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Biomedical subjects

M D Mayes

Publications and source records attributed to M D Mayes.

At least 19 recordsLinked to original sources
PubMed2006

Minimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study.

OBJECTIVE: To estimate minimally important differences (MIDs) in scores for the modified Rodnan Skin Score (mRSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) in a clinical trial on diffuse systemic sclerosis (SSc). PARTICIPANTS AND METHODS: 134 people participated in a 2-year, double-blind, randomised clinical trial comparing efficacy of low-dose and high-dose D-penicillamine in diffuse SSc. At 6, 12, 18 and 24 months, the investigator was asked to rate the change in the patient's health since entering the study: markedly worsened, moderately worsened, slightly worsened, unchanged, slightly improved, moderately improved or markedly improved. Patients who were rated as slightly improved were defined as the minimally changed subgroup and compared with patients rated as moderately or markedly improved. RESULTS: The MID estimates for the mRSS improvement ranged from 3.2 to 5.3 (0.40-0.66 effect size) and for the HAQ-DI from 0.10 to 0.14 (0.15-0.21 effect size). Patients who were rated to improve more than slightly were found to improve by 6.9-14.2 (0.86-1.77 effect size) on the mRSS and 0.21-0.55 (0.32-0.83 effect size) on the HAQ-DI score. CONCLUSION: MID estimates are provided for improvement in the mRSS and HAQ-DI scores, which can help in interpreting clinical trials on patients with SSc and be used for sample size calculation for future clinical trials on diffuse SSc.

Adult↗
PubMed2006

Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients.

OBJECTIVE: To obtain a global view of the immunological alterations occurring in early systemic sclerosis (SSc) by transcriptional profiling of peripheral blood cells (PBCs). METHODS: Oligonucleotide microarrays were used to compare PBC gene expression profiles in 18 SSc cases (<2 yr duration) and 18 controls matched for race, gender and ethnicity. SSc cases had no prior or current exposure to cytotoxic drugs. PAXgene tubes were used to stabilize RNA during phlebotomy. Changes in gene expression were independently validated by real-time polymerase chain reaction. RESULTS: SSc PBCs demonstrated differential expression of 18 interferon-inducible genes. Six of these genes were identical to the interferon signature genes in lupus peripheral blood mononuclear cells. Notably, SSc PBCs also had increased expression of allograft inflammatory factor (AIF1) and several selectins and integrins involved in cellular adhesion to the endothelium. Global analysis of 284 known biological pathways revealed that 13 were differentially regulated in SSc PBCs, including two pathways (IL2RB and GATA3) that lead to T(H)2 polarization. CONCLUSIONS: Transcriptional profiling reliably discriminates between PBCs from SSc and normal donors despite the fact that they represent a heterogeneous cell population. Multiple biological pathways were differentially regulated in SSc PBCs, but a common thread across these pathways was alterations in protein tyrosine kinase 2beta and mitogen-activated protein kinase signalling. Although the SSc PBC gene expression profile demonstrated some parallels with the lupus interferon gene signature, there was also increased expression of transcripts encoding proteins that target PBCs to the endothelium, which might be relevant to the vasculopathy of SSc.

Adult↗
PubMed2005

Cooling-induced contraction and protein tyrosine kinase activity of isolated arterioles in secondary Raynaud's phenomenon.

