Significance of white blood cell count and its subtypes in patients with acute coronary syndrome

Background Inflammation plays a role in the pathogenesis of coronary atherosclerosis. Materials and methods Six hundred twenty‐three patients with acute coronary syndrome (ACS) referred for coronary angiography for the first time in our hospital were enrolled in this study. White blood cell and its subtypes were measured on admission. The study population was divided into three groups based on total white blood cell count and followed up. Clinical end points were major adverse cardiac events (MACEs), including cardiogenic death, stroke, heart failure, non‐fatal myocardial infarction, rehospitalization for angina pectoris. Results The median age was 68 years (range 31–92) and 64·2% of the patients were men. The median white blood cell count was 6·48 × 10⁹ L⁻¹ (range 2·34–27·10 × 10⁹ L⁻¹). The median follow‐up duration was 21 months (range 1–116) and MACEs occurred in 167 patients. The multivariable Cox proportional hazards regression model revealed that neutrophil count [Relative risk = 1·098, 95% Confidence interval (CI): 1·010–1·193, P = 0·029) was a risk factor for MACEs. The logistic regression model revealed that lymphocyte count [Odds ratio (OR) = 1·075, 95% CI: 1·012–1·142, P = 0·018] and monocyte count (OR = 8·578, 95% CI: 2·687–27·381, P < 0·001) were predictive of stenosis ≥ 75%; Neutrophil proportion (OR = 1·060, 95% CI: 1·007–1·115, P = 0·026), monocyte count (OR = 12·370, 95% CI: 1·298–118·761, P = 0·029) were predictive of the presence of multivessel disease. Kaplan–Meier analysis of short‐term and long‐term cumulative survival showed no significant statistical differences among three groups. Conclusions Neutrophil count adds prognostic information to MACEs in ACS. Monocyte count and lymphocyte count are predictive of severity of coronary atherosclerosis.     

Head‐to‐head comparison between Actigraph 7164 and GT1M accelerometers in adolescents

We compared, head‐to‐head, the old generation Actigraph model 7164 with the new generation Actigraph GT1M accelerometer. A total of 15 randomly selected teenagers (eight girls and seven boys) were investigated. They performed a treadmill test wearing the two kinds of accelerometers around the waist simultaneously. The treadmill test consisted of three different levels of speed 4, 6 and 8 km h^?1 for four consecutive minutes. Accelerometer counts per 1 sec epoch for the Actigraph GT1M versus the Actigraph 7164 were at 4 km h^?1 21·6 ± 12·9 versus 26·5 ± 11·5 counts, at 6 km h^?1 56·0 ± 23·2 versus 62·9 ± 25·6 counts and at 8 km h^?1 142·6 ± 37·2 versus 156·4 ± 34·9 counts (P<0·01 for all levels of speed). Data from the old generation Actigraph 7164 and the new generation Actigraph GT1M accelerometers differ, where the Actigraph GT1M generates 10‐23% lower values. Correction equation for Actigraph GT1M was Actigraph 7164 = 5·2484 +  Actigraph GT1M counts × 1·0448. These results need to be taken into consideration when using these devices.     

Effects of walking with blood flow restriction on limb venous compliance in elderly subjects

Venous compliance declines with age and improves with chronic endurance exercise. KAATSU, an exercise combined with blood flow restriction (BFR), is a unique training method for promoting muscle hypertrophy and strength gains by using low‐intensity resistance exercises or walking. This method also induces pooling of venous blood in the legs. Therefore, we hypothesized that slow walking with BFR may affect limb venous compliance and examined the influence of 6 weeks of walking with BFR on venous compliance in older women. Sixteen women aged 59–78 years were partially randomized into either a slow walking with BFR group (n = 9, BFR walk group) or a non‐exercising control group (n = 7, control group). The BFR walk group performed 20‐min treadmill slow walking (67 m min^?1), 5 days per week for 6 weeks. Before (pre) and after (post) those 6 weeks, venous properties were assessed using strain gauge venous occlusion plethysmography. After 6 weeks, leg venous compliance increased significantly in the BFR walk group (pre: 0·0518 ± 0·0084, post: 0·0619 ± 0·0150 ml 100 ml^?1 mmHg^?1, P<0·05), and maximal venous outflow (MVO) at 80 mmHg also increased significantly after the BFR walk group trained for 6 weeks (pre: 55·3 ± 15·6, post: 67·1 ± 18·9 ml 100 ml^?1 min^?1, P<0·01), but no significant differences were observed in venous compliance and MVO in the control group. In addition, there was no significant change in arm compliance in the BFR walk group. In conclusion, this study provides the first evidence that 6 weeks of walking exercise with BFR may improve limb venous compliance in untrained elder female subjects.     

