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Biomedical subjects

C Michael Stein

Publications and source records attributed to C Michael Stein.

13 recordsLinked to original sources
PubMed2026

Inherited Susceptibility to Urinary Tract Infections from Kidney Papilla to Bladder.

Urinary tract infections (UTIs) are traditionally viewed as environmentally driven, yet their inherited susceptibility remains largely unexplored. We conducted a cross-biobank genome-wide association study of recurrent UTIs in 1,860,836 individuals (213,869 cases and 1,646,967 controls). We identified 36 genetic susceptibility loci and performed tissue-based multi-omic mapping to prioritize candidate causal genes. UTI risk alleles preferentially modulated epithelial gene expression in kidney and bladder, converging on urinary epithelia structure and function. PSCA, encoding a secreted epithelial surface protein, emerged as the strongest candidate under genetic control; the gene product is constitutively secreted into the urine from kidney papilla and bladder epithelia, binds uropathogenic E. coli, and inhibits bacterial growth in vitro. Our findings define the polygenic architecture of UTIs and highlight the critical role of uroepithelial surface defenses, providing a new framework for host-directed, non-antibiotic interventions.

Journal Article↗
PubMed2003

Nitric oxide production decreases after salt loading but is not related to blood pressure changes or nitric oxide-mediated vascular responses.

BACKGROUND: Nitric oxide production is a homeostatic mechanism that may regulate blood pressure during salt loading. Salt-sensitive hypertension in animal models and in humans is characterized by increased blood pressure and decreased nitric oxide production after salt loading. It is not known if this impaired nitric oxide production is the result of hypertension or is a mechanism contributing to the blood pressure response to salt. METHODS AND RESULTS: The effects of salt loading on blood pressure, nitric oxide-mediated vasodilation and nitric oxide production were measured in 25 normotensive subjects after 6 days on either a high (400 mmol/day) or low (10 mmol/day) sodium, low nitrate diet. Mean arterial pressure increased during the high-salt diet [4 +/- 1 mmHg (mean +/- SEM)] in 12 subjects and remained unchanged or decreased (-4 +/- 1 mmHg) in 13 subjects. Plasma nitrite and nitrate, a measure of nitric oxide production, decreased significantly from 39 +/- 3.3 micromol/l during the low-salt diet to 22.4 +/- 2.4 micromol/l during the high-salt diet (P = 0.0001). However, changes in mean arterial pressure from low- to high-salt diet did not correlate with changes in plasma nitrite and nitrate (r = 0.14, P = 0.51). Forearm blood flow increased significantly (P <0.0001) in response to mental stress, a nitric oxide-mediated response, but was not affected by sodium intake (from 7.8 +/- 0.9 to 11.2 +/- 1.4 ml/min per 100 ml during low salt versus 8.5 +/- 1.2 to 10.4 +/- 1.3 ml/min per 100 ml during high salt,P = 0.3). CONCLUSIONS: Salt loading results in a decrease in nitric oxide production in both salt-sensitive and salt-resistant normotensive subjects, which is independent of changes in blood pressure and does not affect the nitric oxide-mediated vascular response to mental stress. In contrast to salt-resistant animal models, salt loading in healthy subjects does not increase nitric oxide production. Therefore, the increased blood pressure response to salt loading may occur through mechanisms other than nitric oxide, or salt-sensitive individuals are more sensitive to the reduced nitric oxide production that occurs after salt loading in both salt-sensitive and salt-resistant subjects.

Adult↗
PubMed2003

G-protein beta(3) subunit 825 C/T polymorphism is associated with weight gain during pregnancy.

A common polymorphism (C825T) of the gene encoding the G-protein beta(3) subunit has been associated with obesity. We examined the hypothesis that this polymorphism affected weight gain during pregnancy. Two hundred and ninety-four women with uncomplicated term deliveries of singleton pregnancies were genotyped. Women homozygous for the T allele (TT) gained significantly more weight than women carrying the C allele (CC and CT groups) (P = 0.006) and had a significantly higher pre-pregnancy body mass index (P = 0.02). The C825T polymorphism of the G-protein beta(3) subunit gene, known to be associated with obesity, is a determinant of weight gain during pregnancy.

Adult↗
PubMed2002

CYP2C9 allelic variants: ethnic distribution and functional significance.

