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Biomedical subjects

J Hofmann

Publications and source records attributed to J Hofmann.

At least 109 records · Page 6Linked to original sources
PubMed1991

Flow cytometric analysis of Eimeria tenella sporozoite populations exposed to salinomycin sodium in vitro: a comparative study using light and electron microscopy and an in vitro sporozoite invasion-inhibition test.

Eimeria tenella sporozoites exposed to 100, 70, 60 and 50 micrograms salinomycin sodium (SAL)/ml medium 199 at 41 degrees C and then stained with propidium iodide/fluorescein diacetate were analysed by means of flow cytometry (FCM). After 20 min exposure, they showed dose-dependent alterations in their size and shape, i.e. ballooning of most cells, and enhanced intracellular esterase activity as compared with untreated controls. After longer exposure periods (40 and 70 min), inflated cells gradually changed into shrivelled or crumpled, nonviable ones, thereby showing a gradual decrease in esterase activity and a gradual loss of membrane integrity (RFA+). As compared with untreated controls, sporozoites treated with 10 micrograms SAL/ml showed negligible RFA+ values (0.4%-2%), whereas those exposed to 1 and 0.1 microgram SAL ml and to the solvent dimethylsulfoxide (DMSO, 1%) did not, even after 70 min exposure. Slight to severe structural changes manifesting as an extremely wavy surface (1 microgram SAL/ml), vacuolization of the cytoplasm, distension or destruction of the mitochondrion and rupture of cell membranes (10 micrograms SAL/ml) were seen not only at higher SAL concentrations but also (rarely) at lower ones. The ability of sporozoites to invade primary chick-kidney cells was significantly inhibited by 70, 60 and 50 micrograms SAL/ml. In general, there were close relationships between findings obtained using FCM, electron microscopy and an invasion-inhibition test. The results indicate that FCM is a reliable and sensitive technique for characterizing the parasiticidal effects on and the possible mode of action of drugs in free coccidian sporozoites.

Animals↗
PubMed1991

[Unstable fractures of the lateral end of the clavicle and principles of their treatment].

25 fractures of the lateral end of the clavicle were treated during the last six years. 22 of them were unstable because of additional rupture of the coracoclavicular ligaments. Only in two patients conservative treatment was successful, in six cases conservative treatment was unsuccessful. Altogether 20 fractures had to be operated. Coracoclavicular screw fixation (Bosworth) is recommended for simple fractures and plating for multifragmental injuries. Operative methods using K-wires are frequently impaired by wire-migration and therefore require a longer period of external immobilization. Independent of the type of surgery objective and subjective results were equally good.

Adolescent↗
PubMed1991

Informative value of a mouse model of Klebsiella pneumoniae infection used as a host-resistance assay.

To obtain a host-resistance assay (HRA) for quantitative evaluation of immunostimulatory effects of various substances, an experimental model of K. pneumoniae inhalatory infection was elaborated. The highly virulent bacterial strain (inhalation LD50 = 400 CFU), applied via the natural route into the respiratory tract elicits an acute infectious process possessing characteristic dynamics. Although the intensity of clearance in the bronchoalveolar lavage after challenge or the mean survival time can be used in individual cases for quantitative resistance determination, the inhalation LD50 values yielded the most standard results. Systemic immunization with the corpuscular K. pneumoniae vaccine provided a high protection expressed by increasing the inhalation LD50 by two orders of magnitude. The antibodies formed, detectable by the ELISA test, are specific for capsular polysaccharide. The type-specific immunity was also found in the protection test. The nonspecific stimulatory effect of the peptidopolysaccharide complex isolated from Listeria monocytogenes (EiF) was manifested at the level of one LD50 only while with higher infectious doses it was absent. However, the adjuvant activity of EiF was significant. The HRA can distinguish and quantitatively determine both nonspecific and specific stimulatory effects of immunomodulatory substances.

Animals↗
PubMed1991

Effect of intraperitoneal recombinant human tumour necrosis factor alpha on malignant ascites.

29 patients with refractory malignant ascites due to metastatic peritoneal spread of adenocarcinomas originating from the ovary, gastrointestinal tract, liver, breast and uterus were treated in a phase I trial of intraperitoneal infusions of recombinant human tumour necrosis factor alpha (rhTNF-alpha). Patients received 40-350 micrograms/m2 rhTNF-alpha intraperitoneally once weekly for 2 months or for a shorter period in case of early resolution of ascites. Systemic side-effects resembled those reported for rhTNF-alpha given intravenously. No dose-limiting toxicities were found and thus a maximum tolerated dose of intraperitoneal rhTNF-alpha was not established. Out of 29 patients, 22 responded with a complete (16) or partial (6) resolution of their ascites. There was a less than 50% reduction in 4, and no increase in ascites in 1. 1 patient showed progressive ascites formation, and another patient was not eligible because of early death unrelated to treatment. Trials in patients with smaller tumour burden are warranted.

