Matrix metalloproteinase-1, -3, and -9 gene polymorphisms and the risk of idiopathic dilated cardiomyopathy in a Chinese Han population

OBJECTIVES: To investigate the association between matrix metalloproteinase (MMP)-1(-1607 1G/2G), MMP-3(-1171 5A/6A), and MMP-9(-1562 C/T) polymorphism and susceptibility to idiopathic dilated cardiomyopathy (IDCM). DESIGN AND METHODS: MMP-1, -3, -9 genotypes were determined by PCR-RFLP analysis. RESULTS: Genotype frequency of MMP-3, but not MMP-1 and MMP-9 in IDCM patients, was significantly different from that in healthy controls. CONCLUSIONS: Our data suggested that MMP-3 5A/6A polymorphism could be a risk factor for the susceptibility to IDCM.     

Vitreous levels of IGF-I, IGF binding protein 1, and IGF binding protein 3 in proliferative diabetic retinopathy: a case-control study

OBJECTIVE: To evaluate vitreous levels of IGF-I and its binding proteins IGFBP-1 and IGFBP-3 in patients with proliferative diabetic retinopathy (PDR). Because intravitreal proteins are elevated in patients with PDR due to the disruption of the blood-retinal barrier, we have corrected vitreal IGF-I and IGFBPs by total vitreal proteins to avoid this confounding factor. RESEARCH DESIGN AND METHODS: We compared 21 diabetic patients with proliferative retinopathy (group A) and 13 nondiabetic patients (group B) in whom a vitrectomy was performed. Both groups were matched by age, serum IGF-I, IGFBP-1, and IGFBP-3 levels. Serum and vitreous levels of IGF-I, IGFBP-1, and IGFBP-3 were measured by immunological methods. Vitreal proteins were assessed by turbidimetric method. RESULTS: Vitreal levels of IGF-I were elevated in group A (median 1.35 ng/ml [range 0.3-8.7]) in comparison with group B (median 0.25 ng/ml [range 0-1.38]), P<0.001. After adjusting by vitreal proteins [ratio IGF-I (ng/ml)/protein (mg/ml)], the differences remain significant (P<0.005). Vitreal levels of IGFBP-1 and IGFBP-3 were also elevated in diabetic patients (IGFBP-1: group A, median 1.6 ng/ml [range 0.6-20.7]; group B, median 0.4 ng/ml [range 0.3-1.9], P<0.001. IGFBP-3: group A, median 102.6 ng/ml [range 53.9-350.8]; group B, median 29.0 ng/ml [range 3.2-87.8], P<0.001). However, when the ratio IGFBP/protein was considered, the differences were not significant. CONCLUSIONS: Intraocular synthesis contributes to elevated vitreous concentrations of IGF-I found in PDR. By contrast, unspecific increase of intravitreal proteins is the main factor explaining the elevated vitreous levels of IGFBP-1 and IGFBP-3 found in diabetic patients.     

Comparison of cardiac output determined by bioimpedance, thermodilution, and the Fick method.

BACKGROUND: Cardiac output can be determined by using a variety of methods. OBJECTIVES: To determine the precision and bias between 3 methods for determining cardiac output: bioimpedance, thermodilution, and the Fick method. METHODS: Cardiac output was determined by using bioimpedance via neck and thorax patches and thermodilution via pulmonary artery catheter in 46 patients in the intensive care unit. A subset of 15 patients also had cardiac output determined by using the Fick method. RESULTS: Mean (SD) cardiac output in all patients was 6.3 (2.2) L/min by thermodilution and 5.6 (2.0) L/min by bioimpedance. In the 15 patients in whom all 3 methods were used, mean cardiac output was 6.0 (1.7) L/min by thermodilution, 5.3 (1.7) L/min by bioimpedance, and 8.6 (4.5) L/min by the Fick method. Bias and precision (mean difference +/- 2 SDs) were 0.7 +/- 2.9 L/min between thermodilution and bioimpedance, 1.7 +/- 3.8 L/min between the Fick method and thermodilution, and 2.4 +/- 4.7 L/min between the Fick method and bioimpedance. CONCLUSION: Bioimpedance, thermodilution, and Fick determinations of cardiac outputs are not interchangeable in a heterogeneous population of critically ill patients.     

