Direct isolation of Yersinia pseudotuberculosis from fresh water in Japan.

Yersinia pseudotuberculosis was recovered from KOH-treated precipitates of 20.6% of 500 freshwater samples. KOH treatment of precipitates is a simple and expedient means of recovering Y. pseudotuberculosis from such samples.


Use of inducible disaccharidases to assess the importance of different carbohydrate sources for Bacteroides ovatus growing in the intestinal tracts of germfree mice.

Patterns of disaccharidase expression were used to determine which polysaccharides were the major sources of carbohydrate for Bacteroides ovatus growing in the intestinal tracts of monocolonized germfree mice. Results indicate that B. ovatus grows on a variety of different carbohydrates, which are present in low concentrations, rather than relying on one type of carbohydrate as the major carbohydrate source.


Temperature-dependent induction of an acid-inducible stimulon of Escherichia coli in broth.

The induction of the inducible lysyl-tRNA synthetase, LysU, and the inducible lysine and arginine decarboxylases of Escherichia coli K-12 grown in AC broth to a pH of 5.5 or less is temperature dependent, being distinctly lower at 24 than at 37 degrees C. This induction does not appear to be under HtpR control.


Trends in cancer mortality, incidence and survival in Japan.

Cancer has been the leading cause of deaths since 1981 in Japan and is still on the increase accounting for 27% of all causes of deaths in 1989. The crude death rate of cancer has been increasing in both sexes, but the age-adjusted death rate has been stable in males and decreasing in females. Among various cancers cancers of the stomach, uterus, liver (females only), and esophagus (females only) have been decreasing. Leukemia and bladder cancer also tend to show a declining trend. Other cancers, especially cancers of the lung, colo-rectum, pancreas, biliary tract liver (males only), prostate, ovary, and breast are increasing in Japan. Trends in the cancer incidence are similar to those of cancer mortality. Causes of the marked secular trends in the cancer mortality and incidence are not clear, but the major causes are suspected to be changes in dietary habits, smoking and drinking habits, and other socio-environmental factors such as marital and reproductive factors. The five year survival rates of several cancers have been improved in the last decades. Thus, progresses in the diagnostic and therapeutic techniques and promotion of cancer screening may have also contributed to the decrease of cancer deaths. If the present trends in cancer mortality and incidence continue, cancer deaths/incidences will still increase and cancers of the lung, colo-rectum, liver (males only), pancreas, biliary tract, etc. will become major cancers in Japan in the future. To combat with ever increasing cancer it is necessary to further promote cancer research, cancer screening, programs for primary prevention of cancer, especially smoking control and improvement of dietary habits.


The facilities and challenges for cancer control in India.

India is a vast subcontinent with 845 million peoples occupying 2.5% of land mass of the earth, but carrying 15% of the world population. It is a multiracial society with widely varying cultures, habits, languages and many different ethnic groups. The pattern of cancer, therefore, mainly depends on their habits and life styles apart from other variations. Head, Neck & Esophagus cancers in the male and cervix and breast cancers in the females are the main cancers. All together they form nearly 60% of all cancers. The incidence rates are around 90/100,000 though this is an underestimate as cancer is not a notifiable disease in India. It is estimated that by the year 2,000 there will be six million cancer patients in India at any given time with nearly 2 million new patients annually. The over-all facilities for cancer treatment vary widely from metropolitan cities to rural areas where 70% of the Indian population lives. In major cities, good to excellent treatment facilities exist in comprehensive cancer centres--yet in the rural setting the facilities are sketchy at best or non-existent at worst. The Government of India in its national cancer policy has recognized regional cancer centres and consolidated other existing centres. There are 10 regional cancer centres thus identified, each one at a different level of development. For optimal requirements at least 600 teletherapy units, (existing 150--not always functional) 100 departments of surgical oncology and an equal number of medical oncology divisions are needed (existing 20). The demand for cancer treatment facilities are, therefore, very high with poor available facility. Nearly 50% of patients present late for treatment and therefore appropriate education in prevention and early diagnosis are important factors. The Government of India through Ministry of Health has identified cancer as a major health problem by the year 2,000 and hence planning by the National Cancer Plan is operative in many States. Major cancer institutions (like the Tata Memorial Centre) have taken a lead to intensify the public and professional educational activities and have developed rural modules for primary and secondary prevention. The author exemplifies this by actual on the spot activities of the rural centre and stresses that in a country like India, the need is to develop small community cancer centres with the rural cancer effort as the base so as to reach out to the community for early diagnosis of treatment.


Present status of cancer treatment in several Asian countries.

Most of Asian Countries are still developing. Hence there are constraints in cancer treatment. There are those countries with fully equipped and fully distributed like western world such as Japan, Korea and Singapore. Other with some comprehensive cancer centers but confine to only big cities with poor coverage of the population resulting in a lot of late cases of cancer patients seen. Such countries are Bangladesh, China, India, Indonesia, Malaysia, Sri-Lanka, Thailand and etc. Still a lot of countries have no facilities to cope with cancer patients such as Brunei, Kampuchea, Laos, Nepal, Vietnam and etc. International collaboration and supports are needed.


Endovesical instillation of mitomycin-C in preventing recurrence of superficial bladder carcinoma.

It is now clear that MMC can be used as endovesical instillation after TUR, partial cystectomy or transurethral laser treatment and at the same time it has chemo-resection and chemoprophylactic efficacy. The success of treatment seems out of question on dosage but with the continuation of the instillation program. Recently, we have adopted 20 mg per instillation once every week for 40 times in the first year and once for 2-4 weeks for the second year, the overall recurrent rate was 17%. Such dosage used is more better than 2 mg, 10 mg or even 40 mg with acceptable side effects.


Present status of periampullary cancer treatment in Korea.

The incidence of periampullary cancer has been steadily risen in Korea. In the present study, we have reviewed 766 cases of surgically treated periampullary cancers, including 122 cases of our own, that were published in the Korean literatures in last ten years. The 6th decade was the most common age group, occupying 37.9% of the patients. Male to female, ratio was 1.7 to 1. C-T scan was the principal modality available for diagnosis and preoperative staging, and recorded 84% of diagnostic accuracy. The accuracy rate of PTC was 72%, ERCP of 68%, and USG of 51%, in order of frequency. For the screening of pancreatic cancer, diagnostic serologic test using serum markers such as CA 19-9, CEA, CA 125, and various combinations were studied. The combinations of these markers recorded higher positivity. Overall resectability was 36.2%. Preoperative C-T scan with antigraphy correlated with better discrimination of the resectable lesion preoperatively than C-T scan alone was performed (63% VS 46%). The morbidity and mortality after pancreaticoduodenectomy were 46% and 13.2%, and 1, 3, and 5-year survival rates after the resection were 68, 25, and 15%, respectively. In non-resected group, none survived at 18 months after treatment. To improve resectability; early detection, precise preoperative staging, and improved surgical approach are imperative. Future studies will be necessary to find a better multimodality therapy.


Radical radiotherapy for carcinoma cervix--preliminary experience with the microSelectron high dose rate machine.

Radiotherapy for uterine cervix carcinoma is an accepted treatment for all stages of invasive malignancy. The radiation modality is usually a combination of brachytherapy and external beam therapy for all except the most extensive tumours (stage IV--FIGO). Satisfactory results have been obtained in the Singapore General Hospital using low dose-rate radium applications in combination with cobalt teletherapy. Five year actuarial survival rates of 86.7% were obtained for FIGO stage I, 65.0% for stage II, 41.4% for stage III, 4.9% for stage IV with an overall rate of 54.0% for all stages. Corresponding 10-year rates were: 79.6%, 60.2%, 35.2%, 0% and 48.2%. Preliminary results of primary radiotherapy in 36 patients with cervical carcinoma treated by high dose-rate brachytherapy (microSelectron HDR) combined with 6MVP photons from a Siemens linear accelerator are presented. The patients were registered at the Mount Elizabeth Oncology Centre from November 1989 to December 1990 inclusive. The morbidity from high dose-rate therapy appears lower (9.1% for vaginal stenosis, 6.1% for non-severe proctitis) than for the radium series (4.1% and 20.8%) although the major complication rate appears similar (3% vs 2.8% respectively). The total failure rate is also lower at 19.4% for the HDR patients compared to 33.5% for the radium group. However, these rates are not strictly comparable as the HDR series consists of a small number of patients with limited follow-up. In the light of the data indicating acceptable morbidity with significant rate of early failure, the HDR brachytherapy doses have been increased whilst keeping within the limits set by other centres.


Allogeneic bone marrow transplantation for the patients with hemopoietic stem cell disorders: CUMC experience.

Bone marrow transplantation from an HLA-identical sibling is increasingly used as a curative therapy for patients with hemopoietic stem cell disorders including acute leukemia, chronic myelogenous leukemia and severe aplastic anemia. Between March 1983 and March 1991, we performed 86 cases of allogeneic bone marrow transplantation (BMT) for the patients with hemopoietic stem cell disorders: 25 acute myelogenous leukemia (AML); 15 acute lymphoblastic leukemia (ALL); 20 chronic myelogenous leukemia (CML); and 26 severe aplastic anemia (SAA). Ten out of 25 AML are in disease free survival (DFS). The causes of death were recurrence of leukemia (12), acute GVHD (3), sepsis (1) and veno-occlusive disease (1). Nine of 15 ALL are in unmaintained remission. Thirteen out of 20 CML are in DFS. Among 26 SAA, 21 are enjoying DFS, but 1 died of engraftment failure, 3 of graft rejection followed by cytomegalovirus (1) and aspergillus pneumonia (1). Comparing the survival between standard [less than or equal to CR1: 9/14 (64%)] and high risk [greater than or equal to CR1: 1/11 (9%)] AML, our data suggest that preparative regimen for high risk AML was not potent enough to eradicate the minimal residual disease in advanced AML. Although our cases are limited and the follow-up period is short, our result of ALL [overall: CCR (60%), standard risk (adult less than or equal to CR1, children less than or equal to CR2; 8/11 (73%) and high risk; 1/4 (25%)] and CML [overall: 65%, CP; 9/10 (90%), AP; 4/6 (67%), BP; 0/4 (0%)] are optimistic. It is of our interest that the incidence of death related with IP (1/33: 3%) and with AGVHD 94/33: 12%) were much less than that of other's observation but the explanation for this still remains to be clear.


High dose mitomycin C for treatment of advanced gastric cancer.

