[Pharmacokinetics of carboplatin after intraperitoneal administration and clinical effect in ovarian cancer].

The patients with ovarian cancer are apt to combine peritonitis carcinomatosa (PC). The effect of intraperitoneal (IP) administration of CDDP against peritonitis carcinomatosa was examined. Hydration was not necessary when CBDCA was injected, because nephrotoxicity of CBDCA was very low compared to CDDP. We studied pharmacokinetics of IP-CBCCA and its efficacy and safety. Four hundreds and fifty mg of CBDCA was dissolved in 1,000 ml of saline and administrated through the subcutaneously implanted Infuse-A-Port for 60 minutes. Complete response was 25%. The platinum concentration in the ascites (injected saline) decreased to 90.8 micrograms/ml at 2 hr after administration and to 3.8 micrograms/ml at 24 hrs, and 79.7 97.5% existed as free Pt. The concentration of serous Pt reached to 6.2 micrograms/ml at 15 min. and was kept at 6-8 micrograms/ml. and 52.4-92.7% existed as free Pt in serum. Pt was excreted to urine and reached to the peak concentration at 4 hr. Adverse effect was mainly myelotoxicity without renal toxicity and emesis. Leukocytopenia of grade 4 was 14.3%, thrombocytopenia was 25.0%. We tried IP administration to the outpatients. The doses were mainly 300 mg, but in some cases, it was escalated to 450 mg, Adverse effect of 300 mg was thrombocytopenia of grade 4 (4.8%). These results suggest that IP administration of CBDCA seemed to be a new method as locosystemic chemotherapy. We demonstrated new chemotherapeutic method to outpatients.


[Phase I study of NK 622 (toremifene citrate)].

A phase I study of NK 622 (toremifene citrate), a novel antiestrogen, was conducted in female patients with cancer. Patients received a single oral dosing or daily once oral dosing for five consecutive days. Any adverse effects were not experienced in the single dosing of 40 or 60 mg of NK 622. In the daily administration of 10, 20, 40, 60, 120, 240 and 480 mg/day, one of three patients who received 20 mg/day experienced grade 1 anorexia, three of four patients received 240 mg/day experienced adverse effects: Grade 1 leukopenia in one patient, Grade 1 general hot flush in one patient, and Grade 1 nausea, hot flush in the face and vertigo, Grade 2 anorexia, fatigue, dull headache and general hot flush in another one patient. These symptoms recovered to normal levels after treatment. Serum hormone levels were examined in postmenopausal patients, and a significant increase of the sex hormone binding globulin level was observed in the patients received 120 and 240 mg/day doses. Serum levels of NK 622 determined as free base (TOR) reached the peak levels in 2 to 4 hours after administration on the 1st and 5th day in daily treatment, while a metabolite N-demethyltoremifene (TOR-1) reached the peak level in 4 to 170 hours. Maximum serum levels and area under the concentration versus time curves of TOR and TOR-1 increased dose-dependently. These values also increased by repetition of the treatment. Half-lives of TOR and TOR-1 in serum ranged in 74.5 to 148.9 hours and 154.1 to 653.1 hours, respectively. From these results, it was concluded that safety and efficacy of NK 622 should be assessed by using 240 mg or less doses in clinical phase II studies where breast cancer patients received long term treatment with NK 622.


[The pharmacokinetics of intraperitoneal (IP) carboplatin (CBDCA) and dose-up study of intravenous (IV) cyclophosphamide (CPM) in combination with IP CBCDA for advanced ovarian cancer patients].

The pharmacokinetics of IP CBDCA was compared with IV CBDCA and a dose-up study of IV CPM was performed in combination with 400 mg/m2 IP CBDCA for advanced ovarian cancer patients. The maximum concentration of free platinum (F-Pt) in serum following IP CBDCA administration was approximately 1/3 that of F-Pt following IV CBDCA. F-Pt in serum remained more than 90% of total platinum following IP CBDCA until 12 hours after administration. The t1/2 of F-Pt in serum after IP CBDCA administration was two times longer when compared with t1/2 following IV CBDCA, showing the slow peritoneal clearance of CBDCA. The area under curve (AUC) following IP CBDCA was approximately 67% of AUC following IV CBDCA. Cumulative urinary secretion (CUS) of platinum following IP CBDCA was 37% of CUS after IV CBDCA. The maximum tolerable dose of IV CPM in combination with 400 mg/m2 IP CBDCA was 550-600 mg/m2. The dose limiting factor of this combination therapy was leukocytopenia. Thrombocytopenia was mild in this study. Combination of 400 mg/m2 IP CBDCA and 550-600 mg/m2 seemed to be a tolerable and repeatable therapy for most patients with advanced ovarian carcinoma. Since thrombocytopenia was mild and the pharmacokinetics showed the smaller AUC of free platinum in serum following IP CBDCA, a dose-up study for IP CBDCA should be considered.


[Salvage therapy for recurrent or refractory non-Hodgkin's lymphoma with etoposide, methotrexate, vindesine and prednisolone (EMVP)].

Seventeen patients with recurrent or refractory non-Hodgkin's lymphoma were treated with EMVP (Etoposide 75 mg/m2 i.v. d 1-5, Methotrexate 100mg/m2 i.v. d 1, Vindesine 3 mg/body i.v. d 1, Prednisolone 60 mg/m2 p.o. d 1-5), repeating every 3 weeks. Six complete responses (35%) and five partial responses (30%) were obtained with an overall response rate of 65%. The median duration of response was 26 months (range 8-49+months) for complete response (CR) and 4 months (range 2-6 months) for partial response (PR). The median duration of survival was 31 months for CR, 11 months for PR and 10 months for all patients, respectively. The major toxic effect was myelosuppression. Leukopenia less than 1,000/mm3 and thrombocytopenia less than 25,000/mm3 occurred in 5 and 3 patients, respectively. The other toxicities were alopecia, nausea and mucositis. However, these toxicities were well tolerated and clinically manageable. These results suggested that EMVP therapy was an effective regimen for patients with recurrent or refractory lymphoma.


[A case of renal cell carcinoma with lung metastasis and local recurrence effectively treated with nephrectomy and UFT].

A 74-year-old woman was admitted on July 18, 1989 for an abnormality on her chest roentgenogram. Right renal tumor with bilateral pulmonary metastasis was detected and right nephrectomy was performed. Because of the progression of pulmonary metastasis and the local recurrence after surgery, UFT was orally administered at a dose of 300 mg everyday since Dec. 12, 1989. The chest roentgenogram on Nov. 21, 1990 showed progression of lung lesions. But at the 20 th month after the beginning of chemotherapy, both lung lesions disappeared completely and local recurrence around the operative wound strikingly improved. This is a rare case of renal cell carcinoma with local recurrence and lung metastasis successfully treated with UFT.


[A case of adenocarcinoma of lung cancer with multiple brain metastasis and lymphangitis carcinomatosa responding well to chemotherapy with carboplatin, etoposide and ifosfamide].

A 75-year-old male who suffered from adenocarcinoma of lung cancer with multiple brain metastases, developed left hemiplegia. After diagnosis, he was treated with 4,000 cGy whole brain radiation, but soon after advanced lymphangitis carcinomatosa set in and his general condition deteriorated. He was administered carboplatin combination with etoposide and ifosfamide. Lymphangitis carcinomatosa disappeared, and the main tumor of lung and brain metastases were not growing. We recommended carboplatin for an old patient or one in poor condition, because it had less cytotoxicity and retained the same antitumor activity compared with cisplatin.


[Case report of a successful stage reduction of gastric carcinoma preoperatively treated by combined chemotherapy of 5-FU(UFT) and cisplatin].

A 52-year-old woman was diagnosed to have IIc+IIa-like advanced gastric carcinoma in the upper stomach by X-ray and endoscopic examination with biopsy. CT scan revealed swelling of the para-aortic lymph nodes which was taken to be evidence of metastases of the gastric carcinoma. The patient was considered to have surgically non-curative gastric carcinoma (Stage IV), and preoperative chemotherapy was initiated. The regimen consisted of CDDP 50 mg (day 1-2, drip), 5-FU 750 mg (day 2-7, drip) and UFT 400 mg (from day 8 to the day before operation, oral). About one month after initiating treatment, total gastrectomy with lymph node dissection was performed. Histopathological examination of the section of the primary tumor revealed that only a few cancer cell nests (poorly differentiated adenocarcinoma) remained in the muscle and subserosal layer. In all of the lymph nodes which were suspected to have metastases preoperatively, cancer cells completely degenerated into mucinous lakes or foam cell nests. No liver metastasis nor peritoneal dissemination was detected, and this case was judged to be stage II after chemotherapy.


[A case of gastric carcinoma with peritonitis carcinomatosa responding remarkably to etoposide, adriamycin and cisplatin (EAP) therapy].

The patient was a 62-year-old male who had Borrmann 4 type gastric cancer. He presented massive ascites due to peritonitis carcinomatosa and the cytology of ascites was class V. He was treated with 3 courses of EAP (etoposide, adriamycin, cisplatin) therapy. Computed tomography showed ascites nearly disappeared. Remarkable improvement was observed by barium meal study and endoscopic examination, and partial remission (PR) was achieved. As for toxicity bone marrow suppression, alopecia and elevation of BUN were observed.


Current practices for the prevention and treatment of malaria in children and in pregnant women in the Brazzaville Region (Congo).

Current practices for the prevention and treatment of malaria in children and in pregnant women in the Brazzaville Region (Congo) were studied in 1989 and 1990. Information was obtained by interviewing a total of 1152 subjects. Overall, chemoprophylaxis was used less than was the systematic treatment of fever. Fever was treated before seeking medical advice in over 50% of the cases. Two-thirds of those interviewed reported that they slept under mosquito nets. Families with lower socio-economic standards were less likely to use chemoprophylaxis, to have antimalarials in the home, and to own mosquito nets; and they were more likely to prefer injections and to purchase drugs in the local markets.


The in vitro and in vivo antimalarial activity of some Mannich bases derived from 4-(7'-trifluoromethyl-1',5'-naphthyridin-4'-ylamino)phenol, 2-(7'-trifluoromethyl-quinolin-4'-ylamino)phenol, and 4'-chloro-5-(7''-trifluoromethylquinolin-4''-ylamino)biphenyl -2-ols.

