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Biomedical subjects

J Schroeder

Publications and source records attributed to J Schroeder.

At least 19 recordsLinked to original sources
PubMed2003

Tumor type M2 pyruvate kinase expression in metastatic renal cell carcinoma.

The M2 isoenzyme of pyruvate kinase (M2-PK) is specifically expressed in tumor cells (TuM2-PK) and has been detected in the peripheral blood of patients with renal cell carcinoma (RCC). TuM2-PK is not useful as a biological marker in localized RCC. We analysed TuM2-PK in 68 patients with metastatic RCC after initial surgery and prior to or during chemoimmunotherapy of metastases. In 50 patients, the levels of TuM2-PK were measured during chemoimmunotherapy with interleukin-2, interferon-alpha2a and 5-fluorouracil for up to 8 months and were correlated to response as assessed by radiological imaging techniques. TuM2-PK was quantified with a commercially available enzyme linked immunosorbent assay kit using a cut off of 15 kU/l. In 48 of 68 patients (71%), TuM2-PK was elevated above the cut-off. TuM2-PK was significantly higher in G3 tumors than in G2 tumors. In 34 of 50 patients (68%) undergoing chemoimmunotherapy, a positive correlation between TuM2-PK values and response to treatment was observed. Based on these data, we would not recommend the routine clinical use of TuM2-PK in metastatic RCC at this point.

Adult↗
PubMed2001

Is frontal lobe involved in the generation of auditory evoked P50?

This study examined the functional substrate of P50 suppression. Auditory evoked potentials (AEPs) and magnetic fields (AEFs) were recorded from healthy subjects simultaneously and analyzed using spatio-temporal source analysis. The resulting equivalent dipole model for the AEP consisted of one source in the auditory cortex (AC) of each hemisphere and an radially oriented medial frontal source, both with maximum AEP activity around 50 ms. The frontal source was functionally separated from the AC sources since it peaked significantly later and showed significantly larger P50 amplitude suppression. P30m showed neither suppression nor substantial frontal activity. In sum, this study relates P50 suppression to reduction of AC source activity and is the first to yield direct evidence for frontal involvement in P50 suppression.

Acoustic Stimulation↗
PubMed2001

Identification of a novel cytokine, ML-1, and its expression in subjects with asthma.

A novel gene, designated ML-1, was identified from a human genomic DNA clone and human T cell cDNA sequences. The second exon of ML-1 gene shares significant sequence identity with the gene encoding IL-17 (IL-17). ML-1 gene expression was up-regulated in activated PBMCs, CD4(+) T cells, allergen-specific Th0, Th1, and Th2 clones, activated basophils, and mast cells. Increased expression of the ML-1 gene, but not IL-17, was seen following allergen challenge in four asthmatic subjects, suggesting its role in allergic inflammatory responses. ML-1 from transiently transfected COS-7 cells was able to induce gene expression and protein production for IL-6 and IL-8 (at 10 ng/ml of ML-1: for IL-6, 599.6 +/- 19.1 pg/ml; for IL-8, 1724.2 +/- 132.9 pg/ml; and at 100 ng/ml of ML-1: for IL-6, 1005.3 +/- 55.6 pg/ml; for IL-8, 4371.4 +/- 280.5 pg/ml; p < 0.05 for both doses vs baseline) in primary bronchial epithelial (PBE) cells. Furthermore, increased expression of ICAM-1 was found in ML-1-stimulated PBE cells (mean fluorescence intensity (MFI) = 31.42 +/- 4.39 vs baseline, MFI = 12.26 +/- 1.77, p < 0.05), a functional feature distinct from IL-17 (MFI = 11.07 +/- 1.22). This effect was not inhibited by a saturating amount of IL-17. These findings demonstrate that ML-1 is a novel cytokine with a distinct function, and suggest a different receptor for ML-1 on PBE cells.

Amino Acid Sequence↗
PubMed2001

A heterologous 3-D coculture model of breast tumor cells and fibroblasts to study tumor-associated fibroblast differentiation.