Thirty five patients (26 males and 9 females) with advanced gastric cancer confirmed by pathology were treated by high-dose mitomycin C. According to the following dose and schedules: Mitomycin C 20 mg intravenously per week and a total of 60 mg. Three weeks later, all the patients received FT-207 600 mg daily and a total of 20-40 g. The ages ranged from 24 to 75 years, 11 had cancer of cardia, 6 had cancer of gastric body, and 18 had cancer of gastric antrum. Eleven patients could not have an operation. Seventeen patients were recurrence of post operation. Eighteen of 35 patients received CR (7/35) and PR (11/35), the response rate was 51.43% of the responders, the median duration of remission and survival were 7.3 (range, 2-16) and 12.2 (range, 3-30) months, respectively. Common doses were instilled. The main side effects were leukopenia (10/35) and thrombocytopenia (7/35). None of these patients had liver and kidney function damage.


Analysis of one hundred and twenty five patients with primary liver cancer surviving more than five years.

During the period of 1958-1986, a series of 125 patients with pathologically proven hepatocellular carcinoma (HCC) surviving more than 5 years was collected in authors' institute. Thirty seven of them survived more than 10 years, the longest being 30 years. Of the entire series, 55.2% of patients was discovered by screening, 48.0% of patients was subclinical HCC, 80.0% of patients had solitary tumor, and 53.6% of patients had tumor size smaller than 5 cm. Pathological findings revealed that 90.2% of tumor was grade I and II (Edmondson grading) and 81.6% of patients associated with cirrhosis. The serum HBsAg was positive in 63% and anti-HBc in 80% of the patients who had checked the HBV markers. Of the 125 patients, 108 patients received resection, 67 patients were small HCC resection, 41 patients were non-small HCC resection, re-resection for subclinical recurrence or solitary lung metastasis was done in 26 patients with resection. Limited resection amounted to 54.6% of patients with resection. Of the 125 patients, 17 patients received palliative surgery other than resection, including hepatic artery ligation, cannulation, or their combination, etc. Eight out of the 17 patients received second stage resection due to marked shrinkage of tumor. It is concluded that early resection remained the major approach to get a long-term survivor, re-resection for subclinical recurrence is also of proved merit. Resection of huge tumor is still useful but less effective. Cyto-reduction and sequential resection is a new trend. Primary liver cancer (PLC) has long been recognized as incurable malignancy with extremely low 5-year survival rate. According to the cancer statistics in the United States, the relative 5-year survival rates for patients with PLC was 2% in 1960-1963, 3% in 1970-1973, 4% in 1974-1976, 3% in 1977-1980 and 5% in 1981-1986. Patients with PLC survived more than 5 years were rarely reported in the literature. In 1971, Curutchet collected worldwide data from 45 authors covering the period for 65 years (1905-1970), only 45 patients with PLC were found to be 5-year survivors. Thanks to the progress in tumor markers, particularly alpha fetoprotin (AFP) and new localization measurements, diagnosis and treatment are possible in subclinical stage. Based on combined strategies to the treatment of PLC including resection of small liver cancer, re-resection of subclinical recurrence after curative resection, multimodality treatment, and sequential resection after shrinkage of tumor, the 5-year survival of PLC has gradually increased.(ABSTRACT TRUNCATED AT 400 WORDS)


Primary chemotherapy for locally advanced uterine cervical carcinoma.

From September 1985 to May 1991, thirty consecutive patients with locally advanced cervical carcinoma stage IB-II (FIGO) with high risk factors of local treatment failure were treated with Epirubicin and Cisplatinum combination as primary chemotherapy. Twenty-five patients were evaluated for response, operability and survival. This combination chemotherapy could induce remarkable clinical complete response of 68% (17/25) and partial response of 28% (7/25), but only 18 patients were permitted for surgery, therefore operability rate was 72% (18/25). Pathological examination revealed complete response at 24% (6/25) and partial response was 48% (12/25) due to the presence of residual tumor at the cervix and dissected lymph nodes. The average number of lymph node dissected was II (range 0-26), which have been usually found in stage IIB-III patients. This combination chemotherapy did not allow to complicate surgery in these circumstances. Toxicities were mild except only leukopenia which was moderate to severe degree (WHO, grading). No death related to treatment has been found. The median time of follow up was 19 months (range 4-72), 24 patients still living, 22 without disease and 2 with diseases at the cervix and bone. The result of pilot study has suggested a beneficial role of primary chemotherapy in this type of malignancy. However, these data require further confirmation and longer follow up before a definite conclusion can be made regarding cure rate and prolong disease free-survival in locally-advanced uterine cervical carcinoma.


Interactive effects of selenium, methionine, and dietary protein on survival, growth, and physiology in mallard ducklings.

Concentrations of over 100 ppm (100 mg/kg) selenium (Se) have been found in aquatic food chains associated with irrigation drainwater. Both quantity and composition of dietary protein for wild ducklings may vary in selenium-contaminated environments. Day-old mallard (Anas platyrhynchos) ducklings received one of the following diets containing 22% protein: unsupplemented (controls), 15 ppm Se (as selenomethionine), 60 ppm Se, methionine supplemented, 15 ppm Se with methionine supplement, or 60 ppm Se with methionine supplement. In a second concurrent experiment the above sequence was repeated with a protein-restricted (11%) but isocaloric diet. In a third concurrent experiment all ducklings received 44% protein with 0, 15, or 60 ppm Se added. After 4 weeks, blood and tissue samples were collected for biochemical and histological examination. With 22% protein and 60 ppm Se in the diet, duckling survival and growth was reduced and histopathological lesions of the liver occurred. Antagonistic interactive effects occurred between supplementary methionine and Se, including complete to partial alleviation of the following Se effects by methionine: mortality, hepatic lesions, and altered glutathione and thiol status. With 11% protein, growth of controls was less than that with 22% protein, Se (60 ppm) caused 100% mortality, and methionine supplementation, although protective afforded less protection than it did with 22% protein. With 44% protein, ducklings experienced physiological stress, and Se was more toxic than with methionine-supplemented 22% protein. These findings suggest the potential for antagonistic effects of Se, methionine, and protein on duckling survival and physiology.


Determination of textile dyes in organs of Oncorhynchus mykiss W. after in vitro exposure.

The quantitative determination in organs of Oncorhynchus mykiss W. of a premetallized dye (C.I. Acid Violet 66) and the azoic base (C.I. Acid Red 217), used in wool dyeing, is studied in this paper. UV-VIS Spectrophotometry was used for the chromatic quantification and atomic absorption spectrophotometry for the detection of the metal. The method described here is as satisfactory for the detection of some commercial dyes as the methods developed by ETAD (Ecological and Toxicological Association of the Dyestuffs Manufacturing Industry).


Stainless steel cookware as a significant source of nickel, chromium, and iron.

Stainless steels are widely used materials in food preparation and in home and commercial cookware. Stainless is readily attacked by organic acids, particularly at cooking temperatures; hence iron, chromium, and nickel should be released from the material into the food. Nickel is implicated in numerous health problems, notably allergic contact dermatitis. Conversely, chromium and iron are essential nutrients for which stainless could be a useful source. Home cookware was examined by atomic absorption spectroscopy: seven different stainless utensils as well as cast iron, mild steel, aluminum and enamelled steel. The materials were exposed to mildly acidic conditions at boiling temperature. Nickel was a major corrosion product from stainless steel utensils; chromium and iron were also detected. It is recommended that nickel-sensitive patients switch to a material other than stainless, and that the stainless steel cookware industry seriously consider switching to a non-nickel formulation.


Comparative teratogenicity of di-n-butyltin diacetate with n-butyltin trichloride in rats.

Teratological tests were conducted on di-n-butyltin diacetate (DBTA), and n-butyltin trichloride (MBTC). Pregnant Wistar rats were treated orally with DBTA at doses of 0, 1.7, 5.0, 10.0, and 15.0 mg/kg/day or with MBTC at doses of 0, 50, 100, 200, and 400 mg/kg/day during days 7-17 of gestation. Cesarean sections were performed on day 20 of gestation. Thymic atrophy of the pregnant rats was observed in a dose-dependent manner by DBTA treatment. The incidence of dead or resorbed fetuses and total resorption fetuses increased at the highest dose of DBTA. The incidence of fetuses with external malformations, such as cleft mandible, cleft lower lip, ankyloglossia (tongue-tie) and schistoglossia (cleft tongue), increased in a dose-dependent manner by DBTA treatment. The incidence of fetuses with skeletal malformations such as anomaly of mandibular fixation, fused ribs, fused cervical vertebral arches and fused thoracic vertebral arches also increased at 10.0 and 15.0 mg/kg. However, MBTC, one of the main metabolites of di-n-butyltin, failed to show any evidence of tetatogenic activity at any doses tested. The results indicate that DBTA has potent teratogenic effects on rat fetuses, and DBTA is different from MBTC with respect to teratogenic effects.


The influence of selected environmental parameters on the toxicity of Bayluscide to Schistosoma mansoni miracidia.

Laboratory studies were conducted to investigate the influence of selected environmental parameters on the toxicity of Bayluscide to Schistosoma mansoni miracidia. Test results indicated that temperature, pH, hardness and salinity of the water exerted profound effects on miracidial survival and that the miracidicidal action of bayluscide was highly influenced by these factors. In summary, this chemical was found to be more effective in killing the miracidia of S. mansoni in waters of higher temperatures, lower values of pH (acidic waters), lower degrees of hardness (soft waters) and lower levels of salt (freshwaters). The implications of such studies in the control of schistosomiasis transmission are addressed.


Organochlorine pesticide contaminations in human milk samples from women living in Amman, Jordan.

Concentration of 15 organochlorine pesticides were determined by capillary gas chromatography in 59 human milk samples collected from the general population during 1989/1990 in the Jordanian capital of Amman. In addition to hexachlorbenzene (HCB), three groups of organochlorine compounds namely, DDT and its metabolites, hexachlorcyclohexane (HCH-isomers) and the cyclopentadiene group (aldrin, dieldrin, endrin, heptachlor, and heptachlor epoxide) were analyzed. The results show that almost all samples contained HCB, beta-HCH, p,p'-DDE and p,p'-DDT, whereas p,p'-DDD, heptachlor, alpha-HCH, gamma-HCH and o,p'DDT were found in 42, 40, 33, 22 and 20 analyzed samples, respectively. The concentration of HCB, beta-HCH, p,p'-DDE, p,p'-DDT and heptachlor expressed on a milk-fat basis (median in mg/kg milk fat): 0.29, 0.4, 2.04, and 0.7 respectively. For the comparative purposes and in order to try to find the possible sources of mother-milk contaminations, different types of locally produced and imported cow milk samples were also analyzed for the same organochlorine compounds. Almost all types of tested milk were contaminated with p,p'-DDE.


