[Enantioselective biotransformation of a new theophylline derivative]. Reductive amination of 4 with (RS)-2 is an improved method to obtain 7-((RS)2-((RS)-1-Methyl-2-phenyl-ethylamino)propyl)-theophylline (3) (ratio of diastereomers 1:1) compared with SN-displacement of proxyphyllintosylate with (RS)-2 (ratio of diastereomers 9:1). Due to steric hindrance 3 is no noteworthy prodrug for the intermediate formation of (RS)-2 in rats. The enantioselectivity of 2 after a single oral dose of 3 is determined in 24-h urine by HPLC on a Cyclobond-column using the isoindole derivatives, formed from o-phthalaldehyde, thioglycolic acid, and 2. The R(-)-amphetamine isomer is formed to a lesser amount (34.8%, range 32-37%) than the S(+)-isomer (65.2%, range 63-68%).


Benzo[b]thiophenes, II: Novel benzo[b]thienylhydrazine and 1,3,4-oxadiazole derivatives as potential antidepressant agents. Three novel series of benzo[b]thiophene derivatives bearing various hydrazone, hydrazine and 1,3,4-oxadiazole moieties were synthesized as potential antidepressant agents. 22 Compounds were evaluated for their in vitro inhibitory effect on monoamine oxidase enzyme (MAO) type A. Several compounds inhibited MAO stronger than pargyline hydrochloride. Maximum inhibitions of 83% and 90% were observed with 1-benzyl-2-(3-chlorobenzo[b]thienyl-2-carbonyl)hydrazine (24) and 1-[2-(4-chlorophenyl)ethyl]-2-(3-chlorobenzo[b]thienyl-2- carbonyl)hydrazine (35), respectively.


Urological long-term follow-up in women with spinal cord injuries. One hundred eight women and 434 men admitted with spinal cord injuries between 1973 and 1987 were observed prospectively to determine the effects of age, sex, neurological classification, and method of bladder management method on renal function and urological complications. The primary method of bladder management for women throughout the study period was indwelling urethral catheterization as compared to condom drainage for their male counterparts. Renal function was determined by effective renal plasma flow and urological complications were determined by clinical symptoms and/or objective findings on intravenous pyelography (IVP). Analysis reveals that as in the general population advancing age and being female were significantly associated with lower ERPF (p < .05). Only in men were neurological classification (quadriplegia) and bladder management (ileoconduit) associated with significant decreases in ERPF (p < .05). Furthermore, women and men showed no significant differences in urological complication rates. From the data it can be concluded that there is no particular method of bladder management for women that necessarily leads to impaired renal function.


Subscapular nerve block in the painful hemiplegic shoulder. Shoulder pain frequently superimposes substantial disability on a limb already limited by hemiplegia. The subscapularis muscle is a major internal rotator of the shoulder and, therefore, plays a role in the flexor synergy pattern commonly seen in spastic hemiplegia. Thirteen patients with spastic hemiplegia, limited range of motion, and painful shoulders underwent percutaneous phenol blocks to the nerves to the subscapularis. Patients' ages ranged from 22 to 76 (x 46 years) and the duration of hemiplegia from two to 13 months. Immediate and significant (p < 0.01) improvements in range of motion were observed in abduction (21 degrees), flexion (40 degrees), and external rotation (38 degrees). Relief of pain was also noted with the previously painful movement. Subscapularis nerve block is a new and potentially useful technique in the management of the painful hemiplegic shoulder.


Phenol block for hip flexor muscle spasticity under ultrasonic monitoring. Hip flexor spasticity, which is often associated with central nervous system (CNS) diseases, is a major impediment in rehabilitation. In order to cope with this problem, lumbar nerve blocking techniques developed by Meelhuysen and major and minor psoas muscle blocking techniques developed by Awad have been used in combination with physical therapies. Based on these techniques, we conducted major and minor psoas muscle phenol block (motor point block or intramuscular nerve block) under ultrasonic monitoring. Phenol block was conducted in nine patients with cerebral infarction (13 blocking procedures) and three with spinal cord injuries (six blocking procedures) while keeping them in a lateral position with the operation side upside. The beginning of the femoral nerves and part of the lumbar artery were visualized by ultrasound in some patients. As a result of the improvement of hip flexor spasticity, the range of hip joint motion (determined by the Mundale technique, prone hip extension and Thomas test) improved shortly after blocking. When physical therapy was conducted after blocking, improvement of skin care management was observed in eight cases, ability to keep in a stable sitting position in nine, improvement of a standing posture in three, increases in the ability to walk in two and alleviation of pain in three. Although nerve block is reported to result in hematoma, decreases in muscle force, pain, cystic/rectal disorders and hypogonadism, we have observed no such complication in our patients.


Associated movement in hemiplegia: the effects of force exerted, limb usage and inhibitory training. The intensity of associated movement or motor overflow in the contralateral limb during a unimanual task was evaluated in postacute traumatic brain injured (TBI) young adults with left side hemiplegia and age-matched controls. Both groups demonstrated increased overflow with increasing active limb force, although the trend was for greater overflow to occur in the TBI group, particularly when the spastic limb was active. Following three successive days of inhibitory training with electromyographic feedback, TBI subjects were able to significantly reduce the amount of overflow in the contralateral limb, greater inhibition occurring in the noninvolved limb during spastic limb movement. The results are discussed in terms of a dual model of inhibitory control and the role of such processes in uncoupling the limbs for independent limb usage.


Negative transfer of training following brief practice of elbow tracking movements with electromyographic feedback from spastic antagonists. This study aimed to overcome gaps in the literature by investigating effects of EMG feedback provided specifically from spastic muscles during antagonist phases of active movement, while controlling for the effects of practicing the movement and while testing for transfer of training without confounding several transfer phenomena. In a single training session, two groups of stroke patients practiced a pursuit tracking task by following a moving target with elbow flexion and extension, simultaneously attempting to reduce the activity of elbow flexors. Both groups tracked the target more accurately following training. Transfer tests failed to demonstrate effects of feedback on accuracy of tracking or on electromyographic activity during performance of the practiced task without feedback. Moreover, the group that was trained with electromyographic feedback exhibited negative transfer on variants of the practiced task: tracking faster or less predictable targets.


Concentric versus combined concentric-eccentric isokinetic training programs: effect on peak torque of human quadriceps femoris muscle. To determine the effects of isokinetic resistance training of the quadriceps, 25 male volunteers were randomly assigned to five training groups: Concentric Slow (CS), Concentric Fast (CF), Concentric-Eccentric Slow (MS), Concentric-Eccentric Fast (MF), and Control (C). In training, subjects performed 20 contractions of each quadriceps using either 60 degrees/sec or 180 degrees/sec, for both sides, five days per week for 12 weeks. Testing consisted of measurement of peak torque, at intervals of 60 degrees/sec across a spectrum of velocities ranging from plus to minus 240 degrees/sec, at 0, 4, 8, and 12 weeks. Repeated MANOVA using planned comparisons showed that all trained subjects made significant peak torque gains (p < .05), but that the gains made by MS and MF were greater. These findings suggest that the addition of an eccentric training component to a concentric isokinetic training program may allow greater peak torque gains regardless of the velocity.


Relationship between two measures of upper extremity strength: manual muscle test compared to hand-held myometry. One hundred and twenty-two individuals with spinal cord injuries at levels C4-6, Frankel classifications A through D, were evaluated to determine the relationship between the manual muscle test (MMT) and hand-held myometry as accurate methods for measuring muscular strength. More specifically, this study attempted to define a range of myometry scores that could be correlated with discrete MMT grades. It also investigated which of the two modalities (MMT or hand-held myometry) is the best reflection of improvement in muscle strength over time. Sequential motor strength examinations using both modalities were performed at 72 hours, one week, and two weeks post SCI and then one, two, three, four, six, 12, 18, and 24 months post injury. The data analyses included calculations of Spearman ranked correlations, analyses of variance, and linear regressions. Results showed that 22 of 24 correlations between MMT and myometry were significant at p values less than .001. The range of myometry measurements for a particular MMT grade appears to be most specific for MMT scores less than 4 (ie, poor-plus to good), and less specific for MMT scores greater than or equal to 4. The results of this study also indicate that myometry measurements detect increases in strength over time, which are not reflected by changes in MMT scores.


Osteoarthritis of the hand and wrist in the post poliomyelitis population. People with a chronic motor disability of the legs become increasingly more dependent upon their upper limbs for mobility and self-care skills as they age. Many of them complain of hand and wrist pain. A cross-sectional study of 61 post-poliomyelitis survivors was done to determine the prevalence of osteoarthritis within this population and to determine any inherent risk factors. Each subject underwent a radiographic evaluation of both hands and wrist as well as a detailed physical examination. A questionnaire was used to ascertain a history of hand activity, use of canes/crutches, walkers and wheelchairs. The mean age of the population sample was 49 +/- 6 with a mean duration of disability of 35 +/- 4 years. The prevalence of moderate or severe osteoarthritis of either the hand or wrist was 13% whereas the prevalence was 68% when cases with mild arthritic changes were also included. The risk factors associated with hand and wrist osteoarthritis in this population included age, lower limb weakness, use of an assistive devices, and severity of disability.


Clinical and laboratory measures of postural balance in an elderly population. The objective of this cross-sectional study was to compare scores on the Balance Scale with laboratory measures of postural sway and other clinical measures of balance and mobility. Thirty-one elderly subjects were assessed on the clinical measures and the laboratory tests of postural sway while standing still and in response to pseudorandom movements of the platform. The average correlation between the Balance Scale and the spontaneous sway measures was -.55. It was slightly lower (r = -.38) for the same parameters measured during the pseudorandom tests. There were high correlations between the Balance Scale and the Balance Sub-Scale developed by Tinetti (r = .91), Barthel Mobility sub-scale (r = .67), and timed "Up and Go" (r = -.76). The Balance Scale was the most efficient measure (effect size > 1) to statistically discriminate between subjects according to their use of each type of mobility aide (walker, cane, no aids). These data contribute to existing information on the performance of the Balance Scale and supports the validity of the Balance Scale in this geriatric population.


