Biomedical subjects

S Martin

Publications and source records attributed to S Martin.

At least 199 records · Page 11Linked to original sources

PubMed2000

Mobilization of CD34+ haematopoietic stem cells is associated with a functional inactivation of the integrin very late antigen 4.

The beta1 integrin very late antigen 4 (VLA-4) plays a central role in mobilization and homing of CD34+ cells. In this study, we examined the activation state of VLA-4 on CD34+ cells from bone marrow (BM) and peripheral blood (PB) by flow cytometry using a vascular cell adhesion molecule I-immunoglobulin (VCAM-I/IgG) fusion protein as soluble ligand. In an intraindividual analysis, we found a significantly reduced affinity and avidity of the VLA-4 receptor on CD34+ cells from PB during granulocyte colony-stimulating factor (G-CSF)-enhanced marrow recovery in comparison with steady-state BM. Moreover, the amount of circulating CD34+ cells during marrow recovery was inversely related to the activation state but not to the expression level of VLA-4, suggesting that a modulation of the functional state of VLA-4 is involved in the mobilization of CD34+ cells. Moreover, VLA-4 function on CD34+ cells from BM was associated with the maturation state of CD34+ cells as high-affinity VLA-4 receptors were observed on the vast majority of more primitive CD34+ cells. In addition, we found that Mg2+ ions as well as co-incubation of CD34+ cells with endothelial cells resulted in an activation of the VLA-4 receptor. In conclusion, modulation of the functional state of VLA-4 appears to be of relevance for the mobilization and homing of CD34+ haematopoietic stem cells.

Antigens, CD34↗

PubMed2000

Cytomegalovirus immune globulin intravenous (human) administration modulates immune response to alloantigens in sensitized renal transplant candidates.

One of the important parameters for prolonged waiting time for potential renal transplant recipients is the presence of preformed antibodies to human leucocyte antigen (HLA) antigens, which is often caused by previous transplants, pregnancy or transfusions. In vivo administration of specific and unselected polyclonal intravenous immunoglobulin (IVIGs) preparations have been shown to inhibit anti-HLA alloantibodies in highly sensitized patients. We sought to determine whether Cytogam (Medimmune Inc., Gaithersburg, MD, USA), a hyperimmune anticytomegalovirus immunoglobulin would (1) effect either in vitro or in vivo alloreactivity, and (2) whether Cytogam therapy could reduce the titre of preformed anti-HLA antibodies in highly sensitized patients. Alloreactivity was assessed by mixed lymphocyte reaction (MLR) and cytotoxic T lymphocyte (CTL) assay. A complement dependent microlymphocytotoxicity assay was done to assess for panel reactive antibody (PRA) status and the presence of anti-idiotypic antibodies in the Cytogam preparation. The MLR was inhibited by Cytogam in vitro in a dose-dependent fashion ranging from 31-92%. Significant inhibition of the MLR responses was not observed in recipients who received Cytogam in vivo (50 mg/kg). This could be a result of adminstration of a low dose of IVIG. However, CTL activity against the alloantigens in all individuals assessed was significantly inhibited after in vivo administration of Cytogam. Three of five individuals experienced a decrease of 5-32% in the PRA status at 4 weeks post administration of Cytogam. Cytogam also blocked the anti-HLA antibody titres in a microlymphocytotoxicity assay, suggesting the presence of anti-idiotypic antibodies. Our study was based on a single prophylactic dose of Cytogam (50 mg/kg), however, higher dose administration could be feasible by removing more fluid at dialysis, but should be given intradialytically to avoid volume overload. Overall, our results suggest that Cytogam can modulate the in vivo and in vitro T cell responses against the alloantigens.

Adult↗

PubMed2000

Peptide immunization indicates that CD8+ T cells are the dominant effector cells in trinitrophenyl-specific contact hypersensitivity.

