ANLL), idarubicin (IDA) and daunorubicin (DNR) were compared for efficacy and safety in combination with cytarabine (Ara-C). IDA 12 mg/m2/day and DNR 40 mg/m2/day were administered iv bolus for 3 consecutive days (day 1-3), respectively, in combination with Ara-C 80 mg/m2 given by 2-hour intravenous infusion, every 12 hours for 7 consecutive days. The number of evaluable patients was 32 for each group previously untreated. The rates of complete remission (CR) were 59.4% (19/32) in the IDA group and 40.6% (13/32) in the DNR group. The clinical equivalence test with delta = 10% demonstrated that the IDA group is equal or superior in remission rates (p = 0.010) compared to the DNR group. In addition, the Cochran-Mantel-Haenszel test for response means with scores of 3 (CR), 2 (PR) and 1 (NR) showed the significant superiority (p = 0.044) of the IDA group to the DNR group. The duration needed to attain less than 5% leukemic cells in bone marrow tended to be shorter in the IDA group (p = 0.072), and in the CR patients the number of days needed to reach the nadir value in leukemic cells were significantly fewer in the IDA group (p = 0.037). The nadir value of WBC was significantly lower in the IDA group (p = 0.022). As for adverse reactions, high incidences of diarrhea and stomatitis were observed in the IDA group, while the incidences of other adverse reactions were similar between the two groups. When effects of the drug on the ECG were examined, significant changes in ECG parameters were observed in the DNR group after treatment but not in the IDA group. From the above, remission induction in adult AN LL, IDA + Ara-C therapy showed better efficacy than DNR + Ara-C therapy, and IDA was considered to be a drug of first choice in the treatment of ANLL patients.

[Respiratory outcome in extremely premature infants following general anesthesia].

This study was aimed to predict the need of postoperative tracheal intubation in premature infants following anesthesia using volatile anesthetics by means of the scoring system derived from our former study of ketamine anesthesia. The subjects consisted of 14 infants (birth weight: 719 +/- 130 g and weight at operation 1882 +/- 312 g) needing cryotherapy for retinopathy and anesthetized with less than 1 MAC of volatile anesthetics. Respiratory outcome was successfully predicted in 9 patients (64%) while no infant was predicted incorrectly to be ready for tracheal extubation. The incidences of postoperative ventilatory support were 28% and 32% after anesthesia with volatile anesthetics and ketamine anesthesia, respectively. However, general anesthesia with volatile anesthetics appeared to be superior in actual outcome to ketamine anesthesia among the patients with high risk scores.

Antinociceptive effect of mexiletine in diabetic mice.

We examined the effect of mexiletine on the threshold for pain perception as determined by the application of mechanical noxious stimuli (tail-pinch) in diabetic mice. Mexiletine produced a pronounced analgesic effect in diabetic mice in a dose-dependent manner. Mexiletine (10(-5)M) significantly inhibited the K(+)-evoked release of substance P from the slices of spinal cord of diabetic mice. These results suggest that the reduction of release of substance P from the nociceptive afferent terminal in the spinal cord is involved in the mechanisms of mexiletine analgesia in diabetic mice.

Effects of diabetes on stress-induced analgesia in mice.

The present studies were designed to determine whether streptozotocin-induced (STZ-induced) diabetes in mice can attenuate the development of antinociception induced by exposure to both foot shock and forced swimming stress. Foot shock stress produced significant analgesia both in control and diabetic mice. However, the extent of foot shock stress-induced analgesia (FSSIA) in diabetic mice was significantly lower than that in control mice. Naloxone (2 mg/kg, i.p.) significantly attenuated FSSIA in control mice, but was without effect on FSSIA in diabetic mice. One-minute swimming stress had no significant effect on tail-pinch latency in control mice, whereas 3-min swimming stress produced significant analgesia in these mice. Diabetic mice exhibited robust swimming stress-induced analgesia (SSIA): one-min swimming stress produced significant analgesia in diabetic mice. These analgesic effects were blocked by naltrindole, a selective antagonist of delta-opioid receptors, but not by pretreatment with beta-funaltrexamine, an irreversible and selective antagonist of mu-opioid receptors. These results suggest that the deficiency in the functioning of mu-opioid receptors caused by diabetes results in significant activation of an endogenous analgesic system, which is mediated mainly by delta-opioid receptors.

