Search PubMed⌕ Search

Biomedical subjects

M Simon

Publications and source records attributed to M Simon.

At least 91 records · Page 5Linked to original sources
PubMed1999

The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues.

Antifilaggrin autoantibodies (AFA) are a population of IgG autoantibodies associated to rheumatoid arthritis (RA), which includes the so-called "antikeratin" Abs and antiperinuclear factor. AFA are the most specific serological markers of RA. We previously showed that they recognize human epidermal filaggrin and other profilaggrin-related proteins of various epithelial tissues. Here, we report further characterization of the protein Ags and epitopes targeted by AFA. All the Ags that exhibit numerous neutral/ acidic isoelectric variants were immunochemically demonstrated to be deiminated proteins. In vitro deimination of a recombinant human filaggrin by a peptidylarginine deiminase generated AFA epitopes on the protein. Moreover, two of three filaggrin-derived synthetic peptides with a citrulline in the central position were specifically and widely recognized by AFA affinity-purified from a series of RA sera. These results indicate that citrulline residues are constitutive of the AFA epitopes, but only in the context of specific amino acid sequences of filaggrin. In competition experiments, the two peptides abolished the AFA reactivity of RA sera, showing that they present major AFA epitopes. These data should help in the identification of a putative deiminated AFA-inducing or cross-reactive articular autoantigen and provide new insights into the pathogenesis of RA. They could also open the way toward specific immunosuppressive and/or preventive therapy of RA.

Amino Acid Sequence↗
PubMed1999

Cloning and characterization of retinol dehydrogenase transcripts expressed in human epidermal keratinocytes.

The normal growth and differentiation of the epidermis require an adequate supply of vitamin A. The active form of vitamin A for normal epidermal homeostasis is retinoic acid (RA). Retinoic acid controls the expression of retinoid-responsive genes via interactions of the retinoic acid/nuclear receptor complexes at specific DNA sequences in their control regions. The message conveyed by RA is likely modulated by the concentration of the ligand available for binding to the receptors. Following the uptake of plasma retinol, epidermal keratinocytes synthesize retinoic acid via two sequential reactions with retinaldehyde as an intermediate. Several retinol dehydrogenase (RDH) enzymes, members of the short-chain dehydrogenase/reductase (SDR) gene superfamily, catalyze the first and rate-limiting step that generates retinaldehyde from retinol bound to cellular retinol-binding protein (holo-CRBP). However, little is known about these enzymes and their genes in the epidermal cells. Our work describes the first member of the RDH family found in epidermis. We show that this gene is expressed predominantly in the differentiating spinous layers and that it is under positive, feed-forward regulation by retinoic acid. It encodes a protein that, using NAD+ as a preferred cofactor, utilizes free and CRBP-bound all-trans-retinol and steroids as substrates.

Alcohol Oxidoreductases↗
PubMed1999

Glycine- and GABA-immunoreactive nerve terminals apposed to alpha-motoneurons during postnatal development in kittens: a quantitative study using the disector.

The distribution of gamma-aminobutyric acid (GABA) and/or glycine-immunoreactive (IR) terminal-like structures apposed to somatic and dendritic membrane of lumbar alpha-motoneurons in column 2 was examined in 1- and 3-week-old kittens and in the adult cat. This quantitative study was carried out using a postembedding technique on semithin sections and a stereological method, the disector. Analysis of immunoreactive terminals showed that the percentages of GABA-IR and glycine-IR terminals (these populations include terminals containing both GABA and glycine) apposed to somatic and proximal dendritic compartments of alpha-motoneurons are almost the same in kittens, while in the adult glycinergic innervation becomes predominant. This change results from: (1) the decrease in numbers of GABA-IR terminals contacting the somatic compartment between 3 weeks and adult stage, while the numbers of glycine-IR terminals show no significant changes after birth and the numbers of terminals containing both neurotransmitters (GABA-IR+glycine-IR) present transient changes and (2) the postnatal increase in the dendritic compartment, in numbers of GABA-IR, glycine-IR and GABA-IR+glycine-IR terminals; the increase being larger for glycine-IR terminals. Furthermore, using a postembedding immunogold technique, observations by electron microscopy showed that GABA-IR P boutons apposed to M boutons can already be identified at 1 week after birth.

Age Factors↗
PubMed1999

Functional evidence for a role of combined CDKN2A (p16-p14(ARF))/CDKN2B (p15) gene inactivation in malignant gliomas.

