Effect of medullary raphe lesions on sexual behavior in male rats with or without treatments of p-chlorophenylalanine.

Male sexual activities were tested in androgen-treated castrated male rats with lesions of the raphe obscurus nucleus (ROBL) or lesions of the raphe magnus nucleus (RMGL). The ROBL male rats showed low levels of mounting, intromission and ejaculation frequencies, and prolonged mount latencies compared to castrated and sham-operated control males. The sexual activity in the RMGL group was comparable to that of the controls. The results suggest that the raphe obscurus nucleus is involved in the neural mechanisms mediating copulatory behavior in male rats, and that the raphe magnus nucleus is not. In several castrated control and ROBL males, serotonin-synthesis inhibitor, p-chlorophenylalanine (PCPA) was injected before the behavioral test, because the raphe obscurus nucleus contains a large number of serotonergic neuronal cells. PCPA-treated control males showed higher frequencies of copulatory patterns than did control males without PCPA. In contrast, the frequencies of ejaculation and intromission were not increased by PCPA in the ROBL males, compared to PCPA-untreated ROBL males, although the mount latency was shortened and mount frequency was increased. This indicates that PCPA facilitates male sexual behavior. However, the suppressive effect of ROBL still remained even after deprivation of serotonin. Moreover, PCPA acts on serotonergic neurons other than those in the raphe obscurus nucleus, thereby facilitating mount activities.


Exposure to the scent of male mice infected with the protozoan parasite, Eimeria vermiformis, induces opioid- and nonopioid-mediated analgesia in female mice.

The present study examined the nociceptive responses of female mice exposed to the scent (soiled cage bedding) of male mice infected with the protozoan parasite, Eimeria vermiformis. A 30-min exposure to the odors of a parasitized male induced naloxone (1.0 mg/kg)-sensitive opioid-mediated analgesia in female mice, whereas a brief 1-min exposure to these odors resulted in a lower amplitude, relatively short, nonopioid analgesia that was insensitive to naloxone and blocked by the serotonin-1A (5-HT1A), agonist, 8-OH-DPAT. Exposure to the odors of nonparasitized males had no significant effects on the nociceptive responses of female mice. These results indicate that female mice are able to distinguish between the odors of parasitized and nonparasitized male mice, and that female mice display both opioid- and nonopioid-mediated aversive responses to the odor cues associated with the parasitized males. The implications of these findings for parasite-based mate choice are discussed.


Etoperidone, trazodone and MCPP: in vitro and in vivo identification of serotonin 5-HT1A (antagonistic) activity.

The Ki values for etoperidone, trazodone and MCPP (m-chlorophenylpiperazine dihydrochloride) at 5-HT1A sites (using rat cerebral cortical synaptosomes and [3H]8-OH-DPAT) were determined to be 20.2, 23.6 and 18.9 nM, respectively. In an effort to elucidate the functional nature of the interaction at 5-HT1A sites in vivo, the ability of each compound to elicit reciprocal forepaw treading (RFT) or to block the RFT induced by 8-OH-DPAT in reserpinized rats was tested. Specifically, 8-OH-DPAT (1.0 mg/kg SC)-challenged or non-challenged (control) reserpinized (1.0 mg/kg SC) rats were administered etoperidone, trazodone or MCPP (IP) and scored for the elicitation of RFT (indicative of 5-HT1A agonistic activity) or for block of RFT induced by 8-OH-DPAT (indicative of 5-HT1A antagonistic activity). Reference compounds confirmed the specificity of the test. We report that etoperidone, trazodone and MCPP inhibited 8-OH-DPAT-induced RFT (ID50 = 17.4, 23.8 and 13.4 mg/kg, respectively). Only marginal RFT was produced in non-challenged animals by etoperidone and trazodone at a high dose (40 mg/kg). Taken together, the results suggest a predominant antagonistic activity of etoperidone, trazodone and MCPP at 5-HT1A receptor sites in rat central nervous system. However, one cannot rule out the possibility that these compounds are weak partial agonists. This activity may be relevant to the antidepressant action of these compounds.


MK-801 prevents the enhanced behavioural response to apomorphine elicited by repeated electroconvulsive treatment in mice.

Repeated administration of electroconvulsive stimuli (ECS) to mice once daily for a period of 7 days results in an enhanced locomotor response induced by apomorphine (1.0 mg/kg, IP). Pretreatment (30 min) with the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (0.01-1.0 mg/kg IP), suppressed ECS-induced seizure activity in a dose-dependent manner. MK-801 (0.01 and 0.033 mg/kg, IP) given 30 min before each ECS dose-dependently decreased apomorphine-mediated responses. Administration of MK-801 (0.033 mg/kg IP) 30 min after each convulsion had the same effect. These results indicate that MK-801 can abolish the ECS-induced enhancement of dopamine-mediated behaviour possibly by interfering with postictal processes. Thus, NMDA receptors seem to be involved in the behavioural changes and presumably also in the neural adaptations produced by repeated ECS.


[Isosexual precocious puberty secondary to a subarachnoid cyst].

A new case of isosexual precocious puberty due to the presence of a subarachnoid cyst is reported. A female patient 16 months old was brought to our outpatient clinic because she had had two episodes of endometrial bleeding. Activity of the hypothalamic-pituitary-ovarian axis was demonstrated by pubertal concentrations of LH, FSH and estradiol. An arteriography and a CT demonstrated the presence of a subarachnoid cyst which was conditioning the pubertal process. Surgical resection of almost all the cyst, along with shunting, did not suppress endocrine activity. Suppressive treatment with medroxyprogesterone acetate was prescribed in order to accomplish the arrest of the pubertal process.


Regulation of dynein-driven microtubule sliding by the radial spokes in flagella.

The regulation of microtubule sliding in flagellar axonemes was studied with the use of Chlamydomonas mutants and in vitro assays. Microtubule sliding velocities were diminished in axonemes from mutant cells missing radial spoke structures but could be restored upon reconstitution with dynein from axonemes with wild-type radial spokes. These experiments demonstrate that the radial spokes activate dynein's microtubule sliding activity.


Studies of immune response to hepatitis B vaccine in Thai blood donors.

The immunogenicity of heat-inactivated plasma derived hepatitis B vaccines were studied in one hundred and eighty-two adult blood donor volunteers whose HBV markers (HBsAg, anti-HBs) were negative. They were randomized for four regimens of 3 micrograms intramuscular Hepaccine-B vaccine at the schedules of 0, 1, 2, 9 months, 0, 1, 3, 9 months, 0, 2, 6, 12 months, 0, 1, 6, 12 months and another regimen of 5 micrograms Hevac-B Pasteur vaccine at 0, 1, 2, 9 months. Blood specimens, tested for serological marker (anti-HBs), were drawn at 1, 3, 6, 9, 12 and 15 months following the initial injection. The outcome revealed that the Hepaccine-B vaccinated group in the schedules of 0, 2, 6, 12 and 0, 1, 6, 12 months yielded seroconversion rates of 48.7% and 56.8%, respectively one month after vaccination. After that, the immune response (anti-HBs titer) regularly increased every three months until it reached 100% with a geometric mean (GMT) of 135 and 130 mIU/ml respectively in the fifteenth month. Taking the Hepaccine-B and the Hevac-B Pasteur with the same schedule (0, 1, 2, 9 months) into consideration, we found that the former yielded the higher seroconversion rate, one month after the initial injection, which increased to the highest rate of 95.8% in the ninth month. After that it was steady until the fifteenth month with higher GMT (584 mIU/ml) than that of Hevac-B Pasteur (323 mIU/ml). The seroconversion rate of Hevac-B Pasteur in the first month was lower than that of Hepaccine-B but it yielded the highest rate of 100% in the sixth month. After that, it gradually decreased and again increased to 100% in the fifteenth month.


A prospective evaluation of preemployment screening methods for acute industrial back pain.

Preemployment screening methods have been ineffective in predicting those at risk, and in curbing the impact of back problems in industry. Such methods have centered on individual physical factors (capacities and clinical examination). This study evaluates commonly used physical examination measures and simple historical data for its ability to predict individuals at risk for future back injury reporting in the aircraft industry. In this study, once simple historical information about previous pain treatment was known, information gained from physical factors added no significant predictive value.


Lumbar disc herniation. Computed tomography scan changes after conservative treatment of nerve root compression.

In 21 patients with computed tomography-diagnosed lumbar herniated nucleus pulposus, nerve root pain resolved after conservative treatment. A subsequent computed tomography scan was performed 6 months or more after presentation. This follow-up computed tomography scan was compared with the initial one. A definite decrease in size of the herniated nucleus pulposus was observed in 14 patients: disappearance in 5, obvious decrease in 5, and moderate decrease in 4. No definite change was observed in seven patients. Major computed tomography scan changes occurred significantly more frequently in large herniated nucleus pulposus than in small ones (p. less than 0.05). This study suggests that large lumbar herniated nucleus pulposus can decrease and even disappear in some patients treated successfully with conservative care.


Functional results after anterior lumbar fusion at L5-S1 in patients with normal and abnormal MRI scans.

The debate continues as to which patient responds best to surgical versus nonsurgical intervention for painful degenerative disc syndrome. Discography is often used as the basis for that decision. In a review of 53 cases followed for an average of 20 months after surgery, only 50% of patients with type I (contained) discography and normal magnetic resonance imaging findings were found to be improved. In those patients with types II and III (noncontained) discography and abnormal magnetic resonance imaging scans, a 75% success rate was seen. There was an overall 80% fusion rate for all patients who underwent anterior lumbar fusion at L5-S1. Average age was 34 years, with average length of disability from low-back pain of 11 months. All patients were placed in a similar presurgery and postsurgery rehabilitation protocol and had failed nonsurgical treatment options. In this matched group of patients, those with abnormal magnetic resonance imaging scans and abnormal discography, clearly fared better, with a 75% percent success rate versus 50% success rate in those with normal magnetic resonance imaging findings. This series raises the question as to whether those patients with normal magnetic resonance imaging findings are surgical candidates.


A modified muscle-splitting approach to the lumbosacral spine.

A modification of a previously reported extraperitoneal approach to the lumbosacral spine is described. The external oblique muscle is split in line with its fibers. The anterior and posterior layers of the rectus sheath are divided vertically medial to the semilunaris without splitting the internal oblique and underlying transversalis abdominus muscles. This allows an extensile retroperitoneal approach suitable for exposure of both the mid-lumbar and lumbosacral spine. There have been no complications of this approach with its use in over 50 patients undergoing anterior lumbar interbody fusion.


Percutaneous laser disc decompression. A new therapeutic modality.

