Search PubMed⌕ Search

Biomedical subjects

D L Nelson

Publications and source records attributed to D L Nelson.

At least 37 records · Page 2Linked to original sources
PubMed2001

A case of X-linked agammaglobulinemia diagnosed in adulthood.

X-linked agammaglobulinemia (XLA), caused by mutations in Bruton's tyrosine kinase (BTK), typically presents in early childhood. We report here the case of a male diagnosed at age 23 years with hypogammaglobulinemia, originally classified as common variable immunodeficiency (CVID). On further analysis at age 40, flow cytometric analysis of lymphocytes showed only 0.1% B cells and Western blot analysis showed a deficiency of BTK protein in peripheral blood mononuclear cells, indicating the patient has XLA. BTK cDNA and genomic DNA analysis revealed a splice site mutation at the 3' end of intron 13. Multiple abnormally spliced mRNA species were identified, one of which was predicted to produce a protein with a 24-amino-acid insertion between the SH2 and kinase domains. In vitro kinase assay of this product showed weak kinase activity, perhaps resulting in milder than usual disease. XLA can present in adult males, and sporadic cases may be misdiagnosed as CVID.

Adult↗
PubMed2001

Distinct interactions of the X-linked lymphoproliferative syndrome gene product SAP with cytoplasmic domains of members of the CD2 receptor family.

X-linked lymphoproliferative syndrome (XLP; Duncan's disease) is a primary immunodeficiency disease that manifests as an inability to regulate the immune response to Epstein-Barr virus (EBV) infection. Here we examine the ability of the product of the gene defective in XLP, SAP (DSHP/SH2D1A), to associate with the cytoplasmic domains of several members of the CD2 subfamily of cell surface receptors, including SLAM, 2B4, and CD84. While recruitment of SAP to SLAM occurred in a phosphorylation-independent manner, SAP was found to bind preferentially to tyrosine-phosphorylated cytoplasmic domains within 2B4 and CD84. Missense or nonsense mutations in the SAP open reading frame were identified in five of seven clinically diagnosed XLP patients from different kindreds. Four of these variants retained the ability to bind to the cytoplasmic tails of SLAM and CD84. While ectopic expression of wild-type SAP was observed to block the binding of SHP-2 to SLAM, mutant SAP derivatives that retained the ability to bind SLAM did not inhibit recruitment of SHP-2 to SLAM. In contrast, SAP binding to CD84 had no effect on the ability of CD84 to recruit SHP-2, but instead displaced SHP-1 from the cytoplasmic tail of CD84. These results suggest that mutations in the gene encoding the XLP protein SAP lead to functional defects in the protein that include receptor binding and SHP-1 and SHP-2 displacement and that SAP utilizes different mechanisms to regulate signaling through the CD2 family of receptors.

Antigens, CD↗
PubMed2001

Comparative genomic sequence analysis of the FXR gene family: FMR1, FXR1, and FXR2.

Mutations in the X-linked gene FMR1 cause fragile X syndrome, the leading cause of inherited mental retardation. Two autosomal paralogs of FMR1 have been identified, and are known as FXR1 and FXR2. Here we describe and compare the genomic structures of the mouse and human genes FMR1, FXR1, and FXR2. All three genes are very well conserved from mouse to human, with identical exon sizes for all but two FXR2 exons. In addition, the three genes share a conserved gene structure, suggesting they are derived from a common ancestral gene. As a first step towards exploring this hypothesis, we reexamined the Drosophila melanogaster gene Fmr1, and found it to have several of the same intron/exon junctions as the mammalian FXRs. Finally, we noted several regions of mouse/human homology in the noncoding portions of FMR1 and FXR1. Knowledge of the genomic structure and sequence of the FXR family of genes will facilitate further studies into the function of these proteins.

3' Untranslated Regions↗
PubMed2001

The clinical spectrum of Bruton's agammaglobulinemia.

X-linked, or Bruton's, agammaglobulinemia (XLA) was described in 1952 as the congenital inability to form antibodies. Patients were typically infants or young children with recurrent, severe bacterial infections. Other, milder cases of hypogammaglobulinemia were considered "acquired," and often presented later in life. Since the discovery of the defective gene in XLA in 1993, it has been shown that a significant number of male patients with sporadic or acquired hypogammaglobulinemia actually have XLA. We present here a case of atypical XLA and discuss similar cases in the literature. We conclude that any male with hypogammaglobulinemia, regardless of age of presentation, might have XLA. Males with low B-cell numbers are particularly likely to have XLA and should have Bruton's tyrosine kinase levels assessed.

