Uric acid and incident chronic kidney disease in dyslipidemic individuals

Background: Elevated uric acid (UA) is a recognized risk factor for chronic kidney disease (CKD). This study aimed to investigate whether this association exists in dyslipidemic patients receiving multifactorial treatment.

Methods: An observational study conducted in Greece including 1,269 dyslipidemic individuals followed-up in a lipid clinic for ≥3 years. Estimated glomerular filtration rate (eGFR) was calculated by CKD-EPI equation and CKD was defined as ≤60?mL/min/1.73 m². The correlation was assessed between UA levels and the CKD risk after adjusting for potential confounding factors, after defining the following UA quartiles: Q1: ?6?mg/dL.

Results: After excluding patients with baseline eGFR <60?mL/min/1.73 m², gout and those taking UA-lowering drugs, 1,095 individuals were eligible; of those, 91% and 69% were treated with statins and anti-hypertensive drugs, respectively. During their follow-up (6 years; IQR?=?4–10), 11.9% of the subjects developed CKD, whereas the median annual eGFR decline was 0.69?mL/min/1.73 m² (IQR?=?0.45–2.33). Multivariate analysis showed that baseline UA levels (HR?=?1.26; 95% CI?=?1.09–1.45, p?=?.001), female gender (HR?=?1.74; 95% CI?=?1.14–2.65, p?=?.01), age (HR?=?1.10; 95% CI?=?1.07–1.12, p?p?=?.03), cardiovascular disease (HR?=?1.62; 95% CI?=?1.02–2.58, p?=?.04), decreased baseline renal function (eGFR <90?mL/min/1.73 m²) (HR?=?2.38; 95% CI?=?1.14–4.81, p?=?.02), and low-density lipoprotein cholesterol reduction (HR?=?0.995; 95% CI?=?0.991–0.998, p?=?.01) were associated with incident CKD. Additionally, patients with UA ≥6?mg/dL exhibited a higher risk of incident CKD compared with those in the lowest UA quartile (HR?=?2.01; 95% CI?=?1.11–3.65, p?=?.02).

Conclusion: Higher UA levels are correlated with a higher risk of incident CKD in dyslipidemic individuals taking multifactorial treatment.     

Microvascular resistance in response to iodinated contrast media in normal and functionally impaired kidneys

Contrast‐induced nephropathy (CIN) is considered to result from intrarenal vasoconstriction, and occurs more frequently in impaired than in normal kidneys. It was hypothesized that iodinated contrast media would markedly change renal blood flow and vascular resistance in functionally impaired kidneys. Thirty‐six patients were enrolled (32 men; mean age, 75.3 ± 7.6 years) undergoing diagnostic coronary angiography and were divided into two groups based on the presence of chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min per 1.73 m² (CKD and non‐CKD groups, n = 18 in both). Average peak velocity (APV) and renal artery resistance index (RI) were measured by Doppler flow wire before and after administration of the iodinated contrast media. The APV and the RI were positively and inversely correlated with the eGFR at baseline, respectively (APV, R = 0.545, P = 0.001; RI, R = ?0.627, P < 0.001). Mean RI was significantly higher (P = 0.015) and APV was significantly lower (P = 0.026) in the CKD than in the non‐CKD group. Both APV (P < 0.001) and RI (P = 0.002) were significantly changed following contrast media administration in the non‐CKD group, but not in the CKD group (APV, P = 0.258; RI, P = 0.707). Although renal arterial resistance was higher in patients with CKD, it was not affected by contrast media administration, suggesting that patients with CKD could have an attenuated response to contrast media.     

