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Biomedical subjects

J M Thomas

Publications and source records attributed to J M Thomas.

At least 55 records · Page 3Linked to original sources

[Prevention of falls and their complications in the elderly].

The number of falls increase with the elderly. The aetiology is in relationship with the age of the patient, his diseases, his medicines and his environment. Falls are responsible of high morbidity, mortality and a loss of autonomy. To evaluate the risk of falls takes part of the comprehensive geriatric assessment. Only multidisciplinary interventions by people with risk factors are effectiveness. The use of hip protector decreases the number of fracture.

Accidental Falls↗

The number of amino acid residues mismatches correlates with flow cytometry crossmatching results in high PRA renal patients.

Highly sensitized renal transplant candidates present a group at high risk for acute and chronic rejection. The probability of finding compatible donors for these recipients is significantly lower in comparison to those who have low PRA values. As a consequence, these patients spend longer time on the waiting list and become tethered to dialysis. The results of final cross match (XM) are critical for making a decision about whether such a candidate receives an organ or not. The degree of donor and recipient HLA compatibility predicts the results of XM. The goal of this study was to expand a variety of acceptable HLA-AB mismatches (MM) for high PRA kidney recipients using the HLAMATCHMAKER algorithm. This strategy focuses on the fine structural features of HLA polymorphism comprising amino acid residues or triplets (AAT), which are located in alpha-helical coils of HLA molecules and are available to antibodies. We analyzed serum samples from thirty-nine highly alloimmunized recipients (PRA > or = 85%). The level of sensitization was detected using FlowPRA Class I Screening Test. This group of transplant candidates included thirteen recipients who demonstrated negative results of final T/B FCXM and twenty-six, who were FCXM positive. The application of the HLAMATCHMAKER algorithm based on the HLA class I donor and recipient typing allowed us to detect the total number of AATMM as well as the number of immunogenic AAT in both FCXM negative and FCXM positive groups of recipients. Significantly greater numbers of both total and highly immunogenic AATMM have been emerged in the group of FCXM positive patients. Furthermore, the results of this analysis have shown a high degree of probability of positive FCXM if the number of highly immunogenic AATMM was > or = 1 (chi(2) = 22.9 Yate's correction; p = 0.000001). We did not observe overlapping between antibody specificity and permissible HLA-AB MM detected using the HLAMATCHMAKER strategy. Thus, the number of highly immunogenic AATMM can serve as a reliable predictive value for final FCXM results in highly sensitized renal transplant candidates. The HLAMATCHMAKER algorithm appears to be the proper strategy to find donors for high PRA recipients.

Adolescent↗

Association of cytokine single nucleotide polymorphisms with B7 costimulatory molecules in kidney allograft recipients.

African-American race is associated with an increased risk of allograft loss, suggesting that African-American patients may form an immunologically higher risk group. Previously, we demonstrated that immune cell costimulatory molecule expression is significantly higher in African-Americans than in Caucasians. Polymorphic variations in the genes for cytokines have been associated with a number of immunological conditions, and with transplant rejection. This study was performed to determine the distribution, in African-American and Caucasian renal transplant recipients, of single nucleotide polymorphisms (SNPs) in the following cytokine genes: tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin (IL)-6, IL-10, and transforming growth factor-beta (TGF-beta). Cytokine production from blood cells was determined, and cell-surface B7 (CD80, CD86) expression was measured. There was a significant link between IL-10 genotype and acute rejection episodes, but only in African-American patients (p < 0.01). Also, African-American patients had a significantly higher probability of having the IL-6 G-allele (p < 0.0001), which is associated with a high production of IL-6 protein. Incubation of blood cells with IL-6 resulted in increased expression of surface CD80 and CD86, while IL-10 decreased CD80 expression. This study demonstrated a clear correlation of the IL-6 G-allele with increased cellular CD80 expression and the IL-10 G-allele with decreased CD80 expression. These data raise the possibility that specific genotypes are associated with local cytokine regulation of cell-surface costimulatory molecule expression. African-American patients may have a genetically determined, quantitatively different immune response than Caucasian patients, contributing to adverse transplant outcomes.

Adult↗

Coxsackievirus-adenovirus receptor genetically fused to anti-human CD40 scFv enhances adenoviral transduction of dendritic cells.