Aerobic capacity with two leg work versus one leg plus both arms work in men with peripheral vascular disease. The purpose of this pilot study was to examine the correlation between ergometry in men with peripheral vascular disease exercising with both legs and with one leg and both arms. Fifteen men with peripheral vascular disease performed three symptom-limited exercise tests on an ergometer that could be operated from a wheelchair with both legs or with one leg and both arms. The three exercise conditions were both legs (arms stabilized), left leg plus both arms, and right leg plus both arms. The exercise parameters compared were maximum oxygen consumption, maximum heart rate, and duration of exercise. Blood pressure was monitored at two-minute intervals and oxygen saturation and electrocardiogram were monitored continuously. The mean VO2 max +/- standard deviation for both legs, right leg plus both arms, and left leg plus both arms were 14.36 +/- 6.15, 14.86 +/- 4.09, 14.01 +/- 4.14 ml O2/kg-min, respectively. The mean duration of exercise +/- standard deviation were 12.01 +/- 5.74, 10.94 +/- 4.68, and 9.81 +/- 4.70 minutes respectively. The mean maximum heart rate +/- standard deviation were 126 +/- 24, 137 +/- 23, 136 +/- 23, respectively for the same exercise conditions. The Pearson Correlation Coefficients for VO2 for both legs versus right leg plus both arms and left leg plus both arms were .639 and .873, respectively. The Pearson Correlation Coefficients for duration of exercise for both legs versus right leg plus both arms and left leg plus both arms were .837 and .877, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Functional electrical stimulation leg cycle ergometer exercise: training effects on cardiorespiratory responses of spinal cord injured subjects at rest and during submaximal exercise. This study investigated the cardiorespiratory (CR) responses at rest and during submaximal (0-W) functional electrical stimulation (FES)-induced leg cycle ergometer (LCE) exercise prior to and following a progressive intensity FES-LCEa exercise training program in spinal cord injured (SCI) subjects. Seven quadriplegics and six paraplegics participated in FES-LCE training three sessions per week for approximately 12 weeks (36 sessions). Monitored CR responses, including oxygen uptake (VO2), pulmonary ventilation (VE), respiratory exchange ratio (RER), arteriovenous O2 difference (a-vO2), blood pressure (BP), heart rate (HR), stroke volume (SV), total peripheral resistance (TPR), and cardiac output (Q), were determined before and after training. Power output (PO) increased significantly (p < .05) over the duration of the training program, indicating increased in strength and endurance of the paralyzed muscles used. Respiratory responses were not significantly altered by training in both groups. FES-LCE training significantly increased resting HR and SBP in quadriplegics and lowered SBP, DBP, and MAP in paraplegics. In both groups, HR and BP during submaximal exercise significantly decreased and SV and Q significantly increased after completion of the training program. These results suggest that FES-LCE training improves peripheral muscular and central cardiovascular fitness in SCI subjects. Posttraining HR and BP may also be more stable in quadriplegics and alleviate hypotension. This therapeutic exercise may ultimately lead to improved rehabilitation outcome and reduced stress during activities of daily living, and possibly reduce the risks for secondary CR disabilities.


Heterotopic ossification in children with burns: two case reports. Heterotopic ossification is the formation of ectopic bone in soft tissue, and has been reported as a rare complication in pediatric burn patients. At our hospital, two 86% body surface area burn patients developed heterotopic ossification in the shoulder, elbows, distal femur, proximal tibia, fibula, and ribs approximately four months after the burn injury. These two rare and unusual cases are presented documenting the clinical involvement, radiological studies, laboratory data, as well as treatment of their heterotopic ossification. Discussion will focus on the incidence, diagnosis, pathophysiology, and treatment of heterotopic ossification in burn patients and how this information relates to the specific diagnosis and management of the complication of heterotopic ossification in the burn child.


Suprascapular neuropathy during progressive resistive exercises in a cardiac rehabilitation program. A 56-year-old man developed left shoulder pain three weeks after starting a cardiac rehabilitation program, which consisted of submaximal aerobic and progressive resistive exercises. Pain in the left shoulder intensified and weakness developed one week later. He sought medical attention ten weeks after the onset. Physical examination showed only weakness of left shoulder abduction and external rotation with mild atrophy of the left supraspinatus and infraspinatus muscles. Electrodiagnostic study showed fibrillation potentials and positive sharp waves in the left supraspinatus and infraspinatus muscles with delayed conduction to the supraspinatus. The left suprascapular notch was injected with local steroid. Within one week, improvement occurred, and one month later the patient was pain free and stronger. The motor latency returned to normal, and no fibrillations nor positive waves were seen. The patient returned to his previous functional level. Suprascapular neuropathy should be considered as a cause of shoulder pain and weakness in a person involved in any strengthening exercise program. A steroid injection of the suprascapular notch performed early may avoid the need for surgery.


Anterior tarsal tunnel syndrome.

Anterior tarsal tunnel syndrome. Anterior tarsal tunnel syndrome is a rarely reported entrapment neuropathy of the deep peroneal nerve under the extensor retinaculum at the ankle. The roof of the tunnel is the inferior extensor retinaculum. The floor is the fascia overlying the talus and navicular. Within the tunnel are four tendons, an artery, a vein, and the deep peroneal nerve. Two patients with foot pain and dysesthesias had prolonged peroneal distal latencies with reduced amplitudes from the extensor digitorum brevis (EDB). Electromyographic (EMG) abnormalities were confined to the EDB. Both patients underwent surgical decompression of the anterior tarsal tunnel with reduction of their pain and dysesthesias. If present, an accessory peroneal nerve, which does not go through the tunnel, can mask EMG findings in the EDB. Diagnosing anterior tarsal tunnel syndrome can also be difficult if there is a tendency to assume that fibrillation potentials in the EDB are due to shoe wear and prolonged peroneal latencies to cool extremities.


An alternative bent-knee prosthesis.

An alternative bent-knee prosthesis. Prosthetic fitting in patients with below-knee amputations and concurrent knee flexion contractures poses inherent difficulties to the prosthetic rehabilitation team. The standard bent-knee prosthesis is bulky and awkward. It treats the patient functionally as a knee disarticulation and yields no potential for improving the patient's degree of contracture. This paper describes a case report with an alternative to the bent-knee prosthesis that not only offered improved function relative to the standard bent-knee prosthesis, but also acted therapeutically by reducing the patient's knee-flexion contracture.


Extended indications for functional limb-sparing surgery in extremity sarcoma using complex reconstruction. From 1980 to 1991, 29 patients underwent complex reconstruction following extremity sarcoma resection. Soft tissue was the site of origin in 15 patients (52%) and bone was the site of origin in 14 patients (48%), with 20 sarcomas (69%) in the lower extremity. Resection consisted of the following procedures: extended anatomical soft-tissue resections (21 patients [72%]), bone resections (18 patients [62%]), and joint resections (14 patients [48%]). Reconstruction involved the following: myocutaneous flaps (20 patients [69%]), joint prosthesis (eight patients [28%]), and bone reconstruction (15 patients [52%]). There was no surgical mortality; one patient required an amputation owing to surgical complications. The site of the first failure was local (four [31%] of 13 patients), lung (five patients [38%]), others (four patients [31%]). At a median follow-up of 23 months, 18 patients (62%) had no evidence of disease, 27 (93%) had no local disease, 21 (72%) had good extremity function, three (10%) had major disabilities, and five (17%) underwent amputations. Local control improved when the margin of resection was larger than 10 mm. Disease-free survival was 67% at 3 years. Overall survival was 51% at 5 years. Tumor size was an independent predictor of overall survival. Local recurrence did not affect overall survival.


Pulmonary resection for metastatic breast cancer. Thirty-three patients treated primarily with surgical excision of pulmonary metastases from breast cancer were compared with 30 patients treated primarily with systemic chemohormonal therapy. Treatment for patients in the surgical group included pulmonary resection alone in 20, resection plus adjuvant systemic therapy in nine, and resection plus adjuvant radiation therapy in four. Treatment for patients in the medical group included systemic therapy alone in 22 and systemic therapy plus local radiation therapy in eight. Mean survival in the surgical group was significantly longer than that in the medical group, even when only those patients who manifested single pulmonary nodules were compared (58 months vs 34 months). The overall 5-year survival rate after treatment of lung metastasis was significantly greater for the surgical group than for the medical group (36% vs 11%). The results of this study indicate that surgical resection should be considered in patients with breast cancer who develop operable pulmonary metastases without evidence for concomitant extrapulmonary disease. In selected patients, such therapy may result in a survival benefit.


Management of small soft-tissue sarcoma of the extremity in adults. To determine the significance of small (< or = 5 cm in diameter) soft-tissue sarcoma of the extremity, 174 adult patients were identified from information that had been entered prospectively into a database of 1742 patients between July 1982 and December 1990. Median follow-up was 48 months. The majority of tumors were high grade (n = 114; 66%). Local recurrence (n = 17) was seen in patients with both high-grade (11%) and low-grade tumors (7%). Distant metastases were seen in 7% of high-grade tumors and in no low-grade tumors. The overall 5-year survival rate was 94% for all patients. Grade, depth, location, type of operation, and sex did not affect 5-year survival or local recurrence-free survival. Neither postoperative adjuvant chemotherapy nor radiation therapy resulted in superior 5-year survival or local recurrence-free survival when compared with no postoperative treatment. The prognosis of these lesions is favorable, and no additional prognostic factors were identified. Inclusion of these patients into adjuvant therapy trials examining survival is inappropriate.


Molecular surgery for cancer.

Molecular surgery for cancer. Advances in the understanding of the process of carcinogenesis may allow prevention, diagnosis, and treatment of cancer to be approached at the molecular level. Studies in our laboratory show that growth factors (transforming growth factor alpha), dominant oncogenes (HER-2/erb B2 and K-ras), and tumor suppressor genes (p53) are functionally important in the maintenance of the malignant phenotype of human non-small-cell lung cancer cells. Application of these findings to clinical problems include the identification of p53 mutations as markers for malignant change in Barrett's epithelium, the use of discordant p53 mutations to diagnose second primary malignant neoplasms in patients with head and neck cancer, and the potential for therapy by the reversal of genetic lesions.


Relationship between disease-free interval and survival in patients with recurrent melanoma. A total of 2468 patients with recurrent melanoma were subdivided on the basis of disease-free interval: group 1 had recurrences within 1 year (n = 810), group 2 at years 1 to 3 (n = 1001), group 3 at years 3 to 5 (n = 363), group 4 at years 5 to 10 (n = 329), and group 5 after 10 years (n = 145). Ten-year survivals were 21%, 23%, 25%, 28%, and 35%, respectively. Patients who had recurrences within 1 year had a decreased median survival compared with those who had later recurrences, although the differences were not clinically significant (only 6 to 8 months). Survival was improved for the few patients who had recurrences longer than 10 years from diagnosis. However, for the majority of patients, who had recurrences between 1 and 10 years, the disease-free interval did not predict subsequent survival. The data support the hypothesis that malignant cells can exist in a state of relative quiescence for extended periods. Once disease reactivation occurs, however, the subsequent survival is relatively predictable and is independent of the initial period of tumor dormancy.


