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Biomedical subjects

J Mohler

Publications and source records attributed to J Mohler.

At least 37 records · Page 2Linked to original sources
PubMed1994

Activity of isepamicin and selection of permeability mutants to beta-lactams during aminoglycoside therapy of experimental endocarditis due to Klebsiella pneumoniae CF104 producing an aminoglycoside acetyltransferase 6' modifying enzyme and a TEM-3 beta-lactamase.

The pharmacokinetics and efficacy of isepamicin were compared with those of amikacin and gentamicin in a rabbit model of endocarditis due to Klebsiella pneumoniae CF104 producing beta-lactamase TEM-3 and aminoglycoside acetyltransferase AAC(6')-IV. Only isepamicin and gentamicin, alone or combined with ceftriaxone, were effective as determined by titration of viable bacteria in vegetations. Variants highly resistant to ceftriaxone without change in MICs of aminoglycosides were isolated at the end of each therapeutic regimen except with the most effective one (ceftriaxone plus gentamicin). Examination of the bacterial outer membrane proteins as well as the 50% inhibition of the beta-lactamase activity in intact and sonified cells suggested a permeability defect as being responsible for the increased MICs of ceftriaxone. The activity of isepamicin was superior to that of amikacin against the TEM-3-AAC(6')-IV-producing strain. The combination of gentamicin plus ceftriaxone was the most effective regimen in terms of efficacy and prevention of emergence of resistant strains. Suboptimal aminoglycoside monotherapy might be responsible for selection of permeability mutants to beta-lactams.

Acetyltransferases↗
PubMed1994

Influence of antimicrobial therapy on kinetics of tumor necrosis factor levels in experimental endocarditis caused by Klebsiella pneumoniae.

The kinetics of tumor necrosis factor (TNF) levels in serum during therapy with cell wall-active agents (ceftriaxone, imipenem) and gentamicin were investigated in rabbits with experimental endocarditis caused by an isogenic pair of Klebsiella pneumoniae strains: a TEM-3 beta-lactamase-producing strain (KpR) or its susceptible variant (KpS). In vitro, KpR was resistant to ceftriaxone and was susceptible to gentamicin and imipenem, while KpS was susceptible to all three antibiotics. Serum TNF levels were determined in control rabbits hourly after bacterial inoculation and then daily; they were determined in treated animals hourly after the first antibiotic injection and then daily during a 4-day therapy with either imipenem (60 mg/kg of body weight four times daily), ceftriaxone (75 mg/kg once daily), or gentamicin (4 mg/kg once daily) alone or in combination with ceftriaxone. After a transient peak (10.2 +/- 3.1 ng/ml) at 90 min following bacterial challenge, serum TNF levels remained low and stable in control animals. The peak in the serum TNF levels occurred 4 h after the first antibiotic injection and with ceftriaxone was significantly higher (P < 0.05) against KpS (1.99 +/- 0.52 ng/ml) than against KpR (1.40 +/- 0.17 ng/ml). Against the KpR strain, the levels observed with ceftriaxone were significantly higher (P < 0.05) than those obtained with the other therapeutic regimens (0.70 to 0.80 ng/ml). On the day of sacrifice, effective regimens were associated with low TNF levels. We concluded that TNF production depends on (i) the antiobiotic's mechanism of action and the susceptibility of the strain at the early phase of therapy, without any effect of the rapidity of bacterial killing, and (ii) the final reduction of the bacterial count at a later stage of therapy.

Animals↗
PubMed1993

Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity.

We have identified three members of a mouse gene family related to the Drosophila segment polarity gene, hedgehog (hh). Like hh, they encode putative secreted proteins and are thus implicated in cell-cell interactions. One of these, Sonic hh (Shh), is expressed in the notochord, the floor plate, and the zone of polarizing activity, signaling centers that are thought to mediate central nervous system (CNS) and limb polarity. Ectopic expression of Shh in the mouse CNS leads to the activation of floor plate-expressed genes. These results suggest that Shh may play a role in the normal inductive interactions that pattern the ventral CNS.

Amino Acid Sequence↗
PubMed1993

Contrasting distributions of patched and hedgehog proteins in the Drosophila embryo.

The segment polarity genes patched (ptc) and hedgehog (hh) are thought to encode a receptor and signal molecule respectively, components of a signal transduction pathway that regulates the transcription of the wingless gene in the Drosophila embryo. Here we describe the production of antibodies specific for the products of these two genes and the patterns of protein distribution that they reveal in the developing embryo. The results are consistent with the hh protein being secreted by cells in which it is expressed and support a role for ptc in the reception of the putative hh encoded signal.