Effect of non-hypotensive haemorrhage on plasma catecholamine levels and cardiovascular variability in man

Background: It is well known from animal research that non‐hypotensive haemorrhage produces sympathoexcitatory responses assessable by both the rise in plasma catecholamine levels and the shift of autonomic influences on the heart to more sympathetic and less parasympathetic control. Data in humans are restricted. Methods: Heart rate variability (HRV), systolic blood pressure (FINAPRES) variability (BPV), and catecholamine plasma levels were measured before and after haemorrhage in 30 healthy blood donors and compared with those from 10 control subjects without blood loss. Spectral power of HRV and BPV in very low (0·02–0·06 Hz), low (0·07–0·14 Hz), and high (0·15–0·40 Hz) frequency bands were calculated by Fourier analysis. Catecholamine plasma levels were assayed by dual column reverse‐phased high‐performance liquid chromatography (HPLC). Results: Haemorrhage of 5·6 ± 1·2 ml kg^?1 body weight increased plasma norepinephrine levels (215 ± 92 pg ml^?1 versus 254 ± 95 pg ml^?1; P = 0·002), increased BPV in the low frequency band (Mayer waves; 1·8 ± 1·0 ln [mmHg²] versus 2·0 ± 0·9 ln [mmHg²]; P = 0·021), and decreased the vagally transmitted high frequency HRV (6·9 ± 1·1 ln [MI²] versus 6·5±1·2 ln [MI²]; P<0·0001), but did not induce significant changes in heart rate (66 ± 11 bpm versus 67 ± 11 bpm; P = 0·79) and arterial blood pressure (mean values: 84 ± 13 mmHg versus 87 ± 13 mmHg; P = 0·12). Conclusions: As suggested by plasma norepinephrine levels, systolic BPV and HRV, non‐hypotensive haemorrhage produces sympathoexcitatory responses as well as vagal withdrawal of heart rate control in humans.     

Lenograstim with or without dexamethasone for neutrophil mobilization in healthy donors: short-term kinetics of white blood cells and effects of granulocyte apheresis

Objectives : To determine the optimal time schedule for neutrophil collection after single mobilization with glycosylated recombinant granulocyte colony‐stimulating factor (G‐CSF, lenograstim) with or without dexamethasone (DXM). Donors and Methods : In this prospective randomized trial, 26 healthy volunteers were randomly assigned to a single subcutaneous dose of lenograstim 6 μg/kg plus 8‐mg DXM (G‐CSF/DXM, n = 13) or placebo (G‐CSF/placebo, n = 13). Hematological and biochemical parameters were analyzed before and 12, 15, 18, 21, 24, 27, 29, 36, 48, 60, 72, and 84 h and 7 and 30 days after mobilization. Six G‐CSF/DXM subjects underwent standard neutrophil apheresis (NA) 12 and 36 h after mobilization. Results : Polymorphonuclear neutrophil (PMN) counts 12 and 21 h after mobilization were 22.7 (16.6?32.8) × 10⁹/L and 22.4 (18.6?30.6) × 10⁹/L for G‐CSF/placebo versus 33.1 (24.2–44.9) × 10⁹/L and 32.5 (17.4–39.6) × 10⁹/L for G‐CSF/DXM. This mobilization plateau was followed by slow normalization at 72–84 h. The six NA subjects had median PMN yields of 62 (47–101) × 10⁹ and 39 (23–42) × 10⁹ per therapeutic unit. After the first apheresis, PMN counts sharply decreased to 21.1 (14.8–26.3) × 10⁹/L and then temporarily recovered to 25.9 (18.9–36.5) × 10⁹/L (P ≤ 0.001) over the next 8 h. Conclusions : Single doses of lenograstim with or without DXM induced a PMN plateau that lasted 9 h (12–21 h after mobilization), with PMN counts suitable for neutrophil collection. Lenograstim plus DXM made it possible to perform NA twice, 12 and 36 h after mobilization. © 2011 Wiley Periodicals, Inc.     