In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes

OBJECTIVES: Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Single-time point phenotypic metabolic ratios were used to determine whether long-term supplementation of goldenseal ( Hydrastis canadensis ), black cohosh ( Cimicifuga racemosa ), kava kava ( Piper methysticum ), or valerian ( Valeriana officinalis ) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4/5 activity. METHODS: Twelve healthy volunteers (6 women) were randomly assigned to receive goldenseal, black cohosh, kava kava, or valerian for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe drug cocktails of midazolam and caffeine, followed 24 hours later by chlorzoxazone and debrisoquin (INN, debrisoquine), were administered before (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4/5, CYP1A2, CYP2E1, and CYP2D6 by use of 1-hydroxymidazolam/midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquin urinary recovery ratios (8-hour collection), respectively. The content of purported "active" phytochemicals was determined for each supplement. RESULTS: Comparisons of presupplementation and postsupplementation phenotypic ratio means revealed significant inhibition (approximately 40%) of CYP2D6 (difference, -0.228; 95% confidence interval [CI], -0.268 to -0.188) and CYP3A4/5 (difference, -1.501; 95% CI, -1.840 to -1.163) activity for goldenseal. Kava produced significant reductions (approximately 40%) in CYP2E1 only (difference, -0.192; 95% CI, -0.325 to -0.060). Black cohosh also exhibited statistically significant inhibition of CYP2D6 (difference, -0.046; 95% CI, -0.085 to -0.007), but the magnitude of the effect (approximately 7%) did not appear to be clinically relevant. No significant changes in phenotypic ratios were observed for valerian. CONCLUSIONS: Botanical supplements containing goldenseal strongly inhibited CYP2D6 and CYP3A4/5 activity in vivo, whereas kava inhibited CYP2E1 and black cohosh weakly inhibited CYP2D6. Accordingly, serious adverse interactions may result from the concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 and CYP3A4/5 substrates. Kava kava and black cohosh may interact with CYP2E1 and CYP2D6 substrates, respectively. Valerian appears to be less likely to produce CYP-mediated herb-drug interactions.     

Effects of propofol, etomidate, and pentobarbital on critical oxygen delivery

OBJECTIVE: To test the hypothesis that propofol, etomidate, and pentobarbital increase critical oxygen delivery in a dose-dependent manner during progressive hemorrhage. DESIGN: Prospective, randomized laboratory investigation. SETTING: University laboratory. SUBJECTS: A total of 40 anesthetized, paralyzed, and mechanically ventilated dogs weighing 29.2+/-4.6 kg. INTERVENTIONS: Dogs were randomly assigned to be anesthetized with propofol (n = 13), etomidate (n = 13), or pentobarbital (n = 14) at either low or high dosages. At 30 mins after splenectomy, the dogs underwent progressive hemorrhage by successive withdrawals of 3-5 mL/kg arterial blood. MEASUREMENTS AND MAIN RESULTS: At each step of hemorrhage, oxygen consumption and oxygen delivery were determined. Oxygen consumption was obtained from expired gas analysis, and oxygen delivery was determined from thermodilution cardiac output and calculated arterial oxygen content. In each animal, critical oxygen delivery and critical oxygen consumption were obtained from a plot of oxygen consumption vs. oxygen delivery as the point of intersection of the two best-fit regression lines determined by a least sum of squares method. Critical oxygen extraction was obtained by dividing critical oxygen consumption by critical oxygen delivery. In the three groups, animals receiving the higher anesthetic infusion had a significantly higher critical oxygen delivery (propofol: 10.5+/-0.8 vs. 13.9+/-2.5 mL/min/m2, p < .05; etomidate: 10.1+/-0.7 vs. 13.4+/-3.0 mL/min/m2, p < .05; pentobarbital: 7.8+/-1.0 vs. 12.3+/-2.5 mL/min/m2, p < .01) attributable to a lower critical oxygen extraction ratio (propofol: 41.1+/-6.4% vs. 54.2+/-2.5%, p < .01; etomidate: 42.7+/-10.2% vs. 60.6+/-7.1%, p < .01; pentobarbital: 42.2+/-7.2% vs. 64.3+/-8.8%, p < .01). CONCLUSIONS: This study indicates that propofol, etomidate, and pentobarbital increased critical oxygen delivery in a dose-dependent manner. This effect was mainly related to a decrease in tissue oxygen extraction capabilities.     

Reference intervals for serum apolipoproteins A-I, A-II, B, C-II, C-III, and E in healthy Japanese determined with a commercial immunoturbidimetric assay and effects of sex, age, smoking, drinking, and Lp(a) level

