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J L Nelson

Publications and source records attributed to J L Nelson.

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

Cutting edge: persistent fetal microchimerism in T lymphocytes is associated with HLA-DQA1*0501: implications in autoimmunity.

The host's MHC genotype plays a critical role in susceptibility to autoimmune diseases. We previously proposed that persistent fetal microchimerism from pregnancy contributes to the pathogenesis of autoimmune diseases such as scleroderma. In the current study, we investigated whether the specific host MHC genotype is associated with persistent microchimerism among T lymphocytes in women with scleroderma and in healthy women. Fetal microchimerism among T lymphocytes was strongly associated with HLA DQA1*0501 of the mother (odds ratio (OR) = 13.5, p = 0.007, p corrected (pc) = 0.06) and even more strongly with DQA1*0501 of the son (OR = infinity; p = 0. 00002, pc = 0.0002). This is the first description of an association between persistent fetal microchimerism in maternal T lymphocytes and specific HLA class II alleles. Although the association was observed in both healthy women and in women with scleroderma, the finding suggests an additional route by which HLA genes might contribute to susceptibility to autoimmune disease.

Adolescent↗
PubMed2000

HLA-DQA1*0501 is associated with diffuse systemic sclerosis in Caucasian men.

OBJECTIVE: Systemic sclerosis (SSc) is uncommon in men, and relatively little is known about factors contributing to its pathogenesis in this population. In the current study, we investigated HLA class II alleles in men with SSc. We also investigated the hypothesis that HLA compatibility of the mother could be a risk factor for SSc in men. METHODS: Sequence-specific oligonucleotide probe typing was used to determine DQA1, DQB1, and DRB1 alleles of SSc patients (50 men and 36 parous women), healthy controls (59 men and 80 parous women), 26 mothers of men with SSc, and 44 mothers of healthy men. All study subjects were Caucasian, and allele frequencies were compared with those of Caucasian controls from the Eleventh International Histocompatibility Workshop as well as those of local controls. RESULTS: The DQA1*0501 allele was significantly increased among men with SSc compared with healthy men (odds ratio [OR] 2.3, P = 0.006, Pcorr = 0.04). DQA1*0501 was associated with diffuse SSc in men (OR 3.0, P = 0.004, Pcorr = 0.03), but not with limited SSc in men. Maternal HLA compatibility was not a risk factor for SSc in men. CONCLUSION: Previous studies have shown associations of DRB1 alleles with SSc, but have rarely determined DQA1 allele frequencies. Our findings indicate that a specific DQA1 allele is associated with SSc, and that DRB1 associations may be due to linkage disequilibrium with DQA1. Moreover, by analyzing genetic susceptibility according to sex, we found that the contribution of HLA genes to the risk of SSc was substantially greater in men than in parous women.

Alleles↗
PubMed2000

The effect of task on determination of maximum phonational frequency range.

The purpose of this study was to investigate if there was an effect of task on determination of maximum phonational frequency range (MPFR). Two tasks commonly used to elicit MPFR in clinical voice evaluations were compared. Normal adult females (N = 30) were examined. No statistically significant effect of task was found. Both tasks (glissando and discrete-step) were found to have a high positive correlation (0.84). Implications of the use of one task for determination of maximum phonational frequency range are discussed, as is the possibility of a task effect on determination of other voice parameters.

Adult↗
PubMed2000

The evolution of vertebrate antigen receptors: a phylogenetic approach.

Classical T cells, those with alpha beta T-cell receptors (TCRs), are an important component of the dominant paradigm for self-nonself immune recognition in vertebrates. alpha beta T cells recognize foreign peptide antigens when they are bound to MHC molecules on the surfaces of antigen-presenting cells. gamma delta T cells bear a similar receptor, and it is often assumed that these T cells also require specialized antigen-presenting molecules for immune recognition, which we term "indirect antigen recognition." B-cell receptors, or immunoglobulins, bind directly to antigens without the help of a specialized antigen-presenting molecule. Phylogenetically, it has been assumed that T-cell receptors and the genes that encode them are a monophyletic group, and that "indirect" antigen recognition evolved before the split into two types of TCR. Recently, however, it has been proposed that gamma delta-TCRs bind directly to antigens, as do immunoglobulins (Ig's). This calls into question the null hypothesis that indirect antigen recognition is a common characteristic of TCRs and, by extension, the hypothesis that all TCR gene sequences form a monophyletic group. To determine whether alternative explanations for antigen recognition and other historical relationships among TCR genes might be possible, we performed phylogenetic analyses on amino acid sequences of the constant and variable regions which encode the basic subunits of TCR and Ig molecules. We used both maximum-parsimony and genetic distance-based methods and could find no strong support for the hypothesis of TCR monophyly. Analyses of the constant region suggest that TCR gamma or delta sequences are the most ancient, implying that the ancestral immune cell was like a modern gamma delta T cell. From this gamma delta-like ancestor arose alpha beta T cells and B cells, implying that indirect antigen recognition is indeed a derived property of alpha beta-TCRs. Analyses of the variable regions are complicated by strong selection on antigen-binding sequences, but imply that direct antigen binding is the ancestral condition.