Homozygous chromosome 9p deletions in gliomas commonly include the CDKN2A and CDKN2B genes, which code for the structurally highly homologous cdk inhibitors/tumor suppressors p16 and p15, respectively. Alternative splicing of the CDKN2A gene results in the expression of p14(ARF). Interestingly, not only p16 and p15, but also the structurally unrelated p14(ARF) appear to function as negative cell cycle regulators. Concerted inactivation of p16, p15 and p14(ARF) could be demonstrated in seven of nine glioblastoma cell lines. Strong suppression of tumorigenicity after transfection with p16 and p15 alone or in combination was seen in cell lines containing neither endogenous p16 nor p15 but functional pRB. Significantly weaker growth suppression was observed in tumors either retaining expression of both p16 and p15 or p15 only. p14(ARF) proved to be a potent tumor suppressor in the presence of wild-type p53, while mutant p53 substantially reduced growth inhibition by p14(ARF). No differences between p16 and p15 effects could be observed, suggesting a largely overlapping function of p16 and p15. To facilitate further research into p16/p15 effects, three cell lines with conditional, tetracycline-controlled p16 expression were established. Reversible growth suppression mediated by p16 was observed in these models. Combined inactivation of CDKN2A and CDKN2B, i.e., loss of both p16 and p15 as well as p14(ARF), results in disruption of two major growth control pathways involving pRB and p53 in malignant gliomas. Therefore, homozygous co-deletions of CDKN2A and CDKN2B rather than mutations targeting individual transcripts are frequently selected for in these tumors.

Base Sequence↗
PubMed1999

Feasibility of tandem autologous stem-cell transplantation (ASCT) in induction failure or very unfavorable (UF) relapse from Hodgkin's disease (HD). SFGM/GELA Study Group.

BACKGROUND: Despite high-dose therapy and ASCT some patients with aggressive HD fail to achieve long-term survival. PATIENTS AND METHODS: Forty-three patients with induction failure (n = 19) or very unfavorable (UF) relapse (n = 24) from HD were included in a multicentric study of tandem ASCT. They planned to receive two course of IVA75 with GCSF and blood stem cell collection. ASCT1 was conditioned with CBV + mitoxantrone (30 mg/m2) and ASCT2 (cytarabine 6 g/m2 melphalan 140 mg/m2 and total body irradiation at 12 Gy or busulfan 16 (n = 4) than 12 mg/kg). After salvage therapy, response > 50% was observed in 63% of the patients (six patients were included for refractory relapse). Four patients had no ASCT for disease progression; seven patients had only ASCT1 (disease progression, n = 3) and thirty-two patients (74%) received the two ASCT. RESULTS: Hematologic recovery was normal after ASCT1 but delayed platelet recovery was observed after ASCT2 with busulfan in the conditioning regimen. Two VOD with one fatal occurred with busulfan at 16 mg/kg and one hemorrhagic cystic, no further grade 4 toxicity was observed with the reduced doses of busulfan (12 mg/kg). After ASCT2, 83% of these UF patients were in remission and 20% relapsed within the first year. On an intent-to-treat analysis, 22 of 43 patients are in continuous CR (including 8 patients with induction failure). For the whole population (n = 43) and for patients receiving the two ASCT (n = 32), the two-year survival from the date of progression were respectively at 65% and at 74%. CONCLUSION: Double ASCT is feasible in very UF relapse from HD and may lead to some prolonged remission.

Adult↗
PubMed1999

The VIM3-AraC regimen followed by autologous stem cell transplantation in refractory or relapsing aggressive non-Hodgkin's lymphoma. A prospective study of 71 consecutive cases.

We evaluated with an intent-to-treat analysis the response rate, the disease-free survival (DFS), and the overall survival after a multidrug salvage regimen (VIM3ARAC), followed by stem-cell transplantation (SCT) in case of response, in patients with aggressive non-Hodgkin's lymphoma (NHL) who progressed on or after the first-line therapy. Seventy-one patients (refractory: 15; relapse 'on therapy': 36; and relapse 'off therapy': 20) received two courses of VIM3ARAC (teniposide, ifosfamide, mitoxantrone, mitoguazone, high-dose methotrexate, high-dose cytarabine, prednisolone). SCT was performed only in patients with minimal disease after the second course. The response rate was 72%. It was not influenced by response to first-line therapy. Forty-eight patients (68%), including 32 complete responders, fulfilled response criteria for SCT. Thirty-six patients underwent SCT (allogeneic: 3; autologous: 33). The 4-year DFS rate of the 48 responding patients was 39%. The actuarial survival at 4 years was 34% for all patients. Relapse off therapy and a performance status <2 at relapse were the only two independent favorable prognostic factors for survival. In conclusion, VIM3AraC is associated with a high response rate in relapsing and refractory aggressive NHL. Up to half of the patients could receive SCT. This chemotherapy, followed by SCT could durably salvage 34% of these patients.