The authors present a new advance in the treatment of herniated disc disease using percutaneous Nd:YAG laser to vaporize a small portion of nucleus pulposus, thereby decompressing the disc. In vitro and in vivo animal data are presented. Three hundred seventy-seven magnetic resonance imaging or computed tomography scan-documented, herniated, nonsequestered lumbar intervertebral discs with corresponding clinical findings in 333 patients were so treated in an outpatient setting. The longest follow-up was 62 months, with a mean of 26 months. According to the Macnab criteria, there was a good to fair response in 261 patients (78.4%), and a poor response in 72 (21.6%); 166 patients experienced relief of pain during the procedure. One-third of repeat magnetic resonance imaging scans at 4-6 months postlaser treatment showed modest to moderate decrease of disc herniation.


Revision surgery for failed back surgery syndrome.

Results of surgical treatment in 50 failed back surgery patients were retrospectively reviewed to determine what factors influenced surgical outcome. Before surgery, all patients had disabling pain and limited function. Overall significant improvement in pain and function was obtained in 66% of the patients. Thirteen of 16 patients (81%) who had successful fusion of pseudarthrosis had a satisfactory outcome, whereas only 3 of 13 patients (23%) who had failed pseudarthrosis repair had a satisfactory outcome. Successful pseudarthrosis repair is the key to a high clinical success rate in revision surgery for failed back surgery syndrome. Pseudarthrosis repair by conventional posterolateral fusion with postoperative lumbosacral corset immobilization showed a high failure rate. The success rate of reoperation on failed back surgery syndrome patients is low.


Back pain and disability after Harrington rod fusion to the lumbar spine for scoliosis.

Back pain questionnaires were completed by a study group of 103 idiopathic scoliosis patients fused with Harrington rods from L3 or lower and a control group of 29 patients fused to L2 or above. Minimum time to follow-up examination was 2 years. The study group had a higher rate of secondary surgeries for complications or late disc disease below the fusion, a higher back pain score, more difficulties with normal daily activities, needed more regular pain medications, and had more episodes of back pain. Patients older than 30 years at surgery had more of these problems if fused to L3 or more caudally. The amount of remaining lumbar lordosis correlated significantly with the difficulty of normal daily activities.


[Effect of the tumor cell associated glycoconjugate (TCA) derived Kato III, human gastric cancer cells on autologous mixed lymphocyte reaction in patients with rheumatoid arthritis].

We have been developing a new treatment for patients with rheumatoid arthritis (RA) by using intradermal injection of carbohydrate molecule complex. Among them, tumor cell associated glycoconjugate (TCA), the membrane structure of Kato III is one of the effective molecules. We studied the immunomodulatory effect of TCA on the autologous mixed lymphocyte reaction (AMLR) using PWM-mitogen induced lymphoblasts as stimulator cells and peripheral blood mononuclear cells (PBMC) as responder cells. In the kinetic study of the AMLR, its maximum proliferation was observed on days five through seven and responding CD4 cells highly expressed HLA-DR antigen. Studied AMLR in 10 patients with RA, proliferative responses of AMLR in these patients were divided into two types, high and low AMLR types. In vitro examination of TCA on AMLR showed that TCA at a concentration of 250 ng/ml significantly suppressed the AMLR response (p less than 0.01, paired T-test) and this phenomenon was found more frequently in high AMLR type patients than in low AMLR type patients. The suppressive effect of TCA on AMLR had a tendency to correlate with the efficacy of TCA therapy in patients studied. These results suggest that TCA may play a role in regulating the function of autoreactive lymphocytes of patients with RA.


Disability beneficiaries who work and their experience under program work incentives.

This research examines the return to work by Disability Insurance beneficiaries who were first entitled to benefits in 1980-81 and who were originally selected to be interviewed in the New Beneficiary Survey. To facilitate an examination of actual labor-force participation by beneficiaries, information on work and participation in program work incentives was collected from their claims folders. The analysis shows that approximately 10 percent of disability beneficiaries work during their initial period of benefit entitlement. About 80 percent are granted a trial work period, and over 70 percent of those granted trial work successfully complete it. More than half of them, however, were not successful in leaving the rolls through their work effort. In fact, benefit terminations due to work occurred for fewer than 3 percent of all beneficiaries in the cohort; approximately one-third of them had returned to the rolls by the end of the period under study. Beneficiaries most likely to make a work attempt were young and had a high level of education. Those with a high Social Security benefit amount were less likely to make a work attempt.


[The assessment of the health of industrial enterprise workers and the means for its strengthening].

The authors provide the results of a sociological interview of the collective of a mixed feed plant. The interview concerned information about health, healthy way of life and routine behavior. Noticeable differences were revealed between the theoretical background of the respondents and daily routine. A rapid method was employed to objectively evaluate the level of the physical health status. A considerable percentage of subjects with low health status were detected. This requires carrying out of the goal-oriented treatment, prophylactic and organizational measures at the plant.


[An analysis of the factors affecting the efficacy of prevention programs].

Methods of multidimensional analysis were used to assay the significance of the physiological and behavioral characteristics of the population of the able-bodied men of the city of Minsk as regards the efficacy of interventions carried out. It has been shown that the population takes a more active part in the implementation of measures of conventionally medical nature. Deviations in the health status and physiological characteristics revealed by screening favour a more careful attitude to the performance of the recommendations made. The low social status and the presence of pronounced harmful habits are significant predictors of a negative attitude towards preventive interventions.


[Experience in evaluating the professional skills of interns in the outpatient office visit].

The author describes a method of the control over the occupational skills of the trainees during outpatient reception with the use of a special chart filled in by the expert teacher. The chart allows one to assess the level of knowledge and skills, to analyze the performance of the occupational skills in all the students of the course, to detect the level of the practical training in disease entities and to evaluate the degree of its correspondence with the requirements to be met by the physicians of a polyclinic. The results of the 3-year observations over the dynamics of the effectiveness of the occupational skills performed and other actions with respect to polyclinical therapy, during medical practice and attestation are provided.


[The efficacy of a program of arterial hypertension prevention among an organized population (the results of a 5-year observation)].

An epidemiological examination of 4323 motor transport workers made according to the program of the All-Union Cardiology Research Center, USSR AMS, revealed high arterial pressure (AP) in 22.6% of cases. The knowledge of hypertension was found to be low (34%) as was the coverage with hypotensive treatment (7.1%) and the efficacy of the latter one (1.8%). The follow-up studies (for 5 years) demonstrated the efficacy of non-medicamentous and medicamentous AP control exercised in motor transport workers. It was proved that in the principle AP might adequately be decreased and maintained for a long time at the safe level in the overwhelming majority of subjects with AP.


[An increase in the knowledgeability of the population on the problem of arterial hypertension as a result of conducting a secondary prevention program in a nonorganized rural population].

The paper is concerned with evaluating the efficacy of sanitary and health measures carried out within the framework of the program of secondary prophylaxis of arterial hypertension (AH) in an open rural population in terms of changes in the information of the community about hypertension. The program included regular radio transmissions, talks and lectures pertaining to the problems of essential hypertension prevention and treatment. During 4 years, the information of the respondents about hypertensive action of table salt increased 4-fold (from 8 to 32.3%), especially among persons suffering from AH. The number of persons who referred to overweight as one of AH causes rose 6-fold (from 2.6 to 18.1%). The information did not depend on the sex, age, or the presence of hypertensive factors in the examinees. Alterations were recorded in the attitude of the examinees to AH and its treatment: the portion of those who took hypotensive drugs increased more than 2-fold (from 10.9 to 23.4%) whereas the percentage of subjects treated successfully from 6.8 to 10.1%. The data obtained attest to a high enough efficacy of sanitary and health measures in relation to AH in the rural population.


[The organization of disability prevention among hypertension patients].

A study was made of the causes and factors that determine disability in 102 able-bodied patients suffering from essential hypertension (a random sample), who were acknowledged invalids for the first time in 1989. Analysis of the shortcomings in the organization of the treatment and prophylactic aid to the population made it possible to outline the main trends in disability prevention in patients suffering from essential hypertension.


[Myocardial infarct in motor transport drivers and the results of long-term observations].

As many as 283 drivers with a history of acute myocardial infarction were examined. In the long-term postinfarction period, the number of the able-bodied accounted for 22.8%, the number of persons with restricted work fitness was 43.3%, that of the disabled amounted to 33.9%. It should be noted that about 60% of the able-bodied and those with restricted work fitness returned to the driving-related work. However, in some cases, the type of the trucking was either changed of the work scope was to be minimized. Criteria forming the basis for predicting the recovery of work fitness of the drivers were as follows: non-transmural character of myocardial infarction for the most part, the effective staged rehabilitation program, positive dynamics and smoothing of the ECG signs of myocardial infarction, the lack of areas of regional hypo- and akinesia of the myocardium, normalization of the ejection fraction, high and mean indicators of physical work fitness, exercise tolerance, coronary reserves, functional class I and II angina pectoris of effort, either the lack or initial clinical signs of circulatory failure, psychological readaptation, high occupational class, and labour orientation.


[Amyloidosis in the autopsy data from a general hospital of Leningrad].

Over the recent 20 years the incidence of amyloidosis did not undergo any noticeable changes, accounting for 1.48% of the total number of autopsies in 1964-1968 and for 1.52% in 1984-1988 (P less than 0.5). The number of cases of the clinically unrecognized amyloidosis increased from 37.5% in the first period to 52.18% in the second one. In most cases amyloidosis affects the kidneys (94.9%), spleen (58.2%), liver (48%) and then, in the descending order, there follow adrenals, intestine, heart, pancreas and other organs (the total data for both the periods).


Euglobulin clot lysis induced by tissue-type plasminogen activator is reduced in subjects with increased levels of lipoprotein (a).

Several reports have evaluated the in vitro effect of lipoprotein(a) [Lp(a)] levels on the fibrinolytic system, suggesting that high Lp(a) levels may inhibit fibrinolysis by competing for plasminogen binding in different systems. We have studied plasminogen activation induced by tissue-type plasminogen activator (t-PA), as well as other fibrinolytic parameters, in 25 subjects with Lp(a) levels greater than 30 mg/dl and the results were compared with those found in 23 subjects with Lp(a) less than 30 mg/dl. Both groups were similar in age, sex distribution, living habits and lipid pattern. Plasminogen activation, when measured by t-PA-induced euglobulin clot lysis, was significantly decreased in the group with elevated Lp(a) levels (lysis time, 16.7 +/- 3.3 min) compared with the group with low Lp(a) levels (11.8 +/- 2.0 min), although 8 of the 25 subjects with high Lp(a) levels showed plasminogen activation within the range of the control group. A positive significant correlation between Lp(a) levels and t-PA-induced euglobulin clot lysis time was found. No statistical differences were demonstrated between groups for the other fibrinolytic parameters studied. Addition of purified Lp(a) to the euglobulin fraction or to plasma resulted in a decrease in euglobulin clot lysis. The present study shows that t-PA induced plasminogen activation is decreased in individuals with high circulating levels of Lp(a) supporting the hypothesis that Lp(a) may interfere with the physiological functions of plasminogen.