Cardiac sympathetic activity is associated with inflammation and neurohumoral activation in patients with idiopathic dilated cardiomyopathy

Background: Idiopathic dilated cardiomyopathy (IDC) is characterized by sympathetic nervous overactivity, inflammation and neurohumoral activation; however, their interrelationships are poorly understood. Methods and results: We studied 99 patients with IDC (age 54 ± 1 years, left ventricular ejection fraction (EF) 40 ± 1%, maximum oxygen uptake (VO₂max) 20 ± 1 ml kg^?1 min^?2, mean ± SEM) by using ¹²³I‐metaiodobenzylguanidine (MIBG) imaging. MIBG washout and MIBG heart/mediastinum (H/M)‐ratio at 4 h postinjection were calculated. In addition, the plasma levels of interleukin (IL)‐6 and N‐terminal B‐type natriuretic peptide (NT‐proBNP) were measured. MIBG washout and MIBG H/M ratio had a significant correlation with IL‐6 (r = 0·42, P<0·001 and r = ?0·31, P<0·01) and NT‐proBNP (r = 0·48, P<0·001 and r = ?0·40, P<0·001). During a median follow‐up of 4·1 years, 20 patients (20%) had an adverse cardiac event (death, heart transplantation or application of biventricular pacemaker or implantable cardioverter–defibrillator). In these patients, MIBG washout was higher (53 ± 4 versus 40 ± 2%, P = 0·01) and H/M ratio lower (1·38 ± 0·04 versus 1·51 ± 0·02, P = 0·01) than in patients without an event. Conclusions: In dilated cardiomyopathy, myocardial sympathetic innervation and activity are related to inflammation and neurohumoral activation. These relationships are at least partly independent of left ventricular function and exercise capacity.     

Vasoactive neuroendocrine responses associated with tolerance to lower body negative pressure in humans

The purpose of this investigation was to test the hypothesis that peripheral vasoconstriction and orthostatic tolerance are associated with increased circulating plasma concentrations of noradrenaline, vasopressin and renin–angiotensin. Sixteen men were categorized as having high (HT, n=9) or low (LT, n=7) tolerance to lower body negative pressure (LBNP) based on whether the endpoint of their pre‐syncopal‐limited LBNP (peak LBNP) exposure exceeded ?60 mmHg. The two groups were matched for age, height, weight, leg volume, blood volume and maximal oxygen uptake, as well as baseline blood volume and plasma concentrations of vasoactive hormones. Peak LBNP induced similar reductions in mean arterial pressure in both groups. The reduction in legarterial pulse volume (measured by impedance rheography), an index of peripheral vascular constriction, from baseline to peak LBNP was greater (P<0·05) in the HT group (?0·041 ± 0·005 ml 100 ml^?1) compared to the reduction in the LT group (?0·025 ± 0·003 ml 100 ml^?1). Greater peak LBNP in the HT group was associated with higher (P<0·05) average elevations in plasma concentrations of vasopressin (pVP, Δ=+7·2 ± 2·0 pg ml^?1) and plasma renin–angiotensin (PRA, Δ=+2·9 ± 1·3 ng Ang II ml^?1 h^?1) compared to average elevations of pVP (+2·2 ± 1·0 pg ml^?1) and PRA (+0·1 ± 0·1 ng Ang II ml^?1 h^?1) in the LT group. Plasma noradrenaline concentrations were increased (P<0·05) from baseline to peak LBNP in both HT and LT groups, with no statistically distinguishable difference between groups. These data suggest that the renin–angiotensin and vasopressin systems may contribute to sustaining arterial pressure and orthostatic tolerance by their vasoconstrictive actions.     

