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Biomedical subjects

K E Sullivan

Publications and source records attributed to K E Sullivan.

At least 55 records · Page 3Linked to original sources
PubMed1997

Defective antigen-induced lymphocyte proliferation in the X-linked hyper-IgM syndrome.

We examined T-cell proliferation in five patients with X-linked hyper-IgM syndrome (XHIM), using a panel of antigens and lectins. All patients had impaired antigen-induced proliferation, whereas their lectin responses were normal. Thus, in addition to severely depressed antibody responses, patients with XHIM have a defect in antigen-specific T-cell proliferation, which may explain their susceptibility to pathogens such as Pneumocystis carinii.

Antigens↗
PubMed1997

Association of toxic shock syndrome toxin-secreting and exfoliative toxin-secreting Staphylococcus aureus with Kawasaki syndrome complicated by coronary artery disease.

Kawasaki syndrome (KS) has been reported to be associated with selective expansion of Vbeta2+ T cells and either staphylococcal toxic shock syndrome toxin-1 or streptococcal pyrogenic exotoxin C in uncomplicated cases. However, there have been no previous studies on the role of superantigens in KS associated with coronary artery disease, the major complication of this illness. The present study characterized bacteria isolated from three acute KS patients who developed coronary artery disease. Staphylococcus aureus secreting either TSST-1 (n = 3) or exfoliative toxin A (n = 1), both known to stimulate expansion of Vbeta2+ T cells, were isolated from all three patients. The percent Vbeta2+ T cells was determined in three patients with coronary artery disease. On presentation, one patient demonstrated reduction, whereas the other two showed expansion, of Vbeta2+ T cells. Repeat analyses of the latter two children showed their percent Vbeta2+ T cells to decrease toward normal. These observations suggest that coronary artery disease in KS may result from superantigenic stimulation of Vbeta2+ T cells. This is also the first demonstration of an association of staphylococcal exfoliative toxin with acute KS. The observation that three different bacterial toxins associated with KS are potent activators of Vbeta2+ T cells suggests an important role for this T cell subset in the pathogenesis of this autoimmune disease.

Aneurysm↗
PubMed1996

Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity.

BACKGROUND: The Canale-Smith syndrome is a childhood disorder characterized by lymphadenopathy and autoimmunity. The similarity between this syndrome and that in mice with the lymphoproliferation (lpr) phenotype or the generalized-lymphoproliferative-disease (gld) phenotype led us to investigate whether it too is caused by mutations of the Fas gene (lpr mice) or the Fas ligand (gld mice), which regulate apoptosis in lymphocytes. METHODS: We studied four patients with the syndrome and their families. T-lymphocyte phenotypes were analyzed, and the susceptibility of activated T cells to Fas-mediated apoptosis in vitro was determined. Mutations of Fas were sought by nucleotide-sequence analysis. RESULTS: Patients with the Canale-Smith syndrome had increased numbers of circulating double-negative T cells (>20 percent) and profoundly impaired apoptosis of activated T cells incubated with an anti-Fas antibody. Three novel Fas mutations were identified, all of which were heterozygous and predicted to impair signal transduction by Fas. Autoimmune manifestations of the disease, such as hemolytic anemia and thrombocytopenia, persisted into adolescence. Two patients followed into adulthood had intermittent lymphadenopathy, which diminished over time. Neoplasms developed in both, and one died of hepatocellular carcinoma at the age of 43. CONCLUSIONS: Patients with the Canale-Smith syndrome have mutations in Fas, which implicates this gene in the accumulation of lymphocytes and the autoimmunity characteristic of the syndrome.

Adult↗
PubMed1996

Mannose-binding protein genetic polymorphisms in black patients with systemic lupus erythematosus.

OBJECTIVE: To determine whether dysfunctional or deficient mannose-binding protein (MBP) variants are found with increased frequency in black patients with systemic lupus erythematosus (SLE) compared with controls. METHODS: Allele-specific polymerase chain reaction amplification of 4 different polymorphic sites was performed on samples from 92 black SLE patients and 86 geographically matched black controls. RESULTS: Two structural polymorphisms of MBP, associated with low serum levels of MBP, were found with significantly increased frequency in the SLE patient population compared with controls. In contrast, a promoter haplotype associated with particularly high serum levels of MBP was negatively associated with SLE. CONCLUSION: Deficiencies of MBP predispose individuals to SLE.

Acute-Phase Proteins↗
PubMed1996

Sarcoidosis and common variable immunodeficiency. Report of 8 cases and review of the literature.