[Experience with laparoscopic nephrectomy].

Laparoscopic procedures are promising techniques which allow less invasive surgery not only for intra-abdominal organs but also for retroperitoneal organs. Laparoscopic nephrectomy was first described by Clayman et al. We removed the left kidney of a 36-year-old male patient using laparoscopic procedures according to Clayman's technique. The kidney had developed hydronephrosis due to congenital ureteropelvic junction stenosis. In the peritoneal cavity the freed kidney was pushed into a Lapsac, minced using scissors and forceps, and removed without elongation of the wound. During the operation, pneumoperitoneum with CO2 gas induced increases in PaCO2, central venous pressure, pulmonary artery wedge pressure and cardiac output, all of which the patient tolerated well. The patient was discharged from the hospital on the 9th postoperative day. Laparoscopic nephrectomy is a useful alternative to the conventional open surgery in selected cases, when surgical techniques and instruments are improved appropriately.


Phase II trial for the evaluation of trimetrexate in patients with inoperable squamous carcinoma of the esophagus.

EST 2287 was a Phase II clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG) designed to evaluate trimetrexate in patients with advanced, measurable, inoperable squamous cell carcinoma of the esophagus. The drug was given at a dose of 12 mg/m2 daily for 5 days every 21 days to patients with carcinoma of the esophagus. The purpose of this study was to evaluate treatment efficacy in terms of tumor response and to assess the toxicity. According to a two-stage stopping rule, the study closed after 15 patients had entered. There were no responses to treatment, and median survival from study entry was 4.3 months. There was one treatment-related death caused by infection. One patient experienced life-threatening hematologic toxicity. Overall severe or worse toxicity occurred in more than half of the patients. It is concluded that additional trials of trimetrexate at this dose and schedule in patients with carcinoma of the esophagus are not warranted.


Stability of ondansetron hydrochloride in injectable solutions at -20, 5, and 25 degrees C.

The stability of ondansetron hydrochloride in 5% dextrose injection and in 0.9% sodium chloride injection when stored frozen, refrigerated, and at room temperature was studied. Solutions of ondansetron 0.03 and 0.3 mg/mL (as the hydrochloride salt) were prepared by adding 1.5 or 15 mg of the drug to 50-mL minibags containing 5% dextrose injection or 0.9% sodium chloride injection. All solutions were prepared in triplicate, and each container was tested in duplicate. Testing at the time of preparation and at each subsequent test interval included visual inspection of color and clarity, determination of pH, and a stability-indicating high-performance liquid chromatographic assay to measure the ondansetron concentration. Conditions assessed included storage at -20 degrees C for two weeks to three months, 5 degrees C for 7-14 days, approximately 25 degrees C for up to 48 hours, and various combinations of these conditions. The concentration of ondansetron in each solution remained above 90% of the original concentration at each observation time under all storage conditions. No changes in color or clarity were observed, and there were only minor changes in pH. Ondansetron 0.03 and 0.3 mg/mL in 5% dextrose injection or 0.9% sodium chloride injection was stable when stored (1) for up to three months at -20 degrees C, followed by up to 14 days at 5 degrees C and by 48 hours at 25 degrees C and (2) for up to 14 days at 5 degrees C, followed by up to 48 hours at 25 degrees C.


[The distribution of dopamine D1 and D2 receptors in the brain of rodents and carnivores].

Studies have been made on the density of receptors and dissociation constants for dopamine D1- and D2-receptors in the striatum, n. accumbens with the olfactory tubercles and in the frontal cortex of Wistar rats, Norway rats and silver foxes. D1 binding was found to be significantly higher than D2 one in all the analysed brain structures of the animals studied, especially in the striatum. Although the analysis of D1- and D2-receptor binding kinetics revealed differences in Wistar and Norway rats, more significant differences were found between rats and silver foxes.


Desensitization to allopurinol in patients with gout and cutaneous reactions.

To determine the efficacy and safety of slow oral desensitization in the management of allopurinol-related pruritic cutaneous eruptions. Nine patients with renal insufficiency and chronic tophaceous gouty arthritis, who had to interrupt their allopurinol therapy because of an allergic-type pruritic maculopapular eruption, were enrolled in an allopurinol oral desensitization protocol using a schedule of gradually increasing doses. Cautious reinstitution of allopurinol was successfully accomplished in all nine patients, but four individuals required dose adjustment because of development of a mild, recurrent, macular rash early during the protocol at allopurinol doses of less than or equal to 5 mg/d. Transient, postdesensitization cutaneous reactions occurred in two patients, one of whom also had an early rash. Oral desensitization to the minor rashes induced by allopurinol is a feasible and acceptably safe approach to therapy, particularly for those with renal insufficiency in whom no substitute urate-lowering drug is available.


Epidemiology of small bowel bacterial overgrowth and rice carbohydrate malabsorption in Burmese (Myanmar) village children.

Breath hydrogen tests were performed after a rice meal (3 g of cooked rice/kg of body weight, equivalent to 1 g of carbohydrate/kg of body weight) on 256 village children (age range 1-59 months) who were known hydrogen (H2) producers. Anthropometric measurements were made every three months and growth rates were calculated. A breath H2 excretion pattern that suggested small bowel bacterial overgrowth (SBBO), which was recognized as a transient maximum level of 10 ppm or more at 20-, 40-, or 60-min breath samples following the rice meal, was present in 53 (20.7%) children, and was more frequent in children 36-47 and 48-59 months old. This breath H2 excretion pattern was detected in 48 (33.3%) of 144 children who were rice malabsorbers (greater than 10 ppm H2 above baseline values in one of the breath samples taken between 90 and 240 min), and in only five (4.5%) of 112 rice absorbers. Children who had SBBO had a high relative risk (10.7) of being rice malabsorbers. Rice malabsorbers have a high relative risk (59.7) of having faltered growth, accompanied by a large etiologic fraction (94%). This same risk (6.68) and an etiologic fraction of 62% exist in children with untreated SBBO. These findings emphasize the need for interventions aimed at reducing the prevalence of SBBO or similar conditions as detected by the breath H2 excretion pattern to prevent rice malabsorption and growth faltering.


Preoperative rectal indomethacin for analgesia after laparoscopic sterilisation.

A randomised, double-blind, placebo-controlled study was conducted among 56 day-case patients to determine the effect of the preoperative administration of rectal indomethacin on postoperative pain and opioid requirements after laparoscopic sterilisation. Outcome in women receiving indomethacin did not differ significantly from the placebo group, but there was a trend to lower subjective pain scores, reduction in early postoperative pain assessed objectively and lower parenteral pethidine requirements in the first three hours postoperatively. Indomethacin did not appear either to cause side-effects or to significantly reduce morbidity from the other postoperative sequelae of laparoscopy. Despite evidence for postoperative analgesic effect, the clinical benefits of premedication with rectal indomethacin were minor.


Effects of a thromboxane synthetase inhibitor on established immune complex glomerulonephritis in dogs.

Twelve Beagles were inoculated with concanavalin A, and after a mean ninefold increase in antibody titer, 1 mg of concanavalin A was infused into each renal artery of each dog to induce in situ immune complex glomerulonephritis. Starting 4 weeks after renal arterial infusion, 6 dogs were treated orally 3 times daily with 30 mg of 3-methyl-2 (3 pyridyl)-1-indolectanoic acid (CGS 12970)/kg of body weight, a thromboxane synthetase inhibitor, and 6 dogs (control group) received a gelatin capsule 3 times daily. Endogenous creatinine clearance and 24-hour urinary excretion of protein and thromboxane B2 were determined for each dog prior to renal arterial infusion, at the initiation of treatment and at 2, 4, 6, and 8 weeks after initiation of treatment. In addition, methyoxy-3H inulin clearance was determined at initiation of treatment and 4 and 8 weeks later. Renal specimens were examined histologically at the initiation of treatment and 4 and 8 weeks later. Glomerular mononuclear profiles/microns 3 were determined from at least 10 equatorially sectioned glomeruli from each dog. Paired t tests were used to compare mean values at the various time points to the respective mean baseline value and 2-sample t tests were used to evaluate differences between treatment groups. At the start of treatment (4 weeks after renal arterial infusion of concanavalin A), histologic evaluation of renal specimens revealed glomerular epithelial crescent formation, mononuclear cell proliferation, and infiltration of neutrophils. Mononuclear cell profiles and urinary excretion of protein and thromboxane B2 were significantly increased, but endogenous creatinine clearance values were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of intra-abdominal pressure on abdominal wall blood flow.

Adverse effects of increased intra-abdominal pressure (IAP) on cardiac, pulmonary, and renal function have been well described. Abdominal wound healing complications seen in the massively injured patient may also be associated with IAP. The effects of IAP on abdominal wall blood flow, however, have not been documented. This study examines rectus sheath (RS) blood flow in a porcine model of increased IAP. Seven domestic swine were anesthetized with pentobarbital and maintained with isoflurane. Swan-Ganz and femoral arterial catheters were placed for measurement of mean arterial pressure (MAP), cardiac output (CO), and pulmonary capillary wedge pressure (PCWP). A midline incision was performed for placement of laser flow probe on the RS and for placement of catheters to raise and measure IAP. Intra-abdominal pressure was then increased by installation of lactated ringers (LRs) into the peritoneum. Mean arterial pressure was maintained throughout the procedure with intravenous LR. Hemodynamics and RS blood flow data were obtained at baseline, 10, 20, 30, and 40 mm Hg IAP. Analysis of data was done by paired t-test with level of significance at P less than 0.05 and linear regression. Rectus sheath blood flow was significantly reduced at all pressure levels when compared to baseline and negatively correlated (r = -0.82) with increasing IAP. Since indices of systemic perfusion were maintained with increasing IAP, the decreased RS blood flow is most likely due to increased compartmental pressure within the abdomen.


Spinal manipulation for low-back pain.

To review the use, complications, and efficacy of spinal manipulation as a treatment for low-back pain. Articles were identified through a MEDLINE search, review of articles' bibliographies, and advice from expert orthopedists and chiropractors. All studies reporting use and complications of spinal manipulation and all controlled trials of the efficacy of spinal manipulation were analyzed. Fifty-eight articles, including 25 controlled trials, were retrieved. Data on the use and complications of spinal manipulation were summarized. Controlled trials of efficacy were critically appraised for study quality. Data from nine studies were combined using the confidence profile method of meta-analysis to estimate the effect of spinal manipulation on patients' pain and functional outcomes. Chiropractors provide most of the manipulative therapy used in the United States for patients with low-back pain. Serious complications of lumbar manipulation, including paraplegia and death, have been reported. Although the occurrence rate of these complications is unknown, it is probably low. For patients with uncomplicated, acute low-back pain, the difference in probability of recovery at 3 weeks favoring treatment with spinal manipulation is 0.17 (for example, increase in recovery from 50% to 67%; 95% probability limits of estimate, 0.07 to 0.28). For patients with low-back pain and sciatic nerve irritation, the difference in probabilities of recovery at 4 weeks is 0.098 (probability limits, -0.016 to 0.209). Spinal manipulation is of short-term benefit in some patients, particularly those with uncomplicated, acute low-back pain. Data are insufficient concerning the efficacy of spinal manipulation for chronic low-back pain.