A series of di-Mannich base derivatives (4 and 5) from 4-(7'-trifluoromethyl-1',5'-naphthyridin-4'-ylamino)phenol and 2-(7'-trifluoromethylquinolin-4'-ylamino)phenol, respectively, and mono-Mannich base derivatives (6) from 4'-chloro-5-(7''-trifluoromethylquinolin-4''- ylamino)biphenyl-2-ol were assayed for activity against the chloroquine-sensitive (FCQ-27) isolate of cultured Plasmodium falciparum using the inhibition of uptake of radiolabelled hypoxanthine. All seven di-Mannich base derivatives (5) revealed a higher activity than chloroquine, whereas the di-Mannich base derivatives (4) were slightly less active (with some derivatives more active and some less active than chloroquine). The mono-Mannich base derivatives (6) were less active than chloroquine. Comparative tests of selected compounds of (4 and 5) using a morphological assay revealed no significant differences in activity between the chloroquine-sensitive (FCQ-27) and chloroquine-resistant (K-1) isolates. Selected di-Mannich bases (4 and 5) and the mono-Mannich bases 5-7''-bromo (and 7-trifluoromethyl)-1'',5''-naphthyridin-4''-ylamino)-3-(t- butylaminomethyl)-4'-chlorobiphenyl-2-ols (7, X = Br, CF3) markedly suppressed parasitaemia in Plasmodium vinckei vinckei infected mice when administered (i.p.) in a single dose of 200 mg kg-1.


The isoenzyme characteristics of Trypanosoma evansi and Trypanosoma equiperdum isolated from domestic stocks in China.

Twelve stocks of Trypanosoma evansi and one of Trypanosoma equiperdum isolated from domestic animals in China were examined for 16 enzymes using cellulose acetate and thin-layer starch gel electrophoresis. Differences were seen between stocks in only two of the enzymes, MDH and ALAT. Three of the T. evansi stocks, isolated from buffalo, and the T. equiperdum stock had the unusual pattern MDH-3, while all the other Chinese stocks had the common MDH-1. Two other stocks of T. evansi and again the T. equiperdum, all from equines, showed a new pattern ALAT-14. Otherwise the Chinese stocks had the same enzyme profile as T. evansi from elsewhere.


Effects of long-term in vitro cultivation on the virulence of cloned lines of Leishmania major promastigotes.

The virulences of several clones from a single Leishmania major strain were studied in BALB/c mice. Clones showed the same pattern of infectivity and virulence two months after cloning as the parental population. After prolonged in vitro culture, however, it was apparent that two types of virulent clones existed: although the level of virulence remained stable in some clones, in others, such as C-11, it progressively decreased, as in the parental population. The progressive loss in virulence in a continuously cultured mixed population was probably due to selection, as the initial mixture of a stable virulent clone and a stable avirulent clone eventually yielded a totally avirulent promastigote population. After cultivation for 12 months, neither clone C-11 nor the parental population produced lesions in inoculated mice but virulent parasites were recovered from the inguinal nodes of the mice, possibly as a result of selection in vivo for virulent parasites.


Post kala-azar dermal leishmaniasis: a neglected aspect of kala-azar control programmes.

Post kala-azar dermal leishmaniasis (PKDL) was studied in relation to the kala-azar epidemic in Bihar, India. Between 1970 and 1989, 530 individuals, 302 males and 228 females, were admitted to the hospital of Patna Medical College with PKDL, the number of cases steadily rising from two in 1970 to 59 in 1989. The age of the patients varied from four to 70 years, with 33% aged 11-20 years and 16% 0-10 years. The prevalence of kala-azar in India also increased in the same period, mostly as the result of an epidemic of the disease in Bihar. There were no cases of this disease admitted to Patna Medical College from 1958-1970, it having become rare in India in the 1950s, possibly as a result of the DDT sprayed during the National Malaria Eradication Programme. In the period 1977-1990, however, there were 301,076 cases of kala-azar reported in Bihar alone, with a mortality rate over 2% (compared with 31,074 cases and a mortality rate below 0.4% for the rest of India). It seems possible that, once DDT spraying stopped, the re-establishment of large sandfly population and infection of these vectors, largely as a result of them feeding on cases of PKDL, provoked the resurgence of kala-azar. The study emphasizes the need to search for cases of PKDL, even in young children, and to monitor and effectively treat them as part of kala-azar control programmes. All patients could be cured if treated with the right dosage for the right period.(ABSTRACT TRUNCATED AT 250 WORDS)


Cutaneous leishmaniasis in Kabul: observations on a 'prolonged epidemic'.

Cutaneous leishmaniasis cases in Kabul have increased steadily in number since the first report, in 1964. This increase is despite insecticide application in houses and intensive detection and treatment of cases. The age distribution of infection remains as it was in 1972, and approximates that of the Afghan population. There is no evidence of accumulating immunity in the population. Multiple lesions are infrequent, but commoner on older people, and tend to be located on the arms and legs rather than the head. A house-to-house survey failed to distinguish risk factors promoting infection. Clustering of lesions on individuals and in households is interpreted as being due to multiple bites from a single infected sandfly. Phlebotomus sergenti numbers were strongly correlated with rainfall in the previous winter, but not with numbers of cases or numbers of houses sprayed. It is suggested that Leishmania tropica is at the limit of its range in Kabul and only remains endemic because of the rapid turnover of people in the City.


Prevalence of Entamoeba histolytica and other intestinal parasites in a community from Maracaibo, Venezuela.

The prevalences of Entamoeba histolytica and other intestinal parasites were assessed in a suburban community of Maracaibo, Venezuela, by examination of a stool specimen from each of 342 individuals, using iron-haematoxylin stained faecal smears and formalin-ether concentration. The overall parasitic infection rate was 80.4%, and 65.8% of the population had multiple infections. The overall amoebic infection rate, which was highest in female adults, averaged 39.7%. The E. histolytica infection rate was 8.7% and most of those infected were passing cysts. Entamoeba polecki was observed in two samples. Amongst the protozoa, Entamoeba coli was observed most frequently (24.8%) and Giardia lamblia was the predominant pathogen (13.0%). Trichuris trichiura (71.9%) and Ascaris lumbricoides (54%) were the most common parasites, particularly in school-children. The high rates of parasitic and multiple infections reflect the low socio-economic status of the community studied.


Prevalence of human hydatid disease in northwestern Libya: a cross-sectional ultrasound study.

A total of 4103 people were screened in an ultrasound survey of the prevalence of hydatid disease (Echinococcus granulosus) in five areas of northwestern Libya; hydatid cysts were seen in 57 (1.4%), an overall prevalence of approximately 2.0% when adjusted for the likelihood of the occurrence of cysts in other sites in the body. All ultrasound-positive cases were confirmed by dot-blot ELISA. The prevalence of hydatid cysts increased with age, and differed between the sexes except in the five to 14 age group. All diagnosed cases, even those with large cysts, were asymptomatic. This study demonstrates the value of ultrasonography for screening field populations for hydatid disease. The technique was well received locally, facilitating the rapid collection of prevalence data from all ages and both sexes. Libyan people keep guard dogs, but there is little direct human:dog contact. Many people own a single dog, invariably kept outside and often chained up. Stray dogs are common, roaming the countryside to scavenge sheep carcases etc., and such dogs could be the main reservoir of E. granulosus in Libya. Because of the minimal direct human:dog contact, transmission of hydatid disease in Libya is probably indirect by ingestion of eggs from contaminated vegetables or drinking water.


A survey of the intestinal helminths of refugees in Juba, Sudan.

A parasitological survey of refugees based in Juba, Sudan, involving 241 faecal samples, revealed that 66% of the population harboured intestinal helminths. The most commonly found infection was hookworm (36%), followed by Schistosoma mansoni (26%), Strongyloides stercoralis (20%), Hymenolepis nana (11%), Ascaris lumbricoides (1.2%), Trichuris trichiura (0.8%) and Taenia sp. (0.4%). Many of the specimens (42%) harboured a single infection, 21% had double, 2% triple and 1% quadruple infections. Parasite prevalences and intensities were analysed in relation to age, sex, religion and occupation: females (70%) were found to be more infected than males (64%); Muslims (50%) were less infected than Christians (68%) and agriculturalists (90%) were the most infected occupational group.


Helminth parasites of carnivores in northern Iran.

A total of 100 jackals, 35 stray dogs, 13 cats, two badgers, one fox and one wild cat were collected from two provinces in northern Iran. On post mortem examination 41 species of helminths were recovered, at least 12 of which have been reported infecting humans in various countries. Hookworms were the most commonly found parasites, and Echinococcus granulosus showed the highest intensity of infection. Seven helminth species from jackals, three species from dogs, four species from cats and four species from badgers are reported for the first time in Iran.


Diethylcarbamazine treatment of bancroftian and malayan filariasis with emphasis on side effects.

A total of 1015 filarial carriers were hospitalized and treated with DEC either in a long course with light doses (6, 7, 8, 9 or 10 mg kg-1 b.w. divided into three doses daily for seven days) or in a short course with heavy doses (15 mg kg-1 b.w. once daily for one, two or three days). The efficacy of the long course (85%) was much higher than that of the short course (59%); but the reaction rate following the heavy dose (87%) was higher than that following the light dose (72%). For Brugia malayi infections the overall efficacy was 92% and the reaction rate 82%, for mixed infections the respective rates were 85% and 77%, and for Wuchereria bancrofti infections 82% and 69%. The cure rates decreased from 93% in carriers with one to 10 microfilariae in 60 microns blood to 63% in those with over 100 Mff in 60 microns blood. Febrile reactions developed in 92% of carriers with mixed infections, in 91% of those with B. malayi, and in 84% of those with W. bancrofti. Overall, 63% of those treated were free of microfilariae on the last day of treatment, and 92% were free 48 months after treatment.


Prevalence of dracunculiasis among Nigerian school children as an index of prevalence in their communities of origin.

A survey of dracunculiasis was carried out among pupils in their schools and among adults in the communities from which the pupils came, to determine whether the prevalence of infection in the pupils was a good index of the prevalence in their village. No significant difference was observed between the prevalence of current infection in pupils and that in their village of origin, although in some instances there were significant differences between the prevalence of previous infection in pupils and that in the corresponding village communities. The relevance and possible benefits of the rapid assessment of the prevalence of dracunculiasis obtained by a survey of school children are discussed.


Distribution of hookworm infection in Cameroon.

Prevalence of hookworm infection was measured in Cameroon during a national survey carried out for a schistosomiasis research project. The survey provided a representative sample of the 10-19 year age group for each one of the 49 administrative divisions. Prevalences were low in the Extreme North province with a sahelian climate. Prevalences were high in the provinces with an equatorial climate except for the Centre province which is more developed. Regions with tropical Cameroonian climate, which receive a very heavy rainfall, showed the highest prevalences. Urbanized areas had lower infection rates than rural areas. It should not be assumed that hookworm prevalence is uniformly high throughout a tropical country. Since hookworm distribution shows wide variations, large control programmes should start with a thorough evaluation of the situation.


A mark-release-recapture experiment with Anopheles lesteri paraliae in northwest Peninsular Malaysia.

