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Biomedical subjects

D George

Publications and source records attributed to D George.

At least 37 records · Page 2Linked to original sources
PubMed2000

Gene expression analysis by massively parallel signature sequencing (MPSS) on microbead arrays.

We describe a novel sequencing approach that combines non-gel-based signature sequencing with in vitro cloning of millions of templates on separate 5 microm diameter microbeads. After constructing a microbead library of DNA templates by in vitro cloning, we assembled a planar array of a million template-containing microbeads in a flow cell at a density greater than 3x10(6) microbeads/cm2. Sequences of the free ends of the cloned templates on each microbead were then simultaneously analyzed using a fluorescence-based signature sequencing method that does not require DNA fragment separation. Signature sequences of 16-20 bases were obtained by repeated cycles of enzymatic cleavage with a type IIs restriction endonuclease, adaptor ligation, and sequence interrogation by encoded hybridization probes. The approach was validated by sequencing over 269,000 signatures from two cDNA libraries constructed from a fully sequenced strain of Saccharomyces cerevisiae, and by measuring gene expression levels in the human cell line THP-1. The approach provides an unprecedented depth of analysis permitting application of powerful statistical techniques for discovery of functional relationships among genes, whether known or unknown beforehand, or whether expressed at high or very low levels.

Cell Line↗
PubMed2000

Stem cell transplantation for the treatment of Fanconi anaemia using a fludarabine-based cytoreductive regimen and T-cell-depleted related HLA-mismatched peripheral blood stem cell grafts.

We have employed a new cytoreductive regimen to transplant two patients with Fanconi anaemia (FA), using T cell-depleted two HLA-allele disparate related peripheral blood stem cell transplants (PBSCTs). Patient 1, a 5-year-old male with FA and aplastic anaemia, initially received an HLA two-antigen mismatched unrelated cord blood transplant and failed to engraft. He received fludarabine (Flu) and cyclophosphamide (Cy), followed by a CD34(+) E-rosette(-) (CD34(+)E(-)), T cell-depleted, granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCT from his HLA B-DRB1 mismatched father. He received anti-thymocyte globulin (ATG), steroids, FK506 and G-CSF after transplant for rejection and graft-versus-host disease (GVHD) prophylaxis. The patient is now 23 months after SCT with no evidence of GVHD and with full haematopoietic and immune reconstitution. Patient 2, a 10-year-old boy with FA and myelodysplastic syndrome, received single-dose total body irradiation (SDTBI), Flu and Cy followed by a CD34(+)E(-), T-cell-depleted, G-CSF-mobilized PBSCT from his HLA B-DRB1 mismatched sister. He also received ATG, steroids, FK506 and G-CSF after transplant. The patient is now 12 months after SCT in complete remission with no evidence of GVHD. Absolute neutrophil counts (ANC) of > 1 x 10(9)/l were achieved on day 11 and day 10 post transplant respectively. Both patients are fully engrafted. In summary, we report two successful T-cell-depleted stem cell transplants from mismatched related donors for the treatment of Fanconi anaemia, using a fludarabine-based cytoreduction. Both patients experienced minimal toxicity, rapid engraftment and no GVHD.

Child, Preschool↗
PubMed2000

Diagnostic value of cervical discography in the management of cervical discogenic pain.

We did a retrospective analysis of patients who had a total of 46 cervical discs examined by cervical discography and then evaluated the postoperative results of 14 of the 16 patients who underwent cervical spine fusion at those levels in accordance with the results of our discograms. The average symptomatic period prior to discography was 12 months, and cervical discogenic pain was successfully localized in all 16 patients. Immediately post-cervical discectomy and anterior fusion, subjectively, all 14 patients had good to excellent results, and after a mean follow-up of 6.5 (1.5 to 14) months, 11 patients (78.6%) continued with good to excellent results and three patients (21.4%) developed related pain patterns. Thus, cervical discography, in a "select group" of patients with chronic intractable neck pain but negative or indeterminate imaging findings who are being considered for surgical intervention, can help localize the symptomatic level and potentially benefit the patients by surgical intervention.

Adult↗
PubMed1999

Severity of depression in abstinent alcoholics is associated with monoamine metabolites and dehydroepiandrosterone-sulfate concentrations.

