Computed tomography in diagnosis of septic sacroiliitis: report of three cases.

Disorders of the sacroiliac joint are often overlooked during an initial physical examination because the patient is usually in a supine position and the posteriorly located joint is not accessible. Local pain and tenderness at the sacroiliac joint on lateral compression of the pelvis, together with Gaenslen and Fabere maneuvers, may direct the physician's attention to the joint. However, these symptoms are not specific or pathognomonic. Unusual presentation of septic sacroiliitis, which does not show radiologic changes during the early stages, may mimic gluteal, lumbar disc or intra-abdominal syndromes, leading to unnecessary abdominal exploration or lumbar discectomy. Computed tomography (CT), with its superb delineation of osseous, synovial and peri-articular structures, was applied to diagnose septic sacroiliitis in three patients. In Patient 1, septic arthritis and juxta-articular osteomyelitis with sequestrum formation were demonstrated by CT four weeks before abnormalities were shown on a roentgenogram. In Patients 2 and 3, inflammatory processes affected the synovium and peri-articular muscles; thus, abnormalities were shown by CT but not by a roentgenogram. We consider CT to be helpful and superior to conventional radiography in the diagnosis of septic sacroiliitis.


Non-mosaic trisomy 20 in cultures of amniotic fluid from a fetus with serious congenital malformation.

We present a case of non-mosaic trisomy 20 in amniotic fluid associated with major congenital anomalies. A detailed prenatal ultrasonic examination was performed, and revealed dilatation of the cisterna magna and the fourth ventricle with hypoplasia of the vermis of the cerebellum. Fetal echocardiography showed overriding aorta and ventricular septal defects with pulmonary atresia. However, the karyotype of the lymphocyte in the cord blood was normal female 46, XX. The occurrence of the Dandy-Walker malformation in non-mosaic trisomy 20 has not been reported before, and the clinical significance of this major defect for prenatal diagnosis is discussed.


Incomplete prepenile scrotum: report of two cases and review of literature.

An incomplete prepenile scrotum is an unusual anomaly. Two cases of incomplete prepenile scrotum are presented here, both of which are associated with a small phallus, hypospadias and a bifid scrotum. No sex chromosome disorder or hereditary factors contribute to such a disorder. Early surgical correction is recommended.


Treatment of symptomatic syringomyelia with ventriculoperitoneal shunt: report of a case.

We report on a 43-year-old female who, for 27 years, had thoracic scoliosis with curve convexity to the left side. She complained of rapid progression of the central cord syndrome in the past two years. Magnetic resonance imaging (MRI) demonstrated a syringomyelia with a direct connection between the fourth ventricle and the syrinx. The patient underwent a ventriculoperitoneal shunt and showed rapid neurologic improvement. A follow-up MRI showed dramatic shrinkage of the syrinx.


Primary medullary hemorrhage: report of a case.

A 40-year-old normotensive man suddenly developed dizziness, vomiting, hoarseness and swallowing disturbance. Neurologic examinations showed bilaterally decreased palatal elevation and gag reflex, upbeat nystagmus and gait ataxia. The diagnosis of medullary hemorrhage was first established by computed tomography (CT). Magnetic resonance imaging study further showed a hematoma in the paramedial medulla oblongata extending dorsorostrally to the pontomedullary junction. It gave the precise anatomic boundary of the intramedullary hematoma and was well correlated with the clinical findings. This patient's subsequent prognosis was good with gradual improvement of the clinical signs and symptoms. A follow-up CT scan showed resolution of the hematoma, and the prognosis was consistent with a good neurologic recovery.


A simple and effective method of compression dressing for skin grafts.

Skin grafting is one of the most common procedures in plastic and reconstructive surgery. Various methods of fixation and dressing, to achieve good approximation and immobilization of skin grafts and, thus, to bring about better graft survival, are described. A simple method utilizing readily available latex and staples provides good fixation and compression. This technique has been applied in 50 patients requiring skin grafts. The morbidity and complications were minimal, and the grafts have taken satisfactorily. Pressure study with an animal model has revealed adequate compression.


Detection of enterovirus RNA in patients with idiopathic dilated cardiomyopathy by polymerase chain reaction.

The pathogenic role of enterovirus in patients with idiopathic dilated cardiomyopathy has been determined through a molecular biologic approach. Sensitivity in the detection of viral genomes in tissues varied between conventional nucleic acid hybridization and polymerase chain gene amplification. To improve diagnosis, we developed a strategy for reverse transcription polymerase chain reaction (RT-PCR) to detect viral RNA. We synthesized two sequence-specific oligonucleotides, primer 1 (5'dACCGACGAATACCACTGTTA3') and primer 2 (5'dCCTCCGGCCCCTGAATGCGGCTAAT3'), complementary to the 5' conserved viral genomic fragments. Viral RNA was amplified by double PCR with these two primers and hybridized with a 32-P labeled inter-primer probe (5'dATGAAACCCACAGGCACAAAG3'). Using this strategy, we detected as little as 10(-8) micrograms of coxsackievirus B3 RNA after amplification with RT-PCR, but detected none in the plasma of eight healthy adults. Among 15 patients with idiopathic dilated cardiomyopathy, viral RNA could be detected in one out of 12 plasmas (8%) and three out of four explanted heart tissues (75%). In contrast, no viral RNA could be detected in six samples of myocardial tissue from patients with other heart diseases. The only patient who had viral RNA in his plasma also had viral RNA in his myocardium. Thus, the high incidence of viral RNA in these patients suggests a possible etiologic link between them. Correct selection of specific PCR primers and the application of double PCR can improve chances of diagnosing enteroviral infection.


Comparison between carotid duplex sonography and angiography in the diagnosis of extracranial internal carotid artery occlusion.

To determine the diagnostic accuracy of extracranial internal carotid artery (ICA) occlusion by carotid duplex sonography and ophthalmic flow direction, we compared both carotid sonograms and angiograms in 82 cases of ischemic cerebrovascular disease. A total of 157 carotid arteries were available for comparison. The overall diagnostic accuracy of ICA occlusion by duplex scanning was 96% (sensitivity, 83%; specificity, 98%; positive predictive value, 91%), by ophthalmic flow examination, 95% (sensitivity, 79%; specificity, 98%; positive predictive value 86%), and by combined study, 98% (sensitivity, 96%; specificity, 98%; positive predictive value 92%). We recommend that the ophthalmic flow examination should be used in combination with other sonographic methods in detecting extracranial carotid artery disease. The combined study gives higher diagnostic accuracy than the single method. When an occlusion or a tight stenosis is uncertain on carotid sonograms, color Doppler or angiography is indicated for further confirmation.


The simultaneous use of electrocochleogram, brainstem auditory evoked potential and facial muscle EMG in cerebellopontine angle tumor removal.

In six cases of acoustic neurilemmoma, electrocochleogram (ECOchG), brainstem auditory evoked potentials (BAEP) and facial muscle electromyograms (EMG) were recorded to monitor facial nerve and brainstem function. Under isoflurane and nitrous oxide anesthesia, we recorded ECOchG from the tympanic membrane, BAEP from the scalp needle, and facial muscle EMG from the mentalis muscle. During surgery, the body temperature was kept above 36.5 degrees C, and PaCO2 above 30 mmHg. In all cases, the peak N1 of ECOchG and wave I of BAEP had identical latencies throughout the monitoring period. The response was faster and the amplitude was higher in the ECOchG recordings. For calculation of the I-III or I-V interpeak latency of BAEP, the wave I of BAEP could be confirmed more quickly and precisely by the peak N1 of ECOchG. During tumor removal, the embedded facial nerve pathway in the tumor was identified by electric stimulation of the intracranial facial nerve, followed by evoked facial muscle EMG. Facial nerve function was confirmed by nerve traction or direct electric stimulation after total removal of the tumor. No facial palsy or other neurologic sequelae was found after the operations.


Delayed traumatic intracerebral hemorrhage: a study of prognostic factors.

Experience in the management of 32 patients with delayed traumatic intracerebral hemorrhage (DTICH) is presented with emphasis on the incidence, clinical significance and factors affecting the outcome. The incidence was 1.4% of all hospitalized head-injury patients, or 5.9% of only those patients with neurologic signs or abnormal findings on computed tomography (CT) identified on admission. After an injury, every patient had an immediate CT scan to diagnose intracranial pathology. Initially, nine patients underwent a craniotomy for intracranial hematomas, and 23 patients had nonoperative treatment. CT follow-up was carried out in 10 patients due to clinical deterioration and on 22 patients due to failure to recover neurologically. The delayed hemorrhage was found after a time interval varying from seven hours to 10 days (average, three days and seven hours). Six patients underwent operations for DTICH, and 26 were treated conservatively. Twenty-four patients (75%) were functional (good or moderately disabled condition) after one year of follow-up treatment, as measured on the Glasgow Outcome Scale. The mortality was 16%. The patients were predicted to have a poor prognosis if associated with an earlier occurrence, the hematoma was large, the patient had a poor Glasgow Coma Scale score at the time of CT follow-up, clinical deterioration was noted, or partial or complete effacement of the suprachiasmatic cistern was noted on the CT scan. The results indicate that the prognosis of DTICH is not as poor as it was previously thought to be, and the factors affecting the outcome in this study seem to justify a more vigilant approach.


Apolipoprotein levels in normolipidemic non-insulin-dependent diabetes mellitus.

The purpose of this study was to examine the change in apolipoprotein and lipoprotein levels in patients with normolipidemic untreated non-insulin-dependent diabetes mellitus (NIDDM). Fifteen untreated, non-obese male NIDDM patients without hyperlipidemia were chosen, and 15 healthy subjects, matched for age, sex, body weight, alcohol consumption and cigarette smoking served as the control group. We observed that the concentrations of plasma total cholesterol (TC), triacylglycerol (TG) and very low density lipoprotein cholesterol (VLDL-C) were identical in both NIDDM and control groups. The levels of low-density lipoprotein cholesterol (LDL-C) were slightly increased in the diabetic group, but the difference did not reach statistical significance in our study. High-density lipoprotein cholesterol (HDL-C) was lower in the NIDDM group than in the controls. Significantly increased TC/HDL-C and LDL-C/HDL-C ratios were found in NIDDM patients compared with controls. The apolipoprotein A-I (apo A-I) and apolipoprotein A-II (apo A-II) levels were decreased in NIDDM patients, while the apolipoprotein B (apo B) level remained similar to that of the control subjects. The ratio of apo A-I/apo B was decreased significantly in the NIDDM group. Our results suggest that NIDDM patients are at higher risk of coronary heart disease, even if they remain normolipidemic.


Clinical experience of octreotide in the treatment of acromegaly.

