Fulminant type 1 diabetes: The clinical and continuous glucose monitoring characteristics in Chinese patients

The purpose of the current study was to investigate the clinical characteristics of fulminant type 1 diabetes mellitus (FT1DM) in Chinese patients and to further determine their glycaemic profiles through continuous glucose monitoring (CGM). Thirty subjects who were diagnosed with FT1DM according to the 2012 JDS criteria were enrolled. Clinical characteristics were compared to those reported in Japanese FT1DM. All subjects received retrospective CGM for 3 days after being converted to subcutaneous insulin injection therapy. Chinese FT1DM patients presented with a shorter duration of symptoms (2.84 ± 2.42 days vs 4.4 ± 3.1 days, P < 0.01), worse islet function (fasting C‐peptide, 0.09 ± 0.11 ng/mL vs 0.30 ± 0.21 ng/mL; 2‐hour C‐peptide, 0.13 ± 0.14 ng/mL vs 0.30 ± 0.30 ng/mL, both P < 0.01), lower prevalence of flu‐like symptoms (46.7% vs 71.4%, P < 0.05), and a significantly higher GADA positive rate (23.3% vs 5.1%, P < 0.01) when compared with Japanese patients. The CGM results showed that the mean time in range (TIR) of FT1DM patients was 49.8 ± 22.1%, while mean amplitude of glycaemic excursion (MAGE) and standard deviations of sensor glucose (SDSG) were 7.58 ± 3.59 mmol/L and 3.19 ± 1.22 mmol/L, respectively, with nearly 1/3 participants coefficient of variation (CV) > 36% (all are male), suggesting a large glucose fluctuation. The female patients were further divided into pregnancy‐related FT1DM (PF) and non‐PF (NPF) subgroups (both n = 5), and we found that PF patients had a significantly higher TIR than NPF patients (77.0 ± 16.1% vs 41.0 ± 22.4%, P < 0.05). There were heterogeneities in the clinical characteristics of FT1DM patients, and the CGM results indicated a very low TIR and large glucose fluctuation which needs careful attention.     

Effect of iloprost on biomarkers in patients with congenital heart disease‐pulmonary arterial hypertension

Some biomarkers play important roles in the endothelial dysfunction of patients with pulmonary arterial hypertension (PAH), including nitric oxide (NO), endothelin‐1 (ET‐1), asymmetric dimethylarginine (ADMA), galectin‐3 (Gal‐3), B‐type natriuretic peptide (BNP), and uric acid (UA). However, studies on these biomarkers in pulmonary artery blood in congenital heart disease‐PAH (CHD‐PAH) and the effect of iloprost on the regulation of biomarkers are lacking. This study investigated potential CHD‐PAH biomarkers and their association with the severity of disease. The effect of iloprost on the regulation of these biomarkers was also studied. A total of 31 patients with CHD‐PAH were enrolled. Seven with positive effects of iloprost (the average reduction in mPAP 11.13±1.73 mm Hg) and 19 with negative effects of iloprost (the average reduction in mPAP 4.21±4.87 mm Hg; iloprost positive group [IPG] vs iloprost negative group [ING], P<.01) and five age‐matched controls were studied. The pulmonary artery blood sample was collected before and after inhaling iloprost, and the plasma concentrations of Gal‐3, ADMA, ET‐1, and NO were measured. A significant positive linear relationship was observed between mPAP and plasma ET‐1, BNP, ADMA, and UA levels in all patients with CHD‐PAH. ET‐1, ADMA, BNP, and UA levels had a significant linear relationship with mean pulmonary arterial pressure, which could be used to predict the severity of CHD‐PAH. ET‐1 might be a potential biomarker to pre‐evaluate the effect of iloprost on CHD‐PAH. Iloprost could affect the expression of Gal‐3 and, therefore, the process of fibrosis could be influenced by iloprost.     

