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Biomedical subjects

L Grimm

Publications and source records attributed to L Grimm.

At least 19 recordsLinked to original sources
PubMed2000

Nonviral glial cell-derived neurotrophic factor gene transfer enhances survival of cultured dopaminergic neurons and improves their function after transplantation in a rat model of Parkinson's disease.

Transplantation of dopaminergic fetal mesencephalic tissue into the striatum is currently being developed for treatment of patients with advanced Parkinson's disease. Ethical concerns regarding the use of human fetal tissue, and the limited availability as well as poor survival and differentiation of dopaminergic neurons after transplantation have reduced the extent and outcome of this approach so far. With the purpose of finding means to increase the yield of dopaminergic neurons in transplants, and to reduce the amount of fetal tissue needed for each transplanted patient, we transfected rat fetal ventral mesencephalic (VM) tissue grown as organotypic free-floating roller tube (FFRT) cultures with a vector encoding human glial cell-derived neurotrophic factor (hGDNF). For transfer of an episomal expression vector (pRep7-GDNF8) a nonviral, nonliposomal cationic transfection technique was applied and optimized. Recombinant hGDNF expression resulted in a higher number of TH-positive neurons in the cultures as measured 6 days after transfection. Ventral mesencephalic cultures expressing hGDNF were then grafted into the striatum of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. Grafting of genetically modified VM cultures resulted in earlier functional recovery compared with grafting nontransfected cultures. We conclude that organotypic free-floating roller tube cultures can be successfully transfected to produce hGDNF with effects on TH-expressing neurons in vitro and functional effects after grafting in a rat Parkinson's disease model.

Animals↗
PubMed1998

Analysis of the human GDNF gene reveals an inducible promoter, three exons, a triplet repeat within the 3'-UTR and alternative splice products.

Glial cell line-derived neurotrophic factor (GDNF), a distant member of the TGF-beta superfamily, is a survival factor for various neurons, making it a potential therapeutic agent for neurodegenerative disorders. Here we present the genomic structure and characterization of the promoter of the human GDNF (hGDNF) gene. It contains three exons coding for a cDNA of 4.6 kb including large 5'- and 3'-untranslated regions (UTRs). The 3'-UTR contains a polymorphic AGG repeat that appears not to be expanded in patients suffering from different neurodegenerative disorders. RT-PCR results in at least three different hGDNF transcripts including one that lacks exon 2. Transient expression experiments reveal that exon 2 is essential for proper cellular processing to yield a secreted form of hGDNF, whereas expression of exon 3 alone is sufficient to code for a mature form of hGDNF retained within the cell. Our data show that the hGDNF gene is driven by a TATA-containing promoter preceding exon 1. A second promoter element has been mapped to a region 5' of exon 2. Both promoters are in close proximity to CpG islands covering exons 1 and 2. Using luciferase as a reporter gene, the TATA-containing hGDNF promoter facilitates a 20- to 40-fold increase in transcription when compared with a corresponding promoterless construct, whereas the second promoter confers only weak activity. Furthermore, fibroblast growth factor 2, tetradecanoyl 12-phorbol acetate, an inflammatory agent, and cAMP increase promoter activity, suggesting that GDNF transcriptional regulation is a target of exogenous signals.

Alternative Splicing↗
PubMed1997

The effect of knee immobilization on degree of hip flexion: a clinical correlation with posterior wall acetabular fractures.

The purpose of this investigation was to determine whether maintaining the knee in extension substantially limits hip flexion. The dominant lower extremity in 22 male subjects was goniometrically evaluated to determine hip flexion both when the knee was allowed to flex and when the knee was held in extension. Pelvic rotation values were subtracted from thigh rotation values to show true flexion of the femur in relation to the pelvis. Hip flexion averaged 49.25 degrees +/- 9.08 degrees in the straight-leg raise test and 94.14 degrees +/- 4.94 degrees in the flexed-knee raise test. This study shows that using a knee immobilizer in the postoperative treatment of posterior wall acetabular fractures should serve to protect the fracture site while still affording early ambulation.

Acetabulum↗
PubMed1996

Genes that regulate apoptosis in the mouse thymus.

Elimination of self-reactive T lymphocytes occurs during T-cell development in the thymus by a process known as negative selection. The mechanism that drives negative selection is apoptosis. To identify genes that regulate apoptosis in the mouse thymus, a library of negatively selected T cells was constructed and, by subtractive screening, several differentially regulated genes were isolated. Two transcripts that are repressed during cell death were identified, in addition to two induced transcripts. Further experiments demonstrated that cell death in thymocytes can occur via several induction pathways and each pathway appears to be regulated by a unique cascade of genes.

