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Biomedical subjects

M Potter

Publications and source records attributed to M Potter.

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

Scleromyxedema: response to high-dose intravenous immunoglobulin (hdIVIg).

We report 2 patients with scleromyxedema, both associated with IgG-lambda paraproteinemia, who were treated with high-dose intravenous immunoglobulin (hdIVIg) 2g/kg per month. The response to treatment was assessed using an objective skin scoring system initially established for patients with scleroderma. This system grades the overall severity of the induration and the reduction in mobility of the skin. Both patients initially had a dramatic response to treatment which was sustained in one patient. The first patient, a 30-year-old black man, showed a reduction in skin scores from 36/60 to 11/60 over a 3-month period, during which time he had 3 infusions of hdIVIg. After an unplanned 2-month break from treatment, severe neuromuscular complications developed. These improved initially with more frequent infusions of hdIVIg but oral corticosteroids were required to treat worsening myopathy. Unfortunately, the initial response to hdIVIg has not been sustained and his skin scores at 1 year returned to baseline. The second patient, a 60-year-old white man, showed a similarly dramatic reduction in skin scores from 36/60 to 15/60 over a 3-month period after having received only 2 infusions of hdIVIg. There has been sustained improvement after 10 months of therapy and the interval between hdIVIg infusions has been increased to 10 weeks without deterioration. HdIVIg may be an effective treatment for some patients with scleromyxedema, a rare condition with few effective treatments and a poor prognosis.

Adult↗
PubMed1999

Inhibition of pristane-induced peritoneal plasmacytoma formation.

While the mechanism of how Indo inhibits PCTGEN is not established, Several hypothetical explanations provide new potential experimental approaches. Indo may block production of cytokines such as Il-6 in accessory cells that are critical for B-cell growth, viability and maturation, or it may directly target B cells via PPAR-gamma receptors. The latter mode of action is described in other cell types but not yet defined in B cells.

Animals↗
PubMed1999

Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield.

Conventional methods for rAAV purification that are based on cesium chloride ultracentrifugation have often produced vector preparations of variable quality and resulted in significant loss of particle infectivity. We report here several novel purification strategies that involve the use of non-ionic iodixanol gradients followed by ion exchange or heparin affinity chromatography by either conventional or HPLC columns. These methods result in more than 50% recovery of rAAV from a crude lysate and routinely produce vector that is more than 99% pure. More importantly, the new purification procedures consistently produce rAAV stocks with particle-to-infectivity ratios of less than 100, which is significantly better than conventional methods. The new protocol increases the overall yield of infectious rAAV by at least 10-fold and allows for the complete purification of rAAV in 1 working day. Several of these methods should also be useful for large-scale production.

Blotting, Western↗
PubMed1999

HHV-6-related secondary graft failure following allogeneic bone marrow transplantation.

We report the case of an 11-year-old boy who underwent allogeneic bone marrow transplantation (BMT) for relapsed acute lymphoblastic leukaemia. Despite adequate engraftment, on day 45 he developed marrow aplasia with haemophagocytosis. HHV-6 was detected in blood and bone marrow by nested PCR. Retrospective testing showed that viraemia had started on day 24. Following therapy with foscarnet and ganciclovir, viral load declined to undetectable levels and his donor marrow recovered contemporaneously. This case suggests that HHV-6 may be a treatable cause of graft failure following BMT and provides clinical and virological evidence for the anti-HHV-6 activity of ganciclovir and foscarnet.

Antiviral Agents↗
PubMed1999

Limited joint mobility in the hands and feet of adolescents with Type 1 diabetes mellitus.