Adenocarcinoma↗
PubMed1991

[Animal experiment studies of the distribution and elimination of radioactively marked endotoxin].

We were able reproduce typical morphological and laboratory changes of endotoxinemia in dogs and small experimental animals by administration of E. coli = 111 K58 endotoxin labelled with 99m Tc. Contrary to the literature our distribution studies in rats showed a high concentration of endotoxin in the kidney. An effective endotoxin elimination was possible by extracorporal hemoperfusion in vitro and vivo. Optimal results were achieved using immunoabsorption in combination with plasmapheresis. However, further experimental studies are necessary to clarify the problem fully.

Animals↗
PubMed1990

Enhancement of the antiproliferative activity of cis-diamminedichloroplatinum(II) by quercetin.

We have shown previously that the flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone) enhances the antiproliferative activity of cis-diamminedichloroplatinum(II) (cis-DDP) in vitro. In order to investigate whether this observation could be exploited in cancer treatment, we tested this drug combination in human tumor xenografts. The established human large-cell cancer of the lung (LXFL 529) was implanted s.c. into nude mice. Tumors were allowed to grow to a mean diameter of approximately 5 mm and the animals were subsequently treated intraperitoneally with quercetin, cis-DDP or a combination of both. Treatment was given 3 times at 3-day intervals. Twenty milligrams quercetin per kg body weight caused no inhibition in tumor growth compared to untreated controls; 3 mg cis-DDP per kg body weight with the same time schedule reduced tumor growth, compared to quercetin-treated and control animals. Concomitant treatment with 20 mg quercetin and 3 mg cis-DDP per kg body weight reduced tumor growth to a significantly greater degree than cis-DDP alone. Toxicity of this treatment was relatively low as determined by measurements of the body weight of the mice. A combination of 4 mg or 5 mg cis-DDP with 20 mg quercetin per kg body weight also reduced tumor growth compared to single cis-DDP treatment. The toxicity of treatment with these increased doses was high, as shown by the high lethality and the loss of body weight of surviving animals.

Animals↗
PubMed1990

Central nervous system relapse prevention in 1165 standard-risk children with acute lymphoblastic leukemia in five BFM trials.

In treatment of childhood ALL, prevention of CNS relapse by cranial irradiation is followed by considerable long-term sequelae. In the three ALL-BFM (Berlin-Frankfurt-Münster) trials 70, 76, and 79, employing radiotherapy (8.5 Gy craniospinal, 18 or 24 Gy cranial irradiation) in all arms, the incidence of CNS relapses (isolated and combined) in standard-risk patients (SR, 60% of all children) was consistently less than 6%. A risk factor (RF) calculated from absolute blast number, liver, and spleen size at diagnosis was used to stratify patients in the subsequent trials ALL-BFM 81 and 83. In ALL-BFM 81, SR patients (RF less than 1.2) were randomized to receive 18 Gy cranial irradiation or intermediate-dose i.v. methotrexate (ID-MTX) (4 x 0.5 g/m2). In ALL-BFM 83, the SR group was further subdivided into group SR low (SR-L, RF less than 0.8) and group SR high (SR-H, RF 0.8 - less than 1.2). SR-L patients received no irradiation, and were tested by randomization for the effectiveness of an intensive reinduction regimen (protocol III). SR-H patients were randomized for 12 or 18 Gy. The results were as follows: In patients of both trials with RF less than 0.8, radiotherapy could be replaced by ID-MTX plus protocol III. Without protocol III, relapses increased from 15.7% to 31.7%. Concomitantly, the fraction of relapses with CNS involvement increased from 26.7% to 36.4%. However, SR patients with RF between 0.8 and 1.2 could not be protected by reinduction alone (isolated/overall CNS relapse rate with irradiation, 4%/5%; without irradiation, 11%/22%). Dosages of 12 and 18 Gy were found to be equally protective.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Improved techniques for the in vitro cultivation of Eimeria tenella in primary chick kidney cells.

Primary kidney cells of 1- to 4-week-old chickens (PCKC) grown in Flexiperm chambers or culture flasks were infected with ultrapure sporozoites of two Eimeria tenella strains. For the 24-h parasite-free adaptation phase of the PCKC culture, Williams E medium plus 10% foetal calf serum (FCS) was used, and for the subsequent parasite-containing 168-h maintenance phase, we used medium 199 plus 2.5% FCS. Monolayers established during that time enabled the routine development of all schizont generations as well as, in general, young oocysts. The parasite stages propagated in FLEX were rendered visible by modified PAS-AO staining. Sporulated oocytes differed in length and width from those recovered after their passage through chickens. These results show that E. tenella can reliably be reproduced from sporozoites to oocysts in PCKC cultures. However, the yield of oocysts was generally low, indicating that mass production of oocysts is achieved only by passaging sporulated oocysts through chickens.