In a coastal village in northwest Malaysia, 3231 fed Anopheles females of eight to 10 species were collected, marked with fluorescent dust, and released on three consecutive nights. In collections made on the 10 nights after the first release, 58 mosquitoes of three species, An. lesteri paraliae, An. subpictus and An. vagus, were recaptured; the recapture rates were 3.42%, 1.19% and 0.97%, respectively. The data for An. subpictus and An. vagus were insufficient for further analysis. Those for An. l. paraliae were plotted against time of recapture and, from the regression coefficient, an estimate of 0.68 was obtained for the daily survival rate. An independent estimate based on the parous rate during the previous year was 0.55. The temporal distribution of the recaptures strongly suggested a gonotrophic cycle and oviposition cycle of two days.


The thigmotropic oviposition response of the sandfly Lutzomyia longipalpis (Diptera: Psychodidae) to crevices.

Two experiments were carried out to investigate if Lutzomyia longipalpis would be attracted and stimulated to lay eggs in crevices. In the first experiment, females were introduced into a chamber and offered the choice of oviposition in a test site consisting of artificial crevices, and an open control site. Significantly more eggs were laid in the crevices of the test site than in the control site. In the second experiment, females were individually isolated in vials containing vertically placed filter papers, either folded to provide artificial crevices or arranged to offer two flat surfaces. The females isolated with the folded papers laid significantly more eggs than those isolated with the flat papers. The post-oviposition survival rates of both groups of females were, however, similar. It is suggested that the oviposition preference of the fly for the surface crevices was due to thigmotropic behaviour.


Evidence for a differential release of nitric oxide and vasoactive intestinal polypeptide by nonadrenergic noncholinergic nerves in the rat gastric fundus.

The roles of vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) in nonadrenergic noncholinergic (NANC) nerve-mediated relaxations were investigated in longitudinal muscle strips of the rat gastric fundus. Transmural stimulation (1-16 Hz for 2 min), VIP and noradrenaline evoked a prolonged relaxation of the rat gastric fundus, whereas NO evoked a transient relaxation. Only the electrically induced responses were blocked by tetrodotoxin. The inhibitor of NO biosynthesis NG-nitro-L-arginine (L-NNA) preferentially inhibited the relaxations induced by low frequency stimulation. In contrast, trypsin mainly reduced the electrically induced relaxations to high frequency stimulation; the NANC relaxations resistant to trypsin were further inhibited by L-NNA. VIP-induced relaxations were abolished by trypsin, but remained unaffected by L-NNA. NO- or noradrenaline-induced relaxations were not inhibited by either L-NNA or trypsin alone, whereas the combination of L-NNA and trypsin slightly reduced the noradrenaline-induced responses. These results suggest that NANC responses in the rat gastric fundus at low frequency are mediated mainly by NO, whereas at higher frequency NO together with a peptide, probably VIP, are released.


Tolerance to the increase in coronary blood flow induced by KRN2391.

We examined whether KRN2391, isosorbide dinitrate and nitroglycerin induced tolerance in coronary arteries. Intracoronary arterial administration of KRN2391 (1 microgram), isosorbide dinitrate (30 micrograms) or nitroglycerin (3 micrograms) produced equipotent coronary vasodilatation. Development of tolerance was determined by whether the increase in coronary blood flow, caused by intracoronary arterial administration of these drugs, was attenuated by intravenous infusion of KRN2391, isosorbide dinitrate or nitroglycerin. The increase in coronary blood flow, caused by intracoronary arterial administration of KRN2391 was not affected by intravenous infusion of KRN2391 (0.3 or 1 micrograms/kg/min), isosorbide dinitrate (30 or 100 micrograms/kg/min) or nitroglycerin (1 or 3 micrograms/kg/min). The increase in coronary blood flow, caused by intracoronary arterial administration of isosorbide dinitrate or nitroglycerin, was significantly diminished by intravenous infusion of isosorbide dinitrate and nitroglycerin, but was unaffected by intravenous infusion of KRN2391. The present results suggest that KRN2391 does not induce acute tolerance by itself or cross-tolerance between KRN2391 and other nitrates.


Comparative cardiovascular effects of KRN2391 and other coronary vasodilators in anesthetized open-chest dogs.

The effect of KRN2391 [N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide monomethanesulfonate] on the cardiovascular system and on myocardial oxygen consumption was compared with that of nicorandil and nifedipine in anesthetized dogs. Intravenous administration of KRN2391 (3-30 micrograms/kg) and nifedipine (1 and 3 micrograms/kg) decreased mean aortic blood pressure and total peripheral vascular resistance, and increased coronary blood flow, cardiac output and stroke volume. Heart rate was not significantly affected by KRN2391, but slightly increased by 1 microgram/kg of nifedipine. Nicorandil (100 and 300 micrograms/kg, intravenously) decreased mean aortic blood pressure, cardiac output, stroke volume and total peripheral vascular resistance, but did not affect heart rate. Nicorandil also showed a tendency to decrease coronary blood flow after an initial increase. All drugs tested decreased the difference in oxygen concentration between arterial and coronary sinus blood, indicating that these drugs increased the oxygen supply to the heart. Myocardial oxygen consumption was significantly decreased by more than 10 micrograms/kg of KRN2391, but was not affected by nifedipine. Nicorandil showed a tendency to decrease the myocardial oxygen consumption, though not significantly. Thus, KRN2391 may be useful to treat ischemic heart disease, because it increases the coronary blood flow and the oxygen supply to the heart, and decreases the afterload and the myocardial oxygen consumption.


Stress-induced antinociception and GABAergic mechanism.

The antinociceptive effects of GABAergic agents in presence or absence of swim-stress were investigated in mice, using the tail-flick test. Swim-stress, the GABAB agonist baclofen and the GABAA agonist muscimol raised the threshold of withdrawal reactions to nociceptive stimulation. The antinociception, induced by an interaction of stress and GABA agonists, was higher than that of stress or a GABA agonist alone. The GABAB antagonist phaclofen and the GABAA antagonists bicuculline and picrotoxin decreased the antinociceptive action induced by stress plus baclofen. Picrotoxin administration also decreased the response of baclofen. Picrotoxin and biculline, but not phaclofen, reduced the antinociceptive response induced by muscimol in stressed mice. Administration of picrotoxin, bicuculline or phaclofen alone did not decrease the stress-induced antinociception. The antagonists even increased the base line latencies in both normal and stressed mice. It is concluded that stimulation of both GABAA and GABAB receptor sites has an antinociceptive effect, but that the involvement of a GABAergic mechanism in stress-induced antinociception is unlikely.


Combined and separate effects of eye patching and visual stimulation on unilateral neglect following stroke.

In Experiment 1, 11 of 13 stroke patients with left-sided neglect benefitted from monocular patching in at least one (of five) tests of neglect. This beneficial effect in most cases was limited to the period when the patch was worn. In Experiment 2, another group of stroke patients (n = 18) with left-sided neglect were tested in a line-bisection task with monocular patching and/or lateralized visual stimulation--a procedure previously shown to reduce neglect. Each procedure resulted in substantial benefits; the two procedures combined resulted in significantly larger benefits than either alone. As in Experiment 1, the degree of benefit of patching (alone or in combination with stimulation) was not related to several demographic factors. These findings suggest that monocular patching, together with lateralized visual stimulation, may significantly reduce neglect in daily activities and may be more beneficial than procedures requiring patients to be aware of their disorder and to use strategies for scanning the neglected side.


Effects of nimodipine and nicergoline on cerebrovascular injuries induced by activation of platelets and leukocytes in vivo.

Cerebral ischemia was induced in rabbits by selective injection of 4 beta-phorbol-12 beta-myristate-13 alpha-acetate (PMA) into the left carotid artery. PMA provoked intravascular platelet and neutrophil aggregation. After PMA injection, a significant decrease in platelet and neutrophil counts was observed. Platelet and neutrophil emboli caused ischemia of the brain and brain barrier damage with accumulation of sodium fluorescein in the cerebrospinal fluid. Regional tissue analysis showed an ipsilateral alteration of the cerebral energy state and increased lactate levels. Pretreatment with the prostacyclin infusion completely blocked the alterations in both platelet and leukocytes counts and decreased the cerebral energy failure. Nimodipine administration decreased the changes in platelet and neutrophil counts and prevented the development of both brain barrier and cerebral energy failure. Nicergoline had no statistically significant beneficial effect on PMA-induced cerebrovascular injury.


Drug-induced modulation of endothelin-1 effects on the tone of electrically stimulated rat vas deferens.

The effects of endothelin-1 on the tone of the epididymal portion of the rat vas deferens were studied under treatment with drugs modulating the electrically evoked (single pulses, 1 msec, 80 V, 0.1 Hz) contractile responses. Endothelin-1 (0.01 nM-0.1 microM) concentration-dependently increased both the smooth muscle tone and the electrically stimulated contractions, the EC50 being 25.4 +/- 4.17 nM and 23.4 +/- 5.0 nM, respectively. The tonic contractions evoked by endothelin-1 persisted in the presence of 0.3 microM of tetrodotoxin or 10 microM of guanethidine. There were no significant differences in the EC50 values after tetrodotoxin (18.8 +/- 2.29 nM) or guanethidine (22.6 +/- 0.08 nM) as compared to controls, while the electrically stimulated contractile responses were completely inhibited. Clonidine (1, 3 or 10 nM) did not induce changes in the dynamic of the endothelin-1 effects on the tone. However, an increase in magnitude of the endothelin-1-induced contractions was observed on the background of the highest concentration of clonidine. Yohimbine, at concentrations of 1, 3 or 10 microM, significantly decreased the EC50 values for endothelin-1 to 16.4 +/- 1.02 nM, 16.1 +/- 1.60 nM and 8.09 +/- 1.15 nM, respectively. It is assumed that the development of the contractile effect of endothelin-1 on the tone of the electrically stimulated epididymal portion of the rat vas deferens does not depend on the integrity of the sympathetic innervation. However, a modulation of the endothelin-1 effects by yohimbine, rather than by clonidine, via postjunctional mechanisms, cannot be excluded.


Video feedback in occupational therapy: its effects in patients with neglect syndrome.

The use of video feedback in occupational therapy was evaluated in four patients with right hemisphere stroke and hemineglect. The study followed a single-case research experimental pretest, posttest, and follow-up (A1, B, A2, A3) design. Phases A1 and A2 included four observation times and phase A3 three, with 12 weeks for each patient. Three household tasks were assessed, and the patients' neglect behavior while performing these was videorecorded. One paper-and-pencil task using a modified Albert's test was also used, but not filmed. In the intervention program, the patients watched the film, which was stopped by the occupational therapist where the neglect behavior was significant. Through dialogue, the patients were led to perceive and interpret their neglect behavior, and strategies for relearning and remediation were recommended. The program seems to be effective for remediation and relearning a functional way of working.