Peripheral blood stem cell mobilization in multiple myeloma patients treat in the novel therapy‐era with plerixafor and G‐CSF has superior efficacy but significantly higher costs compared to mobilization with low‐dose cyclophosphamide and G‐CSF

Studies comparing the efficacy and cost of peripheral blood stem and progenitor cells mobilization with low‐dose cyclophosphamide (LD‐CY) and granulocyte‐colony stimulating factor (G‐CSF) against plerixafor and G‐CSF, in multiple myeloma (MM) patients treated in the novel therapy‐era are not available. Herein, we report mobilization outcomes of 107 patients who underwent transplantation within 1‐year of starting induction chemotherapy with novel agents. Patients undergoing mobilization with LD‐CY (1.5 gm/m²) and G‐CSF (n = 74) were compared against patients receiving plerixafor and G‐CSF (n = 33). Compared to plerixafor, LD‐CY was associated with a significantly lower median peak peripheral blood CD34+ cell count (68/µL vs. 36/µL, P = 0.048), and lower CD34+ cell yield on day 1 of collection (6.9 × 10⁶/kg vs. 2.4 × 10⁶/kg, P = 0.001). Six patients (8.1%) in the LD‐CY group experienced mobilization failure, compared to none in the plerixafor group. The total CD34+ cell yield was significantly higher in the plerixafor group (median 11.6 × 10⁶/kg vs. 7 × 10⁶/kg; P‐value = 0.001). Mobilization with LD‐CY was associated with increased (albeit statistically non‐significant) episodes of febrile neutropenia (5.4% vs. 0%; P = 0.24), higher use of intravenous antibiotics (6.7% vs. 3%; P = 0.45), and need for hospitalizations (9.4% vs. 3%; P = 0.24). The average total cost of mobilization in the plerixafor group was significantly higher compared to the LD‐CY group ($28,980 vs. $19,626.5 P‐value < 0.0001). In conclusion, in MM plerixafor‐based mobilization has superior efficacy, but significantly higher mobilization costs compared to LD‐CY mobilization. Our data caution against the use of LD‐CY in MM patients for mobilization, especially after induction with lenalidomide‐containing regimens. J. Clin. Apheresis 28:359–367, 2013. © 2013 Wiley Periodicals, Inc.     

CD41+ and CD42+ hematopoietic progenitor cells may predict platelet engraftment after allogeneic peripheral blood stem cell transplantation