Ochratoxin A production in Bavarian cereal grains stored at 15 and 19% moisture content.

Wheat, barley, and maize, each in 15-kg parcels at 15 and 19% initial moisture content (IMC), were kept in a Bavarian farm granary from June through November 1990. During this period, the grain at each IMC was analyzed for mycotoxins and monitored for grain temperature, carbon dioxide, seed germination, and microfloral incidence and abundance. Barley and maize stored for 20 weeks at 19% IMC contained ochratoxin A in amounts of 70 and 90 microg/kg, respectively. This mycotoxin was not detected in wheat stored at 19% IMC, nor in the grains stored at 15% IMC. Aflatoxin B1, sterigmatocystin, citrinin, and zearalenone were also assayed but not detected in grains stored at either IMC. Principal component analysis of the data indicated that ochratoxin A was produced in a damp niche in maize, when abundant metabolic activity and CO2 production by Penicillium glandicola and Aspergillus spp. were common.


[Various properties of erythromycin basicity].

Erythromycin (Er) as a weak base showed some specific properties when dissolved in aqueous solutions. The basic ability of Er had a tendency to become weaker during storage in the room settings and especially at high temperatures. The temperature gradient within the ranges of 10 to 25 degrees C was dpH/dt = -0.03 (for 2 x 10(-3) M Er solution). However, the basic properties of the Er base partly renewed when Lewis' bases such as dimethyl carboxide, dimethylformamide and dimethyl sulfoxide were added to Er aqueous solutions previously stored for days or weeks. In chloroform solutions, either the thermodynamics or the kinetics of Er protonization showed no abnormalities as compared to nitric bases. It was supposed that in aqueous solutions of Er base there was transformation linked with intramolecular or extramolecular interactions which provoked shielding of the tertiary basic atom of nitrogen due to formation of the nitrogen linkage.


[Ultrastructure of liposomes (interliposomal bonds)].

Interliposomal bonds (ILBS) analogous to intercellular bonds (ICBs) in microbial cultures were detected by electron microscopy in the liposomal materials obtained after encapsulation of substances of various chemical structure. Possible nonspecific formation of the bonds between biological membrane-limited objects (ILBs and ICBs) was suggested and formation of such bonds in liposome encapsulated drugs was believed to be of importance.


[Sensitivity of Shigella to antibiotics].

Three hundred and twenty two Shigella cultures isolated from dysentery patients within 1986-1989 were tested with the use of standard paper disks for their sensitivity to levomycetin, streptomycin, tetracycline, monomycin, neomycin, kanamycin, erythromycin, gentamicin, carbenicillin, ampicillin, oxacillin, methicillin and doxycycline. The number of the cultures belonging to Shigella sonnei amounted to 85.1 per cent of the total number of the strains studied. 91.9, 89.5, 87.3, 87.3, 80.1 and 80.1 per cent of the cultures were sensitive to gentamicin, kanamycin, carbenicillin, neomycin, levomycetin and ampicillin, respectively. 99.4 per cent of the isolates were resistant to streptomycin and 97.2 per cent were resistant to tetracycline. The sensitivity to erythromycin remained rather high (70.2 per cent). The overwhelming majority of the Shigella sonnei isolates had multiple resistance.


[Study of general toxic and organotropic properties of ampicillin combined with sulbactam].

The effect of sulacillin, a combination of sulbactam and ampicillin (1:2), on the functions of the liver and kidneys, peripheral blood count, cardiovascular and central nervous systems was studied in acute and chronic experiments on animals of various species. The allergenic and local irritating properties of the combination were also studied. It was shown that the combination was low toxic and the interaction of sulbactam and ampicillin by the lethal effect was additive. When the combination was administered intravenously to mice, its LD50 amounted to 6 g/kg. In chronic experiments on rats parenterally given the combination in doses equivalent to the therapeutic ones there were no changes in the examined systems and organs. When used in the doses exceeding the therapeutic ones, sulacillin used during long periods induced a transitory elevation of blood levels of transaminases and alkaline phosphatases, an increase in the relative weight of the liver and kidneys, elongation the typhlon and an increase in glycogen levels in the hepatocytes without morphological changes. The combination had no significant effect of sulacillin and the painful injections alleviated by local anesthesia were recorded. The allergenic properties of the combination were moderate and did not differ from those of ampicillin. The data indicate that the combined sulacillin preparation greatly resembles its foreign analogue.


[Multifactorial analysis of combined use of an antibiotic and peptidoglycan of microbial origin in experimental plague].

The combined effect of doxycycline and microbial peptidoglycan was studied with multifactorial analysis. The drugs were used preventively and therapeutically. The preventive use of doxycycline in the subtherapeutic doses in combination with the immunomodulator resulted in a significant increase in the survival rate rather than the average life-span (ALS) of the experimental animals. The therapeutic use of the drugs was more efficient than the preventive one and resulted in higher survival and ALS. By the results of the experiments polynomial statistic models of the second order were developed and the equal level curves characterizing the survival rate and ALS were plotted. The dose-time regimens of the combined use of doxycycline an peptidoglycan were optimized.


[Study of biosynthesis of mycoheptin, mycopentene and fatty acids by Streptoverticillium mycoheptinicum strain 255 in various conditions of its cultivation].

The effect of the fat content in the medium for cultivation of Streptoverticillium mycoheptinium-255 and the effect of glucose intake on the rate of carbohydrate utilization and intensity of incorporation of labeled sodium acetate and propionate to mycoheptin, mycopentene and fatty acids were studied. It was shown that a lower fat content in the medium in comparison with the optimal one resulted in intensification carbohydrate catabolism during an idiophase, increased production rates of mycopentene, an accompanying antibiotic, and fatty acids and a decrease in the heptaene/pentaene ratio. The optimal contents of the oil in the medium provided a decrease in the rate of the carbohydrate consumption and preferable production of the required antibiotic or mycoheptin accompanied by a decrease in the synthesis rate of mycopentene and fatty acids.


[Multifactor study of combined effects of an antibiotic and polysaccharide in experimental infection].

Multifactorial analysis was applied to the study of the combined effect of doxycycline and a polysaccharide of microbial origin in experimental plague infection. A marked synergistic action of the antibiotic and polysaccharide used in subtherapeutic doses in treatment of the infection was observed. By the results of the experiments polynomial statistic models of the 2nd order were designed and nomographs or equal level lines were plotted. The models and nomographs described the animal survival rate and lifespan within a wide range of the control parameters. The dose/time regimens for the use of the polysaccharide combination with doxycycline were optimized on the basis of the multifactorial analysis.


[Leukinferon in immunological correction of acute inflammatory diseases of the abdominal organs].

Addition of (intramuscular+intravenous) leukinferon (LF) to the schemes for the treatment of acute peritonitis promoted a more rapid positive development of the time course of clinical signs and decreasing of leukocytosis in the presence of a pronounced tendency to normalization of the main immunological indices i. e. the counts of differential T-lymphocytes and T-helper cells. There was also activation of neutrophil phagocytic function. A rapid decrease in objective signs of endotoxicosis was recorded: the intoxication leukocytic index and the level of medium-mass molecules. In parallel with the decrease in the intoxication leukocytic index, there was a decrease in cytosis of the peritoneal exudate. The use of LF in the treatment of elderly patients with acute cholecystitis eliminated the clinical signs and normalized the main laboratory indices without surgical interventions which allowed one to make a planned operation with the minimum risk.


[Characteristics of obtaining protoplasts from 2 strains of Tolypocladium inflatum subsp. Blastosporum].

The optimal conditions for preparing protoplasts with high yields by using the cells of two (low and high potent) isogenic cyclosporine-producing Tolypocladium strains were developed. A specific medium containing 0.5 per cent yeast autolysate (by dry weight) and 3 per cent glucose was used. When grown on this medium the cells of the highly potent strain 847 acquired a yeast-like shape. High yields of protoplasts prepared from the low potent strain 43 mycelium were obtained via prior incubation with 0.01 M dithiothreitol followed by treatment with a complex of enzymes from Helix pomatia for 1.5 to 2 hours was used. For preparation of the protoplasts with employing the highly potent strain 847 cells the prior incubation with dithiothreitol was not required, but it was necessary to employ a mixture of the enzyme complex (Helix pomatia), drizilase (Irpex lacteus) and chitinase (Streptomyces griseus) for 18 hours. The electron microscopic data on the two isogenic strains and their protoplasts are presented. The protoplasts proved to be a suitable initial material for investigating bioenergetic processes at the subcellular level and further genetic improvement of the strains.


[Sensitivity of Vibrio and Aeromonas to antibiotics].

The antibiotic sensitivity of 696 cultures belonging to the family Vibrionaceae (V. cholerae O1, V. cholerae non-O1, V. albensis, V. parahaemolyticus, V. alginolyticus and Aeromonas spp.) was studied and general regularities of the antibiotic sensitivity were shown: a high sensitivity to broad-spectrum antibiotics (tetracycline and chloramphenicol) and a low sensitivity to ++beta lactams (carbenicillin and ampicillin). The comparative examinations revealed similarity in the antibioticograms of V. cholerae O1 (el Tor++), V. cholerae non-O1 and V. albensis, especially the latter two groups, as well as the tested halophilic Vibrio cultures by the range of the MICs, Mo, Me and the nature of the antibiotic resistance. Cultures of V. cholerae and luminescent Vibrio tended to preserve a high sensitivity. High resistance levels were noted in the halophilic Vibrio and Aeromonas cultures. No significant differences in the sensitivity of the strains of various origin (from man and environmental objects) were detected. However, several more resistant strains were isolated from the environmental objects.


[Drug resistance of Mycobacterium tuberculosis].

Drug resistance of Mycobacterium tuberculosis was followed up within a period of 1986 to 1989. There was a tendency to stabilization of resistance to streptomycin (42 per cent), tubazid (45.2 per cent) and ethionamide (up. to 1.4 per cent). Resistance to kanamycin slowly increased (by 3 to 6 per cent every year). Resistance to rifampicin markedly increased (almost 15 times). Resistance to ethambutol decreased (10 times). It was shown that the drug resistance could be lowered by using the drug combinations.


[Antimicrobial and membranolytic activities of anti-burn drug fenozan].