BACKGROUND: Apolipoproteins, which are contained in lipoprotein particles, play important roles in the transport of lipids. METHODS: Serum levels of apolipoproteins (apo) A-I, A-II, B, C-II, C-III, and E were determined by immunoturbidimetry in a healthy Japanese study population (1018 men and 1167 women, age 20-69 years) to establish reference intervals. RESULTS: Among the 2185 subjects examined, the mean serum value for apoA-I was 1.42 +/- 0.20 g/l, for apoA-II was 0.30 +/- 0.05 g/l, for apoB was 0.87 +/- 0.18 g/l, for apoC-II was 29 +/- 13 mg/l, for apoC-III was 75 +/- 20 mg/l, and for apoE was 36 +/- 9 mg/l. A sex difference was detected in the mean serum concentrations of all six apolipoproteins. Alcohol consumption and cigarette use had a slight effect on serum apolipoprotein concentrations. Age effects were observed among women in apoB, apoC-II, and apoC-III concentrations. Moreover, individuals with elevated serum lipoprotein (a) [Lp(a), >300 mg/l] also displayed increased serum apoB and apoC-II levels and an increased apoB/apoA-I ratio. CONCLUSION: The reference intervals for apolipoproteins in Japanese adults that we established, using commercially available reagents for automated analyzers, will be helpful for assessing risk of coronary heart disease and pathological conditions of patients with hyperlipidemia. We recommend use of these reference intervals for the clinical interpretation of serum apolipoprotein concentrations.     

Enteral feeding with a solution enriched with antioxidant vitamins A, C, and E enhances the resistance to oxidative stress

OBJECTIVE: To assess whether dietary supplementation with the antioxidant vitamins A, C, and E enhances parameters of oxidative stress and influences the course of critically ill patients. DESIGN: Prospective, randomized, double-blinded, placebo-controlled study. SETTING: Department of medicosurgical intensive care of an academic hospital. PATIENTS: Fifty-one patients expected to require at least 7 days of enteral feeding. Thirty-seven of these patients (age, 57 +/- 7 yrs; Simplified Acute Physiology Score II, 33 +/- 6 points) completed the study. INTERVENTIONS: Twenty patients were randomized to receive the formula supplemented with vitamins A (67 microg/dL), C (13.3 mg/ dL), and E (4.94 mg/dL), and 17 patients received an isocaloric and isonitrogenous control solution. MEASUREMENTS AND MAIN RESULTS: Plasma levels of antioxidant vitamins, lipid peroxidation (estimated by the malonyldialdehyde assay), and low-density lipoprotein (LDL), and erythrocyte resistance to experimental oxidative stress were determined on samples drawn two consecutive days before the initiation of feeding and at the end of the 7-day period. Clinical outcome measures included documented infection and intensive care unit and 28-day survival. Administration of the supplemented solution increased significantly the concentration of plasma beta-carotene (from 0.2 +/- 0.0 microg/mL to 0.6 +/- 0.1 microg/mL; p < 0.01) and plasma and LDL-bound alpha-tocopherol (from 6.0 +/- 0.4 microg/mL and 2.9 +/- 0.9 microg/mL to 9.7 +/- 0.5 microg/mL and 4.3 +/- 1.2 microg/mL, respectively; p < 0.05), and improved LDL resistance to oxidative stress by 21 +/- 4% (p < 0.05). No such change was observed in the control group. There was no significant difference in clinical outcome between the two groups. CONCLUSIONS: Supplemental antioxidant vitamins added to enteral feeding solutions are well absorbed. Dietary supplementation with vitamins A, C, and E is associated with an improvement in antioxidant defenses, as assessed by ex vivo tests.     

Determination of lysozyme in serum, urine, cerebrospinal fluid and feces by enzyme immunoassay

Conjugates of human lysozyme and horseradish peroxidase (HRP) were prepared by means of the heterobifunctional reagent N-succinimidyl 3-(2-pyridyldithio) propionate. A conjugate containing 2 mol HRP/mol lysozyme was isolated by gel filtration and used as a labeled antigen in competitive enzyme immunoassays, in which anti-lysozyme rabbit IgG had been bound to wells of microtiter plates. The assay can detect as little as 1 microgram lysozyme/l. The following reference intervals have been established: 950-2450 micrograms/l for serum, 1.7-123 micrograms/l for urine, 17.6-118 micrograms/l for cerebrospinal fluid and 0.04-1.5 microgram/g for feces.     

Sepsis-induced cholestasis, steatosis, hepatocellular injury, and impaired hepatocellular regeneration are enhanced in interleukin-6 -/- mice