Streptozotocin-induced diabetes selectively alters the potency of analgesia produced by mu-opioid agonists, but not by delta- and kappa-opioid agonists.

To investigate the possible mechanisms of the alterations in morphine-induced analgesia observed in diabetic mice, we examined the influence of streptozotocin-induced (STZ-induced) diabetes on analgesia mediated by the different opioid receptors. The antinociceptive potency of morphine (10 mg/kg), administered s.c., as determined by both the tail-pinch and the tail-flick test, was significantly reduced in diabetic mice as compared to that in controls. Mice with STZ-induced diabetes had significantly decreased sensitivity to intracerebroventricularly (i.c.v.) administered mu-opioid agonists, such as morphine (10 micrograms) and [D-Ala2,N-Me Phe4,Gly-ol5]enkephalin (DAMGO, 0.5 micrograms). However, i.c.v. administration of [D-Pen2,5]enkephalin (DPDPE, 5 micrograms), a delta-opioid agonist, and U-50,488H (50 micrograms), a kappa-opioid agonist, produced pronounced antinociception in both control and diabetic mice. Furthermore, there were no significant differences in antinociceptive potency between diabetic and control mice when morphine (1 microgram), DAMGO (10 micrograms), DPDPE (0.5 micrograms) or U-50,488H (50 micrograms) was administered intrathecally. In conclusion, mice with STZ-induced diabetes are selectively hyporesponsive to supraspinal mu-opioid receptor-mediated antinociception, but they are normally responsive to activation of delta- and kappa-opioid receptors.

Streptozotocin-induced diabetes in mice reduces the nociceptive threshold, as recognized after application of noxious mechanical stimuli but not of thermal stimuli.

We report herein that streptozotocin (STZ)-induced diabetes selectively alters the nociceptive threshold with respect to noxious mechanical stimuli. Mice were rendered diabetic by an injection of STZ (200 mg/kg, IV). In the tail-pinch test, the latency of the biting response to forceps was significantly decreased in animals with diabetes of 2 weeks and 8 weeks duration as compared to that in age-matched controls. However, the nociceptive threshold, as determined by the tail-flick test, was not significantly altered. The level of substance P in the spinal cord was significantly increased in mice that has been diabetic for 2 weeks, while, there was a significant decrease, as compared to control levels, in level of substance P in mice diabetic for 8 weeks. However, the level of somatostatin was not significantly altered in mice diabetic for either 2 weeks or 8 weeks. These data suggest that STZ-induced diabetes selectively alters a neuronal system that involves substance P but not somatostatin in the spinal cord.

Alterations in the potassium-evoked release of substance P from the spinal cord of streptozotocin-induced diabetic rats in vitro.

1. The release of SPLI evoked by high levels of K+ (50 mM) from the spinal cord of diabetic rats was greater than in the case of spinal cord from control rats. 2. Morphine (10(-5) M) significantly inhibited the K(+)-evoked release of SPLI release in both the groups. However, in spinal cord from diabetic rats, morphine reduced the K(+)-evoked release of SPLI only to the levels that were observed in material from control rats prior to treatment with morphine. 3. Glucose (20 mM) and dibutyryl cyclic-AMP (10(-4) M) significantly potentiated the K(+)-evoked release of SPLI in spinal cord from control rats. 4. These findings suggest that excessive release of SPLI from the spinal cord may be associated with the reported abnormalities in nociceptive transmission in diabetic rats, and that excessive release of SPLI may be modulated by levels of glucose and/or cyclic-AMP in the spinal cord.

Comparative study on glycosaminoglycans synthesized in peripheral and peritoneal polymorphonuclear leucocytes from guinea pigs.