The objective of our study was to establish spheroid cocultures as a valid 3-D in vitro model mimicking tumor-fibroblast interactions in scirrhous breast tumors. The experimental setup was designed to verify if in cocultures (a) adherence and migration reflect the invasive potential of breast tumor cells, (b) breast tumor cells induce tumor-associated fibroblast differentiation, and (c) tumor-derived fibroblasts better reflect the in vivo situation than normal skin fibroblasts. Only one (SK-BR-3) out of five tumor cell types showed extensive fibroblast infiltration, MCF-7 cells frequently invaded fibroblast spheroids; BT474, T47D, and ZR-75-1 were noninvasive. While tumor cell invasion was independent of fibroblast origin, tumor-associated myofibroblast differentiation defined by alpha-SMA expression was demonstrated for tumor-derived but not normal skin fibroblasts in coculture indicating that (a) tumor cell invasion and myofibroblast differentiation are autonomous processes and (b) cocultures with tumor-derived fibroblasts resemble advanced stages of desmoplastic carcinomas while cocultures with normal skin fibroblasts rather reflect the early tumor development. The latter is also implied by fibroblast-associated alterations in tumor cell morphology and ECM distribution in the system. By using RNA arbitrarily primed PCR and cells isolated from cocultures by fluorescence-activated and magnetic cell separation, peripheral myelin protein PMP22/SR13 has been identified as a novel candidate with potential relevance in the interaction between tumor cell and normal fibroblast since PMP22 mRNA was significantly reduced in normal skin fibroblasts in coculture with BT474 cells.

Breast Neoplasms↗
PubMed2001

Antibodies to Toxoplasma gondii in individuals with first-episode schizophrenia.

We employed enzyme immunoassay (EIA) and Western blotting techniques to measure the level of antibodies to Toxoplasma gondii proteins in serum samples from 38 individuals undergoing their first episode of schizophrenia and from a group of matched control subjects. We found that the individuals with first-episode schizophrenia had significantly increased levels of IgG, IgM, and IgA class antibodies to Toxoplasma proteins, as compared with the control subjects.

Adult↗
PubMed2001

Plasma 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) levels and immune response.

For determination of whether plasma 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) pesticide levels (< or =1-32 ppb) are associated with immune suppression or DNA damage in lymphocytes, 302 individuals residing in Moore County, North Carolina, in 1994-1996 provided a blood specimen, underwent a skin test, and answered a questionnaire concerning factors affecting plasma organochlorine pesticide levels and the immune system. The blood specimens were analyzed for levels of plasma DDE (a metabolite of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane), numbers and types of blood cells, immunoglobulin levels, mitogen-induced lymphoproliferative activity, and lymphocyte micronuclei. When DDE levels were categorized as 1 or less, more than 1 to 2, more than 2 to 4.3, more than 4.3 to 7.6, and more than 7.6 ppb, individuals with higher plasma DDE levels had lowered mitogen-induced lymphoproliferative activity (concanavalin A, range: 74,218 dropping to 55,880 counts per minute, p = 0.03) and modestly increased total lymphocytes (range: 2.0-2.3 x 10(3)/microl, p = 0.05) and immunoglobulin A levels (range: 210-252 mg/dl, p = 0.04). There were no consistent differences in response to the skin tests by plasma DDE levels. Plasma DDE levels were not associated with a higher frequency of micronuclei. The authors conclude that relatively low levels of plasma DDE are associated with statistically significant changes in immune markers, although the magnitude of the effects are of uncertain clinical importance.

Adolescent↗
PubMed2001

Quantification of mucosal leucocyte endothelial cell interaction by in vivo fluorescence microscopy in experimental colitis in mice.

Leucocyte recruitment to sites of intestinal inflammation is a crucial, multi-step process that leads ultimately to the accumulation of cells in the inflamed tissue. We established a new in vivo model system of experimental colitis to quantify leucocyte-endothelial cell interaction and leucocyte extravasation in the inflamed mucosa of the colon. Furthermore, we investigated the pathophysiological role of ICAM-1 in the intestinal microcirculation in vivo. Using the model of dextran sodium sulphate (DSS)-induced acute and chronic colitis in mice, in vivo microscopy was performed in the colonic submucosal postcapillary venules and the submucosal collecting venules in normal or inflamed murine colonic segments. ICAM-1 expression was blocked by an anti-ICAM-1 monoclonal antibody or by suppressing NF-kappaB activation by gliotoxin. Significant increases in leucocyte adhesiveness (51-fold in postcapillary venules, 30-fold in collecting venules, P < 0.01) and extravasation (6.5-fold) could be demonstrated as early as day 2 of DSS-application in acute colitis (P < 0.01). This was paralleled by increases in both the histological damage scores and myeloperoxidase activities. In chronic dextran sodium sulphate-induced colitis significant increases in leucocyte-endothelium interactions and leucocyte extravasation were observed. Blocking ICAM-1 expression with a monoclonal antibody or gliotoxin, leucocyte sticking and extravasation were significantly down-regulated in vivo compared to controls (> 70%; P < 0.01). This new model system offers the possibility to specifically assess the role of adhesion molecules in the colonic mucosa in vivo as well as to investigate and quantify the effectiveness of experimental therapeutic approaches in acute or chronic intestinal inflammation.