OBJECTIVE: Hepatic dysfunction is an important but poorly understood component of sepsis. In severe sepsis, liver dysfunction is characterized by cholestasis, steatosis, hepatocellular injury, impaired regeneration, a decreased response to the cytokine interleukin-6, and high mortality. To determine whether loss of interleukin-6 activity caused hepatic dysfunction and mortality, we induced sepsis in wild-type (interleukin-6 +/+) and interleukin-6 knockout (interleukin-6 -/-) mice. We hypothesized that sepsis in interleukin-6 -/- mice would increase cholestasis, steatosis, hepatocellular injury, and mortality and impair hepatocyte regeneration. DESIGN: Randomized prospective experimental study. SETTING: University medical laboratory. SUBJECTS: Male adolescent C57Bl6 interleukin-6 +/+ and interleukin-6 -/- mice. INTERVENTIONS: Mild sepsis was induced using cecal ligation and single puncture (CLP). Severe, lethal sepsis was induced using cecal ligation and double puncture (2CLP). Some mice received recombinant human interleukin-6 at the time of CLP/2CLP. All animals were fluid resuscitated at the time of surgery and every 24 hrs thereafter. In survival cohorts, mortality at 16, 24, 48, and 72 hrs was recorded. In separate cohorts, surviving animals were killed at 24 and 48 hrs, and liver tissue was harvested. A separate cohort of mice received bromodeoxyuridine for detection of regeneration. MEASUREMENTS AND MAIN RESULTS: 2CLP was 100% fatal within the first 12 hrs in interleukin-6 -/- mice. Mortality from 2CLP in interleukin-6 +/+ mice before 24 hrs was nil but was 90% by 72 hrs. At 72 hrs, CLP was 40% fatal in interleukin-6 +/+ mice but 90% in interleukin-6 -/- mice. CLP induced cholestasis, steatosis, and hepatocellular injury in interleukin-6 -/-, but not interleukin-6 +/+, mice. Regeneration was absent following CLP in interleukin-6 -/- animals but occurred in interleukin-6 +/+ mice. Early administration of recombinant human interleukin-6 did not reverse abnormalities in interleukin-6 -/- mice. CONCLUSIONS: The absence of interleukin-6 is an important determinant of hepatic dysfunction and mortality in sepsis.     

Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms

OBJECTIVE: Patients initiating docetaxel chemotherapy were genotyped for CYP3A4, CYP3A5, MDR1, GSTM1, GSTT1, GSTM3, and GSTP1 to identify variability factors of docetaxel pharmacokinetics and toxicity. METHODS: Genotyping was performed by direct sequencing (CYP3A4), real-time polymerase chain reaction (CYP3A5), and polymerase chain reaction-restriction fragment length polymorphism (MDR1 and GST). The clearance and area under the curve of docetaxel were calculated by use of a Bayesian approach. Absolute neutrophil count was recorded twice weekly. RESULTS: With regard to the pharmacokinetic analysis, 58 patients were included. CYP3A4*1B carriers (*1A/*1B, n=4), who are also CYP3A5*1/*3 carriers, had a significantly higher clearance and lower dose-normalized area under the curve of docetaxel than those with the wild genotype (*1A/*1A, n=53): 55.2+/-13.5 L/h versus 37.3+/-11.7 L/h (P=.01) and 31.4+/-6.2 (microg . h/L)/(mg/m(2)) versus 52.7+/-18.2 (microg . h/L)/(mg/m(2)) (P=.005), respectively. No influence of MDR1 was evidenced. With regard to the pharmacodynamic analysis, febrile neutropenia occurred more frequently in GSTP1*A/*B carriers (31.6% versus 3.7% in *A/*A carriers and 0% in *A/*C, *B/*B, and *B/*C carriers) (P=.037). Grade 3 neutropenia occurred more frequently in 3435TT MDR1 genotype carriers: TT, 100%; CT, 77.3%; and CC, 54.5% (P=.046). No influence of GSTM1, GSTT1, or GSTM3 polymorphisms was evidenced on docetaxel toxicity. CONCLUSIONS: Patients carrying the CYP3A*1B allele may have enhanced docetaxel clearance and may be underexposed, whereas those carrying GSTP1*A/*B and 3435TT genotypes may have excessive hematologic toxicity. Further studies are warranted to determine the usefulness of genotyping before docetaxel treatment.     

Acidosis induced by lactate,pyruvate, or HCl increases blood viscosity

PURPOSE: Serum lactate correlates with the severity of disease and the mortality in shock. It is not clear if lactate is only a marker or a mediator of disease. We tested the hypothesis that acidosis induced by lactate and pyruvate affects blood flow properties. MATERIALS AND METHODS: Human blood was incubated with additional lactate (0-50 mmol/L) or pyruvate (0-25 mmol/L) for 1 hour at 37 degrees C. Blood viscosity was measured at high (94.5 s(-1)) and low (0.1 s(-1)) shear rate. Hematocrit was measured with an electronic particle counter as well as centrifugation. RESULTS: A total of 50 mmol/L additional lactate produced acidosis (pH 6.4) and increased whole-blood viscosity at high shear rate (94.5 s(-1): 6.53 +/- 0.51 mPa.s vs 4.94 +/- 0.18 mPa.s for control, n = 5, P <.001) and low shear rate (0.1 s(-1): 93.9 +/- 18.6 mPa.s vs 53.5 +/- 7.7 mPa.s, n = 5, P <.001). Simultaneously, an increased centrifuged hematocrit was observed (about 7% with 50 mmol/L lactate, P <.001), indicating eryth-rocyte swelling. These changes were reversible on removal of lactate. The addition of 25 mmol/L pyruvate also induced acidosis and increased blood viscosity and centrifuged hematocrit. When HCl was used to induce a comparable pH level decrease, a similar increase in blood viscosity and hematocrit were observed. CONCLUSIONS: Pronounced acidosis induced by either lactate, pyruvate, or HCl impairs blood flow properties, which may contribute to the understanding of the pathophysiology of critical illness.     

