Sleepless nights for SART investigators?
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Chromosome Aberrations↗
Biomedical subjects
R Martin
Publications and source records attributed to R Martin.
Chemoenzymatic synthesis of iminocyclitol derivatives: a useful library strategy for the development of selective fucosyltransfer enzymes inhibitors.
A chemoenzymatic strategy has been developed for the synthesis of libraries of iminocyclitol derivatives for the discovery of new and selective fucosidase inhibitors.
Enzyme Inhibitors↗
Intensive care for patients with medical complications of haematological malignancy: is it worth it?
Appropriately aggressive treatment of haematological malignancies can be complicated by a variety of life threatening events. Usually such acute events are, at least theoretically, potentially reversible and in view of the much improved prognosis of the underlying malignancy it is now generally considered to be appropriate to offer intensive care to selected cases, provided there is a reasonable prospect of cure or at least worthwhile palliation. A few remain concerned, however, and question whether the provision of intensive care for such patients is worthwhile. Hospital mortality rates of between 69-80% have been reported for patients admitted to intensive care with medical complications of haematological malignancy and this rises to 80-90% in those with respiratory failure. Overall mortality rates are generally even higher (87-95%) in those who have received a bone marrow transplant (BMT). The median duration of survival following discharge from hospital is in the region of 12-23 months, but a few survive much longer, a number must be presumed cured and their quality of life is good. These disappointing short- and long-term survival rates are achieved at considerable cost and, as is the case in many other categories of critically ill patients, expense and utilisation of resources is much higher in non-survivors than in survivors. Factors associated with a poor short-term outcome include the need for mechanical ventilation, hypotension, the administration of inotropes or vasopressors, an increasing number of failed organs, relapsed or unresponsive malignancy and persistent neutropenia. A poor prognosis may also be associated with increasing age, time on the ventilator and time in intensive care. BMT recipients have a particularly poor prognosis, especially when they require mechanical ventilation, and survival is unprecedented when ventilated BMT recipients either receive vasopressors or develop hepatic and renal insufficiency. It has not been possible to identify any features of the acute illness which influence the duration of long-term survival: this seems to depend solely on the progress of the underlying malignancy, something which is often difficult to predict before or during intensive care. In our view patients with life threatening complications of haematological malignancy should be offered intensive care unless or until it is clear that there is no prospect of recovery from the acute illness or that the underlying malignancy cannot be controlled.
Bone Marrow Transplantation↗
Prognosis following prenatal diagnosis of heart malformations.
Our objective was to document the prognosis of cases with fetal heart malformations (FHM). Forty-two fetuses assessed both in a regional fetal medicine and paediatric cardiology unit were classified prenatally into isolated FHM or those associated with extra-cardiac structural or karyotypic anomalies (ECA) and this classification was not changed subsequently (analogous to an intention to treat analysis). The end points studied included chromosomal abnormality, pregnancy outcome and follow-up at one year of age. FHM were isolated in 16 (38%) and associated with ECA in 26 (62%) of cases. The karyotypic abnormality rate was 8/42 (19%) overall and 8/26 (31%) in ECA cases. The pregnancy outcome included termination of pregnancy in 19 (45%), intrauterine death of two (5%) and live birth in 21 (50%). 12/16 (75%) of isolated FHM cases were live born compared with 9/26 (35%) of ECA cases (P < 0.03). Of the isolated FHM live born babies, 8/12 (67%) were alive at the end of the first year and seven of these were growing normally and did not require cardiac medication. However, a considerable proportion of their first year was spent in hospital (median 8%, interquartile range 5-10). Only one of nine ECA live born cases was alive but with poor growth and dependence on cardiac drugs at one year. These data confirm previous findings in prenatal diagnosis series that the prognosis for FHM is worse than that reported in studies of congenital heart disease at birth and is strongly dependent upon the presence of ECA. In their absence, outcome is better than previously published. Counselling must take place only after full fetal medicine assessment and should be based upon prenatal data.
Female↗
Inhibitors of dipeptidyl peptidase IV/CD26 suppress activation of human MBP-specific CD4+ T cell clones.