口服碳酸氢钠对慢性肾病进程的影响

目的探讨口服碳酸氢钠能否延缓慢性肾病(chronic kidney disease,CKD)肾功能下降的速率。方法 110例CKD患者随机分为碳酸氢钠组或安慰剂组,分别口服碳酸氢钠或安慰剂治疗2年,估算治疗前后肾小球滤过率(eGFR)下降的速率,eGFR快速下降[>3 mL.min 1.(1.73 m)2.y 1]和发展成终末期肾病(ESRD)患者人数[eGFR<10 mL.min 1.(1.73 m)2]比。同时测量血清白蛋白和饮食蛋白摄入。结果治疗2年后,与安慰剂组相比,碳酸氢钠组eGFR下降较慢(P<0.05),快速进展的患者少(P<0.05),发展成ESRD的患者也少(P<0.05)。碳酸氢钠组营养参数明显改善。结论碳酸氢钠可延缓CKD发展成ESRD的速率,且可改善CKD患者的营养状态。     

Chitosan‐Fe (III) Complex as a Phosphate Chelator in Uraemic Rats: A Novel Treatment Option

Phosphate retention and hyperphosphataemia are associated with increased mortality in patients with chronic kidney disease (CKD). We tested the use of cross‐linked iron chitosan III (CH‐FeCl) as a potential phosphate chelator in rats with CKD. We evaluated 96 animals, divided equally into four groups (control, CKD, CH‐FeCl and CKD/CH‐FeCl), over 7 weeks. We induced CKD by feeding animals an adenine‐enriched diet (0.75% in the first 4 weeks and 0.1% in the following 3 weeks). We administered 30 mg/kg daily of the test polymer, by gavage, from the third week until the end of the study. All animals received a diet supplemented with 1% phosphorus. Uraemia was confirmed by the increase in serum creatinine in week 4 (36.24 ± 18.56 versus 144.98 ± 22.1 μmol/L; p = 0.0001) and week 7 (41.55 ± 22.1 versus 83.98 ± 18.56 μmol/L; p = 0.001) in CKD animals. Rats from the CKD group treated with CH‐FeCl had a 54.5% reduction in serum phosphate (6.10 ± 2.23 versus 2.78 ± 0.55 mmol/L) compared to a reduction of 25.6% in the untreated CKD group (4.75 ± 1.45 versus 3.52 ± 0.74 mmol/L, p = 0.021), between week 4 and week 7. At week 7, renal function in both CKD groups was similar (serum creatinine: 83.98 ± 18.56 versus 83.10 ± 23.87 μmol/L, p = 0.888); however, the CH‐FeCl‐treated rats had a reduction in phosphate overload measured by fractional phosphate excretion (FEPi) (0.71 ± 0.2 versus 0.4 ± 0.16, p = 0.006) compared to the untreated CKD group. Our study demonstrated that CH‐FeCl had an efficient chelating action on phosphate.     

Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

Acute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca²⁺ homeostasis, slows myocardial action potential conduction, and exerts pro‐arrhythmic effects. Loose patch‐clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na⁺ current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage‐dependent Na⁺ currents. Plots of peak current against depolarisation from resting potential gave pretreatment maximum atrial and ventricular currents of ?20.23 ± 1.48 (17) and ?29.8 ± 2.4 (10) pA/μm² (mean ± SEM [n]). Challenge by 8‐CPT (1 μmol/L) reduced these currents to ?11.21 ± 0.91 (12) (P < .004) and ?19.3 ± 1.6 (11) pA/μm² (P < .04) respectively. Currents following further addition of the RyR2 inhibitor dantrolene (10 μmol/L) (?19.91 ± 2.84 (13) and ?26.6 ± 1.7 (17)), and dantrolene whether alone (?19.53 ± 1.97 (8) and ?27.6 ± 1.9 (14)) or combined with 8‐CPT (?19.93 ± 2.59 (12) and ?29.9 ± 2.5(11)), were indistinguishable from pretreatment values (all P >> .05). Assessment of the inactivation that followed by applying subsequent steps to a fixed voltage 100 mV positive to resting potential gave concordant results. Half‐maximal inactivation voltages and steepness factors, and time constants for Na⁺ current recovery from inactivation in double‐pulse experiments, were similar through all the pharmacological conditions. Intracellular sharp microelectrode membrane potential recordings in intact Langendorff‐perfused preparations demonstrated concordant variations in maximum rates of atrial and ventricular action potential upstroke, (dV/dt)_max. We thus demonstrate an acute, reversible, Na⁺ channel inhibition offering a possible mechanism for previously reported pro‐arrhythmic slowing of AP propagation following modifications of Ca²⁺ homeostasis, complementing earlier findings from chronic alterations in Ca²⁺ homeostasis in genetically‐modified RyR2‐P2328S hearts.     