Results of a comparative, phase III, 12-week, multicenter, prospective, randomized, double-blind assessment of the efficacy and tolerability of a fixed-dose combination of telmisartan and amlodipine versus amlodipine monotherapy in Indian adults with stage II hypertension

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of a new fixed-dose combination (FDC) of telmisartan 40 mg + amlodipine 5 mg (T+A) compared with amlodipine 5-mg monotherapy (A) in adult Indian patients with stage II hypertension. METHODS: This comparative, Phase III, 12-week, multicenter, prospective, randomized, double-blind study was conducted in Indian patients aged 18 to 65 years with established stage II hypertension. Patients were treated with oral FDC of T+A or A QD before breakfast for 12 weeks; blood pressure (BP) and heart rate were measured in the sitting position. Primary efficacy end points were reduction in clinical systolic BP (SBP)/ diastolic BP (DBP) from baseline to study end and number of responders (ie, patients who achieved target SBP/ DBP <130/<80 mm Hg) at end of study. Tolerability was assessed by treatment-emergent adverse events, identified using physical examination, laboratory analysis, and electrocardiography. RESULTS: A total of 210 patients were enrolled in the study; 203 patients (143 men, 60 women) completed the study while 7 were lost to follow-up (4 patients in the T+A group and 3 in the A group) and considered with-drawn. At study end, statistically significant percentage reductions from baseline within groups and between groups were observed in SBP (T+A [-27.4%]; A [-16.6%]) and DBP (T+A [-20.1%]; A [-13.3%]) (all, P < 0.05). Response rates were 87.3% (89/102) in the T+A group and 69.3% (70/101) in the A group (P < 0.05). The prevalences of adverse events were not significantly different between the 2 treatment groups (T+A, 16.0% [17/106]; A, 15.4% [16/104]). Peripheral edema was reported in 8.5% patients (9/106) in the T+A group compared with 13.5% (14/104) in the A group, and cough was reported in 3.8% patients (4/106) in the T+A group and 1.0% (1/104) patients in the A group; these differences did not reach statistical significance. The incidences of headache, dizziness, and diarrhea were similar between the 2 groups. CONCLUSIONS: Among these Indian patients with stage II hypertension, the FDC of T+A was found to be significantly more effective, with regard to BP reductions, than A, and both treatments were well tolerated.     

Continuous infusions of lorazepam, midazolam, and propofol for sedation of the critically ill surgery trauma patient: a prospective, randomized comparison

OBJECTIVE: To compare the efficacy, safety, and cost of continuous infusions of lorazepam, midazolam, and propofol in a critically ill trauma/surgery patient population. DESIGN: A prospective, randomized, nonblinded, single center. SETTING: A 16-bed intensive care unit. PATIENTS: A total of 30 ventilated patients who were 18-70 yrs of age and required pharmacologic sedation. Patients with renal and/or liver failure, a history of alcohol abuse, a head injury, or in a coma were excluded. INTERVENTIONS: Patients were randomized by block design to receive lorazepam, midazolam, or propofol. Initial boluses and infusion rates were as follows: lorazepam 0.05 mg/kg, then 0.007 mg/kg/hr; midazolam 0.05 mg/kg, then 0.003 mg/kg/hr; and propofol 0.25 mg/kg, then 0.06 mg/kg/hr. Sedation was assessed and agents titrated every 5-10 mins to achieve > or =2 and <5 on the modified Ramsay scale. Once adequate response was achieved, agents were titrated to maintain the desired level of sedation. MEASUREMENTS AND MAIN RESULTS: Maintenance doses of lorazepam 0.02+/-0.01 mg/kg/hr, midazolam 0.04+/-0.03 mg/kg/hr, and propofol 2.0+/-1.5 mg/kg/hr achieved the desired level of sedation 68%, 79%, and 62% of the time, respectively. Oversedation occurred most often with lorazepam, compared with midazolam and propofol, at 14%, 6%, and 7% of the assessment times, respectively. Undersedation occurred most frequently with propofol compared with lorazepam and midazolam, at 31%, 18%, and 16% of the assessment times, respectively. The mean number of dosage changes per day was 7.8+/-4.3 for lorazepam, 4.4+/-2.9 for midazolam, and 5.6+/-6.0 for propofol (p = .91). Sedation costs per patient day (mean +/- SD) were $48+/-$76 (lorazepam), $182+/-$98 (midazolam), and $273+/-$200 (propofol) (p = .005). The potential savings, if all study patients had received lorazepam, is $14,208 compared with $8,808 if all received midazolam. CONCLUSIONS: The data suggest that lorazepam appears to be a cost-effective choice for sedation; however, oversedation may be problematic. Midazolam is the most titratable drug in our population, avoiding excessive oversedation or undersedation. Trauma patients may respond inadequately to propofol even at higher doses. Lorazepam may be the sedative of choice in critically ill trauma/surgery patients.     