Adult↗
PubMed2001

Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors.

The blockade of serotonin (5-HT) and norepinephrine (NE) transporters in vitro and in vivo by the dual 5-HT/NE reuptake inhibitors duloxetine and venlafaxine was compared. Duloxetine inhibited binding to the human NE and 5-HT transporters with K(i) values of 7.5 and 0.8 nM, respectively, and with a K(i) ratio of 9. Venlafaxine inhibited binding to the human NE and 5-HT transporters with K(i) values of 2480 and 82 nM, respectively, and with a K(i) ratio of 30. Duloxetine inhibited ex vivo binding to rat 5-HT transporters and NE transporters with ED(50) values of 0.03 and 0.7 mg/kg, respectively, whereas venlafaxine had ED(50) values of 2 and 54 mg/kg, respectively. The depletion of rat brain 5-HT by p-chloramphetamine and depletion of rat hypothalamic NE by 6-hydroxydopamine was blocked by duloxetine with ED(50) values of 2.3 and 12 mg/kg, respectively. Venlafaxine had ED(50) values of 5.9 and 94 mg/kg for blocking p-chloramphetamine- and 6-hydroxydopamine-induced monoamine depletion, respectively. Thus, duloxetine more potently blocks 5-HT and NE transporters in vitro and in vivo than venlafaxine.

Animals↗
PubMed2001

NF-kappaB signaling and human disease.

Despite substantial progress in understanding the NF-kappaB signaling pathway, the connections between this pathway and human disease are only now being elucidated. Genes that function within or upstream of the NF-kappaB pathway have been found to cause four distinct disorders and two allelic conditions. Investigation of these genes and disorders has brought significant insight into the role of NF-kappaB in various aspects of physiological development.

Animals↗
PubMed2001

The ties that bind what is known to the recognition of what is new.

Recognition success varies with how information is encoded (e.g., level of processing) and with what is already known as a result of past learning (e.g., word frequency). This article presents the results of experiments showing that preexisting connections involving the associates of studied words facilitate their recognition regardless of whether the words are intentionally encoded or are incidentally encoded under semantic or nonsemantic conditions. Words are more likely to be recognized when they have either more resonant connections coming back to them from their associates or more connections among their associates. Such results occur even though attention is never drawn to these associates. Regression analyses showed that these connections affect recognition independently of frequency, so the present results add to the literature showing that prior lexical knowledge contributes to episodic recognition. In addition, equations that use free-association data to derive composite strength indices of resonance and connectivity were evaluated. Implications for theories of recognition are discussed.

Adult↗
PubMed2001

Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding protein.

Bruton's tyrosine kinase (Btk) is required for human and mouse B cell development. Btk deficiency causes X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency in mice. Unlike Src proteins, Btk lacks a negative regulatory domain at the COOH terminus and may rely on cytoplasmic Btk-binding proteins to regulates its kinase activity by trans-inhibitor mechanisms. Consistent with this possibility, IBtk, which we identified as an inhibitor of Btk, bound to the PH domain of Btk. IBtk downregulated Btk kinase activity, Btk-mediated calcium mobilization and nuclear factor-kappaB-driven transcription. These results define a potential mechanism for the regulation of Btk function in B cells.

Adaptor Proteins, Signal Transducing↗
PubMed2001

A comparison of the positive and negative work attitudes of home health care and hospital nurses.

This article compares the positive and negative stress response work attitudes of 126 home health care registered nurses (RNs) and 145 hospital RNs. Home health care nurses reported significantly lower levels of the negative work attitudes, anger/hostility, and frustration with the system. There was no significant difference between the two groups of RNs among the positive work attitudes of job satisfaction, positive affect, hope, meaningfulness, manageability, and trust in the supervisor and the negative work attitudes frustration with the supervisor, job alienation, and negative affect.

Adult↗
PubMed2001

Eustress at work: the relationship between hope and health in hospital nurses.