The natural history of mammographic calcifications subjected to interval follow-up. The purpose of this investigation was to determine the natural history and risk of malignancy associated with isolated indeterminate microcalcifications subjected to interval follow-up. During a 2-year study, 91 patients were identified with indeterminate microcalcifications alone. Specific roentgenographic features of the calcifications were evaluated on initial and follow-up mammograms. During a mean follow-up of 36 months, 19 (21%) of the women exhibited mammographic changes. Ten patients (11%) with suspicious changes underwent a needle-directed biopsy 6 to 30 months after the initial mammographic screening. Five women (5.5%) were diagnosed as having breast carcinoma; three had invasive ductal carcinoma and two had purely intraductal lesions. Four patients had axillary lymph node dissections and no metastatic disease was found. We found no significant differences in the roentgenographic features associated with malignant vs benign lesions apart from an increased overall estimation of the probability of malignancy rating in the five patients with breast carcinoma. We recommend that patients be followed up with mammography at regular intervals for at least 18 months following recognition of indeterminate microcalcifications.


Effect of supplemental dietary glutamine on methotrexate concentrations in tumors. This study evaluated the effects of supplemental dietary glutamine (GLN) on methotrexate sodium concentrations in tumors and serum of sarcoma-bearing rats following the initiation of methotrexate. After randomization to a GLN diet (+GLN) or GLN-free diet (-GLN), tumor-bearing rats received 20 mg/kg of methotrexate sodium by intraperitoneal injection. The provision of supplemental GLN in the diet increased methotrexate concentrations in tumor tissues at 24 and 48 hours (38.0 +/- 0.20 nmol/g for the +GLN group vs 28.8 +/- 0.10 nmol/g for the -GLN group and 35.6 +/- 0.18 nmol/g for the +GLN group vs 32.5 +/- 0.16 nmol/g for the -GLN group, respectively). Arterial methotrexate levels were elevated only at 48 hours (0.147 +/- 0.007 microns/L for the +GLN group vs 0.120 +/- 0.006 microns/L for the -GLN group). Tumor morphometrics were not different between the groups but significantly greater tumor volume loss was seen even at 24 hours (-2.41 +/- 1.3 cm3 for the +GLN group vs -0.016 +/- 0.9 cm3 for the -GLN group). Tumor glutaminase activity was suppressed in both groups at 48 hours, but more so in the +GLN group (0.94 +/- 0.13 mumol/g per hour for the +GLN group vs 1.47 +/- 0.22 mumol/g per hour for the -GLN group). This study suggests that GLN may have therapeutic as well as nutritional benefit in oncology patients.


99mTc-IMMU-4 monoclonal antibody scan in colorectal cancer. A prospective study. A blinded prospective study of 34 patients with colorectal adenocarcinoma using the Fab' fragment of the anticarcinoembryonic antigen monoclonal antibody type IMMU-4 labeled with technetium 99m was conducted to compare, on a lesion-by-lesion basis, the findings of radioimmunoscintigraphy, preoperative computed tomography, and exploratory celiotomy. Of 115 lesions detected at surgery, 113 were adenocarcinoma. Radioimmunoscintigraphy detected 59 lesions and computed tomography detected 62; both studies combined detected 72. Twenty-nine (54%) lesions missed by radioimmunoscintigraphy and 24 (45%) missed by computed tomography were 1 cm or smaller. When both studies were combined, the sensitivities were 90%, 24%, and 42%, and the specificities were 52%, 86%, and 61% for hepatic, extrahepatic intra-abdominal, and pelvic lesions, respectively. In 10 patients, additional information obtained with the radioimmunoscintigram could have altered the treatment of these patients. In this study, radioimmunodetection scan was complementary to computed tomographic scan in the examination of patients with colorectal carcinoma.


Hepatic metastasis alters the immune function of murine liver nonparenchymal cells. To examine the effect of a single hepatic focus of metastatic colon tumor on the immune function of liver non-parenchymal cells (NPCs) from C57Bl/6 mice, we injected 2.5 x 10(5) liver-derived murine colon adenocarcinoma (LD-MCA-38) cells beneath the liver capsule. Three weeks following injection of the tumor cells, the immune function of the NPCs was studied. The NPCs from tumor-bearing mice exhibited increased cytotoxic and proliferative activity. The NPCs from tumor-bearing mice also contained a greater percentage of CD8+ and T-cell receptor gamma/delta+ liver-associated T lymphocytes. Levels of interleukin 6 and tumor necrosis factor were increased in the NPC supernatant, and interleukin 6 levels were increased in serum from tumor-bearing mice. We conclude that the presence of a single hepatic focus of metastatic tumor results in augmented immune function of murine liver NPCs.


Cholera toxin pretreatment protects against tumor necrosis factor lethality without compromising tumor response to therapy. Antitumor therapy with tumor necrosis factor is limited by systemic toxic effects. We studied whether cholera toxin, a bacterial exotoxin that adenosine diphosphate-ribosylates the alpha-subunit of Gs proteins, could separate the lethal from the antitumor effects of tumor necrosis factor. A single dose of intravenous cholera toxin protected non-tumor-bearing mice from a lethal dose of Escherichia coli endotoxin administered 6 or 24 hours later. On the basis of these results, tumor-bearing mice were randomized to receive either cholera toxin or saline, followed 6 hours later by either human tumor necrosis factor (400 micrograms/kg) or saline. Tumor-bearing mice pretreated with cholera toxin had (1) reduced treatment-related mortality (0/11 vs 5/11 for saline controls) and (2) tumor regression similar to that of controls. In a separate experiment in tumor-bearing mice, intravenous human tumor necrosis factor treatment induced an increase in serum levels of murine tumor necrosis factor to a peak of 500 pg/mL at 1 hour in saline-pretreated controls, while a similar increase could not be detected in those mice pretreated with cholera toxin. These results suggest that pretreatment with cholera toxin can reduce the endogenous tumor necrosis factor response to administered tumor necrosis factor and separate the lethal from the antitumor effects. Cholera toxin may prove to be a useful tool for investigating the mechanisms underlying the varied effects of tumor necrosis factor.


Surgical resection following interleukin 2 therapy for metastatic renal cell carcinoma prolongs remission. Records of 399 patients with metastatic renal cell carcinoma treated with interleukin 2 with or without lymphokine-activated killer cell immunotherapy enrolled in 14 separate clinical trials from multiple institutions were reviewed to determine whether patients with a partial response to interleukin 2 therapy would benefit from surgical resection of residual tumor. Sixty-two patients demonstrated objective responses (15.5%), 18 (4.5%) complete and 44 (11.0%) partial. Eleven patients underwent resection of residual tumor in the lung, kidney, retroperitoneum, or pelvis so that they had "surgically no evidence of disease" (SNED). Of these, 10 had partial responses, and one patient with progressive disease had a complete response. Comparison of response duration showed no difference between the complete response and SNED groups, but there was a significant difference between each of these groups and the partial response group. At this writing, all 11 patients in the SNED group remained alive without evidence of disease (median follow-up, 21 months). In contrast, only 14 patients (76%) with complete responses and 15 patients (35%) with partial responses remained free of disease progression. Enhanced survival of the complete response and SNED groups compared with the partial response group borders on significance and awaits longer follow-up. These data suggest that surgical resection, if technically feasible, may benefit patients who show a partial response to interleukin 2 treatment for metastatic renal cell carcinoma.


Surgical glove powders bind latex antigens. Latex surgical gloves have recently been identified as a potential source of allergens. Much of the current information suggests that the soluble proteins in latex may cause significant reactions in sensitive individuals. The starch powders used as a lubricant on some latex gloves have also been identified as potential allergens in some patients. In this study, we determined these powders to act as potential carriers of latex allergens. We have produced a polyclonal antiserum to be used as a reagent to study latex proteins. By Western blot analysis, we identified a significant interaction between latex proteins and starch powders. The binding of latex proteins to starch particles results in a glove particle that may have an increased potential to act as an allergen. The latex protein-starch particles represent a potential mechanism for exposure and sensitization of health care workers to latex allergens. Elimination of these particles from the operating room should reduce the route of sensitization and the potential for adverse reactions to latex.


A new procedure for management of extrahepatic portal obstruction. Proximal splenic-left intrahepatic portal shunt. For management of obstruction of the extrahepatic portal trunk in patients with healthy livers, we designed an end-to-side anastomosis between the proximal splenic vein and the umbilical portion of the left intrahepatic portal vein and performed a splenectomy to relieve portal hypertension, treat hypersplenism, and restore hepatic portal flow. To our knowledge, no other procedure more adeptly restores original hepatic blood flow. Creation of an anastomosis between the coronary vein and umbilical portion of the left intrahepatic portal vein is an alternative method.


Massive intra-abdominal hemorrhage from a hepatic laceration caused by vomiting. We present a case report of a previously undocumented incident of massive hemoperitoneum from a liver laceration secondary to vomiting. The patient presented with the complaint of vomiting and abdominal pain. Computed tomography revealed perihepatic and perisplenic fluid collections. With this evidence and a rapidly falling hematocrit, she underwent emergency laparotomy. Intraoperative findings included 3 L of blood in the abdomen and a liver laceration at the juncture of the liver and the falciform ligament.


Studies on the prenatal toxicity of toluene in rabbits following inhalation exposure and proposal of a pregnancy guidance value. Prenatal toxicity of toluene was determined in two separate studies by inhalation exposure of Himalayan rabbits. In the first study 15 artificially inseminated females per group were exposed to 30, 100, or 300 ppm and in the second study 20 artificially inseminated females per group inhaled 100 or 500 ppm. In each case the rabbits were exposed for 6 hours per day from day 6 post-insemination (p.i.) to day 18 p.i. The respective controls inhaled conditioned clean air under the same exposure conditions. No signs of maternal toxicity were observed. All data obtained on gestational parameters were found to be within the variation range reported for this rabbit strain. The fetal external, soft tissue and skeletal findings were seen in toluene exposed fetuses in a frequency similar to the corresponding and/or historical controls. Differences observed between the groups were not concentration dependent and were considered incidental rather than compound related. Therefore, toluene was not embryotoxic, fetotoxic, or teratogenic for rabbits exposed during the period of organogenesis. The highest concentration tested under these conditions (500 ppm) was found to be a no-observable-adverse-effect level (NOAEL) for both the adult and the fetal Himalayan rabbit. Based on these and previous results of animal studies of prenatal toxicity, a safety or uncertainty factor approach is considered for setting limits of exposure for women at workplaces. A pregnancy guidance value of 20 ppm is proposed.