Role of mechanistic target of rapamycin (mTOR) in renal function and ischaemia–reperfusion induced kidney injury

Despite the presence of many studies on the role of mechanistic target of rapamycin (mTOR) in cardiorenal tissues, the definitive role of mTOR in the pathogenesis of renal injury subsequent to ischaemia–reperfusion (IR) remains unclear. The aims of the current study were to characterize the role of mTOR in normal kidney function and to investigate the role of mTOR activation in IR‐induced kidney injury. In euvolemic anaesthetized rats, treatment with the mTOR inhibitor rapamycin increased blood pressure (121 ± 2 to 144 ± 3 mmHg; P<.05), decreased glomerular filtration rate (GFR; 1.6 ± 0.3 to 0.5 ± 0.2 mL/min; P<.05) and increased urinary sodium excretion (UNaV; 14 ± 1 to 109 ± 25 mmol/L per hour; P<.05). In rats subjected to IR, autophagy induction, p‐mTOR expression and serum creatinine increased (1.9 ± 0.2 to 3 ± 0.3 mg/dL; P<.05); treatment with rapamycin blunted p‐mTOR expression but further increased autophagy induction and serum creatinine (3 ± 0.3 to 5 ± 0.6 mg/dL; P<.05). In contrast, clenbuterol, an mTOR activator, blunted the effect of rapamycin on serum creatinine (4 ± 0.6 vs 2.3 ± 0.3 mg/dL; P<.05), autophagy induction and p‐mTOR expression. IR also increased 24 hour protein excretion (9 ± 3 to 17 ± 2 mg/day; P<.05) and kidney injury molecule‐1 (KIM‐1) expression, and rapamycin treatment further increased KIM‐1 expression. Clenbuterol exacerbated protein excretion (13 ± 2 to 26 ± 4 mg/day; P<.05) and antagonized the effect of rapamycin on KIM‐1 expression. Histopathological data demonstrated kidney injury in IR rats that was worsened by rapamycin treatment but attenuated by clenbuterol treatment. Thus, mTOR signalling is crucial for normal kidney function and protecting the kidney against IR injury through autophagy suppression.     

Metformin prevents vascular prostanoid release alterations induced by a high‐fat diet in rats

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Analysis of cis and trans 3‐methylfentanyl by liquid chromatography–high resolution mass spectrometry and findings in forensic toxicology casework

3‐methylfentanyl (3‐MF), N‐(3‐methyl‐1‐phenethyl‐4‐piperidyl)‐N‐phenyl‐propanamide, has reappeared on the US illicit drug market since its disappearance after a series of overdose deaths in 1988. 3‐MF presents an analytical challenge, due to presence of cis and trans stereoisomers, each with different potencies, and ultimately very low concentrations in the blood after use. A method was developed using liquid chromatography–time‐of‐flight–mass spectrometry for the analysis of (±)‐cis‐3‐MF and (±)‐trans‐3‐MF in blood specimens after solid phase extraction. The linear dynamic range of this method was 0.1–10 ng/mL. Blood samples from 25 postmortem cases and 2 human performance case involving 3‐MF were submitted for quantitative analysis. The mean and median concentration for the (±)‐cis‐3‐MF were 0.84 ng/mL (±0.81) and 0.67 ng/mL, respectively, range 0.14–3.43 ng/mL. The resulting (±)‐trans‐3‐MF mean concentration was 0.46 ng/mL (±0.38) and the median concentration was 0.37 ng/mL with a range of 0.11–1.90 ng/mL. The resulting (±)‐cis‐3‐MF and (±)‐trans‐3‐MF concentrations were summed to give the total amount of 3‐MF present in the case with the resulting average concentration at 1.28 ng/mL (±1.16), median at 1.01 ng/mL and range 0.18–5.18. As the estimated dose of this compound is approximately 0.1 mg–0.5 mg with the resulting concentrations in the sub‐nanogram range, it is necessary for forensic toxicology laboratories to obtain instruments sensitive enough to detect these substances in driving under the influence of drugs and postmortem cases. Quantitation of 3‐MF with separation of (±)‐cis and (±)‐trans‐3‐MF provides additional detail for more specific toxicological interpretation.     

