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Biomedical subjects

B White

Publications and source records attributed to B White.

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

Skin thickness score as a predictor and correlate of outcome in systemic sclerosis: high-dose versus low-dose penicillamine trial.

OBJECTIVE: To study the clinical implications of a skin thickness score > or =20 at first visit and of softening of sclerodermatous skin in a cohort of systemic sclerosis (SSc) patients with diffuse cutaneous scleroderma. METHODS: Skin and visceral involvement were assessed in 134 SSc patients with diffuse scleroderma (mean +/- SD duration of SSc 10 +/- 4 months) as they entered a multicenter drug trial and again at 2 years of followup. Advent of mortality and scleroderma renal crisis (SRC) were assessed during a followup of 4.0 +/- 1.1 years (mean +/- SD). Logistic and linear regression were used to examine the relationship of baseline skin score to morbidity, mortality, and visceral involvement and the relationship of changes in skin score to changes in physical examination, laboratory, and functional variables over 2 years. RESULTS: A baseline skin score > or =20 was associated with heart involvement at baseline (odds ratio [OR] 3.10, 95% confidence interval [95% CI] 1.25-7.70) and was predictive of mortality (OR 3.59, 95% CI 1.23-10.55) and SRC (OR 10.00, 95% CI 2.21-45.91) over 4 years. Multivariate linear regression demonstrated that a model with skin score at baseline (P = 0.0078) and changes in large joint contractures (P = 0.0072), tender joint counts (P = 0.0119), handspread (P = 0.0242), and Health Assessment Questionnaire disability index (HAQ-DI) (P = 0.0244) explained the change in skin score over 2 years (R2 = 0.567). Multivariate logistic regression demonstrated that the investigator's global assessment of improvement was best explained by a model with skin score and HAQ-DI (R2 = 0.455). CONCLUSION: A baseline skin score > or =20 was associated with heart involvement at baseline and predicted mortality and SRC over the subsequent 4 years. Improvement in skin score in these patients with diffuse cutaneous scleroderma was associated with improvement in hand function, inflammatory indices, joint contractures, arthritis signs, overall functional ability, and the examining investigator's global assessment of improvement.

Adult↗
PubMed2000

Diversity and plasticity of the anti-DNA topoisomerase I autoantibody response in scleroderma.

OBJECTIVE: To examine domain recognition by anti-DNA topoisomerase I (anti-DNA topo I, or anti-topo I) antibodies over time in scleroderma patients. METHODS: Serial serum samples from scleroderma patients with known reactivity to Scl-70, a 70-kd topo I breakdown product, were tested by immunoblot for IgM, IgG, IgA, kappa, and lambda reactivity to Scl-70 and 8 overlapping recombinant peptide fragments (F1-F8) that span the human topo I molecule. RESULTS: IgM, IgG, kappa, and lambda anti-topo I antibodies in both early-disease and late-disease serum samples preferentially recognized the Scl-70 molecule rather than the F1-F8 peptides, suggesting preferential recognition of conformational determinants on Scl-70 throughout the disease course. Amounts of both primary and secondary anti-topo I antibodies to Scl-70 varied over time, including increases in primary antibody responses late in the disease course. Striking variability in recognition of the F1-F8 peptides by IgM, IgG, IgA, kappa, and lambda anti-topo I antibodies was seen in serial samples. Most often, the change in FI-F8 recognition from one sample to the next was unpredictable, although occasionally patterns of antibody recognition were reciprocal in serial samples. Of note, in several patients, what could have been interpreted as domain spreading among F1-F8 in 2 successive samples was just a part of changing antibody reactivity to these peptides that again became more restricted in a third sample. CONCLUSION: Titers and immunodominant domains recognized by both primary and secondary anti-topo I antibodies are highly variable over time. This suggests continual antigen presentation and regulation of the anti-topo I antibody response in scleroderma, even late in the disease course.

Adolescent↗
PubMed2000

Extensive surface phenotyping of alveolar macrophages in interstitial lung disease.