Tributyltin increases cytosolic free Ca2+ concentration in thymocytes by mobilizing intracellular Ca2+, activating a Ca2+ entry pathway, and inhibiting Ca2+ efflux.

The immunotoxic environmental pollutant tri-n-butyltin (TBT) kills thymocytes by apoptosis through a mechanism that requires an increase in intracellular Ca2+ concentration. The addition of TBT (EC50 = 2 microM) to fura-2-loaded rat thymocytes resulted in a rapid and sustained increase in the cytosolic free Ca2+ concentration ([Ca2+]i) to greater than 1 microM. In nominally Ca(2+)-free medium, TBT slightly but consistently increased thymocyte [Ca2+]i by about 0.11 microM. The subsequent restoration of CaCl2 to the medium resulted in a sustained overshoot in [Ca2+]i; similarly, the addition of MnCl2 produced a rapid decrease in the intracellular fura-2 fluorescence in thymocytes exposed to TBT. The rates of Ca2+ and Mn2+ entry stimulated by TBT were essentially identical to the rates stimulated by 2,5-di-(tert.-butyl)-1,4-benzohydroquinone (tBuBHQ), which has previously been shown to empty the agonist-sensitive endoplasmic reticular Ca2+ store and to stimulate subsequent Ca2+ influx by a capacitative mechanism. The addition of excess [ethylenebis(oxyethylenenitrilo)]tetraacetic acid to thymocytes produced a rapid return to basal [Ca2+]i after tBuBHQ treatment but a similar rapid return to basal [Ca2+]i was not observed after TBT treatment. In addition, TBT produced a marked inhibition of both Ca2+ efflux from the cells and the plasma membrane Ca(2+)-ATPase activity. Also, TBT treatment resulted in a rapid decrease in thymocyte ATP level. Taken together, our results show that TBT increases [Ca2+]i in thymocytes by the combination of intracellular Ca2+ mobilization, stimulation of Ca2+ entry, and inhibition of the Ca2+ efflux process. Furthermore, the ability of TBT to apparently mobilize the tBuBHQ-sensitive intracellular Ca2+ store followed by Ca2+ and Mn2+ entry suggests that the TBT-induced [Ca2+]i increase involves a capacitative type of Ca2+ entry.


Phospholipid binding of annexin V: effects of calcium and membrane phosphatidylserine content.

We studied the binding of fluorescein-labeled annexin V (placental anticoagulant protein I) to small unilamellar phospholipid vesicles at 0.15 M ionic strength as a function of calcium concentration and membrane phosphatidylserine (PS) content. As the mole percentage of PS in the membrane increased from 10 to 50%, the stoichiometry of binding decreased hyperbolically from 1100 mol phospholipid/mol annexin V to a limiting value of 84 mol/mol for measurements made at 1.2 mM CaCl2. Over the same range of PS content, Kd remained approximately constant at 0.036 +/- 0.011 nM. A similar hyperbolic decrease in stoichiometry was observed with vesicles containing 10 or 20% PS when the calcium concentration was increased from 0.4 to 10 mM. Thus, the density of membrane binding sites is strongly dependent on the membrane PS content and calcium concentration. The effect of calcium on annexin V-membrane binding is proposed to be due to the formation of phospholipid-calcium complexes, to which the protein binds, rather than to an allosteric effect of calcium on protein-phospholipid affinity.


Dinitrophenyl S-glutathione ATPase purified from human muscle catalyzes ATP hydrolysis in the presence of leukotrienes.

Dinitrophenyl S-glutathione (Dnp-SG) ATPase has been purified from human muscle to apparent homogeneity using Dnp-SG affinity chromatography and immunoaffinity chromatography using antibodies raised against human erythrocyte Dnp-SG ATPase. The enzyme purified from human muscle showed a subunit M(r) value of about 38 kDa in denaturing gels. The M(r) value of the native enzyme as determined by Sephadex G-200 gel filtration was found to be about 80 kDa, which indicates that it is a dimer. The N-terminus of the enzyme was blocked. Its immunological and kinetic properties were similar to Dnp-SG ATPase of human erythrocytes. Besides catalyzing the ATP hydrolysis in the presence of Dnp-SG, the muscle enzyme also catalyzed ATP hydrolysis in the presence of various leukotrienes, namely LTC4.LTD4, LTE4, and N-acetyl LTE4. The specific activity of the enzyme toward LTC4 was relatively higher than other GSH-xenobiotic conjugates. The muscle enzyme exhibits a low Km value for all leukotrienes as compared to Dnp-SG, indicating high affinity of the enzyme for leukotrienes as activators. The enzyme also catalyzed ATP hydrolysis in the presence of GSH conjugates of endogenously generated fatty acid epoxides. Our results might suggest that Dnp-SG ATPase is involved in the transport of GSH conjugates, leukotrienes, and other organic anions in muscle, erythrocytes, liver, and probably other tissues.


Lymphocyte subset changes in persons infected with human immunodeficiency virus.

The severe complications of the acquired immunodeficiency syndrome represent the final phase of a prolonged course of immune system destruction during the infection by human immunodeficiency virus (HIV). Many of these complications can be predicted by measuring the depletion of CD4 positive lymphocytes. The CD4 positive lymphocyte counts are now widely accepted as a surrogate marker to assess the stage of disease and to determine immune response in major clinical trials. Other lymphocyte subsets are candidate surrogate markers for antiretroviral therapy. Our laboratory has utilized flow cytometry to perform lymphocyte subset testing, including CD4, CD8, CD4/CD8 ratio, and others for more than three years on persons with suspected immune deficiency. Results from our laboratory are presented to illustrate the use of these procedures in an urban, predominantly inner city population. The role of flow cytometry in monitoring patients with HIV infection is discussed.


Different susceptibility of red cell membrane proteins to calpain degradation.

The presence of low levels of calpastatin activity in erythrocytes of hypertensive rats affects regulation of calpain activity so it is highly susceptible to activation within physiological fluctuations in [Ca2+]. Under identical conditions, in red cells of normotensive rats, calpain activation is efficiently controlled by the high levels of calpastatin activity, and a progressive increase in proteinase activity can only be observed in parallel with a decrease in the level of calpastatin. In intact erythrocytes from hypertensive rats exposed to small variations in [Ca2+], degradation of anion transport protein (band 3) and Ca(2+)-ATPase appears as a primary event indicating that these two transmembrane proteins are probably early recognized as targets of intracellular calpain activity. Furthermore, band 3 protein seems to be structurally modified in erythrocytes from hypertensive rats, as indicated by its increased susceptibility to degradation in the presence of 10-50 microM Ca2+. In addition, when exposed to progressive and limited increases in [Ca2+], erythrocytes from hypertensive rats, but not those from normotensive rats, show a high degree of fragility that can be restored to normal values by inhibition of calpain. These results indicate that, within fluctuations in [Ca2+] close to physiological values, regulation of calpain activity is efficiently accomplished in normal erythrocytes but is completely lost in cells from hypertensive animals. Regulation is of critical importance in maintaining normal structural and functional properties of selective red cell membrane and cytoskeletal proteins, among which band 3 and Ca(2+)-ATPase appear to be the substrates with highest susceptibility to digestion by calpain.


Limb perfusion. An objective measure of hemodynamic improvement after angioplasty.

Forty-four patients undergoing femoropopliteal angioplasty were studied by magnetic resonance blood flowmetry to determine quantitative limb perfusion. Baseline limb perfusion averaged 0.52 +/- 0.15 mL/min per 100 cc of tissue. Perfusion values for successful angioplasties rose within 72 hours to a mean of 1.40 +/- 0.31 mL/min per 100 cc of tissue. There were five early failures (less than 30 days), in which perfusion fell to 0.54 +/- 0.10 mL/min per 100 cc of tissue; at 6 months, 12 additional angioplasties had failed, with limb perfusion values of 0.68 +/- 0.16 mL/min per 100 cc of tissue. At 6 months, perfusion in four additional limbs had decreased to between 0.7 and 1.0 mL/min per 100 cc of tissue, with a mean change of 0.59 mL/min per 100 cc of tissue; duplex ultrasound imaging at these sites showed restenoses ranging from 50% to 75%. We conclude that lower-leg limb perfusion appears to be a reliable measure of hemodynamic improvement after femoropopliteal angioplasty and may provide an early indicator of impending failure.


Immunological techniques to differentiate lymphoma from other malignancies.

Seven patients, who had lymph nodes or masses examined by both immunoperoxidase staining and flow cytometry, are presented to illustrate the value of each technique including a critical analysis of the current application of these techniques in the pathology laboratory. All seven patients had diagnoses established by immunoperoxidase staining using antibodies directed against: Leukocyte Common Antigen (LCA), Epithelial Membrane Antigen (EMA), Neuron Specific Enolase (NSE), Leu M1, B4 or chromagrafin and synaptosin. Flow cytometry, which could be more rapidly performed, when sufficient cells could be separated from the node or mass, was diagnostic in two of the seven cases. Flow cytometry failed to show abnormalities in Hodgkin's disease or solid tumors, but it was useful in rapid diagnosis of lymphoma, provided that the sample contained mostly involved tissue. Nodes in which there was a minor infiltration with lymphoma cells could only be detected by immunoperoxidase technique.


Treatment and outcome of right colon cancers adherent to adjacent organs or the abdominal wall.

Fifty-four (4%) of 1284 patients treated for adenocarcinoma of the colon and rectum during a 10-year period ending in 1989 underwent potentially curative resection of right colon lesions found during surgery to be adherent to adjacent organs, abdominal wall, or retroperitoneum. Final pathologic staging was as follows: modified Dukes' class B1 (n = 2), B2 (n = 24), C1 (n = 1), and C2 (n = 27). Thirteen (24%) patients had postoperative complications, including two (3.7%) with sepsis. One patient died after surgery (mortality, 1.9%). Survival rates at 1, 3, and 5 years were 74%, 52%, and 37%, respectively. Only one (11%) of nine patients with pancreatic or duodenal adherence treated with limited resection was free of disease during follow-up. Adjuvant radiation therapy and chemotherapy did not improve survival. Histologic depth of tumor penetration could not be predicted by intraoperative assessment, and therefore radical resection is recommended whenever possible.


Cloning and sequencing of influenza C/Yamagata/1/88 virus NS gene.