Cytochrome P-450 (CYP) 2C9 CYP2C9 is a polymorphically expressed enzyme responsible for the metabolism of several clinically important drugs, some with a low therapeutic index. This review summarizes the structure-function relationship of the CYP2C9 promoter and coding regions, known polymorphisms, the functional significance of various CYP2C9 alleles in vitro and in vivo, and their population frequencies. In addition, possible molecular mechanisms underlying ethnic variability in the metabolism of CYP2C9 substrate drugs are discussed.

Aryl Hydrocarbon Hydroxylases↗
PubMed2002

COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease.

Results of premarketing and postmarketing trials have raised doubts about the cardiovascular safety of the non-steroidal anti-inflammatory drug (NSAID) rofecoxib, especially at doses greater than 25 mg. Between Jan 1, 1999, and June 30, 2001, we did a retrospective cohort study of individuals on the expanded Tennessee Medicaid programme (TennCare), in which we assessed occurrence of serious coronary heart disease (CHD) in non-users (n=202916) and in users of rofecoxib and other NSAIDs (rofecoxib n=24 132, other n=151 728). Participants were aged 50-84 years, lived in the community, and had no life-threatening non-cardiovascular illness. Users of high-dose rofecoxib were 1.70 (95% CI 0.98-2.95, p=0.058) times more likely than non-users to have CHD; among new users this rate increased to 1.93 (1.09-3.42, p=0.024). By contrast, there was no evidence of raised risk of CHD among users of rofecoxib at doses of 25 mg or less or among users of other NSAIDs.

Aged↗
PubMed2002

Disproportionate decrease in alpha- compared with beta-adrenergic sensitivity in the dorsal hand vein in pregnancy favors vasodilation.

BACKGROUND: Altered vascular responses to adrenergic agonists during pregnancy are thought to play an important role in the regulation of blood pressure and placental blood flow. Because alpha1-adrenergic and beta2-adrenergic sensitivity act in opposing directions to determine vascular tone, we simultaneously evaluated alpha-adrenergic-mediated vasoconstriction and beta-adrenergic-mediated vasodilation in dorsal hand veins during and after pregnancy. METHODS AND RESULTS: Twenty healthy pregnant women were studied at 32 to 37 weeks of gestation and again 12 weeks after delivery. Vascular response to phenylephrine (PE) and isoproterenol (ISO) was measured in a dorsal hand vein using the linear variable differential transformer technique. The dose of PE resulting in 50% constriction (CD50) was determined. The response to ISO was measured after the PE preconstriction. Pregnant and postpartum values, expressed as geometric mean (95% CI), were compared by paired t test. alpha-Adrenergic sensitivity during pregnancy (CD50 2.7 micro g/min [95% CI, 1.5 to 5.0]) was markedly decreased, approximately 7-fold, compared with postpartum (0.4 micro g/min [95% CI, 0.3 to 0.7] [P<0.01]). beta-Adrenergic vasodilation was also attenuated during pregnancy. The ED50 of ISO (dose of ISO resulting in 50% of the maximal response, E(max)) was greater during pregnancy (20 ng/min [95% CI, 11 to 35]) than postpartum (8 ng/min [95% CI, 5 to 12]) (P<0.05). ISO E(max) was also significantly less during pregnancy (81% [95% CI, 65 to 97] compared with postpartum (105% [95% CI, 97 to 113]) (P<01.01). CONCLUSIONS: Normal pregnancy is characterized by decreased venous sensitivity to both alpha1-adrenoceptor-mediated vasoconstriction and beta2-adrenoceptor-mediated vasodilation. The greater decrease in alpha1 compared with beta2 response may contribute to the vasodilated state characteristic of human pregnancy.

Adolescent↗
PubMed2002

Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study.

BACKGROUND: Non-aspirin, non-steroidal anti-inflammatory drugs (NANSAIDs) have complex effects that could either prevent or promote coronary heart disease. Comparison of the NANSAID rofexocib with naproxen showed a substantial difference in acute myocardial infarction risk, which has been interpreted as a protective effect of naproxen. We did an observational study to measure the effects of NANSAIDs, including naproxen, on risk of serious coronary heart disease. METHODS: We used data from the Tennessee Medicaid programme obtained between Jan 1, 1987, and Dec 31, 1998, to identify a cohort of new NANSAID users (n=181 441) and an equal number of non-users, matched for age, sex, and date NANSAID use began. Both groups were 50-84 years of age, were not resident in a nursing home, and did not have life-threatening illness. The study endpoint was hospital admission for acute myocardial infarction or death from coronary heart disease. FINDINGS: During 532634 person-years of follow-up, 6362 cases of serious coronary heart disease occurred, or 11.9 per 1000 person-years. Multivariate-adjusted rate ratios for current and former use of NANSAIDs were 1.05 (95% CI 0.97-1.14) and 1.02 (0.97-1.08), respectively. Rate ratios for naproxen, ibuprofen, and other NANSAIDs were 0.95 (0.82-1.09), 1.15 (1.02-1.28), and 1.03 (0.92-1.16), respectively. There was no protection among long-term NANSAID users with uninterrupted use; the rate ratio among current users with more than 60 days of continuous use was 1.05 (0.91-1.21). When naproxen was directly compared with ibuprofen, the current-use rate ratio was 0.83 (0.69-0.98). INTERPRETATION: Absence of a protective effect of naproxen or other NANSAIDs on risk of coronary heart disease suggests that these drugs should not be used for cardioprotection.