Fenozan, an anti-burn preparation, was shown to have antimicrobial activity against freshly isolated clinical strains of Staphylococcus aureus and Streptococcus faecalis, as well as against collection strains of the other gram-positive bacteria. The antimicrobial action of the preparation was possibly due to impairment of permeability of the cytoplasmic membranes in the sensitive bacterial cells and their liberation of intracellular low molecular weight compounds to the environment. The membranolytic and minimum inhibitory concentrations of fenozan with respect to the sensitive bacterial cells were one order of magnitude lower than the concentration stabilizing the membranes of animal cells in the treatment of burns. Combination of the antioxidant and antimicrobial properties in fenozan was likely to provide its satisfactory therapeutic effect in the treatment of burn wounds.


[Study of general toxic and organotropic properties of clindamycin in long-term experiments].

The action of clindamycin monohydrate on the general state and weight rise, liver and kidney functions, peripheral blood count and pathomorphological state of the viscera was studied on rats in chronic experiments. Clindamycin was administered to laboratory animals orally in doses of 50, 100, 150 and 300 mg/kg. It was shown that some adverse reactions to the drug and in particular disorders in blood coagulation and morphological changes in the intestine did not depend on its dose and were due to duration of the drug use and probable development of dysbacteriosis. At the same time the disorders in the liver and kidney functions though transitory did depend, to a greater extent, on the dose and were evident after the antibiotic overdosage.


[Eremomycin in the treatment of antibiotic-associated colitis in golden hamsters].

The efficacy of eremomycin, a new glycopeptide antibiotic, was studied on a model of antibiotic-associated colitis in golden hamsters. The colitis was induced by intraperitoneal or intragastric administration of lincomycin. In a dose of 100 mg/kg administered orally once a day for 5 days eremomycin protected the animals from the lincomycin-induced colitis: some animals survived, the others died in later periods. When the animals were infected with a pathogenetic strain of Clostridium difficile followed by exposure to lincomycin the use of eremomycin produced the similar effect.


[Effect of rifampicin and doxycycline on leukocyte chemotaxis].

It was shown experimentally that in a dose corresponding to the average therapeutic one for man rifampicin was able to stimulate in vivo directed migration of neutrophils to the inflammation foci in mice CBA. Doxycycline used in a dose corresponding to the average therapeutic one was able to activate neutrophils and to increase chemotaxis. Intraperitoneal administration of doxycycline to guinea pigs induced liberation of large counts of neutrophils with marked segmentation of the nuclei to the peritoneal cavity. The cells induced by doxycycline had a higher capacity for chemotaxis under agarose as compared to the control.


[Study of embryotoxic and teratogenic effects of amphotericin B and a methyl derivative of amphotericin B in rats after their intravenous and intra-amniotic administration].

The embryotoxic action of amphotericin B and its methyl derivative was compared in rats after their intravenous and intraamniotic administration. The concentrations of amphotericin B and its methyl derivative in the amniotic cavity on days 13, 14 and 15 of pregnancy were 1.5 and 36 micrograms/ml, respectively. When administered intravenously during the preimplantation period the antibiotics had no embryotoxic action. Intravenous administration of amphotericin B in a dose of 500 micrograms/kg and its derivative in a dose of 2000 micrograms/kg during organ genesis induced a decrease in the craniocaudal size. In a dose of 3000 micrograms/kg administered intravenously the methyl derivative of amphotericin B induced an increase in postimplantation death rates. Administration of amphotericin B to the amniotic cavity had no damaging action. Administration of the methyl derivative on day 15 of pregnancy led to anomalous development of the lower extremities and slower ossification. The threshold doses by the embryotoxic action for intravenous administration are 500 micrograms/kg for amphotericin B and 2000 micrograms/kg for the methyl derivative. Administration of the antibiotics to the amniotic cavity revealed potential teratogenic properties of the amphotericin B methyl derivative.


[Effects of interferon preparations on the course of Salmonella infection (experimental and clinical studies)].

The effect of type I interferons on the process of experimental salmonellosis in mice and rabbits, as well as their effect on salmonellosis in patients was studied. It was shown that homologous interferon increased the animal survival rate, activated bactericidal activity of the phagocytic cells and increased elimination of the infectious agents from the host. The complex of the etiotropic and pathogenetic treatment of 32 patients with salmonellosis included human leukocytic interferon, leukinferon. It was administered intramuscularly in a dose of 1 x 10(4)-2 x 10(4) IU: three injections at intervals of 48 to 72 hours (the treatment course). The course was repeated 10 days after the last injection of the first course. Addition of leukinferon to the routine scheme of the medicinal treatment of salmonellosis provided recovery of all the patients without complications or appearance of the bacteria carriers (the observation period of more than 3 years).


[Extracorporeal immunosuppressive effect of papain].

Exposure of allogenic erythrocytes to papain induced their immunosuppressing properties within relatively narrow ranges of the incubation medium temperature (42 but not 37 or 40 degrees C) and the papain concentration (10 but not 2 or 50 micrograms/ml). Markedly pronounced immunosuppressing properties were acquired by the erythrocyte light fraction after heating and exposure to papain. The supernatant layer of adhesive spleen cells incubated in the presence of erythrocytes heat treated and exposed to papain suppressed development of the humoral immune response and DTH during the allogenic transfer and accelerated and increased excretion of the antigen specific immunosuppressing factor by the nonadhesive spleen cells of hyperimmunized sheep red blood cells.


[Isolation of nisin from native solution and its purification on cationites].

It was found possible to use organic sorbents and in particular carboxylic cationites for isolation of nisin from the fermentation broth filtrate and its purification. Nisin is known as a polypeptide antibiotic applied as a preservative. The sorbents were shown to have high exchange capacities by the isolated substance and mechanical strength and resistance. They also proved to be highly stable.


[A rapid method of evaluation of the effectiveness of antibacterial drugs].

Efficacy of antibiotics in the treatment of experimental tularemia was studied comparatively on various biological models. It was shown that the antibiotics which proved active against the tularemia microbe in albino mice when studied by the rapid and routine methods were highly efficient in the treatment and prevention of experimental tularemia in rabbits and baboons (hamadryas). The experiments showed basic possibilities to perform rapid estimation (for at least 2 days) of drug efficacy in experimental glanders and melioidosis in golden hamsters. The rapid method developed by the authors was recommended for the use in primary estimation of the efficacy of new drugs in the treatment of tularemia, glanders and melioidosis.


Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive-compulsive disorder.

We used positron emission tomography to investigate local cerebral metabolic rates for glucose (LCMRG1c) in patients with obsessive-compulsive disorder before and after treatment with either fluoxetine hydrochloride or behavior therapy. After treatment, LCMRG1c in the head of the right caudate nucleus, divided by that in the ipsilateral hemisphere (Cd/hem), was decreased significantly compared with pretreatment values in responders to both drug and behavior therapy. These decreases in responders were also significantly greater than right Cd/hem changes in nonresponders and normal controls, in both of whom values did not change from baseline. Percentage change in obsessive-compulsive disorder symptom ratings correlated significantly with the percent of right Cd/hem change with drug therapy and there was a trend to significance for this same correlation with behavior therapy. By lumping all responders to either treatment, right orbital cortex/hem was significantly correlated with ipsilateral Cd/hem and thalamus/hem before treatment but not after, and the differences before and after treatment were significant. A similar pattern was noted in the left hemisphere. A brain circuit involving these brain regions may mediate obsessive-compulsive disorder symptoms.


Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Revisualization during pharmacotherapy.

To investigate the effects of drug treatment in childhood-onset obsessive-compulsive disorder (OCD), we repeated positron emission tomographic scans in 13 adults with OCD (eight taking clomipramine, two taking fluoxetine, and three taking no drug) after at least 1 year of pharmacotherapy. As a group, the patients had a significant improvement on all OCD and anxiety ratings. Positron emission tomography revealed a significant decrease in normalized orbitofrontal regional cerebral glucose metabolism (relative to global metabolism) bilaterally. Among the treated patients, the decrease in right orbitofrontal metabolism was directly correlated with two measures of OCD improvement. These results extend previous positron emission tomographic findings of regional dysfunction in OCD and suggest involvement of the orbitofrontal regions in the pathophysiology of OCD.


Regional xenon 133 cerebral blood flow and cerebral technetium 99m HMPAO uptake in unmedicated patients with obsessive-compulsive disorder and matched normal control subjects. Determination by high-resolution single-photon emission computed tomography.

We measured regional cerebral blood flow (rCBF) with the xenon 133 (133Xe) inhalation method and with regional cerebral uptake of technetium 99m d,l-hexamethyl propyleneamine oxime (99mTc-HMPAO) by single-photon emission computed tomography in 10 adult male patients with obsessive-compulsive disorder (OCD) and in 10 age-matched adult male normal controls. With the 133Xe method, there were no significant differences in cortical or basal ganglia blood flow between the patients with OCD and their matched controls. In the patients, there was a positive relationship between rCBF and the severity of both obsessive and compulsive symptoms (average r = .48). These rCBF findings were consistent with those of earlier reports of increased rCBF in patients with OCD who were undergoing imaginal flooding and who had exacerbation of symptoms following m-CPP administration. 99mTc-HMPAO is a lipophilic molecule that crosses the blood-brain barrier and is converted to a hydrophilic form that is trapped in the brain. The amount that is trapped is determined primarily by blood flow, but also by membrane permeability and kinetics of conversion of the 99mTc-HMPAO to the hydrophilic form. Compared with their matched controls, the patients with OCD had significantly increased 99mTc-HMPAO uptake in the high dorsal parietal cortex bilaterally, in the left posterofrontal cortex, and in the orbital frontal cortex bilaterally. Possible explanations include (1) increased rCBF that was not detected with 133Xe, (2) increased permeability of the blood-brain barrier and/or cell membranes, and (3) increased conversion and trapping of the lipophilic, injected form of 99mTc-HMPAO in these regions.(ABSTRACT TRUNCATED AT 250 WORDS)


Risks of affective illness among first-degree relatives of bipolar I old-order Amish probands.

Data from bipolar I old-order Amish families suggest that the morbid risk of illness is not significantly different in this population when compared with estimates of risk from previous studies. The age-corrected rates of bipolar I, bipolar II, and major depressive disorder among first-degree relatives are 8.7, 3.7, and 11.6, respectively. Risk of illness is not significantly different among male and female relatives and among relatives of male and female probands. Consistent with other reports, the rate of illness is higher among relatives of probands with early-onset disease. In contrast with previous reports, there does not appear to be a cohort effect in this population.


An intriguing association between ancestral mortality and male affective disorder.