OBJECTIVE: To investigate the response of skin arterioles from control subjects and patients with scleroderma and Raynaud's phenomenon (RP/SSc) to cooling and modulators of protein tyrosine kinase (PTK) activity. METHODS: We used the microvessel perfusion technique to characterize the response of isolated dermal arterioles (100-200 microm, outside diameter) from normal (n = 17) and RP/SSc (n = 17) subjects to cooling from 37 degrees to 31 degrees C. Fluorescent immunohistochemistry was used to measure tyrosine phosphorylation. RESULTS: Arterioles from control subjects exhibited dilation in response to cooling from 37 to 31 degrees C whereas those from RP/SSc subjects contracted (+4.3 +/- 1.7 vs -16.7 +/- 3.1%, P < 0.05, n = 6). In the presence of the protein tyrosine phosphatase inhibitor sodium orthovanadate (SOV, 10 microM), the response of arterioles from control subjects did not change; however, arterioles from RP/SSC subjects exhibited a significantly greater contraction (-72.6 +/- 19.7%; P < 0.05, n = 6). Tyrosine phosphorylation of arterioles at 37 degrees C from control and RP/SSc subjects was similar. In response to cooling to 31 degrees C, however, arterioles from RP/SSc subjects exhibited a significantly greater increase in tyrosine phosphorylation compared with those from control subjects (43 +/- 7.0% vs 10 +/- 3.8%; P < 0.01). SOV increased tyrosine phosphorylation in arterioles from both groups (73 +/- 11.6% vs 42 +/- 5.6%; P < 0.05, n = 5). Arterioles from RP/SSC subjects precontracted with norepinephrine exhibited greatly attenuated relaxation to acetylcholine compared with those from control subjects. CONCLUSION: The results of this study support the view that the hallmark of Raynaud's phenomenon associated with scleroderma, cooling-induced vasospasm, appears to be mediated by an increase in PTK activity possibly exacerbated by impaired endothelium-dependent vasodilation.

Adult↗
PubMed2003

Assessment of kidney involvement.

Scleroderma renal crisis (SRC) represents the classic manifestation of kidney involvement in SSc. It particularly occurs in patients with early, rapidly progressive, diffuse skin involvement. Its detection requires the assessment of a few core set variables: arterial blood pressure, serum creatinine, and urinalysis. In clinical investigations SSc patients developing arterial hypertension after the disease onset (new onset hypertension) without SRC should also be reported.

Humans↗
PubMed2001

Potential risk factors for undifferentiated connective tissue disease among women: implanted medical devices.

A case-control study was conducted among 205 women in Michigan and Ohio who were diagnosed with undifferentiated connective tissue disease (UCTD) to investigate the significance of self-reported past exposures to implanted silicone-containing or non-silicone-containing medical devices. The 205 UCTD cases were compared with 2,095 controls who were sampled by random digit dialing. When silicone-containing devices, including shunts and catheters, were analyzed collectively, a significant association was observed (odds ratio (OR) = 2.81, 95% confidence interval (CI): 1.34, 5.89). The odds ratio for exposure to breast implants was increased, but not significantly (OR = 2.22, 95% CI: 0.65, 7.57). Among the non-silicone-containing devices, artificial joints (OR = 5.01, 95% CI: 1.60, 15.71) and orthopedic metallic fixation devices (OR = 1.95, 95% CI: 1.05, 3.60) were associated with UCTD. The estimations of risk associated with implanted medical devices in UCTD cases were explored in a comparison with 660 scleroderma patients who were ascertained concurrently in Michigan and Ohio. In general, the associations that were observed with non-silicone-containing devices, and more specifically with the fixation devices, persisted in the comparison of UCTD cases with scleroderma patients. The studies conducted among populations in Michigan and Ohio are intended to stimulate new hypotheses, innovative approaches, and the fostering of understanding of the environmental determinants of autoimmune disease.

Adolescent↗
PubMed2001

Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts.

OBJECTIVE: To determine the frequency with which scleroderma (systemic sclerosis; SSc) recurs in families and the familial relative risk (lambda) in the US. METHODS: Family histories of SSc were prospectively surveyed in 3 large US cohorts of SSc patients, 2 in Texas and 1 in Michigan. Diagnoses of familial SSc were verified by rheumatologist evaluation and/or review of medical records. Familial relative risks for first-degree relatives (lambda1) and siblings (lambdas) were calculated using actual reported counts of first-degree relatives in 2 cohorts and recent estimates of SSc prevalence in the US. RESULTS: Compared with the estimated prevalence of SSc in the US (2.6 cases/10,000 population [0.026%]), the disease occurred in 1 or more first-degree relatives in 1.5-1.7% of SSc families in the 3 cohorts (or 11 of 703 families [1.6%]), a significant increase. Familial relative risks in first-degree relatives in the 3 cohorts ranged from 10 to 16 (13 combined), and in siblings they ranged from 10 to 27 (15 combined). CONCLUSION: SSc occurs significantly more frequently in families with scleroderma (1.6%) than in the general population (0.026%). A positive family history of SSc is the strongest risk factor yet identified for SSc; however, the absolute risk for each family member remains quite low (<1%).