To evaluate the efficacy and safety of octreotide (a somatostatin analogue) in the treatment of acromegaly, 10 patients were injected subcutaneously with octreotide, 50 micrograms, thrice daily before each meal for two days, followed by 100 micrograms thrice daily for six months. One case dropped out at the initial stage because of diarrhea, and another quit due to a lack of improvement in headaches after treatment for three months. Eight patients completed the study. The results showed that the circumference of the fourth finger and hand volume significantly decreased after treatment. Laboratory data demonstrated that serum growth hormone (GH) and somatomedin-C levels also decreased significantly. However, in six patients without a history of trans-sphenoidal adenomectomy, the serum GH and somatomedin-C levels returned to normal in only one case who had a serum GH level < 20 mU/L before treatment. In the oral glucose tolerance test, paradoxic elevation of GH subsided after treatment. In the TRH test, paradoxic elevation of GH improved after treatment. In the bromocriptine test, octreotide had a synergistic effect on the suppression of GH. All cases had the side effect of injection pain, especially at the initial stage. An increase in intestinal peristalsis and bowel movement occurred in the first week, but symptoms later subsided. Two out of these eight patients had gallbladder sludge after six months of treatment. In conclusion, octreotide is effective in the treatment of acromegaly; however, it is better used in patients who have serum GH levels < 20 mU/L, or after a trans-sphenoidal adenomectomy, and may be combined with bromocriptine to treat the patient.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of fibrin glue on hemostasis.

In order to decrease complications following incomplete hemostasis, we tried to make a safe, efficient and highly concentrated fibrin glue by thawing single-donor fresh frozen plasma. Using a unique animal model, in which arterial bleeding was created, fibrin glue and some related hemostatic agents were tested to evaluate their hemostatic effectiveness. The results demonstrated that: 1) the concomitant use of cryoprecipitate-thrombin tissue glue with adjuvant (aprotinin or calcium chloride) had a better hemostatic effect than the use of cryoprecipitate-thrombin tissue glue alone (p < 0.05); 2) impregnation of fibrin glue with a suitable vehicle was advisable to accelerate the coagulation plug formation and to enhance the mechanical strength of the adhesive plug; 3) Gelform, used as a vehicle to hold the fibrin glue, had a more efficient hemostatic effect than gauze, collagen fleece and Surgicel (p < 0.05); 4) systemic heparinization attenuated the effectiveness of the hemostatic agents and aggravated the bleeding problem, but a low hematocrit level did not; 5) fibrin glue had its own limitations, especially under systemic heparinization, on hemostatic effectiveness in a high-pressure system. Understanding the characteristics of fibrin glue, as mentioned above, definitely improved the hemostatic effectiveness of the glue, especially after failure of the usual methods of controlling bleeding.


Characterization of a newly established human bladder carcinoma cell line, NTUB1.

A new human bladder cancer cell line, NTUB1, has been derived from the surgical specimen of a 70-year-old female patient diagnosed with poorly differentiated transitional cell carcinoma. It has been successfully propagated in vitro for over 24 months without evidence of reaching senescence. Population doubling time was about 21 hours at the 32nd passage. It was tumorigenic in nude mice, and the histologic findings of the heterotransplanted tumor resembled the original tumor. Expression of keratin proteins confirmed its epithelial origin. Cytogenetic analysis showed multiple chromosome changes. Anticancer drugs, including thiotepa and adriamycin, were tested in vitro, and the cytotoxicity did not exceed 50% of the control value; likewise, in this patient chemotherapy was not effective. On the other hand, a combination of recombinant tumor necrosis factor and interferon tau in vitro was more effective against this tumor.


Evaluation of the A-60 IgG ELISA serodiagnostic test for tuberculosis in Taiwan.

To assess the applicability of a serologic test of specific IgG antibody for tuberculous infection in the Taiwan population, serum samples obtained from 118 subjects were analyzed by an ELISA test using mycobacterial antigen 60. There were 50 patients with a documented active infection caused by Mycobacterium tuberculosis (39 pulmonary tuberculosis, five pleurisy, three cervical lymphadenitis and three miliary tuberculosis with extrapulmonary involvement). Of these 50 patients, 42 (84%) showed a positive ELISA test (titer > 200 U). Of the 19 patients with inactive pulmonary tuberculosis, seven (37%) had a positive titer. Of the 22 patients with pulmonary disease other than tuberculosis, four (18%) showed a false-positive. In eight patients with autoimmune diseases, only the patient with rheumatoid arthritis had a positive reaction. One of the 19 healthy controls (5.3%) showed a false-positive result. The overall false-positive rate for the nontuberculous group was 12%. Follow-up examinations in 20 patients with active tuberculosis one month after treatment revealed that seven had an elevation in titers (three of them were initially negative and became positive later), five remained high and eight decreased in titers. Further examinations in six patients two months after treatment showed a decrease in titers. We conclude that this ELISA assay of specific IgG antibody is a valuable serologic test for diagnosis of M. tuberculosis infection. It may be useful in areas with a high prevalence of M. tuberculosis infection.


Gestational and congenital syphilis in Hualien.

From September 1987 to April 1991, 19 pregnant women (0.97%) with syphilis were detected out of 1,955 pregnant women who received prenatal serologic screening at the Buddhist Tz'u-Chi General Hospital. The ages ranged from 17 to 34 years (average, 26). Three cases had recurrent gestational syphilis. The time of diagnosis was: the third trimester, 11 cases; the second trimester, six cases; and the first trimester, two cases. The reasons for late (third trimester) diagnosis were: delay of prenatal care, four cases; failure to screen syphilis in the pregnancy, four cases; and negative first test and late infection, three cases. Late diagnosis and treatment often resulted in poor fetal outcome: syphilitic stillbirth, two cases; probable and possible congenital syphilis, seven cases; and normal infant, two cases. Patients (delivered, five; undelivered, two; abortion, one) who had been diagnosed before the third trimester had a better fetal outcome: possible congenital syphilis, one case; and normal infant, four cases. The perinatal mortality and morbidity were significantly higher in the late diagnosis group (9/11) than in the early diagnosis group (1/5). Pregnant women should be screened in early pregnancy by a serologic test for syphilis. In areas of high prevalence, or in patients at high risk, screening should be repeated in the third trimester and again at delivery.


Aicardi's syndrome in a female infant with a family history of miscarried male siblings.

Aicardi's syndrome is thought to be an X-linked genetic disease, although the mechanism for transmission remains uncertain. We report on a four-month-old female patient with Aicardi's syndrome. She was born prematurely at 28 weeks' gestation, weighing 1,500 g. Asymmetric myoclonic jerks developed at one month of age. Her left eye showed chorioretinal lacunae and a coloboma on the optic disc, while the right eye was microphthalmic with total retinal detachment. A CT scan disclosed heterotopia and dysgenesis of the corpus callosum. Abnormal development of the thoracic vertebrae was also evident. The most remarkable aspect of this case was that the patient's mother had suffered three miscarriages. Two are known to have been male, but the other gender is unknown. This family history may support the theory that there is a factor, lethal for males, involved in the genetic transmission of Aicardi's syndrome.


Resolution of cerebral white matter lesions following long-term penicillamine therapy for Wilson's disease: report of a case.

Although lenticular gray matter lesions in Wilson's disease (WD) may resolve following long-term decoppering therapy, response of cerebral white matter lesions to such a treatment has not been reported. A patient with WD developed dystonia of the left hand and focal seizures involving the left upper limb with occasional generalization. CT disclosed a low density area in the right frontal white matter. Initiation of penicillamine therapy resulted in worsening of clinical manifestations, further extension of the right frontal lesion, and development of a new left parietal lesion. However, after five years of continued penicillamine therapy, clinical improvements were noted, including disappearance of the left parietal lesion and almost complete resolution of the right frontal lesion. The present case suggests that cerebral white matter lesions in WD may also respond to long-term chelating therapy.


Chronic recurrent multifocal osteomyelitis: report of a case.

We report on a Chinese boy with chronic recurrent multifocal osteomyelitis (CRMO). The eight-year-old boy presented with intermittent exacerbation and spontaneous remission of bone pain at two bone sites, associated with local erythema, swelling and tenderness. The white blood cell count, erythrocyte sedimentation rate, alkaline phosphatase, lactate dehydrogenase, calcium and phosphate were normal or mildly elevated. The roentgenogram and scintigram were consistent with osteomyelitis. The pathologic feature of the bone biopsy specimens was compatible with osteomyelitis. However, no organisms were consistently isolated from culture, and the disease was unaffected by antimicrobial therapy. CRMO is an uncommon childhood disease of still unknown etiology. It is the purpose of this paper to present our experience with the first case in a Chinese person and to review the literature with a discussion of what is currently known about CRMO.


Internal mammary artery to pulmonary artery fistula associated with sick sinus syndrome: report of a case.

A 77-year-old woman presented with general weakness, dizziness and slow, irregular heart beats. An electrophysiologic study revealed a markedly prolonged sinus node recovery time of up to 5,900 msec, accompanied with dizziness. A permanent pacemaker with an AAIR mode was implanted. An abnormal shadow in the right lower lung field was found on chest x-ray. Selective arteriography revealed a right internal mammary to right pulmonary artery fistula. No significant hemodynamic abnormalities were found. This anomaly is extremely rare. Our patient is the oldest among 20 cases reported in the literature, and is the first one associated with sick sinus syndrome. Most reported cases have involved surgical ligation and excision, due to the risk of rupture of the malformation, endarteritis and congestive heart failure. Our patient refused surgical intervention and has done well during the past year.


Desmoplasia and regression of lung adenocarcinoma after intratumor injection of OK-432: report of a case.

Intratumor injections of an immune modulator, OK-432, were administered to a 61-year-old man with inoperable lung adenocarcinoma. He received intratumor injections of OK-432, 20 K.E., twice weekly, under chest ultrasound guidance. A total dose of 240 K.E. was given in a six-week period. The tumor size decreased during a six-month follow-up period after the OK-432 injections. The immunologic profile of the patient showed neutrophilia, a decrease in the lymphocyte count in the peripheral blood and an increase in immunoglobulins after the OK-432 injections. The peripheral T-lymphocyte subsets showed a significant reduction in cytotoxic T cells and a decrease in the OKT4/OKT8 ratio. Histologic examination of the tumor after OK-432 injections showed extensive desmoplastic fibrosis. There was no evidence of lymphocyte infiltration. Intratumor injections of OK-432 may be an alternative for local control of inoperable lung cancer.


Familial nephrogenic diabetes insipidus: report of two families.

Familial nephrogenic diabetes insipidus is a hereditary disorder, generally transmitted by sex-linked recessive genes with varying degrees of penetrance in females. The onset of this disorder occurs in infancy, usually characterized by unexplained fever, recurrent dehydration and failure to thrive. If left unrecognized, recurrent hyperosmolality and hypernatremia will lead to retarded growth and neurologic sequelae. Intracranial hemorrhage, consciousness disturbance and even mortality may occur in cases of acute dehydration episodes. We report on two families with nephrogenic diabetes insipidus, whose various symptoms and signs were studied to establish an accurate diagnosis. In pediatric practices, it is very important to recognize early those infants with obscure symptoms in order to preserve their psychomotor development and growth potential.