Acute Disease↗
PubMed2001

Do rodents have a gene encoding glycogenin-2, the liver isoform of the self-glucosylating initiator of glycogen synthesis?

The discovery of a second human gene, GYG2, encoding a liver-specific isoform of glycogenin, the self-glucosylating initiator of glycogen biosynthesis, raised the possibility for differential controls of this protein in liver and muscle. The new protein, glycogenin-2, had several properties similar biochemically to the muscle isoform, glycogenin-1, but unlike glycogenin-1, stable expression in fibroblasts led to a significant overaccumulation of glycogen. Ensuing attempts to generate reagents suitable for use with rodents, to examine the physiological regulation of glycogenin-2 by nutritional and hormonal factors, have been unsuccessful. Proof of a negative is difficult but the weight of the evidence is beginning to mitigate against the existence of a second glycogenin gene in rodents leading us to hypothesize that the presence of the GYG2 gene is limited to primates.

Animals↗
PubMed2001

Genitourinary tuberculosis.

The worldwide prevalence of tuberculosis is still high and has remained almost unchanged over the past century as a result of increasing incidence in countries of the Third World. Twenty per cent of patients with tuberculosis will develop an extrapulmonary manifestation over time, the most common site being the genitourinary tract. The patient's history can lead to the sometimes difficult diagnosis. Radiological imaging helps in depicting genitourinary tuberculosis. However, the diagnosis of genitourinary tuberculosis is made on the basis of culture studies and is supported by polymerase chain reaction. The latter has impressive sensitivity and specificity, but lacks the ability to determine biological activity. The combination of three or four anti-tuberculosis drugs over a course of 6 to 9 months remains the treatment of choice. Drug resistance is increasing and necessitates tight therapy control. Tuberculosis of the male seminal duct may be an important cause of male infertility as a result of multiple epididymidal scarring. In these cases testicular sperm extraction is the method of choice for sperm retrieval. The outcome of sperm retrieval followed by intracytoplasmatic sperm injection is not affected.

Humans↗
PubMed2001

Abscisic acid activation of plasma membrane Ca(2+) channels in guard cells requires cytosolic NAD(P)H and is differentially disrupted upstream and downstream of reactive oxygen species production in abi1-1 and abi2-1 protein phosphatase 2C mutants.

The hormone abscisic acid (ABA) regulates stress responses and developmental processes in plants. Calcium-permeable channels activated by reactive oxygen species (ROS) have been shown recently to function in the ABA signaling network in Arabidopsis guard cells. Here, we report that ABA activation of these I(Ca) Ca(2)+ channels requires the presence of NAD(P)H in the cytosol. The protein phosphatase 2C (PP2C) mutant abi1-1 disrupted ABA activation of I(Ca) channels. Moreover, in abi1-1, ABA did not induce ROS production. Consistent with these findings, in abi1-1, H(2)O(2) activation of I(Ca) channels and H(2)O(2)-induced stomatal closing were not disrupted, suggesting that abi1-1 impairs ABA signaling between ABA reception and ROS production. The abi2-1 mutation, which lies in a distinct PP2C gene, also disrupted ABA activation of I(Ca). However, in contrast to abi1-1, abi2-1 impaired both H(2)O(2) activation of I(Ca) and H(2)O(2)-induced stomatal closing. Furthermore, ABA elicited ROS production in abi2-1. These data suggest a model with the following sequence of events in early ABA signal transduction: ABA, abi1-1, NAD(P)H-dependent ROS production, abi2-1, I(Ca) Ca(2)+ channel activation followed by stomatal closing.