Black People↗
PubMed2001

Effects of the American College of Rheumatology systemic sclerosis trial guidelines on the nature of systemic sclerosis patients entering a clinical trial.

OBJECTIVES: To compare the systemic sclerosis (SSc) patients entered into the d-penicillamine trial with SSc patients entered into previous controlled SSc trials. It was hypothesized that the d-penicillamine trial patients, who conformed to the American College of Rheumatology (ACR) guidelines for clinical trials in SSc were different from patients entered into previous trials. METHODS: Patients entering a double-blind, randomized trial of low- vs high-dose d-penicillamine were described carefully and completely. Their characteristics were then compared with previously published data on SSc and its treatment. RESULTS: One hundred and thirty-four patients had early [mean duration 9.5 (s.d. 4.2) months], diffuse [skin score 21 (8)] disease. Organ involvement in the patients was as follows: pulmonary 54%, cardiac 20%, joints 38%, muscular 20%. Thirty-three per cent had mild proteinuria and 13% were hypertensive when first seen. Compared with patients in most previous studies, these SSc patients had earlier disease and uniformly had diffuse disease. They had less muscular involvement, less dyspnoea, less abnormal pulmonary function and less cardiac and less renal involvement than patients in earlier studies. CONCLUSIONS: The use of the new ACR guidelines for SSc trials may change the nature of patient populations entering future studies.

Adult↗
PubMed2001

Abnormal responses to endothelial agonists in Raynaud's phenomenon and scleroderma.

OBJECTIVE: To further specify the site of vascular dysfunction in patients with Raynaud's phenomenon (RP) and scleroderma. METHODS: Ten patients with RP and scleroderma and 11 healthy control subjects received brachial artery infusions of sodium nitroprusside, an endothelium independent vasodilator, bradykinin, and substance P while bilateral finger blood flow was measured with venous occlusion plethysmography. RESULTS: Both groups showed vasodilation to sodium nitroprusside. However, in response to the endothelium dependent compounds bradykinin and substance P, the controls showed vasodilation, whereas the patients showed vasoconstriction. CONCLUSION: The vascular defect in RP and scleroderma does not lie at the site of the muscarinic receptor, but possibly in a distal signaling mechanism.

Blood Flow Velocity↗
PubMed2001

Effect of temperature and modulators of protein tyrosine kinase activity on the reactivity of isolated venules in secondary Raynaud's phenomenon.

OBJECTIVE: To investigate the response of skin venules from healthy controls and scleroderma patients with Raynaud's phenomenon (RP/SSc) to cooling and to modulators of protein tyrosine kinase (PTK) activity at normal and reduced temperature. METHODS: We used the microvessel perfusion technique to characterize the response of isolated dermal venules (200-400 microm outside diameter) from normal (n = 10) and RP/SSc (n = 8) subjects to cooling and to contractile agents at 37 and 31 degrees C. RESULTS. The response to clonidine at 37 degrees C was less in venules from patients with RP/SSc compared to controls; the contraction to serotonin was greater in venules from RP/SSc patients versus controls; at 31 degrees C, venules from RP/SSc patients contracted to both clonidine and serotonin to a greater extent versus controls; and contraction to these agonists was reversed by cumulative addition of genistein (1-100 microM). Venules from controls and patients with RP/SSc exhibited slight vasodilation to cooling from 37 to 31 degrees C. In the presence of the protein tyrosine phosphatase inhibitor sodium orthovanadate (10 microM), venules from controls now exhibited a small contraction (-5.1 +/- 3.2%) and venules from RP/SSC subjects a significantly greater contraction (-38.7 +/- 9.0%; p < 0.05). CONCLUSION: Our study supports the view that RP/SSc is the result of defects in the peripheral vasculature.