Age Distribution↗
PubMed2002

Underutilization of gastroprotective measures in patients receiving nonsteroidal antiinflammatory drugs.

OBJECTIVE: To determine the frequency of use of recommended gastroprotective strategies in a cohort of patients receiving recurrent treatment with nonsteroidal antiinflammatory drugs (NSAIDs). METHODS: A cross-sectional study was performed using administrative data from the Tennessee Medicaid (TennCare) program. The study population consisted of 76,765 recurrent recipients of NSAIDs (NSAID users), comprising 24% of the 319,402 persons ages 50 years or older enrolled in the TennCare program from January 1999 through June 2000. Frequency of use of either of 2 recommended gastroprotective strategies, involving either traditional NSAIDs combined with recommended anti-ulcer cotherapy or use of a selective cyclooxygenase 2-inhibiting drug (coxib), was measured and categorized by risk for ulcer complication. RESULTS: Among this cohort of recurrent NSAID users, 16% received 1 of the 2 recommended gastroprotective therapies: 10% received traditional NSAIDs along with antiulcer drugs at the recommended doses and 6% received coxibs. Among those patients with > or=2 risk factors for ulcer complications (age 75 years or older, peptic ulcer or gastrointestinal bleeding in the past year, or concurrent use of oral anticoagulants or corticosteroids), 30% received such gastroprotective therapy. CONCLUSION: Use of recommended strategies to decrease ulcer complications in vulnerable populations is relatively uncommon.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: a six-month, double-blind, randomized, dose-ranging study.

OBJECTIVE: To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA). METHODS: This phase II, randomized, double-blind, placebo-controlled monotherapy study was set in 12 community sites and 9 university-based sites. Two hundred sixty-eight patients with RA who were resistant to or intolerant of methotrexate (mean dose 15.2 mg/week) and had active disease for at least 6 months (mean tender joint count 28.2, mean erythrocyte sedimentation rate 46.5 mm/hour) were randomized to receive treatment after discontinuation of methotrexate. Those who received at least 1 dose of tacrolimus were analyzed; 141 completed the study. Stable dosages of nonsteroidal antiinflammatory drugs and low-dose prednisone were allowed during treatment. All patients were given 1, 3, or 5 mg of tacrolimus or placebo once daily for 24 weeks. The American College of Rheumatology definition of 20% improvement (ACR20) and the tender and swollen joint counts at the end of treatment were the primary outcomes. RESULTS: ACR20 response rates demonstrated a clear dose response. The ACR20 response was observed in 15.5% of patients receiving placebo (95% confidence interval [95% CI] 7.1-23.9%), 29% of the 1 mg tacrolimus group (95% CI 18.3-39.7%) (P < 0.058); 34.4% of the 3 mg group (95% CI 22.7-46.0%) (P < 0.013), and 50% of the 5 mg group (95% CI 37.8-62.3%) (P < or = 0.001). The tender joint count improved statistically significantly in all tacrolimus groups. The swollen joint count, physical function, and patient-assessed pain improved statistically significantly in the 3 mg and 5 mg groups. The incidence of creatinine elevation > or =40% above baseline levels increased in a dose-dependent manner. Dropout rates were high (41-59%) and were more common for inefficacy in the placebo patients (71.4%), whereas they were more common for toxicity in the high-dose tacrolimus groups (31-33%). Discontinuation for creatinine elevation occurred in the 3 mg (3.1%) and 5 mg (10.9%) tacrolimus groups. CONCLUSION: Tacrolimus improved disease activity in methotrexate-resistant or -intolerant patients with RA. A dose response was observed when efficacy and toxicity were assessed at different doses. The optimal dose of tacrolimus appears to be >1 mg but < or=3 mg daily.

Anti-Inflammatory Agents, Non-Steroidal↗