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Biomedical subjects

M Simon

Publications and source records attributed to M Simon.

At least 109 records · Page 6Linked to original sources
PubMed2000

A sensitized genetic system for the analysis of murine B lymphocyte signal transduction pathways dependent on Bruton's tyrosine kinase.

Modifier screens have been powerful genetic tools to define signaling pathways in lower organisms. The identification of modifier loci in mice has begun to allow a similar dissection of mammalian signaling pathways. Transgenic mice (Btk(lo)) expressing 25% of endogenous levels of Bruton's tyrosine kinase (Btk) have B cell functional responses between those of wild-type and Btk(-/-) mice. We asked whether reduced dosage or complete deficiency of genes previously implicated as Btk regulators would modify the Btk(lo) phenotype. We used two independent assays of Btk-dependent B cell function. Proliferative response to B cell antigen receptor cross-linking in vitro was chosen as an example of a relatively simple, well-defined signaling system. In vivo response to type II T-independent antigens (TI-II) measures complex interactions among multiple cell types over time and may identify additional Btk pathways. All modifiers identified differentially affected these two assays, indicating that Btk mediates these processes via distinct mechanisms. Loss of Lyn, PTEN (phosphatase and tensin homolog), or SH2-containing inositol phosphatase suppressed the Btk(lo) phenotype in vitro but not in vivo, whereas CD19 and the p85alpha form of phosphoinositide 3-kinase behaved as Btk(lo) enhancers in vivo but not in vitro. Effects of Lyn, PTEN, or p85alpha haploinsufficiency were observed. Haploinsufficiency or complete deficiency of protein kinase C beta, Fyn, CD22, Galphaq, or Galpha11 had no detectable effect on the function of Btk(lo) B cells. A transgenic system creating a reduction in dosage of Btk can therefore be used to identify modifier loci that affect B cell responses and quantitatively rank their contribution to Btk-mediated processes.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2000

Evidence from mutational specificity studies that yeast DNA polymerases delta and epsilon replicate different DNA strands at an intracellular replication fork.

Although polymerases delta and epsilon are required for DNA replication in eukaryotic cells, whether each polymerase functions on a separate template strand remains an open question. To begin examining the relative intracellular roles of the two polymerases, we used a plasmid-borne yeast tRNA gene and yeast strains that are mutators due to the elimination of proofreading by DNA polymerases delta or epsilon. Inversion of the tRNA gene to change the sequence of the leading and lagging strand templates altered the specificities of both mutator polymerases, but in opposite directions. That is, the specificity of the polymerase delta mutator with the tRNA gene in one orientation bore similarities to the specificity of the polymerase epsilon mutator with the tRNA gene in the other orientation, and vice versa. We also obtained results consistent with gene orientation having a minor influence on mismatch correction of replication errors occurring in a wild-type strain. However, the data suggest that neither this effect nor differential replication fidelity was responsible for the mutational specificity changes observed in the proofreading-deficient mutants upon gene inversion. Collectively, the data argue that polymerases delta and epsilon each encounter a different template sequence upon inversion of the tRNA gene, and so replicate opposite strands at the plasmid DNA replication fork.

Alleles↗
PubMed2000

First Mass-resolved Measurement of High-Energy Cosmic-Ray Antiprotons.

We report new results for the cosmic-ray antiproton-to-proton ratio from 3 to 50 GeV at the top of the atmosphere. These results represent the first measurements, on an event-by-event basis, of mass-resolved antiprotons above 18 GeV. The results were obtained with the NMSU-WIZARD/CAPRICE98 balloon-borne magnet spectrometer equipped with a gas-RICH (Ring-Imaging Cerenkov) counter and a silicon-tungsten imaging calorimeter. The RICH detector was the first ever flown that is capable of identifying charge-one particles at energies above 5 GeV. The spectrometer was flown on 1998 May 28-29 from Fort Sumner, New Mexico. The measured p&d1;/p ratio is in agreement with a pure secondary interstellar production.

Journal Article↗
PubMed2000

[Pathogenesis of porphyria cutanea tarda].

Porphyria cutanea tarda (PCT) results basically from decreased activity of uroporphyrinogen decarboxylase (UROD) in the liver. PCT is not a homogeneous disease; it can be either inherited or acquired. Not only alterations at the UROD gen locus but also other genetic factors outside the locus take part in the inactivation of UROD, that support polygenic inheritance of PCT. In every case, acquired factors take also part in development of the overt form of PCT. Iron has a key-role in the oxidative damages.

Animals↗
PubMed2000

Epidermal growth factor signaling pathway influences retinoid metabolism by reduction of retinyl ester hydrolase activities in normal and malignant keratinocytes.