Enhancement by cimetidine of neuromuscular paralysis induced with atracurium in rats.

The neuromuscular action of cimetidine, the prototype of H2 antagonists, was examined in urethane-anaesthetized and mechanically ventilated rats that were paralyzed with the non-depolarizing agent atracurium. Cimetidine, administered i.v. at doses of 3.2 to 56.2 mg/kg (13 to 223 microM/kg), produced an immediate potentiation of a steady 50% atracurium paralysis which was observed within 28 +/- 5 sec and which plateaued after 24 +/- 3 min. The dose of cimetidine that produced a 50% potentiation during peak effect was 14.5 mg/kg (58 microM/kg) and was associated with a serum cimetidine concentration of 47.5 micrograms/ml (or 188 microM). In a separate experiment, cimetidine, administered i.v. in a dose of 56.2 mg/kg (223 microM/kg), shifted the atracurium dose-effect curve to the left by 1.32-fold. Cimetidine alone, at either 10 or 100 mg/kg, did not affect the neuromuscular function by itself. These results suggest that high doses of cimetidine potentiate the neuromuscular paralysis induced with atracurium. This effect is opposite to that noted previously with ranitidine, a newer H2 antagonist which reverses atracurium neuromuscular paralysis in rats.


Electrogoniometric feedback: its effect on genu recurvatum in stroke.

The purpose of this study was to determine the effect of combining electrogoniometric feedback with contemporary physical therapy procedures for treatment of genu recurvatum following stroke. Twenty-six patients suffering knee hyperextension resulting from cerebrovascular disorders were allocated to either a control group or an experimental group. Both groups received treatment for knee hyperextension during two consecutive phases. During phase I the control group received physical therapy and the experimental group received electrogoniometric feedback as an adjunct to physical therapy. In phase II both groups received physical therapy alone. Each phase lasted four weeks, during which time patients were treated 45 minutes daily, five days every week. Subjects in the experimental group showed greater reduction in knee hyperextension. This was particularly evident in phase II when the difference between groups for reduction in knee hyperextension reached statistical significance (U = 40, p = 0.011). These results suggest that the addition of electrogoniometric feedback to standard physical therapy enhanced the effectiveness of treatment for genu recurvatum in stroke.


Changes in nerve conduction and Pi/PCr ratio during denervation-reinnervation of the gastrocsoleus muscles of rats.

The purpose of this investigation was to study the changes in nerve conduction and phosphate metabolites of the gastrocsoleus muscles of rats during denervation-reinnervation. Sixteen male Sprague-Dawley rats underwent unilateral crush-denervation of the left sciatic nerves at the sciatic notch. Six rats were used for measurement of motor conduction latency and action potential amplitude of the gastrocsoleus muscle by stimulating the sciatic nerve at one, two and eight weeks after nerve crush. The other ten rats were designated for evaluation of the ratio of inorganic phosphorous (Pi) to phosphocreatine (PCr) by a 31P-phosphoenergetic spectrometer at two weeks and eight weeks after nerve crush. None of the sciatic nerves showed conduction to the gastrocsoleus at one or two weeks after nerve crush. At eight weeks postcrush, the motor conduction latency returned to within normal limits, whereas the action potential amplitude was only 55% of the normal. For the eight-week period of study, the Pi/PCr ratio of the normal control muscles ranged between 0.09 +/- 0.02 and 0.11 +/- 0.02 (mean +/- SD). The denervated muscles showed an increase of Pi/PCr ratio by 54% at two weeks postcrush, compared to the respective contralateral control sides. The ratios returned to the normal value by eight weeks postcrush. In summary, these data suggested that the metabolic recovery of the crush-denervated muscle followed the same pattern as the parameters of nerve conduction.


Exploration of variables related to children's behavioral distress during electrodiagnosis.

To investigate variables potentially related to children's distress during electromyography/nerve conduction studies (EMG/NCS), mothers of 39 children ages two to 17 years reported the child's gender, experience with EMG/NCS, previous negative medical/dental experiences, general response to painful procedures, information-seeking style prior to procedures, health care fears, and information about the mothers' own health care fears and their anxiety regarding EMG/NCS. Physicians who performed the studies completed a behavioral distress checklist for each child. Results indicated that children exhibiting more behavioral distress were younger, had been uncooperative with previous painful procedures, were more likely to have had more negative medical/dental experiences, and had mothers who themselves reported greater fear and anxiety about undergoing EMG/NCS. Regression analyses indicated that previous negative medical/dental experiences accounted for additional variance in distress beyond that attributed to the child's age. Significant positive correlations between children's distress and specific previous negative medical/dental experiences were found.


Center of mass location and segment angular orientation of below-knee-amputee and able-bodied children during walking.

This investigation compared the center of mass (COM) locations and segment angular orientations of the gait of below-knee-amputee (BKA) children to those of able-bodied (AB) children. Eleven AB children (mean age, 8.4 years) and three BKA children (mean age, 7.5 years) volunteered to participate as subjects. Film data (100 frames per second) of a typical walking stride, were collected for the children during four experimental sessions held at six-month intervals. Two 16mm cameras were used to obtain frontal and lateral views of the subjects. The same approximate rate of walking (1.2m/s +/- 10%) was enforced for all testing sessions and at least three trials of data were collected for each subject during each session. Segmental endpoints of each subject from the film of each camera were digitized and the direct linear transformation (DLT) method was used to obtain three-dimensional segmental location-time data for a complete stride. These data were then used to determine whole body COM locations and angular orientations for the segments. Discrete values describing normalized locations at touchdown, midsupport, and takeoff were determined for whole body COM and the angular orientation of the trunk, thighs, and legs. In the sagittal plane the COM was lower and more anterior for the BKA children when compared to that of the AB children. This was primarily due to the greater forward flexion of the trunk.(ABSTRACT TRUNCATED AT 250 WORDS)


Social discomfort and depression in a sample of adults with leg amputations.

We examined the relationship between social discomfort and depression in a sample of 89 adults with leg amputations at two outpatient clinics. It was hypothesized that individuals who reported being uncomfortable with social contacts involving acknowledgement of their amputation or prosthesis were more prone to depression than other patients. A set of questions addressing different aspects of social discomfort demonstrated internal consistency and were used as a scale. Social discomfort was significantly correlated with scores on the Center for Epidemiologic Studies-Depression Scale depression scale (r = .41). Multiple regression analysis showed that social discomfort was a significant independent predictor of depression, after holding constant the effects of age, gender, social support, time since amputation, reason for amputation, and perceived health. These data indicate that health care professionals should view the expression of social discomfort by amputee patients as a possible "marker" for depression. Further studies are planned to develop and validate an expanded social discomfort scale.


Energy expenditure during walking in subjects with tibial rotationplasty, above-knee amputation, or hip disarticulation.

The surgical treatment of osteosarcoma with a tibial rotationplasty seems to offer functional advantages in comparison with an above-knee amputation. It has not been established whether the functional advantages are accompanied by a lower rate of energy expenditure during walking. In children with a tibial rotationplasty (n = 15), an above-knee amputation (n = 6), or a hip disarticulation (n = 5), energy expenditure was measured during treadmill walking at various walking velocities. The subjects with a tibial rotationplasty were able to walk faster, but there were no differences between the groups in energy expenditure per unit time or per unit distance. Correction for confounding variables including age, sex, height, time since operation, level of activity, and support during walking in a multiple linear regression model did not reveal any significant differences in energy expenditure during walking between groups. 1992 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation.


Effects of cervical collars on standing balance.

The effect of cervical collars on standing balance in two age groups was examined. Twenty healthy women aged 60 to 78 years and 20 healthy women aged 18 to 29 years stood on a Kistler force platform with and without a cervical collar. Total, lateral and anteroposterior sway velocity were measured in each of three positions; long-base stance and eyes open, wide-base stance and eyes open, and wide-base stance and eyes closed. Analysis of variance showed no significant difference (p < .05) between the collar and no collar conditions for any of the standing balance measures. Older women had significantly more sway velocity (p < .001) than younger women during long-base standing both with and without the collar. Also they showed significantly more sway velocity in both the total (p < .01) and the anteroposterior (AP) directions (p < .001) of wide-base standing. There were no significant lateral sway velocity differences (p < .05). With eyes closed, sway velocity was greater in all age groups. In the wide-based condition there were significant differences in sway velocity between AP (p < .001) and total and lateral (p < .01). These results indicate that a cervical collar does not disturb standing balance in healthy women in the age groups tested.


Measurement standards for interdisciplinary medical rehabilitation.

Rehabilitation must address problems inherent in the measurement of human function and health-related quality of life, as well as problems in diagnosis and measurement of impairment. This educational document presents an initial set of standards to be used as guidelines for development and use of measurement and evaluation procedures and instruments for interdisciplinary, health-related rehabilitation. Part I covers general measurement principles and technical standards, beginning with validity, the central consideration for use of measures. Subsequent sections focus on reliability and errors of measurement, norms and scaling, development of measures, and technical manuals and guides. Part II covers principles and standards for use of measures. General principles of application of measures in practice are discussed first, followed by standards to protect persons being measured and then by standards for administrative applications. Many explanations, examples, and references are provided to help professionals understand measurement principles. Improved measurement will ensure the basis of rehabilitation as a science and nourish its success as a clinical service.


Cephaloridine-induced nephrotoxicity in the Fischer 344 rat: proton NMR spectroscopic studies of urine and plasma in relation to conventional clinical chemical and histopathological assessments of nephronal damage.

The acute toxicological effects of the nephrotoxic antibiotic cephaloridine (CPH, 0-1500 mg/kg) in male Fischer 344 (F344) rats, have been investigated over 48 h using clinical chemistry, histopathology and proton nuclear magnetic resonance (1H NMR) spectroscopy of urine and plasma. High field (400 and 600 MHz)1H NMR urinalysis revealed increased excretion of lactic acid, acetoacetate, alanine, valine, lysine, glutamine and glutamate and a severe, time-dependent glycosuria. A major change observed in urine of CPH-treated animals was the dose-dependent increase in HB which may relate to altered energy metabolism. CPH also caused dose-dependent decreases in the urinary excretion of hippurate, allantoin and protein (conventional assay). This abnormal metabolic profile is consistent with a functional defect in the S1/S2 regions of the proximal tubule, and was confirmed by histology post mortem. Functional changes observed included elevations in blood urea nitrogen (BUN) and urine flow rate (UFR) and dose-related decreases in urine osmolality. Spin-echo 1H NMR spectroscopic analysis of lyophilised plasma, reconstituted with 2H2O revealed an abnormal phase modulation of the methyl signal from free alanine and it is postulated that this is due to the release of transaminases from damaged tissue which via a reversible conversion to pyruvate, cause variable deuteration of alanine at the alpha-CH position. This observation suggests that 1H NMR spectral patterns are also dependent on the level of plasma transaminases and this may provide a novel indicator of tissue damage.