Abscisic Acid↗
PubMed2000

Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) who experience persistent multiorgan dysfunction, despite standard doses of intravenous cyclophosphamide, represent a subset of patients at high risk of early death. We investigated the safety and efficacy of immune suppression and autologous haemopoietic stem-cell infusion to treat such patients. METHODS: From 1996, we selected patients with persistent SLE despite use of cyclophosphamide. Patients underwent dose-intense immune suppression and autologous haemopoietic stem-cell (CD34) infusion. Peripheral blood lymphocytes were analysed by flow cytometry, ELISA, and T-cell-receptor spectratyping before and after transplantation. We mobilised autologous haemopoietic stem cells with 2.0 g/m2 cyclophosphamide and 10 microg/kg granulocyte colony stimulating factor daily, enriched with CD34-positive selection, and reinfused after immunosuppression with 200 mg/kg cyclophosphamide, 1 g methylprednisolone, and 90 mg/kg equine antithymocyte globulin. RESULTS: Nine patients underwent stem-cell mobilisation but two were excluded before transplantation because of infection. The remaining seven received high-dose chemotherapy and stem-cell infusion. Median time to an absolute neutrophil count higher than 0.5x10(9)/L and nontransfused platelet count higher than 20x10(9)/L was 9 days (range 8-11) and 11 days (10-13), respectively. At a median follow-up of 25 months (12-40), all patients were free from signs of active lupus. Renal, cardiac, pulmonary, and serological markers, and T cell phenotype and repertoire had normalised. INTERPRETATION: Patients remained free from active lupus and improved continuously after transplantation, with no immunosuppressive medication or small residual doses of prednisone. T-cell repertoire diversity and responsiveness was restored. Durability of remission remains to be established.

Adolescent↗
PubMed2000

Intense immune suppression for systemic lupus--the role of hematopoietic stem cells.

The treatment of severe autoimmune diseases has been recently revitalized by the introduction of intense immune suppression with immune ablative intent followed by three different procedures. These are allogeneic hematopoietic stem cell transplantation (HSCT), autologous HSCT (using either marrow or peripheral blood), and intense immune suppression without stem cell support. Current trials suggest that high dose immune suppressive therapy with or without autologous hematopoietic stem cell support can induce remission of previously refractory disease. Follow-up is too brief to determine if intense immune suppression, and more specifically autologous HSCT, will ultimately cure SLE. It is conceivable that an allogeneic source of stem cells from a normal donor (e.g. HLA matched sibling) will be required to achieve a cure. It is also possible that autologous HSCT, even if not curative, may prolong the life of patients with otherwise high-risk features. In carefully selected patients, the potential benefits of this procedure may outweigh the risks.

Animals↗
PubMed2000

Effects on the immune system associated with living near a pesticide dump site.

In this paper, we report results of the second phase of a larger study designed to evaluate the effects on the immune system of living near a Superfund site containing organochlorine pesticides, volatile organic compounds, and metals. Phase II was conducted to determine whether living near the site, consisting of six locations in Aberdeen, North Carolina, is associated with higher plasma organochlorine levels, immune suppression, or DNA damage. Each of 302 residents of Aberdeen and neighboring communities provided a blood specimen, underwent a skin test, and answered a questionnaire. Blood specimens were analyzed for organochlorine pesticides, immune markers, and micronuclei. Of 20 organochlorines tested, only DDE was detected in the blood of participants (except for one individual). Age-adjusted mean plasma DDE levels were 4.05 ppb for Aberdeen residents and 2.95 ppb (p = 0.01) for residents of neighboring communities. Residents of 40-59 years of age who lived within a mile of any site, but particularly the Farm Chemicals site, had higher plasma DDE levels than residents who lived farther away. Residents who lived near the Farm Chemicals site before versus after 1985 also had higher plasma DDE levels. Overall, there were few differences in immune markers between residents of Aberdeen and the neighboring communities. However, residents who lived closer to the dump sites had statistically significantly lower mitogen-induced lymphoproliferative activity than residents who lived farther away (p < 0.05). Residential location was not consistently associated with frequency of micronuclei or skin test responses. Although some statistically significant differences in immune markers were noted in association with residential location, the magnitude of effects are of uncertain clinical importance.

Adolescent↗
PubMed1999

Induction of the cell cycle regulatory gene p21 (Waf1, Cip1) following methylmercury exposure in vitro and in vivo.