Pretreatment with clonidine caused desensitization to WIN 55,212‐2 in guinea pig ileum

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Cystatin C measurement leads to lower metformin dosage in elderly type 2 diabetic patients

The aim of this study was to provide evidence for the hypothesis that estimated glomerular filtration rate from serum Cystatin C (eGFRcys) is better to be determined for all elderly type 2 diabetes mellitus (T2DM) patients based on eGFRcys upward and downward reclassification rate for hypothetical metformin dose reduction by eGFRcys at the GFR decision point of 45 mL/min/1.73 m². A total of 265 consecutive T2DM elderly patients (age range 65‐91 years) from outpatient diabetic clinic were included in the study. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines for metformin dosing were strictly followed. Estimated glomerular filtration rate from serum creatinine (eGFRcrea) led to results of metformin eligibility. Each of the results of eGFRcrea‐based eligibility was further compared to eGFRcys‐based eligibility. Creatinine was measured by enzymatic method standardized against international reference material SRM 967. Cystatin C was determined by method traceable to DA ERM 471 international standard. eGFRcrea and eGFRcys were calculated according to Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equations. A downward reclassification rate was higher than upward reclassification rate (31 vs 3, respectively; P < 0.0001). The median (IQR) eGFRcrea was higher than eGFRcys (73 (58‐85) vs 63 (50‐75) mL/min/1.73 m², respectively; P < 0.0001). eGFRcys reclassified significant proportion of patients with T2DM from metformin eligible CKD stages to less or non‐eligible stages. The downward reclassification was more frequent in patients older than 80 years (P < 0.01). Cystatin C‐based eGFR selects more complicated patients, where lower doses of metformin are possibly advisable. We recommend calculating both eGFRcrea and eGFRcys for metformin dosing in elderly patients with T2DM.     

Early sex differences in central arterial wave reflection are mediated by different timing of forward and reflected pressure waves

Non‐invasive assessment of central arterial pulse wave augmentation has been proved to be useful in predicting cardiovascular adverse events. Previous studies have shown that pre‐pubescent girls had greater central augmentation pressure compared with height‐matched boys. This study sought to investigate which factors contribute to the body height‐independent sexual differences in central arterial wave reflection observed in childhood. This cross‐sectional study involved 819 children and adolescents (6‐18 years of age) of both sexes. Phenotypes of central haemodynamic were obtained by radial applanation tonometry. Heart rate corrected augmentation index (Aix@75) was greater in girls compared with boys (2.9 ± 10.7 vs ?1.7 ± 12.9%, P < .001) as well as the central augmented pressure (cAP; 1.3 ± 3.3 vs 0.1 ± 3.8 mm Hg, P < .001), even adjusting for age, heart rate and body height. Left ventricular ejection duration (ED) was longer (320 ± 26 vs 314 ± 24 ms, P = .004) and time to inflection point (Tr) was shorter in girls (139 ± 14 vs 141 ± 21 ms, P = .014). The reduction of Aix@75 with increasing body height was steeper in boys (?0.499 ± 0.030 vs ?0.428 ± 0.036%/cm, P < .001) as well as the reduction of cAP with increasing body height (?0.108 ± 0.010 vs ?0.066 ± 0.013 mm Hg/cm, P < .001). Body height‐independent sexual differences observed in the pulse wave reflection indices from early adolescence were mediated by different timing of forward and reflected pressure waves.     