Efficacy, tolerability, and safety of a novel once-daily extended-release metformin in patients with type 2 diabetes

OBJECTIVE: The purpose of this study was to determine the efficacy and safety of a novel extended-release metformin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes (newly diagnosed, treated with diet and exercise only, or previously treated with oral diabetic medications) were randomly assigned to receive one of three extended-release metformin treatment regimens (1,500 mg/day q.d., 1,500 mg/day twice daily, or 2,000 mg/day q.d.) or immediate-release metformin (1,500 mg/day twice daily) in a double-blind 24-week trial. RESULTS: Significant decreases (P < 0.001) in mean HbA(1c) (A1C) levels were observed by week 12 in all treatment groups. The mean changes from baseline to end point in the two groups given 1,500 mg extended-release metformin (-0.73 and -0.74%) were not significantly different from the change in the immediate-release metformin group (-0.70%), whereas the 2,000-mg extended-release metformin group showed a greater decrease in A1C levels (-1.06%; mean difference [2,000 mg extended-release metformin - immediate-release metformin]: -0.36 [98.4% CI -0.65 to -0.06]). Rapid decreases in fasting plasma glucose levels were observed by week 1, which continued until week 8, and were maintained for the duration of the study. The overall incidence of adverse events was similar for all treatment groups, but fewer patients in the extended-release metformin groups discontinued treatment due to nausea during the initial dosing period than in the immediate-release metformin group. CONCLUSIONS: Once- or twice-daily extended-release metformin was as safe and effective as twice-daily immediate-release metformin and provided continued glycemic control for up to 24 weeks of treatment.     

Definition, Klassifikation und Diagnose des Fibromyalgiesyndroms

BACKGROUND: Interdisciplinary guidelines for the definition, classification and diagnosis of chronic widespread pain (CWP) and fibromyalgia syndrome (FMS) were developed by collaboration of 10 German medical and psychological associations and 2 patient self-help organizations. METHODS: A systematic literature search was performed in the Cochrane Library (1993-12/2006), Medline (1980-2006), PsychInfo (1966-12/2006), and Scopus (1980-12/2006). Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine. Grading of the strength of recommendation was done according to the German program for disease management guidelines. Standardized procedures to reach a consensus on recommendations were used. RESULTS: CWP is defined by the criteria of the American College of Rheumatology (ACR--strong consensus). FMS can be diagnosed for clinical purposes by symptom-based criteria (without tender point examination) as well as by the ACR criteria (strong consensus).     

Open, randomized, multicentre italian trial on PEG-IFN plus ribavirin versus PEG-IFN monotherapy for chronic hepatitis C in HIV-coinfected patients on HAART

BACKGROUND: Chronic hepatitis C is common and aggressive in HIV-positive patients, so the development of a well-tolerated HCV therapy is a priority. We evaluated the efficacy and safety of pegylated interferon alpha2b (PEG-IFN) plus ribavirin (RBV) versus PEG-IFN monotherapy in HIV/HCV-coinfected patients undergoing highly active antiretroviral therapy (HAART), and analysed the predictive factors of response. METHODS: An Italian, multicentre, open-label trial including 135 coinfected patients, randomized to PEG-IFN 1.5 microg/kg/week plus RBV 400 mg twice daily (n=69, arm A) or PEG-IFN 1.5 microg/kg/week (n=66, arm B) for 48 weeks. We assessed the predictive values of early virological response (EVR) at week 8 (HCV-RNA drop >2 log10 compared with baseline or undetectable levels) on sustained virological response (SVR). RESULTS: Fifty-five patients (28 from arm A and 27 from arm B) completed 48 weeks of therapy. At the end of treatment, 20/28 patients in arm A and 11/27 in arm B had HCV-RNA <50 IU/ml. In a per-protocol analysis, SVR was reached by 54% of patients in arm A (genotype 2-3, 11/16; genotype 1-4, 4/12) and 22% in arm B (genotype 2-3, 3/15; genotype 1-4, 3/12). In an intention-to-treat analysis, the SVR was 22% in arm A (genotype 2-3, 11/32; genotype 1-4, 4/37) versus 9% in arm B (genotype 2-3, 3/32; genotype 1-4, 3/34). The best predictors of SVR were the use of combination therapy, infection with HCV genotype 3 versus genotype 1, and EVR at week 8. Thirty patients (15 from arm A and 15 from arm B) dropped out of the trial prematurely due to side effects. The positive predictive value of EVR at week 8 was 65%, the negative predictive value was 86%. CONCLUSIONS: PEG-IFN plus RBV can be considered a solid option for the treatment of HIV/HCV-coinfected patients. The key to successfully improving efficacy is strong compliance through strict overall patient monitoring, in order to best manage drug toxicity. EVR assessment at week 8 may become a useful stategy in the management of therapy.     

