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Biomedical subjects

J A Winkelstein

Publications and source records attributed to J A Winkelstein.

At least 19 recordsLinked to original sources
PubMed1998

Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an inherited disorder of phagocyte function in which defective superoxide production results in deficient microbicidal activity. CGD patients suffer from recurrent, life-threatening infections, and nearly half develop chronic gastrointestinal (GI) complications (colitis, gastric outlet obstruction, or perirectal abscess) and/or autoimmune/rheumatologic disorders (AIDs). To identify genetic modifiers of disease severity, we studied a cohort of 129 CGD patients, in whom seven candidate genes (myeloperoxidase [MPO], mannose binding lectin [MBL], Fcgamma receptors IIa, IIIa, IIIb, TNF-alpha, and IL-1 receptor antagonist), each containing a physiologically relevant polymorphism predicted to influence the host inflammatory response, were selected for analysis. Genotypes of MPO (P = 0.003) and FcgammaRIIIb (P = 0.007) were strongly associated with an increased risk for GI complications, while an FcgammaRIIa (P = 0.05) genotype was suggestive for an association. Patients with all three associated genotypes had the highest risk for GI complications (P < 0.0001). The risk of AIDs was strongly associated with variant alleles of MBL (P = 0.01) and weakly associated with an FcgammaRIIa genotype (P = 0.04). Patients with variant forms of both MBL and FcgammaRIIa had the highest risk of developing an AID (P = 0.003).

Autoimmune Diseases↗
PubMed1998

Molecular analysis of the third component of canine complement (C3) and identification of the mutation responsible for hereditary canine C3 deficiency.

Genetically determined deficiency of the third component of complement (C3) in the dog is characterized by a predisposition to recurrent bacterial infections and to type 1 membranoproliferative glomerulonephritis. The current studies were undertaken to characterize the cDNA for wild-type canine C3 and identify the molecular basis for hereditary canine C3 deficiency. Amplification, cloning, and sequence analysis indicated that canine C3 is highly conserved in comparison with human, mouse, and guinea pig C3. Southern blot analysis failed to show any gross deletions or rearrangements of DNA from C3-deficient animals. Northern blot analysis indicated that the livers of these animals contain markedly reduced quantities of a normal length C3 mRNA. The full-length 5.1-kb canine C3 cDNA was amplified in overlapping PCR fragments. Sequence analysis of these fragments has shown a deletion of a cytosine at position 2136 (codon 712), leading to a frameshift that generates a stop codon 11 amino acids downstream. The deletion has been confirmed in genomic DNA, and its inheritance has been demonstrated by allele-specific oligonucleotide hybridization.

Amino Acid Sequence↗
PubMed1998

Thymoma and cellular immune deficiency in an adolescent.

Thymoma has been associated with both humoral immunodeficiency and cellular immunodeficiency, but the latter association has never been described in the pediatric age group. We report a 15-year-old female with thymoma, recalcitrant oropharyngeal candidiasis, recurrent generalized cutaneous herpes simplex virus type 2 infection, recurrent pneumonia and myasthenia gravis. Pathology of the thymic lesion showed a 10x5x6 cm extensively hyalinized mass with residual regions of spindle cell predominant and lymphocyte-rich thymoma. There was no evidence of humoral immunodeficiency but there was clinical and laboratory evidence of cellular immunodeficiency with cutaneous anergy and absence of T cell proliferation to Candida antigen. Six weeks after the thymoma was resected, she was no longer anergic and Candida proliferation was normal, although she continued to experience infections. This is the first reported pediatric patient with an association of cellular immunodeficiency with thymoma.

Adolescent↗
PubMed1998

Adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency in common variable immunodeficiency.

The clinical presentations of adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency are widely variable and include clinical and immunologic findings compatible with common variable immunodeficiency. The screening of 44 patients with common variable immunodeficiency failed to identify any individuals with deficiencies of these enzymes.

Adenosine Deaminase↗
PubMed1998

Consequences of the delayed diagnosis of ataxia-telangiectasia.