The effects of EGFR signaling on retinol metabolism were evaluated in the squamous cell carcinoma cell lines defective in LRAT. In a 24-h incubation, the presence of EGF resulted in a 20-25% increase in retinyl ester accumulation. Assessment of retinol esterification and retinyl ester utilization (hydrolysis), in cell cultures and in cell homogenates, revealed that the increase in retinyl ester mass was the result of a reduction in retinyl ester hydrolysis. When grown in the absence of EGF, the cultures used about 40% of their retinyl esters, compared to about 21% in cultures grown with EGF. This effect of EGF was blocked by an EGF receptor-neutralizing antibody, an EGF receptor tyrosine-kinase inhibitor (PD153035), and a specific inhibitor of MEK kinase influencing the mitogen-activated protein kinase (MAPK) cascade (PD98059). Both transcription and translation were required, suggesting that signaling from the EGF receptor through the MAPK cascade controls the expression of modulators or inhibitors of the retinyl ester hydrolase(s). Thus EGFR signaling can alter the intracellular concentration of retinol by suppressing the access to the retinyl ester pool. Similar EGF effects were seen in cultures of normal keratinocytes.

Carboxylic Ester Hydrolases↗
PubMed2000

[Cowpox and catpox infection. 2 Clinical case reports].

In patients with painful, possibly hemorrhagic vesicles or black crusts, especially on hands/fingers or face/neck with typical history (contact to cows or feral/cats) the possibility of a cowpox/catpox infection has to be considered. The clinical diagnosis can be confirmed with the electron microscopy; cytoplasmic inclusions may be detected histologically. Further useful diagnostic tools are the identification of the cowpox/catpox virus by PCR or in cell culture as well as serological tests to detect virus specific antibodies. We report the development of typical skin lesions of a cowpox/catpox infection in two female patients who had contact with cows or cats. Recent diagnostic and therapeutic approaches are also discussed.

Adult↗
PubMed2000

[Single coronary artery with a long left main trunk].

Coronary anomalies are rare and usually benign. The case of a symptomatic woman aged 53 years is presented. Here the single coronary artery with a long left main trunk was treated by bypass grafting.

Coronary Angiography↗
PubMed2000

Large plaque parapsoriasis: clinical and genotypic correlations.

Twelve patients with large plaque parapsoriasis (LPP) were investigated for the presence of predominant T-cell clones, analyzing the T-cell receptor (TCR) gamma-chain gene. The diagnostic and prognostic significance of TCR gene rearrangement status was assessed by a correlation with the long-term clinical follow-up. Six out of 12 patients showed a clonal T-cell population. Clinically, among the patients with clonal disease one developed clearcut mycosis fungoides (MF) after a follow-up of 8 years, in the other 5 patients no such diagnosis could be made after follow-up of 2-21 years (median: 9 years). In patients with polyclonal infiltrates the lesions remained virtually unchanged. These findings indicate that in LPP TCR gene rearrangement status has no prognostic significance and does not allow distinction of LPP and early MF. Both conditions show a clonal T-cell infiltrate with similar frequency, are very similar in clinical and histologic presentation and according to recent studies share the same low risk to develop overt MF. Therefore both terms refer to the identical clinical situation. This should be designated as early MF and efforts should concentrate on identifying those patients that are at risk to develop aggressive disease.

Adult↗
PubMed2000

Myofibroblast phenotype and apoptosis in keloid and palmar fibroblasts in vitro.

Keloid formation is a wound healing response, which fails to resolve and leads to formation of a raised collagen mass extending beyond the original wound margins. Keloids are typically excluded from palms and soles. Therefore we compared keloid and palmar fibroblasts in vitro using fibroblasts from nonaffected individuals as controls. Collagen I, alpha-smooth muscle actin and thrombospondin-1 were found at higher levels in keloid than in palmar fibroblasts. These differences were ameliorated by addition of TGFbeta1. The potential for resolution of the wound healing response was estimated analyzing apoptosis during serum starvation. Annexin V and TUNEL assays showed that palmar fibroblasts underwent faster apoptosis, than did the keloid fibroblasts, and started detaching. Addition of TGFbeta1 counteracted this effect. The weak expression of the myofibroblast phenotype and the advanced apoptosis of palmar fibroblasts suggest mechanisms for the exclusion of keloids from palmar sites.

Apoptosis↗
PubMed2000

Dedifferentiation of intrinsic response properties of motoneurons in organotypic cultures of the spinal cord of the adult turtle.