We examine the relationship between ancestral age at death and affective disorder. A cohort of 204 socioeconomically favored men was selected for mental and physical health 50 years ago and followed up until age 69 +/- 1 (+/- SD) years in an interdisciplinary study. During follow-up, 49 of these men were identified at some point as being psychosocially impaired. Of these 49 men, 25 were identified as having probable affective disorder based on family history of affective illness, clinical signs, subjective symptoms, clinical diagnosis, and choice of pharmacological treatment. Objective signs and symptoms distinguished these 25 men from the remaining 24 men, whose adjustment over the 50 years was equally psychosocially impaired, but who were never noted to be significantly depressed. The mean age at death of the maternal grandfathers for the 25 depressed men was 60.4 years, significantly younger than the mean age at death of maternal grandfathers for either the total sample (70.1 years) or the 25 psychosocially impaired but not depressed men (68.8 years). The mean age at death of the depressed men's other five first-degree ancestors was not significantly different from the age at death of the ancestors of the rest of the sample. If depressed alcohol abusers were excluded, the mean age at death of maternal grandfathers of alcohol abusers did not differ from that of the controls' maternal grandfathers. The evidence for possible X-chromosome linkage in male psychobiological vulnerability to affective spectrum disorder is discussed.


Major depression and generalized anxiety disorder. Same genes, (partly) different environments?

Bivariate twin analysis can determine the extent to which two disorders share common genetic, familial environmental, or individual-specific environmental risk factors. We applied this method to lifetime diagnoses of major depression and generalized anxiety disorder as assessed at personal interview in a population-based sample of 1033 pairs of female same-sex twins. Three definitions of generalized anxiety disorder were used that varied in minimum duration (1 vs 6 months) and in the presence or absence of a diagnostic hierarchy. For all definitions of generalized anxiety disorder, the best-fitting twin model was the same. Familial environment played no role in the etiology of either condition. Genetic factors were important for both major depression and generalized anxiety disorder and were completely shared between the two disorders. A modest proportion of the nonfamilial environmental risk factors were shared between major depression and generalized anxiety disorder. Within the limits of our statistical power, our findings suggest that in women, the liability to major depression and generalized anxiety disorder is influenced by the same genetic factors, so that whether a vulnerable woman develops major depression or generalized anxiety disorder is a result of her environmental experiences.


Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples.

We examined 140 probands with attention deficit hyperactivity disorder, 120 normal controls, and their 822 first-degree relatives using "blind" raters and structured diagnostic interviews. Compared with controls, probands with attention deficit hyperactivity disorder were more likely to have conduct, mood, and anxiety disorders. Compared with relatives of controls, relatives of probands with attention deficit hyperactivity disorder had a higher risk for attention deficit hyperactivity disorder, antisocial disorders, major depressive disorder, substance dependence, and anxiety disorders. Patterns of comorbidity indicate that attention deficit hyperactivity disorder and major depressive disorders may share common familial vulnerabilities, that attention deficit hyperactivity disorder plus conduct disorder may be a distinct subtype, and that attention deficit hyperactivity disorder and anxiety disorders are transmitted independently in families. These results extend previous findings indicating family-genetic influences in attention deficit hyperactivity disorder by using both pediatrically and psychiatrically referred proband samples. The distributions of comorbid illnesses in families provide further validation for subgrouping probands with attention deficit hyperactivity disorder by comorbidity.


There is more than one way to collect data for linkage analysis. What a study of epilepsy can tell us about linkage strategy for psychiatric disease.

The most popular strategy for finding genes in psychiatric diseases has been to focus on large pedigrees with many affected members. While this strategy has sound advantages, it also has drawbacks that have seldom been addressed. The strategy of using smaller families also has its place in a linkage analysis. To illustrate the point, I discuss herein the successful search for a gene for another common complex disease, namely, idiopathic primary generalized epilepsy. There, investigators in the Los Angeles (Calif) Epilepsy Program used mostly nuclear families who were chosen through a proband with highly specific characteristics. An independent study, using a different strategy but one still focused on small families, then confirmed the linkage. However, investigators of both epilepsy projects put much care into determining which clinical characteristics would be used to define the index cases. The implications for the study of psychiatric disease are as follows: (1) careful attention must be paid to clinical presentation, and (2) there is room for both large-pedigree and small-family strategies in designing linkage studies.


Recovery following complete paraplegia.

Motor and sensory recovery were quantified by serial examinations prospectively performed on 148 persons with paraplegia. Of the 142 patients who remained complete injuries at follow-up, none with an initial neurologic level of injury (NLI) above T9 regained any lower extremity motor function at follow-up. Thirty-eight percent of patients with an initial NLI at or below T9 had some return of lower extremity motor function, primarily in the hip flexors and knee initial NLI at or below T9 had some return of lower extremity motor function, primarily in the hip flexors and knee extensors. Twenty percent of the patients with an initial NLI at or below T12 regained sufficient hip flexor and knee extensor strength to reciprocally ambulate using conventional orthoses and crutches. Unlike motor function, recovery of light touch and sharp-dull discrimination was independent of the initial NLI. Six (4%) of the 148 patients demonstrated "late" conversion (more than 4 months after injury) from complete to incomplete spinal cord injury (SCI) status. Two of the 6 patients with an initial NLI at T12 and subsequent annual NLI at L1 and L2 reciprocally ambulated, and three of the 6 patients regained voluntary bladder/bowel control.


Extensor carpi radialis recovery predicted by qualitative SEP and clinical examination in quadriplegia.

This prospective study examined the efficacy of the qualitative somatosensory evoked potential (SEP) and the initial clinical neurologic evaluation to predict motor power recovery of the extensor carpi radialis muscle (ECR). Twenty three C5-6 Frankel A-D spinal cord injured (SCI) subjects had SEPs of the median nerve (MN) and superficial radial nerve (SRN) performed within 72 hours to one week post injury. The MN and SRN cortical SEPs were qualitatively graded as either present or absent. Fifteen subjects whose initial ECR muscle strength was less than or equal to 3/5 and eight subjects whose muscle strength was greater than 3/5 were followed up to 12 to 18 months post injury for improvement in ECR muscle strength. The subject's ECR strength was evaluated by manual muscle testing (MMT) at 72 hours, weekly for three weeks, monthly for three months, and then at six, 12, and 18 months. The pin sensation at the C-5 dermatome was also tested at the above intervals and graded as either present or absent. A one tail Fisher Exact test compared the presence or absence of the MN and SRN SEPs to the recovery of the ECR to 3/5. The same one tail test also compared the presence or absence of the 72 hour C-5 pin sensation and the 72 hour MMT to the ECR recovery. Among the 15 subjects with an initial MMT of less than or equal to 3/5, ten subjects had successful ECR recovery (greater than 3/5); 5 did not. The C-5 pin sensation correctly predicted ECR recovery in all subjects studied (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Intrathecal baclofen in hereditary spastic paraparesis.

Intrathecal baclofen has not been previously evaluated for the treatment of the disabling hypertonia associated with hereditary spastic paraparesis. Muscle tone and deep-tendon reflexes were evaluated in three patients with hereditary spastic paraparesis after a double-blind, cross-over bolus injection of intrathecal baclofen. Patients underwent placement of a subcutaneous pump for continuous infusion of intrathecal baclofen. Three months after implantation the muscle tone decreased 2.04 points (p less than .0001) and the reflex score decreased 2.25 points (p less than .001). Patients initially reported subjective weakness, but muscle testing revealed either an increase or no change in voluntary motor function. Baclofen doses of 60 to 264 micrograms per day were required for effective control of muscle tone and spasticity. Much of the disability in familial spastic paraparesis may be related to the loss of suprasegmental inhibition of spinal reflexes overwhelming the residual voluntary motor function.


Clean and sterile intermittent catheterization methods in hospitalized patients with spinal cord injury.

The purpose of this study was to compare the incidence of urinary infection using clean intermittent catheterization with the incidence of infection using sterile intermittent catheterization in patients hospitalized with spinal cord injury who were not receiving prophylactic antibiotics. Forty-six patients were assigned randomly to a clean (n = 23) or sterile (n = 23) study group. Catheterizations were done at least every six hours. Infection was defined as bacteriuria greater than or equal to 100,000 organisms/mL or greater than or equal to 10,000 organisms per mL with fever of 100 degrees F or greater. Results of urinary dipslides were recorded daily. Twenty-eight subjects (60.9%) converted to greater than or equal to 100,000 organisms per mL. Method of catheterization was neither associated significantly with development of greater than or equal to 100,000 organisms per mL. (X2[1,46] = .36, p = .55) nor with symptomatic infections (X2[1,46] = .15, p = .70). Data support the use of clean intermittent catheterization under the conditions used in this study, including the use of a sterile catheter each day and careful monitoring of infection and technique. Before using this method with other diagnostic groups or in different clinical settings, further investigation is needed.


Pressure ulcer, fibronectin, and related proteins in spinal cord injured patients.

Pressure ulcer is a common occurrence in spinal cord injured (SCI) patients and can lead to serious complications. With proper management, some patients exhibit satisfactory healing whereas others show slow or nonhealing ulcers. Fibronectin has been shown to accumulate in wound, opsonize macroaggregate debris for phagocytosis, promote revascularization, and facilitate fibroblast migration and proliferation. We explored the relationship of plasma fibronectin with healing potential in 21 SCI men with pressure ulcer. They received standard wound care and were observed for eight weeks. Ten otherwise healthy SCI men without pressure ulcer (SCI-controls) and 32 able-bodied normal individuals (normal controls) were also studied. Plasma fibronectin and related proteins, ie, fibrinogen, plasminogen, alpha 2-antiplasmin and Factor XIII, were measured. Ten of 21 SCI patients with pressure ulcer showed rapid healing within four weeks and had significantly higher fibronectin levels as compared with the 11 patients with poor healing ulcers, SCI controls, and normal controls. Factor XIII and alpha 2-antiplasmin were mildly reduced and fibrinogen values were significantly increased in all SCI groups. Plasminogen concentrations were comparable in all groups studied. It thus appears that plasma fibronectin rises in patients with fast healing ulcers but fails to do so in those with poor healing ulcers and as such may be predictive of the course of pressure ulcers.


Contractures in neuromuscular disease.

The percentage of subjects with contractures, mean maximal loss of range, and relative contracture indices are reported in 230 patients, with 11 diseases seen in a neuromuscular disease clinic during a five-year period. The highest percentage of contractures occurred in patients with Duchenne muscular dystrophy. The number of contractures was significantly greater (p less than .001) (1) in the lower than in the upper extremities; (2) in diseases considered myopathic than in those considered neuropathic; (3) in diseases that are X-linked than in those that are not; and (4) in rapidly progressive than in slowly progressive diseases.