Rapid and reliable genotyping of human platelet antigen (HPA)-1, -2, -3, -4, and -5 a/b and Gov a/b by melting curve analysis

BACKGROUND: The probability for occurrence of neonatal alloimmune thrombocytopenic purpura (NAITP) depends largely on the frequency of each individual phenotype in various populations. In caucasians, antibodies to human platelet antigen (HPA)-1a are the major cause of neonatal alloimmune thrombocytopenic purpura, whereas in the Japanese population, antibodies to HPA-4b is most frequently involved in NAITP. Conventional PCR techniques for platelet antigen genotyping rely on sequence-specific primers (SSPs) and detection by gel electrophoresis, a method which is laborious and time consuming. New PCR technology, measuring the match of a hybridization probe with its target and thereby allowing simultaneous detection of both alleles, provides an efficient tool for genotyping of the HPA systems. STUDY DESIGN AND METHODS: A total of 105 healthy blood donors were genotyped for HPA-1, -2, -3, -4, and -5 a/b and Gov a/b with new primers and probes designed for mutation detection by melting curve analysis (using LightCycler technology). Donor DNA was independently genotyped by an allele-specific assay, using SSPs, in a reference laboratory. RESULTS: There was full concordance between the two genotyping methods, and genotype frequencies were comparable with previous studies in caucasians. CONCLUSION: We present rapid and reliable detection systems for HPA-1, -2, -3, -4, and -5 a/b and Gov a/b based on mutation detection of both alleles simultaneously by melting curve analysis. As the Gov system has been reported to have similar frequency of involvement in alloimmune thrombocytopenia as HPA-5, the opportunity for genotyping should aid the diagnosis of such patients.     

The relationship among homocysteine, creatinine clearance, and albuminuria in patients with type 2 diabetes

OBJECTIVE: Although it is accepted that elevated plasma homocysteine (tHcy) levels occur in end-stage renal disease and type 2 diabetes, the changes with milder renal dysfunction (e.g., microalbuminuria) are less clearly established. This study explores the relationship among tHcy, creatinine clearance (Ccr), and albumin excretion rate (AER) in a population with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 260 patients with type 2 diabetes were screened in our outpatient clinic during 10 months. Fasting blood samples were collected, and AER was calculated from an overnight timed urine sample. Ccr was calculated using the Cockroft-Gault formula. RESULTS: A total of 198 subjects (76%) had normoalbuminuria (<20 microg/min), 50 subjects (19%) had microalbuminuria (20-200 microg/min), and 12 subjects (5%) had macroalbuminuria (>or=200 microg/min). Those with microalbuminuria had higher levels of tHcy than those with normoalbuminuria (13.2 +/- 7.8 vs. 11.3 +/- 4.6 micromol/l, P < 0.05). Patients were then subdivided based on low Ccr (<80 ml x min(-1) x 1.73 m(-2)) and normal Ccr (>or=80 x min(-1) x 1.73 m(-2)). None of the patients with macroalbuminuria had normal Ccr. In those with normoalbuminuria, tHcy levels were higher than in those with low Ccr than in those with normal Ccr (12.0 +/- 4.6 vs. 10.0 +/- 4.4 micromol/l, P < 0.01). The same was found for those with microalbuminuria (low Ccr versus normal Ccr: 14.6 +/- 9.0 vs. 10.2 +/- 2.8 micromol/l, P < 0.02). For normal Ccr, tHcy was similar irrespective of AER (normoalbuminuria versus microalbuminuria: 10.0 +/- 4.4 vs. 10.2 +/- 2.8 micromol/l, NS). For low Ccr, tHcy was higher in those with microalbuminuria versus normoalbuminuria (14.6 +/- 9.0 vs. 12.0 +/- 4.6 micromol/l, P = 0.01). Using multivariate regression, Ccr, but neither AER nor the presence of albuminuria, was an independent predictor of tHcy. CONCLUSIONS: These data strongly suggest that in patients with type 2 diabetes, the relationship between plasma tHcy and AER is largely due to associated changes in renal function, as defined by Ccr.     

