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Biomedical subjects

S Nelson

Publications and source records attributed to S Nelson.

At least 55 records · Page 3Linked to original sources
PubMed2000

Cloning and characterization of a Na+-driven anion exchanger (NDAE1). A new bicarbonate transporter.

Regulation of intra- and extracellular ion activities (e.g. H(+), Cl(-), Na(+)) is key to normal function of the central nervous system, digestive tract, respiratory tract, and urinary system. With our cloning of an electrogenic Na(+)/HCO(3)(-) cotransporter (NBC), we found that NBC and the anion exchangers form a bicarbonate transporter superfamily. Functionally three other HCO(3)(-) transporters are known: a neutral Na(+)/ HCO(3)(-) cotransporter, a K(+)/ HCO(3)(-) cotransporter, and a Na(+)-dependent Cl(-)-HCO(3)(-) exchanger. We report the cloning and characterization of a Na(+)-coupled Cl(-)-HCO(3)(-) exchanger and a physiologically unique bicarbonate transporter superfamily member. This Drosophila cDNA encodes a 1030-amino acid membrane protein with both sequence homology and predicted topology similar to the anion exchangers and NBCs. The mRNA is expressed throughout Drosophila development and is prominent in the central nervous system. When expressed in Xenopus oocytes, this membrane protein mediates the transport of Cl(-), Na(+), H(+), and HCO(3)(-) but does not require HCO(3)(-). Transport is blocked by the stilbene 4,4'-diisothiocyanodihydrostilbene- 2, 2'-disulfonates and may not be strictly electroneutral. Our functional data suggest this Na(+) driven anion exchanger (NDAE1) is responsible for the Na(+)-dependent Cl(-)-HCO(3)(-) exchange activity characterized in neurons, kidney, and fibroblasts. NDAE1 may be generally important for fly development, because disruption of this gene is apparently lethal to the Drosophila larva.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2000

Immune modulation in the treatment of respiratory infection.

The limitations of currently available treatment for severe respiratory infection are demonstrated by the relatively fixed mortality associated with these infections despite advances in nutrition, vaccines, antibiotics, and critical care. This might be due in part to the changing spectrum of pathogens and development of drug resistance. Cytokines are potent molecules that function as growth factors and orchestrate both innate and adaptive immune responses. Several of these factors have entered the clinical arena to support or augment the immune response. Moreover, the use of cytokines has recently been expanded to patients without an overtly defective immune system but who have either significant infection or infection with drug resistant organisms. The use of cytokines as adjuvants in the treatment of respiratory infections is reviewed.

Adjuvants, Immunologic↗
PubMed2000

Requirement of endogenous stem cell factor and granulocyte-colony-stimulating factor for IL-17-mediated granulopoiesis.

IL-17 is a novel, CD4+ T cell-restricted cytokine. In vivo, it stimulates hematopoiesis and causes neutrophilia consisting of mature granulocytes. In this study, we show that IL-17-mediated granulopoiesis requires G-CSF release and the presence or induction of the transmembrane form of stem cell factor (SCF) for optimal granulopoiesis. However, IL-17 also protects mice from G-CSF neutralization-induced neutropenia. G-CSF neutralization completely reversed IL-17-induced BM progenitor expansion, whereas splenic CFU-GM/CFU-granulocyte-erythrocyte-megakaryocyte-monocyte was only reduced by 50% in both Sl/Sld and littermate control mice. Thus, there remained a significant SCF/G-CSF-independent effect of IL-17 on splenic granulopoiesis, resulting in a preservation of mature circulating granulocytes. IL-17 is a cytokine that potentially interconnects lymphocytic and myeloid host defense and may have potential for therapeutic development.

3T3 Cells↗
PubMed2000

A phase I trial of solubilized DR2:MBP84-102 (AG284) in multiple sclerosis.