Animals↗
PubMed1992

The embryonically active gene, unkempt, of Drosophila encodes a Cys3His finger protein.

The unkempt gene of Drosophila encodes a set of embryonic RNAs, which are abundant during early stages of embryogenesis and are present ubiquitously in most somatic tissues from the syncytial embryo through stage 15 of embryogenesis. Expression of unkempt RNAs becomes restricted predominantly to the central nervous system in stages 16 and early 17. Analysis of cDNAs from this locus reveals the presence of five Cys3His fingers in the protein product. Isolation and analysis of mutations affecting the unkempt gene, including complete deletions of this gene, indicate that there is no zygotic requirement for unkempt during embryogenesis, presumably due to the contribution of maternally supplied RNA, although the gene is essential during post-embryonic development.

Amino Acid Sequence↗
PubMed1992

Molecular organization and embryonic expression of the hedgehog gene involved in cell-cell communication in segmental patterning of Drosophila.

hedgehog is a segment polarity gene necessary to maintain the proper organization of each segment of the Drosophila embryo. We have identified the physical location of a number of rearrangement breakpoints associated with hedgehog mutations. The corresponding hh RNA is expressed in a series of segmental stripes starting at cellular blastoderm in the posterior portion of each segment. This RNA is localized predominantly within nuclei until stage 10, when the localization becomes primarily cytoplasmic. Expression of hh RNA in the posterior compartment is independent of most other segment polarity genes, including en, until the late extended germ-band stage (stage 11). Sequence analysis of the hedgehog locus suggests the protein product is a transmembrane protein, which may, therefore, be directly involved in cell-cell communication.

Animals↗
PubMed1991

Segmentally restricted, cephalic expression of a leucine zipper gene during Drosophila embryogenesis.

The expression pattern and DNA sequence of a newly identified gene, CNC (cap'n'collar), suggest a role for this gene in cephalic patterning during Drosophila embryogenesis. In situ hybridization reveals transcripts localized to the mandibular segment and the hypopharyngeal and labral primordia first detectable in late blastoderm stages. Sequence analysis of cDNA clones from the CNC locus shows the CNC gene product to be related to transcription factors of the leucine zipper (bZIP) class. Based on its protein sequence, we propose that CNC is a subunit of a heterodimeric regulatory protein involved in the control of head morphogenesis.

Amino Acid Sequence↗
PubMed1990

High-performance liquid chromatographic determination of the binding of ceftriaxone to human serum albumin solution and albumin from diluted human serum.

The binding of ceftriaxone to human serum albumin has been studied by high-performance liquid chromatography. The gel permeation method of Hummel and Dreyer was used. Ceftriaxone was tested with two sources of albumin (aqueous solution and diluted serum). After internal calibration the binding parameters were determined for each albumin, and results compared. These data are in agreement with those from classical methods for the determination of protein binding of ceftriaxone.

Buffers↗
PubMed1990

Activity of sulbactam in combination with ceftriaxone in vitro and in experimental endocarditis caused by Escherichia coli producing SHV-2-like beta-lactamase.

We studied the efficacy of sulbactam, a beta-lactamase inhibitor, in combination with ceftriaxone in vitro and in experimental endocarditis due to an Escherichia coli strain producing an extended-spectrum beta-lactamase most similar to SHV-2, a new mechanism of resistance to broad-spectrum cephalosporins among members of the family Enterobacteriaceae. In vitro, ceftriaxone demonstrated an important inoculum effect (MICs were 2 and 256 micrograms/ml with 5 X 10(5) and 5 X 10(7) CFU of inoculum per ml, respectively). Sulbactam inhibited the beta-lactamase degradation of ceftriaxone and enhanced the killing by ceftriaxone with both inocula tested. In vivo, sulbactam (100 mg/kg every 8 h) or ceftriaxone (15 or 30 mg/kg every 24 h) alone were ineffective after a 4-day therapy. The addition of sulbactam to ceftriaxone (15 mg/kg) or to the ceftriaxone (15 mg/kg)-netilmicin (6 mg/kg every 24 h) combination produced a reduction of 2 log10 CFU/g of vegetation greater than that produced by therapy without sulbactam. The sulbactam-ceftriaxone (30 mg/kg) combination produced a reduction of almost 5 log10 CFU/g of vegetation greater than that produced by single-drug therapy (P less than 0.01), sterilized five of eight vegetations (versus none of seven for ceftriaxone [30 mg/kg] alone; P less than 0.05), and was as effective as the ceftriaxone (15 mg/kg)-sulbactam-netilmicin combination. We concluded that (i) SHV-2 production was responsible for ceftriaxone failure in vivo, probably because of the high inoculum present in vegetations; (ii) sulbactam used in a regimen which provided levels in serum constantly above 4 micrograms/ml and a vegetation/serum peak ratio of approximately 1:3 enhanced the activity of a broad-spectrum cephalosporin in a severe experimental infection; and (iii) the highest dose of ceftriaxone in combination with sulbactam was as effective as the lowest dose of ceftriaxone plus sulbactam plus an aminoglycoside.