AUGMENTED EXERCISE PLASMA NORADRENALINE WITH IMPAIRED CHRONOTROPIC RESPONSIVENESS IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY*

1. There is controversy regarding plasma catecholamine levels in patients with hypertrophic cardiomyopathy (HCM) and few data exist on serial plasma catecholamine measurements during exercise. The present study determined whether cardiovascular and plasma catecholamine responses to exercise were altered in patients with HCM. 2. Plasma noradrenaline (NA) and adrenaline were measured at rest, at the end of each stage during exercise and immediately and 5 min after submaximal treadmill exercise in 15 patients with non-obstructive HCM (13 males, two females; mean (±SEM) age 54 ± 3 years) and in 15 age- and sex-matched controls. The ratio of the increment in heart rate (HR) divided by the increment in plasma NA during exercise (ΔHR/ΔNA) was used as an index of chronotropic sympathetic responsiveness to exercise. 3. Exercise duration was shorter (11.2 ± 0.6 vs 8.7 ± 0.6 min for control vs HCM, respectively; P<0.01) and diastolic blood pressure was significantly higher at stages I and II of modified Bruce protocol HCM. 4. Resting plasma NA levels (149 ± 17 vs 167 ± 28 pg/mL for control vs HCM, respectively; NS) were not different, but plasma NA levels at stages I and H were significantly higher in HCM than in controls (243 ± 26 vs 399 ± 69pg/mL (P<0.05) and 308 ± 30 vs 548 ± 110pg/mL (P<0.05), respectively). 5. Peak plasma NA levels were not significantly higher in HCM than in controls (578 ± 59 vs 918 ± 184 pg/mL, respectively; NS). 6. The ratio AHR/ANA was significantly lower in HCM compared with control at stages I and II (0.49 ± 0.10 vs 0.21 ± 0.05 (P<0.05) and 0.38 ± 0.06 vs 0.20 ± 0.05 (P < 0.05), respectively). There were no differences in plasma adrenaline responses during exercise between the two groups. 7. Patients with HCM had augmented plasma NA levels during submaximal exercise with a higher diastolic blood pressure response. Chronotropic sympathetic responsiveness was impaired during the early stages of exercise in patients with HCM.     

Fixed dose of long‐acting erythropoietic stimulating agents at higher frequency improves appetite,reduces inflammation and corrects anaemia in patients on haemodialysis

Anaemia is an important issue in patients undergoing haemodialysis. We aimed to identify a better dosing schedule of a fixed monthly dose of continuous erythropoietin receptor activator (CERA) in patients with chronic kidney disease (CKD) on haemodialysis. The CERA dosing schedule included 100 μg once monthly for 2 months, 50 μg twice monthly for 2 months and then 100 μg once monthly for two months. The effectiveness was determined by comparing haematocrit, nutritional status (serum protein and albumin) and inflammatory markers (tumour necrosis factor (TNF)‐α, interleukin (IL)‐1, IL‐6 and Hepcidin) at the beginning of the study with those at the end of the study. Forty‐seven out of 67 patients completed the trial. At the end, haematocrit was significantly higher (34.51 vs 33.22%, P=.004), levels of inflammatory markers were significantly lower (TNF‐α (30.71 vs 35.67 ng/mL, P=.007), IL‐6 (5.12 vs 7.95 ng/mL, P=.033), hepcidin (60.39 vs 74.39 ng/mL, P=.002)), blood glucose levels were significantly lower (112.40 vs 139.02 mg/dL, P=.003) and albumin was significantly higher (4.11 vs 3.98, P=.001). Patients with a better than average response had a lower initial number of red blood cells (3.3 vs 3.6 × 10⁶/mm³, P=.025) and a lower IL‐1 (3.8 vs 12.9 ng/mL, P=.01). They also had significantly lower blood glucose levels at the end. (91.3 vs 124.0 mg/dL, P=.03). We demonstrate that a fixed monthly dose of CERA at a twice monthly dosing schedule improves nutrition, reduces the inflammation and corrects anaemia in patients on haemodialysis. This finding may provide a new strategy for treating CKD‐related anaemia.     