Adolescent↗
PubMed1999

Granulocyte-macrophage colony-stimulating factor (GM-CSF) to increase efficacy of intensive sequential chemotherapy with etoposide, mitoxantrone and cytarabine (EMA) in previously treated acute myeloid leukemia: a multicenter randomized placebo-controlled trial (EMA91 Trial).

The EMA86 study showed efficacy of intensive sequential chemotherapy with mitoxantrone, 12 mg/m2 day on days 1-3, etoposide, 200 mg/m2/day as a continuous infusion on days 8-10 and cytarabine (araC), 500 mg/m2/day as continuous infusion on days 1-3 and 8-10 (EMA regimen) in previously treated patients with AML. The goal of the EMA91 study was to determine whether administration of GM-CSF between the two sequences of EMA chemotherapy and during the second sequence could increase therapeutic efficacy by potentially increasing leukemic cell recruitment into the S phase of cell cycle before the second sequence. One hundred and ninety-two patients aged less than 65 years with previously treated AML received GM-CSF, 5 microg/kg/day or placebo from day 4 to day 8 of EMA chemotherapy. One hundred and twenty were refractory and 72 were in first relapse after a complete remission (CR) of more than 6 months duration. CR rates after one course of chemotherapy were 65% in the GM-CSF group (refractory: 51%; first relapse: 89%), not significantly different from the 59% CR rate (refractory: 46%; first relapse: 81%) in the placebo group. Median time to recovery of neutrophils was 38 and 37 days and median time to last platelet transfusion 32 and 32 days respectively in the GM-CSF and placebo groups. WHO grade > or = 3 non-hematologic toxicities were mainly sepsis (45% and 51%, respectively) and mucositis (34% and 31%) and did not differ between the two groups. Toxic death rate was 5% and 8%, respectively, in the GM-CSF and placebo groups. Patients achieving CR were scheduled to receive six courses of maintenance with reduced-dose EMA. Time to progression tended to be longer in the GM-CSF group (median 154 vs 115 days, progression-free rate at 18 months 33% vs 19%, P = 0.08), particularly in refractory patients (P = 0.06). However, at the current follow-up, this did not translate into a significantly longer disease-free survival and survival. Cell cycle studies showed increased recruitment of cells in the S phase between day 4 and day 8 in the GM-CSF group compared to placebo (P = 0.006). However, this did not significantly relate to prognosis in this cohort of patients. GM-CSF might marginally increase efficacy of sequential chemotherapy without increasing its toxicity in the absence of any detected relationship between this effect and observed leukemic cell recruitment into the cell cycle.

Acute Disease↗
PubMed1999

Quantitative systolic and diastolic transmyocardial velocity gradients assessed by M-mode colour Doppler tissue imaging as reliable indicators of regional left ventricular function after acute myocardial infarction.