The identity of the effector T cell population involved in contact hypersensitivity is still questionable with evidence promoting both CD4+ or CD8+ T cells. Previous experimental studies have relied on the in vivo depletion of T cell subsets using antibody, or the use of knock-out mice with deficiencies in either CD4+ or CD8+ T cell-mediated immunity. To address the role of the class I- and class II-mediated pathways of T cell activation in contact hypersensitivity responses in mice with an intact immune system, we utilized various trinitrophenyl-derivatized peptides, which bind specifically with H-2Kb (major histocompatibility complex class I) or H-2I-Ab (major histocompatibility complex class II). The subcutaneous injection of major histocompatibility complex class II-specific, but not of class I-binding, hapten-derivatized peptides in incomplete Freund's adjuvant induced specific, albeit low, contact hypersensitivity responsiveness to trinitrochlorobenzene. When bone-marrow-derived dendritic cells, however, were pulsed with the same peptides and administered intradermally, the opposite result was observed, namely that the class I binding peptides induced contact hypersensitivity responses similar to that observed after epicutaneous trinitrochlorobenzene application. In contrast, dendritic cells pulsed with major histocompatibility complex class II binding peptides did not reproducibly sensitize for contact hypersensitivity responses. Surprisingly, both immunization protocols efficiently induced CD8+ effector T cells. These results support the notion that CD8+ T cells are the dominant effector population mediating contact hypersensitivity responsiveness and that the CD4+ T cell subset only contributes little if at all.

Animals↗

PubMed2000

Fibrodysplasia ossificans progressiva, a heritable disorder of severe heterotopic ossification, maps to human chromosome 4q27-31.

Fibrodysplasia ossificans progressiva (FOP) is a severely disabling, autosomal-dominant disorder of connective tissue and is characterized by postnatal progressive heterotopic ossification of muscle, tendon, ligament, and fascia and by congenital malformation of the great toes. To identify the chromosomal location of the FOP gene, we conducted a genomewide linkage analysis, using four affected families with a total of 14 informative meioses. Male-to-male transmission of the FOP phenotype excluded X-linked inheritance. Highly polymorphic microsatellite markers covering all human autosomes were amplified by use of PCR. The FOP phenotype is linked to markers located in the 4q27-31 region (LOD score 3.10 at recombination fraction 0). Crossover events localize the putative FOP gene within a 36-cM interval bordered proximally by D4S1625 and distally by D4S2417. This interval contains at least one gene involved in the bone morphogenetic protein-signaling pathway.

Chromosome Mapping↗

PubMed2000

Production of new thermoluminescent mini-dosimeters.

A method of producing CaSO4:Dy thermoluminescent mini-dosimeters was reported in 1986 by B W Wessels for determination of the in vivo absorbed dose in radioimmunotherapy, a field in which absorbed dose gradients are important. These dosimeters, which undergo dissolution when used in a liquid environment, showed a sensitivity loss of up to 30% after 4 days of immersion in our tests. Moreover, several studies have shown that biocompatibility problems can occur during in vivo studies in animals. This paper describes the production and testing of a new type of thermoluminescent mini-dosimeter obtained by microextrusion of a mixture of LiF:Mg,Cu,P polypropylene and plastic adjuvants. These dosimeters, in the form of long 400 microm diameter filaments, can be cut to the desired length. The production process allows an LiF:Mg,Cu,P load of up to 50%. Results obtained in external irradiation indicate that these new miniature LiF:Mg,Cu,P dosimeters have good sensitivity (about 1.6 times that of CaSO4:Dy mini-TLDs), homogeneous response within a production batch (mean +/-4%), response stability in water (0.7% of variation in sensitivity after 2 weeks of immersion) and stability in aqueous solutions at different pH. LiF:Mg,Cu,P mini-dosimeters appear to be highly promising for internal dosimetry, and evaluation is in progress in animals.

Calcium Sulfate↗

PubMed2000

Cystic fibrosis gene mutations and infertile men with primary testicular failure.