There is increasing evidence implicating activated macrophages in the pathogenesis of interstitial and other lung diseases. We investigated whether there was a unique pattern of cell surface expression that constituted a disease-specific phenotype on alveolar macrophages from patients with interstitial lung disease (ILD). Macrophage cell surface receptor expression of 19 selected markers was assessed by indirect immunofluorescence and flow cytometry in bronchoalveolar lavage (BAL) fluids from patients with idiopathic pulmonary fibrosis (IPF, n = 4), scleroderma (SCL-ILD, n = 14), mild asthma (n = 7), allergy without asthma (n = 2), and normal subjects (n = 9). There was increased expression of adhesion receptors (CD11c, CD29, CD36, CD44, CD49e, CD54), receptors involved in signal transduction and/or inflammation (CD13, CD45, CD53), and other markers (CD9, CD52, CD71, CD98, HLA Class I) on macrophages from ILD patients compared to the non-ILD group. Most markers upregulated on macrophages in ILD were significantly inversely correlated with clinical parameters of disease activity such as FEV(1), FVC, and DL(CO) and positively correlated with numbers of BAL neutrophils and eosinophils. Increased expression of several cell surface markers suggests that activated alveolar macrophages may contribute to the pathophysiology of IPF and SCL-ILD.

Adult↗
PubMed2000

Randomized comparison of unfractionated heparin with corticosteroids in severe active inflammatory bowel disease.

BACKGROUND: Heparin therapy may be effective in steroid resistant inflammatory bowel disease. AIM: A randomized pilot study, to compare unfractionated heparin as a first-line therapy with corticosteroids in colonic inflammatory bowel disease. METHODS: Twenty patients with severe inflammatory bowel disease (ulcerative colitis, n=17; Crohn's colitis, n=3) were randomized to either intravenous heparin for 5 days, followed by subcutaneous heparin for 5 weeks (n=8), or high-dose intravenous hydrocortisone for 5 days followed by oral prednisolone 40 mg daily, reducing by 5 mg per day each week (n=12). After 5 days, non-responders in each treatment group were commenced on combination therapy. Response to therapy was monitored by: clinical disease activity (ulcerative colitis: Truelove and Witt Index; Crohn's colitis: Harvey and Bradshaw Index), stool frequency, serum C-reactive protein and alpha1 acid glycoprotein, endoscopic and histopathological grading. RESULTS: The response rates were similar in both treatment groups: clinical activity index (heparin vs. steroid; 75% vs. 67%; P=0.23), stool frequency (75% vs. 67%; P=0.61), endoscopic (75% vs. 67%; P=0.4) and histopathological grading (63% vs. 50%; P=0.67). Both treatments were well-tolerated with no serious adverse events. CONCLUSION: Heparin as a first line therapy is as effective as corticosteroids in the treatment of colonic inflammatory bowel disease. Large multicentre randomized comparative studies are required to determine the role of heparin in the management of inflammatory bowel disease.

Administration, Oral↗
PubMed2000

Desmopressin: therapeutic limitations in children and adults with inherited coagulation disorders.

Desmopressin (DDAVP), a synthetic analogue of vasopressin has been successfully used in the treatment of type I von Willebrand's disease (VWD), mild factor VIII (FVIII) deficiency and intrinsic platelet function defects (PFDs) for almost three decades. However, there is limited published data documenting its efficacy and the reliability of circulating plasma FVIII:C as a surrogate marker of response to therapy in VWD. We report the haemostatic response to DDAVP in 133 consecutive patients (91 type I VWD, 20 mild FVIII deficiency and 22 PFDs). Minimal therapeutic response to DDAVP (0.3 microg/kg) was defined by normalization 30 min post- infusion of bleeding time for PFDs, factor VIII:C (FVIII:C) for mild haemophilia A, and von Willebrand factor antigen (VWF:Ag), von Willebrand factor functional activity (VWF:Ac) and FVIII:C for VWD. Nine out of 91 (10%) VWD patients failed to achieve minimal therapeutic response to DDAVP; plasma FVIII:C levels were an unreliable surrogate marker of DDAVP response as 6 out of 9 (67%) of these patients had normal post-infusion FVIII:C levels. Five out of the 20 (25%) patients with mild FVIII deficiency and 5 out of 22 (23%) patients with PFDs failed to achieve a minimal therapeutic response to DDAVP. DDAVP is an effective therapy in the majority of patients with type I VWD, PFDs and mild FVIII deficiency. The significant failure rate associated with this therapy supports the recent recommendations that response should be assessed in all patients at the time of diagnosis. FVIII:C is an unreliable guide of response to DDAVP in patients with VWD and therefore VWF:Ag and VWF:Ac should also be assessed. Failure to demonstrate the response of VWF:Ag, VWF:Ac and FVIII:C to DDAVP in patients with VWD is likely to increase the risk of haemorrhagic complications in patients with bleeding episodes or who are undergoing surgery.