OBJECTIVE: To assess the safety, tolerability, and biologic and clinical activity of a solubilized complex comprised of human leukocyte antigen-DR2 with myelin basic protein84-102 (AG284)in patients with secondary progressive MS. BACKGROUND: Soluble species-specific major histocompatibility complex myelin basic protein91-103 complexes ameliorate disease in a dose-dependent manner when administered to SJL/J mice with chronic relapsing experimental allergic encephalomyelitis. Preincubation with AG284 reduces the proliferative response of a DR2-restricted, myelin basic protein84-102-reactive T cell clone, derived from a MS patient, to myelin basic protein84-102 in the presence of autologous antigen-presenting cells. METHODS: Thirty-three patients with secondary progressive MS were randomly assigned to receive three alternate day IV doses of AG284 or placebo in a double-masked dose escalation study. The primary outcome was safety and tolerability. Secondary outcomes included a comparison of pre- and post-treatment gadolinium-enhanced brain MRI activity, Kurtzke Expanded Disability Status Scale, and Nine Hole Peg Test scores. RESULTS: The frequency of adverse events was similar in the AG284 and placebo recipients. No significant treatment effect was detected by Expanded Disability Status Scale, Nine Hole Peg Test, or number of new gadolinium-enhancing MRI lesions. CONCLUSIONS: AG284 as administered during this study was safe and well tolerated. Further studies are warranted to determine the biologic activity and clinical efficacy of this potential treatment for MS.

Adult↗
PubMed2000

Orthotopic human lung carcinoma xenografts in BALB/c mice immunosuppressed with anti-CD4 monoclonal antibodies and chronic alcohol consumption.

BACKGROUND: The role of the immune system in the surveillance of the body for cancer cells is well established. Human tumor cells do not survive in mice with intact immune systems, but they propagate in athymic nude mice. Presumably, the lack of a thymus gland and consequent loss of T lymphocytes results in a seriously compromised immune system without adequate cell-mediated immunity and tumor surveillance. In patients infected with the human immunodeficiency virus (HIV), a progressive loss of cell-mediated immunity is associated with the development of malignancies and opportunistic infections. This effect may be exacerbated in patients who chronically consume alcohol. METHODS: Normal and alcoholic BALB/c mice were treated with a monoclonal antibody to deplete CD4(+) lymphocytes before orthotopic implantation of human lung adenocarcinoma xenografts. Tumor volume and weight were measured and compared between groups. RESULTS: The authors' data show that a single treatment of anti-CD4 antibody causes almost complete depletion of CD4(+) lymphocytes and permits the formation of large intrapulmonary human nonsmall lung carcinoma xenografts in 100% of treated mice. All control animals injected with heat-denatured antibody failed to produce tumors. Chronic alcohol consumption by CD4-depleted mice resulted in larger tumors, compared with mice that did not receive ethanol in their diet (P = 0.05). CONCLUSIONS: Depletion of CD4(+) lymphocytes allows for the orthotopic growth of human lung adenocarcinoma xenografts in BALB/c mice. Furthermore, the consumption of alcohol reduces the ability of the impaired immune system to reject tumors.

Adenocarcinoma↗
PubMed2000

Very selective suppression pulses for clinical MRSI studies of brain and prostate cancer.

Focal three-dimensional magnetic resonance spectroscopic imaging (3D MRSI) methods based on conventional point resolved spectroscopy (PRESS) localization are compromised by the geometric restrictions in volume prescription and by chemical shift registration errors. Outer volume saturation (OVS) pulses have been applied to address the geometric limits, but conventional OVS pulses do little to overcome chemical shift registration error, are not particularly selective, and often leave substantial signals that can degrade the spectra of interest. In this paper, an optimized sequence of quadratic phase pulses is introduced to provide very selective spatial suppression with improved B1 and T1 insensitivity. This method was then validated in volunteer studies and in clinical 3D MRSI exams of brain tumors and prostate cancer.

Brain Neoplasms↗
PubMed2000

Inhibition of TNF-alpha processing and TACE-mediated ectodomain shedding by ethanol.