It has been proposed that the gene responsible for cystic fibrosis, called the cystic fibrosis transmembrane conductance regulator (CFTR) gene, may play an important role in the process of spermatogenesis. A group of azoospermic men with primary testicular failure underwent CFTR mutation analysis, including assessment of the intron 8 polythymidine tract (IVS8-T tract). An association was not found between CFTR mutations or the 5T variant of the IVS8-T tract and the primary testicular failure phenotype. This finding suggests that CFTR does not play a significant role in the aetiopathogenesis of primary spermatogenic dysfunction. Therefore, the abnormal testicular histological findings in some post-pubertal men with cystic fibrosis may be a result of nutritional deficiency or testicular obstruction rather than a primary defect in spermatogenesis. In addition, the decreased sperm count in oligozoospermic men with CFTR mutations may be secondary to partial reproductive tract obstruction and not abnormal spermatogenesis. Lastly, routine screening of men with primary testicular failure for CFTR gene mutations is not warranted.

Adult↗

PubMed2000

Delivery of enteral nutrition.

There is increasing evidence that enteral feeding is superior to parenteral nutrition with regard to maintaining gut structure and function. Selection of the enteral access route depends on the type and anticipated duration of nutrient delivery. At present, enteral feeding devices can be divided into two major categories: those entering the gastrointestinal tract through the oral or nasal cavity (oroenteric or nasoenteric tubes) and those entering through the abdominal wall including gastrostomy, duodenostomy, or jejunostomy tubes. This article provides a review of methods to insert and confirm gastric and intestinal feeding tube placement. Care of the patient with an enteric tube will be described.

Acute Disease↗

PubMed2000

Pharmacokinetics of orally administered omeprazole in children. International Pediatric Omeprazole Pharmacokinetic Group.

OBJECTIVES: The aim of this study was to examine the pharmacokinetics of orally administered omeprazole in children. METHODS: Plasma concentrations of omeprazole were measured at steady state over a 6-h period after administration of the drug. Patients were a subset of those in a multicenter study to determine the dose, safety, efficacy, and tolerability of omeprazole in the treatment of erosive reflux esophagitis in children. Children were 1-16 yr of age, with erosive esophagitis and pathological acid reflux on 24 h-intraesophageal pH study. The "healing dose" of omeprazole was that at which subsequent intraesophageal pH study normalized. Children remained on this dose for 3 months, and during this period the pharmacokinetics were measured. RESULTS: A total of 57 children were enrolled in the overall healing phase of the study. Pharmacokinetic study was optional for subjects and was performed in 25 of the 57 enrolled. The doses of omeprazole required were substantially higher doses per kilogram of body weight than in adults. Values of the pharmacokinetic parameters of omeprazole were generally within the ranges previously reported in adults. However, the plasma levels, area under the plasma concentration versus time curve (AUC), plasma half-life (t(1/2)), and maximal plasma concentration (Cmax), were lower in the younger age group, when the AUC and Cmax were normalized to a dose of 1 mg/kg. Furthermore, within the group as a whole, these values showed a gradation from lowest in the children 1-6 yr of age to higher in the older age groups. CONCLUSIONS: The pharmacokinetics of omeprazole in children showed a trend toward higher metabolic capacity with decreasing age, being highest at 1-6 yr of age. This may explain the need for higher doses of omeprazole on a per kilogram basis, not only in children overall compared with adults but, in many cases, particularly in younger children.

Administration, Oral↗

PubMed2000

COL2A1 exon 2 mutations: relevance to the Stickler and Wagner syndromes.