The ectoenzyme dipeptidyl peptidase IV (DP IV, EC 3.4.14.5, CD26) has been shown to play a crucial role in T cell activation. Specific inhibitors of DP IV suppress DNA synthesis as well as cytokine production (IL-2, IL-10, IL-12, IFN-gamma) of stimulated human and mouse T cells suggesting a potential application of these effectors in transplantations and autoimmune diseases. In the present study, we have examined the expression of DP IV/CD26 on six myelin basic protein (MBP)(87-99)-specific, CD4+ T cell clones (TCC) derived from patients with multiple sclerosis (MS) as well as the biological effects of the two synthetic DP IV inhibitors Lys[Z(NO2)]-thiazolidide and Lys[Z(NO2)]-pyrrolidide on the function of these cells. All TCC expressed high levels of DP IV/CD26, as shown by flow cytometry and by enzymatic DP IV assay. Enzymatic activity of resting TCC was found to be three to fourfold higher than on resting peripheral blood T cells and close to that of T cells 48 h after PHA stimulation. The DP IV inhibitors suppress DNA synthesis and IFN-gamma, IL-4, and TNF-alpha production of the antigen-stimulated TCC. These data suggest that CD26 plays a role in regulation of activation of autoreactive TCC. Further in-vivo investigations, first in experimental models, will clarify, whether the inhibition of the enzymatic activity of DP IV could be a useful tool for therapeutic interventions in MS or other autoimmune diseases.
CD4 Antigens↗
Serum CD95 of relapsing remitting multiple sclerosis patients protects from CD95-mediated apoptosis.
Failure of CD95-mediated apoptosis as a potential negative regulatory mechanism of T cell expansion may be involved in T cell-mediated autoimmune diseases such as multiple sclerosis (MS). Recently, soluble CD95 has been shown to be elevated in MS patients with active disease. Here, we report that the sera of MS patients inhibit CD95 ligand-induced apoptosis of susceptible target cells in a concentration-dependent manner and dependent on the amount of serum CD95 levels. Thus, MS sera contain biologically active inhibitors of T cell apoptosis that may allow for prolonged abnormal immune responses.
Apoptosis↗
Relationships among TCR ligand potency, thresholds for effector function elicitation, and the quality of early signaling events in human T cells.
Determining how receptor ligand quality and quantity together control the biologic responses of T cells is central to understanding normal and pathologic T cell immunity. Here we have carefully examined how variations in antigenic peptide structure and dose affect multiple functional responses of human T cell clones and have correlated these observations with proximal TCR signaling events induced by the same set of related ligands. As the Ag concentration increases, effector functions are elicited according to a clone-specific hierarchy. The absolute amount of each peptide required to stimulate the entire set of effector functions (potency) differs markedly among ligands for a single TCR, correlating with the efficiency of TCR down-modulation and the extent of ZAP-70 activation. However, distinct patterns of TCR zeta-chain phosphorylation were observed, with the ratios of TCRzeta isoforms relating to ligand agonist potency. The appearance of partially phosphorylated TCRzeta isoforms was paralleled by relative changes in certain response thresholds within the hierarchy. Thus, a combination of density, potency, and quality of signaling all contribute to the distinct effects of agonist ligands on T cell immunity.
Cells, Cultured↗
Predictable TCR antigen recognition based on peptide scans leads to the identification of agonist ligands with no sequence homology.
The potential of CD4+ T cells for cross-recognition of self and foreign Ags has important implications for the understanding of thymic selection, lymphocyte survival, and the occurrence of autoimmune diseases. Here, we define the extensive flexibility of Ag recognition for three human CD4+ autoreactive T cell clones (TCC) by using ligands with single and multiple amino acid (aa) substitutions. Our results demonstrate that the spectrum of tolerated ligands and the resulting stimulatory potency of peptides for a TCC can be predicted by the relative influence of each aa. Using this approach, we have identified stimulatory ligands not sharing a single aa in corresponding positions with the Ag used to establish the TCC. These results argue for an independent contribution of each aa in the peptide sequence to the affinity of the MHC/peptide complex to the TCR.
Amino Acid Sequence↗
Lack of over-expression of T cell receptor Vbeta5.2 in myelin basic protein-specific T cell lines derived from HLA-DR2 positive multiple sclerosis patients and controls.
Based on studies reporting an overexpression of certain V genes in myelin basic protein (MBP)-specific T cells from MS patients, immunotherapies targeting single TCR (Vbeta5.2, Vbeta6.1) are currently under way. In order to assess the basic assumption for one of these therapeutic strategies, i.e. the overexpression of Vbeta5.2 by MBP-specific T cells, we analyzed 100 MBP-specific T cell lines (TCL) for Vbeta5.2 expression. Only 4 out of 100 TCL expressed Vbeta5.2, and expression of this TCR gene is therefore not more frequent than expected from the normal peripheral blood distribution.
Adult↗
Variable penetrance of familial pheochromocytoma associated with the von Hipple Lindau gene mutation, S68W. Mutations in brief no. 150. Online.