Animals↗
PubMed2000

Reproductive ethics and the family.

The phrase 'reproductive ethics', as used by bioethicists, typically refers to concerns over morally appropriate employment of assisted reproductive technologies and, perhaps somewhat less commonly, to issues arising from technologies that block conception or end pregnancies. I here recommend to the attention of the field a more commodious use of 'reproductive ethics', one that takes seriously how humans are brought into the world as moral and social beings, and not simply as biological individuals. As a focus for this expanded agenda, I examine prevalent disagreements over the patterns and sources of the responsibilities and prerogatives that help define family structures, both as these are reflected in assisted reproductive practices involving the purchase of gametes, and in U.S. legal controversies about whether parents, or family courts, should determine who has the right to a relationship with children.

Civil Rights↗
PubMed1999

Long-term fetal microchimerism in peripheral blood mononuclear cell subsets in healthy women and women with scleroderma.

Fetal CD34(+) CD38(+) cells have recently been found to persist in maternal peripheral blood for many years after pregnancy. CD34(+) CD38(+) cells are progenitor cells that can differentiate into mature immune-competent cells. We asked whether long-term fetal microchimerism occurs in T lymphocyte, B lymphocyte, monocyte, and natural-killer cell populations of previously pregnant women. We targeted women with sons and used polymerase chain reaction for a Y-chromosome-specific sequence to test DNA extracted from peripheral blood mononuclear cells (PBMC) and from CD3, CD19, CD14, and CD56/16 sorted subsets. We also asked whether persistent microchimerism might contribute to subsequent autoimmune disease in the mother and included women with the autoimmune disease scleroderma. Scleroderma has a peak incidence in women after childbearing years and has clinical similarities to chronic graft-versus-host disease that occurs after allogeneic hematopoietic stem-cell transplantation, known to involve chimerism. Sixty-eight parous women were studied for male DNA in PBMC and 20 for PBMC subsets. Microchimerism was found in PBMC from 33% (16 of 48) of healthy women and 60% (12 of 20) women with scleroderma, P =.046. Microchimerism was found in some women in CD3, CD19, CD14, and CD56/16 subsets including up to 38 years after pregnancy. Microchimerism in PBMC subsets was not appreciably more frequent in scleroderma patients than in healthy controls. Overall, microchimerism was found in CD3, CD19, and CD14 subsets in approximately one third of women and in CD56/16 in one half of women. HLA typing of mothers and sons indicated that HLA compatibility was not a requirement for persistent microchimerism in PBMC subsets. Fetal microchimerism in the face of HLA disparity implies that specific maternal immunoregulatory pathways exist that permit persistence but prevent effector function of these cells in normal women. Although microchimerism in PBMC was more frequent in women with scleroderma than healthy controls additional studies will be necessary to determine whether microchimerism plays a role in the pathogenesis of this or other autoimmune diseases.

Adult↗
PubMed1999

Fetal microchimerism alone does not contribute to the induction of primary biliary cirrhosis.

Microchimerism has been implicated in the etiology of autoimmune diseases. It has also been implicated in the induction/maintenance of fetal tolerance. We used polymerase chain reaction (PCR) analysis to determine whether microchimerism occurred in patients who subsequently developed primary biliary cirrhosis (PBC), and thus may be involved in its etiology. We performed PCR amplification of sequences unique to both the X and Y chromosomes from the livers of 37 women with PBC and 39 female controls using WAVE technology; a very sensitive technology based on an ion-pair reverse-phase high-performance liquid chromatography system. All patients were known to have had at least 1 son and it was confirmed that PBC was diagnosed after the birth of the son. Data were analyzed for both detection of the Y chromosome gene and the ratio of the yield of the Y chromosome PCR products to the X chromosome. The prevalence of Y chromosome detection in PBC was 26 of 37 (70%) compared with 28 of 39 (72%) in controls, and the ratio of Y chromosome to X chromosome was similar between the PBC and control groups, 0.402 +/- 0.143 vs. 0.271 +/- 0.055, respectively. Our results, using our more sensitive technology, showed that microchimerism is a very common event in human liver and supported the thesis that this may contribute to the induction/maintenance of fetal tolerance. However, although we cannot exclude the possibility that select fetal major histocompatibility complex (MHC) haplotypes might contribute to disease susceptibility, our data suggest that microchimerism by itself does not play a significant role in the development of PBC.