It was previously shown that the shortest RNA of influenza C/California/78 virus contains 934 nucleotides and codes for two nonstructural proteins of 286 amino acids (NS 1) and 121 amino acids (NS 2). In this report, we determined the nucleotide sequence of the NS gene of the recently isolated influenza C/Yamagata/1/88 strain by using cloned cDNA derived from the viral RNA. Compared with the NS gene of C/California/78, one nucleotide insertion has occurred in the NS gene of C/Yamagata/1/88. This caused frame shifts of both the NS 1 and NS 2 reading frames, directing the synthesis of the NS 1 and NS 2 proteins consisting of 246 and 182 amino acids, respectively.


Annexin V-crystal structure and its implications on function.

Annexins constitute a family of cytosolic, water soluble proteins, which bind to negatively charged phospholipids in a calcium-dependent manner. They display structural and functional features of both soluble and integral membrane proteins. The annexins face the hydrophilic as well as the hydrophobic phase (Janus-faced proteins) and mediate ion transport in vitro. We present the refined structure and molecular model of annexin V at 2.0 A resolution. The molecule is almost entirely alpha-helical, and each of the four repeats of annexin V is folded into a compact domain of similar structure. The four domains are arranged in an almost planar, cyclic array. In the center of the molecule, one can find a prominent hydrophilic pore, which we associate with the calcium-selective channel found in annexin V. Annexin V has an overall flat, slightly curved shape with two faces, one convex and one concave. The three calcium binding sites Ca1 to Ca3, all located at the convex face of the molecule, are assumed to be phospholipid binding sites, as suggested by their structural similarity to the calcium site of phospholipase A2. Soluble and membrane-bound annexin have closely similar structures, as shown by electron microscopic analysis. Several other observations provide evidence that the membrane-anchoring region of the annexin V molecule is located on the convex face. In the last part of this article, the electrophysiology of the annexins is described. Ion permeation occurs in discrete conductance states and is regulated by voltage across the membrane. A model for the annexin V-membrane interaction, the ion channel formation, and the ion conduction pathway is proposed.


Coagulation and fibrinolysis in cancer.

Haemostasis is a system of finely adjusted interactions between cells, enzymatic reaction cascades and inhibitors. Disturbances of this balance occur in many disorders, especially in inflammatory processes, septicaemia and cancer. In such cases malignant cells and infectious organisms activate the plasmatic enzyme cascades, especially of the coagulation and fibrinolysis cascades. The resulting consumption and proteolytic degradation of the regulatory proteins contribute to hypercoagulability and secondarily to reactive fibrinolysis, and these may then lead to local thromboses and haemorrhages. These pathogenic events culminate in disseminated intravascular coagulation (DIC), frequently with organ failure and death. Factors of both plasmatic systems are also "misused" by malignant cells for the purposes of growth and metastasis. Prominent examples of this misuse are the formation of a protective fibrin shield against the endogenous defence mechanisms and the local degradation of tissues for tumor proliferation as well as for cell permeation and invasion. In the search for a potential therapy a number of protease inhibitors, predominantly of enzymes of coagulation and fibrinolysis, have been tested in vivo with regard to their efficacy. So far, however, it has not been possible to find a new uniform treatment principle to inhibit the growth and/or metastasis of different types of tumor. The haemorrhagic diathesis and thromboses frequently associated with tumors are generally treated by substitution with plasma components, especially concentrates of coagulation factors and inhibitors.


Suppression of immune responses by cloned T cells and their products.

We have established a number of IL-2 dependent T cell clones with a definite suppressor function for the antibody response. Our collection included CD4+ helper (Th) and suppressor T cell (CD4+ Ts), and CD8+ cytotoxic (Tc) and suppressor T cell (CD8+ Ts) clones. Ts clones were defined by their suppressive activity on antigen-induced proliferative response and on helper functions of other CD4+ Th clones without detectable cytotoxicity and production of known helper type interleukins. The I-J expression was found to be present on both Th and Ts clones, and was generally associated with the H-2 restriction specificity of TcR of these clones. We have shown that the activated CD4+ Ts cells could inhibit the increase of intracellular Ca2+ of Th clones induced by antigen-pulsed antigen-presenting cells (APC). The identity of MHC restriction-specificities was required for the instant suppression of Ca2+ influx of Th clones, while a longer period of activation of Ts clones was needed to suppress the response of Th clones having different MHC restrictions. A strict selectivity was found in the suppressive activity of Ts clones in that Ts clones could suppress the Ca2+ responses of Th1 or Th2 clones but not of other CD4+ Ts clones. Ts clones could suppress the Ca2+ influx of Th clones induced only by antigen-pulsed APC or anti-TcR antibody but not by Con A or IL-2. Both CD4+ and CD8+ Ts clones released soluble immunosuppressive factors upon stimulation with immobilized anti-CD3 antibody.(ABSTRACT TRUNCATED AT 250 WORDS)


The current status of PET scanning with respect to schizophrenia.

PET scan studies of regional brain energy metabolism in schizophrenia have hitherto not been consistent in demonstrating any specific perturbation in heterogenous groups of patients. In some studies there was a tendency to reduced metabolic values in several regions in chronic patients. The variance of metabolic rates also tended to be greater in the group of schizophrenic subjects, but rates for most patients overlapped with those of the controls. Studies of regional brain energy metabolism also failed to disclose consistent effects of clinical antipsychotic drug treatment in schizophrenic patients. PET measurements of dopamine receptor functions in the major basal ganglia using different radioligands for D2 dopamine receptors also gave inconsistent results. One group reporting elevated densities of D2 dopamine receptors in the major basal ganglia of drug-naive schizophrenic patients could not be confirmed. PET measurements of dopamine receptor binding demonstrated profound and selective effects of clinical antipsychotic drug treatment on D2 and D1 dopamine receptor occupancy in schizophrenic patients. All chemically different categories of antipsychotic drugs induced a substantial occupancy of D2 dopamine receptors in relation to clinical treatment. This effect has been shown to be dose dependent and fully reversible. It appears much earlier than the antipsychotic effect and it is also present in neuroleptic-resistant patients. Accordingly, neuroleptic resistance is not related to individual pharmacodynamic or pharmacokinetic factors. Drug resistance is in all probability related to heterogeneity of biologic factors causing schizophrenia. Some, but not all, of the antipsychotic drugs also induce a significant D1 dopamine receptor occupancy. This effect was most marked for the unconventional drug clozapine, which showed about the same degree of D1 and D2 dopamine receptor blockade when given in conventional clinical doses. Further refinements of the resolution of PET scan instruments in the years to come and the development and application of new tracers will supply powerful tools for the further search for fundamental alterations of brain function in schizophrenia.


A monoclonal antibody to common acute lymphoblastic leukemia antigen (CALLA) and its expression on several human tumor cell lines.

We describe a newly-made murine monoclonal antibody to the common acute lymphoblastic leukemia antigen (CALLA), named SHB-10. The antigen detected by SHB-10 has a molecular weight of about 105 kDa. This antibody is very similar to that of conventional anti-CD10 Ab on indirect flowcytometric analysis using lymphoid malignant cell lines and peripheral lymphocytes of acute lymphoblastic leukemia (ALL) patients. The binding of anti-CD10 to Daudi cell and peripheral lymphocytes of ALL patients is blocked by SHB-10. Thus this monoclonal antibody is thought to detect the CALLA. The distribution of antigen detected by SHB-10 on several cell lines of neuroectodermal tumor and lymphoid malignancy was analysed and a slight difference in their cell surface expression is observed when compared with that by conventional anti-CD10. Further biochemical analysis is now under way for a better characterization of this antigen.


Micromorphological relationship between resin and dentin in vivo and in vitro.

This study examined the relationship between resin and dentin both in vitro and in vivo using phosphoric acid conditioning. Four groups of 10 teeth each had standardized Class V preparations made with the gingival cavosurface margin in the root. In Group 1, involving freshly extracted teeth, the enamel and dentin was conditioned with 37% phosphoric acid gel for 15 seconds. NTG-GMA/PMDM was applied to the enamel and dentin followed by an application of BIS-GMA/HEMA and restoration with P50. Group 2 served as a control omitting the conditioning step. Groups 3 and 4 were treated similarly to Groups 1 and 2 except in vivo and extracted 2 weeks after restoration placement. All teeth were sectioned longitudinally through the restoration. Impressions were taken of the tissue/restoration interface and examined by SEM for disclosure of gaps. The teeth were then demineralized and the fitting surface of the restoration was examined by SEM for evidence of resin penetration into the tissue. The results showed a total absence of gaps both in vitro and in vivo after acid conditioning compared to the controls commonly showing gaps. Penetration of resin into the dentin to form a zone of diffusion or hybrid layer was observed only in the conditioned specimens. The phenomenon was observed both in vivo and in vitro. It was concluded that a significant potential exists for phosphoric acid conditioning of dentin to promote bonding.


Cloning and characterization of the human muscle phosphofructokinase gene.

A 35-kbp region of genomic DNA encoding the human muscle phosphofructokinase (HPFK-M) gene including all of the coding exons (1-22) plus 2.2-kbp of 5'-flanking sequence has been cloned. The exon boundaries are the same as has been observed for the rabbit muscle phosphofructokinase (RPFK-M), the human liver phosphofructokinase (HPFK-L), and the mouse liver phosphofructokinase (MPFK-L) genes. Characterization of the structure of the HPFK-M gene and its transcript in Epstein-Barr virus transformed B-cell lines derived from patients with glycogen storage disease type VII (GSDVII or Tarui's disease) demonstrated that this single-copy gene encodes a normal sized 3.0-kb transcript in the four cases examined. This suggests the lesion in these cases represents either a point mutation or possibly a small insertion or deletion resulting in the synthesis of a defective HPFK-M protein. Analysis of the 5'-flanking region demonstrated the presence of a functional promoter located within 114 nucleotides of a proposed transcription initiation site. This promoter was active in the human cervical carcinoma cell line, HeLa S3, the dedifferentiated human hepatoma cell line, HepG2.1, and the mouse myoblast cell line, C2C12, suggesting this promoter has a broad cell-type specificity. In addition, from the known HPFK-M cDNA sequences, this observation indicates that the HPFK-M gene has a second promoter located upstream from the genomic region isolated in this study.


Inhibition of vasopressin and aldosterone release by atrial natriuretic peptide in conscious rabbits.