Sciatica caused by piriformis muscle syndrome: report of two cases.

The diagnosis of piriformis muscle syndrome, an unusual cause of sciatica, is difficult. However, with the advancement of imaging techniques, it has become clear that the condition is not just clinical speculation, but is a definite entity. We report on two cases with piriformis muscle syndrome, diagnosed on the basis of: a history of sciatica; physical findings, such as a tender point at the sciatic notch and around the piriformis muscle by palpation of the gluteal region, and by a digital pelvic examination; and computed tomography (CT) to demonstrate hypertrophy of the piriformis muscle. In both cases, a tenotomy of the piriformis muscle at the greater trochanter relieved entrapment of the sciatic nerve and gave satisfactory results. Since local tenderness at the piriformis muscle is the most reliable physical finding, a pelvic examination is recommended in the evaluation of suspected cases of piriformis muscle syndrome. CT is helpful in showing hypertrophy of the piriformis muscle. Detailed history taking, a careful physical examination, and versatile use of CT or magnetic resonance imaging can lead to an early, accurate diagnosis and proper treatment.


[Projected supply and geographic distribution of physicians in Taiwan for the year 2000].

Using the data from the Physician Masterfile of the Department of Health, Executive Yuan, and reports from all of the medical colleges in Taiwan and the Ministry of Defense, this study projects the future supply of physicians as well as their geographic distribution. The components of the projection include a study of current supply, future increments and losses. Three sources of future increments are identified: new native medical graduates, foreign medical graduates and medical transfers from the military. Age-specific and year-of-graduation-specific active rates are used to estimate losses. The results of this study show: There will be 25,956 active physicians in Taiwan by the year 2000, or 118 physicians per 100,000 people; and the ratio of the highest to the lowest (Taipei city vs Yunlin county) in terms of the physician-population ratio will become worse from 4.5 in 1990 to 5.4 in 2000, ceteris paribus. Finally, this study discusses the projection process as well as the implications for the physician manpower policy in Taiwan.


[A clinicopathological study in primary biliary cirrhosis].

Twenty-two patients with clinical, biochemical, immunological and pathological characteristics compatible with primary biliary cirrhosis were studied. There were 17 women and 5 men with a mean age of 57.4 +/- 15.2 years and a mean follow-up of 24.1 +/- 20.1 months. Four of them expired during the follow-up and eighteen patients now survive. The most common complaints were fatigue (63.6%) and itching (59.1%). Only one case (4.5%) was asymptomatic in this series. The major physical findings were jaundice (50%) and hepatomegaly (50%). The significant laboratory findings were: elevation of alkaline phosphatase (91% of the cases greater than 3 times the upper limit of normal), gamma-glutamyl transpeptidase (100% of the cases greater than 4 times the upper limit of normal), aspartate transaminase (95%) and alanine transaminase (100%), presence of anti-mitochondrial antibodies (91%), antinuclear antibodies (73%) and the elevation of IgM (88%). One case was associated with ulcerative colitis. Pathological staging in this series revealed 57.9% of stage II, 26% of stage III, 10% of stage IV and 5.3% of stage I. All patients with granuloma survived but 4 of the 5 patients with cholestasis died during follow-up. The results show that the features in this series of PBC were similar to those observed in western countries. The very high ALP and gamma-GT level as well as only one asymptomatic case in this series, suggest that our patients were diagnosed at a late stage. The reason(s) for the higher positivity of ANA, particularly the speckled type and a lower rate of associated auto-immune disease requires further study. Liver biopsy in predicting a prognosis is valuable.


[Factors in recurrence after curative resection of rectal cancer].

Data on 409 Patients who had a curative resection for rectal cancer at the National Taiwan University Hospital between 1977 and 1989 were analysed to determine the independent effect on recurrence. In our series, the total operative mortality rate was 1.7% and the resectability rate was 88.1%. For these cases who received curative resection, the overall 5-year survival rate was 62.6%. The 5-year survival rate varied according to the Dukes' stage: stage A, 96.4%; stage B, 73.3% and stage C, 39.6%. The total recurrence rate after curative resection was 35.9%, including local recurrence 18.3%, systemic recurrence 12.0%, and combined recurrence 5.6%. According to Dukes' staging system, the recurrence rate for stage A, B and C were 0%, 22.4% and 63.8%, respectively. We used Cox's regression model to analyse the patients characteristics and pathological variables on recurrence and to assess the independent influence of each when all other factors were held constant. The pathological stage of the cancer had the strongest association. Other variables found to have an independent yet significant importance, were CEA level and tumor size. The identification of the patient group, at a high risk of recurrence, might promote a more judicious selection for surgical procedure and trials of adjuvant therapy.


[Dento-facial structural characteristics in Angle Class II malocclusion associated with abnormal facial divergency].

Lateral cephalometric radiographs of 60 adult patients with Angle class 11 malocclusion associated with abnormal facial divergency were collected from the Orthodontic Department of the National Taiwan University Hospital. They were divided into a hyperdivergent group (35 cases) and a hypodivergent group (25 case), according to mandibular plane angle (SN-MP). The 19 landmarks on each cephalometric tracing were digitized into a computer, then computer-aided cephalometric analysis was performed to calculate the 17 skeletal measurements and 13 dentoalveolar measurements. The dento-facial structural characteristics of the hyperdivergent and hypodivergent groups were compared. It was found that the subjects of the hyperdivergent group revealed a greater tendency of divergency in the anterior cranial base plane, Frank-fort horizontal plane, palatal plane, occlusal plane, and mandibular plane. Hyperdivergent facial type, supposedly indicating an open bite or a tendency toward an open bite, has a longer lower anterior facial height, shorter posterior facial height, longer upper anterior and posterior dental height. While, the majority of dentofacial characteristics of the hypodivergent facial type observed in is study were directly opposite to those of the hyperdivergent facial type. The relationships of incisor overbite depth and other skeletal and dentoalveolar parameters were illustrated by Pearson's correlation coefficient and stepwise multiple regression analysis by means of the SPSS/PC statistic program. With the incisor overbite depth as the dependent variable, the independent variables included on the regression analysis were the 10 items of skeletal and dentoalveolar parameters. The compared parameters showed a statistically significant correlation with the incisor overbite depth (P < 0.001). By the stepwise method, the variables included on the regression equation were (1) N-Go-Gn, (2) A-Gn-Ar, (3) N-Ans/ans-Me, and (4) U1L1. The value of R square (R2) in the regression analysis was 0.543. It demonstrated that only a 54.3% variation in incisor overbite depth can be explained by variations in those skeletal and dentoalveolar variables.


[Mouse embryos co-cultured with various generations of human ampullary cells].

The pregnancy rates for the gamete intra-fallopian transfer (GIFT) and tubal embryo transfer (TET) methods have been shown to be high. The oviductal environment appears to be suitable for fertilization and subsequent cleavage. Many authors have reported that when co-cultured with human ampullary cells, the embryos can develop in vitro as well as in vivo. Thus, significantly more embryos reach the early blastocyst stage, and more successful implantation may be obtained. However, the characteristics of the ampullary cells may change after a series of sub-cultures. In this study, we compared the first and the seventh sub-culture ampullary cell co-cultured systems with a control group. There were significantly more embryos cleaved to blastocysts in these two co-cultured systems than in the control group, but no significant difference between these two co-cultured systems. Detoxification of the medium by co-cultured cells may play an important role in improving embryo quality.


[Peutz-Jeghers syndrome: report of two cases and review of the literature].

Two cases brothers of Peutz-Jeghers syndrome are reported, in which the gastrointestinal polyps were resected by laparotomy and enterotomy. One of the polyps was in the cecum and was found to have atypia cellular change, though no malignancy was found in the others, which were thought to be hamartomas. The hamartomatous polyps were initially thought to have little potential for malignancy, and the disease was believed to have a relatively benign course. However, reports in the literature have associated this syndrome with various kinds of malignancies, and the overall risk of cancer in this population is regarded as higher than normal. The analysis of our cases and a review of the literatures are presented for clarification of the predisposition of the development of malignancies in these patients.


[Kaposi's sarcoma in Tainan: report of five cases].

Kaposi's sarcoma (KS) is an uncommon cutaneous neoplasm with an increased incidence among Jews and Italians of Europe and North America and Negroes of equatory Africa. In recent years, several cases have been diagnosed in AIDS patients and in patients who have undergone organ transplantation or received immunosuppressant treatments. We have diagnosed five cases of KS over a 3-year period in our department. They include four men and one women, aged from 58 to 79 years, and who were born and had lived in Tainan. They all denied a history of homosexuality, multiple sexual partners, or drug abuse. HIV (Human immunodeficiency virus) screening test were negative. Two patients had taken 'black pills' (usually containing steroids) for a long period of time and also had generalized dermatophytosis. One of these two patients had a cytomegalovirus infection and died of Salmonella septicemia and upper GI bleeding. Although the English literature seems to indicate that KS is rare among Asians. Our present experience coupled with two other recently reported cases from Taiwan and the unpublished observations of some other dermatologists suggest that KS is not all that rare in Taiwan.


[Continuous arteriovenous hemodialysis in critical patients with acute renal failure].

Continuous arteriovenous hemodialysis (CAVHD) offers a modified therapeutic approach for the patient with acute renal failure. The system is modified fron the CAVH write out method by adding two pumps to control the flow rate of the dialysis solution and to reduce the nursing load. The blood flow through the dialyzer is dependent on the net blood pressure gradient. Peritoneal dialysis or bicarbonate dialysate is infused through the dialysate ports utilizing both diffuse and convective transport for an average blood flow rate of 0.9 L/hour. The two pumps control the dialysate inflow and outflow rates. Ten patients with complications and acute renal failure were treated with CAVHD for periods ranging from 10 to 154 hours. Average urea clearance was 9.39 mL/min. Average creatinine clearance was 9.12 mL/min, and in stable patients, the mean BUN was maintained at 60 mg/dL and the mean serum creatinine level was 4.6 mg/dL. The average ultrafiltration rate obtained was 100 mL/hr and was adjusted for the body fluid condition. most patients tolerated CAVHD without further hemodynamic instability and did not develop serious complications. In conclusion, CAVHD is a safe and technically simple procedure, which is particularly suitable for hemodynamically unstable patients requiring fluid removal.


[Laparoscopic orchiectomy for intraabdominal cryptorchism and varicocelectomy].

Laparoscopic procedures have recently been used in the evaluation and treatment of some urogenital diseases. A case of right intraabdominal cryptorchism associated with left varicocele was successfully treated by laparoscopic orchiectomy and ligation of the contralateral internal spermatic vein concomitantly. This new technology can be easily performed and has the advantages of less tissue trauma, easy application for bilateral lesions, and less patient morbidity. We consider laparoscopy is a promising method for the diagnosis and treatment of intraabdominal testis.