Lower extremity amputation in scleroderma.

Scleroderma or Systemic Sclerosis (SSC) is a disorder characterized by fibrosis of the skin and multiple internal organs. The pathological lesion is a triad of small artery intimal proliferation, medial thinning and adventitial scarring. Autoamputation of fingers and toes is often seen, but only a few cases of limb amputation in scleroderma patients have been reported. The Pittsburgh Scleroderma databank includes 1,030 patients with SSC. Among these were seven patients who sustained lower limb amputation. There were four patients with the CREST variant of SSC, two with diffuse scleroderma, and one who had SSC/rheumatoid arthritis/polymyositis overlap who sustained limb amputation. Of the seven, three were male and five had a significant smoking history. Ages ranged from 46 to 71 years. All patients underwent amputation for nonhealing ulcerations. No problems with postoperative wound healing were seen. Pathologic changes typical of SSC in addition to atherosclerotic peripheral vascular disease were described in one case. Three patients were successfully fitted with prostheses and became independent ambulators. Four patients could not be fitted with prostheses. No skin problems were reported related to prosthetic use. Our review demonstrates that SSC patients who undergo amputation can become successful prosthetic users and should be considered for prosthetic prescription.


Muscle and bone pressure pain threshold and pain tolerance in fibromyalgia patients and controls.

Pressure pain thresholds and pressure pain tolerances on non-trigger-point muscle and bone were measured with a dolorimeter in 46 female patients with primary fibromyalgia and in 50 healthy women of the same age. The pressure pain thresholds and the pressure pain tolerances on both muscle and bone were lower in the fibromyalgia patients than in the healthy controls. All the differences were statistically highly significant, though there was a certain degree of overlapping between the patients and the controls. It is concluded that patients with primary fibromyalgia have a generalized amplification of pain sensitivity, a sign that might be useful in the diagnosis of fibromyalgia.


Thermographic imaging of myofascial trigger points: a follow-up study.

Thermographic evaluation was performed on 11 adult volunteers with myofascial trigger points and on 11 asymptomatic controls. Infrared thermography was used to obtain a series of images to compare the sensory referral areas of myofascial trigger points with their thermal referral patterns. A series of images was then taken at, and distal to, the sensory referral area of each trigger point during quantitative compression of the trigger point, and dynamic temperature changes were monitored. Asymmetric thermal patterns were observed at all trigger points in the sensory referral area and distal to the referred area before compression. The thermal referral areas showed a reduction in temperature from precompression levels during compression. When similar but asymptomatic areas were compressed, no significant changes in temperature were noted at distal sites.


Correlation analysis of somatosensory evoked potential waveforms.

Somatosensory evoked potential (SEP) waveforms were recorded over the spine and scalp in response to tibial nerve stimulation at the ankle for 28 subjects. The scalp data were analyzed with the correlation coefficient (CC) to determine the reproducibility of the signals and to identify side-to-side symmetry. The test for reproducibility uses the CC to verify validity, a low CC implying that the data are defective. The symmetry test uses the CC to obtain a measure of similarity of the responses to stimulation from opposite sides of the body. Statistics are presented showing the normal ranges of the CC values and their standard deviations. We conclude that the CC can provide objective and quantitative waveform information that complements latency and amplitude measurements in the clinical interpretation of tibial SEP waveforms.


Computer algorithms to characterize individual subject EMG profiles during gait.

Three methods of precisely determining onset and cessation times of gait EMG were investigated. Subjects were 24 normal adults and 32 individuals with gait pathologies. Soleus muscle EMG during free speed level walking was obtained with fine wires, and was normalized by manual muscle test (%MMT). Linear envelopes were generated from the rectified, integrated EMG at each percent gait cycle (%GC) of each stride in individual gait trials. Three methods were used to generate EMG profiles for each tested subject. The ensemble average (EAV) was determined for each subject from the mean relative intensity of the linear envelopes. Low relative intensity or short duration EMG was removed from the ensemble average to create the intensity filtered average (IFA). The packet analysis method (PAC) created an EMG profile from the linear envelopes in successive strides whose respective centroid %GC locations were within +/- 15%GC of each other. Control values for onset and cessation times of individual gait trials were calculated after spurious outliers were removed. Mean onset and cessation times across subjects for control values and the experimental methods (EAV, IFA, and PAC) were calculated. Dunnett's test (p less than .05) was performed to compare control and experimental groups in patient and normal trials. EAV differed from control values for onsets (p less than .01), cessations (p less than .01), and durations (p less than .01) in both normal and patient trials. IFA and PAC had no significant differences from control value means. IFA was selected for clinical use as automatic analysis could be performed on all trials and a minimum number of decision rules were needed.


Ulnar palmar cutaneous nerve and hypothenar sensory conduction studies.

The ulnar palmar cutaneous nerve (UPCN) is potentially useful to the electrodiagnostician. However, no definitive nerve conduction study techniques for the UPCN have been reported. The UPCN supplies sensory innervation to the hypothenar palm. This study describes an orthodromic sensory conduction technique for the hypothenar palm. Data were collected from 20 normal limbed patients (ages 22-58). Potentials were recorded over the ulnar nerve 10cm proximally and at the elbow. Distal latency was 2.19 +/- 0.17msec, and distal amplitude was 12.7 +/- 6.9uv. Additionally, a modified collision technique was used in several subjects to examine the possibility of volume conduction to more than one ulnar nerve branch. The techniques described may be useful in selected cases of distal ulnar nerve pathology. A case is reported in which injury to the superficial sensory branch of the ulnar nerve, with sparing of the UPCN was demonstrated electrodiagnostically. Further study is needed to determine if the UPCN can consistently be electrophysiologically isolated.


Functional screening of lower-limb amputees: a role in predicting rehabilitation outcome?

The Functional Independence Measure (FIM), a single-score instrument used to measure independent functioning in six areas of basic self-care skills, was used to evaluate 68 patients following lower-limb amputation. Patients in a rehabilitation hospital were assessed with the FIM upon admission and discharge. Admission scores averaged 52.7, ranging from 25.2 to 70.0. Patients scoring in the lowest and highest quartiles were compared: no remarkable gender, ethnic, or age differences were evident. Persons with the lowest scores (ie, lowest functioning) had a higher prevalence of hypertension, coronary artery disease, and noninsulin-dependent diabetes mellitus. The success of rehabilitation in patients in the lower two quartiles upon admission was variable and not predicted well by the FIM. In contrast, predictability of rehabilitation success was high in patients functioning higher at admission, the majority achieving near-perfect scores by discharge. Length of hospitalization appeared to be largely unrelated to the net difference in FIM scores over the course of hospitalization.


Functional recovery in young stroke patients.

Thirty young stroke patients were retrospectively assessed for levels of activities of daily living and of basic functional movements. Scores upon admission, discharge, and follow-up were compared in order to evaluate course of rehabilitation and functional outcome. Mean length of stay in the rehabilitation ward was 87 +/- 17 days, and duration of follow-up was 31 +/- 8 months. Multivariate analysis of covariance confirmed significant improvements during hospitalization, in transfer, standing, sitting and walking abilities (F = 3.5, p less than 0.02), as well as in activities of daily living (F = 4.7, p less than 0.01). Further improvement during the follow-up period was observed for standing and walking abilities (F = 10.2, p less than 0.001) only. No fatalities occurred among the patients during the study period. Eighty-one percent of the patients resumed their previous or other jobs six months after discharge. We conclude that for young stroke patients admitted to a rehabilitation ward shortly after the event, prognosis in terms of survival and functional outcome is favorable, and independent of precipitating factor, age, sex, or side of weakness.


Clonidine transdermal system for treatment of spasticity in spinal cord injury.

Clonidine tablets have been used in the past for treatment of spasticity with some success. The use of clonidine, however, has been limited by adverse effects, mainly hypotension. Over a two-year period, 17 patients were started on clonidine transdermal delivery system. They were followed for up to 18 months. Twelve of the 17 patients had a beneficial response and have continued on the patch. In ten of these 12 patients, other antispasticity drugs were either reduced or discontinued. In another three of the 17 patients, the response was good, but the patch was discontinued. No patient demonstrated persistent problematic hypotension. Clonidine Transdermal Patch appears to be an effective treatment for spasticity after a spinal cord injury. Adverse effects appear to be minimized using this mode of delivery.


Galactorrhea: a complication of spinal cord injury.

Galactorrhea, a secretion of milk or milk-like products from the breast in the absence of parturition, has been reported to occur in women with spinal cord injuries in association with amenorrhea and hyperprolactinemia. Four cases of galactorrhea in association with spinal cord injury are reported. Galactorrhea developed in four spinal cord injured women who had thoracic paraplegia. The onset of galactorrhea was from one month to five months after injury. Although the onset of galactorrhea may have been related to prescribed medications in all four cases, insufficient data exist to draw conclusions. The three women whose galactorrhea persisted declined treatment and galactorrhea continuing for more than two years in one instance. We conclude that galactorrhea with or without amenorrhea may develop after a spinal cord injury and that spinal cord injured women may have an enhanced sensitivity to medication-induced galactorrhea.


Avulsion fracture of the anterior superior iliac spine in a collegiate distance runner.

Overuse injuries are a common occurrence with distance runners, yet injuries to the iliac crest are rare in this population. When an iliac crest injury occurs, it is usually associated with the weak unossified growth plate. The condition may present itself as apophysitis and may progress to an avulsion fracture. This is a report of a rare case in which a collegiate distance runner had an avulsion fracture of his anterior superior iliac spine (ASIS). Treatment consisted of rest followed by nonweight-bearing graded exercise performed in the pool and on a Schwinn Airdyne. The graded exercise not only strengthened and stabilized the muscles acting on the hip and thigh, but it also enabled the athlete to maintain his cardiorespiratory endurance. He returned to competition three weeks after the injury.


Isokinetic exercise system modification for short below-the-knee residual limbs.

The use of isokinetic exercise has been shown to be an effective way of strengthening debilitated muscles. In the below the knee amputee, significant quadriceps and hamstring muscle wasting has been documented. Although isokinetic strengthening of the debilitated knee extensors and flexors in the below the knee amputee would be beneficial, there are no fully described isokinetic equipment modifications in literature that would allow a short below the knee amputee to effectively use isokinetic equipment. This article describes such a modification.


Icons in surgery.