A promising approach to immunotherapy involves the loading of dendritic cells (DCs) with genetic material to facilitate sustained expression of a relevant antigen in this population of potent antigen presenting cells (APC). Viral vectors such as adenovirus (Ad) have been used for this purpose. Existing methods for DC infection are limited by lack of specificity and a requirement for DC exposure to high viral doses. Targeting of Ad to DCs with bispecific antibodies has significantly augmented levels of transgene expression. Genetic fusion of the extracellular portion of coxsackievirus-adenovirus receptor (CAR) to cell-specific ligands has also proved successful in targeting Ad to cells of interest. We report here the production and primary characterization of a new fusion protein comprising the ecto-domain of CAR connected to a single chain antibody (scFv) G28-5 against human CD40 present on the surface of DCs. We demonstrate that the fusion protein (CAR/G28) specifically interacts with both recombinant Ad fiber knob and the ecto-domain of human CD40 in a binding assay (ELISA). Finally, we show that the CAR/G28 fusion protein promotes highly efficient transduction of DCs of both rhesus monkey and human origin.

Adenoviridae↗

Soft-tissue tumours of the perineum.

AIM: Primary perineal tumours in adults are rare entities that have been infrequently reported (one clinical series of nine patients with sarcoma and isolated case reports). We present our experience of perineal tumours better to characterize and define the natural history of this condition. METHODS: Perineal tumours occurring in adults (>18 years) from January 1990 were identified from the Royal Marsden Hospital's Sarcoma Unit prospective database. RESULTS: Nineteen perineal soft-tissue tumours (12 malignant and seven benign) were evaluated and treated at the Royal Marsden Hospital during this period. Liposarcoma (n=3) and aggressive angiomyxoma (n=4) were the most frequent histological subtypes. Three malignant and four benign tumours were larger than 10 cm. Most tumours were located deep to the deep fascia. Local recurrence in those with sarcoma occurred in one of five patients with negative microscopic margins and in one of two patients who had positive microscopic margins. One patient each with aggressive angiomyxoma and fibromatosis recurred locally. CONCLUSION: Aggressive treatment in the form of wide local excision is associated with fewer local recurrences in adults with primary perineal soft-tissue tumours. The aim of surgical treatment should be to obtain negative resection margins without causing disturbance to urinary or anorectal function.

Adolescent↗

Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis.

BACKGROUND: Certain infections can trigger chronic fatigue syndromes (CFS) in a minority of people infected, but the reason is unknown. We describe some factors that predict or are associated with prolonged fatigue after infectious mononucleosis and contrast these factors with those that predicted mood disorders after the same infection. METHODS: We prospectively studied a cohort of 250 primary-care patients with infectious mononucleosis or ordinary upper-respiratory-tract infections until 6 months after clinical onset. We sought predictors of both acute and chronic fatigue syndromes and mood disorders from clinical, laboratory, and psychosocial measures. FINDINGS: An empirically defined fatigue syndrome 6 months after onset, which excluded comorbid psychiatric disorders, was most reliably predicted by a positive Monospot test at onset (odds ratio 2.1 [95% CI 1.4-3.3]) and lower physical fitness (0.35 [0.15-0.8]). Cervical lymphadenopathy and initial bed rest were associated with, or predicted, a fatigue syndrome up to 2 months after onset. By contrast, mood disorders were predicted by a premorbid psychiatric history (2.3 [1.4-3.9]), an emotional personality score (1.21 [1.11-1.35]), and social adversity (1.7 [1.0-2.9]). Definitions of CFS that included comorbid mood disorders were predicted by a mixture of those factors that predicted either the empirically defined fatigue syndrome or mood disorders. INTERPRETATION: The predictors of a prolonged fatigue syndrome after an infection differ with both definition and time, depending particularly on the presence or absence of comorbid mood disorders. The particular infection and its consequent immune reaction may have an early role, but physical deconditioning may also be important. By contrast, mood disorders are predicted by factors that predict mood disorders in general.