AIMS: Limited joint mobility (LJM) in the foot has not been assessed in adolescents with Type 1 diabetes mellitus (DM) but is associated with neuropathic ulceration in adults. This study was designed to determine the presence of LJM in adolescents with Type 1 DM and its association with microvascular disease. METHODS: The hands, feet and hips were examined in 302 diabetic adolescents and 51 nondiabetic controls (aged 11.5-20 years). LJM was defined as less than the fifth percent reference for controls. RESULTS: Reduced motion was found in 35% of diabetic adolescents at the subtalar (ST) joint, 18% at the first metatarsophalangeal (MTP) joint, 26% at the fifth metacarpophalangeal (MCP) joint and 13% had limited passive extension of the interphalangeal (IP) joints of the hands. Limited passive IP joint extension of the hands was not present in the controls. Limited active IP joint extension, a positive 'prayer sign', occurred in 35% of diabetic adolescents and 14% of controls. Diabetic adolescents showing LJM in any of these areas, except the prayer sign, were more likely to have retinopathy (odds ratio 2.53, CI: 1.53-4.18). Those with LJM in the foot were more likely to have albumin excretion rates >7.5 microg/min (OR 2.06, CI: 1.16-3.68). CONCLUSION: LJM in the feet of adolescents with Type 1 DM is associated with microvascular disease and is a useful routine clinical measure.

Adolescent↗
PubMed1999

BALB/c.CBA/N mice carrying the defective Btk(xid) gene are resistant to pristane-induced plasmacytomagenesis.

The X-chromosome from the CBA/N mouse which carries the defective Bruton's tyrosine kinase (Btk) allele (Xxid) has been introgressively backcrossed onto the plasmacytoma (PCT) induction-susceptible BALB/cAN. Inbred BALB/c.CBA/N-xid/xid (C.CBA/N) mice raised and maintained in our conventional colony were given three 0.5 ml injections of pristane and were highly refractory to PCT induction. Only one PCT was found among 59 mice followed for > or =300 days. Twenty mice were examined at day 200 for foci of plasma cells in the oil granuloma. Ten mice had small foci of plasma cells, most of which were plasmacytotic, embedded in the inflammatory oil granuloma. In one there were multiple foci, but most of the mice had only one or two foci. F1 hybrid XxidY males derived from CBA/N females crossed to BALB/cAnPt were also resistant to PCT induction, while heterozygous and homozygous XY males were susceptible. C.CBA/N mice can develop extensive mucosal plasma cells as well as plasma cell accumulations in oil granuloma tissue, but the precursors of these plasma cells do not give rise to PCT in genetically susceptible hosts. The failure of C.CBA/N mice to develop PCT is probably due to the elimination of B cell clones that can be perpetuated by repeated exposure to thymus-independent type 2 antigens.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1998

The wst gene regulates multiple forms of thymocyte apoptosis.

Mice homozygous for the autosomal recessive mutation Wasted (wst/wst) display a disease characterized by immunodeficiency, cerebellar dysfunction, and sensitivity of their hematopoeitic cells to gamma radiation. Wasted mice die by 30 days of age. In this report, we show that the Wasted thymus shows evidence of dramatically increased apoptosis in situ. Moreover, wst/wst thymocytes are more sensitive to apoptosis induced by gamma radiation, heat shock, alpha-CD3 stimulation, and dexamethasone treatment in vitro. Thus, wst gene is a regulator of thymocyte apoptosis both in vitro and in vivo. The elevated levels of thymocyte apoptosis may be a major contributor to the lymphoid dysfunction and ultimate death in wst/wst mice.

Animals↗
PubMed1998

Consistent loss of functional transforming growth factor beta receptor expression in murine plasmacytomas.

Murine plasmacytomas are tumors of Ig-secreting plasma cells that can be induced in genetically susceptible BALB/c mice. The deregulation of the c-myc protooncogene is a critical oncogenic event in the development of plasmacytomas (PCTs) although it is not sufficient for their malignant transformation. We have demonstrated that PCTs produce active transforming growth factor beta (TGF-beta) in vitro. Because TGF-beta is a potent negative regulator of the proliferation and differentiation of B lymphocytes, we examined its role in plasmacytomagenesis by comparing responsiveness to TGF-beta of nonneoplastic plasma cells and PCTs. The nontransformed plasma cells that accumulate in interleukin 6 transgenic mice undergo accelerated apoptosis upon treatment with TGF-beta, but the 15 PCTs studied, including primary and transplanted tumors as well as established cell lines, were refractory to TGF-beta-mediated growth inhibition and apoptosis. Although PCTs lack functional TGF-beta receptors as demonstrated by chemical crosslinking to radiolabeled TGF-beta1, they nonetheless contain mRNA and protein for both type I and II TGF-beta receptors, suggesting a potential defect in receptor trafficking or processing. The results clearly show the consistent inactivation of TGF-beta receptors in plasmacytoma cells, demonstrating for the first time that interruption of a tumor suppressor pathway contributes to plasmacytomagenesis.