The objective of this study was to quantify subpopulations of CD34+ cells such as CD41+ and CD42+ cells that might represent megakaryocyte (MK) precursors in peripheral blood stem cell (PBSC) collections of normal, recombinant human granulocyte‐colony stimulating factor (rhG‐CSF) primed donors and to determine whether there is a statistical association between the dose infused megakaryocytic precursors and the time course of the platelet recovery following an allogeneic PBSC transplantation. Twenty‐six patients with various hematologic malignancies transplanted from their HLA identical siblings between July 1997 and December 1999 were used. All patients except one with severe aplastic anemia who had cyclophosphamide (CY) alone received busulfan‐CY as preparative regimen and cyclosporine‐methotrexate for GVHD prophylaxis. Normal healthy donors were given rhG‐CSF 10 μg/kg/day subcutaneously twice daily and PBSCs were collected on days 5 and 6. The median number of infused CD34+, CD41+ and CD42+ cells were 6.61 × 10⁶/kg (range 1.47–21.41), 54.85 × 10⁴/kg (5.38–204.19), and 49.86 × 10⁴/kg (6.82–430.10), respectively. Median days of ANC 0.5 × 10⁹/L and platelet 20 × 10⁹/L were 11.5 (range 9–15) and 13 (8–33), respectively. In this study, the number of CD41+ and CD42+ cells infused much better correlated than the number of CD34+ cells infused with the time to platelet recovery of 20 × 10⁹/L in 26 patients receiving an allogeneic match sibling PBSC transplantation (r = ?0.727 and P < 0.001 for CD41+ cells, r = ?0.806 and P < 0.001 for CD42+ cells, r = ?0.336 and P > 0.05 for CD34+ cells). There was an inverse correlation between the number of infused CD41+ and CD42+ cells and duration of platelet engraftment. Therefore, as the number of CD41+ and CD42+ cells increased, duration of platelet engraftment (time to reach platelet count of ≥ 20 × 10⁹/L) shortened significantly. Based on this data we may conclude that flow cytometric measurement of CD41+ and CD42+ progenitor cells may provide an accurate indication of platelet reconstitutive capacity of the allogeneic PBSC transplant. J. Clin. Apheresis. 16:67–73, 2001. © 2001 Wiley‐Liss, Inc.     

Persistence and compliance of deferoxamine versus deferasirox in Medicaid patients with sickle-cell disease

What is known and Objective: Patients with sickle‐cell disease (SCD) receiving chronic transfusions of red blood cells are at risk of developing serious adverse effects. Iron chelation therapy (ICT) helps eliminate iron overload by binding with plasma iron to form a non‐toxic conjugate that can be safely excreted from the body. Two iron chelating agents are currently available in the United States: Deferoxamine (DFO) is an injectable formulation, and deferasirox (Exjade^®) is an oral suspension. This study compared the frequency of hospitalizations, persistence and compliance of patients with SCD from Medicaid programmes treated with DFO vs. deferasirox. Methods: Health care claims from Medicaid Florida (1998–2007), Missouri (1993–2008) and New Jersey (1996–2008) were analysed. Patients with continuous enrolment for ≥6 months prior to ICT initiation and ≥1 SCD diagnosis were included in the analysis. Patients were divided into four cohorts: patients treated with DFO (any‐DFO group) and patients treated with deferasirox (any‐deferasirox group); the latter was further divided into patients initiated on DFO and then switched to deferasirox (deferasirox switchers), and patients treated with deferasirox‐only (deferasirox‐only group). Frequency of hospitalization for crisis conditions related to SCD as well as length of stay pre‐ and post‐ICT treatment initiation were assessed. Persistence was defined as time to drug discontinuation with ≥1 Rx gap, using Kaplan–Meier approach. Compliance was estimated using a medication possession ratio (MPR) based on the drug exposure approach. Adjusted analyses of persistence and compliance were also conducted. Results: A total of 217 (mean age: 19·4 years, 39·2 men), 275 (20·1 years, 41·5% men), 105 (19·4 years, 42·9% men) and 166 (20·4 years, 41·6% men) patients were included in the any‐DFO, any‐deferasirox, deferasirox switchers and deferasirox‐only groups, respectively. After ICT initiation, the any‐deferasirox and deferasirox‐only groups experienced a statistically significant reduction in the frequency of hospitalizations relative to pretreatment [any‐deferasirox: from 0·09 to 0·06 hospitalizations per patient per month (pmpm), P = 0·0105; deferasirox‐only: from 0·11 to 0·07 hospitalizations pmpm, P = 0·0188], whereas it remained stable in the any‐DFO group at 0·08 hospitalizations pmpm (P = 0·9483). The Kaplan–Meier rates of medication persistence assessed at 6 and 12 months of follow‐up were significantly lower for DFO patients (6 months: 0·34, 12 months: 0·21) as compared to all deferasirox (0·51, 0·29, P = 0·0002), deferasirox switchers (0·56, 0·37, P = 0·0002) and deferasirox‐only (0·47, 0·24, P = 0·0176) patients. Similarly, compliance to treatment was significantly lower for patients treated with DFO (mean MPR: 0·64) compared with any‐deferasirox (0·78, P < 0·0001), deferasirox switchers (0·75, P = 0·0002) and deferasirox‐only (0·80, P < 0·0001) patients. Adjusted analyses of persistence and compliance yielded similar results. What is new and Conclusions: Based on a Medicaid population, patients treated with deferasirox were more compliant and persistent with their treatment than those treated with DFO. Frequency of hospitalizations was significantly reduced after treatment initiation for the any‐deferasirox and deferasirox‐only groups. Prospective studies controlling for potential clinical and treatment pattern differences between deferasirox and DFO patients are needed to assess whether the decreased hospitalizations after initiation of deferasirox are related to better treatment compliance.     