Van Hippel-Lindau disease (VHL) is an autosomal dominantly inherited disorder, characterised by the development of clear cell renal carcinomas, CNS hemangioblastomas, retinal angiomas, pancreatic tumors, pheochromocytomas and hepatic cysts. Recently a number of families with dominant familial pheochromocytoma as the only clinical manifestation have been reported to carry mutations in the HVL gene. We describe a family in which a novel VHL S68W mutation was segregating and carrier individuals manifested with variable penetrance of isolated pheochromocytomas. Investigation of this kindred confirmed that a mutation in the VHL gene could produce isolated pheochromocytomas as the only clinical feature and was variably penetrant.
Genes, Tumor Suppressor↗
Is the incidence of upper respiratory tract infection independent of drug treatment in large cohort studies of longer term use drugs?
In observational cohort studies which monitor drug safety, the patterns of reported events are likely to be influenced by a number of factors. We hypothesized that the distribution of events which are unlikely to be adverse events associated with drug use, differ from that for events which may be adverse drug reactions. In 39 individual Prescription-Event Monitoring (PEM) studies, the incidence rates for upper respiratory tract infections (URTI) and back pain, in the first month of treatment and in the subsequent 5 months, were compared to those for nausea/vomiting and malaise/lassitude. For URTI and back pain there was no statistically significant difference in the event rates between these time periods. This pattern may be characteristic of events which are independent of the disease being treated and are unlikely to be adverse events associated with drug use. However, for nausea/vomiting and malaise/lassitude, which can be adverse events associated with drug treatments, the event rates in the first month of treatment were significantly greater than in subsequent months. These observations confirm that doctors are reporting events irrespective of whether or not they suspect the event to be an adverse event associated with the drug. This provides a simple validation of the PEM methodology.
Journal Article↗
Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study.
OBJECTIVE: To evaluate the efficacy and tolerability of an oral preparation of iloprost, a prostacyclin analog, in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (scleroderma). METHODS: A multicenter, randomized, parallel-group, placebo-controlled double-blind study was performed at university and community-based medical centers. Patients were randomly assigned to receive either 50 microg of iloprost orally twice daily or an identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures included average total daily duration of RP attacks, average number of RP attacks, and RP condition scored via a standardized daily diary. RESULTS: Three hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years [range 18-80]) were enrolled. One hundred fifty seven were assigned to receive iloprost and 151 to receive placebo. One hundred forty-three patients in the iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed to complete all of the followup visits. The mean reduction in the average duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynaud's condition score, a patient-completed assessment of the severity of RP attacks, was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P = 0.323). The lack of significant difference between treatment groups did not change when a variety of factors, including use of other vasodilators, duration of disease, classification of scleroderma (limited versus diffuse), or number of baseline digital ulcers were taken into account. Premature withdrawal from the study due to adverse events occurred in 10 patients (6.4%) in the iloprost group and 3 (2.0%) in the placebo group (P = 0.058). CONCLUSION: Oral iloprost at a dosage of 50 microg twice daily is no better than placebo for management of RP secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of posttreatment followup.
Administration, Oral↗
Increased serum levels of soluble CD95 (APO-1/Fas) in relapsing-remitting multiple sclerosis.
CD95/CD95 ligand interactions are critically involved in the negative regulation of peripheral T-cell responses. Here, we report that serum levels of soluble CD95 are significantly elevated in patients with relapsing remitting multiple sclerosis. In a transectional study, CD95 levels did not correlate with clinical disability or lesion formation on magnetic resonance imaging. Longitudinally, Expanded Disability Status Scale changes were associated with high CD95 levels. Interferon-beta (IFNbeta) treatment led to an initial increase and subsequent decline of serum CD95 levels. Interestingly, patients generating neutralizing antibodies to the drug had significantly higher baseline CD95 levels before IFNbeta treatment than those without neutralizing antibodies.
Adjuvants, Immunologic↗
Rhodopsin mutation G109R in a family with autosomal dominant retinitis pigmentosa.
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Amino Acid Substitution↗
Rocuronium is the best non-depolarizing relaxant to prevent succinylcholine fasciculations and myalgia.