The effect of age,sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity

BACKGROUND: The relative susceptibility of intestinal and hepatic cytochrome P450 (CYP) 3A to induction by rifampin (INN, rifampicin), as a function of age and sex, was investigated with the CYP3A substrate midazolam. METHODS: Fourteen young women (mean age, 26 +/- 4 years), 14 young men (mean age, 27 +/- 4 years), 14 elderly women (mean age, 72 +/- 5 years), and 10 elderly men (mean age, 70 +/- 4 years) received simultaneous intravenous doses (0.05 mg/kg over a 30-minute period) and oral doses of midazolam (3-8 mg of a stable isotope, (15)N(3)-midazolam) before and after 7 days of rifampin dosing (600 mg once daily in the evening). Serum and urine samples were assayed for midazolam, (15)N(3)-midazolam, and metabolites by liquid chromatography-mass spectrometry. RESULTS: No significant difference (P > or =.05) in the baseline systemic and oral clearance of midazolam was observed between male and female or young and old volunteers. Rifampin significantly (P <.0001) increased the systemic and oral clearance of midazolam from 0.44 +/- 0.2 L. h/kg and 1.56 +/- 0.8 L x h/kg to 0.96 +/- 0.3 L x h/kg and 34.4 +/- 21.2 L x h/kg, respectively. Likewise, the oral clearance of midazolam was significantly (P <.0001) increased in women and men, from 1.64 +/- 0.87 L x kg/h and 1.46 +/- 0.7 L x kg/h to 28.4 +/- 13.2 L x kg/h and 41.6 +/- 26.5 L x kg/h, respectively. A significant (P =.0023) effect of sex was noted in the extent of induction of the oral clearance of midazolam, being greater in men than in women. In contrast, the extent of midazolam systemic clearance induction was greater in women than in men (P =.0107). Age did not influence the extent of intestinal and hepatic CYP3A induction as determined by the oral and systemic clearance of midazolam. Rifampin dosing significantly (P <.0001) reduced the oral availability by 88%, from 0.32 +/- 0.13 to 0.04 +/- 0.02. Correspondingly, hepatic and intestinal availabilities were significantly (P <.0001) reduced after rifampin administration. After rifampin, the correlation coefficient for the relationship between oral availability and intestinal availability was significantly (P <.0001) reduced from 0.96 to 0.67, which reflects the increasing contribution of hepatic extraction to the determination of midazolam oral availability. A significant nonlinear inverse relationship was observed between the percent change in systemic clearance of midazolam and the initial baseline midazolam systemic clearance (r = -0.68, N = 52, P <.0001). Likewise, a significant inverse relationship was observed between the percent change in oral clearance and the baseline oral clearance (r = -0.39, N = 52, P =.0041). A significant inverse relationship between the ratio of hepatic intrinsic clearance in the presence of rifampin to that in the absence of rifampin and the corresponding ratio of intestinal intrinsic clearance was observed (Spearman correlation coefficient [r] = -0.68, P <.0001) and indicates that in a given individual the extent of induction was high at either the hepatic or the intestinal site but not both. CONCLUSION: Sex-related differences exist in the extent of intestinal and hepatic CYP3A induction by rifampin. The extent of induction at hepatic and intestinal sites was inversely dependent and reflected the independent regulation of CYP3A expression at these sites. The large interindividual variation in the extent of induction is explained in part by the variation in baseline expression of CYP3A. Sex-related differences in response to CYP3A inducers will be substrate-dependent and reflect the relative contribution of hepatic and intestinal sites of metabolism.     

Relationship of fasting and hourly blood glucose levels to HbA1c values: safety, accuracy, and improvements in glucose profiles obtained using a 7-day continuous glucose sensor

OBJECTIVE: In this study, we evaluated the safety and efficacy of 7-day transcutaneous, real-time, continuous glucose monitoring (CGM) in subjects with insulin-requiring diabetes. RESEARCH DESIGN AND METHODS: Eighty-six subjects were enrolled at five U.S. centers. Subjects wore a sensor inserted under the skin of the abdomen for 7 days during each of three consecutive periods. Data were blinded during period 1 and unblinded during periods 2 and 3. RESULTS: Of the 6,811 matched self-monitoring of blood glucose to sensor values prospectively analyzed, 97.2% fell in the Clarke error grid zones A and B, and median absolute relative difference was 11.4%. After unblinding, subjects reduced time spent at <55 mg/dl by 0.3 h/day, reduced time spent at >240 mg/dl by 1.5 h/day, and increased time in the target zone (81-140 mg/dl) by 1.4 h/day (P < 0.05 for all three comparisons). Improvements were seen in both types 1 and 2 diabetes and with use of both multiple daily injections and continuous subcutaneous insulin infusion. Modal day graphs were generated in six groups of subjects based on HbA1c (A1C) (10%). Mean glucose levels from midnight to 7:00 a.m. (fasting and dawn phenomenon periods) were only normal for subjects with A1C 相似文献