REDUCED LUNG WATER TRANSPORT RATE ASSOCIATED WITH DOWNREGULATION OF AQUAPORIN-1 AND AQUAPORIN-5 IN AGED MICE

• 1 The purpose of the present study was to examine lung water transport properties and the expression and regulation of the alveolar endothelial water channel aquaporin (AQP)‐1 and the epithelial water channel AQP‐5 in aged mouse lung using gene expression analysis and water permeability measurements.
• 2 In aged (20–24‐month‐old) mice, AQP‐1 and AQP‐5 mRNA expression decreased by 55.5 and 50.3%, respectively, compared with that in young (8–10‐week‐old) mice (P < 0.01). In addition, AQP‐1 and AQP‐5 protein expression decreased in aged mice by 36.9 and 44.6%, respectively, compared with that in young mice (P < 0.01).
• 3 The osmotically driven water transport rate between the airspace and capillary compartments was reduced by 31.7% in aged mice compared with young mice (2.8 ± 0.3 vs 4.1 ± 0.3 mg/s, respectively; P < 0.01). The hydrostatically driven lung water accumulation rate in response to a 10 cmH₂O increase in pulmonary artery pressure was also reduced in aged mice by 21.9% compared with young mice (0.32 ± 0.06 vs 0.41 ± 0.04 mg/s, respectively; P < 0.01).
• 4 There was a 62.7% decrease in serum glucocorticoids in aged mice compared with young mice (67.6 ± 26.8 vs 181.3 ± 44.4 nmol/L, respectively; P < 0.01). In vivo administration of dexamethasone (4 mg/kg) for 5 consecutive days to aged mice increased lung AQP‐1 mRNA and protein expression by 2.1 ± 0.1 fold (P < 0.01) and 1.8 ± 0.2 fold (P < 0.01), respectively. Accordingly, osmotically and hydrostatically driven water transport rates increased by 35.6% (P < 0.01) and 31.2% (P < 0.01), respectively.
• 5 The present study provides the first evidence of altered lung water transport associated with downregulation of AQPs in aged lung. Blood glucocorticoid hormone levels are important to maintain normal AQP‐1 expression in the lung microvascular endothelium. Corticosteroid‐induced AQP‐1 upregulation may contribute to the role of corticosteroids in accelerating oedema clearance in aged lung.

     

The prevalence of anemia in patients with chronic kidney disease

SUMMARY

Objective: Anemia is a complication of chronic kidney disease and may contribute to adverse clinical outcomes. Early identification and treatment of anemia may improve cardiovascular morbidity and mortality. No large-scale population data are available specifically for patients with chronic kidney disease regarding prevalence of anemia, subpopulations at risk, and relationships between anemia and kidney function. This study was undertaken to address these questions in patients with chronic kidney disease, and investigate the relationship between anemia and glomerular filtration rate.

Research design and methods: Large-scale, cross-sectional, US multicenter survey; 5222 patients (mean age, 68.2?years; 46.6% male); 237 physician practices. Eligible patients: ≥ 18?years of age; serum creatinine: 1.5?mg/dL–6.0?mg/dL (females), 2.0?mg/dL–6.0?mg/dL (males).

Main outcome measures: Primary study end point: prevalence and severity of anemia (hemoglobin ≤ 12?g/dL). Data further stratified by hemoglobin (≤ 12?g/dL, ≤ 10?g/dL).

Results: Primary etiologies of chronic kidney disease (5222 evaluable patients): diabetes (49.5%); hypertension (33.0%). Glomerular filtration rate: < 60?mL/min/1.73?m² for 97.7% of evaluable patients. Mean ± SD serum creatinine level: 2.2?mg/dL ± 0.9?mg/dL; 2.5?mg/dL ± 1.0?mg/dL for males, 2.0?mg/dL ± 0.8?mg/dL for females. Mean ± SD hemoglobin: 12.2?g/dL ± 1.6?g/dL (47.7% had hemoglobin ≤ 12?g/dL; 8.9% had hemoglobin ≤ 10?g/dL). Prevalence of anemia was strongly associated with declining glomerular filtration rate. Percentage of patients with hemoglobin ≤ 12?g/dL increased from 26.7% to 75.5% when glomerular filtration rate decreased from ≥ 60?mL/min/1.73?m² to < 15?mL/min/1.73?m². Prevalence of hemoglobin ≤ 10?g/dL increased substantially from 5.2% to 27.2% when glomerular filtration rate diminished from ≥ 60?mL/min/1.73?m² to < 15?mL/min/1.73?m². After controlling for other patient characteristics associated with increased prevalence of anemia, the prevalence odds ratio for hemoglobin ≤ 10?g/dL was 0.54 (0.49–0.60) and for hemoglobin ≤ 12?g/dL was 0.68 (0.65–0.72), with each 10-mL/min/1.73?m² increase in glomerular filtration rate. Predictors of anemia: diabetes, female sex, and race/ethnicity.