The granulocytes in neutropenia 1 (GIN 1) study: a safety study of granulocytes collected from whole blood and stored in additive solution and plasma

Objective/Aim: To evaluate the safety of transfusing pooled, whole blood‐derived granulocytes in additive solution and plasma (GASP) in 30 recipients. Background: Demand for granulocytes in England has increased five‐fold. With the advantages of reduced red cell, plasma and overall volume, GASP maintains function in vitro. Methods and Materials: Observations were recorded prior to and post transfusion. Increments were recorded at 1 h and the following morning. Leucocyte antibody screening was undertaken prior to and at 1–6 months following transfusion. Results: Thirty patients aged between 8 months and 68 years received 221 GASP in 148 transfusion episodes. GASP contained an average of 1·0 ×10¹⁰ granulocytes in 207 mL. Adults usually received two packs and children 10–20 mL kg^–1. Children and adults received a median [interquartile range (IQR)] dose of 12·5 (9·1–25·3) and 19·7 (12·0–25·8) ×10⁹ granulocytes per transfusion, respectively. There was one episode of transfusion‐associated circulatory overload (TACO) in a patient with chronic cardiac failure following 600 mL of unpooled granulocytes, other fluids and one GASP. New l eucocyte alloimmunisation occurred in 3/30 recipients 10%. No other significant reactions were reported. Median peripheral blood neutrophil increments at 1 h post transfusion were 0·06 (IQR, 0·01–0·17) in children and (0·03) (IQR, 0–0·16) in adults. Conclusion: GASP has a similar safety profile to other sources of granulocytes for patients with refractory infection or in need of secondary prophylactic transfusion. Further studies are required to clarify the role of GASP in the treatment of neutropenic patients.     

Interventions to reduce vasovagal reactions in blood donors: a systematic review and meta‐analysis

Vasovagal reactions (VVRs) in blood donors have significant implications for the welfare of donors, donor retention and the management of donor sessions. We present a systematic review of interventions designed to prevent or reduce VVRs in blood donors. Electronic databases were searched for eligible randomised trials to March 2015. Data on study design and outcomes were extracted and pooled using random effects meta‐analyses. Sixteen trials met the inclusion criteria: five trials (12 042 participants) of pre‐donation water, eight trials (3500 participants) of applied muscle tension (AMT) and one trial each of AMT combined with water, caffeine, audio‐visual distraction and/or social support. In donors receiving pre‐donation water, the relative risk (RR) compared with controls for VVRs was 0·79 [95% confidence interval (CI) 0·70–0·89, P < 0·0001] and the mean difference (MD) in severity of VVRs measured with the Blood Donation Reactions Inventory (BDRI) score was ?0·32 (95% CI ?0·51 to ?0·12, P < 0·0001). Excluding trials with a high risk of selection bias, the RR for VVRs was 0·70 (95% CI 0·45–1·11, P = 0·13). In donors who received AMT, there was no difference in the risk of chair recline in response to donor distress from controls (RR 0·76, 95% CI 0·53–1·10, P = 0·15), although the MD in BDRI score was ?0·07 (95% CI ?0·11 to ?0·03, P = 0·0005). There was insufficient data to perform meta‐analysis for other interventions. Current evidence on interventions to prevent or reduce VVRs in blood donors is indeed limited and does not provide strong support for the administration of pre‐donation water or AMT during donation. Further large trials are required to reliably evaluate the effect of these and other interventions in the prevention of VVRs.     

