Neonatal ethanol exposure from ethanol-based hand sanitisers in isolettes.

OBJECTIVE: The aims of this study is to measure the ethanol vapours in the isolette after use of hands cleaned with ethanol-based hand sanitiser (EBHS). METHODS: Two squirts (1.5 mL) of hand sanitiser were rubbed on hands for 10 or 20 s before inserting the hands in the isolette for 5 min. Ethanol vapours were measured in the isolette with photoionisation detector and alcohol breathalyser for 30 min. RESULTS: Peak ethanol concentration in the isolette was considerably higher with a 10 s hand rub (381±192 ppm) compared with a 20 s hand rub (99±50 ppm), and dissipated to ≤5 ppm within 30 min. Under routine care, EBHS use by care providers exposes neonates in isolettes to 3.7-7.3 or 1.4-2.8 mg/kg ethanol per day with 10 or 20 s hand rubs, respectively. The expected blood level from average single exposure is 0.036 mg/dL with 10 s hand rub and may increase further with multiple exposures in a short period. CONCLUSION: Preterm neonates in the isolette are at risk of inadvertent exposure to ethanol. The expected blood alcohol level from this exposure is small and below 1 mg/dL level recommended by European Medicines Agency to limit the ethanol exposure in children. The unintended ethanol exposure can be avoided by rubbing hands for at least 20 s after applying EBHS.

Intestinal Barrier Maturation in Very Low Birthweight Infants: Relationship to Feeding and Antibiotic Exposure.

OBJECTIVE: To test the hypothesis that feeding and antibiotic exposures affect intestinal barrier maturation in preterm infants, we serially measured intestinal permeability (IP) biomarkers in infants <33 weeks gestation (gestational age [GA]) during the first 2 weeks of life. STUDY DESIGN: Eligible infants <33 weeks GA were enrolled within 4 days of birth in a prospective study of IP biomarkers (NCT01756040). Study participants received the nonmetabolized sugars lactulose/rhamnose enterally on study days 1, 8, and 15 and lactulose/rhamnose were measured in urine by high-performance liquid chromatography. Serum zonulin and fecal alpha-1-anti-trypsin, 2 other IP markers, were measured by semiquantitative Western blot and ELISA, respectively. RESULTS: In a cohort of 43 subjects, the lactulose/rhamnose ratio was increased on day 1 and decreased over 2 weeks, but remained higher in infants born at ≤28 weeks of gestation compared with IP in infants born at >28 weeks of gestation. Exclusive breastmilk feeding was associated with more rapid maturation in intestinal barrier function. A cluster analysis of 35 subjects who had urine samples from all time points revealed 3 IP patterns (cluster 1, normal maturation: n = 20 [57%]); cluster 2, decreased IP during the first week and subsequent substantial increase: n = 5 [14%]); and cluster 3, delayed maturation: n = 10 [29%]). There were trends toward more prolonged antibiotic exposure (P = .092) and delayed initiation of feeding ≥4 days (P = .064) in infants with abnormal IP patterns. CONCLUSIONS: Intestinal barrier maturation in preterm infants is GA and postnatal age dependent, and is influenced by feeding with a maturational effect of breastmilk feeding and possibly by antibiotic exposures. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01756040.

Developmental Exposure to Environmental Toxicants.

Children interact with the physical environment differently than adults, and are uniquely susceptible to environmental toxicants. Routes of absorption, distribution, metabolism, and target organ toxicities vary as children grow and develop. This article summarizes the sources of exposure and known adverse effects of toxicants that are ubiquitous in our environment, including tobacco smoke, ethanol, solvents, heavy metals, volatile organic compounds, persistent organic pollutants, and pesticides. Preventive strategies that may be used in counseling children and their families are highlighted.

A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease.