Chi-Square Distribution↗

Pharmacological characterization of the putative cADP-ribose receptor.

cADP-ribose (cADPR), a naturally occurring metabolite of NAD(+), has been shown to be an important regulator of intracellular Ca(2+) release. Considerable evidence suggests that cADPR is the endogenous modulator of the ryanodine receptor (RyR), which mediates Ca(2+)-induced Ca(2+) release (CICR). Indeed, cADPR-mediated Ca(2+) release is subject to functional regulation by other modulators of CICR, including Ca(2+), caffeine and calmodulin. However, the underlying basis behind the effect of such agents on cADPR activity (in particular whether they regulate cADPR binding), as well as the precise nature of the cADPR receptor remains unclear. In the present study, use of (32)P-radiolabelled cADPR has enabled a detailed pharmacological characterization of cADPR-binding sites in sea urchin egg homogenates. We report that cADPR binds specifically to a single class of high affinity receptor. Retainment of binding to membranes after a high-salt wash suggests the involvement of either an integral membrane protein (possibly the RyR itself) or a peripheral protein tightly associated to the membrane. Insensitivity of [(32)P]cADPR binding to either FK506 or rapamycin suggests that this does not concern the FK506-binding protein. Significantly, binding is highly robust, being relatively insensitive to both endogenous and pharmacological modulators of RyR-mediated CICR. In turn, this suggests that such agents modulate cADPR-mediated Ca(2+) release primarily by tuning the 'gain' of the CICR system, upon which cADPR acts, rather than influencing the interaction of cADPR with its target receptor. The exception to this is calmodulin, for which our results indicate an additional role in facilitating cADPR binding.

Adenosine Diphosphate Ribose↗

An essential role for natural killer cells in augmentation of allograft survival mediated by donor spleen cells.

BACKGROUND: Previous studies have shown that skin allograft survival can be augmented by the administration of donor spleen or donor bone marrow in antithymocyte serum (ATS) treated recipients. Because natural killer cells (NK) have been reported to possess immunoregulatory properties, we investigated whether the ability of donor spleen or bone marrow cells to enhance allograft survival was dependent on the presence of donor NK cells. METHODS: Recipient (C57BL/6 x A/J)F1 strain mice (H2 haplotypes Kb/k, Ab/k, E-/k, Db/d) were treated with ATS on days -1 and +2 relative transplantation of a C3H (H-2k) skin allograft. On day +7, each recipient was randomly assigned to one of the following groups that received i.v. donor C3H cell infusions via the tail vein: 1) 5.0x10(7) wild-type donor spleen cells (SPC); 2) 5.0x10(7) spleen cells from C3H/HeJ-Lystbg-2J/+ mice (commonly called beige mice and have selectively impaired NK cell function); 3) 2.5x10(7) wild-type donor bone marrow cells (BMC); 4) 2.5x10(7)beige C3H bone marrow cells; and 5) no donor cell infusion (ATS controls). In another experiment, each recipient was randomly assigned to one of the following groups that received injections of: 1) 4.75x10(7) spleen cells depleted of NK cells; 2) 2.5x10(6) purified splenic NK cells; 3) a coinfusion of 5.0x10(7) beige spleen cells and 2.5x10(6) purified wild-type splenic NK cells. RESULTS: Recipients infused with wild-type SPC exhibited significant augmentation of allograft survival compared with ATS controls. However, graft survival was reduced in recipients that were infused with spleen cells from beige mice compared with recipients infused with wild-type SPC (median survival time (MST): 38 vs. 92 days, P=0.02). In contrast, infusions of beige BMC augmented allograft survival as well as wild-type BMC (MST: 47 vs. 49 days, P=0.76). Furthermore, the ability of wild-type SPC to augment allograft survival was abrogated by the depletion of NK cells (MST=92 vs. 34 days, respectively, P=0.005). The co-infusion of beige SPC and purified splenic NK cells enhanced allograft survival as well as wild-type SPC (MST=56 days, P=0.65). Finally, recipients infused with purified NK cells did not experience increased graft survival compared to recipients that received no infusion (MST=29 vs. 33 days, respectively, P=0.6). CONCLUSIONS: Donor splenic NK cells are necessary, but not sufficient, for the extension of graft survival by infusion of donor splenocytes, suggesting that they may work in concert with another cell-type. In contrast, the extension of graft survival by donor bone marrow does not depend on the presence of donor NK cells.

Animals↗

Solvent-free routes to clean technology.

A major aim for the chemical technology of the future is the avoidance of noxious and environmentally unacceptable organic solvents. In this concept article we discuss more environmentally friendly and highly selective alternatives which we have evolved for carrying out a number of important chemical conversions. These entail the use of porous heterogeneous catalysts in which the active sites have been atomically engineered and fully characterized. Such solid catalysts operate under solvent-free conditions and usually entail one-step processes.

Journal Article↗

Cytoprotection of pancreatic islets before and soon after transplantation by gene transfer of the anti-apoptotic Bcl-2 gene.