Alcohol (EtOH) is a well-documented immunosuppressant. Acute EtOH-induced immunosuppression is partially due to suppression of tumor necrosis factor alpha (TNF-alpha) secretion. We investigated the mechanism of acute EtOH-induced TNF-alpha suppression in two monocytic cell lines, Mono Mac 6 and DRM. EtOH inhibited TNF-alpha secretion in a dose-dependent manner. However, TNF-alpha transcription was not affected by EtOH. Enzyme-linked immunosorbent assay and confocal microscopy showed that EtOH treatment increased cell-associated TNF-alpha. Ectodomain shedding of TNF-alpha from the cell surface is mediated by TNF-alpha converting enzyme (TACE). In contrast with TNF-alpha, EtOH did not inhibit interleukin-8 (IL-8) secretion, which does not require shedding. Furthermore, TNF p75 receptor shedding, a biomarker for TACE activity, was inhibited by EtOH in both cell lines. EtOH also inhibited TNF p75 receptor shedding in TACE-reconstituted fibroblasts, suggesting that EtOH inhibits the shedding process. These data show that acute EtOH exposure can posttranscriptionally suppress TNF-alpha production, resulting in specific defects in immune defense.

ADAM Proteins↗
PubMed2000

Innate immunity and pulmonary host defense.

The lung, in order to facilitate gas exchange, represents the largest epithelial surface area of the body in contact with the external environment. As normal respiration occurs, the upper and lower airways are repeatedly exposed to a multitude of airborne particles and microorganisms. Since these agents are frequently deposited on the surface of the respiratory tract, an elaborate system of defense mechanisms is in place to maintain the sterility of the lung. Innate defenses are primarily responsible for the elimination of bacterial organisms from the alveolus. Early bacterial clearance is mediated by a dual phagocytic system involving both alveolar macrophages and polymorphonuclear leukocytes. The recruitment and activation of inflammatory cells at a site of infection involves the orchestrated expression of leukocyte and vascular adhesion molecules, as well as the establishment of chemotactic gradients via the generation of proinflammatory cytokines and chemokines. Immunologic manipulation of innate immunity may serve as an important adjuvant therapy in the treatment of both immunocompromised and immunocompetent patients with severe lung infections. As the complexities of the host-pathogen interaction are further dissected and elucidated, it is likely that the therapeutic benefits from these approaches will be realized.

Anti-Infective Agents↗
PubMed2000

Genome-wide analysis of single-nucleotide polymorphisms in human expressed sequences.

Single-nucleotide polymorphisms (SNPs) have been explored as a high-resolution marker set for accelerating the mapping of disease genes. Here we report 48,196 candidate SNPs detected by statistical analysis of human expressed sequence tags (ESTs), associated primarily with coding regions of genes. We used Bayesian inference to weigh evidence for true polymorphism versus sequencing error, misalignment or ambiguity, misclustering or chimaeric EST sequences, assessing data such as raw chromatogram height, sharpness, overlap and spacing, sequencing error rates, context-sensitivity and cDNA library origin. Three separate validations-comparison with 54 genes screened for SNPs independently, verification of HLA-A polymorphisms and restriction fragment length polymorphism (RFLP) testing-verified 70%, 89% and 71% of our predicted SNPs, respectively. Our method detects tenfold more true HLA-A SNPs than previous analyses of the EST data. We found SNPs in a large fraction of known disease genes, including some disease-causing mutations (for example, the HbS sickle-cell mutation). Our comprehensive analysis of human coding region polymorphism provides a public resource for mapping of disease genes (available at http://www.bioinformatics.ucla.edu/snp).

Base Sequence↗
PubMed2000

The role of the inflammatory response in chronic bronchitis: therapeutic implications.

Chronic bronchitis is diagnosed clinically by a chronic productive cough. As implied by the term "bronchitis," chronic airway inflammation is typically found in the central airways in patients with persistent cough and mucous hypersecretion. Although the exact pathogenesis of chronic bronchitis remains unclear, bacterial colonization and the resulting inflammatory response are thought to be of central importance. The generation of pro-inflammatory cytokines and chemotactic stimuli by the airway epithelium likely play central roles in propagating the inflammatory response in patients with chronic bronchitis. Further insights into the initiating events and underlying mechanisms that result in the clinical syndrome of chronic bronchitis will likely provide novel opportunities for therapeutic interventions.