Fresh blood for transfusion in adults with beta thalassaemia

Background: Patients with beta‐thalassaemia major require life‐long blood transfusion with the aim of achieving normal growth and development whilst minimising iron overload. A pre‐transfusion Hb between 9·5 and 10 g/dL is thought to achieve this balance. UK consensus is that fresh blood (less than 14 days) is better at maintaining this target pre‐transfusion Hb but there is no firm stipulation in place and no robust evidence supporting this. Methods: After introduction of a universal fresh blood policy for adult beta‐thalassaemics in 2010, we reviewed locally transfused adult patients to determine if there was any significant difference in pre‐transfusion Hb using fresh blood. Nine adult thalassaemic patients were analysed for two consecutive 6‐month periods in 2009 and 2010 (periods 1 and 2). Results: Mean pre‐transfusion Hb was significantly higher by an average of 0·5 g/dL in period 2 than period 1 (P < 0·05). The average unit age was 18 vs 9·5 days for periods 1 and 2 respectively (P < 0·05). There were no significant differences in potential confounders such as transfusion volume (P = 0·06), number of units transfused, ferritin or transfusion interval. Discussion: Use of fresh blood produced significantly higher pre‐transfusion Hb, giving credence to UK consensus. Lesser volumes of fresh blood appeared to achieve the target pre‐transfusion Hb, which may translate to reduced iron overload and chelation costs. Whether the assumption that the use of blood less than 7 days old in these patients would result in greater benefit requires further study.     

Population pharmacokinetics of high‐dose methotrexate in Japanese adult patients with malignancies: a concurrent analysis of the serum and urine concentration data

Objective: This study aimed to develop a population pharmacokinetic model for high‐dose methotrexate (MTX), specifically focusing on the drug urinary excretion process. Methods and results: Three hundred and forty‐eight serum samples and 416 urine samples from 51 Japanese adult patients with malignancies were concurrently fitted into a multi‐compartment model using the nonmem program. In the final model, creatinine clearance (CCR, mL/min) and the MTX dose (DOSE10G; 0 when <10 g, 1 when ≥10 g) were the most significant factors that affected the renal clearance (CL_r) and non‐renal clearance (CL_nr), respectively: CL_r(L/h) = 5·57 × (CCR/80·0)^0·112, V₁(L) = 26·9, Q(L/h) = 0·0778, V₂(L) = 2·27, CL_nr(L/h) = 0·567 × 3·39^DOSE10G, where V₁ and V₂ are the volumes of distribution of the central and peripheral compartments, respectively, and Q is the inter‐compartmental (central–peripheral) clearance. For another nine patients, the model enabled a satisfactory Bayesian estimation using two time‐point serum concentrations. Conclusion: The newly developed population pharmacokinetic model should improve the quality of serum concentration monitoring of high‐dose MTX to predict and control toxic events.     

Exhaled nitric oxide and its long‐term variation in healthy non‐smoking subjects

Exhaled nitric oxide (NOexp) is an indicator of inflammation in the airways. Reference values obtained from healthy adults or information on long‐term variation of NOexp are not yet available. The aims of this pilot study were to collect values of NOexp from a selected group of healthy adults and to assess their long‐term variation. We studied 26 healthy subjects (age 21–48, 16 male, 10 female) with normal findings in flow‐volume spirometry, pulmonary diffusing capacity, relative amount of blood eosinophils, chest X‐ray and ECG at rest. NOexp was determined according to the European Respiratory Society guidelines during slow expiration against an airflow resistance. The measurements were repeated after 7 (n=13) and 23 days (n=17). The mean value of NOexp (n=26) was 6·9 ng g^–1 (95% confidence interval, 6·0–7·9 ng g^–1). The upper limit of intra‐individual variation (+2 SD) was 11·9 ng g^–1 and the lower limit (–2 SD) 1·9 ng g^–1, respectively. The mean (SD) value of NO production (NO output) was 39·1 pmol s^–1 (20 pmol s^–1). We found no correlation between NOexp and age (r=–0·06, P=0·78) and no association of NOexp with the gender (male vs. female, P=0·40). The intraindividual coefficient of variation (CoV) was 15·8% of NOexp and 20·7% of NO output within the interval of 7 days. CoV was 16·8% of NOexp and 18% of NO output within the interval 23 days. The results suggest that NOexp values over 12 ng g^–1 are abnormally high in healthy subjects. According to the results the change of NOexp by 30–35% or more within the interval of 1–3 weeks would be abnormal.     