Animals↗
PubMed1989

A novel spatial transcription pattern associated with the segmentation gene, giant, of Drosophila.

The segmentation gene, giant, is located in 3A1 within a cloned chromosome region surrounding the zeste locus. Rearrangement breakpoints associated with giant mutations were localized on the genomic clone map, and nearby transcription units were identified. One transcription unit is active during early embryogenesis and its transcripts are spatially localized from blastoderm into extended germband stages, consistent with expected expression patterns predicted by the 'gap' phenotype of giant mutants. Germ line transformation experiments using a 10-kb DNA fragment containing this transcription unit gave complete rescue of the abdominal giant defect but only partial correction of the head defect. The effect of mutations in three other gap loci, Kr, kni and hb, were also analyzed.

Alleles↗
PubMed1989

Comparison of muscarinic cholinergic and alpha adrenergic receptors in canine ileum, colon, intestinal urinary reservoirs and bladder.

The muscarinic cholinergic (MCh) and alpha 2 adrenergic receptor densities in canine ileum, colon, ileal and colonic urinary reservoirs and bladder were determined using radioligand receptor binding methods in order to provide a rational basis for pharmacologic management of urinary incontinence following bladder replacement with intestinal segments. Muscarinic cholinergic and alpha 2 adrenergic receptor binding sites were studied in these tissues using saturation experiments with 3H-NMS and 3H-rauwolscine, respectively. The mean equilibrium dissociation constants for 3H-NMS binding (0.13 to 0.17 nM) in these tissues were similar (p greater than 0.05) indicating homogeneity of muscarinic cholinergic binding sites. The mean equilibrium dissociation constants for 3H-rauwolscine binding (1.27 to 1.98 nM) in these tissues were also similar (p greater than 0.05). A substantial density of MCh (1.06 to 1.22 fmol/mg. wet wt.) and alpha 2 adrenergic (0.47 to 1.11 fmol/mg. wet wt.) binding sites was identified in the intestinal tissues assayed. The density of ileal and colonic MCh and alpha 2 adrenergic binding sites was not altered following construction of urinary intestinal reservoirs. The presence of a substantial density of MCh and alpha 2 adrenergic binding sites in the intestinal tissues suggests that MCh and alpha 2 adrenergic analogs may be utilized for the management of urinary incontinence following bladder replacement with intestinal urinary reservoirs.

Animals↗
PubMed1989

Pharmacokinetics of cefsulodin in rat cerebrospinal fluid during experimental Pseudomonas aeruginosa meningitis.

Experimental meningitis was induced in rats with Pseudomonas aeruginosa. Bacteria were inoculated in the second ventricle. Twenty hours later cefsulodin penetration was studied in CSF by on-line cannula system which permitted sampling of CSF in the third ventricle. Comparison with healthy animals indicated breakdown of the blood-CSF barrier and high concentrations of cefsulodin were found in CSF.

Animals↗
PubMed1989

Permeability of two nitrosoureas, carmustine and fotemustine in rat cortex.

Carmustine and fotemustine were perfused using a bolus retrograde infusion into the right external carotid artery of rats. The right jugular vein gave blood samples. Using a previously described method, nitrosoureas were continuously measured in rat brain by voltammetry and in blood samples by high-performance liquid chromatography for 15 min. Cerebrovascular permeability coefficients calculated in the first 2 min were 0.9.10(-4) cm.s-1 for carmustine and 0.5.10(-4) cm.s-1 for fotemustine. These high brain permeability coefficients were compared to literature values for carmustine and other nitrosoureas determined with a radioactive procedure.