Anti-Bacterial Agents↗
PubMed2000

The inflammatory response in chronic bronchitis.

Chronic bronchitis is diagnosed clinically by a chronic productive cough and is characterized by a variety of pathological changes, including bronchial gland hyperplasia, goblet cell metaplasia, and peribronchiolar fibrosis. As implied by the term ;;bronchitis,'' chronic airway inflammation is typically found in the central airways in patients with persistent cough and mucus hypersecretion. Although the exact pathogenesis of chronic bronchitis remains unclear, bacterial colonization and the resulting inflammatory response are thought to be of central importance. The generation of proinflammatory cytokines and chemotactic stimuli by the airway epithelium likely plays a central role in propagating the inflammatory response in patients with chronic bronchitis. Typically, an inflammatory mononuclear cell infiltrate is found in the airway wall, and the airway lumen is filled with neutrophils and their products. Further insights into the initiating events and underlying mechanisms that result in the clinical syndrome of chronic bronchitis will likely provide novel opportunities for therapeutic interventions.

Journal Article↗
PubMed2000

Serine/threonine phosphorylation in cellular signaling for alveolar macrophage phagocytic response to endotoxin.

Protein serine/threonine (ser/thr) phosphorylation is an early signaling event in macrophage activation. We investigated the changes in stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) activity and effects of phosphatase inhibition on alveolar macrophage (AM) function in rats challenged with intratracheal endotoxin. Animals were sacrificed 90 min post intratracheal lipopolysaccharide (LPS, 100 microg/rat) challenge. AMs were incubated with or without phosphatase inhibitors at 37 degrees C for 30 min. Phagocytosis, CD18 expression, SAPK/JNK and phosphatase activities of AMs were determined. LPS challenge activated SAPK/JNK activity and enhanced phagocytosis of AMs without altering phosphatase activity in these cells. Inhibition of phosphatase 1 and 2A activity with okadaic acid and calyculin A exerted a bi-phasic effect on AM phagocytic function. Okadaic acid at a concentration of 1 microM increased the mean channel fluorescence intensity (MCF) and the percentage of cells engaged in phagocytosis (percent phagocytosis) in AMs from saline-treated rats. This inhibitor at concentrations of 0.5 and 1 microM enhanced both the MCF and percent phagocytosis of AMs from LPS-challenged rats. Calyculin A at a concentration of 10 nM increased the MCF phagocytosis of AMs from LPS-challenged rats. At higher concentrations (20 and 30 nM), calyculin A showed a suppression on both the MCF and percent phagocytosis of AMs in both saline and LPS groups. AM CD18 expression was not altered following LPS challenge. Phosphatase inhibitors at doses that enhanced AM phagocytosis showed either no effect (okadaic acid) or inhibition (calyculin A) of AM CD18 expression. These results suggest that ser/thr phosphorylation and dephosphorylation participate in mediating the phagocytic response of AMs to LPS.

Animals↗
PubMed2000

Comprehensive PCR-based assay for detection and species identification of human herpesviruses.

The description and evaluation of a PCR-based assay for the detection and species identification of the eight known human herpesviruses are presented. Two primer pairs targeting well-conserved regions of the genome allowed the amplification of the DNAs of all known human herpesviruses at a high level of sensitivity (10 to 100 genome copies for most viruses). Identification of the virus species was achieved through restriction enzyme digestion with BamHI and BstUI, which yielded fragment sizes that were characteristic for each herpesvirus. Furthermore, it was demonstrated that this restriction enzyme panel allowed the discrimination between human herpesvirus 6 variant A and variant B. This assay format was validated over the course of 1 year in a clinical virology laboratory setting, where it was shown that it readily detected human herpesviruses, including occasional multiple infections, in a variety of clinical samples. The PCR assay was compared to isolation and electron microscopy for the detection of herpes simplex (HSV) and varicella-zoster virus (VZV) in clinical samples. All specimens positive by conventional methods were also positive by PCR. However, in a number of clinical specimens in which HSV or VZV could not be detected by conventional methods, PCR was able to demonstrate the presence of the virus.