Adult↗
PubMed2000

Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Relaxin is a pregnancy-related hormone that has tissue remodeling and antifibrotic effects. Systemic sclerosis (scleroderma) is characterized by fibrosis of the skin, vasculature, and internal organs. OBJECTIVE: To assess the efficacy, safety, and dose-response effect of recombinant human relaxin in patients with scleroderma. DESIGN: Multicenter, parallel-group, randomized, double-blind, placebo-controlled trial. SETTING: Academic referral centers. PATIENTS: 68 patients who had had stable, diffuse scleroderma (moderate to severe) for less than 5 years. INTERVENTION: Recombinant human relaxin, 25 or 100 microg/kg of body weight per day, or placebo administered by continuous subcutaneous infusion over 24 weeks. MEASUREMENTS: Modified Rodnan skin score was the primary efficacy measure. Secondary measurements were pulmonary function, the Health Assessment Questionnaire, and other measures of scleroderma that reflected fibrosis. RESULTS: Patients who received 25 microg/kg of recombinant human relaxin per day had significantly lower skin scores than those who received placebo (mean change, -3.6 at 4 weeks [P = 0.021], -7.5 at 12 weeks [P < 0.001], and -8.7 at 24 weeks [P = 0.040]). Similar trends were noted in other outcome measures, including forced vital capacity, measures of oral aperture and hand extension, functional status, and global assessment. Patients who received 100 microg/kg of relaxin per day did not differ from those who received placebo. Drug-related adverse events included menometrorrhagia, reversible anemia, and complications of the subcutaneous drug administration system (site irritation and local infection). CONCLUSIONS: Twenty-four weeks of recombinant human relaxin, 25 microg/kg per day, is associated with reduced skin thickening, improved mobility, and improved function in patients with moderate to severe diffuse scleroderma.

Adolescent↗
PubMed2000

The establishment and utility of a population-based registry to understand the epidemiology of systemic sclerosis.

Epidemiologic studies establish a pattern of disease occurrence that predicts annual incidence (the number of new cases per year in a defined population), prevalence (the total number of cases in a defined population), and mortality. If this pattern changes over time or within certain groups, the assumption can be made that causal factors for disease expression are also changing. This information can lead to the development of testable hypotheses regarding disease causation and disease registries can provide a population for study. The autoimmune diseases are relatively rare, presenting a challenge to the epidemiologist. The Scleroderma Registry is a population-based census of systemic sclerosis in the Detroit, MI, area established to determine these baseline epidemiology parameters and to provide a framework to study this disease.

Disease Progression↗
PubMed2000

Photopheresis and autoimmune diseases.

Although several case reports and case series suggest efficacy for photopheresis in the treatment of autoimmune diseases, few controlled studies have been conducted to test this hypothesis. After a decade of interest, multiple case reports, open trials, and one controlled study, the role of photopheresis in autoimmune disease remains to be established. Controlled multi-center trials in rheumatoid arthritis, SLE, and scleroderma may be costly but are clearly necessary for proper evaluation of this therapy.

Autoimmune Diseases↗
PubMed1999

Petroleum distillate solvents as risk factors for undifferentiated connective tissue disease (UCTD).

Occupational solvent exposure may increase the risk of connective tissue disease (CTD). The objective of this case-control study was to investigate the relation between undifferentiated connective tissue disease (UCTD) and solvent exposure in Michigan and Ohio. Women were considered to have UCTD if they did not meet the American College of Rheumatology classification criteria for any CTD but had at least two documented signs, symptoms, or laboratory abnormalities suggestive of a CTD. Detailed information on solvent exposure was ascertained from 205 cases, diagnosed between 1980 and 1992, and 2,095 population-based controls. Age-adjusted odds ratios (OR) and 95 percent confidence intervals (CI) were calculated for all exposures. Among 16 self-reported occupational activities with potential solvent exposure, furniture refinishing (OR = 9.73, 95 percent CI 1.48-63.90), perfume, cosmetic, or drug manufacturing (OR = 7.71, 95 percent CI 2.24-26.56), rubber product manufacturing (OR = 4.70, 95 percent CI 1.75-12.61), work in a medical diagnostic or pathology laboratory (OR = 4.52, 95 percent CI 2.27-8.97), and painting or paint manufacturing (OR = 2.87, 95 percent CI 1.06-7.76) were significantly associated with UCTD. After expert review of self-reported exposure to ten specific solvents, paint thinners or removers (OR = 2.73, 95 percent CI 1.80-4.16) and mineral spirits (OR = 1.81, 95 percent CI 1.09-3.02) were associated with UCTD. These results suggest that exposure to petroleum distillates increases the risk of developing UCTD.