AIMS: To compare the clinical and molecular genetic features of two phenotypically distinct subgroups of families with type 1 Stickler syndrome. BACKGROUND: Stickler syndrome (hereditary arthro-ophthalmopathy, McKusick Nos 108300 and 184840) is a dominantly inherited disorder of collagen connective tissue, resulting in an abnormal vitreous, myopia, and a variable degree of orofacial abnormality, deafness, and arthropathy. Stickler syndrome is the commonest inherited cause of rhegmatogenous retinal detachment in childhood with a risk of giant retinal tear (GRT) which is commonly bilateral and a frequent cause of blindness. METHOD: Pedigrees were identified from the vitreoretinal service database and subclassified according to vitreoretinal phenotype. Ophthalmic, skeletal, auditory, and orofacial features were assessed. Linkage analysis was carried out with markers for the candidate genes COL2A1, COL11A1, and COL11A2. The COL2A1 gene was amplified as five overlapping PCR products. Direct sequencing of individual exons identified mutations. RESULTS: Eight families exhibiting the type 1 vitreous phenotype were studied. Seven were consistent for linkage to COL2A1, with lod scores ranging from 2.1 to 0.3. In most instances linkage to COL11A1 and COL11A2 could be excluded. One family was analysed without prior linkage analysis. Three of the families exhibited a predominantly ocular phenotype with minimal or absent systemic involvement and were found to have mutations in exon 2 of COL2A1. Five other pedigrees with an identical ocular phenotype plus orofacial, auditory, and articular involvement had mutations in others regions of the COL2A1 gene. None of the pedigrees exhibited the characteristic lenticular, retinal pigment epithelial, or choroidal changes seen in Wagner syndrome. CONCLUSIONS: These data confirm that type 1 Stickler syndrome is caused by mutations in the gene encoding type II collagen (COL2A1). In addition, data are submitted showing that mutations involving exon 2 of COL2A1 are characterised by a predominantly ocular variant of this disorder, consistent with the major form of type II procollagen in non-ocular tissues having exon 2 spliced out. Such patients are all at high risk of retinal detachment. This has important implications for counselling patients with regard to the development of systemic complications. It also emphasises the importance and reliability of the ophthalmic examination in the differential diagnosis of this predominantly ocular form of Stickler syndrome from Wagner's vitreoretinopathy.

Collagen↗

PubMed2000

Immunologic stimulation of mast cells leads to the reversible exposure of phosphatidylserine in the absence of apoptosis.

BACKGROUND: Loss of phospholipid asymmetry represents one of the hallmarks of apoptosis and results in the surface exposure of phosphatidylserine (PS) which can be indirectly monitored by the calcium-dependent binding of annexin V. METHODS AND RESULTS: Here, we provide evidence that the IgE-dependent stimulation of a rat mast cell line, as well as murine and human nontransformed mast cells, leads to the exposure of PS at the plasma membrane. The appearance of PS was quantitatively related to allergic mediator release. Pharmacological agents that prevent stimulus-secretion coupling blocked PS cell surface exposure and calcium ionophore-induced PS appearance, suggesting that it is a direct consequence of exocytosis rather than early signaling events initiated by the aggregation of the high-affinity IgE receptor (FcepsilonRI). The surface exposure of PS in mast cells was reversible even in the continuous presence of stimulus and was not associated with the appearance of apoptotic nuclei, demonstrating that it was independent of physiological cell death. CONCLUSIONS: In addition to providing a means of monitoring exocytosis at the single cell level, our results indicate that PS externalization in mast cells is not necessarily related to apoptosis but could be an important feature of the degranulation process.

Animals↗

PubMed2000

Clinical risk associated with appointment noncompliance in heart transplant recipients.

This study examined the prevalence of appointment noncompliance in 101 heart transplant recipients and how appointment noncompliance is related to patient profile and clinical risk. Appointment noncompliance was defined as patients not showing up at 1 or more planned clinic appointments (at a minimal frequency of every 3 months) during the previous year. Clinical variables were collected from medical files. Psychosocial variables were measured using established instruments. Medication noncompliance was assessed using electronic event monitoring. Paired t test, Wilcoxon 2-sample test, chi-square test, or Fisher exact test were used for statistical analysis as appropriate. The prevalence of appointment noncompliance was 7%. Appointment noncompliers were significantly younger, were less likely to live in a stable relationship with a partner, were more depressed, perceived their health as poorer, experienced more symptom distress, and had significantly more drug holidays. Fifty-seven percent of the appointment noncompliers experienced 1 or more late acute rejection episodes, compared to 2% of the appointment compliers. Appointment noncompliance is a critical behavioral risk factor in the occurrence of late acute rejection episodes in heart transplant patients. Patient profiles allow the identification of patients at risk for appointment noncompliance.

Adult↗

PubMed2000

Effects of insulin on intracellular GLUT4 vesicles in adipocytes: evidence for a secretory mode of regulation.