On the bioactivation and genotoxic action of fluoranthene.

Fluoranthene (FA) was studied with respect to possible mechanisms of its high mutagenicity but low carcinogenicity, in comparison with the corresponding properties of benzo[a]pyrene (BaP), and with regard to the synergism of these two compounds shown by van Duuren and Goldschmidt (J Natl Cancer Inst 56, 1976, 1237). FA and BaP activated by S9 from Aroclor 1254 (PCB)-treated rats induce HPRT mutations in CHO cells with about equal effectiveness at the same exposure doses, which also lead to the same frequencies of repairable DNA adducts, enzyme-induced strand breaks being used as an indirect measure of adducts to DNA. FA was also shown to be an efficient inducer of SCE in human peripheral lymphocytes cocultivated with PCB-treated HepG2 cells or with liver cells from PCB-pretreated rats. For the induction of SCE, FA and BaP were shown to act additively. From metabolic studies with liver microsomes from C57Bl/6 mice it is concluded that, whereas BaP induces the metabolism of BaP to the mutagenic epoxide, neither BaP nor FA is able to induce the metabolism of FA. In mutation experiments with V79 cells (XEM2) constitutive for P450 IA1 activity, BaP 7,8-diol but not FA 2,3-diol provokes a high frequency of HPRT mutations. In cells constitutive for P450 IA2 enzymatic activity FA and BaP are but weakly mutagenic and practically nonmutagenic, respectively. Due to the additivity of the genotoxic effects of FA and BaP, induction of an error-prone condition by the latter compound seems to be excluded.(ABSTRACT TRUNCATED AT 250 WORDS)


A mathematical approach to benzo[a]pyrene-induced hematotoxicity.

Benzo[a]pyrene (BaP) has been reported to exert a differential effect on murine hematopoiesis that is mouse strain specific. Interpretation of these results based solely on experimental data is restricted and leaves important questions unanswered. Therefore, a mathematical model of murine hematopoiesis was applied in order to: (1) identify the targets of BaP, (2) quantify the damage to target cells and (3) based on these results, interpret differences in strain susceptibility. Model analysis of the hematopoietic response of D2 and BDF1 mice to a daily oral administration of 125 mg/kg BaP showed that proliferating hematopoietic cells are the targets of BaP. Within this group it was found that: (a) erythropoietic cells were the most susceptible to BaP, (b) granulopoietic cells showed a susceptibility half that of erythropoietic cells and (c) the susceptibility of stem cells ranged between that of erythropoietic and granulopoietic cells. This damage pattern was the same for both strains, indicating that the difference between the strains was quantitative. As cell destruction rates were about 3-fold higher for D2 than BDF1 mice, it was concluded that D2 mice were about three times as susceptible to BaP as BDF1 mice. The study showed that the mathematical model, in addition to experimental methods, provided an efficient tool for the analysis of BaP hematotoxicity.


Abnormal thymus development and impaired function of the immune system in rats after prenatal exposure to aciclovir.

Aciclovir (synonym: acyclovir) causes abnormal thymus development in rats. After treatment on day 10 of gestation a weight reduction of the organ is obvious in 21-day-old fetuses which persists postnatally. Adult male rats exposed in utero to one or three injections of 100 mg aciclovir/kg body wt given to the dam on day 10 of pregnancy showed a reduction of the thymus weight to 333 +/- 158 mg and 276 +/- 61 mg (control: 428 +/- 92 mg; n = 10). Corresponding alterations were detectable in female offspring. Liver weight was also decreased and spleen weight (in relation to body wt) was significantly increased in the offspring after the three exposures. In a host resistance model with Trichinella spiralis the function of the immune system of rats prenatally exposed to aciclovir was examined. Six weeks postnatally 10-12 randomly selected male rat offspring of one control and two treatment groups (1 or 3 injections of 100 mg aciclovir/kg body wt on day 10 of gestation) were infected orally with 500 Trichinella spiralis muscle larvae. Before and several times after the infection blood was taken from a tail vein or obtained by decapitation for examination of the antibody titers (IgM, IgG, IgA, IgE) to antigens of T. spiralis. Six weeks after the infection the weight of relevant organs was determined and tongue preparations were used for T. spiralis muscle larvae counting. Aciclovir exposed animals showed a different immune response than control rats. IgM titers in both treatment groups were higher than in controls two weeks after the infection but not different by the end of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)


Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin. 3. Effects of single doses on the testis of male rats.

The effects of a single dose of TCDD on the testis were studied in rats. The animals were treated (subcutaneously) once with TCDD doses of 0, 0.5, 1.0, 3.0, 5.0 micrograms/kg body weight. Doses of 3.0 or 5.0 micrograms TCDD/kg reduced the number of spermatids/testis significantly (60% of the controls). Electron microscopic inspection revealed that both doses led to a dissolution on the germinal epithelium. Altered germ cells at all developmental stages occurred in all testes evaluated. Doses of 0.5 or 1.0 micrograms TCDD/kg did not induce any effects in the testis; therefore, under these experimental conditions of single exposure to rats the dose of 1.0 micrograms TCDD/kg can be considered as NOAEL.


Distribution and inducibility of a P450I activity in cellular components of the avian immune system.

The level of expression of the cytochrome P450 system in an immune tissue could influence the sensitivity of that immune tissue to damage by xenobiotics. The capacity of immune organs and their cellular components for P450I-catalyzed metabolism was assayed in the 4-week-old chicken using the P450I-specific ethoxyresorufin-O-deethylase (EROD) assay and the P450I-inducer, 3,4,3',4'-tetrachlorobiphenyl (TCB). After induction by TCB, EROD was detectable in microsomes from whole thymus, bursa and in peritoneal exudate cells (containing primarily macrophages) at levels of 28.3, 7.2 and 1.3 pmol/mg microsomal protein/min, respectively; the level in control liver was 89.9 pmol/mg microsomal protein/min. No activity was detected in these immune tissues without induction. The P450I specific in vitro inhibitor, alpha-naphthoflavone (NF) inhibited the TCB-induced liver and immune tissue EROD by 50% at concentrations in the range of 0.07-0.1 microM. The cellular distribution of EROD in the bursa and thymus was studied in lymphocytes and supporting tissue cells after their separation by density gradient centrifugation. Much higher TCB-induced EROD was detected in immune tissue supporting cells than in lymphocytes, particularly in the thymus. The P450I in the supporting tissue of the bursa and thymus at 1 week post-hatch was also measured after eradication of the lymphocytes in both immune tissues by in ovo administration of CP. TCB-induced EROD was 12-fold higher in the lymphocyte-depleted thymus than in normal thymus, with a less marked but similar pattern in the bursa.(ABSTRACT TRUNCATED AT 250 WORDS)


Hepatotoxic interaction between carbon tetrachloride and chloroform in ethanol treated rats.

The effect of coadministration of CHCl3 on CCl4-induced hepatic damage was investigated at low dose inhalation. Coexposure of CHCl3 did not influence CCl4-induced changes in any index of hepatic damage in control rats. Coadministration of CHCl3, however, enhanced CCl4 (10 ppm)-induced hepatic damage of ethanol treated rats in a dose- and duration-dependent manner: simultaneous exposure of 50 ppm CHCl3 potentiated CCl4-induced increase in plasma GPT activity and number of necrotic hepatocytes; the enhancement of CCl4-induced hepatic damage by 50 ppm CHCl3 was found over the 4 h exposure; simultaneous exposure of 10 and 25 ppm CHCl3 potentiated the CCl4-induced increase in liver malondialdehyde (MDA) content. In contrast, coadministration of 50 ppm trichloroethylene and 200 ppm 1,1,1-trichloroethane decreased CCl4-induced increase in plasma GPT activity, though these exposures did not influence the liver MDA content. These results suggest that the concentration of 10 ppm CCl4 may be significant for CHCl3 to potentiate the hepatic damage caused by CCl4 in ethanol-treated rats. Heavy drinkers may have a higher hepatotoxic risk for a mixture of CCl4 and CHCl3 than for a single exposure to CCl4 or CHCl3, and a particular attention should be therefore given to the joint exposure to CCl4 and CHCl3.


Effect of tetrakis-mu-3,5-diisopropylsalicylatodiaquodicopper(II) on the status of reduced glutathione in freshly isolated hepatocytes.

Effects of different concentrations of tetrakis-mu-3,5-diisopropylsalicylatodiaquodicopper(II) (Cu(II)2(3,5-DIPS)4(H2O2)2) on the reduced status of glutathione (GSH), the major nonprotein thiol in tissues, were investigated using freshly isolated hepatocytes. Cu(II)2(3,5-DIPS)4 below 100 microM did not have any significant effects on either the GSH content or viability of the hepatocytes, but at 150-250 microM it decreased both parameters after 1 h of incubation. The decrease in cellular GSH was not followed by an increase in the oxidized form of GSH (GSSG) in the cell suspension. The addition of deferoxamine with Cu(II)2(3,5-DIPS)4 to the hepatocyte suspension prevented depletion in GSH content and loss of cell viability by Cu(II)2(3,5-DIPS)4. Both GSH depletion and loss of cell viability were found to be Cu(II)2(3,5-DIPS)4 dose dependent. From these results, it appears that Cu(II)2(3,5-DIPS)4 penetrated the cell membrane and acted by decreasing the GSH level by forming a copper-glutathione complex.


Increased urinary cadmium excretion and its relationship to urinary N-acetyl-beta-D-glucosaminidase activity in smokers.

To assess the renal effects of low-level exposure to cadmium due to smoking we examined blood and urinary levels of cadmium and urinary excretions of N-acetyl-beta-D-glucosaminidase (NAG), beta 2-microglobulin (BMG) and metallothionein in 94 male workers aged 18-55 years. Both blood and urinary cadmium levels indicated excess exposure to cadmium caused by smoking. The urinary cadmium concentration ranged between 0.1 and 5.0 micrograms/g creatinine and increased significantly with age in the smokers. Neither urinary NAG nor BMG was increased in the smokers compared from non-smokers. A positive relationship between urinary cadmium and metallothionein was obtained not only in the smokers but also in the non-smokers. Furthermore, in the smokers urinary cadmium and metallothionein was positively related with urinary NAG. Since NAG in urine mostly originates from tubular cells by lysosomal exocytosis, the results may reflect an early cadmium effect on the lysosomal functions. Inhibitory effect of cadmium on the lysosomal degradation activities was discussed as a possible explanation of the positive relationship of urinary cadmium and metallothionein to urinary NAG.


