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Biomedical subjects

S R Paul

Publications and source records attributed to S R Paul.

At least 19 recordsLinked to original sources
PubMed2001

Visual function is stable in patients who continue long-term vigabatrin therapy: implications for clinical decision making.

PURPOSE: Vigabatrin (VGB) has been shown to cause visual field constriction and other forms of mild visual dysfunction. We determined the safety of continuing VGB therapy in patients who had received prolonged treatment (>2 years) with the drug by serially monitoring changes in visual function over a 1-year period of continued therapy. We also followed up patients who discontinued VGB to see whether alternative therapies are effective. METHODS: Fifteen of 17 patients who continued VGB therapy had visual-function testing (visual acuity, color vision, kinetic and static perimetry) every 3 months for 1 year. Eighteen patients who discontinued VGB were given alternative antiepileptic drugs (AEDs); their seizure responses were measured after > or =3 months of treatment. RESULTS: Patients continuing VGB showed no worsening of visual acuity, color vision, or visual-field constriction beyond that measured in the initial test. Many patients who discontinued VGB had good seizure control with either newer or previously unsuccessful AEDs. CONCLUSIONS: For patients who have an excellent response to VGB and only mild visual changes, continued therapy may be safe with close visual monitoring. Patients who do not have a significant reduction in seizures or who experience considerable visual dysfunction with VGB may respond well to alternative therapies.

Adult↗
PubMed2000

Visual function loss from vigabatrin: effect of stopping the drug.

OBJECTIVE: To determine if visual function loss from vigabatrin use recovers after the drug is discontinued. BACKGROUND: Vigabatrin is an effective antiepileptic drug, but it is known to cause a variety of changes in visual function, including reductions in the visual field, visual acuity, color vision, and in electroretinogram (ERG) and electro-oculogram amplitudes. It is not known whether these changes are reversible. METHODS: Measurements of static and kinetic visual fields, visual acuity, color vision, and the ERG were recorded while patients were taking vigabatrin and again in 13 patients who had discontinued the drug because of lack of efficacy or reductions in visual field. Most of the patients had been off the drug for 3 to 6 months, although two patients had been drug-free for almost 1 year. RESULTS: Although ERG cone implicit time improved, most of the patients did not show improvement in either clinical measures of visual function (i.e., visual acuity, color vision, visual fields) or in ERG amplitudes. However, several patients who showed minimal visual field loss while on the drug had substantial recovery of ERG amplitudes. There was no statistical association between recovery of function and either duration of treatment or cumulative dosage. The multifocal ERG showed a diffuse loss of function that was not isolated to the periphery. CONCLUSIONS: Although the visual deficits in patients taking vigabatrin tend to be mild, most patients do not show improvement after they stop taking the drug. Visual field loss resulting from vigabatrin was not reversible. Visual acuity, color vision, and ERG amplitude loss may be reversible in patients with minimal or no field loss.

Adult↗
PubMed1999

Visual dysfunction in patients receiving vigabatrin: clinical and electrophysiologic findings.

BACKGROUND: Vigabatrin is an antiepileptic drug that, although relatively well tolerated, is associated with visual field constriction and other visual disturbances of unclear origin. METHODS: We performed a complete neuroophthalmologic examination and electrophysiologic studies on 39 patients receiving vigabatrin and on 11 control patients. RESULTS: Nearly 50% of patients receiving vigabatrin had constricted visual fields compared with control patients. Some of the vigabatrin patients also had reduced visual acuity and abnormal color vision. In addition, most vigabatrin patients had abnormal electroretinographic results, the severity of which correlated strongly with the degree of visual field constriction. CONCLUSIONS: Vigabatrin can cause electrophysiologic evidence of retinal dysfunction and clinically detectable disturbances of visual sensory function.

Adult↗
PubMed1997

Propantheline protects the oral mucosa after high-dose ifosfamide, carboplatin, etoposide and autologous stem cell transplantation.