It has been suggested that soluble urokinase receptor (suPAR) is a causative circulating factor for and a biomarker of focal and segmental glomerulosclerosis (FSGS). Here we undertook validation of these assumptions in both mouse and human models. Injection of recombinant suPAR in wild-type mice did not induce proteinuria within 24 h. Moreover, a disease phenotype was not seen in an inducible transgenic mouse model that maintained elevated suPAR concentrations for 6 weeks. Plasma and urine suPAR concentrations were evaluated as clinical biomarkers in 241 patients with glomerular disease from the prospective, longitudinal multicenter observational NEPTUNE cohort. The serum suPAR concentration at baseline inversely correlated with estimated glomerular filtration rate (eGFR) and the urine suPAR/creatinine ratio positively correlated with the urine protein/creatinine ratio. After adjusting for eGFR and urine protein, neither the serum nor urine suPAR level was an independent predictor of FSGS histopathology. A multivariable mixed-effects model of longitudinal data evaluated the association between the change in serum suPAR concentration from baseline with eGFR. After adjusting for baseline suPAR concentration, age, gender, proteinuria, and time, the change in suPAR from baseline was associated with eGFR, but this association was not different for patients with FSGS as compared with other diagnoses. Thus these results do not support a pathological role for suPAR in FSGS.

Restoration of Glucose Counterregulation by Islet Transplantation in Long-standing Type 1 Diabetes.

Patients with long-standing type 1 diabetes (T1D) may exhibit defective glucose counterregulation and impaired hypoglycemia symptom recognition that substantially increase their risk for experiencing severe hypoglycemia. The purpose of this study was to determine whether intrahepatic islet transplantation improves endogenous glucose production (EGP) in response to hypoglycemia in T1D patients experiencing severe hypoglycemia. We studied longitudinally subjects (n = 12) with ∼30 years, disease duration before and 6 months after intrahepatic islet transplantation using stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-(2)H2-glucose and compared the results with those from a nondiabetic control group (n = 8). After islet transplantation, HbA1c was normalized, and time spent while hypoglycemic (<70 mg/dL) was nearly abolished as indicated by continuous glucose monitoring. In response to insulin-induced hypoglycemia, C-peptide (absent before transplant) was appropriately suppressed, glucagon secretion was recovered, and epinephrine secretion was improved after transplantation. Corresponding to these hormonal changes, the EGP response to insulin-induced hypoglycemia, which was previously absent, was normalized after transplantation, with a similar effect seen for autonomic symptoms. Because the ability to increase EGP is ultimately required to circumvent the development of hypoglycemia, these results provide evidence that intrahepatic islet transplantation can restore glucose counterregulation in long-standing T1D and support its consideration as treatment for patients with hypoglycemia unawareness experiencing severe hypoglycemia.

Pretreatment vitamin D level and response to neoadjuvant chemotherapy in women with breast cancer on the I-SPY trial (CALGB 150007/150015/ACRIN6657).

Laboratory studies suggest that vitamin D (vitD) enhances chemotherapy-induced cell death. The objective of this study was to determine whether pretreatment vitD levels were associated with response to neoadjuvant chemotherapy (NACT) in women with breast cancer. Study patients (n = 82) were enrolled on the I-SPY TRIAL, had HER2-negative tumors, and available pretreatment serum. VitD levels were measured via DiaSorin radioimmunoassay. The primary outcome was pathologic residual cancer burden (RCB; dichotomized 0/1 vs. 2/3). Secondary outcomes included biomarkers of proliferation, differentiation, and apoptosis (Ki67, grade, Bcl2, respectively) and 3-year relapse-free survival (RFS). Mean and median vitD values were 22.7 ng/mL (SD 11.9) and 23.1 ng/mL, respectively; 72% of patients had levels deemed "insufficient" (<30 ng/mL) by the Institute of Medicine (IOM). VitD level was not associated with attaining RCB 0/1 after NACT (univariate odds ratio [OR], 1.01; 95% CI, 0.96-1.05) even after adjustment for hormone receptor status (HR), grade, Ki67, or body mass index (BMI). Lower vitD levels were associated with higher tumor Ki67 adjusting for race (OR, 0.95; 95% CI, 0.90-0.99). VitD level was not associated with 3-year RFS, either alone (hazard ratio [HzR], 0.98; 95% CI, 0.95-1.02) or after adjustment for HR, grade, Ki-67, BMI, or response. VitD insufficiency was common at the time of breast cancer diagnosis among women who were candidates for NACT and was associated with a more proliferative phenotype. However, vitD levels had no impact on tumor response to NACT or short-term prognosis.