Auditory degeneration after exposure to toluene in two genotypes of mice. Two inbred strains of mice, CBA/Ca (with a moderate hearing loss starting late in life) and C57BL/6J (with an early onset of spontaneous auditory degeneration), were exposed to toluene by inhalation (1000 ppm, 12 h/day, 7 days) at either 1 or 6 months of age. Thresholds of auditory brainstem response (ABR) were measured 3-5 days after exposure and assessed repeatedly up to the age of 16 months (C57) or 23 months (CBA). Both strains of mice exposed to toluene at 1 month of age showed a mild loss of sensitivity at a high frequency (31.5 kHz) shortly after exposure. With increasing age, toluene exposure had little effect on the aging process of the auditory system in CBA mice but accelerated age-related hearing loss in C57 mice. The results indicate that toluene exposure can aggravate auditory deterioration only in mice with a strong genetic predisposition to spontaneously precocious age-related hearing loss.


Effects of p,p'-DDE and some other chlorinated hydrocarbons on the formation of prostaglandins by the avian eggshell gland mucosa. Some structurally related chlorinated hydrocarbons were investigated for their effects on the production of prostaglandins by the eggshell gland mucosa of ducks and domestic fowl. Formation of PGF2 alpha, PGE2 and TxB2 by homogenates of domestic fowl eggshell gland mucosa was significantly inhibited by in vitro addition of p,p'-DDE, Arochlor 1242 and, to a lesser extent, Arochlor 1260, but not by p,p'-DDT and o,p'-DDE. Comparatively, in duck eggshell gland mucosa homogenates, synthesis of the same prostaglandins was somewhat more sensitive to inhibition by 5 microM p,p'-DDE added in vitro. Eggshell gland mucosa synthesized significantly more PGF2 alpha, PGE2 and TxB2 than did the mucosa of the magnum and isthmus regions of the oviduct. Duck eggshell gland mucosa homogenates synthesized significantly more prostaglandins than similar homogenates from the domestic fowl, and, considering the former synthesis of PGF2 alpha was significantly higher when ducks were slaughtered at 08:00 than at 16:00 hours. In ducks, dietary administration of 40 ppm, p,p'-DDE for 45 days resulted in 21% eggshell thinning compared to the contemporary control values. This treatment also resulted in notable effects in homogenates of the eggshell gland mucosa, as compared to controls: Ca2+ uptake was reduced by 43%, synthesis of PGF2 alpha, PGE2 and TxB2 was reduced by 26%, 38% and 53%, respectively; the Ca content was increased to 145%. The role of p,p'-DDE in inhibiting prostaglandin formation in the eggshell gland is discussed as a mechanism of the eggshell thinning action of this chlorinated hydrocarbon.


Manganese induced brain lesions in Macaca fascicularis as revealed by positron emission tomography and magnetic resonance imaging. A series of positron emission tomography scans was made on two monkeys during a 16-month period when they received manganese(IV)oxide by subcutaneous injection. The distribution of [11C]-nomifensine uptake, indicating dopamine terminals, was followed in both monkey brains. The brain distributions of [11C]-raclopride, demonstrating D2 dopamine receptors, and [11C]-L-dopa, as a marker of dopamine turnover, were followed in one monkey each. The monkeys developed signs of poisoning namely unsteady gait and hypoactivity. The [11C]-nomifensine uptake in the striatum was reduced with time and reached a 60% reduction after 16 months exposure. This supports the suggestion that dopaminergic nerve endings degenerate during manganese intoxication. The [11C]-L-dopa decarboxylation was not significantly altered indicating a sparing of [11C]-L-dopa decarboxylation during manganese poisoning. A transient decrease of [11C]-raclopride binding occurred but at the end of the study D2-receptor binding had returned to starting values. The magnetic resonance imaging (MRI) revealed that the manganese accumulated in the globus pallidus, putamen and caudate nucleus. There were also suggestions of gliosis/edema in the posterior limb of the internal capsule. MRI might be useful to follow manganese intoxication in humans as long as the scan is made within a few months of exposure to manganese, i.e. before a reversal of the manganese accumulation.


Paracetamol toxicity in hamster isolated hepatocytes: the increase in cytosolic calcium accompanies, rather than precedes, loss of viability. Paracetamol is cytotoxic to hamster isolated hepatocytes by a mechanism that does not involve an early increase in [Ca2+]i. Although an increase in [Ca2+]i does occur, it accompanies rather than precedes, loss of viability. Studies with the ionophore, 4-bromo-A23187, suggest that although sustained elevations of [Ca2+]i per se can initiate cell death, this occurs at levels of [Ca2+]i only above 500 nM. This concentration was not achieved on exposure of cells to a cytotoxic concentration of paracetamol for 30 min. The [Ca2+]i-response of hepatocytes to vasopressin stimulation was not altered by exposing the cells to toxic concentrations of paracetamol. This demonstrates that paracetamol does not cause any impairment in the mobilisation or redistribution of Ca2+. The role of elevated levels of [Ca2+]i in mediating chemically-induced cell-killing requires re-evaluation.


Effects of the oxazolidinedione anticonvulsants trimethadione and dimethadione and the barbiturate homolog 5,5-dimethylbarbituric acid on N-nitrosodiethylamine-initiated renal and hepatic carcinogenesis in the F344/NCr rat. The oxazolidinedione anticonvulsant trimethadione (3,5,5-trimethyl-2,4-oxazolidinedione, TMO) as well as its major metabolite, dimethadione (5,5-dimethyl-2,4-oxazolidinedione, DMO), and a structural analog from the barbiturate series, 5,5-dimethylbarbituric acid (DMB), were fed to F344/NCr male rats previously given a single initiating injection of N-nitrosodiethylamine (NDEA). The known promoter, phenobarbital (5-ethyl-5-phenylbarbituric acid, PB), was employed in this study as a positive control. At dosage levels equimolar to 500 ppm PB, none of the three compounds promoted development of hepatocellular adenomas or carcinomas, in contrast to PB. The two oxazolidinedione analogs and DMB caused minimal or no induction of cytochrome P450 isozyme 2B1 (CYP2B1)-mediated alkoxyresorufin O-dealkylase activities following short-term (2 weeks) feeding to separate groups of 6-week-old male F344/NCr rats, in contrast to the dramatic induction caused by PB. Promotion of neither thyroid nor renal neoplasia was observed following prolonged feeding of any of the tested compounds, although a significantly higher frequency of premalignant renal cortical tubular lesions (dysplasias) was seen in rats exposed to TMO following NDEA initiation than in those treated with NDEA alone. These studies provide important additional data on structure/liver tumor promoting activity relationships, and yield further evidence that within this group of structurally related anticonvulsants, it is possible to separate anticonvulsant activity from tumor promoting activity in the rat liver.


Acute infection of mice with highly virulent group B streptococci as a host resistance model for immunotoxicity assessment. This report describes a unique model for immunotoxicity evaluation in mice. The model is adapted from previously described mouse models for group B streptococcus (GBS) infections in human neonates. In this disease as well as a number of human diseases caused by highly virulent pathogens, the mechanisms of innate immunity are unable to protect the host, and survival is strictly dependent on acquired immunity. Unlike other host resistance models widely used in immunotoxicity studies, the GBS model utilizes bacteria that are highly virulent for mice (LD50 = 5-17 colony forming units). GBS is not virulent for adult humans and can be safely handled with typical precautions. Acquired immunity in the GBS model is induced during a 2 week period by two injections of heat-killed GBS. The immunizing doses are the minimum which will allow survival of 80-100% of mice in response to challenge with an otherwise lethal dose of live GBS (100 bacteria). Administration of the immunotoxic agents cyclophosphamide, carrageenan, or cobra venom factor during the immunization period and/or shortly before challenge significantly suppressed host resistance. For example, the composite mortality rate for unimmunized mice was 98% and the rate for immunized mice was 8.5%. For all groups treated with cyclophosphamide (one 75 mg/kg dose 48 h before each immunization) the mean mortality was 41 +/- 18%. The consistency of the model was evaluated by repetition of several treatments in independent experiments, and the model's consistency is comparable to that of other host resistance models.(ABSTRACT TRUNCATED AT 250 WORDS)


Decrease of epinephrine-induced arrhythmia threshold in ethanol exposed rats. An association between cardiac arrhythmias and ethanol use has been observed for some time. The sympathetic nervous system presumably plays an important role in the manifestation of cardiovascular ethanol responses. Therefore, we investigated the effects of ethanol treatment on epinephrine-induced arrhythmias. Female Wistar rats received 10 vol% ethanol or 2.5% glucose (control group) in their drinking water for 45 days. In ether anesthetized animals of both groups epinephrine (10 micrograms/kg.min) was infused via a lateral tail vein. The threshold dose for arrhythmias after epinephrine infusion (mainly 2nd and 3rd degree AV-blocks) was reduced beginning 2 days after the start of the ethanol treatment and the incidence of AV-blocks during epinephrine infusion was increased. During the ethanol treatment the prohypertensive epinephrine effect was slightly increased. The reflex bradycardia was not changed after repeated epinephrine infusion by ethanol treatment, whereas it was nearly abolished in the control group. No blood ethanol could be detected during the time of epinephrine infusion (9-12 a.m.), but determinations at 11 p.m. yielded a concentration of 0.13 +/- 0.02 mg/g. The results show that the epinephrine-induced bradyarrhythmia threshold is reduced and the frequency of arrhythmic events is augmented in rats exposed to ethanol in the drinking fluid.


Cellular toxicity of toluene on mouse gamete cells and preimplantation embryos. Toluene is an aromatic hydrocarbon, which has been used in the paint, lacquer and glue industry. It has been detected in municipal water supplies. Previous mouse in vivo studies indicated that toluene administrated by gavage increased the embryonic mortality. The present in vitro study demonstrated that a concentration of toluene higher than 8.67 micrograms/ml not only decreased sperm motility and inhibited fertilization, but also significantly increased preimplantation embryo degeneration. At lower levels no effects were observed and the adverse effect levels were approximately 780 fold higher than reported levels in municipal water supplies.


Hair analysis for drugs of abuse. V. The facility in incorporation of cocaine into hair over its major metabolites, benzoylecgonine and ecgonine methyl ester. We studied the incorporation of cocaine (COC), benzoylecgonine (BE) and ecgonine methyl ester (EME) into hair from blood. At first, the time courses of three drugs in rat plasma following i.p. administration of cocaine were investigated over 360 min. AUCs of COC, BE and EME in plasma were 14.2, 60.7 and 53.4 micrograms/ml/min, respectively. In contrast, the concentrations of the three compounds in hair were 16.4, 1.7 and 0.8 ng/mg. In spite of that, the AUC of COC in plasma was much lower than that of the other two compounds in plasma, the concentration of COC in hair was much higher than that of the other two compounds. The incorporation of COC into hair was much greater than that of BE and EME. If the incorporation of drugs from blood into hair is compared by [concentration in hair]/[AUC in plasma], that of COC, BE and EME is represented by 77:1.9:1. Our results suggest that the incorporation of drugs into hair from blood unexpectedly depends upon the physical properties of each drug.