The true incidence of sarcoidosis in common variable immunodeficiency (CVID) is unknown. We report here 8 cases of sarcoidosis among 80 patients with CVID followed in our clinics, along with 22 well-documented cases reported in the literature. Sarcoidosis, therefore, represents an important entity to consider among patients with CVID who exhibit clinical, radiographic, laboratory, and biopsy findings compatible with sarcoidosis. Conversely, the diagnosis of CVID should be considered in patients with sarcoidosis who do not exhibit the characteristic hypergammaglobulinemia and who have a history of recurrent infections. Although many features of sarcoidosis are similar in patients with CVID to those in patients with sarcoidosis alone, there are many important differences. Patients with CVID in whom sarcoidosis develops present with hypogammaglobulinemia rather than hypergammaglobulinemia and have a higher prevalence of recurrent infections, thrombocytopenia, and splenic involvement. Steroids, in most cases, appeared helpful in reducing adenopathy and splenomegaly, improving uveitis, lowering serum alkaline phosphatase, and reversing hematologic abnormalities. The underlying pathophysiology responsible for the association of these 2 disorders in the same patient remains obscure. However, as more patients are identified, it may be possible to gain a better understanding of the immunologic defect responsible for the dual presentation of these 2 relatively uncommon diseases.

Adult↗
PubMed1996

Regulation of early complement components C3 and C4 in the synovium.

To determine the cytokine inducibility of early complement component (C3 and C4) expression in the synovium, explant tissue was maintained in culture for 7 days. C3 and C4 production was measured by specific enzyme-linked immunosorbent assay, and RNA was evaluated by semiquantitative PCR. The effects of leukemia inhibitory factor (LIF), gamma interferon (IFN-gamma), IFN-alpha, and estrogen on C3 and C4 expression were evaluated. C3 levels were unaffected by 7 days of LIF, IFN-gamma, or IFN-alpha treatment. In contrast, C4 levels were significantly induced in synovial samples treated for 7 days with either IFN-gamma or IFN-alpha. LIF had no effect on C4 levels in this system. Estrogen was found to down-modulate the induction of expression due to IFN-gamma. These data provide evidence for cytokine regulation of C4 expression in the synovium and for estrogen modulation of those effects.

Base Sequence↗
PubMed1996

What do physicians tell patients with end-stage COPD about intubation and mechanical ventilation?

BACKGROUND: At some point in time, many patients with end-stage COPD require intubation and mechanical ventilation (MV) to sustain life. MV decisions are most effective when the patient and physician have discussed the options in advance. The purpose of this study was to examine how the physician perceives the decision-making process. METHODS: Fifteen respirologists were interviewed to elicit information regarding intubation and MV, and the exchange of information between patients and physicians. Emergent themes were coded using a qualitative approach and were verified by a blinded researcher. RESULTS: Respondents included ten academic and five community-based respirologists from seven hospitals. Most physicians were men with between 4 and 37 years experience. Narratives were very similar in content and seemed well rehearsed. Approach and delivery, however, were unique to each physician. Fourteen respirologists emphasized the importance of knowing patients as individuals prior to initiating this discussion. This period of familiarization often dictated when the physician believed the ventilation discussion is appropriate. Individual physician comfort also appeared to affect the timing of the discussion. Physicians discussed the many elements that make the MV discussion difficult for physicians and patients. Intubation details included a tube being placed down the throat, the discomfort associated with the tube, the inability to speak, and the availability of pain reducing medication. All physicians discussed the possibility of death with their patients, although many preferred euphemisms in initial discussions. All physicians indicated that intubation is presented as the patient's choice. However, all but one physician commonly framed their discussions in order to influence patient choice. The positive or negative framing seemed contingent on the physician's expectations for that patient. CONCLUSIONS: Our interviews demonstrated considerable agreement between physicians about the content and timing of the intubation MV discussion. Physicians all agreed that knowing the patient and his or her situation was important in determining the timing of the intubation and MV discussion. Practice style and individual physician comfort with end-of-life decisions may influence the timing of the discussion and possibly the number of patients who are finally approached. All physicians advocated a shared decision-making approach, but they strongly influence the deliberation process. Thus, the decision-making model seemed to be physician driven in this study.