ABO Blood-Group System↗
PubMed2000

Activated protein C inhibits lipopolysaccharide-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line.

Activated protein C (APC) protects against sepsis in animal models and inhibits the lipopolysacharide (LPS)-induced elaboration of proinflammatory cytokines from monocytes. The molecular mechanism responsible for this property is unknown. We assessed the effect of APC on LPS-induced tumour necrosis factor alpha (TNF-alpha) production and on the activation of the central proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) in a THP-1 cell line. Cells were preincubated with varying concentrations of APC (200 microg/ml, 100 microg/ml and 20 microg/ml) before addition of LPS (100 ng/ml and 10 microg/ml). APC inhibited LPS-induced production of TNF-alpha both in the presence and absence of fetal calf serum (FCS), although the effect was less marked with 10% FCS. APC also inhibited LPS-induced activation of NF-kappaB, with APC (200 microg/ml) abolishing the effect of LPS (100 ng/ml). The ability of APC to inhibit LPS-induced translocation of NF-kappaB is likely to be a significant event given the critical role of the latter in the host inflammatory response.

Analysis of Variance↗
PubMed2000

Prevalence of the factor VR506Q mutation in two Irish control populations: use of a novel nested polymerase chain reaction approach.

The prevalence of factor V (FV) Leiden among normal populations has primarily been determined using blood donors. This control group is carefully selected and therefore may not accurately reflect the true prevalence within the population. We assessed the prevalence of FV Leiden within the Irish population using Guthrie card samples randomly selected from all newborns. We compared this result with the prevalence of FV Leiden within blood donors. A novel nested polymerase chain reaction (PCR) method for FV Leiden was developed for analysis of the Guthrie card samples. There was no significant difference between the allele frequency within the Guthrie card samples and blood donors (2.07% vs. 2.35%, P = 0.66)

Adult↗
PubMed2000

High responding factor VIII inhibitors in mild haemophilia - is there a link with recent changes in clinical practice?

The development of high responding inhibitors is an increasingly recognized complication of mild Haemophilia. Inhibitors tend to develop in adolescence and adulthood and this is frequently preceded by high-intensity factor replacement therapy. We report two patients with mild Haemophilia who developed high responding inhibitors after continuous infusion with recombinant factor VIII (Kogenate) as prophylaxis for surgery. We discuss whether recent changes in clinical practice could be responsible for the apparent increase in high responding inhibitors in mild Haemophilia.

Adult↗
PubMed2000

Optimization of routine plasma homocysteine monitoring.

An elevated plasma homocysteine (Hcy) level is now considered to be an important risk factor in arterial and venous thromboembolic events. As a result of this relatively recent finding, there has been a dramatic increase in the number of requests for Hcy measurement. In our laboratory, this demand has been met by employing an automated immunoassay and improving the pre-analytical handling of blood samples. An automated fluorescent polarization immunoassay (FPIA) gave similar results to a reference high-pressure chromatographic (HPLC) method (r2 = 0.98, enzyme immunoassay = 0.998 HPLC - 0.3) and excellent between-run reproducibility (coefficient of variation <3%). The new assay also required less specialized technical input, and improved the sample throughput two-fold. Pre-analytical stability of plasma Hcy concentrations in blood samples is crucial to the accuracy of Hcy monitoring. This stability was improved 10-fold by adopting the anticoagulant acidic citrate instead of ethylenediamine tetraacetic acid for Hcy screening by FPIA. Acidic citrate dramatically inhibits time-related plasma contamination by red-cell Hcy, resulting in improved accuracy and a reduced number of 'spoiled' specimen discards.