[CT and MRI of parasellar cavernous hemangioma in two cases].

Extracerebral cavernous hemangioma is a rare entity, only 51 cases have been reported up to 1991. Most of the extracerebral cavernous angiomas occur in the parasellar region and easily extend to the sella; with CT and MRI views entirely different from those of intracerebral cavernous hemangiomas. The CT scan shows a good, homogeneous enhanced tumor, similar to a meningioma, yet lacking calcification or bony hyperostosis. In MRI, the characteristic findings of extracerebral cavernous hemangioma are the very high signal intensity in the T2 weighted image, and strong homogeneous enhancement by Gadolinium-DTPA. Here we report two cases of parasellar cavernous hemangioma. A 68-year-old male patient shown to have a dumbbell tumor in the parasellar and sellar regions by CT scan, showed a high density before contrast, and good enhancement by an iodine contained contrast medium. The tumor had a very high signal intensity in the T2 weighted image of MRI and a good, homogeneous enhancement by Gadolinium-DTPA, yet a carotid angiogram showed it was avascular. Surgical removal was abandoned in view of the probability of massive bleeding. The second case was a 34-year-old man, who had had a skin hemangioma on the right side of the face since his childhood. For the past 3 months, he had suffered from ptosis, and limitation of eye movement which was found to be due to 3rd and 4th cranial nerve palsy. CT showed a good enhanced tumor mass in the left side of the parasellar region with sellar extension. MRI also showed a high intensity in T2WI and good, homogeneous enhancement by Gadolinium-DTPA. A carotid angiogram revealed some tumor stain. Surgical removal. in this case, was also impossible due to its intracavernous sinus location and the probability of massive bleeding.


[Study on P450c21 gene].

Yeast cells harboring mutant plasmids were incubated with 0.1, 0.15, 0.2, 0.3, 0.4, 0.45, 0.6, or 1.0 mM (14C)-17-hydroxyprogesterone for 1h. The steroids in the media were then separated by thin layer chromatography and counted to calculate enzymatic activities. Wt = wild type enzyme. Pt: patient enzyme.


[Willingness to share costs of health insurance].

The purpose of this investigation, undertaken in 1988, was to find out citizens' willingness to share the costs of health insurance in metropolitan Taipei. The individuals sampled were from three groups: government employee insurer GEI, Labor insurer LI, and others OT. A stratified random sampling method and a closed-format questionnaire were used in this study. A total of 300 samples were taken from GEI, 500 form LI and 300 from OT. The total number of effective questionnaires were 1065. The questionnaire had 8 parts including individual basic data, consciousness of self health conditions, knowledge of LI, knowledge of GEI, degree of satisfaction with medical services, medical care utilization, willingness of health insurance, and willingness to share costs. The results showed that most people pay, most respondents would only be willing to pay a limited amount. The different factors positively influencing a willingness to cost share were level of education, average income and knowledge of health insurance, while the degree of satisfaction towards medical services was a negative influence. Since the public is not yet willing to accept a cost-sharing system, this study was of limited value in trying to find out the explanatory or predicting factors. Nevertheless, because of the negative reactions of respondents, we are obliged to more carefully and circumspectly rethink the implementation of a cost-sharing system.


General practitioners' management of hypertension in elderly patients.

To assess general practitioners' attitudes to the diagnosis and management of hypertension in elderly patients. Postal questionnaire to all general practitioners in Leicestershire. 360 of 451 general practitioners (80%) responded. 81% (292) reported rechecking an initially high blood pressure on two or three occasions before starting treatment, 56% (202) measured sitting blood pressure only, and just 28% (100) took sitting and standing levels. 36% (128) had no upper age limit for starting anti-hypertensive treatment; of the 58% (206) who did, the median was 80 (range 70-99) years. Blood pressure levels reported for starting treatment in patients aged 70-79 years were 180 (150-240)/106 (90-120) mm Hg. 34% of general practitioners (121) would not treat isolated systolic hypertension. The most popular first line treatment for an elderly hypertensive patient was a thiazide diuretic; only 17% of general practitioners (61) initially tried non-pharmacological methods. 34% (122) would continue anti-hypertensive treatment unchanged in the period immediately after stroke. The variation among general practitioners in the criteria for the measurement, diagnosis, and treatment of hypertension in elderly patients emphasises the need for clear management guidelines in this age group.


Experience with peripheral blood stem cell collection for autografts in children with active cancer.

This report examines laboratory and clinical experience with peripheral blood stem/progenitor cell harvest for autografts in 71 consecutively referred children with various types of cancer from one institution. The age of the patients ranged from 7 months to 17 years with a median of 8 years. Ten of the 71 referred children were removed from the collection procedure because of failure to induce clinical remission (nine) or deteriorating chemotherapy-induced liver failure (one). A total of 215 aphereses were performed on a CS 3000 cell separator in 61 patients, including 18 children aged 4 years or less. The methylcellulose progenitor assay was used as an index of stem cell collection. A minimum of greater than or equal to 3 x 10(5) colony-forming units-granulocyte/macrophage (CFU-GM)/kg body weight were collected in 31 of 71 children (44%) with a mean of 3.1 (range, 1-5) aphereses, and greater than or equal to 1 x 10(5) CFU-GM/kg in 46 children (65%). The incidence of serious morbidity was low. When apheresis or chemotherapy was repeated, the progenitor yields decreased rapidly. By multivariate analysis, the age of the patients was the only significant predictor of CFU-GM yield (p = 0.009). In our experience with 12 children with acute leukemia or non-Hodgkin's lymphoma, regimens containing high-dose cytarabine (2.0 g/m2 x 10) were effective for mobilization. Our results extend the earlier findings that harvesting PBSCs for autografts in children with active cancer is a safe and reliable procedure with a low incidence of serious morbidity.


Prompt haemopoietic reconstitution following hyperthermia purged autologous marrow and peripheral blood stem cell transplantation in acute myeloid leukaemia.

We report a case of acute myeloid leukaemia in a 35-year-old woman where marrow and chemotherapy-mobilized peripheral blood stem cells (PBSC) were obtained in first complete remission and heat treated at 42 degrees C for 1 h to minimize the likelihood of leukaemic relapse. Transplantation of marrow and PBSC was undertaken following busulphan/cyclophosphamide conditioning 9 months after diagnosis in CR1. Hyperthermic purging did not impair the rate of engraftment and the patient was independent of blood product support by day 21. Studies on this patient's committed normal granulocyte-macrophage progenitor cells (CFU-GM) on samples from marrow and peripheral blood following treatment at 42 degrees C for 1 h, showed minimal and acceptable loss of activity comparable with the loss seen in other marrow progenitor activity treated in a similar fashion in our laboratory. We conclude that hyperthermia-purged PBSC can be used to hasten recovery in autologous haemopoietic progenitor transplantation without compromising rate of engraftment. This is part of an ongoing pilot study to evaluate the role of hyperthermic purging to reduce the risk of leukaemic relapse.


[The effect of an alpha-adrenoblocker and a calcium-channel blocker on the spontaneous tonus of an isolated blood-perfused artery].

The existence of spontaneous myogenic tone was shown on an experimental model of an isolated artery perfused "ex vivo" with blood from the rat donor. Administration of the alpha-adrenoblockers prasosine and yohimbine into the perfusion medium in the bath was followed by a 60% decrease in the myogenic tone. The nonspecific blocker of calcium channels CaCl2 decreased the rest of the tone by 15%. The remaining 20-25% of the initial myogenic tone was inhibited by sodium nitroprusside. Urethane (300 mg/kg) or nembutal (20 mg/kg) injected intravenously into the rat donor may lead to an increase or a decrease in the myogenic tone, respectively. The conclusion is made that the advantage of the experimental model proposed lies in the existence of the spontaneous myogenic tone of an arterial vessel depending on humoral catecholamines and some other vasoconstrictor factors.


[The mechanism of the antiarrhythmic action of dalargin in experimental myocardial ischemia].

It has been found that injection of dalargin before the occlusion of the left anterior coronary artery prevents an increase of cAMP content in the myocardium and blood plasma. In the myocardium of rats given dalargin before acute myocardial ischemia, the content of cGMP was increased and the level of somatostatin was reduced. It is assumed that the increase of the content of cGMP and the reduction of cAMP and somatostatin levels in the myocardium play an important role in antiarrhythmic action of dalargin.


Characterization of adrenoceptors involved in the electrogenic chloride secretion by cultured rat epididymal epithelium.

1. Short-circuit current (SCC) technique was used to study the adrenoceptors involved in the electrogenic chloride secretion by cultured cauda epididymal epithelium of rats. Stimulation of the epithelium with noradrenaline (primarily beta 1-adrenoceptor selective agonist), salbutamol (beta 2-adrenoceptor selective agonist) and adrenaline (non-selective beta-adrenoceptor agonist) led to a rise in SCC. At a low chart-speed (2 mm min-1), the response profile to these agonists consisted of a peak followed by a sustained response considerably higher than the basal SCC. 2. The EC50s (doses of agonist producing 50% maximum response) of noradrenaline, salbutamol and adrenaline were 300, 115 and 10 nM respectively. Pretreating the tissues with 1 microM atenolol (beta 1-selective antagonist) and 10 microM butoxamine (beta 2-selective antagonist) shifted the dose-response curves of noradrenaline (shifted EC50 = 4000 nM) and salbutamol (shifted EC50 = 1050 nM) to the right. Atenolol (1 microM) and butoxamine (10 microM) shifted the dose-response curve of adrenaline to the right with new EC50s of 30 nM and 115 nM, respectively. 3. The rapidly rising phase of the SCC response to noradrenaline and adrenaline observed at low chart-speed consisted of a brief and transient retraction followed by a rebound increase in SCC. At a high chart-speed (1 mm s-1), the retraction and rebound phenomenon manifested as a fast initial spike which could be blocked by phentolamine (non-specific alpha-adrenoceptor antagonist) in a dose-dependent fashion. Similar initial spikes were observed when the tissues were stimulated with phenylephrine (alpha-selective agonist) but not with isoprenaline (non-selective beta-agonist) or forskolin (activator of adenylate cyclase). The response of the initial spike triggered by noradrenaline was dose-dependent and the EC50 was 2000 nM.4. The present study showed that the electrogenic chloride secretion by rat epididymis could be stimulated by (alphaxi-, beta131- and beta2-adrenoceptor agonists. The al-mediated response had a faster onset and more transient action than the 3-counterpart. It is postulated that epididymal chloride secretion might be regulated by neural (noradrenaline-mediated) and humoral (adrenaline-mediated) controls and that the stimulus-secretion coupling mechanisms might involve both Ca2+(alpha-mediated response) and adenosine 3':5'-cyclic monophosphate (beta-mediated response) as intracellular second messengers.


[The effect of the new nonsteroidal anti-inflammatory agent glucamine on oxidative phosphorylation processes].