Assessment of driving performance in patients with retinitis pigmentosa.

The driving performance of 21 subjects with retinitis pigmentosa (RP) and varying degrees of peripheral field loss was compared with the performance of 31 normally sighted control subjects who did not differ statistically from the subjects with RP in age, gender, years of driving experience, or miles driven per year. Driving performance was assessed by self-reported accident frequency and by an evaluation of performance on an interactive driving simulator. A significantly greater proportion of individuals had self-reported accidents in the RP group than in the normal group. Likewise, a significantly greater proportion of subjects with RP than normal subjects had accidents on the driving simulator. Logistic regression analyses indicated that binocular horizontal field extent and binocular field area significantly differentiated between those having no self-reported accidents and those subjects with RP having one or more self-reported accidents. Because the simulator indexes were correlated with visual field measures for the subjects with RP, no additional information was incorporated into the regression model by adding the simulator measures. Therefore, our results indicate that visual field loss is a primary correlate of automotive accidents in individuals with RP.


Diode laser photocoagulation for retinopathy of prematurity. Preliminary results.

In a prospective, randomized clinical trial comparing transscleral cryotherapy with laser photocoagulation in the treatment of "threshold" stage 3+ retinopathy of prematurity, 32 infants were treated with diode laser photocoagulation in one eye. Twenty-eight infants have been followed up for at least 3 months, and seven have been followed up for at least 1 year. Twenty-five of 28 eyes treated with diode laser photocoagulation and followed up for at least 3 months have undergone regression. Of 24 fellow eyes treated with cryotherapy and followed up for at least 3 months, 20 have undergone regression. All seven eyes treated with diode laser photocoagulation and followed up for at least 1 year have undergone regression. Of seven fellow eyes treated with cryotherapy and followed up for at least 1 year, all have undergone regression. Our results suggest that diode laser photocoagulation is as effective as cryotherapy in the treatment of retinopathy of prematurity.


Posterior chorioretinopathy and retinal detachment after organ transplantation.

Four patients, three after renal transplantation and one after heart-lung transplantation, developed visual loss in both eyes associated with geographic zones of disruption and coarse clumping of the pigment epithelium in the posterior fundi. Secondary retinal detachment occurred bilaterally in three patients. Localized choroidal intravascular coagulation is the suspected but unproven cause.


Pneumatic retinopexy perfluoroethane (C2F6) in the treatment of rhegmatogenous retinal detachment.

Due to differences in expansile properties and duration, perfluorethane gas may offer advantages over other gases presently used for pneumatic retinopexy. Seventeen eyes with retinal detachments with single retinal breaks or groups of breaks no greater than 1 clock hour in extent were prospectively treated with perfluoroethane gas injection and retinocryopexy and followed up for a minimum of 6 months. Twelve eyes (71%) were attached with one procedure, and five eyes (29%) were attached with two or three procedures. Post-operative proliferative vitreoretinopathy occurred in two eyes (12%), new or missed breaks in three eyes (18%), and premacular fibroplasia in one (6%) eye. No eyes had an apparent progression of cataracts. Seven (88%) of eight eyes with preoperative macular detachments had improved visual acuity after surgery. All nine eyes (100%) with preoperative macular attachment had the same or improved visual acuity after surgery. The efficacy of perfluoroethane appears similar to that of other perfluorocarbon gases.


Peripheral visual field testing in glaucoma by automated kinetic perimetry with the Humphrey Field Analyzer.

A Humphrey automated perimeter was used to measure the central 24 degrees of vision with static threshold targets and the peripheral field with two automatic kinetic stimuli in 100 eyes of 100 patients with glaucoma or a suspicion of glaucoma and to compare the additional information gained with the peripheral tests. The peripheral visual field supported the diagnosis made with central field testing in approximately one third of the eyes and added additional diagnostic information in another fourth of the cases. In 4% of patients a normal central field was associated with a glaucomatous peripheral defect. Virtually all peripheral defects were in the nasal quadrant, and the more sensitive isopter uncovered the vast majority of the defects.


Intraocular pressure reduction with PhXA34, a new prostaglandin analogue, in patients with ocular hypertension.

In a randomized, double-masked, parallel study, one drop of 0.003% (1 microgram; n = 9) or 0.01% (3 micrograms; n = 10) PhXA34, a new phenyl-substituted prostaglandin F2 alpha analogue (13,14-dihydro-15[R,S]-17-phenyl-18,19,20-trinor-prostaglandin F2 alpha-1-isopropyl ester), or its vehicle (n = 10) was applied topically twice daily for 6 days to one eye in each of 29 patients with ocular hypertension. Compared with either baseline, contralateral, or vehicle control values, PhXA34 caused a significant (P < .001) dose-dependent reduction of intraocular pressure. The reduction lasted at least 12 hours after each drop and 24 to 48 hours after the last drop, with a significant (P < .0001) mean +/- SEM reduction of as much as 10 +/- 1 mm Hg (40%). Conjunctival hyperemia was not produced by 0.003% PhXA34, but was noted in some eyes treated with 0.01% PhXA34, and after repeated tonometry with either concentration. The prostaglandin analogue did not produce clinically obvious miosis, anterior chamber flare or cellular response, or any subjective adverse effects. PhXA34 is a potent, effective, and well-tolerated ocular hypotensive agent based on our results in this small, short-term study. Its potential as a new drug for glaucoma therapy warrants further investigation in long-term, larger studies.


Peters' anomaly and associated congenital malformations.

We reviewed the clinical findings in 29 patients with Peters' anomaly. There was developmental delay in 15 patients, congenital heart disease in eight patients, external ear abnormalities in five patients, structural defects of the central nervous system in four patients, genitourinary malformations in four patients, cleft lip/palate in three patients, hearing loss in three patients, spinal defects in two patients, and single cases of other less common defects. One patient had fetal alcohol syndrome; one, Pfeiffer's syndrome; and one, short stature, ulnar hypoplasia, and joint laxity. Colobomatous microphthalmia was present in seven patients, and persistent hyperplastic primary vitreous in three patients. Ten patients developed glaucoma, and three had retinal detachment unrelated to ocular surgery. Peters' anomaly may be due to a developmental field defect, or the complex ocular and systemic malformations may be the result of a contiguous gene syndrome or of a defective homeotic gene controlling the development of the eye and other body structures.


Surgical dissection of capillary hemangiomas. An alternative to intralesional corticosteroids.

Intralesional corticosteroids are often successful in reducing the size of functionally significant capillary hemangiomas. While they may have a better benefit-risk ratio than some earlier treatment methods, a number of serious complications have been reported recently. We believe these resulted from the hemodynamic continuity of capillary hemangiomas with the orbital and systemic circulation and that intralesional injections are intravascular. Surgery has generally been avoided because capillary hemangiomas are not encapsulated and piecemeal resection can produce significant bleeding. In carefully selected patients, we have used a surgical approach that involves dissection on the tumor's surface without entering its substance. Hemangiomas were removed en bloc from five patients with insignificant blood loss and excellent anatomic restoration.


Endoscopy of the lacrimal outflow system.

Management of obstructions in the lacrimal drainage system would be greatly aided by improvements in the ability to visualize the blockages. We describe a new method of observation using miniature fiberoptics to view the entire lacrimal excretory system. We employed flexible endoscopes of fiberoptic bundles with outside diameters of from 0.5 to 0.7 mm. These endoscopes were inserted through the puncta and canaliculi. Sixteen patients were examined. A range of pathologic conditions were found, including slightly stenosed passages and severely destroyed canalicular mucosal lining. Our results indicate that this technique is feasible and useful in the diagnosis of lacrimal excretory disease.


Pseudoexfoliation syndrome. Ocular manifestation of a systemic disorder?

The pseudoexfoliation syndrome has recently been suggested to represent the local manifestation of a more widespread disorder. In this study, a case of classic bilateral pseudoexfoliation syndrome with systemic distribution of pseudoexfoliation material involving a variety of organ systems is described. Using transmission electron microscopy, typical pseudoexfoliation fibers were identified in autopsy tissue specimens of skin, heart, lungs, liver, kidney, and cerebral meninges in addition to the classic intraocular locations. The pseudoexfoliation material was mainly localized to connective-tissue portions or septa traversing the various organs. The pseudoexfoliation fibers were consistently associated with connective-tissue components, particularly fibroblasts and collagen and elastic fibers; myocardial tissue specimens; and heart-muscle cells. These findings provide evidence for the systemic nature of the pseudoexfoliation syndrome, which apparently involves an aberrant connective-tissue metabolism throughout the body.


Pseudoexfoliative fibrillopathy in visceral organs of a patient with pseudoexfoliation syndrome.

Evidence is increasing that pseudoexfoliative material develops in widespread areas of skin and parabulbar tissues as well as intraocularly. To determine whether this process is even more diffusely distributed, ultrastructural examination was performed on visceral and ocular tissues of a patient with long-standing glaucoma found to have bilateral ocular pseudoexfoliation at autopsy. Aggregates consistent with pseudoexfoliative material were present in the lung, heart, liver, and gallbladder, in addition to the classic intraocular sites. The aggregates were in the fibrovascular septa and stroma of these organs, most frequently adjacent to elastic and oxytalan fibers. They stained positively for elastin and human amyloid P protein, like the ocular sites, in preliminary immunologic testing. Rare atypical aggregates were seen in one of the four control patients. These findings suggest that pseudoexfoliation is a systemic process involving abnormal matrix synthesis, particularly as related to elastic tissue components.


Rapid detection of gram-negative endotoxin contamination of contact lens saline solutions.

The use of the limulus amoebocyte lysate for the early and rapid detection of gram-negative endotoxin contamination of contact lenses and their solutions could reduce the risk of a keratitis developing that is associated with these devices. Using multiple aliquots from 17 unopened brands of commercially available contact lens saline solutions (15 for soft, two for hard), plus multiple aliquots from these solutions mixed with bacterial endotoxin, we evaluated the ability of two limulus amoebocyte lysate (0.125 endotoxin units/mL) products to detect the presence or absence of gram-negative endotoxin contamination. Sensitivity ranged from 65% (11/17) to 82% (14/17) when the solutions were tested undiluted. When diluted 1:8, the sensitivity increased to 100%. Specificity was 100% for undiluted and diluted specimens. The solutions used for hard contact lenses had the highest false-negative results. The limulus amoebocyte lysate can be used to detect the presence of gram-negative endotoxin in contact lens solutions.


Outflow obstruction in pigmentary and primary open angle glaucoma.