This company of surgeons, the Pacific Coast Surgical Association, has honored me greatly, and I am grateful. In a turbulent, changing world, as physicians, you are among the most important people on earth. More important, by far, than any technologic aspect of your craft, is your character. As the pen is mightier than the sword, your beliefs and values are the sustaining force that will guide you in troubled times. Icons are Everyman's "pointers of the way" in meeting the challenges of tomorrow.


Breast conservation management of breast tumors 4 cm or larger.

Randomized studies of stage I and II breast cancer have shown that breast conservation treatment is equivalent to modified radical mastectomy in regard to local-regional control and survival. Little has been published on breast conservation for patients with large tumors. We analyzed 68 patients with tumors measuring 4 cm or larger (range, 4 to 12 cm) treated with breast-conserving surgery and radiation therapy. The median follow-up was 46 months; the mean tumor size was 5 cm. The 5-year actuarial local-regional recurrence rate was 8.5%, and the overall survival and disease-free survival rates were 76% and 68%, respectively. We conclude that breast conservation treatment may be a reasonable alternative to mastectomy in patients with tumors 4 cm or larger without compromise in local-regional control or survival, while achieving acceptable cosmesis.


Long-term efficacy of octreotide in the treatment of Zollinger-Ellison syndrome.

Nine patients with Zollinger-Ellison syndrome were treated with octreotide acetate (100 micrograms delivered subcutaneously three times daily) and followed up for 1 to 48 months. Serum gastrin levels were obtained at predetermined intervals. All patients had elevated baseline fasting gastrin levels (greater than 150 ng/L [greater than 150 pg/mL]). One month after administration of octreotide, gastrin levels were in the reference range for five (62%) of eight patients, and a mean gastrin suppression rate of 76% was achieved (ie, values were a mean of 76% less than baseline values). One year after administration of octreotide, five (71%) of seven evaluable patients had gastrin levels of less than 200 ng/L (200 pg/mL), and the mean gastrin suppression rate was more than 80% for these seven patients. During the second year, control at these levels was maintained in four patients; one patient continued to have controlled levels for 42 months. Complete symptomatic response occurred in seven patients (78%), and partial response in two patients (22%). All six patients with diarrhea before treatment were cured of it. Octreotide acetate provides efficacious long-term suppression of elevated gastrin levels and excellent symptomatic relief in patients with Zollinger-Ellison syndrome.


Long-segment Hirschsprung's disease.

We identified 21 children (14 boys and seven girls) with long-segment Hirschsprung's disease defined as aganglionosis extending proximal to the ileocecal valve. Long-segment Hirschsprung's disease is difficult to diagnose and treat; symptoms may be mild, and diagnosis delayed. Abdominal distention and constipation or delayed passage of meconium are the most common symptoms. Radiologic studies are unreliable in establishing the diagnosis. The morbidity rate is high because of the high transition zone and short gut. The long-term outcome of patients after the standard Duhamel procedure is satisfactory, except with extremely high transition zones. Pull-through procedures should not be performed in the small infant, but should be delayed until patients are old enough to be continent.


Examination of the patient with a knee dislocation. The case for selective arteriography.

One hundred fifteen patients with a unilateral knee dislocation underwent arteriography to examine the popliteal artery. The incidence of popliteal artery injury was 23% (27 patients). Clinically, 29 (25%) of the 115 patients had an abnormal ipsilateral pedal pulse and 23 (79%) of these 29 patients had an arteriographically identified popliteal artery injury. Twenty-two arteries were surgically repaired and one was treated without surgery. Eight-six patients had normal pulses; the arteriogram showed no abnormalities in 77, demonstrated spasm in five, and revealed an intimal flap in four. All 86 patients were treated without surgery and had no delayed vascular complications. This demonstrates that the vascular examination is an accurate predictor of major popliteal artery injury following knee dislocation. Patients with an abnormal pedal pulse warrant arteriography due to a high incidence (79%) of popliteal artery injury. Patients with normal pulses may be monitored by clinical examination only. Popliteal artery injuries in this group are minor and rarely require intervention.


Neonatal cardiac transplantation. Intermediate-term results and incidence of rejection. Loma Linda University Pediatric Heart Transplant Group.

Early age at cardiac transplantation may favor successful engrafting with minimal chronic immunosuppression. Fifty-two newborns underwent orthotopic heart transplantation; 47 (90%) survived the operation, and 44 (85%) were late survivors. Actuarial survival was 92% at 1 month, 86% at 1 year, and 84% at 5 years. Forty-four infants who survived 12 weeks and the corresponding 100 rejection episodes were analyzed. Mean follow-up was 2.2 years. The mean number of rejections per year of follow-up was 1.2. No episodes of rejection were identified in six patients. Seven patients had a late rejection episode more than 1 year after transplantation, and only one had a late rejection episode after 2 years. Neonatal cardiac transplantation is effective and durable therapy for uncorrectable heart disease. Intermediate-term results are excellent. Severe rejection is uncommon, and few episodes occur after 1 year of follow-up.


Surgical treatment and chemotherapy for pulmonary metastases from osteosarcoma.

Between 1971 and 1991, 247 patients with stage I osteosarcoma were treated at UCLA. Patients were treated in four sequential groups, with group 1 receiving surgery alone, and groups 2 through 4 receiving various adjuvant chemotherapeutic regimens. The incidence of lung metastases in these patients decreased from 92% (group 1) to 31% (group 4), while the proportion of patients undergoing pulmonary resection increased (17% vs 82%). Overall 5-year survival rate among patients with pulmonary metastases increased from 0 in group 1 to 41% (actuarial) in group 4. No clinical factor correlated significantly with outcome using univariate analysis, although there was a trend toward prolonged survival in those with longer disease-free intervals. Adjuvant chemotherapy and resection of pulmonary metastases have transformed a uniformly fatal condition into one with a reasonable expectation of long-term survival.


Management of bile duct strictures. An evolving strategy.

In an effort to determine the role of interventional radiologic and endoscopic techniques in the management of benign biliary strictures, a retrospective analysis was carried out on 194 consecutive patients with bile duct strictures treated at UCLA between 1955 and 1990. Patients were classified as group 1 (1955 through 1979; n = 138) or group 2 (1980 through 1989; n = 56). Follow-up was for a minimum of 24 months and was in excess of 3 years in 179 patients (92%). Although the incidence of recurrent strictures was similar in the two groups (21% and 23%), the reoperation rate was significantly lower (P less than .02) in group 2 (6%) than in group 1 (21%). Percutaneous transhepatic biliary dilatation, used in 20 patients in group 2, was successful in 13 (93%) of 14 patients with anastomotic strictures and three (50%) of six patients with primary strictures (P less than .05). We conclude that surgical reconstruction remains the standard therapy for patients with primary bile duct strictures. Percutaneous transhepatic biliary dilatation has limited usefulness for these patients, but may be more appropriate for those with anastomotic strictures.


Care for victims of urban violence and the education of trauma and critical care surgeons. A troubled partnership?

This article reviews the current status of trauma care education and its relationship to critical care education. The critical linkage of both of these endeavors with urban hospitals oriented to indigent care is stressed. Within the specialty of surgery, the recent progress toward resolution of conflicts that have threatened trauma and critical care education programs is reviewed. The partnership between the trauma programs of urban hospitals will be strengthened by this resolution.


The MEE/PEE ratio as a predictor of excess weight loss for up to 1 year after vertical banded gastroplasty.

Thirteen morbidly obese individuals were studied prospectively for 1 year after vertical banded gastroplasty (VBG) to determine the relationships between energy balance equation parameters and excess weight loss. The measured energy expenditure (MEE), as determined by indirect calorimetry, was not correlated with weight loss. However, when this parameter was expressed as a ratio to the predicted energy expenditure (PEE), the ratio was significantly correlated with the postoperative excess weight loss at 2, 6, and 12 months. The mean daily energy intake after the VBG was 2715 +/- 865 kJ. The postoperative energy intake was not correlated with the excess weight loss. Diet-induced thermogenesis was studied in eight patients. The mean diet-induced thermogenesis was 10.31% +/- 13.92%. The diet-induced thermogenesis was not correlated with the postoperative excess weight loss. The preliminary findings of this trial suggest that the MEE/PEE ratio is useful in predicting excess weight loss after VBG.


Detection of occult tumor using indium 111-labeled anticarcinoembryonic antigen antibodies.

Even with the advancement of radiologic techniques, metastatic cancers can still be difficult to detect. In this study, 48 patients suspected of having occult metastases were studied by radioimmunodetection following the administration of 92.5 to 181.3 MBq of indium 111-labeled monoclonal anticarcinoembryonic antigen antibody. All but seven patients were thought to have metastatic colorectal carcinoma. In the majority of cases, physical examinations and computed tomographic scans had failed to detect a lesion. At least one lesion that was later proved to exist was detected in 34 of the 50 studies performed on these patients. Seven of eight patients with normal radioimmunodetection scans remain free of disease. One hundred one sites were detected overall; 60 were considered true-positive sites and 27 false-positive sites. Fourteen sites remained in question. Nineteen false-negative sites occurred. Radioimmunoimaging appears valuable for the detection of occult cancer where standard, noninterventional techniques have failed to detect the suspected disease.


Bacterial translocation after major hepatectomy in patients and rats.

Bacterial infections are frequent complications after liver resection. Of 138 patients who underwent major hepatectomy, 11 patients (8%) developed intra-abdominal sepsis in the postoperative period. Seven bacterial strains of gut origin were isolated from the abdominal cavity. Eight patients had multiple bacteria cultured. In the experimental studies on rat models, positive mesenteric lymph node cultures were seen 2 hours after removal of 70% and 90% of the total weight of the rat liver, and 12 hours after 50% hepatectomy, persisting for 3 and 4 days after 50% and 70% hepatectomy, respectively. The incidences of bacteremia 2 and 4 hours after 90% hepatectomy were 80% and 100%, respectively; 6 hours after 70% liver resection, the incidence of bacteremia was 33%. Blood cultures were positive in only 6% of the rats following 50% hepatectomy, and in none of the controls. Thus, bacterial translocation occurs in the early course after hepatectomy, the incidence being proportional to the amount of liver tissue removed.


A decade of oral anticoagulant treatment to maintain autologous vein grafts for femoropopliteal atherosclerosis.