PURPOSE: To determine which non-depolarizing relaxant among d-tubocurarine, vecuronium, atracurium, mivacurium and rocuronium prevented muscular fasciculations and myalgia following succinylcholine. METHODS: In this double blind randomized study, 120 female patients scheduled for laparoscopic procedures were studied. They were divided into six groups of 20 according to the non-depolarizing pretreatment used: NaCl 0.9% (control), 0.05 mg.kg-1 d-tubocurarine, 0.01 mg.kg-1 vecuronium, 0.05 mg.kg-1 atracurium, 0.02 mg.kg-1 mivacurium and 0.06 mg.kg-1 rocuronium. Four minutes after the pretreatment, 1.5 mg.kg-1 succinylcholine was injected. Side effects of the pretreatment, the presence and magnitude of fasciculations, the ease of tracheal intubation, myalgia 1, 24 and 48 hr after surgery were observed. A Puritan Bennett Datex 221 NMT Relaxograph monitor was used to evaluate the neuromuscular block. RESULTS: Muscle fasciculations were observed in 19 of the 20 patients in the control group and in 3 of the 20 patients in the rocuronium group, the best of the pretreatments in that aspect. Four patients in the mivacurium group were unable to sustain more than four seconds head-lift after pretreatment (P < 0.05). Tracheal intubation conditions were better and the onset of block was faster and longer after succinylcholine in the control group (P < 0.05). Myalgias were present in 71% of the patients 24 hr postoperatively and the frequency was not different among the groups. CONCLUSION: Among the pretreatments tested, 0.06 mg.kg-1 rocuronium was the best to prevent muscular fasciculations following succinylcholine injection. In the population studied, pretreatment did not prevent postoperative myalgia. Succinylcholine 1.5 mg.kg-1 was more effective without a non-depolarizing pretreatment.
Adult↗
Volumetric MRI of the limbic system: anatomic determinants.
The limbic system comprises the hippocampal formation, fornix, mamillary bodies, thalamus, and other integrated structures. It is involved in complex functions including memory and emotion and in diseases such as temporal lobe epilepsy. Volume measurements of the amygdala and hippocampus have been used reliably to study patients with temporal lobe epilepsy but have not extended to other limbic structures. We performed volume measurements of hippocampus, amygdala, fornix and mamillary bodies in healthy individuals. Measurements of the amygdala, hippocampus, fornix and mamillary bodies revealed significant differences in volume between right and left sides (P < 0.001). The intraclass coefficient of variation for measurements was high for all structures except the mamillary bodies. Qualitative image assessment of the same structures revealed no asymmetries between the hemispheres. This technique can be applied to the study of disorders affecting the limbic system.
Adult↗
Human sperm chromosome complements in chemotherapy patients and infertile men.
Our studies of human sperm karyotypes and interphase sperm analyzed by fluorescence in situ hybridization (FISH) have both yielded estimates of disomy frequencies of approximately 0.1% per chromosome with an overall aneuploidy frequency in human sperm of approximately 5%-6%. However, the distribution of aneuploidy in sperm is not even, as our data from sperm karyotypes and multicolour FISH analyses both demonstrate a significant increase in the frequency of aneuploidy for chromosome 21 and the sex chromosomes. We have studied men at increased risk of sperm chromosomal abnormalities including cancer patients and infertility patients. Testicular cancer patients were studied before and 2-13 years after chemotherapy (CT) with BEP (bleomycin, etoposide, cisplatin). Sperm karyotype analysis on 788 sperm demonstrated no significant difference in the frequency of numerical or structural chromosomal abnormalities post-CT vs pre-CT. Similarly, multicolour FISH analysis for chromosomes 1, 12, XX, YY and XY in 161,097 sperm did not detect any significant differences in the frequencies of disomy before and after treatment. However, recent evidence has suggested a significant increase in the frequency of disomy and diploidy during CT. We have found that infertile men, who would be candidates for intracytoplasmic sperm injection, have an increased frequency of chromosomally abnormal sperm karyotypes. Also, FISH analysis for chromosomes 1, 12, 13, 21, XX, YY and XY in 255,613 sperm demonstrated a significant increase in chromosomes 1, 13, 21, and XY disomy in infertile men compared with control donors.
Adult↗
CD95 expression and CD95-mediated apoptosis of T cells in multiple sclerosis. No differences from normal individuals and no relation to HLA-DR2.
CD95-mediated apoptosis is a potent endogenous pathway of T cell elimination that has been suggested to be altered in multiple sclerosis (MS). MS is associated with the HLA-DR2, Dw2, DQ6 HLA class II haplotype. We have previously reported that T cell lines from HLA-DR2-positive individuals show enhanced production of tumor necrosis factor (TNF), a cytokine homologous to CD95 ligand, in response to specific antigen. Here we have studied CD95 expression and susceptibility to CD95-mediated apoptosis in peripheral blood mononuclear cells (PBMC) and activated T cells of 20 healthy individuals and 20 MS patients, half of whom were HLA-DR2-positive. MS patients did not differ from healthy individuals in either parameter. There was also no difference in CD95 expression or CD95-mediated apoptosis when MS patients and healthy individuals were grouped and compared according to HLA-DR status. These data reveal no differential regulation of PBMC/T cell apoptosis induced by CD95 receptor ligation in MS and show no impact of HLA-DR2 status on PBMC/T cell susceptibility to the same apoptotic stimulus. However, to assess the contribution of T cell apoptosis to the pathogenesis of MS further studies on other details of the complex system leading to T cell apoptosis are required.
Apoptosis↗