OBJECTIVES: Ataxia-telangiectasia (AT) is a rare, autosomal recessive neurodegenerative disorder in which the diagnosis is obvious when ataxia and telangiectasia are both present. However, the diagnosis can be made upon the onset of ataxia and before the appearance of telangiectasia if confirmed by laboratory tests. Early diagnosis is important for genetic counseling, appropriate care, and avoidance of unnecessary tests. The purpose of this study is to identify factors responsible for delays in the diagnosis of AT. DESIGN: The records of all patients seen at the Ataxia-Telangiectasia Clinical Center from July 1, 1995 to April 1, 1997 were reviewed to determine age of onset of gait abnormality, recognition of telangiectasia, and diagnosis. RESULTS: In 48 patients with AT, who were the index cases in their respective families, the median age of diagnosis (78 months) occurred after the onset of gait abnormalities (15 months) and closely corresponded to the development of telangiectasia (72 months). In the majority of cases (34/48), telangiectasia appeared before the diagnosis was established. The most common misdiagnosis was cerebral palsy (29/48 cases). Twenty-one children (4 with AT) were born after the start of symptoms in the index case, but before the establishment of a diagnosis. CONCLUSIONS: The term AT, although a concise and memorable label for the disorder, is also a barrier to early diagnosis. We recommend the use of routine serum alpha-fetoprotein testing for all children with persistent ataxia.

Adolescent↗
PubMed1997

Adenosine deaminase deficiency in adults.

Adenosine deaminase (ADA) deficiency typically causes severe combined immunodeficiency (SCID) in infants. We report metabolic, immunologic, and genetic findings in two ADA-deficient adults with distinct phenotypes. Patient no. 1 (39 years of age) had combined immunodeficiency. She had frequent infections, lymphopenia, and recurrent hepatitis as a child but did relatively well in her second and third decades. Then she developed chronic sinopulmonary infections, including tuberculosis, and hepatobiliary disease; she died of viral leukoencephalopathy at 40 years of age. Patient no. 2, a healthy 28-year-old man with normal immune function, was identified after his niece died of SCID. Both patients lacked erythrocyte ADA activity but had only modestly elevated deoxyadenosine nucleotides. Both were heteroallelic for missense mutations: patient no. 1, G216R and P126Q (novel); patient no. 2, R101Q and A215T. Three of these mutations eliminated ADA activity, but A215T reduced activity by only 85%. Owing to a single nucleotide change in the middle of exon 7, A215T also appeared to induce exon 7 skipping. ADA deficiency is treatable and should be considered in older patients with unexplained lymphopenia and immune deficiency, who may also manifest autoimmunity or unexplained hepatobiliary disease. Metabolic status and genotype may help in assessing prognosis of more mildly affected patients.

Adenosine Deaminase↗
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↗
PubMed1996

Discriminant quantitation of posttransplant hepatic reticuloendothelial function. The impact of ischemic preservation.

This study focuses upon two discrete components of posttransplant hepatic reticuloendothelial system (RES) function-phagocytosis and killing of bacteria-under various conditions of ischemic preservation. We had previously reported that, following intravenous injection of rats with 51Cr and 125I double-labeled Escherichia coli, hepatic 51Cr levels can be used to reliably quantify hepatic phagocytic clearance of the bacteria from the blood (HPC), while the subsequent release of 125I from the liver accurately parallels hepatic bacterial killing. Here, Wistar rats were transplanted with syngeneic livers perfused with either normal saline (NS) or University of Wisconsin solution (UW) and stored at 4 degrees C for 1, 2, or 3 hr prior to implantation. Control rats underwent laparotomy and hepatic artery ligation. Using the double-labeled E coli assay, HPC was decreased in all transplanted animals when compared with controls, reaching a nadir on the third postoperative day (P < 0.05). In rats transplanted with livers preserved in NS, the fraction of phagocytosed organisms that were subsequently killed (hepatic killing efficiency=HKE) was increased to 142%, 129%, or 112% of normal following 1, 2, or 3 hr of cold ischemia, respectively; P < 0.05). Conversely, preservation of donor allografts in UW was associated with marked depression of HKE. Moreover, rats receiving NS- or UW-preserved livers tolerated an intravenous challenge with Streptococcus pneumoniae poorly (50% mortality) compared with hepatic artery ligated controls (12% mortality) at 7 days. Ischemic preservation of rat livers in NS resulted in a dose (of ischemia)-dependent reduction of hepatic phagocytosis coupled with a potentiation of HKE. Preservation in UW, however, produced a striking suppression of both components of hepatic RES function. Following a septic challenge survival was reduced in both groups of transplanted rats.

Adenosine↗
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

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

Platelet activating factor inhibition reduces lung injury after cardiopulmonary bypass.