Animals↗
PubMed1990

Down-regulation of androgen receptor by progestins and interference with estrogenic or androgenic stimulation of mammary carcinoma cell growth.

The regulatory influence of medroxyprogesterone acetate (MPA) on estrogen and androgen receptors of the human breast cancer cell lines MCF-7 and EFM-19 was explored in conjunction with the growth-promoting properties of these steroids. In the absence of steroidal stimulation, up to 1 microM MPA had no effect on the proliferation of the MCF-7 cell strain used and of EFM-19 cells. Under stimulation with 10 nM 17 beta-estradiol or 1 microM dihydrotestosterone, dose-dependent inhibition of the cell proliferation rates by 0.1-1 microM MPA was observed. Binding of MPA to the androgen receptor (Kd = 2.1 nM) but not to the estrogen receptor was demonstrable. During incubation of MCF-7 or EFM-19 cells with 1 microM MPA for 7 days, the estrogen and androgen receptor contents were down-regulated by approximately 50% and 60%, respectively. Likewise, the number of androgen-binding sites was reduced to 35% of the untreated controls after incubation of MCF-7 cells with 1 microM synthetic progestin R5020 for 7 days. The results indicate down-regulation of estrogen and androgen receptors by progestins in the absence of stimulatory effects on the proliferation of mammary carcinoma cells.

Breast Neoplasms↗
PubMed1990

Dose-dependent increase in plasma interleukin-6 after recombinant tumour necrosis factor infusion in humans.

Several studies have shown that the cytokine interleukin-6 (IL-6) is produced in response to tumour necrosis factor (TNF) in vitro. This study examines the in vivo relation between these two cytokines with assays of plasma IL-6 and TNF levels in subjects with chronic hepatitis B undergoing immunomodulatory therapy with recombinant TNF (rTNF). Plasma IL-6 was detected from 20 min after rTNF infusion with levels peaking after 2-3 h and levels correlated with the dose of rTNF administered (r = 0.67, P = 0.004). Peak levels of IL-6 (mean 295, range 266-297 ng/l) were lower than those seen in certain disease states despite the very high peak levels of rTNF (mean 11,750, range 5623-18,620 ng/l). These findings suggest that the very high levels of IL-6 found in certain disease states are not purely the result of circulating TNF. Other factors such as endotoxin or other cytokines may also play a role in determining levels of plasma IL-6.

Dose-Response Relationship, Drug↗
PubMed1990

Possibilities and limitations of immunological marker analyses for the detection of minimal residual disease in childhood acute lymphoblastic leukemia.

Specific application of immunological markers in acute lymphoblastic leukemia (ALL) for detection of inadequate blast cell reduction after induction therapy or early recognition of a relapse requires a precise characterization of the immunophenotype at the time of diagnosis and an understanding of the biology of the disease. Therefore, the ALL-BFM 83 study is first used to demonstrate the incidence, antigen expression and dynamics of relapse occurrence of immunological subtypes in childhood ALL. This is then followed by a discussion of the different immunological features hitherto applied for identification of residual leukemia cells in ALL (terminal deoxynucleotidyl transferase--TdT; common acute lymphoblastic leukemia-associated antigen--CALLA, CD10; various T-cell differentiation antigens; kappa/lambda labelling); these are, however, not leukemia-specific and are expressed to varying degrees by normal lymphoid progenitor cells. The sensitivity of these analyses is therefore largely determined by the markers applied and the type of investigational material. Finally, suitable markers are presented for detecting residual leukemia cells in the different immunological subtypes of ALL. Their clinical relevance still remains to be evaluated in prospective therapy studies.

Antibodies, Monoclonal↗
PubMed1989

Antimalarial activity of new floxacrine-related acridinedione derivatives: studies on blood schizontocidal action of potential candidates against P. berghei in mice and P. falciparum in vivo and in vitro.