Adolescent↗
PubMed1999

IL-1 rescues scleroderma myofibroblasts from serum-starvation-induced cell death.

Normal senescent adult human fibroblasts are relatively insensitive to the effects of serum deprivation in culture. In contrast, the myofibroblast phenotype, which is predominant in scleroderma-affected skin and cultured fibroblasts from scleroderma-affected skin, shows signs of deterioration within 3 days of serum starvation. The addition of IL-1 (5 ng/ml) prevents this deterioration. We propose that IL-1 is a factor promoting myofibroblast longevity with consequent fibrosis in scleroderma skin.

Adult↗
PubMed1999

Epidemiologic studies of environmental agents and systemic autoimmune diseases.

Systemic lupus erythematosus and systemic scleroderma are autoimmune diseases thought to have an exogenous trigger. This review summarizes relevant case-control and cohort studies that investigated exogenous sex hormones, silica, silicone, solvents, pesticides, mercuric chloride, and hair dyes as putative risk factors for the development of these diseases. These studies indicate that estrogen replacement therapy in postmenopausal women increases the risk of developing lupus, scleroderma, and Raynaud disease, although the increase in risk is relatively modest. Oral contraceptives may also play a role in disease susceptibility in lupus but not apparently in scleroderma. Environmental endocrine modulators, in the form of pesticides, may represent another opportunity for estrogenlike effects to occur, but there is scant evidence that these agents play a role in human systemic autoimmune disease. Although exposure to silica dust increases the risk of scleroderma in men occupied in the industry, this does not explain most male scleroderma cases. When this exposure was investigated among women, no significant risk was found. Additionally, silicone in implanted devices as well as occupational exposure to silicone-containing compounds did not pose an increased risk among women for scleroderma. The role of solvent exposure has been investigated as a risk factor for scleroderma with mixed findings. One study suggested a potential role in male patients or in those individuals with Scl-70 antibody positivity either male or female. Two other studies were unable to corroborate this finding. Mercuric chloride causes antifibrillarin antibodies and immune complex glomerulonephritis in susceptible mouse strains. Antifibrillarin antibodies, but not glomerulonephritis, occur in a subset of scleroderma patients and preliminary evidence suggests that mercury levels may be higher in this group of individuals. Hair products have been studied as possibly raising the risk of developing lupus, since such products contain an aromatic amine similar to a compound known to cause drug-induced lupus. A 1986 study suggested a positive association, but two subsequent studies did not support this association.

Animals↗
PubMed1999

Endothelial and adrenergic dysfunction in Raynaud's phenomenon and scleroderma.

OBJECTIVE: To investigate the involvement of endothelial and adrenergic mechanisms in patients with Raynaud's phenomenon (RP) and scleroderma. METHODS: Ten patients with RP and scleroderma and 10 healthy volunteer controls were studied. Intraarterial methacholine, sodium nitroprusside, and clonidine were administered while bilateral finger blood flow was measured with venous occlusion plethysmography. RESULTS: Compared to the controls, the patients showed diminished responses to methacholine, an endothelium dependent vasodilator, and to clonidine, an alpha2-adrenergic agonist. However, both groups showed similar responses to sodium nitroprusside, an endothelium independent vasodilator. CONCLUSION: The findings were consistent with previous histological evidence of endothelial damage in scleroderma blood vessels. Failure to release nitric oxide from vascular endothelium may play a role in RP in patients with scleroderma.

Adrenergic Agonists↗