Animals↗
PubMed1998

A fluorescence video-endoscopy technique for detection of gene transfer and expression.

The green fluorescent protein (GFP) has previously been adapted as a reported for gene transfer and expression in mammalian cells in culture and in tissue sections. Herein is described a new method for detecting GFP in situ within epithelia accessible to fiberoptic endoscopy by incorporating fluorescent filters for detection of GFP into an existing fiberoptic endoscopy system. This device was used to detect expression of GFP from adeno-associated virus (AAV; does of 3 x 10(7) IU) and adenovirus (Ad; does of l x 10(9) to 1 x 10(10) p.f.u.) vectors within the bronchial epithelium of New Zealand white rabbits. GFP expression was confirmed by fluorescence-activated cell sorting (FACS), direct fluorescence microscopy of cytospin preparations of brushed cells, and by fluorescence microscopy of fixed tissue sections. This reporter gene/detection system was then used to track the time course of expression of the AAV vector in the bronchial epithelium over the first 30 days after administration. The transduction frequency in the treated region of the epithelium peaked at around 50% at 21 days after transduction. Vector expression was still present at around 20% efficiency at 30 days after administration. This example indicates how this method could be used to reliably track gene transfer in living animals or patients.

Adenoviridae↗
PubMed1997

The plasmacytoma resistance gene, Pctr2, delays the onset of tumorigenesis and resides in the telomeric region of chromosome 4.

Mouse plasmacytomas share pathogenetic features in common with both multiple myeloma and Burkitt's lymphoma in humans. Susceptibility to plasmacytoma induction by intraperitoneal pristane in mice is controlled by multiple genes. At least two of these genes reside on mouse chromosome 4 in regions of the genome sharing linkage homology with human chromosomes 9p21, 1p32, and 1p36. A series of congenic strains recombinant for regions of mouse chromosome 4 in the vicinity of the Pctr2 predisposition locus were created and typed for their tumor susceptibility/resistance phenotypes. These strains were derived by introgressively backcrossing alleles from resistant DBA/2 mice onto the susceptible BALB/cAnPt background. Six resistant and two susceptible strains were allelotyped for 10 genes and 49 random DNA markers to identify the smallest region of overlap in the resistant strains. These studies have determined that the Pctr2 locus resides in either a 500-kb interval proximal to Nppa, or in a 1- to 2-centiMorgan (cM) interval distal to Nppa. In these congenic strain analyses, the Nppa and Fv1 loci, in addition to genes within about 1 cM of these loci, have been excluded as candidates for the Pctr2 locus. A relevant locus that may reside in this interval is Rep2; it is associated with the efficiency of repairing X-ray induced DNA damage sustained during the G2 phase of the mitotic cycle. The Pctr2 locus acts in a codominant fashion. F1 hybrids between resistant and susceptible congenic strains exhibit a reduced tumor incidence and a significant delay in the onset of tumorigenesis. Identification and eventual cloning of the Pctr2 locus may assist in the identification of genes involved in many types of cancer showing aberrations in human chromosome 1p36.

Alleles↗
PubMed1997

Indomethacin is a potent inhibitor of pristane and plastic disc induced plasmacytomagenesis in a hypersusceptible BALB/c congenic strain.