Animals↗
PubMed1988

Requirements for hedgehog, a segmental polarity gene, in patterning larval and adult cuticle of Drosophila.

Mutations of the hedgehog gene are generally embryonic lethal, resulting in a lawn of denticles on the ventral surface. In strong alleles, no segmentation is obvious and the anteroposterior polarity of ventral denticles is lost. Temperature shift analysis of a temperature-sensitive allele indicates an embryonic activity period for hedgehog between 2.5 and 6 hr of embryonic development (at 25 degrees) and a larval/pupal period from 4 to 7 days of development (at 25 degrees). Mosaic analysis of hedgehog mutations in the adult cuticle indicates a series of defined defects associated with the failure of appropriate hedgehog expression. In particular, defects in the distal portions of the legs and antenna occur in association with homozygous hedgehog clones in the posterior compartment of those structures. Because the defects are associated with homozygous clones, but are not co-extensive, a type of "domineering" nonautonomy is proposed for the activity of the hedgehog gene.

Alleles↗
PubMed1988

Determination of antibiotic lipophilicity with a micromethod: application to brain permeability in man and rats.

Lipophilicity of the injectable form of some antibiotics was measured with a micromethod. The antibiotic was dissolved in a small volume (1 ml) of phosphate buffer at a physiological pH (pH = 7.4) and was extracted by a small volume of octanol (1 ml). HPLC determinations of the antibiotic were performed in the two phases. log P ranged from +1.3 for chloramphenicol to -4.3 for ceftriaxone. A linear relationship was established for a few antibiotics between the log P values found in our experiments and the log permeability calculated from data in the literature for human and rat brain. This linear relationship enabled the brain concentrations of antibiotics to be predicted in man and rats.

Animals↗
PubMed1987

Alteration of gentamicin and cefazolin kinetics with control of the hypothyroid state in humans.

We studied the effect of the control of the hypothyroid state in humans on the pharmacokinetic parameters of cefazolin and gentamicin after a single intravenous injection. These two antibiotics were chosen because of their different patterns of binding to serum albumin (0% for gentamicin and 82% for cefazolin). In hypothyroidism, the behavior of cefazolin only was altered, with a decrease in the total body clearance, possibly due to reduced urinary excretion, and a decrease in the volume of distribution without a significant alteration of cefazolin binding to serum protein.

Cefazolin↗
PubMed1986

Analysis of 75 operated thoracolumbar fractures and fracture dislocations with and without neurological deficit.

Seventy-five surgically treated patients with thoracolumbar fractures and fracture dislocations, operated on between 1978 and 1982 at the Orthopedic Department of the University of Basel, were analyzed. The follow-up ranged from 18 months to 6 years. There were 45 men and 21 women, and 60% of the patients were not more than 30 years old. Additional injuries were common: 30% of the patients had craniocerebral injuries and 20% were polytraumatized. Ninety-six percent of all patients reached a hospital within 6 h, but only 23% initially presented at a center for spinal surgery. Sixteen patients had anterior surgery (fusion alone or with plating), and two of these had laminectomy as a second operation. Fifty-seven patients had posterior surgery, in 34 cases combined with a laminectomy. The Harrington instrumentation was used 45 times (29 distraction, 14 compression, and two combinations of distraction and compression rods). Luque rods with segmental sublaminar wiring was used seven times, the locking-hook distraction-rod system of Jacobs twice, and miscellaneous procedures five times. A total of 24 patients (greater than 30%) presenting neurological deficits improved postoperatively. None of the 18 patients with normal neurological findings deteriorated during the operation. Neurological improvement was seen more frequently after early than after delayed surgery, but the difference was not statistically significant. Laminectomy had no statistically significant effect on postoperative neurological status. Twenty-two patients required reoperation because of insufficient or failed instrumentation. Luque instrumentation had the highest rate of reoperations. Anterior surgery did not prove superior to posterior procedures. Hospitalization and immobilization time was significantly reduced with surgery for the neurologically normal or minimally damaged patients, but not for completely or incompletely paraplegic patients. Postoperative back pain occurred in 22 patients, of whom 14 had nonanatomic postoperative reductions. Complications directly due to the surgery were rare. It is our conclusion that the instrumentation used in this series was not good enough to be proposed for standardized use. These technically unsatisfactory results induced the development of the internal fixator system in the senior author's (E.M.) department.

Adolescent↗