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Biomedical subjects

A Markus

Publications and source records attributed to A Markus.

At least 37 records · Page 2Linked to original sources
PubMed1996

p21ras supports the survival of chick embryonic motor neurones.

Various trophic factors present in muscle extract can promote the survival of cultured motor neurones. However, little is known about the signal transduction pathways used in these cells. The proto-oncogene product p21ras has been shown to play an important role in proliferative and differentiative signalling pathways. We report here that cytoplasmic introduction of its oncogenic form, p21ras(G12V), fully supports the in vitro survival of chick embryonic motor neurones. The proto-oncogenic form of p21ras also showed a dose-dependent survival effect, while a C-terminally truncated counterpart of p21ras(G12V) was ineffective. These results suggest an involvement of p21ras in signal transduction pathways leading to motor neurone survival and may be of relevance for the development of therapeutic strategies for motor neurone disease.

Animals↗
PubMed1996

Active p21Ras is sufficient for rescue of NGF-dependent rat sympathetic neurons.

We have examined whether p21Ras proteins can rescue nerve growth factor-deprived rat sympathetic neurons from death, to test further our hypothesis that p21Ras is a central mediator in the nerve growth factor-to-survival signalling pathway. After crosslinking [125I]nerve growth factor to live neurons, two forms of Trk (molecular weight approximately 140,000 and 115,000) were immunoprecipitated with anti-Trk antibodies. Nerve growth factor induced tyrosine phosphorylation of both Trk forms and at least two additional proteins. When these phosphorylations were prevented by staurosporine (in a protein kinase C-independent manner) the neurons died. However, neurons were rescued from death due to staurosporine treatment by intracellular loading of oncogenic Ha-Ras(val12) protein. Both Ha-Ras(val12) and cellular Ha-Ras proteins maintained survival for several days in the absence of nerve growth factor and mimicked other actions of nerve growth factor, inducing rapid c-Fos protein expression and robust neurite outgrowth. Conversely, Fab fragments of neutralizing antibodies to p21Ras which blocked the capacity of nerve growth factor to promote neuron survival were also found to inhibit the early expression of c-Fos protein in these neurons. The close correspondence observed between the timing of onset of c-Fos responsiveness and acquisition of nerve growth factor-dependence in embryonic day 17 sympathetic neurons, and the coordinate increase found in both parameters until embryonic day 19 indicates that c-Fos protein expression is a good biochemical indicator of the presence of a functional nerve growth factor-to-survival signal transduction pathway. Nevertheless, expression of c-Fos is not sufficient for survival since phorbol esters induce c-Fos with no effect on survival. These data strengthen our proposal that p21Ras proteins are crucial anti-apoptotic mediators of survival in rat sympathetic neurons by demonstrating that p21Ras is both necessary and sufficient to rescue neurons which are disabled from signalling through Trk receptors.

Animals↗
PubMed1996

Ras p21 protein promotes survival and differentiation of human embryonic neural crest-derived cells.

We have previously shown that the oncogene product p21 Ras is essential for the survival and neurite outgrowth-promoting activity of nerve growth factor on cultured chick embryonic sensory, but not sympathetic neurons. In order to extend our observations to the human system and to non-neuronal cells, we introduced the oncogenic form of p21 Ras into the cytoplasm of three different types of cultured human embryonic neural crest derivatives (8th-11th gestational week): dorsal root ganglion neurons, sympathetic neurons, and adrenal chromaffin cells. These cells are dependent on nerve growth factor for survival and/or fibre outgrowth in vitro. In dorsal root ganglion neurons, p21 Ras promoted survival and fibre outgrowth which was quantitatively and qualitatively comparable to the nerve growth factor effect (84% vs. 95%, control 18%). Sympathetic neurons showed a similar effect, albeit with a higher background survival (91% vs. 93%, control 58%). On chromaffin cells, which respond to nerve growth factor with pronounced fibre outgrowth in culture, the effect of p21 Ras was again comparable to that of nerve growth factor (35% vs. 30%, control 5%). The survival and fibre outgrowth-promoting effects of p21 Ras on human embryonic dorsal root ganglion neurons, sympathetic neurons and chromaffin cells suggest an involvement of p21 Ras in the intracellular signal transduction of nerve growth factor in human neural crest-derived cell populations.