Drug Monitoring↗
PubMed2000

Prevalence of the prothrombin G20210A mutation in the Irish populations: use of a novel polymerase chain reaction approach.

The prothrombin G20210A polymorphism is associated with a threefold-increased risk of venous thrombosis. There is considerable variation in the reported prevalence of this polymorphism within normal populations, ranging from 0 to 6.5%. The prevalence within the Irish population has not been determined. A restriction fragment length polymorphism (RFLP)-based assay is commonly used for the detection of the prothrombin 20210A allele. This assay does not include a control restriction digest fragment and, consequently, failure of the enzyme activity or lack of addition of enzyme to the sample cannot be distinguished from wild-type prothrombin. We developed a RFLP-based assay, which incorporates an invariant digest site, resulting in the generation of a control digest fragment. Furthermore, we developed a nested polymerase chain reaction (PCR) method for the amplification and digestion of poor-quality or low-concentration DNA. In the Irish population studied, five of 385 (1.29%) were heterozygous and one patient was homozygous for the prothrombin 20210A polymorphism. This is the first reported data on an Irish or Celtic population and suggests that the allele frequency is similar to Anglo-Saxon populations. The nested PCR method successfully amplified and digested 100/100 (100%) of the archived samples; none of these samples could be analyzed by the standard single-round PCR method. In conclusion, nested PCR should be considered in the analysis of archived samples. Single-round PCR is appropriate for recently collected samples; however, an invariant control digest site should be incorporated in RFLP-based assays to validate the integrity of the digestion enzyme and limit the risk of false-negative results.

Base Sequence↗
PubMed2000

Successful use of recombinant VIIa (Novoseven) and endometrial ablation in a patient with intractable menorrhagia secondary to FVII deficiency.

Menorrhagia is a well-recognized complication of inherited bleeding disorders. In the past, the only viable option for women who were unresponsive to medical therapy was hysterectomy. Endometrial ablation has been recently developed as an alternative therapy for these patients and is associated with decreased morbidity. We report the successful use of activated recombinant factor VII (FVIIa) and endometrial ablation in the treatment of excessive menstrual blood loss in a 34-year-old women with severe factor VII (FVII) deficiency. Recombinant FVIIa (40 microg/kg) was administered pre-operatively and every 6 h (20 microg/kg) for 24 h postoperatively. The procedure was uncomplicated with a 200 ml surgical blood loss. FVIIa was used because it allowed FVII replacement with a recombinant product and also has the ability to bind to tissue factor expressed at the site of vascular injury, resulting in site-specific thrombin generation. We believe that endometrial ablation with recombinant VIIa should be considered in patients with severe FVII deficiency and menorrhagia unresponsive to medical therapy.

Adult↗
PubMed2000

Lung transplantation and systemic sclerosis.

We performed lung transplantation in nine patients with Scleroderma related lung disease. Patient characteristics included: 7 (78%) females, 6 (67%) with limited and 3 (33%) with diffuse Scleroderma. Pulmonary fibrosis was present in 7 (78%) and pulmonary hypertension in 4 (44%). All patients were carefully screened by the Johns Hopkins and University of Maryland Scleroderma Center and only referred for transplantation when concomitant renal insufficiency (creatinine clearance < or = 50 ml/min), aspiration, and skin brakdown were excluded. When compared to a similar group of transplant patients with nonscleroderma lung disease (primary pulmonary fibrosis), there was no significant difference in post-transplant survival at four years (76.2 +/- 0.15% vs. 69.2% +/- 0.12%), mean annual incidence rate for acute rejection (0.14 +/- 0.14 vs. 0.47 +/- 0.13) and infection (viral 0.17 +/- 0.17 vs. 0.29 +/- 0.11) (bacterial 0.17 +/- 0.17 vs. 1.4 +/- 0.4) (fungal 0.99 +/- 0.69 vs. 0.36 +/- 0.16) or serum creatinine (1.55 +/- 0.34 mg/dl vs. 1.15 +/- 0.09 mg/dl). We conclude that lung transplantation is viable option for carefully selected patients with scleroderma related lung disease.

Contraindications↗