Explant cultures from the spinal cord of adult turtles were established and used to study the sensitivity of the intrinsic response properties of motoneurons to the changes in connectivity and milieu imposed by isolation in culture. Transverse sections 700 microm thick were explanted on cover slips and maintained in roller-tube cultures in medium containing serum and the growth factors brain-derived neurotrophin factor (BDNF), neurotrophin-3 (NT3), glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF). The gross morphology of acute sections was maintained after 4 weeks in culture. Cell bodies of motoneurons remained stainable in fixed cultures with an antibody against choline acetyltransferase (ChAT) throughout the culture period. During culture, motoneurons maintained stable resting membrane potentials and were contacted by functional synapses. The ability to generate action potentials was also preserved as was delayed inward rectification and generation of calcium spikes in the presence of tetra-ethyl ammonium (TEA). In response to depolarization, however, motoneurons presented strong outward rectification, and only 41% of the cells recorded from maintained the ability to fire repetitively. By the second week in culture, a fraction of motoneurons displayed fast and slow transient outward rectification and low-threshold calcium spikes, features not seen in turtle motoneurons in acute slices. On the other hand, properties mediated by L-type Ca2+ channels disappeared during the first few days in culture. Our observations show that the phenotypical intrinsic response properties of mature spinal motoneurons are modified in explant cultures. The properties acquired resemble the properties in juvenile motoneurons in several species of terrestrial vertebrates.

Action Potentials↗
PubMed2000

Differential effects of NT-3 on reinnervation of the fast extensor digitorum longus (EDL) and the slow soleus muscle of rat.

Previous studies of gastrocnemius muscle reinnervation showed specific normalization of the proportion and diameter of fast type 2b muscle fibres following NT-3 delivery to the proximal stump of the cut sciatic nerve. Here, we investigate if normalization was related to greater improvement of muscle reinnervation of fast (extensor digitorum longus; EDL) than slow (soleus) motor units. NT-3-impregnated (NT-3 group) or plain fibronectin (FN group) mats were inserted into a sciatic nerve gap. Neuromuscular junctions (NMJs) labelled with TRITC-alpha-bungarotoxin were colabelled with calcitonin gene-related peptide (CGRP) or 4E2 antisera and imaged using confocal microscopy. CGRP and 4E2 were used as markers for newly reinnervated and structurally mature NMJs, respectively. At 40 days postsurgery, denervated NMJs in EDL and soleus muscles of both groups presented a 50% decrease of surface area due to decreased width. At day 80 in EDL, more NMJs were reinnervated by CGRP-immunoreactive terminals in the NT-3 (7.1%) than in the FN group (4.2%); there was no difference between groups for soleus. At 120 days, 4E2-immunoreactive NMJs were more numerous in EDL of the NT-3 (40.0%) than in the FN group (7.3%), unlike in soleus (NT-3, 1. 6%; FN, 1.8%), and presented a partial size recovery. These results indicate that NT-3 preferentially improves reinnervation of fast muscles over slow muscle, although the mechanism of this improvement is still unclear.

Animals↗
PubMed2000

Efficacy of a new neuroprotective agent, gacyclidine, in a model of rat spinal cord injury.

Prevention of the immediate excitotoxic phase occurring in response to spinal cord injury (SCI) is a major issue to reduce the neuronal damage responsible for any ensuing motor deficits. The present study evaluated the neuroprotective efficacy of three noncompetitive NMDA receptor antagonists: Gacyclidine (GK-11), a new compound, Dizocilpine (MK-801), and Cerestat (CNS-1102) in a rat spinal cord contusion model. To mimic human SCI, a standardized model of rat spinal cord closed contusion in which animals spontaneously and progressively recover from the induced paraplegia was employed. Such model, characterized by a slow recovery of hindlimb locomotor function enables easy quantification of the neuroprotection at both the behavioral and cellular level. The animals were treated intravenously with the respective drugs 10 min after the spinal contusion. The dose range study suggested that 1 mg/kg of Gacyclidine was the most effective dose to promote functional recovery in reducing by half the time needed to reach full locomotor recovery. Racemate and enantiomers of Gacyclidine showed similar neuroprotective effects, but treatment with the enantiomers were not as efficacious in promoting full functional recovery. Similarly, a prolonged treatment with the racemate was not as efficious as a single dose, suggesting that a prolonged blockade of the amino-excitatory neurotransmission may be deleterious. Finally, Dizocilpine and Cerestat treatments induced only a partial and delayed neuroprotective effect compared to Gacyclidine. Neuroprotection characterized by a reduction of the cystic cavity and of the astrogliosis was observed with all treatments. As Gacyclidine is already in clinical trials, the present findings suggest the premise that it is a promising agent for limiting the initial neuronal damage induced by CNS trauma leading to better functional recovery.

Animals↗
PubMed2000

Reconstruction of aplasia cutis congenita of the trunk in a newborn infant using acellular allogenic dermal graft and cultured epithelial autografts.