Cell Differentiation↗
PubMed1996

The Politano-Leadbetter antireflux plasty. Investigation of complications in 245 children.

From 1981 to 1988 245 children aged 2 months to 15 years underwent ureteral reimplantation in 326 renal units in our department. The VUR was primary in 180 patients (253 ureters) and 65 patients (73 ureters) showed associated pathologies. The follow-up program, including physical examination, urine sampling and isotope studies (including NMCU), was from 4 to 11 years after surgery. Intraoperative and early surgical complications were found in 29 cases, but no complications affected the late results, especially kidney function. Late complications have been observed in 15 cases, while in 10 cases reoperation because of persistent reflux (n = 4) obstruction (n = 3) and loss of kidney function (nephrectomy n = 3) was required. In 4 cases bladder stones required ESWL, and one patient developed hypertension.

Adolescent↗
PubMed1995

Lues maligna, or ulceronodular syphilis, in a man infected with human immunodeficiency virus: case report and review.

A 30-year-old bisexual man who was infected with human immunodeficiency virus (HIV) and had a history of anaphylaxis to penicillin developed lues maligna, or ulceronodular secondary syphilis. Therapy with parenteral erythromycin failed, and he was subsequently treated with ceftriaxone following penicillin desensitization. A review of the English-language literature identified 14 cases of lues maligna reported between the early 1900s and 1988. From 1989 to 1994, an additional 12 cases (including the current case) were reported. Of those 12 cases, 11 occurred in patients who either were infected with HIV or were at high risk for HIV infection. Patients infected with HIV may be at increased risk of developing this severe form of secondary syphilis. Lues maligna should be considered in the differential diagnosis of HIV-infected patients who present with ulceronodular lesions.

AIDS-Related Opportunistic Infections↗
PubMed1995

Chemotherapeutic activity of levofloxacin (HR 355, DR-3355) against systemic and localized infections in laboratory animals.

Ofloxacin, its optical isomers levofloxacin (HR 355, DR-3355) and D-ofloxacin (DR-3354) and ciprofloxacin were administered orally to mice and rats which had systemic and localized infections. Both levofloxacin and ciprofloxacin were equally effective in treating systemic murine infections caused by staphylococci. Enterobacteriaceae or Pseudomonas aeruginosa with ED50s ranging from 0.18 to 15.8 mg/kg and 0.42 to 16.3 mg/kg respectively and both these agents were twice as effective as ofloxacin which had an ED50 0.41 to 39.7 mg/kg. In contrast, D-ofloxacin was either inactive or exhibited only modest chemotherapeutic activity against the staphylococci and the Gram-negative organisms tested. When given to mice to treat staphylococcal abscesses and lung infections due to Klebsiella pneumoniae DT-S levofloxacin was up to four times more effective and produced a more pronounced bactericidal effect against the pathogens in vivo than the reference compounds. Despite possessing a similar, if not lesser, in-vitro activity against the infecting pathogens, levofloxacin was more effective than ofloxacin and ciprofloxacin in rats with localized infections caused by Enterobacteriaceae and P. aeruginosa.

Abscess↗
PubMed1995

Mode of action of the lantibiotic mersacidin: inhibition of peptidoglycan biosynthesis via a novel mechanism?

Mersacidin is an antibiotic peptide produced by Bacillus sp. strain HIL Y-85,54728 that belongs to the group of lantibiotics. Its activity in vivo against methicillin-resistant Staphylococcus aureus strains compares with that of the glycopeptide antibiotic vancomycin (S. Chatterjee, D. K. Chatterjee, R. H. Jani, J. Blumbach, B. N. Ganguli, N. Klesel, M. Limbert, and G. Seibert, J. Antibiot. 45:839-845, 1992). Incubation of Staphylococcus simulans 22 with mersacidin resulted in the cessation of growth and slow lysis. Biosyntheses of DNA, RNA, and protein were not affected, whereas incorporation of glucose and D-alanine was inhibited and a regular reduction in the level of cell wall thickness was observed. Thus, unlike type A lantibiotics, mersacidin does not form pores in the cytoplasmic membrane but rather inhibits cell wall biosynthesis. Comparison with tunicamycin-treated cells indicated that peptidoglycan rather than teichoic acid metabolism is primarily affected. Mersacidin caused the excretion of a putative cell wall precursor into the culture supernatant. The formation of polymeric peptidoglycan was effectively inhibited in an in vitro assay, probably on the level of transglycosylation. In contrast to vancomycin, the activity of mersacidin was not antagonized by the tripeptide diacetyl-L-Lys-D-Ala-D-Ala, indicating that on the molecular level its mode of action differs from those of glycopeptide antibiotics. These data together with electron microscopy suggest that mersacidin acts on a novel target, which opens new perspectives for the treatment of methicillin-resistant S. aureus.