Conclusions: Anemia was present in 47.7% of 5222 predialysis patients with chronic kidney disease. Prevalence of anemia increased as kidney function decreased. Certain subgroups are at increased risk for anemia.     

Discontinuation of Proton Pump Inhibitors in Patients With Chronic Kidney Disease

Purpose: Proton pump inhibitors (PPIs) are commonly used medications and are historically well tolerated. Recent studies have linked PPI use to the development of chronic kidney disease (CKD) and end-stage renal disease. This study investigated the impact of discontinuing PPIs on renal function in patients with CKD. Methods: We conducted a retrospective chart review of patients with established CKD, defined as 2 eGFR (estimated glomerular filtration rate) measurements of less than 60 mL/min/1.73 m² at least 90 days apart, who were on a PPI from January 1, 2014 to December 31, 2014, with a medication possession ratio greater than or equal to 70%. We compared baseline eGFR to a final eGFR after at least 6 months of discontinuation or continuation of a PPI. After power analysis, we targeted an enrollment of 200 patients (100 in each group) to achieve a power of 0.80 and an alpha of 0.05. Summary: A total of 97 patients in the PPI discontinuation group and 100 patients in the PPI continuation group met the study inclusion criteria. Baseline eGFR in the PPI continuation group was 47.9 mL/min/1.73 m² and 50.7 mL/min/1.73 m² in the discontinuation group. Final eGFR in the PPI continuation group was significantly higher than baseline at 51.1 mL/min/1.73 m² (+3.25 ± 12.8, P = .01). Final eGFR in the PPI discontinuation group was 51.8 mL/min/1.73 m² (+1.09 ± 12.8, P = .3). The average time between baseline and final eGFRs was 270 days in the PPI continuation group and 301 days in the discontinuation group. There was no statistically significant difference in the change in eGFRs between groups (95% confidence interval [CI] = −5.48-2.03, P = .37). Conclusions: Proton pump inhibitor discontinuation after prolonged continuous use in patients with CKD was not associated with a significant change in renal function after 1 year.     

Design,synthesis, and negative inotropic evaluation of 4‐phenyl‐1H‐1,2,4‐triazol‐5(4H)‐one derivatives containing triazole or piperazine moieties

In this study, four novel series of 4‐phenyl‐1H ‐1,2,4‐triazol‐5(4H )‐one derivatives containing triazole or piperazine moieties were designed, synthesized, and evaluated for negative inotropic activity by measuring the left atrium stroke volume in isolated rabbit heart preparations. Almost all of the compounds showed an ability to moderate the cardiac workload by decreasing the heart rate and contractility. Among them, 7h was found to be the most potent with a change in stroke volume of ?48.22 ± 0.36% at a concentration of 3 × 10^?5 mol/L (metoprolol: ?9.74 ± 0.14%). The cytotoxicity of these compounds was evaluated using the human cervical cancer cell line HeLa, the liver cancer cell line Hep3B, and the human normal hepatic cell line LO 2. A preliminary study of the mechanism of action for the compound 7h on the regulation of atrial dynamics with ATP ‐sensitive K⁺ channel and L‐type Ca²⁺ channel blockers glibenclamide and nifedipine was performed in the isolated perfused beating rabbit atria.     

Topical anaesthesia does not affect cutaneous vasomotor or sudomotor responses in human skin

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Effects of short-term addition of NSAID to diuretics and/or RAAS-inhibitors on blood pressure and renal function