A study was made of the action of the nonsteroidal antiinflammatory agent glucamin on the processes of oxidation and phosphorylation (OP) in isolated mitochondria of the liver. It has been established that glucamin does not exhibit the properties of a separator in the explored concentrations (10(-2)-10(-7) M). Unlike the standard drug voltaren that separates OP processes, it slightly enhances interaction of liver mitochondria which oxidize NAD-dependent substrates. The effect of voltaren is dose-dependent, being pronounced to a greater measure when succinate is applied as a substrate of mitochondria oxidation.


The effects of beta 2-adrenoceptor agonists and a corticosteroid, budesonide, on the secretion of inflammatory mediators from monocytes.

1. The in vitro effects of the beta 2-adrenoceptor agonists (1 x 10(-9)-10(-5) M), terbutaline, salmeterol, and formoterol, on the release of inflammatory mediators, i.e. the eicosanoids leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) and the cytokine interleukin-1 beta (IL-1 beta), were assessed in cultures of human blood monocytes. For comparison, the effects of a 5-lipoxygenase inhibitor, BW A4C (1 x 10(-9)-10(-5) M), and a corticosteroid, budesonide (1 x 10(-10)-10(-5) M) were also examined. Sotalol was used to investigate whether the actions of beta 2-agonists were mediated through beta-adrenoceptors. 2. Terbutaline, like budesonide, had no significant effect on LTB4 release, whereas BW A4C (IC50 = 2 x 10(-8) M) was a potent inhibitor. All concentrations of formoterol approximately halved the LTB4 secretion, whereas high concentrations (1 x 10(-7)-10(-5) M) only, of salmeterol, inhibited release. Only salmeterol, at high concentrations (greater than 1 x 10(-6) M), lowered the secretion of PGE2 in monocyte cultures. Formoterol and salmeterol reduced the secretion of IL-1 beta only at the highest dose (1 x 10(-5) M). In contrast, budesonide (greater than or equal to 1 x 10(-9) M) was a potent suppressant of this secretion. 3. Treatment of monocyte cultures with sotalol (1 x 10(-5) M) did not significantly antagonize the inhibitory effects of salmeterol and formoterol. These results suggest that the inhibitory action of these beta 2-agonists on the release of eicosanoids or IL-1 beta, is not mediated via beta 2-adrenoceptors.4. This study does not support a therapeutic importance of the anti-release effects of beta2-agonists since high concentrations were generally required. Furthermore, the anti-secretory action of beta2-agonists was distinct from that of corticosteroids.


Involvement of nitric oxide pathway in the PAF-induced relaxation of rat thoracic aorta.

1. The mechanism of the vasorelaxant effect of platelet activating factor (PAF) on rat thoracic aorta and the effect of aging on the PAF-induced relaxation were investigated. 2. PAF at concentrations causing relaxation induced marked increases in guanosine 3':5'-cyclic monophosphate (cyclic GMP) production, but did not induce an increase in adenosine 3':5'-cyclic monophosphate (cyclic AMP). 3. Removal of the endothelium by mechanical rubbing, and treatment with the PAF antagonists CV-3988, CV-6209 and FR-900452, the nitric oxide biosynthesis inhibitor, NG-nitro L-arginine, the radical scavenger, haemoglobin, and the soluble guanylate cyclase inhibitor, methylene blue, inhibited PAF-induced relaxation and abolished or attenuated PAF-stimulated cyclic GMP production. 4. The relaxation was greatest in arteries from rats aged 4 weeks. With an increase in age, the response of the arteries to PAF was attenuated. 5. Endothelium-dependent cyclic GMP production also decreased with increase in age of the rats. 6. These results suggest that PAF stimulates production of nitric oxide from L-arginine by acting on the PAF receptors in the endothelium, which in turn stimulates soluble guanylate cyclase in the smooth muscle cells, and so increases production of cyclic GMP, thus relaxing the arteries. Age-associated decrease in PAF-induced relaxation may result from a reduction of cyclic GMP formation.


Determination of alpha 1-adrenoceptor subtype selectivity by [3H]-prazosin displacement studies in guinea-pig cerebral cortex and rat spleen membranes.

1. [3H]-prazosin homogeneously labels alpha 1-adrenoceptors in guinea-pig cerebral cortex and rat spleen membranes with dissociation constants of 1.28 and 1.49 x 10(-10) M respectively. 2. Phentolamine and WB 4101 displacement studies show that guinea-pig cerebral cortex contains 30% alpha 1A- and 70% alpha 1B-adrenoceptor subtypes, whereas rat spleen contains a virtually homogeneous alpha 1B-adrenoceptor subtype population. The alpha 1-adrenoceptor population of rat thoracic aorta is predominantly of the alpha 1A-adrenoceptor subtype, and in guinea-pig thoracic aorta it is mainly of the alpha 1B-adrenoceptor subtype. 3. Half of the compounds displacing [3H]-prazosin bound to guinea-pig cerebral cortex membranes display alpha 1A-adrenoceptor selectivity. Among these compounds, WB 4101 and methoxamine are most selective, displaying selectivity ratios of approximately 38 and approximately 26 respectively. 4. The affinity constants of the non-selective compounds for the alpha 1-adrenoceptor in guinea-pig cerebral cortex membranes correlate well with the affinity constants obtained for alpha 1B-adrenoceptors in rat spleen membranes. The affinities of selective compounds for the alpha 1B-adrenoceptor subtype in guinea-pig cerebral cortex correlate very well with their affinity for alpha 1B-adrenoceptor in the rat spleen homogenate. Both regression lines coincide with the line of identity. The affinity constants of selective compounds for the alpha 1A-adrenoceptors in guinea-pig cerebral cortex only apparently correlate with the affinity for either the alpha 1B-adrenoceptors in guinea-pig cerebral cortex or in the rat spleen. Regression analyses indicate a straight line relationship (r2>0.9) between pKEA and Pk1B but the regression lines deviate from the line of identity.


Different patterns of protein kinase C redistribution mediated by alpha 1-adrenoceptor stimulation and phorbol ester in rat isolated left ventricular papillary muscle.

1. In rat left ventricular papillary muscle, phenylephrine, an alpha 1-adrenoceptor agonist, had a staurosporine-sensitive positive inotropic effect and increased the particulate-associated protein kinase C (PKC) activity without significant changes in total PKC activity or in cytosolic Ca2+/phospholipid-independent kinase (PKI) activity. 2. A PKC stimulant, phorbol 12,13-dibutyrate (PDBu), decreased contractility and slightly increased PKC activity in the particulate fractions, with a marked decrease and increase in total PKC and PKI activities, respectively. 3. The PDBu-induced negative inotropic response was attenuated by two protease inhibitors, leupeptine and a microbial peptide isolated from Aspergillus japonicus (E-64), which are known to inhibit the conversion of particulate-associated PKC to PKI. 4. Such differences in the patterns of PKC redistribution, i.e. marked increases in particulate PKC and cytosolic PKI activities caused by phenylephrine and PDBu, respectively, may account for the opposite inotropic effects of PKC stimulation by an alpha 1-agonist and a phorbol ester.


The alpha 2-adrenoceptors of the human retinoblastoma cell line (Y79) may represent an additional example of the alpha 2C-adrenoceptor.

1. In agreement with the literature, correlation of the ability of a series of agonists and antagonists to displace [3H]-rauwolscine binding shows the alpha 2-adrenoceptors of HT29 cells, NG108-15 cells, OK cells and homogenates of rat sublingual gland to represent four distinct subtypes. 2. [3H]-rauwolscine also bound with high affinity (KD = 0.30 +/- 0.10 mM) to a human retinoblastoma cell line (Y79). Specific binding represents 73% of total binding, and a Bmax of 38 +/- 1 fmol mg-1 protein was determined. 3. Correlation of antagonist affinities against [3H]-rauwolscine with corresponding values in the other four tissue sources showed the Y79 cells to resemble most closely the OK cells, the prototype example of an alpha 2C-adrenoceptor, with a correlation coefficient of 0.90 and a regression slope of 1.01 being obtained for 10 antagonists in these two systems. 4. Comparison of KD values for [3H]-rauwolscine also showed a similarity between the OK cells (0.19 +/- 0.07 nM) and Y79 cells. 5. These data suggest that the human retinoblastoma cell line may represent an additional example of the alpha 2C-adrenoceptor subtype.


Pharmacological characterization of presynaptic alpha 2-autoreceptors in rat submaxillary gland and heart atrium.

1. The pharmacological properties of presynaptic alpha 2-autoreceptors were studied in rat isolated submaxillary glands and atria. Tissue pieces were preincubated with [3H]-noradrenaline, then superfused with medium containing desipramine, and stimulated electrically. In one series of experiments, pEC30 values of 12 alpha-adrenoceptor antagonists were determined, i.e., negative logarithms of concentrations that increased the electrically evoked overflow of tritium by 30%. In another series, pKD values of 9 alpha-adrenoceptor antagonists against the release-inhibiting effect of 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14304), and of 3 antagonists against the release-inhibiting effect of methoxamine, were determined. 2. In submaxillary glands, the pEC30 values of the antagonists correlated well with their pKD values against UK 14304 (r = 0.93). The same was true for atria (r = 0.92). 3. In submaxillary glands, the pKD values of 3 antagonists against UK14304 were very similar to their pKD values against methoxamine, with a maximal difference of 0.4. The same was true for atria where the maximal difference was 0.3. 4. The pEC30 values obtained in submaxillary glands correlated significantly with those obtained in atria (r = 0.81). The same was true for the pKD values (r = 0.79). However, the pEC30 and pKD values also indicated consistent differences between the two tissues. 5. It is concluded that the sites of action of the imidazoline UK 14304 (alpha 2-selective), the phenylethylamine noradrenaline, and the phenylethylamine methoxamine (alpha 1-selective) are exclusively alpha 2-adrenoceptors. There is no indication for presynaptic alpha 1-adrenoceptors or for an effect of UK 14304 mediated by presynaptic imidazoline receptors.The 02-autoreceptor population in the submaxillary gland differs from that in the atrium.6. Comparison with studies from the literature indicates that the submaxillary autoreceptors are closely similar to the a2D radioligand binding site found in the bovine pineal gland and probably the rat submaxillary gland. The atrial autoreceptors also conform best to this site, but the agreement is more limited; the atrial autoreceptors may represent a type related to, but distinct from, the a2D site, or a mixture of different types.


Modulation of non-adrenergic non-cholinergic inhibitory neurotransmission in rat gastric fundus by the alpha 2-adrenoceptor agonist, UK-14,304.