The roles of a novel inflammatory neopterin in subjects with coronary atherosclerotic heart disease

Coronary atherosclerotic heart disease (CHD) is currently regarded as a chronic inflammatory disease. The inflammatory cytokine neopterin (NP) is a new predictor of the stable type of atherosclerotic plaque, and this study focused on the relationship between neopterin, Gensini score and high-sensitivity C-reactive protein (Hs-CRP) to explore the important role of neopterin in patients with CHD. This study enrolled 176 patients into the control group and 266 patients into the experimental group. The Gensini score was used to assess the severity of the coronary lesions, enzyme-linked immunosorbent assays (ELISAs) were used to measure the serum NP level, and other indicators were assessed using a fully automatic biochemical analyzer. The data were analyzed using SPSS19.0 statistical software.The serum NP level was higher in the experimental group than in the control group (132.23 ± 6.40 ng/mL vs. 40.95 ± 2.67 ng/mL, P < 0.001). Compared with the stable angina (SA) group, the serum NP level was significantly increased in the unstable angina (UA) group (135.99 ± 12.45 ng/mL) and the acute myocardial infarction (AMI) group (173.66 ± 13.59 ng/mL) (P < 0.05). In addition, the serum NP level was positively correlated with the Gensini score (r = 0.687, P < 0.001) as well as with the level of Hs-CRP (r = 0.190, P < 0.001).The serum level of NP was significantly higher in patients with CHD and was positively correlated with the severity of CHD. Thus, NP may become a new indicator for the assessment of the inflammatory response in coronary atherosclerosis.     

Elevated serum HMGB1 in pulmonary arterial hypertension secondary to congenital heart disease

AimsThis study investigated the potential value of serum high mobility group box-1 (HMGB1) level in the diagnosis, staging and treatment response of patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD).Methods and resultsThis was a single-center prospective study in 106 CHD patients. Serum HMGB1 levels were measured by enzymelinked immunosorbent assay. HMGB1 levels were significantly increased in patients with PAH compared to patients without PAH (P < 0.01) and healthy controls (P < 0.001). HMGB1 levels significantly correlated with pulmonary arterial pressure (P < 0.001) and pulmonary vascular resistance (PVR) (P < 0.001). In patients with severe PAH, HMGB1 levels were significantly higher in patients with Eisenmenger syndrome (ES) than in patients exhibiting low PVR (P < 0.001). Severe PAH and ES was identified by serum HMGB1 with a cutoff value of 13.62 ng/mL (P < 0.001) with a specificity of 82.8% and a sensitivity of 90%, and a cutoff value of 21.62 ng/mL (P = 0.001) with a specificity of 85.2% and a sensitivity of 64.3%, respectively. HMGB1 levels were significantly decreased after sildenafil therapy for 6 months (P < 0.01).ConclusionsOur study suggests that serum HMGB1 level may be used as a biomarker to identify PAH in CHD patients, assess pulmonary vascular remodeling, and evaluate the treatment response to sildenafil.     

Ergogenic properties of metformin in simulated high altitude

Metformin augments glucose/glycogen regulation and may acutely promote fatigue resistance during high‐intensity exercise. In hypobaric environments, such as high altitude, the important contribution of carbohydrates to physiological function is accentuated as glucose/glycogen dependence is increased. Because hypoxia/hypobaria decreases insulin sensitivity, replenishing skeletal muscle glycogen in high altitude becomes challenging and subsequent physical performance may be compromised. We hypothesized that in conditions where glycogen repletion was critical to physical outcomes, metformin would attenuate hypoxia‐mediated decrements in exercise performance. On three separate randomly ordered occasions, 13 healthy men performed glycogen‐depleting exercise and ingested a low‐carbohydrate dinner (1200 kcals, <10% carbohydrate). The next morning, in either normoxia or hypoxia (FiO₂=0.15), they ingested a high‐carbohydrate breakfast (1225 kcals, 70% carbohydrate). Placebo (719 mg maltodextrin) or metformin (500 mg BID) was consumed 3 days prior to each hypoxia visit. Subjects completed a 12.5 km cycle ergometer time trial 3.5 hours following breakfast. Hypoxia decreased resting and exercise oxyhemoglobin saturation (P<.001). Neither hypoxia nor metformin affected the glucose response to breakfast (P=.977), however, compared with placebo, metformin lowered insulin concentration in hypoxia 45 minutes after breakfast (64.1±6.6 μU/mL vs 48.5±7.8 μU/mL; mean±SE; P<.001). Post‐breakfast, pre‐exercise vastus lateralis glycogen content increased in normoxia (+33%: P=.025) and in hypoxia with metformin (+81%; P=.006), but not in hypoxia with placebo (+27%; P=.167). Hypoxia decreased time trial performance compared with normoxia (P<.01). This decrement was similar with placebo (+2.6±0.8 minutes) and metformin (+1.6±0.3 minutes). These results indicate that metformin promotes glycogen synthesis but not endurance exercise performance in healthy men exposed to simulated high altitude.     