AIMS: The aim of this study was to determine whether myocardial velocity gradients assessed by M-mode colour Doppler tissue imaging could be of clinical relevance and represent reliable indicators of regional left ventricular function after acute myocardial infarction. METHODS AND RESULTS: Among 64 consecutive patients with a first acute myocardial infarction, in 50 who had a marked asynergy in the parasternal short-axis view at the mid-papillary muscle level, myocardial velocities and velocity gradients were assessed in the anteroseptum and posterior wall by M-mode Doppler tissue imaging. Similar measurements were obtained in 11 matched healthy volunteers who served as a control group. In patients with anterior myocardial infarction, the peak myocardial velocity gradient in the anteroseptum was significantly lower when compared with controls (mean +/- [SD] 0.0 +/- 0.5 vs 1.1 +/- 0.7 s-1 during systole, P < 0.01; and 0.3 +/- 0.6 vs 2.0 +/- 0.5 s-1 during diastole, P < 0.01). Conversely, the peak systolic myocardial velocity gradient in the posterior wall was significantly higher than in controls (2.6 +/- 1.2 vs 1.8 +/- 1.2 s-1, P < 0.05). In patients with inferior myocardial infarction, the peak velocity gradient in the posterior wall was significantly lower when compared with healthy subjects (0.9 +/- 0.6 vs 1.8 +/- 1.2 s-1 during systole and 1.4 +/- 1.4 vs 4.9 +/- 1.2 s-1 during diastole, both P < 0.01). The peak systolic tissue velocity gradient in the anteroseptum was significantly higher than in controls (2.1 +/- 1.0 vs 1.1 +/- 0.7 s-1, P < 0.01). CONCLUSION: The present study indicates that myocardial velocity gradients assessed by M-mode Doppler tissue imaging are of clinical relevance for the characterization of ischaemic myocardial dysfunction after infarction and may provide quantitative assessment of segmental left ventricular function in this clinical setting.

Aged↗
PubMed1999

Expression of bone morphogenetic protein-7 mRNA in normal and ischemic adult rat kidney.

BMP-7, a member of the bone morphogenic protein subfamily (BMPs) of the transforming growth factor-beta superfamily of secreted growth factors, is abundantly expressed in the fetal kidney. The precise role of this protein in renal physiology or pathology is unknown. A cDNA that encodes rat BMP-7 was cloned and used as a probe to localize BMP-7 mRNA expression by in situ hybridization in the adult rat kidney. The highest expression of BMP-7 mRNA could be seen in tubules of the outer medulla. In glomeruli, a few cells, mainly located at the periphery of the glomerular tuft, showed specific and strong signals. Also, high BMP-7 mRNA expression could be localized to the adventitia of renal arteries, as well as to the epithelial cell layer of the renal pelvis and the ureter. Preliminary evidence suggests that BMP-7 enhances recovery when infused into rats with ischemia-induced acute renal failure. We examined BMP-7 mRNA expression in kidneys with acute renal failure induced by unilateral renal artery clamping. BMP-7 mRNA abundance as analyzed by solution hybridization was reduced in ischemic kidneys after 6 and 16 h of reperfusion compared with the contralateral kidney. In situ hybridization in ischemic kidneys showed a marked decrease of BMP-7 mRNA in the outer medulla and in glomeruli. Utilizing rat metanephric mesenchymal cells in culture, we also demonstrate that BMP-7 induces epithelial cell differentiation. Taken together, these data suggest that BMP-7 is important in both stimulating and maintaining a healthy differentiated epithelial cell phenotype.

Animals↗
PubMed1999

A low-cost, full-function picture archiving and communication system using standard PC hardware and the traditional 4-over-4 display format.

OBJECTIVE: With a 12-year background of our completely digital nuclear medicine picture archiving and communication system (PACS), we have recently implemented a novel PACS, OpenPACS, which can be used for interpretation and display of CT, MR imaging, sonography, nuclear medicine, and computed and digital radiography studies. OpenPACS uses low-cost standard PC hardware and software that is widely available and is readily serviced and maintained. The OpenPACS application program is available over the Internet. CT or MR imaging slices from one or multiple studies can be presented simultaneously or in cine mode on a wall-sized multimonitor display. The assembly, with a total resolution of 6400 x 4800 pixels, resembles a traditional array of eight standard X-ray viewboxes. A wireless mouse is used to vary attenuation and other display parameters. Multiple backup and redundancy are provided. Currently, six CT and six MR imaging scanners of different vendors are networked to OpenPACS, which is also networked to our nuclear medicine PACS. CONCLUSION: After only a brief introduction, radiologists rapidly become familiar with the system because it is based on the use of standard Windows icons and procedures and offers a display that resembles a standard X-ray film presentation.

Data Display↗
PubMed1999

[Cholesterol embolism: an often unknown disease; a report of two cases].

We report on a case of post-invasive acute renal insufficiency and a case of acute necrotizing pancreatitis, both histologically proven to have been caused by cholesterol embolisms. A survey of the literature with discussion of diagnostic and therapeutic options is given.

Acute Kidney Injury↗
PubMed1998

Assembled tau filaments differ from native paired helical filaments as determined by scanning transmission electron microscopy (STEM).