Background The combined post-operative use of diuretics and/or renin-angiotensin-aldosterone system (RAAS) inhibitors may increase the risk of nonsteroidal anti-inflammatory drug (NSAID) associated renal failure because of a drug?Cdrug interaction. Objective The aim of this study was to investigate the effect of the short-term (<4 days) post-operative combined use of NSAIDs with diuretics and/or RAAS inhibitors on renal function and blood pressure. Setting One teaching hospital in the Netherlands. Method The study-design was a prospective, observational cohort-study. Based on postoperative treatment with NSAIDs, the intervention-group was compared to a control-group (no NSAIDs treatment). Main outcome measure Systolic blood pressure and renal function expressed by the estimated glomular filtration rate (eGFR) calculated with the modification of renal desease formula. Results 97 patients were included in the intervention-group, 53 patients in the control-group. Patient characteristics were comparable except for one variable: ??combined use of a diuretic with a RAAS inhibitor?? which was higher in the control-group (62 vs. 43?%, p?=?0.046). Odds ratio for clinically relevant increase in systolic blood pressure was 0.66 (CI95?% 0.3?C1.5). Odds ratio for clinical relevant decrease in renal function was 2.44 (CI95?% 1.1?C5.2). On day 4 eGFR of 3 patients in the intervention- and 1 in the control-group was <50?ml/min/1.73?m². Conclusion Odds ratios showed no significant difference of a clinically relevant increase in systolic blood pressure but showed a higher risk for a clinically relevant decrease in renal function in the intervention group. However this decrease resulted in a relevant impaired renal function (<50?ml/min/1.73?m²) in only 3 patients in the interventiongroup and 1 patient in the control-group. In the post-operative patient, without preexisting impaired renal function, concurrent diuretics and/or renin-angiotensinaldosterone system inhibitor therapy can be combined with short-term NSAID treatment.     

Epidemiology,clinical and economic outcomes of admission hyponatremia among hospitalized patients

ABSTRACT

Background: Hyponatremia, the most frequent electrolyte derangement identified among hospitalized patients, is associated with worsened outcomes in patients with pneumonia, heart failure and other disorders.

Research design and methods: We performed a retrospective cohort study of hospitalized patients to quantify the attributable influence of admission hyponatremia on hospital costs and outcomes. Data were derived from a large administrative database with laboratory components, representing 198,281 discharges from 39 US hospitals from January 2004 to December 2005. Hyponatremia was defined as admission serum [Na⁺]?<?135?mEq/L.

Results: The incidence of hyponatremia at admission was 5.5?%?(n?=?10,899). Patients with hyponatremia were older (65.7?±?19.6 vs. 61.5?±?21.8, p?<?0.001) and had a higher Deyo-Charlson Comorbidity Index score (1.8?±?2.1 vs. 1.3?±?1.8, p?<?0.001) than those with normal [Na⁺]. A higher proportion of hyponatremic patients required intensive care unit (ICU) (17.3?%?vs. 10.9?%?, p?<?0.001) and mechanical ventilation (MV) (5.0?%?vs. 2.8?%?, p?<?0.001) within 48?hours of hospitalization. Hospital mortality (5.9?%?vs. 3.0?%?, p?<?0.001), mean length of stay (HLOS, 8.6?±?8.0 vs. 7.2?±?8.2 days, p?<?0.001) and costs ($16,502?±?$28,984 vs. $13,558?±?$24,640, p?<?0.001) were significantly greater among patients with hyponatremia than those without. After adjusting for confounders, hyponatremia was independently associated with an increased need for ICU (OR 1.64, 95?%?CI 1.56–1.73) and MV (OR 1.68, 95?%?CI 1.53–1.84), and higher hospital mortality (OR 1.55, 95?%?CI 1.42–1.69). Hyponatremia also contributed an increase in HLOS of 1.0 day and total hospital costs of $2,289.

Conclusions: Hyponatremia is common at admission among hospitalized patients and is independently associated with a 55?%?increase in the risk of death, substantial hospital resource utilization and costs. Potential for bias inherent in the retrospective cohort design is the main limitation of our study. Studies are warranted to explore how prompt normalization of [Na⁺] may impact these outcomes.     