Glycosaminoglycans synthesized in polymorphonuclear (PMN) leucocytes isolated from blood (peripheral PMN leucocytes) and in those induced intraperitoneally by the injection of caseinate (peritoneal PMN leucocytes) were compared. Both peripheral and peritoneal PMN leucocytes were incubated in medium containing [35S]sulphate and [3H]glucosamine. Each sample obtained after incubation was separated into cell, cell-surface and medium fractions by trypsin digestion and centrifugation. The glycosaminoglycans secreted from peripheral and peritoneal PMN leucocytes were decreased in size by alkali treatment, indicating that they existed in the form of proteoglycans. Descending paper chromatography of the unsaturated disaccharides obtained by the digestion of glycosaminoglycans with chondroitinase AC and chondroitinase ABC identified the labelled glycosaminoglycans of both the cell and the medium fractions in peripheral PMN leucocytes as 55-58% chondroitin 4-sulphate, 16-19% chondroitin 6-sulphate, 16-19% dermatan sulphate and 6-8% heparan sulphate. Oversulphated chondroitin sulphate and oversulphated dermatan sulphate were found only in the medium fraction. In peritoneal PMN leucocytes there is a difference in the composition of glycosaminoglycans between the cell and the medium fractions; the cell fraction was composed of 60% chondroitin 4-sulphate, 5.5% chondroitin 6-sulphate, 16.8% dermatan sulphate and 13.9% heparan sulphate, whereas the medium fraction consisted of 24.5% chondroitin 4-sulphate, 28.2% chondroitin 6-sulphate, 33.7% dermatan sulphate and 10% heparan sulphate. Oversulphated chondroitin sulphate and oversulphated dermatan sulphate were found in the cell, cell-surface and medium fractions. On the basis of enzymic assays with chondro-4-sulphatase and chondro-6-sulphatase, the positions of sulphation in the disulphated disaccharides were identified as 4- and 6-positions of N-acetylgalactosamine. Most of the 35S-labelled glycosaminoglycans synthesized in peripheral PMN leucocytes were retained within cells, whereas those in peritoneal PMN leucocytes were secreted into the culture medium. Moreover, the amount of glycosaminoglycans in peritoneal PMN leucocytes was significantly less than that in peripheral PMN leucocytes. Assay of lysosomal enzymes showed that these activities in peritoneal PMN leucocytes were 2-fold higher than those in peripheral PMN leucocytes.

[Phase II study with methyl-6[[[2-chloroethyl) nitrosoamino] carbonyl] amino]-6-deoxy-alpha-D-glucopyranoside (MCNU) in hematological malignancies].

A total of 117 cases with hematological malignancies were treated with MCNU at doses of 70-100 mg/m2. Following are the results obtained. 1. MCNU showed a marked depression of cells in the cases with CML, polycythemia vera and thrombocythemia. The low level of cells was maintained for 2 to 7 months. 2. A good response was observed in several cases with blastic crises of CML. 3. No response was observed in two cases with acute leukemia. 4. Although a fair response was observed in several cases with malignant lymphoma or multiple myeloma, moderate bone marrow suppression was observed in a majority of the cases.

Effect of intravenously administered fluid on hemodynamic change and respiratory function in extensive thermal injury.

In 53 extensively burned patients, a comparative study was conducted on lactated Ringer's solution, colloid plus lactated Ringer's solution and hypertonic lactated saline solution on their hemodynamic and respiratory effects. The total amount of infusion required to resucitate the initial hypovolemic phase was the least in the hypertonic lactated saline solution group; whereas, the total sodium intake was the greatest in the lactated Ringer's solution group. Elevation of the respiratory index in the hypertonic lactated saline solution group was slightly more than the normal range, but insignificant. Cardiac output decreased initially in all three groups, but a hyperdynamic state with a simultaneous increase in the respiratory index occurred rapidly in the lactated Ringer's solution group; however, it occurred after five to seven days in the other two groups. Arteriovenous oxygen content difference increased in the hypertonic lactated saline solution group and decreased in the colloid plus lactaed Ringer's solution group, with no significant change in the lactated Ringer's solution group. From this study, the use of hypetonic lactated saline solution seems to be the best choice in the initial resuscitation of thermal injury.