Depressed mood increases the relapse risk of abstinent alcoholics; its neurobiological correlates may include reduced serotonin and norepinephrine turnover rates and increased cortisol concentrations during detoxification stress. Neurosteroids such as dehydroepiandrosterone and its sulfate (DHEA and DHEA-S) may antagonize cortisol action and may have mood-elevating effects on their own. We measured severity of depression with Beck's Depression Inventory (BDI) and Hamilton's Depression Rating Scale (HDRS), plasma concentrations of cortisol, DHEA and DHEA-S, and CSF concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and the dopamine metabolite homovanillic acid (HVA) in 21 abstinent alcoholics after 4 weeks of abstinence and in 11 age-matched healthy control subjects. Only CSF MHPG concentrations were reduced in alcoholics compared to control subjects (41.4 +/- 6.6 vs. 53.3 +/- 8.6 pmol/ml). Self-rated depression was significantly correlated with CSF MHPG (Spearman's R = +0.57, P < 0.01), CSF 5-HIAA (R = +0.51, P < 0.05) and plasma cortisol concentrations (R = +0.50, P < 0.05). Negative correlations were found between DHEA-S concentrations and both self-rated depression (R = -0.45, P < 0.05) and observer-rated depression (R = -0.55, P < 0.05). The ratio of DHEA-S to cortisol serum concentrations was also negatively correlated with depression (BDI: R = -0.55, P < 0.01; HDRS: R = -0.63, P < 0.005). Anxiety (Spielberger's State Anxiety Scale) was only associated with CSF MHPG concentrations (R = +0.58, P < 0.01). Our findings point to the importance of noradrenergic dysfunction in the pathogenesis of depression among abstinent alcoholics and indicate that their mood states may also be modulated by a low DHEA-S to cortisol ratio, hypothetically indicative of low stress protection capacities.

Adult↗
PubMed1999

Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions.

Unrelated bone marrow transplantation (BMT) is often complicated by fatal opportunistic infections. To evaluate features unique to immune reconstitution after unrelated BMT, the lymphoid phenotype, in vitro function, and life-threatening opportunistic infections after unrelated and related T-cell-depleted (TCD) BMT were analyzed longitudinally and compared. The effects of posttransplant donor leukocyte infusions to treat or prevent cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infections on immune reconstitution were also analyzed. This study demonstrates that adult recipients of TCD unrelated BMTs experience prolonged and profound deficiencies of CD3(+), CD4(+), and CD8(+) T-cell populations when compared with pediatric recipients of unrelated BMT and adults after related BMT (P <.01), that these adults have a significantly increased risk of life-threatening opportunistic infections, and that the rate of recovery of CD4 T cells correlates with the risk of developing these infections. Recovery of normal numbers of CD3(+), CD8(+), and CD4(+) T-cell populations is similar in children after related or unrelated BMT. This study also demonstrates that adoptive immunotherapy with small numbers of unirradiated donor leukocytes can be associated with rapid restoration of CD3(+), CD4(+), and CD8(+) T-cell numbers, antigen-specific T-cell responses, and resolution of CMV- and EBV-associated disease after unrelated TCD BMT.

Adolescent↗
PubMed1999

Sialidase gene transfection enhances epidermal growth factor receptor activity in an epidermoid carcinoma cell line, A431.

Glycosphingolipids expressed in cancer cells have been implicated in the modulation of tumor cell growth through their interaction with transmembrane signaling molecules such as growth factor receptors. For glycosphingolipids to interact with growth factor receptors, the presence of sialic acid seems to be essential. Stable transfection of a gene encoding a soluble Mr 42,000 sialidase into a human epidermoid carcinoma cell line (A431) provided an approach by which the level of terminal lipid-bound sialic acid on the cell surface could be altered. In the sialidase-positive clones, the level of ganglioside GM3 was diminished, and little change was observed in protein sialylation. Sialidase-transfected cells grew faster than control cells. Sialidase expression did not modify the binding of epidermal growth factor (EGF) to its receptor but enhanced EGF receptor (EGFR) tyrosine autophosphorylation as compared to that of parental cells or cells transfected with the vector (pcDNA3) alone. Moreover, the phosphorylation of the EGFR, as well as other protein substrates, was observed at low EGF concentrations, suggesting an increase in the receptor kinase sensitivity. These data provided evidence that changes in ganglioside expression in cancer cells by appropriate gene transfection can dramatically affect EGFR kinase activity. Hence, the modulation of ganglioside expression may represent an approach to alter tumor cell growth.