To elucidate the regulatory role of atrial natriuretic factor (ANF) on vasopressin (AVP) and aldosterone release in conscious rabbits, ANF was administered systematically at a rate of 15 pmol min-1 (kg body wt)-1 for 15 min in two series of experimental animals in which AVP and/or aldosterone production was stimulated. In euhydrated rabbits (series I), systemic administration of angiotensin II (Ang II) (10 pmol min-1 (kg body wt)-1, 15 min) stimulated aldosterone release threefold from basal plasma concentrations (140 pg ml-1). The co-application of ANF inhibited the Ang II-induced release of aldosterone without influencing the non-stimulated AVP system. In dehydrated rabbits (series II) with elevated plasma osmolality and AVP concentration, exogenously applied ANF increased plasma ANF fourfold at marginally reduced arterial pressure. Plasma AVP concentrations were reduced by 3.4 pg ml-1 (25%) on average, and plasma aldosterone concentrations were lowered by 34 pg ml-1 (23%) at unchanged levels of plasma corticosterone. Receptor binding studies using [125I]ANF as radioligand revealed Ang II-independent high-affinity receptors for ANF in the zona glomerulosa of the adrenal gland. With regard to the hypothalamo-neurohypophyseal AVP system, ANF binding sites were localized to the median eminence and neurohypophysis, but not to the magnocellular nuclei. ANF receptors were also labelled in structures lacking a blood-brain barrier such as the subfornical organ and the choroid plexus.


Stimulus-induced coordinate changes in mRNA abundance in single postsynaptic hippocampal CA1 neurons.

The molecular effects of use-dependent changes in synaptic transmission were studied in individual CA1 pyramidal neurons from rat hippocampal slices. Potentiation of excitatory postsynaptic currents was associated with coordinate changes in the relative abundance of several mRNAs 30 min to 3 hr after stimulation. There was a 300% increase in calcium/calmodulin-dependent protein kinase II mRNA levels concordant with a 50% decrease in protein kinase C beta 1 isoform mRNA. A 2-fold increase in zif-268 mRNA was seen, while increases in c-fos and c-jun mRNA levels were inconsistent, gamma-Aminobutyric acid A receptor beta 1 subunit mRNA levels increased 3-fold. Potentiation-induced changes were prevented by N-methyl-D-aspartate receptor blockade. Changes in mRNA abundance in individual cells, with synaptic and glial interactions intact, combine to produce a molecular fingerprint of a potentiated CA1 neuron.


Variations in chloroplast proteins and nucleotide sequences of three chloroplast genes in Triticum and Aegilops.

Two alloplasmic wheat lines having the same common wheat nucleus but the cytoplasms of Aegilops crassa and Ae. columnaris together with the corresponding normal line (control) were used in the two-dimensional gel electrophoresis of soluble and thylakoid membrane proteins of the chloroplast. Three chloroplast polypeptides: the Rubisco large subunit, the beta subunit of ATP synthase, and an unidentified 31 kDa protein, differed in the common wheat and two Aegilops cytoplasms. Three chloroplast genes, atpB, atpE and trnM, that respectively encode the beta and epsilon subunits of ATP synthase and tRNA(met), were sequenced. The atpB gene differed by two synonymous base substitutions, whereas the other two genes were identical in the two Aegilops cytoplasms. From the predicted amino acid sequences, the beta subunits of the ATP synthase in the Aegilops cytoplasms were assumed to have three amino acid substitutions: Ala by Val, Asp- by Ala, and Gln by Lys+, in contrast to the cytoplasm of common wheat. This accounts for the difference in pI values found for the common wheat and Aegilops cytoplasms. The two base substitutions for the atpE genes of common wheat and the Aegilops cytoplasms were synonymous. The differences detected in the genes encoding the two subunits of ATP synthase do not appear to be ascribable to the differences in phenotypic effects for the common wheat and Aegilops cytoplasms. The base substitution rate of the atpB-atpE-trnM gene cluster was similar to that of the rbcL gene. From the rate for the atpB gene alone, evolutionary divergence of the wheat-Aegilops complex is assumed to have begun ca. 3.0 x 10(6) years ago, as compared to ca. 8.0 x 10(6) years ago for the divergence of the wheat-Aegilops complex and barley.


Isolation and characterization of a new acetate-requiring mutant strain, ace-9, of Neurospora crassa.

A new acetate-requiring mutant strain of Neurospora crassa, ace-9, has been isolated. The mutant gene was mapped between nuc-2 and arg-12 on the right arm of the second linkage group. The ace-9 mutant strain shows very weak activity of pyruvate dehydrogenase complex (PDHC). Three strains that show no activity of PDHC had already been found, i.e., ace-2, ace-3, and ace-4. Thus the ace-9 is the fourth gene that causes the deficiency in PDHC activity by a mutation. Deficiency of PDHC activity in ace-9 strain seems to be due to defective E1 component, because (1) the activity of E1 component enzyme is very weak in ace-9 mutant strain, and (2) normal PDHC activity was resumed when a preparation of ace-9 was mixed with E1-E2 fraction of wild type or with E1 component of wild type E. coli. Difference in thermostability of both E1 component enzyme and PDHC between ace-9 and the wild type strains supports this conclusion.


Interaction of fibronectin and fibronectin binding protein (FnBP) of Staphylococcus aureus with murine phagocytes and lymphocytes.

In the present study we examined the in vitro and in vivo interactions of a cloned staphylococcal fibronectin binding protein (FnBP) and plasma fibronectin (Fn) with polymorphonuclear cells (PMNs) and macrophages, and how antibodies against FnBP affect the phagocytosis process in vitro. Moreover, the interaction of FnBP and Fn coupled on latex beads as 'artificial bacteria' and 'artificially opsonized bacteria' with murine spleen cells and peritoneal macrophages was tested. The major finding of the present study is that antibodies against the FnBP of Staphylococcus aureus (S. aureus) and low concentration of antibodies recognized two IgG-binding domains of protein A (SpA) are effective in the promotion of phagocytosis in vitro. It was also observed that FnBP has a chemoattractant activity and causes accumulation of PMNs and macrophages in the mouse peritoneal cavity when injected 24 h before irritation of peritoneal exudate. It seems likely that this activity is connected with binding to Fn molecules since formalin inactivation of FnBP (60%) abolished it. In the in vitro phagocytosis assay in the presence of FnBP (in a medium supplemented with serum depleted of Fn), ingestion of bacteria by phagocytes was identical to assay carried out in the presence of BSA. However, addition of plasma fibronectin caused an increased uptake of bacteria by macrophages and to a lesser degree by PMNs. We observed that in a population of normal splenocytes, those cells that effectively bound FnBP- and Fn-coated latex beads were mostly those cells exhibiting macrophage and dendritic morphology. In populations of spleen cells of animal infected with S. aureus, T lymphocytes were also found to bind FnBP- and Fn-coated latex beads. These data suggest that FnBP may have the ability to promote aggregation of immune cells, either directly or by interaction with plasma Fn, which can be helpful in certain cell-cell interactions taking place at the initial stages of specific immune response.


Effect of D-myo-inositol on platelet function and composition and on cataract development in streptozotocin-induced diabetic rats.

Diabetes is known to be associated with an increase in aldose reductase activity, platelet hyperaggregability, lipid peroxidation, and cataract formation. A molecule, D-myo-inositol 1,2,6-trisphosphate (PP-56), derived from phytic acid, could in principle, by supplying myoinositol to tissues and acting as an antioxidant, counteract some of the manifestations of diabetes. Thus, the effects of PP-56 on platelet aggregation, fatty acids, and polyols were investigated in uncontrolled streptozotocin-induced diabetes in rat in relation to cataract and lipid peroxidation. A decrease in the response of platelet aggregation to thrombin and ADP (P less than 0.05, P less than 0.001) and in the level of sorbitol and the ratio sorbitol/myo-inositol (P less than 0.01) in platelets was observed in the rats treated by PP-56 for 7-8 weeks. These beneficial effects were associated with an incidence of cataract reduced by 26 to 44% (P less than 0.05 to P less than 0.001) depending on the duration of treatment. They were also accompanied by a significant lower plasma level of malondialdehyde (P less than 0.05), and, more markedly, of conjugated dienes (P less than 0.001) as well as an increase in platelet lipids of the 20:4(n-6)/20:3(n-6) ratio, an index of delta 5 desaturase activity. PP-56 appears to modulate fatty acid desaturases and aldose reductase in platelets and delay by a few weeks the development of cataract in this acute model of diabetes.


Antitumour synergism between non-toxic dietary combinations of isotretinoin and glucarate.

Dietary calcium glucarate (CGT) increased the activity of non-toxic levels of dietary isotretinoin against pre-established tumors in the chemically-induced rat mammary tumour model. In the range of 1.0-1.5 mmol/kg diet, isotretinoin enhanced tumour growth by 20% over a 4 week course of treatment. Tumour growth inhibition not exceeding 15% was observed only at dosages as high as 2.0 mmol/kg, i.e. in the cumulative toxicity range. Growth inhibition by 64 mmol/kg diet of CGT alone was marginal, varying from zero to 8%. In contrast, the combination of 1.0 mmol/kg of isotretinoin and 64 mmol/kg of CGT caused a reversible inhibition of tumour growth, culminating in a net decrease in tumour volume of 20%. This study documents the marginal enhancement of tumour growth by high sub-optimal concentrations of isotretinoin alone, and describes conditions for inhibition of tumour growth by sub-optimal concentrations of the natural retinoid. Related in vitro studies on retinoid sensitive and insensitive cell lines suggest that the anticancer activity of the combination is dependent on sensitivity of the cells to retinoids.


Goserelin depot in the treatment of premenopausal advanced breast cancer.

333 pre- and peri-menopausal patients with breast cancer entered a programme of open studies on the effect of goserelin. Of the 333 patients, 265 patients were entered into assessable efficacy studies. Efficacy data were analysed from 228 eligible patients receiving 3.6 mg of goserelin administered as a subcutaneous injection of a depot formulation once every 28 days. Mean serum luteinising hormone (LH) and oestradiol concentrations were suppressed by day 22 after the first injection. Subjective response occurred in 68.3% of patients assessed. Objective response (UICC criteria) occurred in 36.4% of patients and the lifetable median duration of response was 44 weeks. Responses were observed in all histological grades of tumour, and regardless of oestrogen receptor status. Treatment was well tolerated with no withdrawals due to possible adverse reactions of which hot flushes (75.9%) and loss of libido (47.4%) were commonly encountered. Goserelin provides an effective well tolerated medical alternative to ovarian ablation in the management of advanced breast cancer.


Intravenous clodronate for the treatment of hypercalcaemia in breast cancer patients with bone metastases--a prospective randomised placebo-controlled multicentre study.

In a double blind randomised multicentre study the effect of intravenous clodronate plus hydration was compared with placebo plus hydration in the treatment of hypercalcaemia in breast cancer patients with bone metastases. The patients were treated either with hydration plus clodronate 300 mg/day or hydration plus placebo, up to 7 days or until serum ionised calcium was below 1.4 mmol/l. 25 patients received clodronate and 19 placebo. A significant difference in favour of clodronate was observed in the time to reach normocalcaemia (P = 0.004) and in the number of patients achieving normocalcaemia (P = 0.0003). 17 patients of 21 evaluable patients on clodronate achieved normocalcaemia compared with 4 of 19 patients on placebo. The only adverse event clearly associated with clodronate was symptomatic hypocalcaemia in 1 patient. Thus, clodronate seems to be a safe and highly efficacious drug for the treatment of hypercalcaemia in breast cancer patients.