Amino Acid Sequence↗
PubMed1994

Bacteremia due to fluoroquinolone-resistant Escherichia coli in two immunocompromised patients.

Two patients with acute leukemia developed Escherichia coli bacteremia while receiving oral ofloxacin for antibacterial prophylaxis during profound neutropenia. The isolates were resistant to ofloxacin (MIC 25 and 12.5 micrograms/ml respectively), other fluoroquinolones and several unrelated agents. Whole cell drug accumulation studies with four different fluoroquinolones suggested major differences between drugs but only minor alterations in individual drug permeability in the two resistant isolates compared with a susceptible control strain. In a supercoiling assay using the purified DNA gyrase and plasmid pBR322, high concentrations (> or = 250 micrograms/ml) of both ofloxacin and ciprofloxacin were needed for visible inhibition of enzyme activity suggesting mutations in the DNA gyrase gene as the significant mechanism of resistance in both strains.

Acute Disease↗
PubMed1993

Involvement of ras p21 in neurotrophin-induced response of sensory, but not sympathetic neurons.

Little is known about the signal transduction mechanisms involved in the response to neurotrophins and other neurotrophic factors in neurons, beyond the activation of the tyrosine kinase activity of the neurotrophin receptors belonging to the trk family. We have previously shown that the introduction of the oncogene product ras p21 into the cytoplasm of chick embryonic neurons can reproduce the survival and neurite-outgrowth promoting effects of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and of ciliary neurotrophic factor (CNTF). To assess the potential signal-transducing role of endogenous ras p21, we introduced function-blocking anti-ras antibodies or their Fab fragments into cultured chick embryonic neurons. The BDNF-induced neurite outgrowth in E12 nodose ganglion neurons was reduced to below control levels, and the NGF-induced survival of E9 dorsal root ganglion (DRG) neurons was inhibited in a specific and dose-dependent fashion. Both effects could be reversed by saturating the epitope-binding sites with biologically inactive ras p21 before microinjection. Surprisingly, ras p21 did not promote the survival of NGF-dependent E12 chick sympathetic neurons, and the NGF-induced survival in these cells was not inhibited by the Fab-fragments. The survival effect of CNTF on ras-responsive ciliary neurons could not be blocked by anti-ras Fab fragments. These results indicate an involvement of ras p21 in the signal transduction of neurotrophic factors in sensory, but not sympathetic or ciliary neurons, pointing to the existence of different signaling pathways not only in CNTF-responsive, but also in neurotrophin-responsive neuronal populations.

Animals↗
PubMed1992

Antibacterial activity in vitro of cefpirome against clinical isolates causing sexually transmitted diseases.

The in-vitro activity of cefpirome was compared with other antibiotics against organisms causing sexually transmitted diseases (STD). The excellent activity of cefpirome against Neisseria gonorrhoeae (MIC90 1.0 mg/L), Haemophilus ducreyi (MIC90 0.5 mg/L), and Gardnerella vaginalis (MIC90 1.0 mg/L) suggests that this agent might be useful in the empirical treatment of a variety of venereal diseases.

Cephalosporins↗
PubMed1992

The in-vitro antibacterial activity of a combination of cefpirome or cefoperazone with vancomycin against enterococci and Staphylococcus aureus.