Erythropoietic effects of low‐dose cobalt application

Cobaltous ions (Co²⁺) stabilize HIFα, increase endogenous erythropoietin (EPO) production, and may, therefore, be used as a performance‐enhancing substance. To date, the dosage necessary to stimulate erythropoiesis is unknown. The aim of this study was, therefore, to determine the minimum dosage necessary to increase erythropoietic processes. In a first double‐blind placebo‐controlled study (n = 5), single oral Co²⁺ dosages of 5 mg (n = 6) and 10 mg (n = 7) were administered to healthy young men. Cubital venous blood and urine samples were collected before and up to 24 hours after Co²⁺ administration. In a second study, the same daily Co²⁺ dosages were administered for five days (placebo: n = 5, 5 mg: n = 9, 10 mg: n = 7). Blood and urine samples were taken the day before administration and at day 3 and day 5. Plasma [EPO] was elevated by 20.5 ± 16.9% at 5 hours after the single 5‐mg administration (p < 0.05) and by 52.8 ± 23.5% up to 7 hours following the 10‐mg Co²⁺ administration (p < 0.001). Urine [Co²⁺] transiently increased, with maximum values 3–5 hours after Co²⁺ ingestion (5 mg: from 0.8 ± 1.1 to 153.6 ± 109.4 ng/mL, 10 mg: from 1.3 ± 1.7 to 338.0 ± 231,5 ng/mL). During the five days of Co²⁺ application, 5 mg showed a strong tendency to increase [EPO], while the 10‐mg application significantly increased [EPO] at day 5 by 27.2 ± 26.4% (p < 0.05) and the immature reticulocyte fraction by 49.9 ± 21.7% (p < 0.01). [Ferritin] was decreased by 12.4 ± 10.4 ng/mL (p < 0.05). An oral Co²⁺ dosage of 10 mg/day exerts clear erythropoietic effects, and 5 mg/day tended to increase plasma EPO concentration.     

Remote ischaemic preconditioning modifies serum apolipoprotein D,met‐enkephalin,adenosine, and nitric oxide in healthy young adults