In vivo and in vitro antitumor activity of mitomycin C conjugates at 7-N position through a linker containing thiocarbamate bond with CD10 monoclonal antibody.

Through a linker containing thiocarbomate bound to the 7-N position of mitomycin C (MMC), conjugates with a monoclonal antibody to CD10 (NL-1) were prepared, and their antitumor activities were examined. All five conjugates, except one, showed in vitro cytotoxicity to two CD10+ lymphoid cell lines superior to MMC. The conjugate displaying the highest cytotoxicity was selected and further tested against three CD10+ and two CD10- lymphoid cell lines in vitro. The conjugate with NL-1 antibody demonstrated higher cytotoxic activity against CD10+ tumor cells than the control conjugate with normal immunoglobulin, while there was no significant difference, when tested against CD10- tumors. The cytotoxic activity of the NL-1 conjugate to CD10+ tumors was significantly blocked by NL-1 antibody. In vivo antitumor activity of the NL-1 conjugate was then tested against a CD10+ tumor transplanted to nude mice, and side effects were recorded. The NL-1 conjugate (4 mg/kg) showed an in vivo antitumor effect similar to MMC (2 mg/kg), which is at nearly maximal tolerable dose; the latter induced decreases in numbers of leukocytes and platelets, while the former did not, suggesting less side effect by the NL-1 conjugate. Since MMC demonstrates a broad spectrum of antitumor activity, the conjugate, as such, may be applicable for the treatment of cancer patients.


The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes.

Paroxetine is a selective serotonin reuptake inhibitor possessing anti-depressant activity. Demethylenation of the methylenedioxy phenyl group is the initial step in its metabolism, the liberated carbon appearing in vitro as formate. A radioassay involving [14C-methylenedioxy] paroxetine was developed and used to examine the role of cytochrome P4502D6 in paroxetine metabolism by human liver microsomes. The rate of formate production was much higher in microsomes from an extensive metaboliser of debrisoquine than from a poor metaboliser. Also, demethylenation of paroxetine was inhibited by the quinidine and quinine isomer pair in microsomes from the extensive metaboliser only. These observations strongly suggested that the process was catalysed by the enzyme cytochrome P4502D6. Metabolism could not be completely inhibited by quinidine, the residual activity representing the contribution of at least one other enzyme. The ability of microsomes from a poor metaboliser of debrisoquine to demethylenate paroxetine provided further evidence for the involvement of an enzyme distinct from P4502D6. This was confirmed by kinetic analysis of the process in microsomes from both poor and extensive metabolisers. It is concluded that, in man, the initial step of paroxetine metabolism is performed by at least two enzymes, one of which is cytochrome P4502D6.


Mammographic screening: efficacy and guidelines.

Over the past year, concerns regarding breast cancer screening guidelines and the benefits of mammography have been raised. These concerns were fueled by a leak of information from the Canadian National Breast Screening study that suggested first an increase in mortality in women aged 40 to 49 years and then, after further investigation, no change in mortality for women screened with mammography as compared with those who relied on physical examination. No benefit from the addition of mammography to physical examination was reported for women aged 50 to 59 years. Published data demonstrate poor mammographic images in the first 3 years of the study. Direct evidence of benefit in women aged 40 to 49 years is available only in the Health Insurance Plan trial in which two-view mammography plus physical examination resulted in a delayed reduction in mortality equal to that in older women. The other trials, except for the Canadian trial, used less sensitive protocols and frequently used single-view mammography at 2- or 3-year intervals. Evidence from the Breast Cancer Detection Demonstration Project suggested benefit in screening women aged 40 years or older with annual mammography and physical examination. This paper reviews 11-year results from the Swedish two-county study and the results of other studies and discusses factors related to frequency, sensitivity, and lead-time.


[Analysis of growth, phenotype and cytotoxic activity of tumor infiltrating lymphocytes expanded in vitro with interleukin-2 and interleukin-4: preliminary results].

Tumor infiltrating lymphocytes (TIL) play an important role in the host immune response to cancer. When these cells are reinfused into cancer patients after in vitro expansion with lymphokines such as interleukin 2 (rIL-2), they often induce regression of tumor metastases. We obtained TIL of enzymatic digestion of 7 human solid tumors and then cultured them with rIL-2 and interleukin 4 (IL-4) at different concentrations for about 36 days. Immunophenotypic analysis was performed at the end of the second and fourth week; cytotoxic activity against autologous and heterologous targets was assessed on the 30th day of culture. The best lymphocytic growth was observed when we used rIL-2 and IL-4 for the first two weeks of culturing and then continued with rIL-2 alone. CD3 and CD56 cells formed the majority of TIL in all cultures. In 4 cases CD4 cells predominated at the initial stage of culturing, with CD8 cells gradually increasing and finally inverting the CD4/CD8 ratio. Autologous cytotoxicity (3/4 cases) appeared to be better in those patients in whom the CD4/CD8 ratio was inverted. These data enable identification of the combination of lymphokines that will will best provide expansion of live TIL active against tumoral cells. This procedure must be followed before in vivo reinfusion of expanded lymphocytes is carried out.


Role of 5 alpha-reduction in progesterone's ability to release FSH in estrogen-primed ovariectomized rats.

In ovariectomized estrogen-primed rats, progesterone as well as 5 alpha-dihydroprogesterone (5 alpha-DHP) are capable of inducing the release of gonadotropins. This study examined the need of 5 alpha-reduction as a prerequisite for the action of progesterone. The 5 alpha-reductase inhibitor, N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide was injected at a 1 or 2 mg dose/rat 2 h prior to an injection of 0.4 or 0.8 mg progesterone/kg body weight at 0900 h to immature ovariectomized, estrogen-primed rats and serum was analyzed for LH and FSH at 1500 h. Pituitary and hypothalamic 5 alpha-reductase activity was measured at the time of progesterone administration and at the time of the surge by incubating tissue homogenates with [3H]progesterone. Substrate, ([3H]progesterone) and product ([3H]5 alpha-DHP), were separated by reverse phase HPLC. The pituitary 5 alpha-reductase activity was not blocked at 1500 h. However, both pituitary and hypothalamic 5 alpha-reductase was blocked at the time of progesterone administration. No effect was seen by acute administration of the 5 alpha-reductase inhibitor upon either the 0.4 or 0.8 mg progesterone/kg-induced release of LH and FSH. There was, however, a specific, significant inhibition of progesterone-induced FSH but not LH release when the 5 alpha-reductase inhibition was sustained throughout the afternoon of the gonadotropin surge. These results indicate a biologically significant role for the irreversible 5 alpha-reduction of progesterone in the modulation of the release of FSH.


Kinetic evidence for separate 3 beta-hydroxysteroid dehydrogenase-isomerases in androgen and 16-androstene biosynthetic pathways in the pig testis.

The microsomal fraction from the testes of immature pigs (less than 1 week old) contains 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD-isomerase) activities that convert dehydroepiandrosterone (DHA) to 4-androstenedione and 5,16-androstadien-3 beta-ol (andien-beta) to 4,16-androstadien-3-one (dienone). These reactions are necessary for the biosynthesis of hormonally and pheromonally active steroids. Kinetic analyses of these activities were done to determine whether they are catalysed by a single enzyme or if there is any interaction between the substrates and products of one reaction on the activity of the other enzyme. Kinetic parameters were determined and the affinities for steroid substrate were similar (7-9 mumol/l) but the Vmaxapp value for the conversion of andien-beta to dienone was 10-fold that of the DHA to 4-androstenedione reaction. In analyses of the conversion of DHA to 4-androstenedione, neither andien-beta nor dienone inhibited the reaction and especially, no effect on the Kmapp for DHA was observed which would have indicated competition between DHA and andien-beta for the same active site (Kiapp from slope and intercept replots were between 3 and 80 times the values of the kinetic constants). Similarly, DHA and 4-androstenedione had minor or negligible effects on the conversion of andien-beta to dienone (Kiapp from slope replots were the same as the Kmapp but the Kiapp from the intercept replot was 12 to 25% of the Vmaxapp). It is concluded that substrate specific 3 beta-HSD-isomerases for andien-beta and DHA exist in the immature pig testis and there is little, if any interaction between these enzymes.


Aromatization inhibition alone or in combination with GnRH agonists for the treatment of premenopausal breast cancer patients.

Aromatase inhibition in postmenopausal women causes a marked fall in the plasma levels of oestrogens and is an effective treatment for breast cancer, however, trials with aminoglutethimide found that this aromatase inhibitor was ineffective in suppressing plasma oestrogen levels in premenopausal breast cancer patients. We found that the more potent inhibitor, 4-hydroxyandrostenedione (4-OHA), which can suppress oestrogen synthesis in rodents and non-human primates with intact ovarian function, was also unsuccessful as an oestrogen suppressant in premenopausal women at its maximum tolerated dose (500 mg/week i.m.). GnRH agonists are effective suppressants of ovarian oestrogen synthesis but oestrogen production from peripheral sites is unaffected. Our studies of a combination of the GnRH agonist goserelin and 4-OHA demonstrated that the combination caused greater oestrogen suppression than goserelin alone and led to objective clinical response in 4/6 breast cancer patients after their relapse from treatment with goserelin as a single agent. The combination of a GnRH agonist and an aromatase inhibitor should be subjected to clinical trials.


Fadrozole hydrochloride, a new nontoxic aromatase inhibitor for the treatment of patients with metastatic breast cancer.

Eighty previously treated postmenopausal women with metastatic breast cancer were randomized to receive fadrozole (CGS 16 949A), a new aromatase inhibitor, 1 or 4 mg orally per day. Seventy eight patients were evaluable for toxicity and response. Only mild to moderate toxicity, namely hot flushes (28%), nausea and vomiting (13%), fatigue (8%) and loss of appetite (5%) occurred. Complete response was documented in 10% and partial response in 13% of patients with 45% having a no change status for at least 2 months. The median time to treatment failure is 4.1 months. The median survival is 23.7 months. The median survival is 23.7 months. The response and survival in patients with estrogen receptor positive and estrogen receptor unknown disease were not significantly different. Neither response nor survival was significantly different between the patients receiving 1 or 4 mg of fadrozole per day. Fadrozole is a well tolerated, effective second line treatment for women with metastatic breast cancer.


Leukemia in Down syndrome: a review.