ROLE OF EXTRACELLULAR Na+, Ca2+-ACTIVATED Cl- CHANNELS AND BK CHANNELS IN THE CONTRACTION OF Ca2+ STORE-DEPLETED TRACHEAL SMOOTH MUSCLE

• 1 In the present study, we investigated the series of events involved in the contraction of tracheal smooth muscle induced by the re‐addition of Ca²⁺ in an in vitro experimental model in which Ca²⁺ stores had been depleted and their refilling had been blocked by thapsigargin.
• 2 Mean (±SEM) contraction was diminished by: (i) inhibitors of store‐operated calcium channels (SOCC), namely 100  µ mol/L SKF‐96365 and 100  µ mol/L 1‐(2‐trifluoromethylphenyl) imidazole (to 66.3 ± 4.4 and 41.3 ± 5.2% of control, respectively); (ii) inhibitors of voltage‐gated Ca²⁺ channels Ca_V1.2 channels, namely 1  µ mol/L nifedipine and 10  µ mol/L verapamil (to 86.2 ± 3.4 and 76.9 ± 5.9% of control, respectively); and (iii) 20  µ mol/L niflumic acid, a non‐selective inhibitor of Ca²⁺‐dependent Cl^? channels (to 41.1 ± 9.8% of control). In contrast, contraction was increased 2.3‐fold by 100 nmol/L iberiotoxin, a blocker of the large‐conductance Ca²⁺‐activated K⁺ (BK) channels.
• 3 Furthermore, contraction was significantly inhibited when Na⁺ in the bathing solution was replaced by N‐methyl–d ‐glucamine (NMDG⁺) to 39.9 ± 7.2% of control, but not when it was replaced by Li⁺ (114.5 ± 24.4% of control). In addition, when Na⁺ had been replaced by NMDG⁺, contractions were further inhibited by both nifedipine and niflumic acid (to 3.0 ± 1.8 and 24.4 ± 8.1% of control, respectively). Nifedipine also reduced contractions when Na⁺ had been replaced by Li⁺ (to 10.7 ± 3.4% to control), the niflumic acid had no effect (116.0 ± 4.5% of control).
• 4 In conclusion, the data of the present study demonstrate the roles of SOCC, BK channels and Ca_V1.2 channels in the contractions induced by the re‐addition of Ca²⁺ to the solution bathing guinea‐pig tracheal rings under conditions of Ca²⁺‐depleted sacroplasmic reticulum and inhibition of sarcoplasmic/endoplasmic reticulum calcium ATPase. The contractions were highly dependent on extracellular Na⁺, suggesting a role for SOCC in mediating the Na⁺ influx.

     

Comparison of lenograstim and filgrastim on haematological effects after autologous peripheral blood stem cell transplantation with high-dose chemotherapy

SUMMARY

Objective: To compare the efficacy of lenograstim and filgrastim on haematological recovery following an autologous peripheral blood stem cell transplantation (PBSCT) with high-dose chemotherapy.

Methods: A retrospective case-controlled study.

Results: Absolute neutrophil count (ANC) recovery above 0.5?×?10⁹?l^?1 and white blood cell (WBC) recovery above 4?×?10⁹?l^?1 for 3 consecutive days was achieved earlier with filgrastim than with lenograstim ((13.2?±?8.0 vs 19.0?±?10.0 days, p?=?0.004), (16.9?±?9.7 vs 29.9?±?16.6 days, p?=?0.001), respectively). The platelet recovery above 20 x 10⁹/l was also achieved earlier with filgrastim than with lenograstim (19.5?±?11.6 vs

27.2?±?13.8 days, p?=?0.006). Furthermore, filgrastim-treated patients received fewer days of granulocyte colony simulating factor (G-CSF) administration (12.5?±?7.0 vs 18.6?±?8.5 days, p?=?0.001) and spent less time in hospital (23.7?±?10.9 vs 32.0?±?17.6 days, p?=?0.009). Duration of antibiotic administration was also significantly shorter in the filgrastim group (13.6?±?7.6 vs 29.1?±?19.8 days, p?=?0.001). Conclusion: In patients undergoing PBSCT following high-dose chemotherapy, filgrastim significantly reduced the duration of neutropenia, thrombocytopenia and days of G-CSF administration, and led to earlier hospital discharge compared with lenograstim.     