Isolated pancreatic islet transplantation is a promising alternative to conventional insulin-dependent diabetes treatment but is not yet a practical clinical therapy. In the first few days after pancreatic islet transplantation, substantial donor pancreatic islet dysfunction and apoptosis commonly occur. Islet apoptosis has been documented after extracellular matrix disruption and exposure to proinflammatory cytokines, and during hypoxia before islet revascularization and rejection. These studies show that targeting the apoptosis pathway by adenoviral-mediated gene transfer of the anti-apoptotic Bcl-2 gene exerts a major cytoprotective effect on isolated macaque pancreatic islets. Bcl-2 transfection ex vivo protects these islets from apoptosis induced by disruption of the islet extracellular matrix during pancreatic digestion. Additionally, overexpression of Bcl-2 confers long-term, stable protection and maintenance of functional islet mass after transplantation of macaque islets into diabetic severe combined immunodeficency mice. Notably, genetic modification of pancreatic islets also reduced the islet mass required to achieve stable euglycemia. Ex vivo gene transfer of anti-apoptotic genes has potential as a therapeutic approach to both minimize loss of functional islet mass after transplant and reduce the high donor islet requirement currently needed for successful stable reversal of insulin-dependent diabetes.

Adenoviridae↗

The role of XAFS in the in situ and ex situ elucidation of active sites in designed solid catalysts.

New mesoporous and microporous catalysts based on silica, aluminophosphates, or aluminophosphates containing one or other of the heteroatoms Ti, Co, Mn, Fe and Cr, are ideally suited for study by X-ray absorption fine structure (XAFS). The information derived from X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) elucidates the nature of the catalytically active site, generally (but not invariably) under in situ conditions. This, in turn, provides new insights into the mechanism of the catalysis and suggests methods of improving the performance of the original catalyst. In this way, significant advances have recently been made in designing catalysts for the selective oxidation of alkanes, for the epoxidation of alkenes and for the dehydration of alcohols to yield olefins. Combined with density functional theory (DFT) computations, XAFS studies have also yielded fresh insights into the architecture of nanoparticle catalysts, such as Ru12Cu4C2 supported on mesoporous silica.

Journal Article↗

Effect of Si(IV) substitution on the stability of microporous ZnAPSO-44 solid acid catalysts: a combined XAS/XRD study.

The combined XAS/XRD technique has been used to investigate the stability of the microporous structure during calcination process for a series of ZnAPSO-44 materials. Incorporation of large amounts of Zn is found to produce materials that are unstable upon removal of the structure directing organic template molecule. However, simultaneous incorporation of Si is found to increase the thermal stability of the materials, yielding catalysts that are well suited for acid catalysed reactions.

Journal Article↗

The architecture of Mg(II) centres in MAPO-36 solid acid catalysts.

The local structure around Mg2+ ions of a Magnesium substituted aluminophosphate, with the ATS structure (MgAPO-36, Mg/P=0.08), in the as-prepared and calcined state has been investigated by Mg K-edge XAS spectroscopy. High quality XAS data were collected using the solid-state fluorescence detector. Mg2+ is found to replace tetrahedrally co-ordinated Al3+ in the as-prepared state and remained intact even after calcination, thus yielding a highly active, solid acid catalyst.

Journal Article↗

Nanopore and nanoparticle catalysts.

The design, atomic characterization, performance, and relevance to clean technology of two distinct categories of new nanocatalysts are described and interpreted. Exceptional molecular selectivity and high activity are exhibited by these catalysts. The first category consists of extended, crystallographically ordered inorganic solids possessing nanopores (apertures, cages, and channels), the diameters of which fall in the range of about 0.4 to about 1.5 nm, and the second of discrete bimetallic nanoparticles of diameter 1 to 2 nm, distributed more or less uniformly along the inner walls of mesoporous (ca. 3 to 10 nm diameter) silica supports. Using the principles and practices of solid-state and organometallic chemistry and advanced physico-chemical techniques for in situ and ex situ characterization, a variety of powerful new catalysts has been evolved. Apart from those that, inter alia, simulate the behavior of enzymes in their specificity, shape selectivity, regio-selectivity, and ability to function under ambient conditions, many of these new nanocatalysts are also viable as agents for effecting commercially significant processes in a clean, benign, solvent-free, single-step fashion. In particular, a bifunctional, molecular sieve nanopore catalyst is described that converts cyclohexanone in air and ammonia to its oxime and caprolactam, and a bimetallic nanoparticle catalyst that selectively converts cyclic polyenes into desirable intermediates. Nanocatalysts in the first category are especially effective in facilitating highly selective oxidations in air, and those in the second are well suited to effecting rapid and selective hydrogenations of a range of organic compounds.