Remote ischaemic preconditioning (RIPC) has been employed as a non‐invasive protective intervention against myocardial ischaemia–reperfusion injury in animal studies. However, the underlying mechanisms are incompletely defined in humans and its clinical efficacy has been inconclusive. As advanced age, disease, and drugs may confound RIPC mechanisms in patients, our aim is to measure whether RIPC evokes release of adenosine, bradykinin, met‐enkephalin, nitric oxide, and apolipoproteins in healthy young adults. Healthy subjects (n = 18, 9 males, 23 ± 1.5 years old; 9 females, 23 ± 1.8 years old) participated after informed consent. RIPC was applied using a blood pressure cuff to the dominant arms for four cycles of 5‐minute cuff inflation (ischaemia) and 5‐minute cuff deflation (reperfusion). Blood was sampled at baseline and immediately after the final cuff deflation (Post‐RIPC). Baseline and Post‐RIPC plasma levels of adenosine, bradykinin, met‐enkephalin, apolipoprotein A‐1 (ApoA‐1), apolipoprotein D (ApoD), and nitric oxide (as nitrite) were measured via ELISA and high‐performance liquid chromatography. Mean (±SD) baseline levels of adenosine, bradykinin, met‐enkephalin, ApoA‐1, ApoD, and nitrite in healthy young adults were 13.8 ± 6.5 ng/mL, 2.6 ± 1.9 μg/mL, 594.1 ± 197.4 pg/mL, 3.0 ± 0.7 mg/mL, 22.2 ± 4.0 μg/mL, and 49.8 ± 13.4 nmol/L, respectively. Post‐RIPC adenosine and nitrite levels increased (59.5 ± 37.9%, P < .0001; 32.2 ± 19.5%, P < .0001), whereas met‐enkephalin and ApoD levels marginally decreased (5.3 ± 14.0%, P = .04; 10.8 ± 20.5%, P = .04). Post‐RIPC levels were not influenced by sex, age, blood pressure, waist circumference, or BMI. RIPC produces increased levels of adenosine and nitrites, and decreased met‐enkephalin and ApoD in the plasma of young healthy adults.     

Clinical relevance of deferasirox trough levels in β‐thalassemia patients

We evaluated the role of deferasirox therapeutic drug monitoring in order to avoid toxicity or treatment failure. Plasma concentrations, measured between two consecutive liver iron determinations, were determined at the end of dosing interval. Fifty‐four β‐thalassemic adult patients were enrolled: 50% were males; median age was 32.3 years (IQR 19.1‐41.7 years) and median body mass index was 22.25 kg/m² (IQR 20.24‐23.75 kg/m²). The mean deferasirox dose was 28.6 ± 6.3 mg/kg/d and mean plasma concentration was 17.3 ± 16.8 μg/mL. Drug levels showed lower results in males. Deferasirox concentration was significantly correlated with serum creatinine levels (P = .01) and serum ferritin (P < .0001). The assessment of deferasirox therapeutic drug monitoring could help clinicians to predict patient responses and to optimize the therapy.     

Serum vitamin D levels are inversely related with non‐alcoholic fatty liver disease independent of visceral obesity in Chinese postmenopausal women

The aim of the present study was to investigate the association between serum vitamin D levels and both visceral adipose and with non‐alcoholic fatty liver disease (NAFLD) in Chinese postmenopausal women. Four hundred and fifty‐one postmenopausal women between 45 and 74 years of age (mean (± SD) age 57.3 ± 4.6 years) were enrolled in the study. All subjects participated in the Shanghai Obesity Study between June and August 2011 and underwent abdominal magnetic resonance imaging and an abdominal ultrasonography. Patients with a visceral fat area (VFA) ≥ 80 cm² were classified as abdominally obese. Serum 25‐hydroxyvitamin D₃ (25(OH)D₃) levels were measured with an electrochemiluminescence immunoassay. The prevalence of NAFLD in the study population was 34.8% (n = 157). Women with abdominal obesity had significantly lower serum 25(OH)D₃ levels than those without abdominal obesity (median (interquartile range) 11.23 (8.64–14.12) vs 12.56 (9.41–15.98) ng/mL, respectively; P < 0.01). Regardless of abdominal obesity status, serum 25(OH)D₃ levels in patients with NAFLD were lower than those without non‐NAFLD (11.14 (8.63–13.81) vs 12.92 (9.48–16.37) ng/mL (P < 0.05) for those without abdominal obesity; 10.86 (8.61–13.56) vs 11.55 (8.82–16.38) ng/mL (P < 0.05) for those with abdominal obesity). Partial correlation analyses demonstrated a negative correlation between serum 25(OH)D₃ levels and VFA (P < 0.05). Logistic regression analysis revealed that high serum 25(OH)D₃ levels were a protective factor against NAFLD after adjusting for risk factors such as VFA. In conclusion, independent of visceral obesity, vitamin D is inversely correlated with NAFLD in Chinese postmenopausal women.     