Cytogenetic analysis of micronuclei and cell death parameters in epithelial cells of pesticide exposed tea garden workers

Buccal micronucleus cytome assay was carried out in 47 exposed (sprayers and leaf harvesters), 47 non-exposed (controls) to determine the extent of damage working in the tea plantations of Terai region of West Bengal, India. As the pesticide exposed male workers were found to consume alcohol and smoked cigarettes/bidis, 35 smokers and 30 alcoholics were also included for comparison. Results showed a significant difference in micronuclei (9.91?±?2.74, p?≤?.001), nuclear bud (4.98?±?1.31, p?≤?.001), binucleate (6.26?±?2.84, p?≤?.001), karyorrhectic (8.36?±?2.28, p?≤?.001), pyknotic (5.62?±?1.78, p?≤?.05) as well as karyolytic (6.81?±?3.00, p?≤?.001) nuclei compared with control. Comparison also revealed a higher frequency of micronuclei (6.11?±?2.55, p?≤?.01), nuclear bud (4.06?±?1.97, p?≤?.05), binucleate (4.34?±?1.85, p?≤?.001), karyorrhectic (6.83?±?2.12, p?≤?.001), and karyolytic (6.20?±?2.54, p?≤?.001) nuclei except pyknotic cell in the smoker than control. Frequency of binucleate (3.80?±?1.73, p?≤?.05), karyorrhectic (5.57?±?2.34, p?≤?.05), pyknotic (5.50?±?1.36, p?≤?.05), and karyolytic (6.30?±?2.71, p?≤?.001) nuclei was higher in the alcoholics than control (non-alcoholics), whereas the micronuclei and nuclear bud were found to be non-significant compared with the control. Our analyses also revealed a higher proportion of the micronucleus and the cell death parameters in the pesticide exposed males than females, which indicated that pesticide, smoking, and alcohol may act synergistically to cause more damage to the buccal epithelial cells. However, age and the exposure duration have no influence on the micronucleus and other cell death parameters.     

Unravelling the cardiovascular effects induced by α‐terpineol: A role for the nitric oxide–cGMP pathway

1. α‐Terpineol is a monoterpene found in the essential oils of several aromatic plant species. In the present study, we investigated the mechanisms underlying the cardiovascular changes induced by α‐terpineol in rats. 2. In normotensive rats, administration of α‐terpineol (1, 5, 10, 20 and 30 mg/kg, i.v.) produced a dose‐dependent hypotension (?10 ± 3, ?20 ± 8, ?39 ± 16, ?52 ± 21 and ?57 ± 23 mmHg, respectively; n = 5) followed by tachycardia. The hypotensive responses to 1, 5, 10, 20 and 30 mg/kg, i.v., α‐terpineol were significantly attenuated following the administration of N^G‐nitro‐l‐ arginine methyl ester (l ‐NAME; 20 mg/kg, i.v.; ?2 ± 1, ?5 ± 2, ?7 ± 3, ?22 ± 9 and ?22 ± 10 mmHg, respectively; P < 0.05; n = 5). 3. In 10 μmol/L phenylephrine (PE)‐precontracted mesenteric artery rings, α‐terpineol (10^?12 to 10^?5 mol/L) caused a concentration‐dependent relaxation (maximum relaxation 61 ± 6%; n = 7). After removal of the endothelium, the vasorelaxation elicited by α‐terpineol was attenuated (maximum relaxation 20 ± 1%; P < 0.05; n = 7). In addition, vasorelaxation induced by α‐terpineol in rings pretreated with 100 or 300 μmol/L l ‐NAME, 30 μmol/L hydroxocobalamin or 10 μmol/L 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one was attenuated (maximum relaxation 18 ± 3, 23 ± 3, 24 ± 7 and 21 ± 1%, respectively; n = 6; P < 0.05). 4. Furthermore, in a rabbit aortic endothelial cell line, 10^?6, 10^?5 and 10^?4 mol/L α‐terpineol induced concentration‐dependent increases in nitric oxide (NO) levels (12 ± 6, 18 ± 9 and 34 ± 12%Δ fluorescence, respectively; n = 3). 5. In conclusion, using combined functional and biochemical approaches in the present study, we were able to demonstrate that α‐terpineol‐induced hypotension and vasorelaxation are mediated, at least in part, by the endothelium, most likely via NO release and activation of the NO–cGMP pathway.