Cefpirome, cefoperazone and ceftazidime were tested for their in-vitro activity against Enterococcus faecalis and methicillin-resistant Staphylococcus aureus (MRSA) isolates. Cefpirome was the most active cephalosporin followed by cefoperazone. Ceftazidime had only very limited activity against these strains. In experiments with cefpirome/vancomycin and cefoperazone/vancomycin combinations, synergy was detected against most MRSA strains and some enterococci. Antagonism did not occur.

Cefoperazone↗
PubMed1992

Pharmacokinetics of cefpirome administered intravenously or intramuscularly to rats and dogs.

The pharmacokinetic profile of cefpirome was evaluated in rats and dogs after a single intravenous or intramuscular dose. A two-compartment open model was used for the calculation of the pharmacokinetic parameters for both routes of administration. The elimination half-lives after intravenous and intramuscular administration of 20 mg/kg cefpirome did not differ significantly and ranged from 0.4 h in rats to 1.1 h in dogs. Cefpirome was mainly excreted via the kidneys. After iv or im dosing of the compound, between 80% (dogs) and 90% (rats) was recovered in urine within 24 h. The bioavailability of cefpirome in rats and dogs after both routes of administration was almost identical when calculated either by the AUC or the urinary recovery rates.

Animals↗
PubMed1992

Antibacterial activity of RU44790, a new N-tetrazolyl monocyclic beta-lactam.

RU44790 belongs to a new class of synthetic monocyclic beta-lactam antibiotics which feature a bioisosteric tetrazole moiety instead of the more classical acidic functions at the N-1 position of the beta-lactam ring. Its antibacterial activity was evaluated against some 900 strains and was compared with those of other recent beta-lactam derivatives, especially aztreonam. RU44790 is endowed with potent activity against gram-negative bacteria. At less than or equal to 0.6 micrograms/ml, RU44790 inhibited 90% of all strains of the family Enterobacteriaceae with the exception of Citrobacter spp. (MIC for 90% of strains tested, 1.2 micrograms/ml). The activity was similar to that of aztreonam against strains that are normally susceptible to expanded-spectrum cephalosporins. On the other hand, the new compound was 10 to 100 times more potent than aztreonam and most of the other antibiotics tested against enterobacteria that produce chromosome-encoded or plasmid-mediated extended-spectrum beta-lactamases. Pseudomonas aeruginosa isolates were equally susceptible to both monobactams. RU44790 was inactive against staphylococci and had only marginal activity against streptococci (MIC for 50% of strains tested, 2.5 micrograms/ml). RU44790 was highly resistant to hydrolysis by various beta-lactamases, particularly cephalosporinases such as P99. The latter enzyme was also inhibited by the compound. RU44790 showed a high affinity for penicillin-binding protein 3 of Escherichia coli. The results suggest that RU44790 has good potential in the treatment of infections caused by gram-negative microorganisms.

Anti-Bacterial Agents↗
PubMed1992

RU 29 246, the active compound of the cephalosporin-prodrug-ester HR 916. I. Antibacterial activity in vitro.

The aminothiazolyl-cephalosporin RU 29 246 is the active metabolite of the prodrug-pivaloyl-oxyethyl-ester HR 916. RU 29 246 in vitro activity includes a wide range of clinically relevant bacterial pathogens. Against methicillin-sensitive Staphylococci RU 29 246 (MIC90 of 0.25 approximately 2 micrograms/ml) was clearly more active than cefaclor, cefuroxime, cefpodoxime, cefixime and ceftibuten, but slightly less active than cefdinir. RU 29 246 inhibited hemolytic Streptococci of the serogroups A, B, C and G as well as penicillin-sensitive Streptococcus pneumoniae at concentrations similar to cefdinir, cefpodoxime and cefuroxime (MIC90 less than or equal to 0.13 micrograms/ml), but less than the other oral cephalosporins investigated (cefixime, cefaclor and ceftibuten). MIC90s of RU 29 246 against Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Salmonella spp., Shigella spp., Proteus mirabilis and Haemophilus influenzae were less than or equal to 0.5 micrograms/ml. Only RU 29 246 and cefdinir demonstrated moderate activity against Acinetobacter baumannii (MIC90 greater than or equal to 4 micrograms/ml). Most strains of Pseudomonas spp., Serratia marcescens, Enterobacter spp., Hafnia alvei and Bacteroides spp. were resistant to RU 29 246. RU 29 246 killed Escherichia coli and Staphylococcus aureus at a rate of 99% to 99.9% at concentrations of two times MIC. The pH value of the medium (range 5.5 to 8.5) and the inoculum size (range 10(5) to 10(7) cfu/ml) had no or only low influence on the antibacterial activity of RU 29 246. RU 29 246 is a broad spectrum cephalosporin including in its activity both Gram-positive and Gram-negative pathogens and therefore--depending on the bioavailability of its prodrug--looks promising as to its therapeutic perspective.