Additional role of serum 25‐hydroxyvitamin D3 levels in atherosclerosis in Chinese middle‐aged and elderly men

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Changes in urinary PGE<Subscript>2</Subscript> after ibuprofen treatment in preterm infants with patent ductus arteriosus

Purpose  To investigate changes in urinary PGE₂ after ibuprofen treatment in preterm infants with patent ductus arteriosus (PDA). Methods  Twenty preterm infants with a hemodynamically significant PDA (gestational age, 28.6 ± 2.3 weeks) and 20 controls (gestational age, 30.4 ± 1.5 weeks) were prospectively enrolled at 48–72 h of life. After enrollment, the former underwent conventional ibuprofen-lysine treatment. At 48–72 h (T₀) and 108–144 h of life (T₁), urine samples were noninvasively collected in both groups to measure urinary PGE₂ concentrations (enzyme immunoassay method), and renal function was investigated. Results  Urinary PGE₂ decreased significantly both in ibuprofen-treated patients (66.95 ± 16.78 vs. 27.15 ± 17.92 pg/mL, P < 0.001) and in controls (71.7 ± 16.2 vs. 53.2 ± 18.4 pg/mL, P < 0.001) from T₀ to T₁. However, urinary PGE₂ at T₁ was significantly lower (P < 0.001) in the ibuprofen group compared to the control group. Acute renal failure occurred in three ibuprofen-treated patients (15%). Conclusions  Ibuprofen markedly reduces (59.4%) urinary PGE₂ and may alter renal function in the newborn.     

Effect of genistein on the activities of cytochrome P450 3A and P-glycoprotein in Chinese healthy participants

1. To determine the effect of genistein on cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) function using the probe substrates midazolam and talinolol, respectively. Eighteen healthy adult male participants were enrolled in a two-phase randomized crossover design. In each phase, the participants received placebo or genistein for 14 days. On the 15th day, midazolam and talinolol were administered and blood samples were obtained. Midazolam and talinolol pharmacokinetic parameter values were calculated and compared before and after genistein administration.

2. Co-administration of genistein decreased the area under the concentration–time curve from 0 to 36?h (AUC 0-36) (143.65?±?55.40?ng h/mL versus 126.10?±?40.14?ng h/mL, p?<?0.05), and the area under the concentration–time curve from zero to infinity (AUC 0-∞) (209.18?±?56.61?ng h/mL versus 180.59?±?43.03?ng h/mL, p?<?0.05), and also maximum concentration (Cmax) of midazolam (48.86?±?20.21?ng/mL versus 36.25?±?14.35?ng/mL p?<?0.05). Similarly, AUC 0-36 (2490.282?±?668.79?ng h/mL versus 2114.46?±?861.11?ng h/mL, p?<?0.05), AUC 0-∞ (2980.45?±?921.09?ng h/mL versus 2626.92?±?1003.78?ng h/mL, p?<?0.05) and Cmax of talinolol (326.58?±?197.67?ng/mL versus 293.42?±?127.19?ng/mL, p?<?0.05) were reduced by genistein co-administration. The oral clearance of midazolam (1.68?±?0.85 h-1 versus 3.98?±?0.59 h-1, p?<?0.05) and talinolol (3.34?±?1.24 h-1 versus 3.79?±?1.55 h-1, p<0.05) were increased by genistien significantly.

3. Administration of genistein can result in a modest induction of CYP3A and possibly P-gp activity in healthy volunteers.

     

Immunosuppression with mycophenolate mofetil attenuates the development of hypertension and albuminuria in deoxycorticosterone acetate‐salt hypertensive rats