The facilitative glucose transporter, GLUT4 undergoes insulin-dependent movement to the cell surface in adipocytes. The magnitude of the insulin effect is much greater for GLUT4 than other recycling proteins such as the CD-MPR. In the present study we have studied the colocalisation of these proteins in adipocytes in an effort to explain this selective insulin-dependent recruitment of GLUT4. Using immunofluorescence microscopy or immuno-EM on 3T3-L1 adipocytes we find that there is considerable colocalisation between these proteins particularly within the area of the TGN. However, the distribution of CD-MPR was not significantly effected by insulin. The insulin-dependent recruitment of GLUT4 was concomitant with a selective decrease in GLUT4 labelling of cytoplasmic vesicles whereas the amount of GLUT4 in the TGN region (approx. 50% of total GLUT4) was relatively unaffected. To explore the possibility that the cytoplasmic GLUT4(+) vesicles represent an intracellular insulin-responsive storage compartment we performed quantitative immuno-EM on whole mounts of intracellular vesicles isolated from basal and insulin-stimulated adipocytes. These studies revealed that: (1) GLUT4 and CD-MPR were concentrated in small (30-200 nm) vesicles at a labelling density of 1-20+ gold particles/vesicle; (2) there was significant overlap between both proteins in that 70% of the total GLUT4 pool colocalised with CD-MPR; (3) a significant amount of GLUT4 (approx. 50% of total) was found in a subpopulation of vesicles that contained as little as 5% of the total CD-MPR pool; (4) the GLUT4(+)/CD-MPR(-) vesicles were highly insulin-responsive, and (5) the total number of GLUT4(+) vesicles, but not CD-MPR(+) vesicles, decreased by approx. 30% in response to insulin treatment. These data are consistent with a model in which GLUT4 is selectively sorted into a vesicular compartment in adipocytes that is recruited to the plasma membrane by insulin stimulation.

3T3 Cells↗

PubMed2000

The role of cytokines and adhesion molecules for mobilization of peripheral blood stem cells.

CD34(+) hematopoietic stem cells from peripheral blood are commonly used for autologous or allogeneic transplantation following high-dose therapy in malignant diseases. The introduction of hematopoietic growth factors such as G-CSF has greatly facilitated the mobilization of CD34(+) cells. The mechanism of stem cell mobilization is not yet clear. It seems to be a multistep process with a crosstalk between cytokines and adhesion molecules. In this review, the role of hematopoietic growth factors, chemokines, and adhesion molecules for mobilization and homing of CD34(+) cells is summarized. In addition, factors influencing the cytokine-induced mobilization in patients and healthy donors are described. The review closes with an overview of new classes of mobilizing drugs such as monoclonal antibodies, specific peptides, or antisense oligonucleotides targeting adhesion molecules.

Antigens, CD34↗

PubMed2000

Role of serotonin in memory impairment.

As a result of its presence in various structures of the central nervous system serotonin (5-HT) plays a role in a great variety of behaviours such as food intake, activity rythms, sexual behaviour and emotional states. Despite this lack of functional specialization, the serotonergic system plays a significant role in learning and memory, in particular by interacting with the cholinergic, glutamatergic, dopaminergic or GABAergic systems. Its action is mediated via specific receptors located in crucial brain structures involved in these functions, primarily the septo-hippocampal complex and the nucleus basalis magnocellularis (NBM)-frontal cortex. Converging evidence suggests that the administration of 5-HT2A/2C or 5-HT4 receptor agonists or 5-HT1A or 5-HT3 and 5-HT1B receptor antagonists prevents memory impairment and facilitates learning in situations involving a high cognitive demand. In contrast, antagonists for 5-HT2A/2C and 5-HT4, or agonists for 5-HT1A or 5-HT3 and 5-HT1B generally have opposite effects. A better understanding of the role played by these and other serotonin receptor subtypes in learning and memory is likely to result from the recent availability of highly specific ligands, such as 5-HT1A, 5-HT1B, 5-HT2A receptor antagonists, and new molecular tools, such as gene knock-out mice, especially inducible mice in which a specific genetic alteration can be restricted both temporally and anatomically.

Aging↗

PubMed2000

[Polyclonal T lymphocyte proliferation in drug lymphocyte activation test].