Effects of testosterone and growth hormone on the structural and mechanical properties of bone by micro-MRI in the distal tibia of men with hypopituitarism.

CONTEXT: Severe deficiencies of testosterone (T) and GH are associated with low bone mineral density (BMD) and increased fracture risk. Replacement of T in hypogonadal men improves several bone parameters. Replacement of GH in GH-deficient men improves BMD. OBJECTIVE: Our objective was to determine whether T and GH treatment together improves the structural and mechanical parameters of bone more than T alone in men with hypopituitarism. DESIGN AND SUBJECTS: This randomized, prospective, 2-year study included 32 men with severe deficiencies of T and GH due to panhypopituitarism. INTERVENTION: Subjects were randomized to receive T alone (n = 15) or T and GH (n = 17) for 2 years. MAIN OUTCOME MEASURES: We evaluated magnetic resonance microimaging-derived structural (bone volume fraction [BVF] and trabecular thickness) and mechanical (axial stiffness [AS], a measure of bone strength) properties of the distal tibia at baseline and after 1 and 2 years of treatment. RESULTS: Treatment with T and GH did not affect BVF, thickness, or AS differently from T alone. T treatment in all subjects for 2 years increased trabecular BVF by 9.6% (P < .0001), trabecular thickness by 2.6% (P < .001), and trabecular AS by 9.8% (P < .001). In contrast, testosterone treatment in all subjects significantly increased cortical thickness by 2.4% (P < .01) but decreased cortical BVF by -4.7% (P < .01) and cortical AS by -6.9% (P < .01). CONCLUSION: Combined T and GH treatment of men with hypopituitarism for 2 years did not improve the measured structural or mechanical parameters of the distal tibia more than T alone. However, testosterone significantly increased the structural and mechanical properties of trabecular bone but decreased most of these properties of cortical bone, illustrating the potential importance of assessing trabecular and cortical bone separately in future studies of the effect of testosterone on bone.

Changes in biomarkers associated with living kidney donation.

Living donor kidneys have been associated with better graft and overall survival in kidney transplant recipients. Although a living kidney donation is generally considered safe in carefully selected living donors, concerns of possible adverse effects related to kidney donation remain, especially in younger and high-risk donors. In this study, we examined the changes in a panel of traditional and novel serum biomarkers linked with cardiovascular conditions in a cohort of 34 healthy living kidney donors with a mean age ± SD of 40 ± 10 years and estimated predonation glomerular filtration rate (GFR) of 86 ± 10 ml/min/1.73 m(2). At 6 months after donation, there were no significant changes in the clinical parameters including body mass index and blood pressure despite a significant decline in the mean estimated GFR to 60 ml/min/1.73 m(2). Among the panel of markers, the levels of symmetric dimethylarginine and fibroblast growth factor 23 increased significantly compared to baseline, suggesting that living kidney donation may result in changes in biomarkers that are associated with cardiovascular risk in other cohorts.

Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin.