A national validation study of the acute-toxic-class method--an alternative to the LD50 test. In a national collaborative study an alternative to the classical LD50 test--the acute-toxic-class method--was validated. With this testing procedure mortality ranges are determined between defined dose levels that are used for classification and labelling in the European Community. The results were compared with LD50 data obtained from the literature which were categorized according to the defined dose levels. The results of this collaborative study have shown that the acute-toxic-class method allows allocation to the toxicity classes of very toxic, toxic, harmful and unclassified in the same manner as on the basis of the classical LD50 tests. The acute-toxic-class method uses fewer animals and subjects fewer animals to pain and distress than the LD50 test and yields the same information on toxic signs in the treated animals. Identical classifications were obtained by the six participating laboratories in 86% of the tests. This demonstrates that the acute-toxic-class method results in excellent reproducibility in comparison to the classical LD50 test and that this new method is a reliable alternative to the LD50 test.


Comparative toxicity of four chlorinated dibenzo-p-dioxins (CDDs) and their mixture. Part I: Acute toxicity and toxic equivalency factors (TEFs). There is presently no scientifically proven method to assess the toxicity of environmental samples containing complex mixtures of chlorinated dibenzo-p-dioxins (CDDs) of known composition. Their risk assessment is currently based on the interim concept of toxicity equivalency factors (TEFs), with the unproven assumption that all interactions of CDDs are additive. To address this problem we conducted acute toxicity studies with four different CDDs, viz 2,3,7,8-tetrachlorodibenzo-p-dioxin (tetra-CDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (penta-CDD), 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (hexa-CDD) and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (hepta-CDD), all containing chlorine substituents in the crucial 2,3,7,8-positions. The homologues, dissolved in corn oil/acetone, were administered to groups of five male Sprague Dawley rats at several doses (at least three) by gastric intubation. The obtained mortality data were employed to calculate the LD20,50 and 80 for each homologue. These data were subsequently used to prepare equipotent doses (expected mortality of 20, 50 and 80%) of a mixture containing all four homologues, each of them contributing one fourth of the toxicity, under the assumption of additive toxicity. The obtained LD50 value and (TEF) was for tetra-CDD 43 micrograms/kg (1), penta-CDD 206 micrograms/kg (0.2) hexa-CDD 887 micrograms/kg (0.05) and hepta-CDD 6325 micrograms/kg (0.007), respectively. The dose-response to the mixture confirmed the hypothesis of strict additivity in the acute toxicity of the four CDD homologues.


Spontaneous neoplasms in aged Sprague-Dawley rats. Incidence of neoplastic lesions in untreated Sprague-Dawley rats (1340 males and 1329 females) used as controls in 17 carcinogenicity studies are tabulated and evaluated. In male rats, the most common neoplasms were benign pheochromocytomas and keratoacanthomas (4.0% in each case) followed by pancreatic islet cell adenomas (3.7%), thyroid parafollicular cell adenomas (3.6%), fibromas and squamous cell papillomas of the skin and hepatocellular adenomas (2.0% in each), malignant lymphoma lymphocytic (1.9%), histiocytic sarcomas (1.4%), and adrenal cortical adenomas (1.2%). In female rats, the most common neoplasms were of mammary gland origin (31.3%: fibroadenoma 19.0%, adenocarcinomas 8.8%, and adenomas 3.5%) followed by thyroid parafollicular cell adenomas (2.9%), uterine endometrial stromal polyps (2.6%), adrenal cortical adenomas (1.9%), malignant lymphoma lymphocytic (1.6%), fibromas in the skin (1.3%), and pancreatic islet cell adenoma (1.1%). Metastases were observed from pheochromocytomas, hepatocellular carcinomas, nephroblastomas, renal pelvis transitional cell carcinoma, interstitial cell tumor and seminoma of the testes, Zymbal's gland adenocarcinomas, and mammary adenocarcinomas.


Poisoning with 2,4-dichlorophenoxyacetic acid treated by hemodialysis. In this paper four patients are presented who had been poisoned by 2,4-dichlorophenoxyacetic acid (2,4-D). The first patient, aged 51 years, had attempted to commit suicide by taking orally 400 ml of a 40% solution of 2,4-D. He was admitted in a coma, 6.5 h after poisoning. Extracorporal hemodialysis was performed and the course of the illness was satisfactory. The second patient, aged 80 years, had accidentally drunk 100 ml of a 40% solution of 2,4-D. He was admitted in a coma a few hours after poisoning. Hemodialysis and resin hemoperfusion were performed and the course of the illness was satisfactory. Prior to the above therapy the patient had a 2,4-D serum concentration of 177 mg/100 ml. 2,4-D clearance was 56.3 ml/min during this therapy. The third patient, aged 24 years, had drunk 200 ml of a 40% solution of 2,4-D in a suicide attempt, and paraquat poisoning was also suspected. He was admitted 10 h after poisoning and immediately hemodialysis and hemoperfusion were carried out: the course of the illness was satisfactory. On admittance the concentration of 2,4-D in serum was 122.5 mg/100 ml, and clearance was 72.9 ml/min during treatment. The fourth patient, aged 50 years, had accidentally drunk 100-200 ml of a 40% solution of 2,4-D. He was admitted in a coma 3 h after poisoning. Hemodialysis was performed and the course of the illness was satisfactory. On admittance the concentration of 2,4-D in serum was 37 mg/100 ml and clearance was 68.7 ml/min.(ABSTRACT TRUNCATED AT 250 WORDS)


Kinetics and renal effects of formic acid in occupationally exposed farmers. Twelve male farmers (38 +/- 14 years of age, mean +/- SD) were exposed to 7.3 +/- 2.2 mg formic acid/m3 for 8 h in the silage making (mean +/- SD, N = 12). Each gave urine samples immediately, 15 h and 30 h after the end of the exposure. The excretion of formate was linearly related to the exposure 15 and 30 h after the exposure. Exposure increased renal ammoniagenesis and urinary calcium at 30 h post-exposure. Both biochemical effects may be explained by the interaction of formic acid with the oxidative metabolism of renal tubular cells, as formic acid is a known inhibitor of the cytochrome oxidase. In view of these renal effects, the current hygienic limits may not entirely protect exposed individuals.


[A new counting method of airborne Japanese cedar (Cryptomeria japonica) pollen allergens by immunoblotting using anti-Cry j I monoclonal antibody]. We produced monoclonal antibodies against the major allergen of Japanese cedar (Cryptomeria japonica) pollen, Cry j I. KW-S10 antibody reacted only with Japanese cedar pollen and KW-S91 antibody reacted to most angiospermae pollens as well as Japanese cedar pollen. Using these antibodies, we devised a new counting method of Japanese cedar pollen allergen particles by an immunoblotting technique. Airborne pollen allergens were collected on vaseline coated glass slides or Burkard's sampling tape and were transferred onto polyvinylidene difluoride (PVDF) membranes. The membranes were treated with anti-Cry j I monoclonal antibody conjugated with alkaline phosphatase. Pollen allergens were detected as spots on the membranes after staining with phosphatase substrate (BCIP/NBT). This method using KW-S10 antibody measured only the amounts of allergen from Japanese cedar pollen, while with KW-S91 antibody, the method measured the amounts of pollens which have antigenicity in common with Japanese cedar pollen.


[Study of liver function in babies with atopic dermatitis by using 13C-methacetin breath test]. We measured serum GOT levels in babies with atopic dermatitis and food allergy. Two hundred and fourteen babies (133 male, 18 female, under 2 years of age) who first visited the Department of Allergy in the National Children's Hospital were examined. Their serum GOT levels were higher than normal; the younger they were, the higher the serum GOT levels were. We carried out the 13-methacetin breath test (MBT) on 11 babies with atopic dermatitis and high serum GOT levels as well as 5 normal babies to estimate their hepatic microsomal function. 13C-methacetin was administered (0.5 mg/kg) orally, and breath was collected at 30 minutes before and immediately before administration. After administration it was collected at 15 minute intervals for the first hour and 45 minute intervals for 90 consecutive minutes afterwards. The level of 13CO2 in their breath was determined with a mass spectrometer. The peak level of 13CO2 excretion (%dose/hr) in the atopic babies with high serum GOT levels was lower and the time required for 13CO2 excretion to reach its maximum level was longer than in normal babies. Also their 13CO2 clearance rate (%/hr) was lower. These results suggested that there was some relationship between atopic dermatitis and liver dysfunction in babies.


[Efficacy of early use of continuous isoproterenol inhalation therapy for severe asthma attacks in children]. The aim of this study was to evaluate the efficacy and safety of continuous isoproterenol inhalation therapy for asthma attacks in children. We used l-body isoproterenol (Proternol L) in 22 children with 32 episodes of severe attacks. One of them did not respond to this therapy, and two had complications (atelectasis and pneumothorax). Twenty-nine cases were divided into three subgroups according to their clinical scores; A) scores less than or equal to 4, which meant that they were in the early stage of severe attack (n = 9), B) scores 5-6, which meant impending respiratory failure (n = 17), C) scores greater than or equal to 7, which meant respiratory failure (n = 3). The values of SpO2 at the start of this therapy were 94.8, 91.5, 82.0%, respectively. The more severe their attacks were, the lower their SpO2 levels were. The periods until their scores became zero were 0.78, 6.3, 17.2 hours, respectively. There were significant differences between each period respectively (p less than 0.001, p less than 0.01). Heart rates decreased when their symptoms improved, and other adverse effects were not detected. These results suggest that this therapy is effective and safe for children with severe asthma attacks, especially in the early stage.


[A study of skin test with regard to age differences and agreement with positive results from the RAST and ELISA methods]. Skin tests of the scratch type were performed on 132 asthmatic patients with 28 allergens. The threshold titers of skin test, RAST and ELISA of house dust, HD mites, Japanese cedar pollen, ragweed pollen and orchard grass pollen were included. The main skin-positive allergens among the patients were as follows: house dust, HD mites, Japanese cedar pollen, orchard grass pollen, timothy grass pollen and ragweed pollen. There are age differences on skin-positive rates among 4 age groups of the patients; 90% of the patients under 40 years old groups reacted positively to any of 28 allergens, while half number of the patients groups over 40 years old reacted positively to the allergens. According to the quantitative analysis between threshold titers of skin test and RAST titers using house dust and HD mites allergens, specific IgE production shall be decreased in the patients over 40 years old. Using 5 main allergens above mentioned, the agreements of positive responses between three methods were compared. RAST positive responses correlated well with the skin test results, while ELISA positive responses correlated rather poorly with the skin test results. However, correlation between RAST and ELISA results was relatively good. The correlation of positive responses to house dust and HD mites by the three methods was very good, but there were some cases where positive responses were obtained by only one of the methods.