To localize the site of outflow obstruction in glaucoma, we evaluated the trabecular meshwork tissues by morphometric methods. Thirty-three specimens from 27 patients with primary open angle glaucoma (n = 13), pigmentary glaucoma (n = 4), and pigment dispersion syndrome (n = 2), and from nonglaucomatous normal subjects (n = 8) were compared. In these specimens, the extent of aqueous channels and the area occupied by these channels where they terminate in cul-de-sacs were measured. In 32 nonglaucomatous normal specimens (six of the eight mentioned plus an additional 26), we discovered that 94% of the surface area of the cul-de-sacs is lined by trabecular cells. These measurements were used to calculate the resistance to aqueous outflow offered by cul-de-sacs. Three new concepts are advanced in this report: (1) the cul-de-sacs provide a major portion of the normal outflow resistance, (2) the cul-de-sac area is markedly reduced in pigmentary glaucoma and primary open angle glaucoma, accounting for a major portion of the increase in resistance in these conditions, and (3) macrophages are the major cell type responsible for trabecular meshwork clearance of pigment and debris. A common pathophysiologic sequence of events is proposed for the development of glaucoma in pigmentary glaucoma and primary open angle glaucoma.


Juxtacanalicular tissue in pigmentary and primary open angle glaucoma. The hydrodynamic role of pigment and other constituents.

We tested the hypothesis that obstruction of the juxtacanalicular tissues, by melanin granules in pigmentary glaucoma and by other impermeable material in primary open angle glaucoma, leads to the development of a chronic glaucomatous condition. The distribution and concentration of melanin and other impermeable materials in the juxtacanalicular tissues and elsewhere in the trabecular meshwork was determined in 13 specimens. Six specimens were from patients with pigmentary glaucoma, two from patients with pigment dispersion syndrome, and three from patients with primary open angle glaucoma, as well as two from normal subjects. The effect of these materials on flow resistance was estimated using two hydrodynamic models. In model A, the electron-lucent spaces of the juxtacanalicular tissue were assumed to be open spaces, while in model B, these spaces and spaces filled with ground substance were assumed to be gel filled. In pigmentary glaucoma, 3.5% of the pigment was found in the juxtacanalicular tissue, while 96.5% was found in the corneoscleral and uveoscleral tissues. Permeabilities calculated according to model A were much higher than those expected from estimates of outflow facility in all groups, in agreement with the previous report of Ethier et al. The gel-filled spaces available for fluid flow, as determined by model B, showed no statistically demonstrable differences (pigmentary glaucoma, 32.9%; primary open angle glaucoma, 36.6%; pigment dispersion syndrome, 43.4%; normal, 44.1%). Furthermore, the amount of pigment present in the juxtacanalicular tissue was determined to have a negligible influence on permeability. Thus, the development of the chronic glaucomatous condition cannot be directly attributed to pigment accumulation in the juxtacanalicular tissue in pigmentary glaucoma.


Response of the retinal pigment epithelium to selective photocoagulation.

Multiple short argon laser pulses can coagulate the retinal pigment epithelium selectively, while sparing the adjacent neural retina and choroid; in contrast, continuous-wave laser irradiation typically damages the neural retina and choroid. The healing response to selective photocoagulation of the retinal pigment epithelium was studied in rabbits during a period of 4 weeks. The lesions were never visible ophthalmoscopically. During the healing period, the epithelium was reformed by a single sheet of hypertrophic retinal pigment epithelial cells. In contrast to continuous-wave photocoagulation, only minimal inflammatory response was found. Retinal pigment epithelial cells showed clear signs of viability, eg, phagocytized outer segments. The local edema in the photoreceptor layer and subretinal space found in the early stage disappeared when the blood-retinal barrier was reestablished. The choriocapillaris remained unaffected. No subsequent damage to the photoreceptors was found. This type of photocoagulation may be useful for retinal pigment epithelium-related diseases, eg, diffuse diabetic macular edema.


Medial canthoplasty with microplate fixation.

Six patients with malpositioned or surgically excised medial canthal tendons underwent repair with titanium microplate, and two patients underwent repair with titanium miniplate fixation. The T-shaped rigid fixation plates were chosen for medial canthal reconstruction to allow for stabilization of the plate along the anterior lacrimal crest and extension of the plate over the posterior lacrimal crest. The medial canthal tissue was reattached to the titanium plate with 3.0 polypropylene (Prolene) suture. This technique appears to be safer, faster, and, in many cases, more effective than traditional techniques for reconstruction of the medial canthus after tendon avulsion or loss from excision of cutaneous carcinoma.


Binding of calcium to myoplasmic buffers contributes to the frequency-dependent inotropy in heart ventricular cells.

In guinea-pig ventricular cells, the Ca2+ buffer capacity of the myoplasm was estimated from the ratio of ionized calcium (from Indo-1 fluorescence) through total calcium (ionized plus bound calcium, from x-ray microprobe analysis). During post-rest potentiation (1 Hz paired-pulses in voltage-clamp), where diastolic sarcomere length remained nearly constant, Ca2+ buffer capacity slowly fell from 5500:1 to 700:1 suggesting that slow Ca2+ binding sites became saturated. We discuss that frequency-inotropy depends not only on the replenishment of intracellular stores with Ca2+, but also on binding of Ca2+ to these slow sites; the slow Ca2+ sites could complete with the fast activator sites on troponin C for systolic Ca2+, or they could enhance the Ca2+ affinity of the fast Ca2+ sites on troponin C by cooperative interaction.


Improvement of relaxation velocity parameters by calcium channel blockers in the aging rabbit myocardium.

Normal aging in man is known to be associated with a reduction in left-ventricular diastolic function, including the rates of relaxation and filling. Calcium channel blockers have been reported to improve left-ventricular diastolic function in patients with various forms of heart disease. Clinically, the action of calcium channel blockers may be related to either a direct myocardial effect or may be secondary to the peripheral or coronary vasodilation effects. The purpose of this study is to investigate a possible direct effect of calcium channel blockers on modulation of the reported age-related reduction in myocardial relaxation. The direct effects on myocardial relaxation of the dihydropyridine calcium channel blocker, nifedipine, were studied in isolated, perfused interventricular septa and left-ventricular wall from eight young (ages 9 to 18 months) and 14 old (ages 3 to 5 years) rabbits. Septa were perfused with oxygenated Ringer's solution and paced at 48 beats/min. Maximum relaxation velocity per unit of developed tension [-dT/dt]/T, and relaxation time per unit of developed tension tR/T were continuously measured before and after infusion of calcium channel blockers. In absence of drugs, the older rabbits demonstrated a mean [-dT/dt]/T which was 32% lower (p < 0.003) and a mean tR/T which was 45% higher (p < 0.005) than the younger rabbits. When nifedipine was introduced at concentrations > 10(-8) M equivalent to doses above the therapeutic free-plasma concentration in humans, all contraction and relaxation parameters were depressed. However, at lower doses, equivalent to doses in the clinical therapeutic range, [-dT/dt]/T was increased in the older rabbit septa by 18% in the presence of nifedipine. tR/T was shortened in the older rabbit septa by 17% in the presence of nifedipine. Myocardial relaxation in older rabbits after drug infusion approximated these parameters in the younger rabbits prior to drug infusion (P = NS). Calcium channel blockers had similar beneficial effects on the relaxation properties of the myocardium in younger rabbits. All beneficial effects were observed at concentrations of calcium channel blockers which were within and below the clinically therapeutic range of plasma free drug concentration, i.e., 5 x 10(-9) to 4 x 10(-8) M. Potential differences in relaxation effects related to different segments of the myocardium and different mechanical recording vectors were evaluated. Isolated left ventricle preparations from aging rabbits demonstrated improvements in tR/T and [-dT/dt]/T similar to those observed in the septum. Furthermore, improvement in mechanical function along the y-axis and x-axis vectors of the septum was similar.(ABSTRACT TRUNCATED AT 400 WORDS)


[Energy intake of adult Great Danes].

Energy intake and weight development were recorded in 5 adult Great Danes kept in outdoor kennels during maintenance, pregnancy and lactation. In periods with constant weights the energy requirement was 0.96 MJ DE/kg BW0.75/d with a minimum in summer (0.82) and a maximum in winter (1.1). In pregnancy (weight gain depending on litter size 7-15 kg) energy intake (ad-lib.-feeding) was similar to maintenance. During lactation energy intake reached 1.6-1.7 MJ DE/kg BW0.75/d with a dry matter intake of 83 g/kg BW0.75/d. Pups of great litters had to be fed with milk substitute for normal weight development.


Release kinetics of cardiac troponin T in coronary effluent from isolated rat hearts during hypoxia and reoxygenation.

A newly developed troponin T (TnT) test for the detection of myocardial cell necrosis has been reported to be very efficient in the detection of acute myocardial infarction. The aim of the present study was to determine whether cardiac TnT in coronary effluent from isolated heart perfused with albumin-free perfusion medium could be detected using the enzyme-linked immuno-sorbent assay developed by Katus et al. Isolated rat hearts were perfused according to the method of Langendorff. Coronary flow rate was measured by timed collection of the coronary perfusate that dripped from the hearts during 5 h of hypoxia (protocol A) or 4 h of hypoxia followed by 1 h of reoxygenation (protocol B). Creatine kinase (CK) and lactate dehydrogenase (LD) levels were compared with that of TnT. Myocardial adenine nucleotides were measured by HPLC. There was a strong correlation between TnT levels in albumin-free coronary effluent and TnT levels in coronary effluent diluted 1:1 with 5% bovine serum albumin (r = 0.996, N = 72). The coefficients of correlation between TnT and CK or LD during hypoxia and reoxygenation were 0.891 (N = 88) and 0.871 (N = 88), respectively. The coefficient of correlation between CK and LD was 0.993 (N = 88). There were no significant differences in either the decrease of coronary flow or the increase of TnT content between the hearts in the two protocols. There was no significant correlation between sigma TnT and energy charge of adenine nucleotides. These results indicate that cardiac TnT levels can be easily measured in albumin-free coronary effluent of isolated heart preparations.(ABSTRACT TRUNCATED AT 250 WORDS)


[Ionized calcium and total calcium in the blood of cattle, sheep, swine and horses of different ages, reproductive stages and uses].

Concentrations of ionized calcium (Cai) in blood and of total calcium (Ca(t)) in serum were determined in 99 cattle, 58 sheep, 74 pigs and 59 horses of different age groups and reproductive periods as well as kinds of use of the animals. The values of Cai in blood in the groups taken into account for comparison of species decreased significantly in the order dairy cows < ewes < sows < horses. In cattle and pigs, there were significant differences in the Cai-level, according to age with the youngest animals having the highest values. In cows from the fourth lactation onward, one day post partum (p.p.) the smallest concentrations were measured, differing significantly from animals in other reproductive periods. In ewes, the lowest values were estimated one week before parturition. The level of Cai in blood of sows decreased between day one and 6 weeks p.p. significantly. No significant differences could be demonstrated between the different groups of horses. With regard to the concentrations of total Ca, differences between the groups were not so clear as with Cai.