BACKGROUND: Low dose aspirin reduces the secondary incidence of myocardial infarction and stroke. Drug resistance to aspirin might result in treatment failure. Despite this concern, no clear definition of aspirin resistance has emerged, and estimates of its incidence have varied remarkably. We aimed to determine the commonality of a mechanistically consistent, stable, and specific phenotype of true pharmacological resistance to aspirin-such as might be explained by genetic causes. METHODS AND RESULTS: Healthy volunteers (n=400) were screened for their response to a single oral dose of 325-mg immediate release or enteric coated aspirin. Response parameters reflected the activity of the molecular target of aspirin, cyclooxygenase-1. Individuals who appeared aspirin resistant on 1 occasion underwent repeat testing, and if still resistant were exposed to low-dose enteric coated aspirin (81 mg) and clopidogrel (75 mg) for 1 week each. Variable absorption caused a high frequency of apparent resistance to a single dose of 325-mg enteric coated aspirin (up to 49%) but not to immediate release aspirin (0%). All individuals responded to aspirin on repeated exposure, extension of the postdosing interval, or addition of aspirin to their platelets ex vivo. CONCLUSIONS: Pharmacological resistance to aspirin is rare; this study failed to identify a single case of true drug resistance. Pseudoresistance, reflecting delayed and reduced drug absorption, complicates enteric coated but not immediate release aspirin administration. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00948987.

Vitamin d deficiency in postmenopausal breast cancer survivors.

PURPOSE: Breast cancer survivors (BCS) taking aromatase inhibitors (AIs) are at an increased risk for decreased bone density and fractures. Given the role vitamin D plays in bone metabolism, we examined the prevalence of and risk factors for vitamin D deficiency in a study of postmenopausal BCS on AIs. METHODS: We collected data on 391 postmenopausal women with stage I-III breast cancer on AI therapy. Vitamin D levels were measured by radioimmunoassay from patients' sera; deficiency was defined as a level < 30 ng/mL. Multivariate models were created to assess risk factors for deficiency. RESULTS: The median vitamin D level was 35 ng/mL (range 6.78-93.15), and 35% of women were vitamin D deficient. When adjusting for age and vitamin D supplementation, minority participants were more likely to be vitamin D deficient than white women, (adjusted odds ratio [AOR] 2.18, 95% confidence interval [CI]1.22-3.89, p=0.009). Both overweight (AOR 3.05, 95% CI 1.72-5.41, p<0.001) and obese participants (AOR 3.21, 95% CI 1.79-5.78, p<0.001) had higher deficiency rates than did normal weight participants. CONCLUSIONS: Hypovitaminosis D is common in BCS, and those who are nonwhite or overweight are at a higher risk of deficiency despite taking vitamin D supplements.

Hematopoietic prostaglandin D synthase (HPGDS): a high stability, Val187Ile isoenzyme common among African Americans and its relationship to risk for colorectal cancer.

Intestinal tumors in Apc(Min/+) mice are suppressed by over-production of HPGDS, which is a glutathione transferase that forms prostaglandin D(2) (PGD(2)). We characterized naturally occurring HPGDS isoenzymes, to see if HPGDS variation is associated with human colorectal cancer risk. We used DNA heteroduplex analysis and sequencing to identify HPGDS variants among healthy individuals. HPGDS isoenzymes were produced in bacteria, and their catalytic activities were tested. To determine in vivo effects, we conducted pooled case-control analyses to assess whether there is an association of the isoenzyme with colorectal cancer. Roughly 8% of African Americans and 2% of Caucasians had a highly stable Val187lle isoenzyme (with isoleucine instead of valine at position 187). At 37°C, the wild-type enzyme lost 15% of its activity in 1h, whereas the Val187Ile form remained >95% active. At 50°C, the half life of native HPGDS was 9min, compared to 42 min for Val187Ile. The odds ratio for colorectal cancer among African Americans with Val187Ile was 1.10 (95% CI, 0.75-1.62; 533 cases, 795 controls). Thus, the Val187Ile HPGDS isoenzyme common among African Americans is not associated with colorectal cancer risk. Other approaches will be needed to establish a role for HPGDS in occurrence of human intestinal tumors, as indicated by a mouse model.

Relation of plasma fatty acid binding proteins 4 and 5 with the metabolic syndrome, inflammation and coronary calcium in patients with type-2 diabetes mellitus.