To determine whether long-term oral anticoagulant treatment was effective in improving graft performance and preventing major amputation following vein bypass surgery for femoropopliteal atherosclerosis, a clinical trial was conducted in one single center and continued during 10 years. After 130 patients had electively received a femoropopliteal vein graft, they were randomly assigned to a therapy group (treatment with phenprocoumon [n = 66]) or to a control group (n = 64) that remained without any anticoagulant treatment. Primary end points of the study were graft reocclusion and limb loss. The median durations of primary patency and limb salvage were significantly longer for treated patients than that for controls. In addition, survival in the therapy group was longer. Following autologous vein bypass surgery in the treated group, the results were superior in terms of graft patency, limb salvage, and survival.


Familial chronic recurrent pancreatitis in identical twins. Case report and review of the literature.

Familial presentation of chronic recurrent pancreatitis in childhood is rare. The etiology of this illness is obscure, and its hereditary properties are not well defined. Simultaneous occurrence of chronic recurrent pancreatitis in identical twins with the same clinical presentation and similar typical pancreatographic abnormalities is exceptional. Twin sisters, aged 9 years, were admitted to the hospital because of recurrent attacks of pancreatitis. Ultrasound examination revealed an enlarged irregular pancreatic duct in both girls, and endoscopic retrograde cholangiopancreatography showed a distorted duct with multiple strictures and dilatations similar to a "chain of lakes" pattern. Both patients underwent longitudinal pancreatojejunostomy within a month. The therapeutic regimen and preoperative and surgical treatment of such patients are discussed, as is the optimal timing of intervention.


Splenopneumopexy to treat portal hypertension produced by venous occlusive disease.

Splenopneumopexy is intended to induce collateral circulation between the portal system and the pulmonary veins. It involves performing a parenchymatous anastomosis between the amputated superior pole of the spleen and the exposed pulmonary venous structures in the left lower lobe. This operative procedure was used to treat four patients with extended portal-splenic-mesenteric venous occlusion who did not respond satisfactorily to sclerotherapy. The patients underwent transfemoral embolization of their splenic arteries before splenopneumopexy. Following the operations, all patients have remained well, experiencing cessation of gastrointestinal bleeding for up to 48 months. Splenopneumopexy may be a therapeutic alternative in selected patients with portal hypertension, including those patients with widespread occlusion of the portal vein and its radicles.


Binding characteristics of ortho-toluidine to rat hemoglobin and albumin.

The binding characteristics of [14C]ortho-toluidine (OT), a suspect human carcinogen, were investigated in male Sprague-Dawley rats. Rats were administered [14C]OT i.p. at 10, 20, 40, 50, or 100 mg/kg body weight, then sacrificed at 2, 4, 8, 18, 24, 48, or 72 h, or 7, 14, or 28 days. Hemoglobin (Hb) and albumin (Alb) were isolated from blood, and OT binding was determined by liquid scintillation counting. For Alb, peak binding occurred at 50 mg/kg at the 4-h time point (15.6 ng OT/mg Alb), while for Hb peak binding was observed at 24 h at the 100 mg/kg dose (23.0 +/- 5.1 ng OT/mg Hb). OT-Alb binding was not linear; however, OT-Hb binding appeared to increase linearly in a dose-dependent manner. Biological half-lives of OT bound to Alb or Hb were observed to be 2.6 and 12.3 days, respectively, after rats were administered a single dose of [14C]OT and sacrificed after 4 h to 28 days. The effect of route of administration on OT-Hb adduct formation was investigated, and approximately a two-fold increase in radioactivity bound to Hb was observed after i.p. administration of 100 mg/kg [14C]OT versus oral intubation. Additional studies were carried out to investigate the effect of microsomal enzyme induction. An increase in OT-Hb binding was seen in rats pretreated with phenobarbital compared to rats pretreated with beta-naphthoflavone or without pretreatment; however, this increase was not statistically significant. These results suggest that OT-Hb and OT-Alb adduct formation may be a valuable biomarker for assessing workplace exposure.


Interlaboratory comparison of microsomal ethoxyresorufin and pentoxyresorufin O-dealkylation determinations: standardization of assay conditions.

Assay conditions and results of cytochrome P-450 dependent 7-ethoxyresorufin (ER) and 7-pentoxyresorufin (PR) O-dealkylation (OD) by rat liver microsomes were compared by four laboratories in the Netherlands. Microsomal mixtures were prepared from control, 3-methylcholanthrene and phenobarbital pretreated animals, resulting in different levels of cytochrome P-450 isozymes. EROD and PROD activities were determined in each laboratory according to their own protocols. Considerable variability was found both between and within laboratories. Further studies demonstrated that protocol differences are important factors causing this interlaboratory variation. Main factors of influence were buffer type, batch of resorufin used for calibration, substrate solvent and substrate concentration. Based on the results obtained, standardized protocols for optimized measurement of microsomal EROD and PROD activities were developed. Additional experiments demonstrated that the use of these standardized protocols reduced intralaboratory variation in both the EROD and the PROD assay, whereas it also reduced the interlaboratory variability for the PROD determinations. The interlaboratory variation for measurement of microsomal EROD activities was only reduced for the laboratories using a Cobas-Bio analyzer. The results of the present study demonstrate clearly that data obtained with EROD and PROD activity measurements are highly sensitive to factors frequently varying from one laboratory to another. In addition, they demonstrate the necessity to be careful with absolute values presented in the literature for these activities, unless well characterized assay conditions are applied.


Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on benzo(a)pyrene hydroxylase activity in embryos of the Japanese medaka (Oryzias latipes).

When Japanese medaka embryos were exposed to 12 ng/l 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) beginning on the day of fertilization (day 0), benzo(a)pyrene hydroxylase (B(a)PH) activity was induced in the whole embryo 105,000 g fraction by day 5 of development, which coincided with liver development. The induction of B(a)PH activity also coincided with the appearance of 2,3,7,8-TCDD induced hemorrhagic and edematous lesions. B(A)PH induction only occurred in embryos exposed to toxic concentrations (greater than 10 ng/l) of 2,3,7,8-TCDD. B(a)PH induction also occurred in embryos after exposure to 10 ng/l 2,3,7,8-tetrachlorodibenzofuran (TCDF) and 50 micrograms/l 1,2,7,8-TCDD. Both 2,3,7,8-TCDF and 1,2,7,8-TCDD are toxic to Japanese medaka embryos at concentrations that resulted in the induction of B(a)PH activity. B(a)PH activity was not induced by the non-toxic congener 1,3,6,8-TCDD at concentrations as high as 50 micrograms/l. The structure activity relationship for B(a)PH induction in Japanese medaka embryos was similar to that which is observed in other species and biological systems, suggesting that the biological activities of these compounds may also be mediated through the putative Ah receptor in these fish embryos. At 50 micrograms/l, beta-naphthoflavone (BNF) induced B(a)PH activity in Japanese medaka embryos to similar levels as 2,3,7,8-TCDD did at toxic concentrations. However, at 50 micrograms/l, BNF was not toxic to Japanese medaka embryos. Therefore, the induction of B(a)PH activity probably did not directly result in the toxicity observed in these fish embryos after exposure to 2,3,7,8-TCDD.


Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 4. Effects of multiple-dose treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on peripheral lymphocyte subpopulations of a non-human primate (Callithrix jacchus).

Non-human primates (Callithrix jacchus) were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) over a period of 30 weeks, and lymphocyte subpopulations of venous blood were monitored using monoclonal antibodies and flow cytometry (FACScan). There was no clear-cut change in the total lymphocyte population during this study. In the first part of the study the new-world monkeys (marmosets) were treated for 24 weeks with a weekly dose of 0.3 ng TCDD/kg body wt. At the end of this treatment period a level corresponding to an actual cumulative dose of about 2.5-2.7 ng TCDD/kg body wt was expected. The percentage and the absolute number of the CD4+CDw29+ cells ("helper inducer" or "memory" cells) surmounted the physiologically occurring increase. Concomitantly the percentage of the CD4+CD45RA+ cells ("suppressor-inducer" or "naive" cells) decreased. There was, at the same period, no change in the total T cell population (CD2+ cells) or in the cells carrying the CD8 or the CD4 epitope. When increasing the weekly dose to 1.5 ng TCDD/kg body wt, a transient increase in the percentage and the absolute number of the CD8+CD56+ cell population ("cytotoxic T cells") was observed 3 weeks after the increase in dosing. At this time the expected decrease in the percentage or the absolute number of CD4+CDw29+ cells was just detectable and this decline was at its maximum 6 weeks after switching to the higher weekly doses. The reduction in the percentage and the absolute number of CD4+CDw29+ cells persisted 5 weeks after discontinuation of the dosing, but this cell population was again within normal limits 7 weeks later. Because the two subpopulations are changed in opposite directions, the ratio CD4+CDw29+/CD4+CD45RA+ is a very sensitive measure of the effect induced by TCDD. There was a pronounced decrease in the percentage of the CD20+ cells (B1 cells), but their percentage and number rapidly normalized, in contrast to the CD4+CDw29+ cells, when the dosing was discontinued. At the end of the treatment period the apparent body burden was calculated to correspond to an actual dose of about 9-10 ng TCDD/kg body wt. Such an actual dose level might be assumed to be reached under steady-state conditions in chronic experiments with daily doses of about 135 pg TCDD/kg body wt (assuming a half-life for TCDD in the marmoset of 6-8 weeks). Extrapolations of the results obtained at higher doses to very low exposures is not justified with respect to the effects induced by TCDD on the immune system of marmosets. At lower doses the effect is clearly reversed.


Plasma concentrations of pralidoxime methylsulphate in organophosphorus poisoned patients.

Using pharmacokinetic data from healthy human volunteers in a bicompartmental pharmacokinetic model, a repeated dose scheme for pralidoxime methylsulphate (Contrathion) was developed producing plasma levels remaining above the assumed "therapeutic concentration" of 4 mg.l-1. Using the same data, it was found that a concentration of 4 mg.l-1 could also be obtained by a loading dose of 4.42 mg.kg-1 followed by a maintenance dose of 2.14 mg.kg-1.h-1. In order to study the pharmacokinetic behaviour of pralidoxime in poisoned patients, this continuous infusion scheme was then applied in nine cases of organophosphorus poisoning (agents: ethyl parathion, ethyl and methyl parathion, dimethoate and bromophos), and the pralidoxime plasma levels were determined. The mean plasma levels obtained in the various patients varied between 2.12 and 9 mg.l-1. Pharmacokinetic data were calculated, giving a total body clearance of 0.57 +/- 0.27 l.kg-1.h-1 (mean +/- SD), an elimination half-life of 3.44 +/- 0.90 h, and a volume of distribution of 2.77 +/- 1.45 l.kg-1.