Methylmercury (MeHg) is recognized as a significant environmental hazard, particularly to the development of the nervous system. To study the molecular mechanisms underlying cell cycle inhibition by MeHg, we assessed the involvement of p21 (Waf1, Cip1), a cell cycle regulatory gene implicated in the G1 and G2 phases of cell cycle arrest, in primary embryonic cells and adult mice following MeHg exposure. Previous literature has supported the association of increased p21 expression with chondrocyte differentiation. In support of this finding, we observed an increasing p21 expression during limb bud (LB), but not midbrain central nervous system (CNS) cell differentiation. Both embryonic LB and CNS cells responded to MeHg exposure with a concentration-dependent increase in p21 mRNA. In the parallel adult study, C57BL/6 female mice were chronically exposed to 10 ppm MeHg via drinking water for 4 weeks. While there was limited or absent induction of Gadd45, Gadd153, and the gamma-glutamylcysteine synthetase catalytic subunit, p21 was markedly induced in the brain, kidney, and liver tissues in most of the animals that showed MeHg-induced behavioral toxicity such as hyperactivity and tremor. Furthermore, the induction of p21 mRNA was accompanied by an increase in p21 protein level. The results indicate that the activation of cell cycle regulatory genes may be one mechanism by which MeHg interferes with the cell cycle in adult and developing organisms. Continued examination of the molecular mechanisms underlying cell cycle inhibition may potentially lead to utilization of this mechanistic information to characterize the effects of MeHg exposure in vivo.

Animals↗
PubMed1999

Autologous hematopoietic stem cell transplantation in refractory rheumatoid arthritis: sustained response in two of four patients.

OBJECTIVE: To investigate the safety and efficacy of immune ablation with subsequent autologous hematopoietic stem cell transplantation (HSCT) in severe rheumatoid arthritis (RA). METHODS: Four patients with refractory RA and poor prognostic indicators were treated. Stem cells were collected and lymphocytes were depleted by 2.3-4.0 logs. The conditioning regimen included cyclophosphamide (200 mg/kg), antithymocyte globulin (90 mg/kg), and, for 1 patient, total body irradiation (TBI) with 400 cGy. Improvement was evaluated according to the American College of Rheumatology (ACR) preliminary definition of improvement in RA (ACR 20), and also according to the ACR 50 and ACR 70 criteria. RESULTS: HSCT was well tolerated. Three patients fulfilled the ACR 70 criteria at 1 month and 3 months post-HSCT. One patient did not fulfill the ACR 20 criteria because of persistent joint tenderness, despite improvement of the joint swelling. At 6 months post-HSCT, 1 patient fulfilled the ACR 70 criteria and 1 fulfilled the ACR 50 criteria, and these 2 patients fulfilled the ACR 70 criteria at 9 months post-HSCT. The other 2 patients (including the patient who received TBI) did not meet the ACR 20 criteria at 6 months and 9 months post-HSCT. The only patient with followup of >9 months fulfilled the ACR 70 criteria at 20 months post-HSCT. CONCLUSION: In this series, autologous HSCT was safe and effective in inducing major clinical response and maintained significant benefit for 2 patients at 9 months and 20 months posttreatment, respectively. Sustained response did not occur for 2 of 4 patients. A regimen dose-response effect may exist, but the addition of TBI did not prevent disease relapse for 1 of the patients. More aggressive T cell depletion of the autograft, use of a myeloablative regimen, or use of an allograft may be necessary to decrease relapse rates.

Adult↗
PubMed1999

Density dependence of vibrational energy relaxation rates in supercritical solution: a hydrodynamic model.

An approximate expression describing the density dependence of vibrational energy relaxation rates in fluids in terms of thermodynamic and transport parameters of the fluid is developed on the basis of a classical statistical mechanical theory of vibrational energy relaxation of highly excited molecules in polyatomic solvents. The energy relaxation rate is expressed via the friction coefficient, which describes the interaction between solute oscillator and solvent molecules. The corresponding force-force time correlation function is expressed in terms of the dynamic structure factor of the solvent and the force of interaction between solute and solvent molecules. Approximating the dynamic structure factor appropriately leads to expressions for the density dependence of vibrational relaxation rates in terms of thermophysical solvent parameters. Using these expressions the density dependence of vibrational relaxation rates in supercritical ethane and propane both in the vicinity of the critical point and far from it are evaluated and compared with measured relaxation rates obtained under the same physical conditions.

Journal Article↗