Adult↗
PubMed1999

Microchimerism and scleroderma.

It is now known that cells traffic between fetus and mother during normal human pregnancy. Moreover, fetal cells have been found to persist in the maternal peripheral blood for decades after childbirth. Chronic graft-versus-host disease, a known condition of chimerism that occurs after allogeneic hematopoietic stem cell transplantation has clinical similarities to some autoimmune diseases, including scleroderma (SSc). SSc has a predilection for women and an increased incidence in women following childbearing years. These observations when considered together with the longterm persistence of fetal cells led to the hypothesis that microchimerism is involved in autoimmune diseases such as SSc. Initial studies of women with SSc lend support to the hypothesis. Microchimerism, however, is also very common in healthy normals, and available data is not sufficient to be conclusive with respect to disease pathogenesis. Microchimerism can also occur due to engraftment from a blood transfusion, from a twin, or from the mother, sources that are applicable to men and women who have never been pregnant. The mechanism(s) by which microchimerism might contribute to SSc are not known, although some insight may be gained from studies of chimerism in transplantation biology. If microchimerism does contribute to the pathogenesis of autoimmune disorders such as SSc, it is likely that new therapeutic strategies could be developed.

Adult↗
PubMed1999

Bioethics as several kinds of writing.

Three different models are described of the relationship of bioethics to the press. The first two are familiar: bioethicists often are interviewed by journalists seeking background and short quotes to insert in a story; alternately, bioethicists sometimes themselves act as journalists of a sort, writing op-eds, articles or even longer works designed for wide readership. These models share the notion that bioethicists can provide information and ideas that increase the quality of people's thinking on moral matters. They share also a common difficulty: do the constraints the media impose on bioethical discourse keep bioethicists from deepening public reflection, and if not, how can those constraints be most effectively kept from distorting what bioethicists wish to say? The third model reverses--in part--the presupposition that bioethics bestows moral sophistication on a public naive about ethical issues, holding rather that matters run both ways; bioethicists stand to learn a great deal from their interactions with various publics and the media that serve them. On this view, the constraints imposed by media conventions constitute opportunities for new and potentially important forms of bioethical writing. Various concerns generated by the first two models are surveyed. It is concluded that while none of the difficulties constitute knock-down arguments against these forms of collaborating with the press, the worries are problematic enough to provide some support for considering the less familiar third approach. Further reason for taking the third model seriously draws on moral theoretic considerations.

Bioethical Issues↗
PubMed1999

Effect of pentoxifylline on survival and intestinal cytokine messenger RNA transcription in a rat model of ongoing peritoneal sepsis.

OBJECTIVE: Septic animals receiving high-protein liquid diets have increased mortality and increased production of cytokines by the gut compared with animals receiving low-protein diets. The purpose of this study was to evaluate the ability of pentoxifylline to alter gut cytokine production in a rat model of prolonged acute peritonitis, to determine its effect on survival in such animals, and to determine whether alteration of gut cytokine production was associated with survival. DESIGN: Prospective, randomized animal study. SETTING: Research laboratory. SUBJECTS: Male Lewis rats weighing between 250 and 300 g. INTERVENTIONS: Anesthetized rats had placement of a gastrostomy, followed 1 wk later by implantation of a bacteria-filled osmotic minipump into the peritoneal cavity. Rats were fed a high-protein (20% total energy) enteral diet. Saline or pentoxifylline (5 or 20 mg/kg im) was administered daily beginning at the time of pump implantation. MEASUREMENTS AND MAIN RESULTS: Septic rats fed the high-protein liquid diet and given pentoxifylline in a dose of 5 mg/kg/day demonstrated improved survival compared with saline-treated animals or animals given the high dose (20 mg/kg/day) of pentoxifylline (p< .05). Administration of pentoxifylline at 5 mg/kg/day also down regulated the production of IL-6 messenger RNA (mRNA) in liver and lipopolysaccharide binding protein mRNA in the liver and intestine of septic animals given the high-protein liquid diet. CONCLUSION: Low-dose (but not high-dose) pentoxifylline administration reduced production of some, but not all, cytokines studied in the gut and liver in a rat model of acute peritonitis and this reduced production was associated with an improved survival in such animals.