Attitude of Health Personnel↗
PubMed1996

Discordant phenotype in siblings with X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is a congenital humoral immunodeficiency caused by a defect in a B-cell-specific signaling molecule, Btk. There has been little concordance of phenotype with genotype in this disorder, and defects in Btk cause immunodeficiencies that range from mild impairment to complete inability to produce antibodies. The factors modifying the phenotype of XLA are not understood. The current study is the first description of two male siblings with identical T134 --> C mutations in the translation initiation ATG of Btk who have different clinical phenotypes. The proband lacks immunoglobulins and B cells and has recurrent infections, while the elder, affected brother has normal levels of IgG and IgM and very few infections. Both have undetectable levels of Btk kinase activity in circulating mononuclear cells. Complete sequencing of Btk gene transcripts in both brothers revealed no additional mutations to account for the discordant phenotypes. This description provides unequivocal evidence that the phenotype of XLA is influenced by factors additional to the Btk gene.

Adolescent↗
PubMed1996

Serum complement determinations in patients with quiescent systemic lupus erythematosus.

OBJECTIVE: To determine whether complement component analyses during a period of inactive disease can define clinically important subgroups and predict morbidity in patients with systemic lupus erythematosus (SLE). METHODS: We identified 277 patients with SLE whose disease became clinically inactive at some point after diagnosis. Serum samples were obtained at that time and tested for total complement activity (CH100) and antigenic levels of C1q, C1r, C1s, C3 and C4. Results of complement determinations were correlated with demographic characteristics and clinical findings in the followup period (mean observation period 4.25 years). RESULTS: We identified 25 (9%) patients with multiple complement determinations below the normal range. 24 other patients (8.5%) had a very low level of a single complement component. The group with multiple complement determinations below the normal range was much more likely than the normocomplementemic SLE controls to progress to renal insufficiency. In other respects, complement component determinations were neither reflective nor predictive of clinical course. CONCLUSION: In this group of patients with inactive SLE, complement component analyses did not generally correlate with longterm outcome; however, multiple low complement component determinations during disease quiescence was associated with increased risk of renal insufficiency.

Autoantigens↗
PubMed1995

Genetic and clinical advances in Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome is an immunodeficiency associated with thrombocytopenia, recurrent infections, eczema, and a predisposition to malignancy. Until this past year, the genetic defect was unknown, and our understanding of the disease was limited to defining the aberrant immunologic and hematologic functions in these patients. The identification of the genetic defect has already improved our understanding of the pathogenesis of this complex disease and has already resulted in the development of a more widely applicable prenatal diagnostic test. Other important developments this past year include the development of a diagnostic assay that should simplify the identification of Wiskott-Aldrich syndrome patients and a retrospective review that characterizes the natural history of the disease.

Child↗
PubMed1994

Transcriptional regulation of the gene for the second component of human complement: promoter analysis.

The 5' flanking region of the human gene for the second component of complement was sequenced and analyzed functionally. RNase protection demonstrated a cluster of four initiation sites in the 5' flanking region utilized in the hepatoma cell line, HepG2. Utilization of all four initiation sites increased in response to gamma-interferon (IFN-gamma). Transient transfection analysis was used to examine cis-acting sequence motifs controlling transcription from the 5'-flanking region. We identified a 228-bp minimal promoter fragment which was able to direct basal and IFN-gamma inducible transcription from authentic initiation sites. Sequence motifs outside of this region may modulate the transcriptional regulation of the second component of complement. Although complement components are not coordinately regulated, we identified four regions of significant homology with the promoters of multiple other complement components. Three of these regions were within the minimal promoter fragment.

Animals↗
PubMed1994

A multiinstitutional survey of the Wiskott-Aldrich syndrome.

The Wiskott-Aldrich syndrome is an X-linked primary immunodeficiency originally characterized by the clinical triad of thrombocytopenia, eczema, and immunodeficiency. We collected clinical and laboratory information on 154 unselected patients with Wiskott-Aldrich syndrome to define better the clinical expression of this disorder. The classic triad of thrombocytopenia with small platelets, recurrent otitis media, and eczema was seen in only 27% of the study population; 5% of the study population had only infectious manifestations, and 20% of the study group had only hematologic manifestations before diagnosis. The results of immunologic evaluations varied from one patient to another and the course of the disorder varied tremendously, even within a single kindred. We conclude that many patients with Wiskott-Aldrich syndrome have an atypical presentation and that a panel of diagnostic tests is often required to establish the diagnosis. Two high-risk subgroups were identified in the study population: patients with platelet counts < 10 x 10(9)/L (< 10,000/mm3) at the time of diagnosis were at high risk of bleeding, and patients with autoimmune disorders were at increased risk of having a malignancy.

Adolescent↗
PubMed1994

Prenatal diagnosis of heterozygous deficiency of the second component of complement.