Oral mucositis is a dose-limiting toxicity of high-dose etoposide regimens. Since etoposide is excreted in saliva, we tested the hypothesis that the induction of xerostomia would reduce the severity of the mucositis. We designed a phase II trial of propantheline in patients receiving high-dose ICE (ifosfamide 20 mg/m2, carboplatin 1.8 g/m2, etoposide 3 g/m2 in divided doses over 6 days) chemotherapy plus autologous hematopoietic stem cell support. We treated 31 consecutive patients and graded the oral mucositis according to WHO criteria. Mild (WHO grade 0, I, II) mucositis occurred in 28 of 31 (90%) (95% CI 74-98%) patients; severe (WHO grade III, IV) mucositis occurred in three of 31 patients (10%) (95% CI 2-25%) patients. In contrast, a published reference group treated with the same doses and schedule of ICE reported mild mucositis in 10 of 46 (22%) (95% CI 11-36%) patients and severe mucositis in 36 of 46 (78%) (95% CI 64-89%). Propantheline therapy had no protective effect on esophagitis and enteritis associated with high-dose ICE. Minor toxicities were constipation and asymptomatic tachycardia; major toxicities were palpitations in one patient and urinary retention in one patient. We conclude that anticholinergic therapy dramatically reduced the oral mucositis associated with high-dose etoposide and should be considered as a supportive care measure for patients receiving etoposide-containing regimens.

Adult↗
PubMed1997

Mesenteric pleomorphic liposarcoma in an adolescent.

We report a case of pleomorphic liposarcoma arising in the root of the mesentery of an adolescent girl. Pleomorphic liposarcoma is an extremely rare tumor in the pediatric age group, and few well-documented cases are found in the literature. To the best of our knowledge, none have been described in the abdomen. The histologic and ultra-structural features of this tumor are described, and the literature concerning pediatric pleomorphic liposarcoma is reviewed.

Adolescent↗
PubMed1996

Use of messenger RNA differential display to identify interleukin-11-responsive genes in human umbilical cord blood mononuclear cells: IL-11 upregulates the expression of the hMAL gene.

Human umbilical cord blood (HUCB) mononuclear cells represent a source of hematopoietic stem and progenitor cells, including cells responsive to interleukin-11 (IL-11). To investigate the molecular mechanisms associated with IL-11 action, we have used HUCB mononuclear cells as a model system to identify genes that are transcriptional targets of IL-11. Using the technique of messenger RNA differential display, we have identified 17 candidate cDNA differentially expressed in mononuclear cells incubated without and with IL-11. Fifteen of these cDNA were recovered, and 11 were sequenced. DNA sequence analysis has identified one of these cDNA as being the human MAL gene, originally identified as a marker for intermediate stages of T cell differentiation. Northern analysis using a MAL-specific probe confirms the upregulation of MAL by IL-11 in HUCB cells.

Cells, Cultured↗
PubMed1996

Regulation of preadipocyte factor-1 gene expression during 3T3-L1 cell differentiation.

Preadipocyte factor-1 (Pref-1), a novel gene product isolated from murine preadipocyte 3T3-L1 cells, is thought to function as a negative regulator of adipocyte differentiation. We investigated the regulation of Pref-1 expression in 3T3-L1 preadipocytes during proliferation, growth arrest, and early differentiation in the presence and absence of three well described differentiation antagonists: interleukin-11 (IL-11), transforming growth factor-beta, and tumor necrosis factor-alpha. Northern blot analysis was used to determine messenger RNA (mRNA) steady state expression of Pref-1 and two differentiation-specific genes, adipsin and glycerol-3-phosphate dehydrogenase. We confirmed that Pref-1 mRNA is abundant in proliferating preadipocytes and that its expression is dramatically reduced early in differentiation. However, proliferating and growth-arrested cells treated with the differentiation inhibitor IL-11 demonstrated a modest decrease in Pref-1 mRNA abundance. Transforming growth factor-beta and tumor necrosis factor-alpha had little effect. The reduction of Pref-1 mRNA was most dramatic in differentiating preadipocytes treated with IL-11, occurring despite inhibition of adipogenesis, as judged by cell morphology and adipocyte-specific gene expression (adipsin and glycerol-3-phosphate dehydrogenase). This effect of IL-11 on Pref-1 suggests that different mechanisms are responsible for the IL-11-induced and the differentiation- associated down-regulation of Pref-1, thus dissociating Pref-1 regulation from differentiation. We conclude that Pref-1 expression is not a reliable marker of preadipocytes, and that decreased Pref-1 abundance does not function as a trigger for adipocyte differentiation.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Molecular cloning and characterization of murine interleukin-11.