Blood↗
PubMed2000

In vitro ethanol suppresses alveolar macrophage TNF-alpha during simian immunodeficiency virus infection.

Pulmonary infections are a significant cause of morbidity and mortality in patients with alcohol abuse and human immunodeficiency virus (HIV) infection, two immunocompromising conditions that frequently coexist. This study examined the separate and combined effects of in vivo lentiviral infection and in vitro alcohol exposure on alveolar macrophage (AM) production of tumor necrosis factor- alpha (TNF-alpha), a proinflammatory cytokine that is critical to normal pulmonary host defense. AMs, recovered by bronchoalveolar lavage (BAL) from uninfected and simian immunodeficiency virus (SIV)-infected rhesus macaques, at the asymptomatic and terminal stages of infection, were cultured in ethanol 2 h prior to stimulation with lipopolysaccharide (LPS). Median TNF-alpha concentrations were measured 15 h later. Spontaneous TNF-alpha production was similar in all groups examined. LPS increased TNF-alpha protein production similarly in SIV(-) (2, 381 +/- 359 pg/ml) and SIV(+) animals at the terminal stage of infection (2,019 +/- 507 pg/ml). In contrast, cells from SIV(+) asymptomatic animals had a depressed response (763 +/- 304 pg/ml). Ethanol (100 mM) suppressed the LPS-induced AM TNF-alpha response by approximately 50% in both SIV(-) and (+) animals. Ethanol-induced suppression of the TNF-alpha response occurred at a post-transcriptional level. These data suggest that ethanol-induced suppression of the pulmonary TNF-alpha response may further increase the susceptibility to and severity of secondary infectious complications in HIV-infected hosts.

Animals↗
PubMed2000

Keratinocyte growth factor prevents ventilator-induced lung injury in an ex vivo rat model.

Mechanical ventilation has been shown to produce lung injury characterized by noncardiogenic pulmonary edema. Keratinocyte growth factor (KGF) is a heparin-binding growth factor that causes alveolar type II pneumocyte hyperplasia. KGF pretreatment and the resultant pneumocyte hyperplasia reduce fluid flux in models of lung injury. We utilized the isolated perfused rat lung model to produce lung injury by varying tidal volume and the level of positive end-expiratory pressure during mechanical ventilation. Pretreatment with KGF attenuated ventilator-induced lung injury (VILI). This was demonstrated by lower wet-to-dry lung weight ratios and less lung water accumulation in the KGF group. Further, KGF prevented the decline in dynamic compliance and alveolar protein accumulation in VILI. KGF pretreatment reduced alveolar accumulation of intravascularly administered fluorescein isothiocyanate-labeled high-molecular-weight dextran. Thus, pretreatment with KFG attenuates injury in this ex vivo model of VILI via mechanisms that prevent increases in permeability.

Animals↗
PubMed2000

Cephalometric assessment of snoring and nonsnoring children.

STUDY OBJECTIVE: To determine the differences in craniofacial cephalometric variables between snoring and nonsnoring children. DESIGN: Cross-sectional. SETTING: Case Western Reserve University Dental School, Department of Orthodontics, and local Cleveland orthodontic private practices. PATIENTS: Twenty-eight snoring and 28 nonsnoring children between the ages of 7 years and 14 years. Nonsnoring subjects were matched to snoring subjects by age, sex, and ethnicity (mean [+/- SD] age, 10+/-2 years; 82% white, 64% female). INTERVENTIONS: None. MEASUREMENTS: Snoring was assessed using a sleep behavior questionnaire administered to parents or guardians. The cephalometric radiographs of the study subjects were traced by a single investigator, and 1 angular measurement and 11 linear measurements of hard and soft tissues were recorded. The paired Student's t test was used to analyze the cephalometric data. RESULTS: Snoring children manifest a significantly narrower anterior-posterior dimension of the pharynx at the superior and most narrow widths. Snoring children also had a greater length from the hyoid to the mandibular plane. CONCLUSIONS: Snoring children appear to present craniofacial factors that differ from those of nonsnoring children.

Adolescent↗