Carcinoma, Squamous Cell↗
PubMed1999

Posterior leukoencephalopathy syndrome may not be reversible.

The association of an acute reversible encephalopathy with transient occipital lobe abnormalities on imaging studies is well known. This condition has been called reversible posterior leukoencephalopathy syndrome. The clinical presentation usually includes seizures, headache, altered mental status, and blindness, often associated with hypertension and immunosuppressants. The authors discuss a two-year-old male with Down syndrome who presented 2 months after allogeneic bone marrow transplantation with severe oculogyric crisis, without other complaints. The patient was being treated for hypertension and was receiving cyclosporine for prophylaxis of graft-vs-host disease. A computed tomography scan of the head revealed marked bilateral lucencies mainly involving the white matter of the occipital lobes, with a few foci of punctate hemorrhage. The condition improved when cyclosporine was discontinued, but an area of leukomalacia was identified on follow-up magnetic resonance imaging. To the authors' knowledge, oculogyric crisis as a presentation of reversible posterior leukoencephalopathy has not been previously described. Recognizing this association is important, because patients receiving cyclosporine are often receiving other medications that can potentially cause dystonic eye movements, possibly leading to a delay in diagnosis and treatment, which can result in an irreversible neurologic deficit.

Bone Marrow Transplantation↗
PubMed1998

Clinical evaluation of a new 10% carbamide peroxide tooth-whitening agent.

NUPRO Gold Tooth Whitening System was evaluated for efficacy according to the proposed ADA guidelines for acceptance. Sixty participants with discolored anterior teeth participated in a 14-day, double-blind, clinical trial. The participants were matched for age, gender, and oral health status and were given either a placebo gel without the active agent or the NUPRO Gold active gel, which they wore in a custom-fabricated mouth guard for home use. The shade of each participant's maxillary anterior teeth was evaluated using a value-oriented Vita Lumin Vacuum Shade Guide before the study. The same shade guide was used to determine shade changes. Time of use of the agent and potential side effects, such as tooth and gingival hypersensitivity and tissue irritation, were assessed at all recall examinations and were recorded by participants in daily diaries. The average shade change for the placebo users was less than one shade. The average shade change for the NUPRO Gold users was 6.96 shades. Tooth hypersensitivity varied from none to severe. Tissue irritation was minimal. The results of these evaluations indicate that NUPRO Gold is effective as a tooth-whitening system, when administered properly under the supervision of a dentist, with commonly reported side effects of transient tooth sensitivity and minimal gingival sensitivity. Little or no change in tissue health was noted. This study was supported by Dentsply Preventive Care (York, Pennsylvania).

Adolescent↗
PubMed1998

Cell cycle-independent death of prostate adenocarcinoma is induced by the trk tyrosine kinase inhibitor CEP-751 (KT6587).

Advanced prostate cancer remains largely incurable, primarily because the very low growth fraction present in these tumors makes them generally resistant to treatment with standard chemotherapeutic agents that target cell division. Effective therapies should therefore induce death of prostate cancer cells, independent of their growth rate. trkA, the high-affinity tyrosine kinase-linked receptor for nerve growth factor, has been implicated in prostatic cancer growth and may represent a molecular target for therapeutic agents. At low mg/kg doses, the trk tyrosine kinase inhibitor CEP-751 (KT6587) inhibits prostatic cancer growth in nine different animal models independent of the tumor growth rate, androgen sensitivity, metastatic ability, or state of tumor differentiation. CEP-751 is selective for cancerous versus normal prostate cells and affects the growth of only a limited number of nonprostate tumors. Importantly, CEP-751 induces cell death of prostate cancer cells in a cell cycle-independent fashion and, therefore, represents a novel therapeutic approach to the management of both hormone-dependent and hormone-independent prostate cancer.

Adenocarcinoma↗
PubMed1997

Detection of S-nitrosothiols and other nitric oxide derivatives by photolysis-chemiluminescence spectrometry.