Continuous indomethacin (INDO) administration in the drinking water (10 to 20 microg/mL) profoundly inhibited plasmacytoma (PCT) development initiated by three 0.2- or 0.5-mL intraperitoneal (i.p.) injections of pristane in hypersusceptible BALB/c.DBA/2-Idh1-Pep3 congenic mice. The most effective inhibitions were obtained with continuous INDO treatment. When treatment was delayed until 50 to 60 days after the first pristane injection, there was approximately a 50% reduction in PCT incidence. The primary action of pristane is the induction of a chronic inflammation in the peritoneal connective tissues and the formation of a microenvironment where PCTs develop. INDO, a powerful inhibitor of prostaglandin synthases (cyclooxygenases 1 and 2), did not inhibit the formation of mesenteric oil granuloma nor the appearance of cells in this chronic inflammatory tissue carrying c-myc illegitimately joined to an Ig heavy chain switch region, ie, the t(12;15) chromosomal translocation. INDO inhibited PCT induction by the i.p. implantation of 21 x 2 mm polycarbonate discs. These solid objects predominantly induce the formation of a patchy fibroplastic tissue on contacting peritoneal surfaces. These and previous data indicate that indomethacin inhibits an intermediate stage in PCT development after the arrival of cells bearing the T(12;15) translocation in the oil granuloma and before these cells acquire transplantability to a pristane-conditioned host. The biological mechanism that explains how INDO inhibits PCT development is not yet established but appears to result from decreased production of prostaglandins in chronic inflammatory tissues (oil granuloma, fibroplasia), suggesting that prostaglandins play an active role in oil and solid plastic induced PCT formation.

Administration, Oral↗
PubMed1997

In vitro mutagenicity of the plasmacytomagenic agent pristane (2,6,10,14-tetramethylpentadecane).

Pristane is known to induce a distinct type of B-cell-derived malignant lymphoma, plasmacytoma, after administration into the peritoneal cavity of genetically susceptible BALB/cAnPt mice. Since the mechanism of pristane-induced plasmacytoma development is poorly understood, we chose to examine the possibility that pristane is mutagenic in rodent cells and decided to use bacteriophage lambda-derived lacI/lacZ genes as target/reporter to quantitate mutagenesis. Here we show that in vitro exposure to micromolar amounts of pristane, delivered as an inclusion complex with beta-cyclodextrin, resulted in 1.7-fold and 6.2-fold increases of mutant frequencies over controls in a cell line of rat fibroblasts and primary mouse B lymphocytes, respectively. We conclude that pristane can be mutagenic to mammalian cells, yet are currently unable to explain the mechanism of mutagenicity. It is suggested that B-cell mutagenesis contributes to the plasmacytomagenic activity of pristane in vivo.

Amino Acid Sequence↗
PubMed1997

Migration of cells with immunoglobulin/c-myc recombinations in lymphoid tissues of mice.

Recombinations between c-myc and immunoglobulin (Ig) sequences that typically occur in pristane-induced mouse plasmacytomas were detected in secondary lymphoid tissues from normal mice, chiefly in the gut-associated lymphoid tissue. Based on the analysis of recombination sequences as clonotypic markers, migration of c-myc recombination-positive cells was observed between Peyer's patches and into the intestine. Treatment of plasmacytoma-susceptible BALB/cAn mice with pristane induced proliferation and migration of these cells into mesenteric lymph node, spleen, and oil granuloma within 7 days. Plasmacytoma-resistant strains of mice (DBA/2N, C3H/HeJ, C57BL/6) differed in that (1) they harbored fewer clones (Ig/c-myc recombinations were detected in 33% of resistant mice versus 91% of BALB/cAn mice after pristane treatment); (2) Ig/c-myc-positive cells were rarely detected in the oil granuloma, and (3) c-myc recombined predominantly with the Ig alpha locus in BALB/cAn mice (72%), but with the Ig mu locus in DBA/2N and in C57BL/6 (67%). The results demonstrate that normal mice generate a large number of lymphocytes with aberrant c-myc in intestinal tissues without developing tumors.

Animals↗