[The dysfunction of human peripheral blood dendritic cells on concanavalin A-induced T cell responses in patients with systemic lupus erythematosus]. The accessory cell (AC) functions of peripheral blood dendritic cells (PDC) in concanavalin A (Con A)-induced T cell proliferation were investigated in patients with systemic lupus erythematosus (SLE). In Con A-induced T cell proliferation using added autologous PDC, AC activity was present in SLE patients (p less than 0.01). The Con A-induced T cell proliferation, however, was significantly lower in SLE patients than in normal subjects (p less than 0.01), and the level of decrease became greater with increased activity of the disease (p less than 0.01). In investigating the Con A-induced T cell proliferation using added allogeneic PDC, we compared T cells from SLE patients + PDC from normal subjects or T cells from normal subjects + PDC from SLE patients with T cells + allogeneic PDC both from normal subjects. The former two combinations showed significantly reduced T cell proliferation in active SLE (p less than 0.01 for each), while no significant differences were found for inactive SLE. The above results suggest that the reduced function of PDC as AC may be involved in reduced Con A-induced T cell proliferation in patients with active SLE.


Is a trypsin-like protease of mites a Der f III allergen? A trypsin-like protease was purified from mite (Dermatophagoides farinae) fecal extract. In SDS-PAGE, the mite trypsin-like protease showed a single band at 34 kD. The purified trypsin-like protease possessed potent allergenic activity. Both the twenty N-terminal amino acid sequence and the amino acid composition of the purified protease were very similar to those of Der f III. These data strongly suggest that the trypsin-like protease in the mite is a Der f III allergen.


[The inhibitory effects of anti-asthmatic agents on ethanol-induced bronchoconstriction in Japanese asthmatic patients]. Asthmatic symptoms are worsened after drinking small amounts of alcoholic beverages in Japanese asthmatic patients. Our previous results showed that the ingestion of pure ethanol caused a fall in FEV1.0 in about half of the Japanese asthmatics we studied. We studied the inhibitory effects of pretreatment with three kinds of anti-asthmatic agents on ethanol-induced bronchoconstriction in six Japanese asthmatic patients. We tested oral cyproheptadine hydrochloride (8 mg), which is an anti histamine agent, inhaled disodium cromoglycate (2 mg), which has an inhibitory effect on the release of chemical mediators from mast cells, and inhaled atropine sulfate (3 mg), which is an anti-cholinergic agent. Pretreatment with cyproheptadine significantly inhibited the fall in FEV1.0 120 minutes after ethanol challenge (p less than 0.05). Inhaled DSCG had significant inhibitory effects on the fall in FEV1.0 15 and 30 minutes after ethanol challenge (p less than 0.05). Inhaled atropine had no inhibitory effect. These results suggest that histamine, released from mast cells, plays an important role in ethanol induced bronchoconstriction in Japanese asthmatic patients.


[Proposal of a new classification of adult bronchial asthma--child onset asthma, adult onset asthma and adult relapse asthma. Project Team for Research into Adult Bronchial Asthma in Japan]. The first nationwide research into adult bronchial asthma in Japan proposed a new classification of adult asthma. Adult asthma was categorized into child onset asthma, adult onset asthma and adult relapse asthma. The frequency of child onset asthma, adult onset asthma and adult relapse asthma in adult asthma was 11.2%, 77.3% and 3.7%, respectively. The frequency of child onset asthma decreased markedly in the older age group. On the other hand, the frequency of adult onset asthma increased, and reached more than 90%, in the older age group. The frequency of the following factors: atopic asthma, complications with other atopic diseases, mild asthma, male patients, experience of mechanical ventilation, visits to night clinics and oxygen therapy on acute attack, was significantly higher in the child onset asthma group than in the adult onset asthma group. The frequency of infectious type, aspirin intolerance, steroid dependent asthma, severe asthma and regular medication was significantly higher in the adult onset asthma group. Adult relapse asthma seemed to fall between these two groups. Based on the above observations, we proposed a new classification of adult asthma which includes child onset asthma, adult onset asthma and adult relapse asthma.


[Studies of lymphocyte activation on late asthmatic response in adult asthma]. Late asthmatic response (LAR) as well as delayed asthmatic response (DeAR) is an important clinical characteristic in adult severe asthma. These responses might be based on cell to cell interaction following lymphocyte activation. Therefore, to clarify the pathogenesis of LAR, we studied the lymphocyte functions of adult asthmatics with LAR provoked by inhalation of house dust and Candida antigen. The results revealed that mite antigen-specific lymphocyte blastogenesis, IL-2 and ECF production were significantly higher in asthmatics with LAR provoked by house dust antigen than in normal subjects and asthmatics with IAR by house dust and LAR by Candida, though there was no significant difference in NCF. Candida antigen-specific lymphocyte blastogenesis, IL-2, ECF and NCF production were significantly higher in asthmatics with LAR provoked by Candida antigen than in normal subjects and asthmatics with IAR or LAR provoked by house dust. There was a positive correlation between Candida antigen-specific IL-2 and NCF production in asthmatics with LAR provoked by Candida antigen. These results suggest that antigen-specific lymphocyte activation may play an important role in the pathogenesis of LAR, especially in asthmatics with LAR provoked by Candida antigen, and that LAR and DeAR should be considered inclusively as cell-mediated allergy.


[Diagnosis of food allergy based on rectal mucosal cytology]. We performed rectal and/or oral challenge tests on 8 patients with suspected but unproven diagnosis of food allergy based on detailed medical history and findings from radioallergosorbent tests (RAST). The cells appearing in the rectal mucosal smear serially for 48 hours after allergen challenge were examined. The following results were obtained: 1) Significant numbers of not only eosinophils but also mast cells appeared in the rectal smears after challenges with suspected-food allergens, but not with unrelated foods. This confirmed the antigen-specificity of the method. 2) In some cases, the appearance of mast cells and eosinophils was bimodal, suggesting the existence of a later allergic response in addition to an immediate-type reaction. 3) The food-specific appearance of mast cells and eosinophils was observed in association with clinical symptoms after challenge, even in patients whose IgE antibodies to the allergen were negative or commercially unavailable. In conclusion, we propose that rectal mucosal cytology in conjunction with rectal and/or oral challenge tests is a reliable and objective method to diagnose unproven or suspected food allergy.


[Evaluation of Oriton IgE, a new kit for measurement of allergen specific IgE antibodies]. To determine whether Oriton IgE kit, a new kit for the measurement of allergen-specific IgE antibodies, is useful in screening allergen-specific antibody, we measured the titers of IgE antibodies against 11 different allergens (house dust 2, Dermatophagoides farinae, Japanese cedar, ragweed pollen, egg white, milk, cat epithelium, dog epithelium, Candida, Alternaria and Aspergillus) with the Oriton IgE kit, and the results were compared to those of intradermal tests and RAST in 103 allergic patients and 10 normal subjects. There was a clear correlation between IgE antibody titers measured by the Oriton IgE kit and the RAST. The correlation coefficient was 0.76 (p less than 0.01) and the total correspondence rate was 85.9%. We also found strong correlation between the Oriton IgE kit and RAST in IgE antibody titer against 5 different allergens, Dermatophagoides farinae, Japanese cedar, ragweed pollen, egg white and Candida. The correlation coefficient was over 0.70. The correspondence rate, sensitivity and specificity of the Oriton IgE kit to intradermal tests was 71.8%, 45.3% and 87.8% respectively. The sensitivity of the Oriton IgE kit was slightly higher, while the specificity was slightly higher in RAST, although the differences were not statistically significant between these methods. Correspondence rate of the Oriton IgE kit was similar to that of RAST. These results suggested that the Oriton IgE kit is useful in screening allergen specific IgE antibodies.


[Evaluation of the sensitized condition of patients with allergic diseases in Okinawa using the MAST allergy system]. We determined, using the MAST system, specific IgE antibodies to allergens in the circulating blood of 127 patients with bronchial asthma, allergic rhinitis and atopic dermatitis in Okinawa. The positive rates to inhalant allergens in all patients examined by the MAST system were as follows: Dermatophagoides farinae 65%, house dust 58%, cat epithelium 17% and Japanese cedar 9%. In addition, the positive rates to food allergens found in all patients were as follows: wheat 16%, shrimp 14%, egg white, rice and crab 12%. The average number of positive allergens in the patients with atopic dermatitis was larger than that in those with allergic respiratory diseases only. The above five specific IgE antibodies were detected simultaneously in 12 (9%) of the 127 patients. In addition, the average number of overlapping positive allergens was 2.0 in all patients. From these results, it was suggested that the number of overlapping positive allergens in patients on Okinawa is smaller than in other areas of Japan as compared with other papers.


[Time course of drug concentrations in nebulizers and nebulized solutions]. The drug concentrations in nebulizers and nebulized solutions generated by the ultrasonic nebulizer OMRON NE-U10B and the jet nebulizer INSPIRON NEBULIZER 002305 were examined. With the ultrasonic nebulizer, increases in the concentrations of saline, DSCG and isoproterenol in the nebulizer were observed; the concentrations of those in the nebulized solutions also increased. The increase was most dramatic just before the solution was emptied. No degradations of DSCG or isoproterenol were detected in the nebulized solutions, indicating that these drugs are stable against ultrasonic nebulization. An increase in the drug concentrations in the jet nebulizer was also observed. The concentrations of the nebulized solutions also increased, but the concentrations in the nebulized solution were lower than those in the nebulizer at any time. On inhalation therapy, it is important to give consideration to these concentration changes. The nebulizer should not, for example, be refilled with a new drug solution.