Animals↗
PubMed1999

Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group.

OBJECTIVES: Recent studies in animal models of sepsis-induced acute respiratory distress syndrome (ARDS) have shown that a low-carbohydrate, high-fat diet combining the anti-inflammatory and vasodilatory properties of eicosapentaenoic acid (EPA; fish oil), gamma-linolenic acid (GLA; borage oil) (EPA+GLA), and antioxidants improves lung microvascular permeability, oxygenation, and cardiopulmonary function and reduces proinflammatory eicosanoid synthesis and lung inflammation. These findings suggest that enteral nutrition with EPA+GLA and antioxidants may reduce pulmonary inflammation and may improve oxygenation and clinical outcomes in patients with ARDS. DESIGN: Prospective, multicentered, double-blind, randomized controlled trial. SETTING: Intensive care units of five academic and teaching hospitals in the United States. PATIENTS: We enrolled 146 patients with ARDS (as defined by the American-European Consensus Conference) caused by sepsis/pneumonia, trauma, or aspiration injury in the study. INTERVENTIONS: Patients meeting entry criteria were randomized and continuously tube-fed either EPA+GLA or an isonitrogenous, isocaloric standard diet at a minimum caloric delivery of 75% of basal energy expenditure x 1.3 for at least 4-7 days. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases were measured, and ventilator settings were recorded at baseline and study days 4 and 7 to enable calculation of PaO2/FIO2, a measure of gas exchange. Pulmonary neutrophil recruitment was assessed by measuring the number of neutrophils and the total cell count in bronchoalveolar lavage fluid at the same time points. Clinical outcomes were recorded. Baseline characteristics of 98 evaluable patients revealed that key demographic, physiologic, and ventilatory variables were similar at entry between both groups. Multiple bronchoalveolar lavages revealed significant decreases (approximately 2.5-fold) in the number of total cells and neutrophils per mL of recovered lavage fluid during the study with EPA+GLA compared with patients fed the control diet. Significant improvements in oxygenation (PaO2/FIO2) from baseline to study days 4 and 7 with lower ventilation variables (FIO2, positive end-expiratory pressure, and minute ventilation) occurred in patients fed EPA+GLA compared with controls. Patients fed EPA+GLA required significantly fewer days of ventilatory support (11 vs. 16.3 days; p = .011), and had a decreased length of stay in the intensive care unit (12.8 vs. 17.5 days; p = .016) compared with controls. Only four of 51 (8%) patients fed EPA+GLA vs. 13 of 47 (28%) control patients developed a new organ failure during the study (p = .015). CONCLUSIONS: The beneficial effects of the EPA+GLA diet on pulmonary neutrophil recruitment, gas exchange, requirement for mechanical ventilation, length of intensive care unit stay, and the reduction of new organ failures suggest that this enteral nutrition formula would be a useful adjuvant therapy in the clinical management of patients with or at risk of developing ARDS.

Antioxidants↗
PubMed1999

Ultrasonic enhancement of antibiotic action on Escherichia coli biofilms: an in vivo model.

Biofilm infections are a common complication of prosthetic devices in humans. Previous in vitro research has determined that low-frequency ultrasound combined with aminoglycoside antibiotics is an effective method of killing biofilms. We report the development of an in vivo model to determine if ultrasound enhances antibiotic action. Two 24-h-old Escherichia coli (ATCC 10798) biofilms grown on polyethylene disks were implanted subcutaneously on the backs of New Zealand White female rabbits, one on each side of the spine. Low-frequency (28.48-kHz) and low-power-density (100- and 300-mW/cm2) continuous ultrasound treatment was applied for 24 h with and without systemic administration of gentamicin. The disks were then removed, and the number of viable bacteria on each disk was determined. At the low ultrasonic power used in this study, exposure to ultrasound only (no gentamicin) caused no significant difference in bacterial viability. In the presence of antibiotic, there was a significant reduction due to 300-mW/cm2 ultrasound (P = 0.0485) but no significant reduction due to 100-mW/cm2 ultrasound. Tissue damage to the skin was noted at the 300-mW/cm2 treatment level. Further development of this technique has promise in treatment of clinical implant infections.

Animals↗