Nitric oxide (EDRF) enhances the vasorelaxing effect of nitrendipine in various isolated arteries.

Recent studies suggest endothelium to be involved in the vasorelaxation of calcium antagonists of the 1,4-dihydropyridine type, which may at least in part be mediated by endothelium-derived relaxing factor (EDRF = NO). To study this effect further, the influence of L-NG-nitro arginine (L-NNA), a specific inhibitor of EDRF-synthesis, on nitrendipine-induced vasorelaxation was examined in different isolated porcine arteries. Coronary, basilary, and tail arteries were bathed in Krebs-Henseleit solution and endothelial function was verified by means of substance P, an EDRF releasing neuropeptide. Vasorelaxation of nitrendipine in PGF2 alpha-precontracted arteries was studied in the presence and absence of L-NNA. Nitrendipine-induced vasorelaxation was markedly reduced by the addition of L-NNA in all vessels studied. Tachyphylactic effects of nitrendipine could be excluded. The obtained results may be explained by an enhancement of nitrendipine action by basally released EDRF, alternatively, by an increased EDRF-release induced by this calcium antagonist. Therefore, in a second series of experiments the release of EDRF was studied in isolated coronary arteries under cumulative application of nitrendipine. Using the nitric oxide scavenging properties of oxyhemoglobin, EDRF release was measured spectrophotometrically by means of methemoglobin formation. The application of nitrendipine resulted in a concentration-dependent increase in the extinction rate, indicating an increased release of NO which could be inhibited by preincubation with L-NNA. It may be concluded that, in functionally intact vessels, vasorelaxation induced by nitrendipine may additionally be mediated by an increased release of EDRF.


[Seroepidemiological studies on the detection of Q fever in sheep in middle Thuringia].

In a random samples test altogether 4337 sheep of varying ages from several herds of different sizes in the middle region of Thuringia were investigated with complement fixing test for the existence of Q fever. In 47.1 per cent of the tested herds and in 5 from 8 of the included districts Q fever reagents were provable. The serological detection quota of all tested sheep amounts to 1.11 per cent, but the percentage of serological reagents in mother-sheep was 1.36 per cent, in the female young sheep 1.04 per cent and in the lambs 0.74 per cent. The investigations of rams and sheep for slaughter were negative. Serological testing in 7 sheep showed a Q fever antibody persistence about 6 until 10 months. Increased animal concentration and adverse conditions led to an increase of the Q fever seroprevalence in the herds.


[Dog slaughtering in Germany in the 19th and 20th centuries with special consideration of the Munich area].

In the 19th century professional dog slaughter and also the public sale of dog flesh arose. These slaughter and the sale was mainly practised by horse butchers. In Germany dogs had been mostly slaughtered in Sachsen, Schlesien, Anhalt and Bayern. From 1905 to 1940 the meat of 235.144 dogs was inspected. But the true number of slaughtered dogs was certainly larger. Yet in the fifties dogs were professionally slaughtered. After 1960 the slaughter dropped. Sporadically dog flesh was used as human food until 1985. The annual number of slaughtered dogs depended on economic factors like wages, prices of meat, availability of meat and dog tax. Dogs had been also slaughtered to produce dog fat for remedy. Slaughter of dogs has been already discussed in the 19th century. After 1930 it was called for abolishing the inspection order for dogs or for the prohibition of dog slaughter. After four bills of the years 1954, 1963 and 1985 the slaughter of dogs to produce human food was finally prohibited in 1986.


Ischemia and reperfusion injury in isolated rat heart: effect of reperfusion duration on xanthine oxidase, lipid peroxidation, and enzyme antioxidant systems in myocardium.

The aim of this work was to assess the catalytic activity of xanthine oxidase, the level of lipid peroxides and enzymic antioxidant systems in isolated rat heart muscle subjected to a globally partial ischemia followed by varying durations of reperfusion. After 40 min of globally partial ischemia (residual perfusion flow rate: 0.1 ml/min), four different durations of reperfusion were investigated (0, 20, 40, and 60 min). After each experimental ischemia/reperfusion sequence, the heart was frozen in liquid nitrogen. Lipid peroxides were assayed in the cardiac homogenate and the catalytic activity of xanthine oxidase and enzymic antioxidant systems (glutathione peroxidase, superoxide dismutase and catalase) were determined in the centrifuged supernatant. In the different experimental protocols studied in this work, there was no significant increase in the activity of cardiac xanthine oxidase or in the level of lipid peroxides when compared to the non reperfused or to the continuously perfused hearts. Indeed, enzymic antioxidant systems were also not significantly modified in the different periods of reperfusion when compared to control hearts (continuously perfused hearts). These results suggest that xanthine oxidase is apparently not a major source of free radicals in the course of an ischemia-reperfusion sequence in heart muscle, in particular, if we consider the early phases of reperfusion. The process of lipid peroxidation, assessed by assaying thiobarbituric acid reactants, is not a predominant phenomenon of reperfusion-induced injury, at least in the experimental model used here. However, enzymic antioxidant systems investigated in this study do not seem modified. This could mean that the small quantity of oxygen free radicals produced does not overwhelm the enzymic antioxidant systems of myocardium which is in agreement with peroxidatized lipid results.


Changes in heart rate by verapamil during carotid sinus stimulation in patients with hyperparathyroidism, pre- and postoperatively.

It has been investigated whether calcium- and verapamil-dependent sensitivities of carotis baroreceptors also exist in man. To answer this question, we pre- and postoperatively measured changes in heart rate during carotid sinus stimulation before and after intravenous administration of 5 mg verapamil in 23 patients with primary hyperparathyroidism. Findings during hypercalcemia were as expected: a more pronounced reduction of heart rate at comparatively low calcium levels. During normocalcemia, we found an opposite effect: a more pronounced reduction at relatively high calcium levels, which was statistically significant. This fact could be explained according to our interpretation. In previous reports, local effects on baroreceptors were examined, whereas we measured the combined effect of several calcium actions. As expected, verapamil attenuated the decrease in heart rate which, however, was not statistically significant.


Causative role of coronary microvessels for the development and progression of chronic myocardial lesions in spontaneously hypertensive rats (SHR).

The pathomechanisms responsible for the development and progression of myocardial alterations in hypertensive heart disease are largely unknown. Using newly developed preparation and measuring procedures in 78 SHR and 82 controls aged 3-78 weeks, topological relations were detected between focal morphological appearances of chronic myocardial ischemia (fml.) and pathological microvessel (mv.) reactions characterized by morphometric signs of chronic contractions. The smallest ramifications are of particular pathogenic importance. A generalized peak of pathological mv. reactions between the 16th and 24th weeks is responsible for the development of first fml. The further progression of the area density of fml. from 1.26 +/- 0.85% (24th week) to 31.82 +/- 8.60% (78th week) is attributable to the further increase in pathological mv. reactions caused by organ-specific influences. The histological and morphometric findings suggest that the pathological mv. reactions are aggravated by their own effects at the local level.


[Tenacity of S. gallinarum in chicken feces].

The survival period of 22 S. gallinarum strains in chicken feces was examined. The suspension of the bacterium was homogenized with a certain feces quantity. The initial ratio was 10(7) to 10(9) colony forming units per gram of feces. The results show that the growth of 5 strains was completely inhibited within 24 hours post homogenization, 7 strains were still positive to S. gallinarum for 24 hours, 5 strains were positive for 48 hours and the last 5 strains were positive for 4 days. Additionally, the effect of tryptose soy (TSB) and Rappaport-Vassiliadis (RV) nutrient broths on the isolation rate of S. gallinarum from feces was examined at 37 degrees C and 43 degrees C. It was shown that the TSB medium was the best at 37 degrees C, in this experiment. The S. gallinarum concentration in RV medium was decreased at 37 degrees C from 9.1 x 10(8) to 1.6 x 10(6) and at 43 degrees C from 9.1 x 10(8) to 4.1 x 10(2).


Influence of selective autonomic decentralization on myocardial deoxyglucose uptake initiated by cardio-cardiac reflexes.

The aim of this study was to evaluate the effect of autonomic reflexes as initiated by stimulation of the right recurrent cardiopulmonary nerve afferent axons on myocardial deoxyglucose uptake and to determine how such uptake can be modified by selective neural ablation. The afferent axon in the right recurrent cardiopulmonary nerve was stimulated 30 s/min for 1 h in five anesthetized open-chest dogs in which 14-C labeled deoxyglucose was i.v. injected at the beginning of the stimulation period. Three additional sham-operated dogs served as neurally intact controls. Concentrations of label and glucose were measured in plasma. Regional myocardial deoxyglucose concentration was measured by quantitative autoradiography, following the calibration of plasma samples autoradiographic density by beta counting. Stimulation of right recurrent cardiopulmonary nerve afferent axons in the intact nervous system preparation did not significantly enhance deoxyglucose uptake as compared to neurally intact controls. When the right cervical vagosympathetic complex was cut a similar uptake was observed. Following decentralization of the right stellate ganglion, uptake was markedly reduced, as well as when the right cervical vagosympathetic was cut and the right stellate ganglion decentralized. Activation of afferent axons from cardiopulmonary receptors does not alter myocardial deoxyglucose uptake. Reduction in uptake occurs following unilateral stellate ganglion decentralization.


[The synchronization of sow parturition using a combined treatment regimen of cloprostenol Jenapharm and depotocin Spofa].

The trials were conducted on a pig farm (German Landrace) over a period of about two years. This farm worked in 7-day cycles using artificial insemination. In trial 1, 209 sows were treated with the prostaglandin F2 alpha analog Cloprostenol (Cloprostenol Jenapharm, 87.5 micrograms i.m.). In trial 2, 646 sows were divided into two groups. Both groups were treated with 100 micrograms Cloprostenol Jenapharm not earlier than on the 113th day of gestation (day 1 of gestation = the day after the first insemination). 24 h later, 119 sows received an additional injection of 1 ml of an oxytocin analog (Depotocin inj. Spofa, 1 ml contains 0.2 mg Carbetocin). In the other group, 120 sows received 2 ml Depotocin. This additional treatment with Depotocin resulted in a mean interval from the injection to the onset of farrowing of 125 minutes (gilts) and 49 minutes (sows). In trial 2, 97.9% of the sows farrowed within 30 hours after Cloprostenol injection (= partus rate 30). The additional treatment with Depotocin resulted in a shortening of farrowing periods, a reduction in mean expulsion time and effected an increase in farrowing during the day time. All these effects were significant (p < or = 0.05).