[A rapid measuring technique for allergen-induced IL2 responsiveness of lymphocytes by the propidium iodide-staining method. Detection of the etiological antigen in patients with allergic diseases]. A method for rapidly measuring the interleukin 2 (IL-2)-responsiveness of allergen-stimulated lymphocytes has been newly developed using propidium iodide (PI) staining and drawing ink quenching of the fluid medium fluorescence. There was a linear correlation between the number of PI-stained cells and the fluorescence intensity. The background was less than 5 percent. This fluorochromasia assay reflected the cell number for the quantitative measurement of lymphocyte proliferation. Antigen-activated patient cells added to IL2, showed greater increase in 3H-TdR uptake than IL-2-untreated cells, and were capable of acquiring IL2 responsiveness. Increased numbers of the cells were observed by both the PI- and trypan blue-staining methods. In contrast, unstimulated cells also showed increased 3H-TdR uptake response without increased cell numbers on stimulation with r-IL2 by a 6.8 to 19.3 fold stimulation index compared to the antigen-activated cells. The results indicated that the unstimulated cells in addition with r-IL2 still remained in the initial phase of the DNA-synthetic (S) period through the cell cycle, whereas the activated cells had passed through the post-synthetic gap (C2) and/or cell division at mitosis (M). 3H-TdR uptake of cultured cells usually demonstrates the presence of antigen-sensitized lymphocytes by in vitro proliferative response, and shows an increased stimulation index in 4 or 7 day cultured cells on stimulation with allergens. However, proliferation of some cell populations decreased; furthermore no distinct differences in cell proliferation between allergic and normal lymphocytes were observed, as is usual in this assay, although the present method was capable of measuring increased-IL2 responsiveness of patient lymphocytes. The results indicate that the 3H-TdR uptake method can not be substituted for cell enumeration in the evaluation of the antigen-specificity of induced-IL2 responsiveness of activated cells. Therefore, cell enumeration using the PI-staining method may be preferable in this system. The induced response was observed in lymphocytes from patients with atopic dermatitis, bronchial asthma and/or allergic rhinitis specifically on stimulation with the antigen causing clinical symptoms. The results obtained using the PI-staining method were very similar to those in previous reports where the trypan blue staining method was employed. The present method appears to be capable of rapidly screening etiological antigens for disease and easily monitoring clinical activity.


[Inhibition of Cls activity by methylprednisolone]. From a clinical study it was found that serum ClINH activity increased 6 hours after methylprednisolone (MP) pulse therapy in all the patients we studied with connective tissue diseases. Furthermore plasma ClINH-Cls complex decreased after pulse therapy. These phenomena lead us to investigate the effect of MP on Cls. 1) When a constant amount of Cls (8 micrograms/ml) was incubated with several concentrations of MP (2-50 mg/ml), the Cls activity of consuming C4 hemolysis was inhibited by MP in a dose-dependent manner. 2) MP inhibited consumption of C2 as well as C4 by Cls in a dose-dependent manner, even when MP had been removed by dialysis following incubation with Cls. These experimental data suggested that the trace amounts of Cls generated by immune complexes could be inhibited by long circulation of MP even at low concentrations in vivo, and resulted in a decrease of ClINH consumption and ClINH-Cls complex formation. These results indicated that the inhibition of Cls activity is one of the most important mechanisms in the process of the anti-inflammatory effect of MP in vivo.


[A relationship between the annual onset day of Japanese cedar pollinosis and pollen dispersion]. A statistical analysis of the annual day of onset of Japanese cedar pollinosis was carried out on a total of 305 patients seen at the out-patient clinic for allergic diseases in the Department of Otorhinolaryngology of Kyoto Prefectural University of Medicine between 1989 and 1991 (3 years). The day of onset varied among individuals and was distributed over a period of about one month, in patient number statistics, however, a clear single peak was seen for all 3 years. The day of onset in most patients showed tendency to peak after January 1, i.e., when the maximum temperature integral is approximately 450 degrees C, on warm days where the maximum temperature exceeds 15 degrees C, on days where there is little rain, and on days when there is a strong southerly wind. This peak onset day is about 3 weeks after first day of pollen count, or 3 or 4 days before the first dispersion peak, which corresponds to the day on which pollen dispersion begins in earnest. Furthermore, it was found that there was a drastic increase in the attack rate (from 10% to more than 50%) in pollinosis patients about 1 week before the peak day of onset. By the first dispersion peak, 70-80% of the patients had experienced an attack. The results of the present study may be useful in pollen forecasting and in treating early pollinosis in the dispersion season.


[Allergy to casein hydrolysate formula. A study of sensitizing allergen]. A six-month old baby, who had been fed for 2 months with casein hydrolysate formula (MA-1) for treatment of milk allergy, developed diarrhea. The baby's RAST score for milk was negative. IgE antibodies to MA-1 but not to MA-1 depleted of lipid (fat-free MA-1), were demonstrated by enzyme-linked immunosorbent assay (ELISA). It was confirmed by the appearance of numerous mast cells and eosinophils in a rectal smear taken after challenge with MA-1 (but not detected after challenge with fat-free MA-1) that some component in the lipid of MA-1 must be an allergen in this patient.


[A case of food-dependent anaphylaxis induced by alcohol]. A 35-year-old male doctor experienced an anaphylactic reaction of urticaria, unconsciousness and hypotension one hour after taking a meal including crab meat and alcohol (beer 350 ml+Japanese sake 100 ml). He recovered within several hours after emergency treatment. Another attack occurred 6 months later after taking a meal including crab meat and alcohol. Serum IgE showed 3073 IU/ml. IgE-RAST and skin tests were positive for crab. A crab meat plus alcohol challenge test revealed a slight increase in plasma histamine level. This is a rare case of food (crab meat)-dependent anaphylaxis possibly induced by alcohol.


[Role of opioid peptide in rheumatoid arthritis--detection of beta-endorphin in synovial tissue]. The presence of beta-endorphin (beta-end) was immunohistologically identified in synovial tissue samples biopsied from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). The amount of beta-end in culture supernatants of synovial tissue explants was also determined by RIA. beta-end was strongly detected in mainly superficial synovial cells, vascular endothelial cells and a few synovial interstitial cells in RA patients, but not in OA patients. In RA patients the beta-end concentration was significantly higher in the supernatants of tissue explants (26.4 +/- 8.3 pg/ml) than in the plasma of the same patients (15.3 +/- 2.5 pg/ml) (p < 0.01). Using isolated synovial cells, the beta-end concentration in the culture supernatants of non-adherent cells (19.4 pg/ml) was higher than that of adherent cells (4.0 pg/ml). It is suggested that beta-end is produced by non-adherent cells such as lymphocytes and neutrophils in addition to synovial lining cells and endothelial cells and may play some role in the pathology of RA synovial inflammation.


Proteoglycan obtained from bovine aorta suppress thrombin-induced platelet aggregation. Proteoglycan (PG), isolated and purified from bovine aorta (intima-media), consisted of 68.6% chondroitin 4/6-sulfate (CS 4/6-S), 30% dermatan sulfate (DS), 1.4% heparan sulfate (HS), and a trace of hyaluronic acid (HA). PG did not affect platelet aggregation induced by ADP, collagen, and epinephrine, but inhibited that induced by thrombin. Of the standard GAGs investigated, hyaluronic acid (HA) and CS-4/6-S slightly inhibited only thrombin-induced platelet aggregation. However, PG and standard GAGs did not affect the thrombin induced aggregation of washed platelets. The effect of PG after papain digestion on thrombin-induced platelet aggregation was less potent than that before. It is suggested by the results of this study that PG in the aorta inactivates plasma thrombin, probably by inhibiting thrombin activators or potentiating substances which inactivate thrombin and that these effect of PG would be mainly due to PG-DS and partly due to PG-HS.


Metabolic aspects of endothelial cells cultured from rat aortae. We measured the lactate production, oxygen uptake and ATP in aortic endothelial cells cultured from young Wistar female rats. For these experiments, thoracic aortae were removed from the animals, minced into small pieces and transferred onto culture plates, to which a growth factor was added. When the endothelial cells had proliferated, the original pieces were removed from the culture and the remaining cells were subcultured until the 3rd passage. Regarding the growth curves of the 3rd passage, a logarithmic growth phase (Pg) was found from the 2nd to the 7th days and a stationary phase (Ps) followed thereafter. The ATP levels in the Pg and Ps were unchanged. Rates of lactate production and oxygen uptake were higher in the Pg than in the Ps. Only in the Ps was an interrelationship between these estimations found, suggesting that the confluent state exhibits metabolic cooperation between the cells in culture.


Parenteral lipid emulsion-induced atherosclerosis in the obese Zucker rat and its lean littermate. We have shown previously that parenterally-administered lipid emulsions can be utilized to induce early atherosclerosis in the aortas of Sprague-Dawley rats. In order to evaluate the effect of obesity on lipid-induced atherogenesis, we have utilized this same approach in the present study to demonstrate that i.v. infusions of the parenteral lipid emulsion, Lipofundin-S, will induce in the genetically obese Zucker rat and its lean littermate aortic endothelial and myofibroelastic changes indicative of early atherogenesis. Four groups of rats were used: 1) obese controls, 2) obese lipid-infused, 3) lean littermate controls, and 4) lean littermate lipid-infused. Observations were made with light and transmission electron microscopy (TEM), using qualitative morphological criteria to evaluate the results. Based on the fact that both untreated control and Lipofundin-S-induced atherosclerosis was more frequent and generally more advanced in the obese animals than in their respective lean counterparts, it appears that the obese Zucker rat is more susceptible to both spontaneous and hyperlipidemia-induced atherosclerosis than its respective lean littermate. Thus, obesity in these animals, as might be the case in humans, could potentiate an atherogenic process already enhanced by hyperlipidemia.


[Monoclonal antibodies to neuron-specific enolase in phenotyping lung cancer]. Morphological assessment of two samples of monoclonal antibodies (mcAB) to gamma-unit of neurospecific human enolase (NSE) is performed. It is established that mcABs interact in the tissue sections with neurons of the brain and spinal cord, gangliocytes of the central and peripheral nervous system this proving their specificity. 56 cases of lung carcinoma are studied using these mcABs; endocrine carcinoma was found in 11 cases, nonendocrine--in 45 cases. Neuroendocrine differentiation is revealed in 8 of 45 cases of non-small cell carcinoma; in all observations of small cell carcinoma NSE was found.


[Morphologic characteristics of microadenomas of the large intestine]. Tissue and cellular atypia, changes of the mucus chemical composition, protein secreting function, ATPase activity, differentiation of the epithelial cells and DNA replication with the widening of proliferation zone were registered morphologically in colon microadenomas. A pronounced increase of labelled small lymphocytes capable of proliferation is observed in the stroma. Fibrocytes are practically absent, fibroblasts are represented by young 3H-labelled forms. All these changes are considered as dysplastic.


[Pathomorphologic verification of the prenatal diagnosis of developmental defects in trimester II fetuses]. 153 foetuses were studied obtained after the artificial abortion for genetical indications. The scheme of the material investigation is given. Isolated, systemic and multiple defects were found in 39.0, 12.1 and 48.9%, respectively, and the contribution of the syndrome forms in the multiple developmental disturbances was 60.9%. The interruption of the pregnancy in 2% of cases was assessed as unfounded: as a consequence of hyperdiagnosis and in cases of treatable defects. The frequency of the discrepancy between prenatal and pathology diagnoses was 31.8% including hyperdiagnosis of the defect (1.3%), nosological disagreement (13.3%), the lack of diagnosis of the additional defects detectable during II trimester by present ultrasound methods (17.2%). The efficacy of the work of the prenatal diagnostic centre is, according to the authors, the number of justified interruptions of pregnancy (98% in this study).