Human interleukin-11 (IL-11) has been shown to have pleiotropic action on hematopoietic, hepatic, stromal, epithelial, neural, and osteoclast cells. In the present work, the murine IL-11 cDNA has been isolated from a fetal thymic cell line, and its structure and function compared with human IL-11. The murine protein was demonstrated to have identical actions on the proliferation of a murine plasmacytoma cell line, murine primitive bone marrow progenitor cells, and megakaryocyte precursors. The murine IL-11 protein was synthesized as a soluble thioredoxin-IL-11 fusion in Escherichia coli and the expression of murine IL-11 was examined by pulse-chase radiolabeling in COS cells. The chromosomal location of the murine IL-11 gene was assigned to the proximal arm of chromosome 7.

Amino Acid Sequence↗
PubMed1995

American Heart Association-Bugher Foundation Centers for Molecular Biology in the Cardiovascular System.

BACKGROUND: The American Heart Association (AHA) and the Henrietta B. and Frederick H. Bugher Foundation in 1985 entered into a partnership to establish a group of Centers for Molecular Biology in the Cardiovascular System. The goal was to recruit and train young scientists with medical training to apply molecular and cellular biology knowledge and techniques to cardiovascular problems. METHODS AND RESULTS: Six Centers have been awarded (three in 1986 and three in 1991), and a total of 110 trainees have been involved as of June 30, 1994. Of these trainees, 77 were recruited and trained by the 1986 Centers. As of June 1994, 88% of these trainees remained in academic medicine and 54% progressed to higher academic ranks; 79% published papers in science and 66% in molecular biology; and 36% obtained extramural funding for their work. On this basis, the 1986 trainees appear to be well on their way to becoming successful academic cardiologists. CONCLUSIONS: The AHA-Bugher Foundation Center program has produced a cadre of cardiovascular scientists who are applying molecular biology knowledge to both basic and clinical problems.

Awards and Prizes↗
PubMed1994

Interleukin-11 expression in donor bone marrow cells improves hematological reconstitution in lethally irradiated recipient mice.

Lethally irradiated mice were transplanted with syngeneic bone marrow cells infected with a recombinant retrovirus vector containing the human interleukin-11 (hIL-11) cDNA under the control of the human cytomegalovirus (CMV) immediate early promoter. The hIL-11 RNA transcript from the vector was detected in the spleen and bone marrow of the recipient mice, and hIL-11 protein accumulated in their serum. The hematological reconstitution of these mice was compared with recipient mice rescued with bone marrow infected with the parental retrovirus vector not containing the hIL-11 cDNA. The hIL-11-expressing mice had an accelerated recovery of circulating platelets and red and white blood cells. Three months after the transplantation, bone marrow was harvested from the mice and used to rescue other lethally irradiated recipients. The hIL-11 mRNA and protein were also detected in these secondary recipients, and the mice showed improved hematological reconstitution relative to a control group. No abnormal cell proliferation or other histopathology was observed in the hIL-11-expressing mice.

Animals↗
PubMed1992

Interleukin-11 promotes accessory cell-dependent B-cell differentiation in humans.