Aplasia cutis congenita, a congenital condition characterized by the absence of all skin layers, occurs mostly on the scalp, but may also involve the trunk and extremities. Conservative treatment using silver sulfadiazine with daily dressing change has been recommended to avoid donor site morbidity and operative risks to the neonate who may have other congenital defects. Others have proposed early surgical intervention to prevent problems associated with delayed wound healing. In this case of a newborn, the authors used an alternative therapy to avoid delayed wound healing and multiple surgical interventions. During one operative procedure, a 130-cm2 lesion on the trunk was covered with allogeneic dermis and cultured epithelial autografts (CEAs). After 2.5 weeks and with three additional applications of CEAs at bedside, 90% of the wound had healed. At 27 months, the grafted area was smooth, and pliable with normal skin texture.

Abdomen↗
PubMed2000

Telomerase activity and expression of the telomerase catalytic subunit, hTERT, in meningioma progression.

OBJECT: In recent reports, 6 to 19% of meningiomas have been classified as atypical or anaplastic/malignant. Some atypical and anaplastic meningiomas appear to arise from benign tumors by progression. Telomerase activation has recently been associated with malignant progression of human tumors. The authors have investigated a series of benign, atypical, and anaplastic/malignant meningiomas for telomerase activity and expression of the telomerase catalytic subunit human telomerase reverse transcriptase (hTERT). METHODS: A quantitative telomeric repeat amplification protocol was used to detect telomerase enzyme activity in seven (21%) of 34 benign, but in nine (75%) of 12 atypical and in seven (100%) of seven anaplastic/malignant meningiomas. Very high levels of telomerase activity were observed only in highly aggressive tumors. Messenger (m)RNA expression of the catalytic subunit hTERT was found in 11 (33%) of 33 benign, 12 (92%) of 13 atypical, and all seven anaplastic/malignant tumors. All telomerase-positive lesions were also positive for hTERT mRNA, whereas no telomerase activity was detected in six (21%) of 29 hTERT-positive tumors. This indicates that upregulation of hTERT is the rate-limiting step for telomerase activation in the majority of meningiomas. Expression of telomerase and hTERT was seen in all four tumors with gross brain invasion. All recurrent tumors or meningiomas recurring during follow up expressed hTERT. CONCLUSIONS: The results are consistent with a role for telomerase activation during the development of malignancy in meningiomas. Hence, expression of telomerase activity and hTERT might prove to be potentially useful markers for the evaluation of these tumors.

Adult↗
PubMed2000

Quality control of test systems waived by the Clinical Laboratory Improvement Amendments of 1988. Perceptions and practices.

CONTEXT: Recent advances in laboratory testing technology have resulted in a rapidly increasing number of test systems targeted for physician office, point-of-care, and home health care settings. With enhanced error detection mechanisms and unitized reagents, these new systems simplify the testing process and the assessment of analytical test performance. Many also meet the criteria set by the Clinical Laboratory Improvement Amendments of 1988 (CLIA) to qualify as waived test systems, and laboratories using only waived tests are subject to very limited regulatory oversight. OBJECTIVE: To evaluate use patterns and perceptions about quality control requirements with respect to waived testing. DESIGN AND SETTING: Survey of a network of 431 hospital, independent, and physician office laboratories in the US Pacific Northwest. RESULTS: Responding laboratories (n = 221) were taking advantage of the availability of waived tests and using them to make definitive diagnoses. We found considerable differences between quality control practices and the laboratories' perceptions of quality control requirements. Most respondents were performing traditional quality control on waived tests, influenced by their interpretation of regulations, the intended use of the test, and the testing personnel employed. CONCLUSIONS: Technology optimized for alternate quality control can represent an improvement in ease of use while meeting expectations for accuracy and providing relief from regulatory burdens. However, laboratory personnel exhibit confusion in applying new quality control systems.

Attitude of Health Personnel↗
PubMed2000

[Good clinical practice in the dietetic management of cancer patients].

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCL CC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feed-back from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of Standards, Options and Recommendations for the dietetic consultation for cancer patient. METHODS: Data have been identified by literature search wing Medline and the expert groups personal reference lists. Once the guidelines were defined, the document was submitted for review to 74 independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the referral of cancer patients for dietary advice are: I) in oncology, there are 3 types of dietetic consultation: diagnostic, preventive and therapeutic; 2) the following cancer patients must have a dietetic consultation: i) those with, or at risk of malnutrition, ii) those without malnutrition but in need of counseling and iii) those at risk of treatment-related nutritional side effects; 3) a nutritional assessment is standard at the time of the first dietetic consultation. Patients must be given individualized and written advice; 4) the dietetic opinion and advice should be brought to the attention of medical staff to facilitate a multidisciplinary approach to cancer treatment; 5) patient's relatives should be involved in the dietetic management; 6) the efficacy of dietetic advice can be assessed by monitoring weight, gastrointestinal signs and patient satisfaction.

Adult↗