Paired helical filaments (PHF) are abnormal, approximately 20-25-nm wide periodically twisted filaments, which accumulate in Alzheimer's disease (AD) brain and other neurodegenerative disorders, including corticobasal degeneration (CBD). PHF are primarily composed of highly phosphorylated tau protein. However, both phosphorylated and non-phosphorylated forms of tau are able to assemble in vitro into filaments similar in the ultrastructural appearance to PHF. In the present study, filaments were assembled in vitro from unmodified recombinant human tau and the physical mass per unit length of filaments and the mass density were determined using scanning transmission electron microscopy (STEM). Two general types of filaments were observed. One type was composed of 11.4 nm-wide, 10-75 nm long, frequently twisted and PHF-like filaments, with a mass per unit length (44 kDa/nm) approximately one third of that observed in isolated AD filaments. The other were straight filaments, approximately 6.8-nm wide and 0.2-2 microm long, which often formed parallel clusters of two or more filaments. Triple clusters were 19. 2-nm wide and had a mass per unit length (70 kDa/nm) approximately two thirds of that seen in isolated AD filaments. Despite different morphology, both twisted and straight filaments had mass densities between 0.48-0.55 kDa/nm3. These values are significantly higher than those reported for PHF found either in AD (0.40 kDa/nm3) or CBD (0.33 kDa/nm3). These results suggest that the packing of tau differs in vivo from that observed in vitro and that specific tau isoform content, elongation of tau molecules by phosphorylation or other factors may be required to reproduce pathological assembly. Therefore mass density determinations appear to be an important criterion in comparing various filaments.

Alzheimer Disease↗
PubMed1998

Expression cloning of human corneodesmosin proves its identity with the product of the S gene and allows improved characterization of its processing during keratinocyte differentiation.

In human epidermis and other cornified squamous epithelia, corneodesmosin is located in the desmosomes of the upper living layers, and in related structures of the cornified layers, the corneodesmosomes. During maturation of the cornified layers, the protein undergoes a series of cleavages, thought to be a prerequisite of desquamation. Partial amino acid sequencing of corneodesmosin fragments suggested that it is related to the product of the S gene, previously identified in the human major histocompatibility complex. We report the expression cloning of corneodesmosin cDNA from a human epidermis library screened with monoclonal antibodies. Sequencing demonstrated that corneodesmosin is really the product of the S gene. However, analysis of 20 alleles of the gene revealed that its product is 27 amino acids longer than initially reported. Two additional polymorphic sites were described, and the position of the unique intron was ascertained. Corneodesmosin cDNA expression in COS-7 cells led to secretion of the protein. Precise epitope mapping allowed further characterization of the molecular forms of corneodesmosin present in the most superficial cornified layers, where fragments corresponding to the central region of the protein were detected. This indicated a cleavage of the N- and C-terminal domains of corneodesmosin before desquamation. These serine- and glycine-rich domains are proposed to mediate an adhesive function.

Amino Acid Sequence↗
PubMed1998

In vivo effects of a bacterial superantigen on macaque TCR repertoires.

A macaque model was employed to explore staphylococcal enterotoxin B (SEB) superantigen-driven T lymphocyte responses. The SEB-reactive Vbeta+ cell subpopulations demonstrated a striking tri-phase response in rhesus monkeys following an SEB challenge in vivo. The hyperacute down-regulation, seen as early as 2 h through 2 days after SEB injection, was characterized by a disappearance of the reactive Vbeta-restricted PBL subpopulations from the circulation and decreased expression of these cell subpopulations in lymphoid tissues. Following this, a dominant expansion of reactive Vbeta-expressing CD4+ cell subpopulations occurred in lymph nodes and spleens, whereas in the peripheral blood a preferential expansion of reactive Vbeta-expressing CD8+ cell subpopulations was seen. An exhaustion of this response was then seen, with a prolonged decrease in the number of the reactive Vbeta+ CD4+ lymphocyte subpopulations. Interestingly, monoclonal or oligoclonal dominance was seen in the reactive Vbeta+ cell subpopulations in the period of the transition from the polyclonal cellular expansion to the exhaustion of the response, suggesting that some Vbeta+ cell clones may be more resistant than others to superantigen-mediated depletion. These results indicate that in vivo SEB superantigen-mediated effect on lymphocyte subpopulations in macaques is complex, suggesting that profound dynamics in the TCR repertoires may in part account for the susceptibility of higher primates to SEB-induced diseases.

Animals↗