BACKGROUND: We examined the clonality of the specific T cell reaction activated with specific drug antigens in patients with a positive lymphocyte activation test. PATIENTS AND METHODS: Ten patients were investigated. Their clinical features suggested drug allergy. Six weeks after a skin reaction, skin tests and lymphocyte activation tests were run. For each lymphocyte activation test, we explored the clonality of the T cell proliferation by examining the VJ rearrangement of the TCR gamma locus using polymerase chain reaction and denaturing gradient gel electrophoresis. RESULTS: All samples gave positive lymphocyte activation tests proving in vitro polyclonal T cell proliferation in reaction to a drug. There was no difference in clonality between the pilot lymphocyte activation test and the lymphocyte activation test after stimulation with phytohemagglutinin or with the drug antigen. DISCUSSION: Our findings show that in vitro T cell proliferation induced by a specific drug antigen as disclosed by the lymphocyte activation test is a polyclonal or oligoclonal cell proliferation. This lack of production of a preferential T clone in a T cell-mediated immune drug reaction implies that many T lymphocytes can recognize the antigen and be stimulated by the same drug.

Adult↗

PubMed2000

A continence index predicts the early return of urinary continence after radical retropubic prostatectomy.

PURPOSE: We evaluated the ability of a newly developed continence index to predict the return of urinary continence 3 months after radical retropubic prostatectomy. MATERIALS AND METHODS: We developed and used a continence index to determine continence level after removal of the urinary catheter on postoperative day 15 in 145 men. A total of 20 patients were evaluated independently by 2 nurse specialists to assess continence index reliability. We evaluated continence level, pad use and degree of bothersomeness due to incontinence 3 months after catheter removal. The association of continence score with outcome variables was calculated using the Mantel-Haenszel trend test and the predictive ability of the continence score was determined by logistic regression to produce cumulative odds ratios. RESULTS: The intraclass correlation coefficient was 0.995 for the independently assessed continence index ratings and the Cronbach coefficient alpha was 0.65 for the 5 continence index parameters. Complete continence or continence with heavy activity but not always was achieved by 96%, 85% and 68% of the men in tertiles 1 (continence score 18), 2 (continence score 15 to 17) and 3 (continence score 14 or less), respectively. The cumulative odds ratio of 2.9 (95% confidence interval [CI] 1.9 to 4. 6) per tertile indicated a 2.9-fold increased chance of incontinence for each successively lower tertile. In addition, 96%, 82% and 68% of the men in tertiles 1 to 3, respectively, required no or 1 small pad daily. The cumulative odds ratio for pad use was 2.3 (95% CI 1.5 to 3.5) per tertile. Of the patients in tertiles 1 to 3 100%, 97% and 80%, respectively, had no or slight bothersomeness due to urinary incontinence. The cumulative odds ratio for bothersomeness level was 2.7 (95% CI 1.7 to 4.3) per tertile. The Mantel-Haenszel trend test showed a significant association of continence score with all 3 outcome variables (p < or =0.001). CONCLUSIONS: Our continence index is a simple and reliable instrument that provides useful prognostic information on the early return of continence after radical retropubic prostatectomy.

Adult↗

PubMed2000

[Apoptosis and pathologies of the central nervous system].

The program of cell death called apoptosis is a biochemical and genetical pathway which has been well conserved throughout evolution. In the past years, the involvement of apoptosis has been shown not only during the embryonic development of the nervous system, but also in neurodegenerative diseases. Moreover, resistance to apoptosis is clearly an important factor in tumor growth and seems to be, at least partially, a major process in chemo- and radio-resistance. In this review, we briefly describe the main molecular events of the apoptotic process, known to date, and discuss possible defects in the central nervous system diseases.

Alzheimer Disease↗

PubMed2000

Hospital, employment, and price indicators for the health care industry: third quarter 1999.

This feature presents highlights from statistics on health care utilization, prices, expenses, employment, and work hours, as well as on national economic activity, with brief analysis of these economic indicators. These statistics provide an early indication of changes occurring in the health care sector and within the general economy. Although most statistics include data for third quarter of 1999, American Hospital Association (AHA) data are through the third quarter of 1998.

Data Collection↗