Interleukin-11 (IL-11) is a recently described stromal-derived cytokine that supports the growth of an IL-6-dependent murine plasmacytoma line in the presence of antibody to IL-6 and appears to act in a manner similar to IL-6 on hematopoietic stem cells. Because IL-6 is known to promote differentiation of normal human B cells, the role of IL-11 on B-cell differentiation in vitro was characterized. IL-11 does not result in significantly increased DNA synthesis or Ig secretion by purified B cells alone or B cells cultured with Staphylococcus Cowan I, a T-cell-independent B-cell mitogen. In contrast, purified B cells cultured in the presence of pokeweed mitogen (PWM), irradiated T cells, and monocytes show increased DNA synthesis at day 3 and increased IgG and IgM secretion at day 7 of culture; addition of IL-11 further augments Ig secretion without change in DNA synthesis, an effect that can only be partially blocked by monoclonal antibody to IL-6. Similar experiments confirmed that increased IgG secretion was demonstrable when either IL-11 or IL-6 was added to B cells + CD4+/45RA- T cells + monocytes + PWM; in contrast, Ig secretion was low and equivalent when CD4+/45RA+ T cells were cultured with B cells+monocytes+PWM with or without IL-6 or IL-11. Neither IL-6 nor IL-11 could significantly increase phytohemagglutinin (PHA)-induced DNA synthesis by CD4+/45RA- or CD4+/45RA+ T cells. Although PWM or IL-11 induced IL-6 mRNA expression in both CD4+/45RA- T cells and monocytes, in neither cell did IL-11 increase IL-6 mRNA expression over that noted to PWM alone. These observations support the view that IL-11 promotes differentiation of human B lymphocytes only in the presence of accessory T cells and monocytes and that a minor component of this effect may be through stimulation of IL-6 production by CD4+/45RA- T cells and monocytes.

Actins↗
PubMed1992

Small sample performance of tests of homogeneity of odds ratios in K 2 x 2 tables.

In this note we study, by simulation, small sample performance in terms of size of ten procedures for testing the homogeneity of odds ratios in K 2 x 2 contingency tables. These ten statistics are derived for 'large-stratum' settings. Our study concerns the behaviour of these statistics for 'small-stratum' settings.

Chi-Square Distribution↗
PubMed1992

The cloning and biological characterization of recombinant human interleukin 11.

Interleukin 11 (IL-11) is a pleiotropic hematopoietic growth factor with stimulatory effects on multiple hematopoietic progenitor cells. An immortalized primate bone marrow stromal cell line was established to facilitate the analysis of interactions between hematopoietic progenitors and the microenvironment. This line was found to produce a novel growth factor that directed the proliferation of a murine plasmacytoma cell line. A cDNA encoding this activity was isolated through functional expression cloning in mammalian cells. Preliminary characterization of the cytokine revealed that IL-11 stimulated T cell-dependent B cell immunoglobulin secretion and synergized with IL-3 in murine megakaryocyte formation. Subsequent analysis of the clone has demonstrated that it also synergizes with IL-3 and steel factor in the stimulation of early progenitors and affects early megakaryocyte formation and maturation. In addition, IL-11 induces secretion of acute phase proteins in the liver and may function in the hematopoietic microenvironment as an adipogenic antagonist in a paracrine manner. Further in vitro and in vivo analysis of IL-11 will be necessary to determine the biologic function and potential therapeutic use of the cytokine.

Animals↗
PubMed1992

Molecular cloning of the cDNA encoding a receptor tyrosine kinase-related molecule with a catalytic region homologous to c-met.

Receptor tyrosine kinases mediate a range of growth and differentiation processes in multiple biological systems. In this work, we report the identification of a novel tyrosine kinase-related molecule, nyk-r, and the molecular cloning of its complete cDNA. Its extra-cellular domain bears no apparent homology with other receptor families, but its intracellular kinase-related region has considerable similarity with members of the insulin-receptor family such as c-met and trk B. Also, the nyk-r gene is expressed in a wide range of tissues and cell lines.

Amino Acid Sequence↗
PubMed1992

Lack of a role of interleukin 11 in the growth of multiple myeloma.

Interleukin (IL) 11 is a recently described lymphokine which, like IL-6, stimulates normal hematopoietic murine and human hematopoietic progenitor cells and therefore has potential value for either enhancing hematopoiesis in disease states or augmenting hematopoietic recovery after myeloablative therapies. Since IL-6 is known to promote the growth of human myeloma, either in an autocrine or paracrine fashion, we examined the effect of IL-11 on the growth of a murine plasmacytoma cell line, human myeloma-derived cell lines, and freshly isolated human myeloma cells. Interleukin 11 does increase DNA synthesis by the murine plasmacytoma line T10 in the presence of neutralizing antibody to IL-6. However, neither human myeloma cells nor derived cell lines express IL-11 mRNA; secrete IL-11; express IL-11 cell surface receptors; or augment either DNA synthesis or Ig secretion in response to exogenous IL-11. These findings strongly suggest that IL-11 does support the growth of a murine plasmacytoma cell line but does not play a role in the growth of either freshly isolated human myeloma cells or derived cell lines.