1. The influence of the alpha 2-adrenoceptor agonist, UK-14,304, on non-adrenergic non-cholinergic (NANC) relaxation induced by electrical field stimulation was investigated in longitudinal muscle strips of the gastric fundus of reserpinized rats. 2. In tissues where tone was raised by 3 x 10(-7) M prostaglandin F2 alpha (PGF2 alpha), the inhibitory effect of 10(-6) M UK-14,304, on the NANC relaxations induced by short train stimulation (40 V, 1 ms, 20 s) was inversely related to the stimulus frequency (1-4-16 Hz). UK-14,304 (10(-6) M) did not influence relaxations induced by administration of exogenous nitric oxide (NO, 2 x 10(-6) M-10(-4) M). The inhibitory effect of UK-14,304 on the electrically induced relaxations was antagonized by 10(-6) M rauwolscine but not by 10(-6) M prazosin. 3. UK-14,304 (10(-6) M) also reduced the amplitude of the sustained NANC relaxation, induced by electrical field stimulation (40 V, 1 ms, 4 Hz) for 5 min. The effect of UK-14,304 was also antagonized by 10(-6) M rauwolscine but not by 10(-6) M prazosin. UK-14,304 (10(-6) M) did not reduce the relaxation induced by 3 x 10(-9) M vasoactive intestinal polypeptide (VIP). 4. These results suggest that the release of the inhibitory NANC neurotransmitter during short train stimulation, thought to be NO, and during sustained stimulation, thought to be VIP, is inhibited by stimulation of presynaptic alpha 2-adrenoceptors in the rat gastric fundus.


Imidazoline antagonists of alpha 2-adrenoceptors increase insulin release in vitro by inhibiting ATP-sensitive K+ channels in pancreatic beta-cells.

1. Islets from normal mice were used to study the mechanisms by which imidazoline antagonists of alpha 2-adrenoceptors increase insulin release in vitro. 2. Alinidine, antazoline, phentolamine and tolazoline inhibited 86Rb efflux from islets perifused with a medium containing 3 mM glucose, i.e. under conditions where many adenosine 5'-triphosphate (ATP)-sensitive K+ channels are open in the beta-cell membrane. They also reduced the acceleration of 86Rb efflux caused by diazoxide, an opener of ATP-sensitive K+ channels. 3. ATP-sensitive and voltage-sensitive K+ currents were measured in single beta-cells by the whole-cell mode of the patch-clamp technique. Antazoline more markedly inhibited the ATP-sensitive than the voltage-sensitive current, an effect previously observed with phentolamine. Alinidine and tolazoline partially decreased the ATP-sensitive K+ current. 4. The four imidazolines reversed the inhibition of insulin release caused by diazoxide (through opening of ATP-sensitive K+ channels) or by clonidine (through activation of alpha 2-adrenoceptors) in a concentration-dependent manner. Only the former effect correlated with the ability of each drug to increase control insulin release stimulated by 15 mM glucose alone. 5. It is concluded that the ability of imidazoline antagonists of alpha 2-adrenoceptors to increase insulin release in vitro can be ascribed to their blockade of ATP-sensitive K+ channels in beta-cells rather than to their interaction with the adrenoceptor.


Investigations into neuropeptide Y-mediated presynaptic inhibition in cultured hippocampal neurones of the rat.

1. We have examined the effects of neuropeptide Y (NPY) on synaptic transmission and [Ca2+]i signals in rat hippocampal neurones grown in culture. [Ca2+]i in individual neurones displayed frequent spontaneous fluctuations often resulting in an elevated plateau [Ca2+]i. These fluctuations were reduced by tetrodotoxin (1 microM) or combinations of the excitatory amino acid antagonists 6-cyano-7-dinitro-quinoxaline (CNQX) (10 microM) and aminophosphonovalerate (APV) (50 microM), indicating that they were the result of glutamatergic transmission occurring between hippocampal neurones. 2. [Ca2+]i fluctuations were also prevented by Ni2+ (200 microM), by the GABAB receptor agonist, baclofen (10 microM) and by NPY (100 nM) or Y2 receptor-selective NPY agonists. Following treatment of cells with pertussis toxin, NPY produced only a brief decrease in [Ca2+]i fluctuations which rapidly recovered. 3. Perfusion of hippocampal neurones with 50 mM K+ produced a large rapid increase in [Ca2+]i. This increase was slightly reduced by NPY or by a combination of CNQX and APV. The effects of CNQX/APV occluded those of NPY. NPY had no effect on Ba2+ currents measured in hippocampal neurones under whole cell voltage-clamp even in the presence of intracellular GTP-gamma-S. On the other hand, Ba2+ currents were reduced by both Cd2+ (200 microM) and baclofen (10 microM). 4. Current clamp recordings from hippocampal neurones demonstrated the occurrence of spontaneous e.p.s.ps and action potential firing which were accompanied by increases in [Ca2+]i. This spontaneous activity and the accompanying [Ca2+]i signals were prevented by application of NPY (100 nM). When hippocampal neurones were induced to fire trains of action potentials in the absence of synaptic transmission, these were accompanied by an increase in cell soma [Ca2+]j. NPY (100 nM) had no effect on these cell soma [Ca2+], signals. NPY (100 nM) also had no effect on inward currents generated in hippocampal neurones by micropipette application of glutamate (50 microM).5. Thus, NPY is able to abolish excitatory neurotransmission in hippocampal cultures through a pertussis toxin-sensitive mechanism. However, no effect of NPY on Ca2+ influx into the cell soma of these hippocampal neurones could be discerned. These results are consistent with a localized presynaptic inhibitory effect of NPY on glutamate release in hippocampal neurones in culture.


Antagonism of synaptic potentials in ventral horn neurones by 6-cyano-7-nitroquinoxaline-2,3-dione: a study in the rat spinal cord in vitro.

1. The rat spinal cord in vitro has been used to assess the effect of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) on the dorsal root evoked extracellular ventral root reflex (DR-VRR) and the intracellular excitatory postsynaptic potential (e.p.s.p.) in ventral horn neurones and motoneurones. 2. CNQX (1-5 microM) produces a selective and dose-dependent reduction in the amplitude of the monosynaptic component of the DR-VRR recorded from lumbar spinal segments. 3. With low intensity dorsal root stimulation CNQX selectively attenuates the amplitude of the short latency intracellular e.p.s.p. (70% reduction, P < 0.005) and its rise-time (75%, P < 0.01) without affecting the half-time to decay. 4. When high intensity stimulation is used CNQX significantly attenuates the amplitude of the e.p.s.p. (56%, P < 0.005), rise-time (76%, P < 0.01) and abolishes the short latency spike. In addition longer latency synaptic components are attenuated and the half-time to decay significantly reduced (47%, P < 0.005). 5. The results with CNQX are compared to D-aminophosphonovalerate and discussed in relation to the recruitment of low versus high threshold afferents. The data supports an involvement of non-NMDA receptors in transmission through both mono- and polysynaptic pathways in the ventral horn.


Calmidazolium, a calmodulin inhibitor, inhibits endothelium-dependent relaxations resistant to nitro-L-arginine in the canine coronary artery.

1. The role of calmodulin in endothelium-dependent relaxations in the canine coronary artery, was investigated by use of the inhibitor of calmodulin, calmidazolium. 2. The endothelium-dependent relaxations to adenosine diphosphate (ADP) and nebivolol, a beta-adrenoceptor antagonist, in control solution, and to bradykinin in high potassium solution (to inhibit endothelium-dependent hyperpolarization), were abolished by nitro-L-arginine (30 microM), an inhibitor of nitro oxide-synthase. Calmidazolium (10 microM) did not inhibit these relaxations. 3. Calmidazolium did not affect the endothelium-independent relaxations to SIN-1, an exogenous donor of nitric oxide (NO). 4. The relaxations to bradykinin and to the calcium ionophore A23187 in control solution were inhibited to a small extent by calmidazolium (10 microM). 5. Bradykinin and A23187 induced relaxations in the presence of nitro-L-arginine (30 microM) that were abolished by calmidazolium (10 microM) but not affected by glibenclamide (10 microM), an inhibitor of ATP-sensitive K+ channels. 6. The endothelium-independent relaxations to lemakalim, an ATP-sensitive K+ channel opener, were not affected by calmidazolium (10 microM) but were inhibited by glibenclamide (10 microM). 7. These results suggest that calmidazolium does not inhibit the endothelium-dependent relaxations due to endothelium-derived NO in the canine coronary artery but inhibits either the production of endothelium-derived hyperpolarizing factor (EDHF) from endothelial cells or its effects on vascular smooth muscle cells. Furthermore these results suggest that EDHF contributes to endothelium-dependent relaxations in the canine coronary artery.


Evidence for a noradrenergic innervation to alpha 1A-adrenoceptors in rat kidney.

1. Experiments were undertaken to characterize the alpha 1-adrenoceptor subtype mediating vasoconstrictor responses to periarterial noradrenergic nerve stimulation (PNS) in the isolated perfused kidney of the rat. 2. Vasoconstrictor responses to nerve stimulation were inhibited by prazosin (10 nM), 5-methyl-urapidil (30 nM), and nitrendipine (1 microM) but were resistant to inhibition by chloroethylclonidine (100 microM). 3. 5-Methyl-urapidil (30 nM), chloroethylclonidine (100 microM) and nitrendipine (1 microM) did not inhibit the neuronal release of tritium from nerves loaded with [3H]-noradrenaline. 4. The results suggest that renovascular alpha 1A-adrenoceptors receive a noradrenergic innervation and that the innervated receptors are coupled to dihydropyridine-sensitive calcium channels.


Effect of histamine and histamine analogues on human isolated myometrial strips.

1. The effect of histamine and histamine H1- and H2-receptor agonists on isolated myometrium strips of premenopausal women has been examined. The effect of acetylcholine was also determined. 2. Histamine, 2-pyridylethylamine, 4-methylhistamine and acetylcholine, but not dimaprit, produced a concentration-related contractile response in human isolated myometrial strips. Histamine also produced a further contraction in human isolated myometrial strips precontracted with KCl (55 mM). 3. The contractile response to histamine was antagonized by the histamine H1-receptor antagonist, clemizole (0.1 microM) but was potentiated by the histamine H2-receptor antagonist, ranitidine (10 microM). Clemizole (0.1 nM to 10 nM) competitively antagonized the contractile effect of 2-pyridylethylamine (- log KB = 10.5 +/- 0.5). The concentration-response curve for acetylcholine was displaced to the right by atropine 0.1 microM. 4. Atropine (0.1 microM), propranolol (0.1 microM), prazosin (0.1 microM) and indomethacin (1 microM) failed to modify the contractile response to histamine. 5. In human isolated myometrial strips precontracted with KCl (55 mM), clemizole at 1 microM completely abolished the contractile response to histamine and revealed a concentration-dependent relaxation. Dimaprit alone and 4-methylhistamine (in the presence of clemizole), produced concentration-related relaxation with a magnitude similar to that in response to histamine. The relaxant response to dimaprit was antagonized by ranitidine. 6. It is concluded that human isolated uterine strips possess histamine H1- and H2-receptors: the former mediating contraction and the latter relaxation. The predominant response to histamine in this tissue is contraction.


Cannabis and psychotic illness.