Journal Article↗

Prognostic index for extremity soft tissue sarcomas with isolated local recurrence.

BACKGROUND: Local recurrence occurs in 10% to 20% of patients with extremity soft tissue sarcomas despite optimal treatment. The association of local recurrence with subsequent survival is controversial and conflicting. There is a need for a staging system to predict outcome in this subset of patients and also to plan optimal treatment, including adjuvant systemic therapy. METHODS: Data collected from 110 patients with locally recurrent extremity soft tissue sarcomas were studied. The influence of clinical and pathologic factors on local recurrence, distant metastasis, and disease-specific survival were analyzed by univariate and multivariate techniques. RESULTS: Of the 110 patients who presented with local recurrence, 92 had an isolated local recurrence and 18 had prior or concomitant distant metastases. The 5-year disease-specific survival for all patients was 63% and for those with isolated local recurrence, it was 69%. Histologic grade, malignant fibrous histiocytoma histology, pathologic margins, previous local recurrence, and prior radiotherapy were independent prognostic factors for subsequent local recurrence. Tumor size, histologic grade, and time to local recurrence were independent prognostic factors for distant metastasis and disease-specific survival. A prognostic index was calculated by assigning a score of 1 to 3 for each of the three independent prognostic factors for survival and added to give the prognostic index for each patient. As the prognostic index increased from 3 to 9, there was a progressive increase in the hazard ratios and a corresponding deterioration in survival. The patients were then categorized into three prognostic groups based on the hazard ratios for disease specific survival. The differences in the survival curves were highly statistically significant (P < .0001). CONCLUSIONS: Tumor size, histologic grade, and time to local recurrence are the primary determinants of distant metastases and survival in locally recurrent extremity soft tissue sarcomas. The impact of local recurrence on survival varies considerably. The nature of the local recurrence, rather than its presence per se, is a more useful guide to prognosis. We propose a simple staging system based on size, grade, and time to recurrence that correlates extremely well with prognosis and may serve as a guide to make therapeutic decisions in patients with locally recurrent extremity soft tissue sarcomas.

Adolescent↗

Phenotypic and functional analysis of T-cell recovery after anti-CD3 immunotoxin treatment for tolerance induction in rhesus macaques.

T-cell reduction utilizing specific antibody has been widely used in human transplantation, and is a cornerstone of several tolerance induction strategies in nonhuman primates. We have established a population of long-term tolerant rhesus macaques induced with an anti-CD3epsilon immunotoxin (IT). This treatment effects transient, specific and profound ablation of T cells in blood and lymphoid tissues. In most instances the IT was used in combination with the NF-kappaB inhibitor, 15-Deoxyspergualin. This 2-week long protocol produces a "window of opportunity" for tolerization in which the animal exhibits an enduring quiescent state of unresponsiveness to the allograft, all accomplished without maintenance immunosuppressive drugs. During this induction period, the treated immune system bears some resemblance to that of the neonate, in that T cell numbers are abnormally low and antigen presentation by dendritic cells is precluded by an arrest in their NF-kappaB dependant maturation. In addition, IL-4 production is prominent during and after the tolerance induction interval. For this study we focused on measuring the monkey's ability to repopulate T cells with particular emphasis on the memory T-cell phenotype. Three "memory" phenotypes were utilized; CD3(+)CD45RO(+), CD3(+)CRTH2(+), and CD3(+)CD4(+)CD8(+). All three phenotypes exhibited different patterns of recovery, all of which included transient bursts in their numbers during repopulation. We also estimated thymic activity after T-cell ablation with the use of a newly-described RTE or recent thymic émigré phenotype (a naïve CD8(+)CD103(+) T cell). This marker revealed production of RTE cells including supranormal levels at approximately 6 months post-transplant, implicating thymic function in the repopulation of T-cells. Finally, we measured antibody responses to a panel of antigens (vaccines, environmental antigen, and foreign proteins) that indicated there was no apparent loss of immunologic function during or after the tolerance induction period. Results of studies of T-cell receptor repertoire expression suggest preservation of the pretreatment repertoire, which is consistent with rapid recovery of immune competence to the test antigens. Taken together, these results suggest that while aggressive, this tolerance induction protocol does not appear to incur a prolonged immunologically-compromised state, if at all.

Animals↗