Fatty acid-binding proteins (FABPs) 4 and 5 play coordinated roles in rodent models of inflammation, insulin resistance, and atherosclerosis, but little is known of their role in human disease. The aim of this study was to examine the hypothesis that plasma adipocyte and macrophage FABP4 and FABP5 levels would provide additive value in the association with metabolic and inflammatory risk factors for cardiovascular disease as well as subclinical atherosclerosis. Using the Penn Diabetes Heart Study (PDHS; n = 806), cross-sectional analysis of FABP4 and FABP5 levels with metabolic and inflammatory parameters and with coronary artery calcium, a measure of subclinical coronary atherosclerosis, was performed. FABP4 and FABP5 levels had strong independent associations with the metabolic syndrome (for a 1-SD change in FABP levels, odds ratio [OR] 1.85, 95% confidence interval [CI] 1.43 to 2.23, and OR 1.66, 95% CI 1.41 to 1.95, respectively) but had differential associations with metabolic syndrome components. FABP4 and FABP5 were also independently associated with C-reactive protein and interleukin-6 levels. FABP4 (OR 1.26, 95% CI 1.05 to 1.52) but not FABP5 (OR 1.13, 95% CI 0.97 to 1.32) was associated with the presence of coronary artery calcium. An integrated score combining FABP4 and FABP5 quartile data had even stronger associations with the metabolic syndrome, C-reactive protein, interleukin-6, and coronary artery calcium compared to either FABP alone. In conclusion, this study provides evidence for an additive relation of FABP4 and FABP5 with the metabolic syndrome, inflammatory cardiovascular disease risk factors, and coronary atherosclerosis in type 2 diabetes mellitus. These findings suggest that FABP4 and FABP5 may represent mediators of and biomarkers for metabolic and cardiovascular disease in type 2 diabetes mellitus.

Association of lower plasma fetuin-a levels with peripheral arterial disease in type 2 diabetes.

OBJECTIVE: Fetuin-A is an inhibitor of vascular calcification and a mediator of insulin resistance. This study evaluated the association of plasma fetuin-A and peripheral arterial disease (PAD). RESEARCH DESIGN AND METHODS: A total of 738 individuals with type 2 diabetes (mean age 58.7 years, 37.1% female) without known cardiovascular or kidney disease were included in this cross-sectional analysis. RESULTS: Subjects with PAD had a significantly lower fetuin-A (264.3 vs. 293.4 ng/dl, P < 0.001). In multivariable analysis, a 1-SD decrease in fetuin-A increased the odds of PAD (odds ratio 1.6, P = 0.02). Subgroup analysis revealed an increased odds even in subjects with glomerular filtration rate >80 (odds ratio 1.9, P = 0.05) or high-sensitivity C-reactive protein <3 mg/dl (odds ratio 2.7, P = 0.002). CONCLUSIONS: Lower circulating fetuin-A is associated with PAD in type 2 diabetes beyond traditional and novel cardiovascular risk factors. Our findings suggest a potentially unique role for fetuin-A deficiency as a biomarker of PAD in patients with type 2 diabetes.

Symptoms in the menopausal transition: hormone and behavioral correlates.

OBJECTIVE: To estimate the association of headache, irritability, mood swings, anxiety, and concentration difficulties with menopausal stage and with reproductive hormones in the menopausal transition. METHODS: Women in the Penn Ovarian Aging Study were assessed longitudinally for 9 years. Data were obtained from structured interviews, a validated symptom questionnaire, menstrual bleeding dates, and early follicular hormone measures of estradiol (E2), follicle-stimulating hormone (FSH), and testosterone. Menopausal stages were based on menstrual bleeding patterns. Other risk factors included history of depression, perceived stress, premenstrual syndrome, current smoking, age, and race. Generalized linear regression models for repeated measures were used to estimate associations among the variables with each symptom. RESULTS: Headache decreased in the transition to menopause and was significantly associated with menopausal stage in univariable analysis (P=.002). Mood swings were inversely associated with mean FSH levels (P=.005). Irritability was inversely associated with mean levels of FSH (P=.017) and testosterone (P=.008). In multivariable models, the independent contributions of other covariates were strongly associated with these symptoms: premenstrual syndrome (P<.001) and perceived stress (P<.001) for irritability and mood swings; P=.018 for headache. There was 80% power with 0.05 alpha to detect a decrease of 13% or more in the prevalence of the symptoms in the postmenopausal stage compared with the premenopausal stage. CONCLUSION: Headache significantly decreased in the transition to menopause. Irritability and mood swings also decreased in the menopausal transition as assessed by hormone levels. The findings indicate that these symptoms that are commonly linked with menopause diminish with the physiologic changes of the menopausal transition. LEVEL OF EVIDENCE: II.