Genetically determined C2 deficiency predisposes an individual to recurrent and invasive bacterial infections as well as a variety of rheumatic diseases. Most C2-deficient individuals carry the same 28-bp deletion in the sixth exon of the C2 gene. The present article reports the first prenatal analysis of a sibling of a C2-deficient patient; the sibling was found to be a heterozygous carrier of the 28-bp deletion of C2.

Adult↗
PubMed1994

Prevalence of a mutation causing C2 deficiency in systemic lupus erythematosus.

OBJECTIVE: In an effort to establish whether a 28 base pair (bp) deletion in the gene for the 2nd component of complement (C2) constitutes a significant genetic risk factor for systemic lupus erythematosus (SLE), we determined the frequency of this mutation in SLE and control populations. The MHC associations of this mutation were also established. METHODS: Polymerase chain reaction (PCR) was used to amplify DNA, and the wild type and mutant alleles were distinguished by gel electrophoresis. RESULTS: Among 122 Caucasoid patients with SLE, 2 homozygous and 2 heterozygous carriers of the 28 bp deletion were found, giving a gene frequency of 0.0246. In contrast, 6 of 427 North American Caucasoid controls were heterozygous for the 28 bp deletion, giving a gene frequency of 0.0070 (p < 0.05). Carriers of the 28 bp deletion in C2 frequently carried the DRB1*1501 allele. The 28 bp deletion in C2 was not found in 194 African-American controls or in 127 African-American patients with SLE. CONCLUSIONS: A direct assay for the most common form of C2 deficiency established that the 28 bp deletion in the C2 gene is significantly more common in Caucasoid patients with SLE compared to controls (p < 0.05). When only heterozygous carriers of the 28 bp deletion were enumerated, they were not found more frequently in the Caucasoid population with SLE compared to controls.

Base Sequence↗
PubMed1992

Ionized calcium concentration in horses with surgically managed gastrointestinal disease: 147 cases (1988-1990).

Packed cell volume, total plasma protein, serum sodium, potassium, and ionized Ca2+ concentrations, and blood pH were determined at the time of admission and following surgery in 147 horses with acute abdominal crisis. Horses were allotted to 3 categories on the basis of the surgical lesion: (1) nonstrangulating obstruction of the ascending or descending colon (category A, n = 76), (2) strangulating and nonstrangulating infarction of the cecum or ascending colon (category B, n = 37), and (3) strangulating and nonstrangulating infarction of the small intestine (category C, n = 25). Horses with low serum ionized Ca2+ concentration following surgery were given 23% calcium gluconate (100 to 300 ml) IV to effect, and ionized Ca2+ concentration was determined following treatment. The serum ionized Ca2+ concentrations of horses in categories A, B, and C before and after surgery were lower than our normal laboratory reference range. Prior to surgery, serum ionized Ca2+ concentration measured from horses in category B and C was lower than that in horses in category A. There was no difference in ionized Ca2+ concentration in serum samples obtained before surgery in horses from category B and C, and in serum samples obtained following surgery. There was a decrease in ionized Ca2+ concentration during surgery in horses in category A. There was no change between preoperative and postoperative ionized Ca2+ concentration in the samples obtained from horses in category B and C. After calcium gluconate administration, all horses with low serum ionized Ca2+ after surgery had concentrations within our normal range. Measurement of serum ionized Ca2+ in horses with an acute abdominal crisis is recommended.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen, Acute↗
PubMed1987

Transcriptional enhancers in the HLA-DQ subregion.

Using transient expression assays, the HLA-DQ alpha and HLA-DQ beta genes of the human major histocompatibility complex were screened for cis-acting regulatory elements. Two regions in the HLA-DQ alpha gene and one in the HLA-DQ beta gene were identified which fulfilled the criteria for transcriptional enhancers.

Chromosome Mapping↗
PubMed1985

Molecular analysis of the bare lymphocyte syndrome.

The bare lymphocyte syndrome is a disorder in which class I histocompatibility antigens fail to be expressed normally on the surface of lymphocytes. Utilizing complementary DNA probes for both beta 2-microglobulin and class I genes, the molecular basis for this syndrome was investigated in a family with two siblings exhibiting the bare lymphocyte syndrome. Southern blot analysis demonstrated no gross internal defect in either class I or beta 2-microglobulin genes. Northern blot analysis of class I and beta 2-microglobulin messenger RNAs also revealed no qualitative difference between affected and unaffected family members. In contrast, quantitation of both class I and beta 2-microglobulin transcripts demonstrated each to be decreased in patients when compared to controls. Moreover, the decrease in both transcripts was coordinate. These results suggest that the bare lymphocyte syndrome may represent a pretranslational regulatory defect of both class I and beta 2-microglobulin gene expression.

Antigens, Surface↗