This study examined the relationship between eustress, the positive response to work demands, and health in 158 hospital nurses. The positive psychological states hope, positive affect, and meaningfulness were used as indicators of eustress, and the psychological state negative affect was used as an indicator of distress. Hope, the belief that one has both the will and the way to accomplish one's goals, had a significant, positive relationship with the perception of health in this sample of hospital nurses.

Adaptation, Psychological↗
PubMed2001

m-CPP hypolocomotion is selectively antagonized by compounds with high affinity for 5-HT(2C) receptors but not 5-HT(2A) or 5-HT(2B) receptors.

The ability of m-CPP [1-(m-chlorophenyl)piperazine] to produce hypolocomotion is well documented. This effect has been postulated to be due to activation of the 5-HT(2C) receptor. It is only recently that the tools necessary to clearly delineate which serotonin receptors are involved in the mediation of m-CPP hypolocomotion have become available. We investigated the effects of the selective 5-HT(2A) antagonists, MDL 100,907 and ketanserin, the selective 5-HT(2B) antagonists, LY 202146 and LY 266097, the 5-HT(2B/2C) antagonist, SB 206553, and the selective 5-HT(2C) antagonist, SB 242084 on m-CPP-induced hypolocomotion and spontaneous locomotor activity in mice. Furthermore, we investigated the effects of the non-selective serotonin antagonists, ritanserin, LY 53857, mianserin and cyproheptadine on m-CPP hypolocomotion. Additionally, receptor-binding studies were employed as an in vitro assessment of relative affinities at the 5-HT(2A), 5-HT92B) and 5-HT(2C) receptors. Antagonists tested alone were without effect on spontaneous activity, with the sole exception of ketanserin, which decreased spontaneous activity at the high dose of 1 mg/kg. m-CPP-induced hypolocomotion was not significantly attenuated by various doses of MDL 100,907, ketanserin, LY 202146, LY 266097, ritanserin or cyproheptadine. In contrast, SB 206553, SB 242084, LY 53857 and mianserin were capable of reversing m-CPP-induced hypolocomotion. Consistent with previous suggestions, a detailed pharmacological evaluation with selective antagonists for the 5-HT2 family of receptors supports a primary role for the 5-HT(2C) receptor, and not 5-HT(2A) or 5-HT(2B) receptors, in mediating the hypolocomotion produced by m-CPP.

Amphetamines↗
PubMed2001

Linking cellular activation to cytoskeletal reorganization: Wiskott-Aldrich syndrome as a model.

The Wiskott-Aldrich syndrome is an inherited X-linked disorder characterized by immune deficiency, eczema, and thrombocytopenia with small platelets. The mutated protein, Wiskott-Aldrich syndrome protein, is an activator of actin cytoskeletal reorganization in hematopoietic cells. Members of the Wiskott-Aldrich syndrome protein family are being shown to be key integrators of cell signalling and cytoskeletal organization in many eukaryotic cell types. This review focuses on recent discoveries that reveal in increasing detail how Wiskott-Aldrich syndrome protein and its related proteins operate.

Cytoskeleton↗
PubMed2001

Molecular cloning of ILP-2, a novel member of the inhibitor of apoptosis protein family.

Inhibitor of apoptosis protein (IAP)-like protein-1 (ILP-1) (also known as X-linked IAP [XIAP] and mammalian IAP homolog A [MIHA]) is a potent inhibitor of apoptosis and exerts its effects, at least in part, by the direct association with and inhibition of specific caspases. Here, we describe the molecular cloning and characterization of a human gene related to ILP-1, termed ILP-2. Despite high homology to ILP-1, ILP-2 is encoded by a distinct gene, which in normal tissues is expressed solely in testis. In contrast to ILP-1, overexpression of ILP-2 had no protective effect on apoptosis mediated by Fas (also known as CD95) or tumor necrosis factor. However, ILP-2 potently inhibited apoptosis induced by overexpression of Bax or by coexpression of caspase 9 with Apaf-1, and preincubation of cytosolic extracts with ILP-2 abrogated caspase activation in vitro. A processed form of caspase 9 could be coprecipitated with ILP-2 from cells, suggesting a physical interaction between ILP-2 and caspase 9. Thus, ILP-2 is a novel IAP family member with restricted specificity for caspase 9.