Animals↗
PubMed1996

Long-range map of a 3.5-Mb region in Xp11.23-22 with a sequence-ready map from a 1.1-Mb gene-rich interval.

Most of the yeast artificial chromosomes (YACs) isolated from the Xp11.23-22 region have shown instability and chimerism and are not a reliable resource for determining physical distances. We therefore constructed a long-range pulsed-field gel electrophoresis map that encompasses approximately 3.5 Mb of genomic DNA between the loci TIMP and DXS146 including a CpG-rich region around the WASP and TFE-3 gene loci. A combined YAC-cosmid contig was constructed along the genomic map and was used for fine-mapping of 15 polymorphic microsatellites and 30 expressed sequence tags (ESTs) or sequence transcribed sites (STSs), revealing the following order: tel-(SYN-TIMP)-(DXS426-ELK1)-ZNF(CA) n-L1-DXS1367-ZNF81-ZNF21-DXS6616- (HB3-OATL1pseudogenes-DXS6950)-DXS6949-DXS694 1-DXS7464E(MG61)-GW1E(EBP)- DXS7927E(MG81)-RBM- DXS722-DXS7467E(MG21)-DXS1011E-WASP-DXS6940++ +-DXS7466E(MG44)-GF1- DXS226-DXS1126-DXS1240-HB1- DXS7469E-(DXS6665-DXS1470)-TFE3-DXS7468E-+ ++SYP-DXS1208-HB2E-DXS573-DXS1331- DXS6666-DXS1039-DXS 1426-DXS1416-DXS7647-DXS8222-DXS6850-DXS255++ +-CIC-5-DXS146-cen. A sequence-ready map was constructed for an 1100-kb gene-rich interval flanked by the markers HB3 and DXS1039, from which six novel ESTs/STSs were isolated, thus increasing the number of markers used in this interval to thirty. This precise ordering is a prerequisite for the construction of a transcription map of this region that contains numerous disease loci, including those for several forms of retinal degeneration and mental retardation. In addition, the map provides the base to delineate the corresponding syntenic region in the mouse, where the mutants scurfy and tattered are localized.

Amino Acid Sequence↗
PubMed1994

Characteristics of antibiotic-resistant Escherichia coli O157:H7 in Washington State, 1984-1991.

The resistance of Escherichia coli O157:H7 to amoxicillin/clavulanic acid, ampicillin, ceftazidime, ceftriaxone, cefuroxime, cephalothin, chloramphenicol, ciprofloxacin, gentamicin, streptomycin, sulfisoxazole, tetracycline, ticarcillin, tobramycin, and trimethoprim-sulfamethoxazole was examined, and resistant strains were characterized. All 56 isolates collected between 1984 and 1987 were susceptible to all antibiotics tested; 13 (7.4%) of 176 strains isolated between 1989 and 1991 were resistant to streptomycin, sulfisoxazole, and tetracycline. lambda-restriction fragment length polymorphism analysis suggested that the 13 resistant strains belonged to nine different clones. The emerging resistance of E. coli O157:H7 to antibiotics could portend an increased prevalence of this pathogen in food animals that receive antibiotics. Antimicrobial resistance of E. coli O157:H7 could be useful as a rapid epidemiologic marker and as a way to select this pathogen from suspected vehicles of transmission, but this resistance could also complicate therapeutic trials with sulfa-containing antibiotics.

Bacterial Toxins↗
PubMed1989

Assessment of thrombogenic potential of liposomes.

The effects of liposomes with positive, neutral and negative surface charges on platelets and the plasmatic coagulation system were investigated in several in vitro and in vivo models. Negatively charged liposomes stimulated the plasmatic contact activating system as demonstrated by significant acceleration of whole blood clotting time measured in containers with nonwettable (siliconized) surface. The same liposomes induced reversible aggregates of human platelets in vitro and circulating reversible platelet aggregates after intravenous infusion in guinea pigs. Liposomes with positive and neutral surface charges had no effect on plasmatic coagulation and platelets. The biological mechanisms and the toxicological relevance of these findings are discussed.

Animals↗
PubMed1985

Thrombogenic effects of xenobiotics.

The mechanisms by which xenobiotics may cause or promote thrombosis include vascular damage, induction of a hypercoagulable state and disturbances of blood flow. This paper discusses the methods available to detect various types of thrombogenic substances. Pathomorphological techniques are best suited to demonstrate thrombosis caused by localized vascular damage or generalized endothelial lesions. For the assessment of disseminated microcirculatory thrombosis, the consumption of platelets and clotting factors and the appearance of specific platelet proteins and fibrinogen and fibrin split products can be determined in the blood. Hypercoagulability which is defined as a perturbation of the hemostatic equilibrium resulting in a shift in the direction of thrombosis, is of particular importance in toxicology. Many in vitro, ex vivo and in vivo methods have been proposed to detect and to measure the ability of xenobiotics to induce a prethrombotic state. Their usefulness is demonstrated with several examples.