Animals↗
PubMed1992

Role of interleukin 6 in the growth of myeloma-derived cell lines.

The role of interleukin 6 (IL-6) in the growth of five multiple myeloma-derived cell lines was characterized. The U266 and RPMI 8226 cell lines demonstrated increased DNA synthesis when cultured with exogenous IL-6, expressed IL-6 cell surface receptors (IL-6Rs) and expressed mRNA for IL-6R. However, these cells did not secrete detectable IL-6 protein, and a neutralizing antibody to IL-6 did not inhibit their growth. Three other myeloma-derived cell lines ARH-77, IM-9 and HS-Sultan did not respond to exogenous IL-6, secrete IL-6 or express cell surface IL-6Rs. The IL-6 responsive cell lines bore late B-cell surface antigens (Ags), CD38 and PCA-1, whereas those lines which were non-IL-6 responsive strongly expressed B1 (CD20) and B4 (CD19) Ags, representing earlier stages in B-cell differentiation. Finally, the two IL-6 responsive cell lines did not express Epstein-Barr virus (EBV) proteins; in contrast, EBV encoded proteins typically expressed during latency could be detected in the three non-IL-6 responsive lines, confirming infection with virus. These studies clarify the heterogeneity observed in the myeloma cell line phenotype and biology and suggest that the U266 and RPMI 8226 cell lines, which express IL-6 cell surface receptors and are IL-6 responsive, may be useful for further study of IL-6 signal transduction in and related IL-6 mediated growth of myeloma in vivo. In contrast, those cell lines which are IL-6-independent provide a model for further study of EBV transformation and IL-6-dependent growth mechanisms in malignancy.

Blotting, Northern↗
PubMed1991

Stromal cell-associated hematopoiesis: immortalization and characterization of a primate bone marrow-derived stromal cell line.

An elucidation of the interaction between the bone marrow microenvironment and hematopoietic stem cells is critical to the understanding of the molecular basis of stem cell self renewal and differentiation. This interaction is dependent, at least in part, on direct cell to cell contact or cellular adhesion to extracellular matrix proteins. Long-term bone marrow cultures (LTMC) provide an appropriate microenvironment for maintenance of primitive hematopoietic stem cells and a means of analyzing this stem cell-stromal cell interaction in vitro. Although LTMC have been successfully generated from murine and human bone marrow, only limited success has been reported in a primate system. In addition, few permanent stromal cell lines are available from nonmurine bone marrow. Because the primate has become a useful model for large animal bone marrow transplant studies and, more specifically, retroviral-mediated gene transfer analysis, we have generated immortalized bone marrow stromal cell lines from primate bone marrow using gene transfer of the Simian virus large T (SV40 LT) antigen. At least one stromal cell line has demonstrated the capacity to maintain early hematopoietic cells in long-term cultures for up to 4 weeks as measured by in vitro progenitor assays. Studies were undertaken to characterize the products of extracellular matrix biosynthesis and growth factor synthesis of this cell line, designated PU-34. In contrast to most murine bone marrow-derived stromal cell lines capable of supporting hematopoiesis in vitro that have been examined, the extracellular matrix produced by this primate cell line includes collagen types I, laminin. Growth factor production analyzed through RNA blot analysis, bone marrow cell culture data, and factor-dependent cell line proliferation assays includes interleukin-6 (IL-6), IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, leukemia inhibitory factor, and a novel cytokine designated IL-11. This immortalized primate bone marrow stromal cell line may be useful in maintaining early progenitor cells for experimental manipulation without the loss of reconstituting capacity and as a potential source of novel hematopoietic growth factors.

Animals↗