In-patients with psychotic symptoms and cannabis-positive urine analysis were assessed by PSE within one week of admission and again at one and six months. Concurrently admitted psychotic patients with drug-free urine analysis were controls. At one week the two groups differed significantly on only five PSE items: changed perception, thought insertion, non-verbal auditory hallucinations, delusions of control, and delusions of grandiose ability. One item (delayed sleep) differed at one month, and none at six months. The symptom cluster at one week is consistent with acute cannabis intoxication. Subjects and controls were mostly single, poorly educated, unemployed people with histories of psychotic disorders, and given major tranquillisers on admission. Compared with controls, subjects were younger, less likely to have psychiatric histories, more often male, Afro-Caribbeans with a history of convictions and compulsory admissions. The commonest diagnosis was schizophrenia. Use of the label 'cannabis-induced psychosis' may obscure a diagnosis of paranoid schizophrenia. A short-lived psychotic episode does occur in clear consciousness after cannabis intoxication, but chronic cannabis-induced psychosis was not found.


The use of image habituation training with post-traumatic stress disorders.

An exposure treatment for patients suffering from post-traumatic stress disorder (PTSD) is described. Image habituation training (IHT) involves the patient in generating verbal descriptions of the traumatic event and recording these onto an audiotape. After the initial training session with the therapist, homework sessions of self-directed exposure in which the patient visualised the described event in response to listening to the audiotape were carried out. Of ten consecutive patients who received this treatment, six improved considerably after ten homework sessions, two showed moderate improvements, and two showed minimal improvement on a range of outcome measures. There were significant decreases in anxiety between and within homework sessions, suggesting that habituation did occur and was responsible for improvement. Treatment gains were maintained at six-month follow-up.


Control of simultaneous movements distinguishes depressive motor retardation from Parkinson's disease and neuroleptic parkinsonism.

Patients with depressive motor retardation, neuroleptic induced parkinsonism or Parkinson's disease were tested on movement tasks requiring control of simultaneous movements. This was in order to determine whether these three groups of patients, who all show slowing of movements, also share the distinctive impairment of simultaneous movement control that is observed in Parkinson's disease. Though all three patient groups showed equivalent slowing on the motor tasks that were studied, the patterns of impairment were different. Only the patients with parkinsonism, either neuroleptic induced or from Parkinson's disease, showed additional slowing of a rapid ballistic elbow flexion movement when it was performed simultaneously with a rapid squeeze of the ipsilateral hand. Only patients with parkinsonism showed a significant increase in dual task interference on a bimanual bead and tapper task, compared with controls. The bead and tapper interference in patients with depressive motor retardation was between that of controls and parkinsonism. Having a bimanual skill had a large effect on the subjects' dual task interference on this task. The measures of dual task interference for the two tasks did not correlate with one another; difficulty running simultaneous motor programs does therefore not explain the interference that is observed when tapping is performed while the other hand simultaneously performs a dextrous motor task. Only patients with parkinsonism showed increased fatigue on the tapping task. The patients with depressive motor retardation did have elevated scores on a clinical rating of parkinsonism. Nevertheless there are clearly defined differences between the movement disorder observed in patients with depression, and that observed in in parkinsonism. The patterns of impairments in patients with neuroleptic parkinsonism were very similar to those of Parkinson's disease.


Characterization of superior cervical ganglion neurons that project to the submandibular glands, the eyes, and the pineal gland in rats.

These studies sought to determine whether the cell bodies of rat superior cervical ganglion neurons projecting to three very different target organs differ in terms of their size, number, location within the ganglion and/or neuropeptide content, and whether these features are altered in response to neonatal deafferentiation of the ganglion. A series of retrograde tracer, immunocytochemical, and double-labeling studies revealed differences in the size, number, location and neuropeptide content of superior cervical ganglion neurons that project to the submandibular salivary glands, eyes, or pineal gland. The mean areas of the cell bodies of neurons projecting to the submandibular gland are largest, those projecting to the eye are smallest, and those projecting to the pineal are intermediate in size. Submandibular gland projecting neurons are found throughout the ganglion, while the eye and pineal projecting populations are localized to the rostral quadrants. The different subpopulations of target organ specific superior cervical ganglion neurons are heterogeneous in their content of vasoactive intestinal peptide-, neuropeptide Y- and somatostatin-like immunoreactivity. A greater percentage of submandibular gland than of pineal projecting neurons display vasoactive intestinal peptide-like immunoreactivity, but there are no differences in the percentage of neurons displaying neuropeptide Y- or somatostatin-like immunoreactivity between the target organ specific groups. Neonatal deafferentiation does not result in changes in the size, number or distribution of target organ specific neurons, or in the percentage of immunoreactive neurons in these populations. In conclusion, these studies provide evidence that the size and distribution of neurons and percentage of peptide-containing neurons in the superior cervical ganglion is related to the target organ innervated, but provides no evidence of exclusive target organ-peptide relationships.


NMDA-receptor mediated electrical epileptogenesis in the organotypic culture of rat hippocampus.

Extracellular field recordings were made in CA1 in the hippocampal explant cultures in oxygenated artificial cerebrospinal fluid. Schaffer collaterals were stimulated with 1-s trains of 60 Hz pulses every 10 min. Seizures were reliably elicited with progressive lengthening over 1-2 h. D-APV, an N-methyl-D-aspartate (NMDA) antagonist, stereoselectively blocked the development of seizures. Thus we have demonstrated that in vitro epileptogenesis occurs in hippocampal explant cultures through NMDA receptor mediated mechanisms.


Projection from the ventrolateral medullary neurons containing tyrosine hydroxylase to the central amygdaloid nucleus in the rat.

By using a double-labeling produce of retrograde horseradish peroxidase (HRP) tracing and the immunocytochemical localization of tyrosine hydroxylase (TH), the present study ascertained that the axonal fibers of catecholaminergic neurons in the caudal ventrolateral medulla projected to the central amygdaloid nucleus in the rat. The majority of double-labeled cells were observed primarily around the level of the obex. 92% of HRP retrogradely labeled cells contained TH-like immunoreactive (TH-IR), but only 31% of TH-IR cells was labeled with HRP.


Glutamate neurotoxicity in the developing rat cochlea is antagonized by kynurenic acid and MK-801.

Glutamate (Glu) is neurotoxic in the neonatal rat cochlea, producing hearing impairment which is largely due to the death of spiral ganglion cells, whereas the receptor hair cells are spared. Dendritic processes of the spiral ganglion are postsynaptic to the primary afferent synapse of the auditory system. The experiments reported here were designed to test whether this apparent excitotoxicity can be blocked by Glu antagonists. The broad-spectrum antagonist kynurenic acid (KYNA) was coadministered with Glu initially to determine whether the high-frequency hearing deficit caused by Glu may be mediated by excitatory amino acid receptors. Subsequently, the N-methyl-D-aspartate (NMDA)-specific receptor blocker MK-801 was used to test whether NMDA receptors may be involved in the effect. Both antagonists partially blocked the high-frequency hearing impairment caused by Glu. The blocker-alone control groups exhibited mid-frequency effects of unknown origin. The significant antagonism of Glu-induced impairment is consistent with the hypothesis that Glu or a similar excitatory amino acid is an important afferent transmitter in the cochlea.


Further evidence for differential affinity states of the serotonin1A receptor in rat hippocampus.

The binding profile of [3H]8-hydroxy-2-(di-N-propylamino)-tetralin ([3H]8-OH-DPAT) to serotonin1A (5-HT1A) sites in rat hippocampal, frontocortical and striatal membranes has been compared. In these regions, [3H]8-OH-DPAT labels both a high and a low-affinity binding site; the affinity values for each of the two sites are comparable in the different brain regions, but have different maximal capacity. By modifying the experimental conditions in a series of hippocampal membrane preparations, reciprocal changes in the proportion of the two sites were observed suggesting that they represent, at least in this region, different conformations or affinity states of a single receptor protein. In contrast to the lower affinity state, it appears that the high-affinity state is stabilized by coupling with a G-protein. Evidence supporting this statement is provided by addition of the guanine nucleotide Gpp(NH)p, breakage of labile disulfide bonds using N-ethylmaleimide and increasing membrane rigidity with ascorbate-induced lipid peroxidation, conditions which all reduced the density of receptors in the high-affinity state. Moreover, the high-affinity state appears to be stabilized at the expense of the lower affinity state in the presence of Mn2+. On the other hand, a complete shift to the low-affinity binding state was observed after a 24 h in vivo treatment with inhibitors of monoamine oxidase A (phenelzine or clorgyline) but not of monoamine oxidase B (deprenyl). This disappearance of the high-affinity state with a concomitant increase in the binding capacity of the low-affinity state was reproduced by inhibiting monoamine oxidase A in vitro, as well as by reducing preincubation washout periods. Also, competitors of the [3H]8-OH-DPAT binding site, such as serotonin and unlabelled 8-OH-DPAT, display two affinity states while others like (+/-)-propranolol, tryptamine and spiperone recognize a single affinity component. These results suggest that the 5-HT1A binding site may exhibit at least two different affinity states depending upon its microenvironment and the intrinsic activity of the ligand used.


Reactive proliferation of astrocytes studied by immunohistochemistry for proliferating cell nuclear antigen.

Astrocyte proliferation in the stab-wounded cerebral cortex of mice was studied using double immunohistochemistry for proliferating cell nuclear antigen (PCNA) and glial fibrillary acidic protein (GFAP). The number of GFAP-positive astrocytes increased markedly from day 0.5 to day 3 after stab wounding. Some GFAP-positive astrocytes in the immediate vicinity of the wound were found to be positive for PCNA. However, the maximum number of these double positive astrocytes was only 5-6% of the number of GFAP-positive astrocytes. This maximum value was observed on days 2.5 and 3. The present study revealed that astrocytes are able to reactively express PCNA, an intrinsic marker of DNA replication. On the other hand, it is suggested that the proliferation of astrocytes in the wounded cerebral cortex is limited, in contrast with their marked reactive up-regulation of GFAP.


Flunarizine induces a transient loss of tyrosine hydroxylase immunoreactivity in nigrostriatal neurons.

Neurotoxic effects of flunarizine (Fz), a selective calcium channel blocker, on the nigrostriatal dopamine system was investigated. Systemic injections of Fz to mice resulted in a transient loss of tyrosine hydroxylase (TH) immunoreactive nigrostriatal neurons without cell loss. TH immunoreactivity in these neurons was greatly reduced as rapidly as one day after drug administration (regardless of dosage used) and thereafter recovered in both dose- and time-dependent manners. Such a novel neurotoxic action of Fz may constitute a morphological substrate for reversible drug-induced parkinsonian signs described in recent clinical case reports.


Specificity of 192 IgG-saporin for NGF receptor-positive cholinergic basal forebrain neurons in the rat.