1. The interplay between the immune and renin–angiotensin systems is emerging as a crucial factor in the development and progression of hypertension. The aim of the present study was to determine the involvement of immune cells in the hypertension and renal injury produced by a non‐angiotensin II‐dependent form of hypertension, namely deoxycorticosterone acetate (DOCA)‐salt‐induced hypertension, in rats. 2. Male Sprague‐Dawley rats underwent uninephrectomy and received either a sustained‐release pellet of DOCA s.c. and 0.9% NaCl (saline) to drink for 21 days or a placebo pellet and water to drink for 21 days. Additional groups of DOCA‐salt‐ and placebo‐treated rats were treated concurrently with the immune suppressant mycophenolate mofetil (MMF; 30 mg/kg per day). Rats were placed in metabolic cages for 24 h urine collection prior to and at weekly intervals during the 21 day experimental period. 3. Mycophenolate mofetil significantly attenuated the development of hypertension in DOCA‐salt rats compared with untreated DOCA‐salt hypertensive rats (mean arterial pressure by telemetry on Day 18 146 ± 7 vs 180 ± 3 mmHg, respectively; P < 0.001), as well as proteinuria (87 ± 27 vs 305 ± 63 mg/day, respectively, on Day 21) and albuminuria (51 ± 15 vs 247 ± 73 mg/day, respectively, on Day 21). Creatinine clearance was better preserved in MMF‐treated DOCA‐salt rats compared with untreated DOCA‐salt rats (0.74 ± 0.07 vs 0.49 ± 0.09 mL/min, respectively; P < 0.05), but was still significantly reduced compared with that in the placebo group (1.15 ± 0.12 mL/min; P < 0.05). Finally, MMF treatment significantly attenuated the DOCA‐salt‐induced rise in renal cortical T‐lymphocyte and macrophage infiltration (P < 0.05). 4. These data indicate that immune cells play a deleterious role in both the hypertension and renal injury associated with DOCA‐salt hypertension.     

Effects of electroacupuncture on endothelial function and circulating endothelial progenitor cells in patients with cerebral infarction

This study evaluated the effects of electroacupuncture (EA) on endothelial function and endothelial progenitor cells (EPC) in patients with cerebral infarction. In a randomized, placebo‐controlled, crossover study, 20 patients with cerebral infarction were randomized into two treatment groups: EA or placebo. Before and after each intervention, pulse amplitude tonometry (PAT) was used to assess endothelial function and peripheral blood was analyzed for the number of EPCs. Circulating EPCs were quantified by flow cytometry as CD45^lowCD34⁺KDR2⁺ cells. Plasma vascular endothelial growth factor (VEGF) and interleukin (IL)‐10 levels were measured. Seven days later, crossover was performed on each group, with each group receiving the other treatment using the same protocol. The PAT hyperemia ratio ranged from 1.57 ± 0.41 to 2.04 ± 0.51 after EA, representing a significant improvement (P = 0.002); however, there was no improvement in the placebo group (P = 0.48). Circulating EPCs, as measured by flow cytometry, increased to 110.6 ± 74.3/100 μL in the EA group (P = 0.001) but did not change in the placebo group (45.9 ± 35.3/100 μL, P = 0.08). The increases in the number of EPCs and the PAT ratio after treatment were correlated (r = 0.78, P < 0.001). Plasma VEGF levels increased with EA compared to baseline (261.2 ± 34.0 vs 334.9 ± 80.5 pg/mL, P = 0.003). The number of circulating EPCs was positively correlated with plasma levels of VEGF (r = 0.50, P = 0.02). In conclusion, EA induced improvement of EPC levels and the PAT ratio in patients with cerebral infarction.     

Assessment of the link between endothelin K198n Snp,endothelin concentration and acute myocardial infarction in Egyptians

The aim of the current study was to assess the link between EDN K198N SNP, ET‐1 serum concentration and acute myocardial infarction (AMI) in Egyptians. The study cohort consisted of 84 patients at AMI onset and 84 age‐matched healthy controls. Endothelin genotypes and concentrations were determined by sequencing and ELISA, respectively. Genotype distribution was not significantly different between AMI patients and controls (P=.8341). The mean serum ET‐1 concentration of patients (13.83±0.7 pg/mL) was significantly higher than controls (7.26±0.2 pg/mL) (P<.0001). ET‐1 serum concentrations did not vary significantly among various EDN genotypes in patients (P=.378) and controls (P=.6164). Hence, we conclude that EDN K198N genotypes were not related to either ET‐1 concentration or incidence of early‐onset AMI in Egyptians. But, AMI patients had higher ET‐1 concentrations than controls.