Anti-Bacterial Agents↗
PubMed1992

RU 29 246, the active compound of the cephalosporin-prodrug-ester HR 916. II. Stability to beta-lactamases and affinity for penicillin-binding proteins.

The aminothiazolyl-cephalosporin RU 29 246, the active metabolite of the prodrug-ester HR 916, is active against strains producing the widespread plasmid-encoded TEM-1, TEM-2 and SHV-1 beta-lactamases. Except for TEM-7 the activity of RU 29 246 against strains producing extended broad spectrum beta-lactamases (TEM-3, TEM-5, TEM-6, SHV-2, SHV-4, SHV-5, CMY-1, CTX-M), however, is low. Relative hydrolysis rates of RU 29 246 are comparable with those of cefpodoxime, the active metabolite of CS-807, and are extremely low for the TEM-1 and SHV-1 beta-lactamases. The compound demonstrates remarkable inhibitory activity against the chromosomal beta-lactamase of Enterobacter cloacae P99. In the presence of 1.7 microM this enzyme loses 50% of its activity. At concentrations of 0.43, 0.003 and 0.01 micrograms/ml the compound binds preferentially to the penicillin-binding protein (PBP) 3 of Escherichia coli K12, to the PBPs 2x and 3 of Streptococcus pneumoniae R6 and to PBP 1 of Staphylococcus aureus SG 511, respectively.

Anti-Bacterial Agents↗
PubMed1992

RU 29 246, the active compound of the cephalosporin prodrug-ester HR 916. III. Pharmacokinetic properties and antibacterial activity in vivo.

The pharmacokinetics of the broad spectrum cephem RU 29 246 and its prodrug-ester HR 916 B were investigated in mice, rats and dogs and compared to those of cefpodoxime proxetil, cefuroxime axetil and cefixime. HR 916 B is well absorbed following oral administration and efficiently converted to the antibacterially active form. In mice, mean peak blood levels of 31.1 micrograms/ml of the parent compound were recorded within 20 minutes after oral administration of a single dose equivalent to 40 mg/kg RU 29 246. The bioavailability calculated on the basis of the areas under the concentration-time curves (AUC) and the urinary recoveries was about 90%. In rats, peak blood levels of 14.5 micrograms/ml were obtained 1 hour after an oral 20 mg/kg dose. The bioavailability was calculated as 70%. In dogs, 40% of an oral 10 mg/kg dose was recovered in the urine within 24 hours. Cmax was 15.9 micrograms/ml at 4.6 hours. Mean elimination half-lives of RU 29 246 were 0.35, 0.5 and 2.1 hours in mice, rats and dogs, respectively. After an oral HR 916 B dose equivalent to 50 mg/kg of RU 29 246, tissue concentrations at 0.5 hour ranged between 0.8 micrograms/g in brain and 95.7 micrograms/g in murine kidneys. These values of HR 916 B are similar to, or distinctly higher than, those of the reference compounds. Of the oral cephalosporins tested, HR 916 B had the most balanced antibacterial spectrum. With ED50s of between 0.9 and 11.5 mg/kg against staphylococci, its activity was similar to that of the additional reference compound cefaclor and higher than that of cefuroxime. Cefixime and cefpodoxime proxetil displayed low antistaphylococcal activity or were inactive. In septicemias with Enterobacteriaceae, cefixime and cefpodoxime proxetil were more potent than HR 916 B and cefaclor. Cefuroxime axetil was inactive against most of these infections. HR 916 B was also highly effective against murine lung infections caused by Klebsiella pneumoniae DT-S or Streptococcus pneumoniae 1147.

Animals↗