Because cardiopulmonary bypass (CPB) produces a diffuse inflammatory reaction that may injure multiple organs and complicate cardiac surgical procedures, we examined the use of a competitive inhibitor of platelet activating factor (SDZ HUL-412) in a porcine model of CPB as a means to ameliorate pulmonary injury after CPB. Thirteen pigs (35 to 40 kg) underwent CPB at 28 degrees C for 2 hours, followed by 2 hours of observation. Group I (n = 6) received SDZ HUL-412 (a quinolinium compound) intravenously (3 mg/kg loading dose and 2 mg.kg-1.h-1 continuous infusion) starting before sternotomy. Group II (n = 7) received a saline vehicle. Peak airway pressure, pulmonary arterial pressure, left atrial pressure, and arterial blood gases were measured and flow cytometry evaluated surface expression of adhesion molecule subunit CD18 on circulating neutrophils. Pulmonary function was significantly improved in group I. Fifteen minutes after CPB, dynamic lung compliance in group I was 91% +/- 12% of baseline versus 49% +/- 5.2% in group II (p = 0.06 by analysis of variance). After CPB, the arterial oxygen pressure was also significantly better in group I than in group II (425 +/- 61 versus 234 +/- 76 mm Hg) (p < 0.05). The rise in pulmonary vascular resistance after CPB was less in group I (p < 0.05) (323 +/- 55 to 553 +/- 106 dynes.s.cm-5) than in group II (531 +/- 177 to 884 +/- 419 dynes.s.cm-5) at the end of the observation period. CD18 up-regulation increased similarly in the two groups during CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1995

Immunologic defects in patients with chronic recurrent sinusitis: diagnosis and management.

Twenty patients with chronic refractory sinusitis or rhinitis were identified to have immune defects on the basis of total immunoglobulin level, immunoglobulin G subclass, and vaccine response. Eight patients were immunoglobulin A deficient, five had low immunoglobulin levels with vaccine hyporesponse, and four had low immunoglobulin levels with normal vaccine responses. Three subjects showed isolated immunoglobulin G1 deficiency. Demographic variables such as age, sex, infection pattern, and any other related disorders were studied retrospectively, which may have contributed to the diagnosis. An immunologic screen was essential for the diagnosis of immunodeficiency in these patients. Treatment options included prophylactic antibiotics, management of associated allergies, functional endoscopic sinus surgery, and replacement therapy with immunoglobulin in selected patients.

Adolescent↗
PubMed1994

The third component of complement protects against Escherichia coli endotoxin-induced shock and multiple organ failure.

We investigated whether the third component of complement (C3) is involved in the pathophysiology of endotoxic shock, and if it is involved, whether it plays a protective role or whether it mediates shock and multiple organ failure. In a prospective, controlled investigation, six Brittany spaniels that were homozygous for a genetically determined deficiency of C3 (C3 deficient, < 0.003% of normal serum C3 levels) and six heterozygous littermates (controls, approximately 50% of mean normal serum C3 level) were given 2 mg/kg of reconstituted Escherichia coli 026:B6 acetone powder as a source of endotoxin, intravenously. All animals were given similar fluid and prophylactic antibiotic therapy, and had serial hemodynamic variables obtained. After E. coli endotoxin infusion, C3-deficient animals had higher peak levels of endotoxin and less of a rise in temperature than controls (P < 0.05). During the first 4 h after E. coli endotoxin infusion, C3-deficient animals had significantly greater decreases in mean central venous pressure and mean pulmonary artery pressure than controls (P < 0.02). During the first 48 h after E. coli endotoxin infusion, C3-deficient animals had significantly greater decreases in mean arterial pH, left ventricular ejection fraction, and mean pulmonary capillary wedge pressure, and greater increases in mean arterial lactate, arterial-alveolar O2 gradient, and transaminases (aspartate aminotransferase and alanine aminotransferase) than controls, (all P < 0.05). After E. coli endotoxin infusion, C3-deficient animals compared to controls had significantly less of a decrease in mean C5 levels (P < 0.01), but similar (P = NS) increases in circulating tumor necrosis factor levels, bronchoalveolar lavage neutrophils, and protein, and similar (P = NS) decreases in blood leukocytes and platelets. Two of six C3-deficient animals and two of six controls died. In summary, after intravenous infusion of E. coli endotoxin, canines with C3 deficiency have decreased endotoxin clearance and worse E. coli endotoxin-induced shock and organ damage. Thus, the third component of the complement system plays a beneficial role in the host defense against E. coli endotoxic shock.

Analysis of Variance↗
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↗