[Autoimmunization and autoimmune diseases]. Autoimmunization is understood as a type of immune reactions to the unchanged autoantigens only. Autoimmune processes can be subdivided into the physiological ("sanitary" and regulatory) and pathological ones. Physiological processes are of importance in supporting natural immunological tolerance while pathological processes develop on the basis of the physiological ones in presence of various defects of suppressive mechanisms of the immune system. Pathological processes are the basis of the autoimmune diseases and diseases with secondary autoimmune disturbances. The distinction between organo-specific and organo-nonspecific autoimmune diseases can be taken as their preliminary tentative classification.


[Epidemiology and prevention of major cardiovascular diseases]. Analysis of the situation in the Russian Federation indicates that despite a small downward tendency, cardiovascular diseases (CVD) remain a leading cause of death among the population. Epidemiology studies of major CVD risk factors detected their high prevalence in several cities of the Republic despite noticeable geographic differences. The claim that prevention of CVD should be started from childhood remains still declarative and needs further large comprehensive studies. The accomplished research prevention programmes turned out to be feasible at community level and allowed one to develop organizational forms of their realization. To bring these projects into everyday life is a challenge as it involves many social problems.


[Ultrastructure of pulmonary squamous cell carcinoma as a prognostic factor in surgical treatment]. 163 operated on patients were divided into 2 groups: the 1st group--those surviving 5 years without recurrence (44.2%) and the 2nd group--those dying earlier from the tumour progression (55.8%). Central carcinoma was in 104, peripheral one in 59 cases. The number of dark cells (DC) and the degree of desmosome development revealed ultrastructurally have the greatest practical importance as the favourable course in the 1st group was associated with the absence or low number of DC (7%) and the high number of desmosomes (89%). These indices were found in the 2nd group in 86 and 41%, respectively. Both indices are of independent importance and are not associated with the spread of the carcinoma. The level of DC is of greater importance. Prognosis of the squamous cell carcinoma is the worse the higher is DC number in the tumour and the lower the desmosome number.


[Clinical morphology of chronic myeloid leukemia]. The morphological features of chronic myeloid leukemia at different stages of the disease were specified basing on the study of bone marrow punch biopsies of 239 patients, surgically removed spleens of 32 patients, marginal liver biopsies of 22 patients and 69 autopsies. It was found valid to distinguish two histological variants: granulocytic and granulocytic-megakaryocytic. It was shown that in the latter form of leukemia myelofibrosis, primarily of reticulin type, often tends to develop. The granulocytic-megakaryocytic variant and the diffuse myelofibrosis were found to be related to the morphological manifestations of unfavourable prognosis of chronic myeloid leukemia. The accumulation of blast cells in the central parts of bone marrow cavities, as revealed in the punch biopsies is the indication of the beginning of the blast transformation.


[Immunopathologic study of the myocardium in dilated cardiomyopathy]. Myocardial tissues of patients with dilated cardiomyopathy were studied by immunofluorescence. While immunoglobulin A fixation was observed in myocardial capillary wall and cardiomyocyte sarcolemma in the majority of patients (11 of 12), immunoglobulin G and C3 complement component were a rare finding. In the vessel wall of heart allografts immunoglobulin A fixation occurred 3-6 days after transplantation. As a result of the intensive immunosuppressive therapy which was used after the operation immunoglobulin A disappeared from heart allografts within 4-5 weeks. Immunoglobulin A fixation in the heart of patients with dilated cardiomyopathy is attributed to the anti-tissue or antivirus antibodies and probably is involved in the development of this disease.


[Changes in the human uterine vascular bed in myoma]. With scanning and transmission electron microscopy characteristic changes in the endothelial lining of myometrial vessels of uterus affected with myoma were revealed. In the presence of longitudinally oriented folds and microgrowths on the luminal surface in a healthy myometrial part, a number of changes were observed in the myoma vessels. These included the disappearance of cell surface derivatives, disturbance of tight junction of endothelial cells borders, the rise of cells over the endothelial monolayer and formation of crateriform pits. The partition of the endothelial cells on myoma vessels was accompanied by the disturbance of the microvesicular transendothelial transport.


[Computer program for the analysis of clinical diagnostic errors based on a pathology database]. The program is tested on the material of 882 autopsy protocols. All parts of clinical and pathology diagnoses were included into the generation of the data base. Automatized analysis allowed to assess main characteristics of the patient material with a histogram demonstration of group statistics according to all positions considered as well as to obtain information on the influence of more complex pathology diagnosis of a main disease, sex and age on the frequency of clinical diagnosis mistakes.


[Cystinosis in an adult].

[Cystinosis in an adult]. The paper reports a case of cystinosis with the involvement of kidneys, myocardium and liver in a female of 43. Late development of kidney failure might be due to a partial deficiency of the enzyme responsible for a cystine transport in the cell.


[Proteins associated with nucleolar organizer regions: practical application in tumor histopathology and relationship to biological properties of the tumor]. The argyrophilic staining of nucleolar organizer regions (AgNOR) has been found to be of increasing use in routine and experimental histopathology in the study of certain neoplastic lesions. The AgNOR reaction demonstrates the presence of argyrophilic non-histone proteins within NORs. The number of detectable NORs depends on several factors: the level of transcriptional activity, the number of NOR-bearing chromosomes in the karyotype, and the stage of the cell cycle in which they are sought. In man, five chromosomes have NORs, and these areas are the sites which hybridize with rRNA and are of importance with respect to the ultimate synthesis of protein. The results of AgNORs might be more informative if this technique would be applied simultaneously in cytological and histological specimens for each patient. It may also be important to examine the AgNORs profiles in stromal cells.


[Incidence of malignant tumors in Russia and their prevention]. Cancer incidence statistics in the Russian Federation and the evidence from epidemiological and experimental studies suggest that the priority in primary prevention of cancer should be given to smoking control. Discontinuation of smoking may prevent in Russia annually about 80,000 cases of cancer, or about 25% of all newly diagnosed cases of cancer in 1989 (excluding skin squamous and basal cell carcinoma). Another very important direction of cancer prevention in Russia is modification of diet in favour of increased consumption of fresh fruit and vegetables. The elimination of occupational carcinogens or a decrease in exposure to them would result in an important decrease in the incidence of certain cancers in highly industrialized areas. A decrease in the exposure to carcinogens in ambient air and the protection from exposure to ionizing radiation are of some, although limited, importance in cancer prevention.


[Anatomical limitations for the performance of angioplasty in coronary multivessel disease]. To study anatomical limitation of coronary angioplasty, as alternative therapy in patients with multivessel disease and submitted to bypass surgery. In 380 patients with multivessel disease and submitted to previous coronary bypass surgery, age ranged from 41 to 72 (average = 51) years, being 68% males. The following parameters were analyzed in the coronary arteriographies: anatomic aspects of the coronary arteries and distribution of the atherosclerotic stenosis. The patients were arranged in accordance to the criteria: complete revascularization, incomplete and no indication for coronary angioplasty. The patients were arranged in 3 different groups: I-80 (21%) patients included those in whom complete revascularization would be possible; II--55 (14.5%) patients in whom only incomplete revascularization but satisfactory would be possible and III--245 (65.5%) those patients in whom coronary angioplasty would no have indication. The data referind the patients of groups I and II were analyzed together--135 (35.5%) and arranged according to the number of arteries involved. It was observed: two vessel disease--71.8%, three vessel--18.6% and 4 or more vessel--9.6%. In group III it was observed 51.0% of the patients with 3 or more vessel disease. The major factors to contra indicate coronary angioplasty in group III included: chronic coronary obstruction 99 (40.4%); diffuse disease 11 (4.5%); technical difficulties 10 (4.1%); left main coronary artery obstruction 5 (2%) or when two or more causes were combined 120 (49%). Patients with multivessel disease and classic indication for coronary bypass surgery, have a basic limitation for angioplasty due to several anatomic factors. However, coronary angioplasty could be beneficial for a selected group of patients (35.5%) whenever a complete or incomplete revascularization could be obtained.


[Electrocardiographic changes in accidental hypothermia]. Electrocardiographic alterations were evaluated in a group of accidental hypothermia patients, and correlated with values of core temperature, pH and plasmatic concentrations of Na+, K+ and Cl-. Conventional 12-lead surface electrocardiograms were obtained in a group of 32 patients with accidental hypothermia after involuntary cold exposure. Cardiac arrhythmias, QRS configuration, ST-T segment and T wave alterations were analyzed. pH, Na+, K+ and Cl- serum concentrations were simultaneously measured. Electrocardiogram and electrolyte abnormalities were then correlated with the core temperature. Twenty-eight patients had abnormal electrocardiogram (90.6%). Sinus bradycardia and idioventricular rhythm were observed in 11 and 3 patients respectively. QT interval enlargement was found in 24 patients and Osborn wave in 28 cases. Altered T waves expressing an abnormal repolarization were observed in 23 cases. A significant negative correlation was obtained when J wave amplitude was correlated with core temperature levels. Hypothermia produces electrocardiographic abnormalities characterized by Osborn waves. Other minor findings include sinus bradycardia, idioventricular rhythm and long QT intervals.


[Occlusion of patent ductus using the Rashkind system. Initial experience]. Three patients were submitted to the Rashkind device technique for closure of a patent ductus arteriosus. The percutaneous transvenous technique was employed in every cases. A 12 mm prosthesis was utilized in one case and 17 mm prostheses in the other two cases. In the first case, after temporary occlusion of the ductus arteriosus, the prostheses was removed due to the technical impossibility of evaluation of the proximal umbrella position. In the second and third cases, the prostheses were duly liberated in the proper position, thus occluding the defects. This technique does not require general anesthesia, is indicated in patients over 6 kgs of body weight, and is a therapeutic alternative to the habitual surgical procedure.


[Dissection in an adult with dilatation of the ascendent aorta diagnosed in childhood]. Dilatation of the ascending aorta is relatively infrequent during childhood. Besides the Marfan syndrome, the congenital origin should be considered. We report a patient with dilatation of the ascending aorta diagnosed at the age of 10 who presented acute aortic dissection and rupture after a 13-year period of follow-up. Several aspects of the proper diagnosis are discussed.


[Malignant schwannoma metastasizing to the heart]. We introduce the case of a 34-year-old male with a malignant metastasizing tumor in the heart associated with skin manifestations. The patient was submitted to heart surgery to resect the tumor. The correct diagnosis was done by pathological findings and immunohistochemical methods and showed, malignant schwannoma.


[Fracture of endocardial electrode at the tricuspid valve level]. Female, 72 years old, had a permanent pacemaker system with endocardial pacing lead, and developed fracture of electrode at the point of passage across the tricuspid valve with episodes of asystole.