Deoxyfloxacrine derivatives (1-hydrazone: S 83 0083; 1-imine: S 84 7277) and floxacrine derivatives (10-methoxy-floxacrine: L 84 7667; 1-imine: L 84 7693) selected from a series of newly synthesized 3-aryl-7-chloro-3,4-dihydro-1,9(2H,10H)-acridinediones were evaluated for blood schizontocidal activities in mice infected with asexual stages of various drug-resistant lines of P. berghei and in New World monkeys infected with blood schizonts of different chloroquine-resistant strains of P. falciparum. All compounds tested showed high activity against drug-resistant lines of P. berghei (ED50: 1.0-4.4 mg/kg x 5, per os) and were distinctly superior in their antimalarial potency to floxacrine. Compounds L 84 7667 and L 84 7693 proved to be highly active against the FCBR strain of P. falciparum in vitro (IC50: 0.73-1.78 nmol); they effected temporary clearance of parasitemias due to the Palo Alto strain of P. falciparum in squirrel monkeys at oral doses of 15 mg/kg given daily for 5 consecutive days. Compounds S 83 0083 and S 84 7277, showing moderate in vitro effects (12.9-24.8 nmol), cleared parasitemias of the FCBR strain of P. falciparum in owl monkeys at oral doses of 20 mg/kg (S 84 7277) given daily for 5 or 7 consecutive days (follow-up period, 17 and 30 days, respectively) or at doses of 20 mg/kg (x 4) (S 83 0083) followed by doses of 40 mg/kg (x 3) within a follow-up period of 30 days. These observations suggest that the range of doses required for the cure of established P. falciparum infections is probably too large to cover infections with strains of the least susceptibility and might evoke toxic reactions by the potential candidates tested.

Acridines↗
PubMed1989

Synergistic enhancement of the antiproliferative activity of cis-diamminedichloroplatinum(II) by the ether lipid analogue BM41440, an inhibitor of protein kinase C.

The new phospholipid analogue 3-hexadecylmercapto-2-methoxy-methyl-propyl-1-phosphocholine inhibits the phospholipid-calcium-dependent protein kinase, partially purified from Walker carcinoma cells with a Ki value of 0.56 microM. The compound inhibits the phorbol ester stimulated phosphorylation of the ribosomal protein S6 indicating that the depression of Ca2+-phospholipid-dependent protein kinase by the alkyl phospholipid also occurs in intact cells. The dose effect curve for the inhibition of cell proliferation by 3-hexadecylmercapto-2-methoxy-methyl-propyl-1-phosphocholine in Walker cells exhibits a close correlation to the dose effect curve for the depression of Ca2+-phospholipid-dependent protein kinase activity. Although alternative mechanisms cannot be excluded, the data suggest that the growth inhibitory activity of 3-hexadecylmercapto-2-methoxy-methyl-propyl-1-phosphocholine correlates with the inhibition of Ca2+-phospholipid-dependent protein kinase. The antiproliferative activity of 3-hexadecylmercapto-2-methoxy-methyl-propyl-1-phosphocholine is synergistically enhanced by cis-diamminedichloroplatinum(II).

Animals↗
PubMed1989

The phospholipid- and calcium-dependent protein kinase as a target in tumor chemotherapy.

Evidence for a constitutive activation of protein kinase C (EC 2.7.1.37) in Ha-ras transformed 3T3 cells is presented. Several compounds which inhibit protein kinase C in vitro have been studied with regard to their antiproliferative activity in cultured tumor cells. The following agents were investigated: 3-hexadecyl-mercapto-2-methoxy-methyl-propyl-1- phosphocholine (BM 41440); 1-octadecyl-2-methyl-sn-glycero-3-phosphocholine (ET-18-OCH3); quercetin, tamoxifen and staurosporine. All compounds decrease protein kinase C activity in vitro as well as in intact cells and inhibit cell multiplication within the same dose range. The results suggest a causal relation between the antiproliferative effects and the inhibition of protein kinase C. All inhibitors of protein kinase C synergistically enhance the antiproliferative activity of cis-diamminedichloroplatinum(II). Available data suggest that the effects of protein kinase C inhibitors should be exploitable for tumor chemotherapy.

Animals↗
PubMed1989

Characterization of epidermal growth factor-related proteins from human urinary chorionic gonadotrophin.

A urinary chorionic gonadotrophin (hCG) preparation, mitogenic for ovarian carcinoma cells, was analysed by gel filtration through Sephadex G-100 Superfine. The resulting fractions were tested for hCG and for properties of the epidermal growth factor (EGF) by radioimmunoassays (RIA) in comparison with their ability to stimulate the growth of EFO-27nu ovarian carcinoma cells. The elution profile of the RIA activities for hCG corresponded to molecular weights of 12 and 71 kDa, whereas the mitogenic activity was found in peak fractions eluting at 7, 11 and 52 kDa, indicating the presence of mitogenic substances distinct from hCG or its beta-subunit. In comparison experiments, radiolabelled recombinant human EGF eluted at 7 kDa from the column. The profile of EGF immunoreactivity determined in the eluant fractions of hCG preparation A correlated with the mitogenic potential. Eluant fractions with growth-promoting activity competed with 125I-labelled EGF in binding to EFO-27nu cells; the inhibition of EGF binding was correlated with the mitogenic potential and the EGF immunoreactivity. We assume that the 7 kDa component of the gel filtration eluate corresponds to monomeric EGF; the high molecular weight mitogens may represent EGF precursor protein fragments of various molecular size classes.

Cell Division↗