We have developed a method for the detection of biologically relevant derivatives of NO. that couples photolysis to chemiluminescence. S-Nitrosothiols, N-nitroso-L-tryptophan, and iron-nitrosyl derivatives can all be detected by this methodology, and these derivatives can be distinguished from free NO. by making measurements with and without photolysis. The limits of detection of this system are in the 10 nM range, with an intraassay variability of less than 2% and an interassay variability of less than 1.5%. The use of cutoff filters and alterations in pH and flow rate through the photolysis cell provide additional useful parameters with which to characterize specific NO. derivatives based on their intrinsic stability. This methodology is a useful addition to the growing armamentarium of techniques used to characterize the biochemistry and metabolism of NO..

Chelating Agents↗
PubMed1997

Concordance of common movement disorders among familial cases.

Multicase families are frequently utilized in studies of movement disorders (MDs). We report families with two or more MD cases seen at the Movement Disorder Clinic, Saskatoon (MDCS). In 30% of the MD probands, there was either a history or documentation of at least one secondary MD case in the family. Only those MD cases that were seen at the MDCS were considered in this study. A total of 56 probands and 77 secondary MD cases were seen at the MDCS between 1968 and 1996. In 24 (31.2%) of the secondary cases, the diagnosis was different from that in the proband. In 46 families (82%), only one secondary case was seen, and the diagnosis was concordant with the proband in 71.7%. In the remaining 10 families with two or more secondary cases, the diagnosis was concordant in 64.5% of cases. The largest subgroup was Parkinson's disease (PD)--40 probands and 53 secondary cases. of these secondary cases, 73.6% had PD. The concordance rate was 91% in essential tremor, but only 12.5% if the proband had essential tremor + parkinsonism. Considering that a large proportion of secondary cases have a diagnosis discordant with the proband, we recommend that, whenever possible, MD diagnosis in secondary cases be based on clinical assessment.

Age of Onset↗
PubMed1997

Seasonal variation of melatonin binding sites in the pars tuberalis of the male mink (Mustela vison).

The seasonal changes of 2-[125I]iodomelatonin binding were studied using quantitative autoradiography in the pars tuberalis (PT) of the mink, a short-day breeder, kept out of doors. Studies were performed at 7 times of the year (July, September, October, January, February, and May), corresponding to different states of responsiveness of the gonadal system to the photoperiod. Melatonin binding was observed in the PT and on the ventral border of the pars distalis. Histological staining revealed that the binding on the border of the pars distalis corresponded to the zona tuberalis, a ventral extension of the PT. The binding was specific and saturable. The density of melatonin binding varied significantly with the time of year. The lowest density of binding was found in July, when animals experienced a long daylength and sexual rest, increased from July to reach a maximum in October, when animals experienced decreasing daylength and the hypothalamo-pituitary activity resumed, then slightly decreased and remained constant from November to May. The saturation study demonstrated that the decrease in melatonin binding density between October and February resulted from a change in the number (Bmax: October 70.6 +/- 4.0 vs February 49.6 +/- 2.8 fmol/mg protein; P < 0.01) but not in the affinity (Kd: October 33.6 +/- 7.1 vs February 20.8 +/- 5.1 pM; P > 0.05) of the binding sites. These results are discussed according to the different phases of mink reproductive cycle and to reported data on the sites of action of melatonin on seasonal reproduction and prolactin secretion.

Animals↗
PubMed1997

Fate of recurrent acute interstitial cellular rejection in an HLA identical kidney transplant recipient: impact of donor microchimerism.

We and others have shown that the incidence of acute interstitial rejection in HLA identical and non-identical kidney transplantation is similar. Chronic vascular rejection is, however, rare in full matched recipients. In light of the known correlation between previous acute cellular and chronic vascular rejections, lack of chronic rejection in full matched kidney allografts suggest that the immunological basis of acute and chronic rejections are different and/or only high-grade acute cellular rejection leads to chronic vascular rejection. Herein, we present the case of an HLA identical kidney transplant from a male donor to a female recipient who, because of poor compliance, had frequent acute interstitial cellular rejection culminating into chronic interstitial fibrosis with no evidence of vasculopathy or glomerulopathy characteristic of chronic vascular rejection. Donor cells, as examined by the presence of the Y chromosome DNA, were present in the peripheral blood during the most recent acute rejection but not thereafter. These findings support the notion that acute interstitial cellular rejection can lead to interstitial fibrosis but not chronic vasculopathy/glomerulopathy, and that microchimerism did not confer protection against acute cellular rejection.

Adult↗