Association of physical activity with reproductive hormones: the Penn Ovarian Aging Study.

BACKGROUND: Physical activity is associated with reduced risk for breast cancer, perhaps through reductions in circulating reproductive hormones (estrogens and androgens). There may also be a role for physical activity in regulating menopausal symptoms. Few studies have examined associations of physical activity on hormone levels. None have examined the potential effect of the menopausal transition on the associations between physical activity and reproductive hormone levels. MATERIALS AND METHODS: Data from the Penn Ovarian Aging Study were used for this analysis. Self-reported physical activity was assessed in 391 women up to four times over 10 years and extending across the menopausal transition. Other assessments included reproductive hormones via RIA (estradiol, luteinizing hormone, follicle-stimulating hormone, testosterone, DHEA sulfate), body weight, and height. Multivariate repeated measures regression models were developed to compare reproductive hormone levels within physical activity tertiles, adjusting for age, follow-up time, smoking, and ethnicity. RESULTS: Activity level was inversely associated with estradiol in the subgroup in the late transition stage. Adjusted means for estradiol were 24.6 and 37.9, a relative difference of 54% in estradiol when comparing highest to lowest activity tertile (P = 0.02). Similarly, in this subgroup, there was an inverse association between physical activity and testosterone levels (means of 11.1 and 15.94 in the highest and lowest tertile, a 47% relative difference; P = 0.01). There were no significant associations of activity with any other reproductive hormone. CONCLUSIONS: These results identify a particular window of the menopausal transition during which physical activity is associated with reduced estradiol and/or testosterone levels.

Salt intake and insulin sensitivity in healthy human volunteers.

The literature on salt intake and insulin sensitivity presents a mixed picture, as some studies have shown an increase, whereas others have shown a decrease, in insulin action as sodium intake is enhanced. In some cases, this may relate to the study of salt intake in patients with co-morbidities such as hypertension or diabetes. In the present study, we selected healthy normotensive lean volunteers who underwent a euglycaemic clamp following 6 days of a low-salt diet (20 mmol sodium daily) and, subsequently, 6 days of a high-salt diet (200 mmol sodium daily). Our results show an increase in insulin-mediated glucose disposal during euglycaemic clamp conditions that was significantly higher following the high-salt diet compared with the low-salt diet (7.41+/-0.41 compared with 6.11+/-0.40 mg x kg(-1) of body weight x min(-1) respectively; P=0.03). We measured calf blood flow before and during insulin infusion (no significant change after the two dietary salt interventions was detected) and plasma non-esterified fatty acids (also no significant differences were detected). We observed the expected increases in renin concentration and aldosterone activity in subjects on the low-salt diet, and also observed a significantly less increase in plasma noradrenaline concentration during euglycaemic insulin infusion following the high-salt compared with the low-salt diet. We propose that the 4-5-fold increase in serum aldosterone and the greater increase in plasma noradrenaline concentration following the low-salt intervention compared with the high-salt period may have contributed to the differences in insulin sensitivity following the adjustment in dietary sodium intake.

Circadian variation of blood pressure and the vascular response to asynchronous stress.