Adrenocorticotropic Hormone↗
PubMed1984

Detection of free endotoxin in cerebrospinal fluid by the Limulus lysate test.

We used a rabbit model of Escherichia coli meningitis to study the basis for positive Limulus lysate tests in infected cerebrospinal fluid. The results indicated that positive Limulus tests are due to endotoxins in cerebrospinal fluid and not to leukocyte proteases or other possible activators of the Limulus clotting system. The results also suggest that bacteria-free endotoxin may be present in localized gram-negative bacterial infections.

Animals↗
PubMed1982

Pharmacokinetics and bacteriological efficacy of cefoperazone, ceftriaxone, and moxalactam in experimental Streptococcus pneumoniae and Haemophilus influenzae meningitis.

The pharmacokinetics and bacteriological efficacy of cefoperazone, cefuroxime, ceftriaxone, and moxalactam were evaluated in the experimental rabbit meningitis model of Haemophilus influenzae type b or Streptococcus pneumoniae infection. The cerebrospinal fluid penetration of these beta-lactam antibiotics was from 3 to 14% and was greater in Haemophilus-infected that in pneumococcus-infected animals. With the exception of moxalactam, the antibacterial activity in cerebrospinal fluid and change in concentration of bacteria during therapy with the test drugs were comparable to those of penicillin G in pneumococcal infection. In animals infected with H. influenzae, cefoperazone, moxalactam, and ceftriaxone were as effective as chloramphenicol in reducing the bacterial counts in cerebrospinal fluid. Moxalactam and ceftriaxone produced the largest cerebrospinal fluid bactericidal titers against this beta-lactamase-producing strain of Haemophilus. On the basis of these data, it was concluded that ceftriaxone and cefoperazone were effective against both pathogens in this meningitis model, whereas moxalactam was effective against only Haemophilus, and cefuroxime was effective against only S. pneumoniae.

Animals↗
PubMed1980

[The galactose breath test. Modification of the method and comparison with galactose elimination capacity and plasma disappearance of bromsulphatein (author's transl)].

The paper describes a modification of the galactose breath test (GBT) for assessing liver function. Following iv injection of 0.5 g galactose per kg body weight, together with 2 mu Ci generally 14C-labelled galactose, 14CO2 is collected in regular intervals during one hour. Since 14C-activity in breath exhibits a linear rise during 70--100 minutes, the curve obtained permits calculation of an initial slope, as well as the "standardized specific activity" after 45 min GBT was performed in 8 liver normals, 8 alcoholic cirrhotics, 4 patients with chronic active hepatitis (CAH) and 6 with primary biliary cirrhosis (PBC). The results were compared with the simultaneously measured galactose elimination capacity (GEC) and the initial plasma disappearance (ki) of bromsulphthalein (BSP). In the liver normals, the values for initial slope and standardized specific activity were 1.08 +/- S.D. 0.3 and 0.42 +/- S.D. 0.1, respectively. In comparison, the values obtained in all patients groups were markedly reduced. CAH patients exhibited the most severe decrease; the reduction was smallest in PBC patients. The GBT discriminated well between liver normals and patients with liver disease (p less than 0.001, t-test). The results of the GBT correlated linearly with GEC (r = 0.86 and 0.87, respectively) and with BSP-ki (r = 0.9 and 0.92, respectively). These results suggest that the GBT may be regarded as a quantitative measure of a cystosolic hepatic function.

Aged↗
PubMed1979

Kallikrein localization in rodent salivary glands and kidney with the immunoglobulin-enzyme bridge technique.

Kallikrein has been localized in rodent kidney and salivary glands by means of an immunoglobulin-enzyme bridge technique. In sections of kidney, anti-kallikrein antibodies bound to the apical region of certain distal tubule segments in the cortex, to reabsorption droplets of proximal convoluted tubules, and to certain duct segments in the papilla. In salivary glands of both male and female rats and mice, and apical rim of most striated duct cells of submandibular, parotid and sublingual glands and granular tubules of submandibular glands exhibited immunoreactivity. Granular intercalated duct cells in female submandibular glands also displayed immunostaining for kallikrein. Phenylephrine administration resulted in loss of immunoreactive granules from the granular convoluted tubule cells of male mouse submandibular gland. This response was paralleled by a biochemically demonstrable decrease in kallikrein-like tosylarginine methyl ester (TAME) esterase activity.

Animals↗