A monoclonal antibody to the rat nerve growth factor (NGF) receptor, 192 IgG, accumulates bilaterally and specifically in cholinergic basal forebrain (CBF) cells following intraventricular injection. An immunotoxin composed of 192 IgG linked to saporin (192 IgG-saporin) has been shown to destroy cholinergic neurons in the basal forebrain. We sought to determine if intraventricular 192 IgG-saporin affected choline acetyltransferase (ChAT) enzyme activity in the CBF terminal projection fields. ChAT assays from 192 IgG-saporin-treated animals showed significant time-dependent decreases in ChAT activity in the neocortex, olfactory bulb and hippocampus, compared to PBS- or OKT1-saporin-injected controls. ChAT and tyrosine hydroxylase activity in the striatum was always unchanged by 192 IgG-saporin. ChAT immunohistochemistry was confirmative of major cell loss in the CBF, while other cholinergic nuclei appeared unremarkable. The data provide further evidence of the selectivity of 192 IgG-saporin in abolishing cholinergic, NGF receptor-positive CNS neurons.


Analgesic actions of dynorphin A(1-13) antiserum in the rat brain stem.

This study was performed to evaluate the effects of dynorphin A(1-3) antiserum when microinjected into an active hyperalgesic region within the rat brain stem. When administered within the dorsal posterior mesencephalic tegmentum (DPMT) of intact conscious rats, dynorphin A(1-13) antiserum produced rapid onset and persistent prolongation of a low intensity thermally evoked tail avoidance response (LITETAR). These analgesic actions of the dynorphin A(1-13) antiserum appeared to be dose dependent. These studies support previous hypotheses about the existence of tonically active brain stem opioid hyperalgesic process. Further, the results provide indirect evidence for a potential role of brain stem dynorphin(s) in facilitating pain.


Afferent and sympathetic innervation of the dome and the base of the urinary bladder of the female rat.

The afferent and sympathetic innervation of different regions of the urinary bladder (bladder dome vs. bladder base) was examined in the female rat using simultaneous injections of two fluorescent tracers. Retrogradely labeled cells were found in the dorsal root ganglia (DRG; L1-L3 and L6-S1), the sympathetic chain (SC; T12-L6), the inferior mesenteric ganglia (IMG) and the major pelvic ganglia (MPG). There were very few double-labeled cells, indicating that the dome and the base of the bladder receive innervation (afferent or sympathetic) from separate and distinct neuronal populations. Most of the sympathetic innervation of the bladder arose from the SC (dome: 77%; base: 89%) and it was carried equally by the hypogastric and pelvic nerves. The distributions of SC postganglionic neurons innervating the dome and the base of the bladder were very similar. In contrast, the contribution of IMG neurons was almost entirely restricted to the dome of the bladder (22%), with less than 1% innervating the base. Tyrosine hydroxylase-immunoreactive (TH) neurons in the MPG displayed a strong sexual dimorphism. Many TH neurons were found in the male MPG, but very few in the female MPG. In the female, these TH neurons projected almost exclusively to the bladder base of the female rat and were responsible for 10% of the sympathetic innervation of the base. Less than 1% innervated the dome. Therefore, prevertebral ganglia (IMG and MPG) show a strong regional selectivity in the innervation of the bladder of the female rat. The possible functional implications of this organization are discussed.


Antitumor activity of tiazofurin in human colon carcinoma HT-29.

Tiazofurin is effective in treating end-stage leukemic patients (Tricot et al., Cancer Res 49:3696-3701, 1989). In sensitive tumors, the active metabolite of tiazofurin, TAD, potently inhibits IMP dehydrogenase activity, resulting in reduced guanylate pools. To elucidate tiazofurin activity in human solid tumors, we examined its activity in human colon carcinoma HT-29. Tiazofurin exhibited an LC50 of 35 microM in cultured HT-29 cells. Incubation of HT-29 cells with 100 microM tiazofurin for 2 h resulted in TAD formation (9.3 nmol/g cells) and in a 64% decrease in GTP pools. For biochemical and chemotherapy studies, athymic nude mice were transplanted s.c. with HT-29 cells. Twenty-four days later, mice were injected i.p. with tiazofurin (500 mg/kg); 6 h later, tumors were removed and analyzed. These tumors formed 17 nmol/g of TAD with decreased GTP pools (56%). To study oncolytic activity, transplanted mice were treated 24 h later with tiazofurin (500 mg/kg, once a day for 10 days). To examine the effectiveness of tiazofurin in established tumors, the drug was administered to mice 14 days after tumor implantation (500 mg/kg, once a day for 5 days, course repeated 4 times with a 10-day rest). Both treatment schedules resulted in significant antitumor activity. This study illustrates the potential usefulness of tiazofurin in treating human colon carcinoma.


Clinical significance of erbB-2 (HER-2/neu) protein.

erbB-2 protein is believed to be a cell membrane receptor for the recently identified ligand gp30. When overexpressed, erbB-2 is an indicator of poor prognosis in adenocarcinomas of breast, stomach, lung, and endometrium. Even more important, clinical data suggest that erbB-2 overexpression may be an indicator of poor response to at least some commonly used adjuvant regimens. However, there is preliminary evidence that these tumors might respond as well to doxorubicin regimen as do erbB-2 negative tumors, at least in gastric cancer. The efficacy of doxorubicin-containing regimen in the treatment of tumors with erbB-2 overexpression needs to be explored further by retrospective analysis of finished clinical trials. Combination of chemotherapeutics with reagents that block erbB-2 signal transduction pathway may be another effective approach.


[Programmed death (apoptosis) of T CD4 lymphocytes and AIDS pathogenesis].

A major characteristic of human immunodeficiency virus (HIV) infection is progressive decline in T CD4+ lymphocytes. Ten years after infection, on average, this cell subpopulation disappears and AIDS develops. In the asymptotic phase T CD4+ lymphocytes no longer respond, in vitro or in vivo, to certain memory antigens constrained by the class II histocompatibility complex, or in vitro to polyclonal activators like pokeweed mitogen. They retain, however, some proliferative response activity and constitute only a small proportion of the T CD4+ population. Indirect mechanisms of depletion are therefore sought. We have proposed a hypothesis for a single mechanism: a programmed death process, apoptosis, reactivated in mature T CD4+ lymphocytes of seropositives. Unlike necrosis, apoptosis has a role in embryogenesis, in the adult in certain cell populations and, in immature thymocytes, in T lymphocyte selection and establishment of self-tolerance. T CD4+ lymphocytes of infected subjects lose their ability to proliferate in vitro, as they undergo a form of suicide in response to certain stimuli. In vivo T CD4+ cell activation induced by various infectious agents, including HIV, progressively reduces the subpopulation, independently of the virus' cytopathogenic effect. Tests were performed that explored the T CD4+ lymphocyte response to super-antigens, which mimic and amplify the effect of memory antigens by way of CMH II molecules of Ag-presenting cells and certain nu beta chains of the alpha beta receptor for the Ag which are expressed by a third of human mature T CD4+ lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)


[Are embryonic forms of NCAM homeobox receptors?].

In a previous study we demonstrated that the homeobox peptide pAntp was able to penetrate into rat embryonic neurons in culture thus provoking their morphological differentiation [1]. In the present work we have started to analyse the process of penetration of the homeobox peptide. As illustrated in Figure 1 pAntp migrating as a homogeneous 7 kDa band could be recovered in the nuclear fraction 2 hrs. only after its addition to cultured embryonic neurons (lane 2). Penetration and nuclear targeting were quantitatively blocked by preincubating pAntp with its cognate recognition sequence present in the promoter of Hox-1.3 (lane 3) or by incubating the cells with an antibody directed against the NCAM-specific alpha 2-8 polysialic acid (lane 4). Similar inhibitions were observed when the peptide was incubated with double stranded DNA or added to cells deprived of alpha 2-8 polysialic acid by EndoN treatment (not shown). As illustrated in Figure 2, the strong pAntp-induced neurite growth was antagonized when pAntp internalization was prevented by the EndoN removal of PSA. This effect of EndoN was not due to the enzyme itself since morphological differentiation was not inhibited if EndoN was added after pAntp penetration (Fig. 2B). Polysialic acid is composed of long chains of neuraminic acids, each pyranose ring carrying a negatively charged carboxylic group linked to carbon in position 1. NMR studies of the molecule in solution have demonstrated that the alpha 2-8 link between each pyranose ring allows specific and stable helical conformation [2].(ABSTRACT TRUNCATED AT 250 WORDS)


Paradoxical sleep deprivation increases glutamine synthetase in rat brain.

The modifications of glutamine synthetase (GS) level, an enzyme mainly located in astrocytes, were investigated in rat after paradoxical sleep deprivation and during recovery. An immunotitration method was used to evaluate the relative level of GS in brain tissue. At the end of a 24 hrs. paradoxical sleep deprivation, a significant increase in GS level was observed both in the frontoparietal cortex and the locus coeruleus area. 4 hrs. later, during recovery, the GS level returned to control level in the cortex but was lower in the locus coeruleus area.


Viruses as precipitants of asthma symptoms. II. Physiology and mechanisms.

The upper and lower airways have complimentary roles in the ultimate object of supplying the body with oxygen whilst removing waste products of metabolism. Pathology in one area may trigger a response in another, the physiology of which, in the case of virus-induced asthma exacerbations remains poorly characterized. Viral infection of the upper airways by common cold viruses frequently triggers a response in the lower airways leading to prolonged morbidity, especially in subjects with significant pre-existing airway disease. The induction or amplification of BHR may be an important mechanism whereby asthmatic symptoms are produced although the cellular and tissue events or reflex mechanisms activated by viral illnesses and underlying BHR changes are poorly defined and may be dependent on the type and the severity of infection. Children and asthmatics tend to develop frequent colds setting in motion a sequence of events culminating in airway obstruction and symptoms of wheezing, coughing and chest tightness. This may reflect independent inflammatory changes caused by a simply additive effect of viral damage to the mucosa superimposed upon pre-existing allergic inflammation (Fig. 1). Few if any symptoms will develop in normal subjects with a mild cold whereas significant symptoms may ensue if the cold is severe and induces marked lower airway swelling, secretions and smooth muscle contraction; pathology to which children who have small calibre airways may be particularly susceptible. In asthmatics even a mild cold frequently induces exacerbation of symptoms, while serious life-threatening asthma attacks may occur associated with a severe cold. Some studies have suggested that this effect is not only additive but also synergistic and brought about by release of the mediators already present in increased quantities, the induction of IgE synthesis, or by the potentiation of neural and epithelial damage. The combined effect of both asthma and viruses may thus be amplified and result in a sustained and refractory period of airway obstruction, severe symptoms and unstable asthma. As most hospital admissions for asthma occur over the winter months and soon after the start of the school terms [115], spread of viruses through the community to susceptible individuals may be the single most important cause of sustained exacerbations of asthma. Definition of the pathological and physiological mechanisms involved will lead to better understanding and may thus provide a basis for prevention and the development of effective forms of treatment for virus-induced asthma.