Amino Acid Sequence↗
PubMed2001

The combination of zidovudine and interferon alpha-2B in the treatment of adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is frequently a very aggressive malignancy with a poor survival despite aggressive multiagent chemotherapy. The combination of the antiretroviral drug zidovudine (AZT) and interferon alpha (IFNalpha) has been reported to induce remissions in patients with ATL. The purpose of this study was to evaluate the clinical response and toxicity following administration of a combination of IFNalpha-2b and AZT in patients with human T-cell lymphotropic virus type I (HTLV-I)-associated ATL. Eighteen patients with ATL (chronic. crisis, acute or lymphoma type) were treated with the combination of AZT (50 - 200 mg orally 5 times a day) and IFNalpha-2b (2.5 - 10 million units subcutaneously daily). Three patients had objective responses lasting more than one month. One patient had a clinical complete remission, lasting 21.6 months and two patients had partial remissions lasting 3.7 and 26.5 months. Six patients were not considered evaluable for response due to short and/or interrupted periods of treatment. Seventeen patients have died with a median survival time after initiation of therapy of 6 months. Neutropenia and thrombocytopenia were the dose limiting toxicities. In conclusion, the response rate in this study was lower than noted in the two previous published series. This may be due to the amount and type of prior treatment our patients had received.

Adult↗
PubMed2000

Haplotypes at ATM identify coding-sequence variation and indicate a region of extensive linkage disequilibrium.

Genetic variation in the human population may lead to functional variants of genes that contribute to risk for common chronic diseases such as cancer. In an effort to detect such possible predisposing variants, we constructed haplotypes for a candidate gene and tested their efficacy in association studies. We developed haplotypes consisting of 14 biallelic neutral-sequence variants that span 142 kb of the ATM locus. ATM is the gene responsible for the autosomal recessive disease ataxia-telangiectasia (AT). These ATM noncoding single-nucleotide polymorphisms (SNPs) were genotyped in nine CEPH families (89 individuals) and in 260 DNA samples from four different ethnic origins. Analysis of these data with an expectation-maximization algorithm revealed 22 haplotypes at this locus, with three major haplotypes having frequencies > or = .10. Tests for recombination and linkage disequilibrium (LD) show reduced recombination and extensive LD at the ATM locus, in all four ethnic groups studied. The most striking example was found in the study population of European ancestry, in which no evidence for recombination could be discerned. The potential of ATM haplotypes for detection of genetic variants through association studies was tested by analysis of 84 individuals carrying one of three ATM coding SNPs. Each coding SNP was detected by association with an ATM haplotype. We demonstrate that association studies with haplotypes for candidate genes have significant potential for the detection of genetic backgrounds that contribute to disease.

Algorithms↗
PubMed2000

LY367265, an inhibitor of the 5-hydroxytryptamine transporter and 5-hydroxytryptamine(2A) receptor antagonist: a comparison with the antidepressant, nefazodone.

The potential antidepressant, LY367265 (1-[2-[4-(6-fluoro-1H-indol-3-yl)-3, 6-dihydro-1(2H)-pyridinyl]ethyl]-5,6-dihydro-1H,4H-[1,2, 5]thiadiazolo[4.3.2-ij]quinoline-2,2,-dioxide) has been shown to have a higher affinity for the 5-hydroxytryptamine (5-HT) transporter (K(i)=2.3 nM) and 5-HT(2A) (K(i)=0.81 nM) receptor than the clinically effective antidepressant, nefazodone. It is a potent inhibitor of [3H]5-HT uptake into rat cortical synaptosomes (IC(50)=3.1 nM) and shows selectivity over that for [3H]noradrenaline (IC(50)>1000 nM). It potentiates potassium-induced [3H]5-HT outflow from prelabelled guinea pig cortical slices both in the presence (EC(50)=950 nM) and absence (EC(50)=250 nM) of a saturating concentration of the 5-HT transport inhibitor, paroxetine, indicating a low level of activity at the 5-HT(1B/1D) autoreceptor. These studies indicate that LY367265 is a putative antidepressant which, because of its 5-HT(2A) receptor antagonist activity, has the potential to produce less sleep disturbance and sexual dysfunction than selective serotonin uptake inhibitors.

Animals↗