The diurnal variation in the incidence of myocardial infarction and stroke may reflect an influence of the molecular clock and/or the time dependence of exposure to environmental stress. The circadian variation in blood pressure and heart rate is disrupted in mice, Bmal1(-/-), Clock(mut), and Npas2(mut), in which core clock genes are deleted or mutated. Although Bmal1 deletion abolishes the 24-h frequency in cardiovascular rhythms, a shorter ultradian rhythm remains. Sympathoadrenal function is disrupted in these mice, which reflects control of enzymes relevant to both synthesis (phenylethanolamine N-methyl transferase) and disposition (monoamine oxidase B and catechol-O-methyl transferase) of catecholamines by the clock. Both timing and disruption or mutation of clock genes modulate the magnitude of both the sympathoadrenal and pressor but not the adrenocortical response to stress. Despite diurnal variation of catecholamines and corticosteroids, they are regulated differentially by the molecular clock. Furthermore, the clock may influence the time-dependent incidence of cardiovascular events by controlling the integration of selective asynchronous stress responses with an underlying circadian rhythm in cardiovascular function.

Glycemic thresholds for activation of counterregulatory hormone and symptom responses in islet transplant recipients.

CONTEXT: In patients with type 1 diabetes and reduced awareness of hypoglycemia, the glycemic thresholds for activation of counterregulatory hormone and symptom responses to hypoglycemia are impaired, in part due to recurrent episodes of hypoglycemia. Islet transplantation can ameliorate occurrences of hypoglycemia in these patients. OBJECTIVE: The objective of the study was to determine whether the avoidance of hypoglycemia achieved through islet transplantation results in improved glycemic thresholds for counterregulatory responses. SETTING: The study was conducted at a general clinical research center. PARTICIPANTS: Seven islet transplant recipients, six type 1 diabetic, and eight nondiabetic control subjects participated in the study. INTERVENTION: We performed a stepped hyperinsulinemic hypoglycemic clamp and, in 12 subjects, a paired hyperinsulinemic euglycemic clamp to calculate the glycemic thresholds for and magnitude of counterregulatory responses. RESULTS: The glycemic thresholds for all counterregulatory hormone and symptom responses in the islet transplant group were comparable with normal and higher than in the type 1 diabetes group (P < 0.01 for glucagon; P < 0.05 for epinephrine). The magnitude of the glucagon and epinephrine responses in the islet transplant group, although greater than in the type 1 diabetes group (P < 0.05 for both), remained less than normal (P < 0.01 for glucagon; P < 0.05 for epinephrine). The magnitude of GH secretion in the islet transplant group was comparable with normal and greater than in the type 1 diabetes group (P < 0.05). CONCLUSIONS: The glycemic thresholds for activation of counterregulatory hormone and symptom responses appear normal after islet transplantation; however, the magnitudes of the glucagon and epinephrine responses remain impaired.

Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2.

BACKGROUND & AIMS: Variability in response to drugs may influence both efficacy and safety. Cyclooxygenase (COX)-2 inhibitors pose a cardiovascular risk by potentially increasing the likelihood of thrombosis, hypertension, and atherogenesis. Differences between individuals in the response to COX-2 inhibitors would be expected to influence their susceptibility to cardiovascular complications. We examined the variability in degree and selectivity of COX-2 inhibition in humans in response to celecoxib and rofecoxib. METHODS: Fifty healthy volunteers received placebo, rofecoxib (25 mg), and celecoxib (200 mg), randomized by order. COX-1 and COX-2 inhibition was determined using ex vivo and in vivo indices of enzymatic activity. A subset of 5 individuals underwent 5 replicate studies to estimate variability in drug response both within and between subjects. RESULTS: Despite the higher COX-2 selectivity of rofecoxib in vitro, the average selectivity attained by 25 mg rofecoxib and 200 mg celecoxib in vivo were not different. However, there was considerable variability at an individual level in the degree of COX-2 inhibition and selectivity attained by both drugs. Approximately one third of the variability was attributable to differences between individuals, suggesting the contribution of genetic sources of variance, such as candidate polymorphisms detected in COX-1 and CYP2C9. CONCLUSIONS: The actual degree of selectivity for inhibition of COX-2 achieved by the coxibs relates both to chemical properties of the drug and to factors within an individual that modulate drug response. These sources of variability might be exploited to identify patients uniquely susceptible to benefit or at developing risk of cardiovascular complications.