The incidence of leukemia is higher in children with Down syndrome (DS) than in normals. In approximately 50% of cases the type of leukemia is acute megakaryoblastic leukemia (AMKL) and it occurs during the first 4 years of life. The leukemic cell also has features of erythroid progenitors and therefore appears to be a precursor cell with biphenotypic properties. In addition, newborns with DS frequently develop transient leukemia (TL), which is characterized by the presence of megakaryoblasts in the blood which disappear during the first 1-3 months of life. The incidence of this disorder is unknown although preliminary studies suggest that megakaryoblasts may be found frequently in the blood of DS newborns. TL does not occur in normal newborn infants. Although TL disappears spontaneously, many of these children will develop AMKL at 1-4 years of age. Recent surveys suggest that 20-30% of newborns with TL will develop AMKL. Preliminary evidence suggests that TL is a clonal proliferation, can be fatal, and may occur in a specific subgroup of DS children. The observations in this report are drawn from our own experience, reports in the literature, and data accumulated in the Canadian Down Syndrome Leukemia Registry.


Tissue androgens and the endocrine autonomy of breast cancer.

To evaluate whether a tumour-directed gradient in androgen levels in fatty tissue can account for the maintenance of intra-tissue oestradiol levels, androstenedione (Adione), dehydroepiandrosterone (DHEA), testosterone (Testo) and androstenediol (Adiol) were assayed in breast tumour tissues and in fatty tissue taken at different distances from the tumour. The concentration of Adione was significantly lower in tumour tissue (5.6 +/- 1.5 pmol/g tissue; mean +/- SEM; n = 14) than in the adjacent fatty tissue (20.4 +/- 2.2; P less than 0.005). Testo, by contrast, occurred in equal concentrations in tumour (0.80 +/- 0.11) and in adjacent fatty tissue (0.70 +/- 0.07). Adione levels tended to be lower after the menopause only in fatty tissue, not in the tumour tissue; for Testo no differences were observed between samples from pre- and postmenopausal patients. Tumour DHEA levels (57 +/- 12 pmol/g tissue) were lower than those in fatty tissue (117 +/- 17; P less than 0.02). As with Adione, fatty tissue DHEA concentrations tended to be higher in pre- than in postmenopausal patients. Adiol showed a similar pattern as Testo. For none of the aromatase substrates nor their precursors a tumour-directed gradient was observed. The concentration of Adione in breast cancer tissue is much lower than the reported Km of the aromatase system for Adione. We have concluded, therefore, that the maintenance of oestradiol concentrations in tumour tissues is not substrate-driven.


Idiopathic hypereosinophilic syndrome terminating in acute lymphoblastic leukemia.

Idiopathic hypereosinophilic syndrome (IHES) is a heterogeneous group of disorders characterized by multisystem dysfunction and persistent, extreme eosinophilia of unknown cause. We describe a 9-1/2-year-old boy whose course included several unusual clinical features and terminated 2 years after diagnosis in acute lymphoblastic leukemia (ALL). Serial studies suggest that leukemia was not present earlier in his course. We speculate that this child may have had an evolving lymphoproliferative syndrome with a terminal blast crisis to which the eosinophilia was a nonmalignant leukemoid reaction.


The Wnt gene family in tumorigenesis and in normal development.

Various members of the Wnt gene family have been identified as activated oncogenes in mouse mammary tumors. We show that some tumors are oligoclonal for activation of a Wnt gene, and clonal variation when those tumors are transplanted to become hormone-independent. The normal function of many Wnt genes is to control pattern formation in early embryos, as shown by expression profiles and by mutant analysis.


The Myo as an oral prophylactic device used by motor skill functionally disabled patients.

The Myo appliance appears to be effective in reducing plaque and gingival inflammation. The advantage of this appliance is that the filament-like projections remove the plaque when the patient chews on the appliance. The use of the appliance is simple, does not require training or manual dexterity and is well accepted by the children.


Trends in dental treatment rendered under general anesthesia, 1978 to 1990.

While it is generally accepted that the prevalence of dental caries is decreasing, many institutions report an increase in the demand for dental rehabilitation under general anesthesia. This paper compares the characteristics of patients and types of dental treatment delivered under general anesthesia at the same hospital during 1978-1980 and 1988-1990. Patient records for children, who received dental care under general anesthesia during the two time periods examined were reviewed. Demographic data as well as data pertaining to types of dental treatment performed were collected from each patient record. Demographic characteristics were analyzed with a chi square analysis, and results regarding the types of dental treatment were analyzed using a Students t-test. Results were considered significant at p less than 0.05. There were no statistically significant differences in gender or ethnicity of the patients treated during 1978-1980 compared to 1988-1990. There were statistically significantly more patients treated in the 4-6 age group during 1988-1990 than during 1978-1980. There were no statistically significant differences in the number of dental procedures completed per patient during 1978-1980 compared to 1988-1990 in any procedure category except for dental sealants. This study indicates that the majority of pediatric dental patients being treated under general anesthesia at this hospital facility, still require an extensive amount of restorative dental care. Although most children can be successfully treated in the dental office, there is a group of pediatric patients, who require dental treatment in the hospital, under general anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)


Preventive dental health practices of non-institutionalized Down syndrome children: a controlled study.

Although Down syndrome children are known to be greatly predisposed to periodontal disease when compared with normal children, the preventive dental health practices of non-institutionalized Down syndrome children have not been well reported. This questionnaire study of 25 Down syndrome children aged 1-14 years compared with 25 normal control children showed that Down syndrome children have poorer dental health practices compared with normal children. Significantly greater numbers of Down syndrome children were weaned from the bottle at greater than 18 months of age (56% vs 24%, p less than 0.05) or had taken a bottle to bed (40% vs 12%, p less than 0.05), indicating their increased risk for the development of nursing bottle caries. In addition, Down syndrome children were receiving less help during tooth brushing (60% vs 84%, p less than 0.05), were older when they first visited the dentist, and less likely to be taking regular fluoride supplements. These results indicate that Down syndrome children are further disadvantaged by poor preventive dental health practices and should be targeted for increased preventive dental care.


Biosynthesis of marsupial milk oligosaccharides. II: Characterization of a beta 6-N-acetylglucosaminyltransferase in lactating mammary glands of the tammar wallaby, Macropus eugenii.

Tammar wallaby (Macropus eugenii) mammary glands contain a UDP-GlcNAc:Gal beta 1----3Gal beta 1----4Glc beta 1----6-N-acetylglucosaminyltransferase (GlcNAcT) whose activity has been characterized with respect to the effect of pH, apparent Km for acceptor, effects of bivalent metal ions, acceptor specificity and identity of products. The enzyme did not show an absolute requirement for any bivalent metal ion but its activity was increased markedly by Mg2+, Ca2+ and Ba2+ and, to a lesser extent, by Mn2+. When Gal beta 1----3Gal beta 1----4Glc was used as acceptor, the product was Gal beta 1----3[GlcNAc beta 1----6]Gal beta 1----4Glc. With Gal beta 1----3Gal beta 1----3Gal beta 1----4Glc as acceptor, the product was shown, by 1H-NMR spectroscopy and exo-beta-galactosidase digestion, to be a novel pentasaccharide with the structure Gal beta 1----3[GlcNAc beta 1----6]Gal beta 1----3Gal beta 1----4Glc, suggesting that the enzyme recognises the non-reducing end of the acceptor substrate, rather than the reducing end.


[Metabolic and functional consequences of complete inhibition of creatine kinase by iodoacetamide in the perfused heart].

Treatment of perfused rat hearts with 0.5 mM iodoacetamide (IAAm) for 15 min at different workloads resulting in a nearly complete inhibition of creatine kinase (CK, 99%) was followed by a rapid decline of the phosphocreatine (PCr) level (30%) and a 2-fold increase of the P(i) level which then stabilized. Conversely, the ATP content started to drop monotonously at the beginning of the IAAm washout and reached 30% 90 min after the IAAm removal under medium load. Under low workload the ATP decay occurred at later periods. Neither the ADP-stimulated mitochondrial respiration in skinned fibers, nor the Ca(2+)-stimulated ATPase activity of myofibrils was affected by IAAm treatment. The sensitivity of the resting tension of skinned fibers to Ca2+ tended to a slight increase. The cardiac work index (PRP-pressure-rate product) decreased by 25%, while the end diastolic pressure (EDP) rose by 15 mm Hg when IAAm acted under medium load. In contrast, under low work these parameters were practically stable. The hearts poisoned with IAAm performed a two times lower maximal work and had reduced (by 35%) oxygen consumption rates. The efficiency of energy utilization for mechanical work decreased by 40%. The changes in PRP and EDP correlated with the cytosolic [ATP]/[ADP] ratio in such a way that the decrease in the latter was associated with a decrease in PRP and the elevation of EDP. These data suggest that the creatine kinase system is necessary for the effective translation of a high [ATP]/[ADP] ratio from the intermembrane space of mitochondria to the cytoplasm, myofibrils and ionic pumps. This provides a high level of mechanical work and good relaxation of the left ventricle and protects cytosolic adenine nucleotides from the breakdown.


Three types of naturally occurring modified lipoproteins induce intracellular lipid accumulation in human aortic intimal cells--the role of lipoprotein aggregation.

Blood monocytes or intimal smooth muscle cells from normal aorta were incubated with low density lipoprotein (LDL) from patients with coronary atherosclerosis, or with LDL from diabetic patients, or with lipoprotein(a) (Lp(a)). In each case there was a 2- to 4-fold rise in the intracellular cholesteryl ester content. LDL from healthy subjects failed to induce intracellular lipid accumulation in these cells. LDL from patients with coronary atherosclerosis, LDL from diabetic patients, and Lp(a) form aggregates under cell culture conditions. The ability of these lipoproteins to increase the cholesteryl ester content of cultured cells is directly correlated to the degree of lipoprotein aggregation. When aggregates were removed from the lipoprotein preparations by filtration, the latter became less effective in promoting intracellular lipid accumulation. Incubation of cells with lipoprotein aggregates, isolated by gel filtration, induced a 3- to 5-fold elevation of the cellular cholesteryl ester content. These results suggest that LDL from atherosclerotic patients, or LDL from diabetic patients, or Lp(a) have a tendency to form aggregates and that these aggregates are avidly taken up by intimal smooth muscle cells followed by lipid accumulation. This aggregation tendency may play a role in atherogenesis.


Bioluminescence enhanced enzyme immunoassay for human alpha-atrial natriuretic peptide using luciferin-luciferase.

A sensitive bioluminescent enzyme immunoassay (BEIA) for the determination of human alpha-atrial natriuretic peptide was developed. The usable ranges of the standard curve extend from 10 pg to 400 pg for the one-step method and from 2.5 to 50 pg for the two-step method.


Extracorporeal membrane oxygenation in lambs through umbilical vessel perfusion: cardiac and hepatic complications.

Twin lambs were delivered by ceasarean section near term, aralyzed, sedated and randomly assigned to either mechanical ventilation or umbilical arteriovenous ECMO for 48 hours. Umbilical arteriovenous ECMO provided adequate gas exchange with minimal or no ventilation of the native lungs. However, at autopsy, animals treated with umbilical ECMO showed right heart dilation and liver necrosis or hemorrhage compared to their twins treated with mechanical ventilation.