Visfatin expression in subcutaneous adipose tissue of pre-menopausal women: relation to hormones and weight reduction

Background A novel adipokine, visfatin, was found to be related to adiposity in humans and regulated by a number of hormonal signals. The aim of this study was to investigate the relationships of visfatin expression in adipose tissue with potential regulatory factors such as insulin, testosterone and tumor necrosis factor‐α (TNF‐α) and to elucidate the effect of a diet induced weight reduction on adipose tissue mRNA expression and plasma levels of visfatin. Materials and methods Biopsies of subcutaneous abdominal adipose tissue (SCAAT) and plasma samples were obtained at the beginning of the study from 47 pre‐menopausal women (age 38·7 ± 1·7 years, body mass index (BMI) 27·9 ± 1·4 kg m^?2), consisting of 15 lean, 16 overweight and 16 obese subjects. The subgroup of 32 overweight/obese women (age 42·1 ± 1·9 years, BMI 31·2 ± 0·9 kg m^?2) underwent a 12 week hypocaloric weight reducing diet and samples were obtained at the end of the diet. Biopsy samples were analysed for visfatin and TNF‐α mRNA levels and plasma was analysed for relevant metabolites and hormones. Results In the group of 47 subjects visfatin mRNA expression in SCAAT was negatively correlated with plasma free testosterone (r = –0. 363, P < 0·05) and BMI (r = –0·558, P < 0·01) and positively associated with adipose tissue TNF‐α mRNA expression (r = 0·688, P < 0·01). The diet resulted in the reduction of body weight and in the decrease of plasma insulin, free testosterone and TNF‐α levels. In the group of overweight/obese subjects visfatin mRNA in SCAAT increased after the diet and the diet induced increase was positively correlated with the magnitude of body weight loss. Conclusion Visfatin mRNA expression in SCAAT is associated with TNF‐α expression, plasma free testosterone and BMI in pre‐menopausal women. A weight reducing hypocaloric diet results in the increase of visfatin mRNA in SCAAT.     

Withdrawal of inhaled steroids in children with non‐cystic fibrosis bronchiectasis

Background: To study the effects of inhaled steroid withdrawal on bronchial hyperreactivity, sputum inflammatory markers and neutrophilic apoptosis in children with non‐cystic fibrosis (non‐CF) bronchiectasis. Objectives: To evaluate the role of inhaled steroids in the treatment of children with non‐CF bronchiectasis with specific emphasis on the bronchial hyperreactivity and neutrophilic apoptosis. Methods: Twenty‐seven children with steady‐state non‐CF bronchiectasis were evaluated primarily with metacholine challenge tests and apoptotic neutrophil ratios in induced sputum and secondarily with symptom scores, pulmonary function tests and tumour necrosis factor‐alpha (TNF‐α), interleukin‐8 (IL‐8) levels and neutrophil ratios in induced sputum before and after 12‐week withdrawal of inhaled steroids. Results: There were 16 girls and 11 boys. Median (interquartile range) age was 11·4 (9·5–13·6) years, follow‐up duration was 3·5 (2–6·5) years. Symptom scores (4 vs. 3; P = 0·27), oxygen saturation (95% vs. 97%; P = 0·06), pulmonary function tests (FEV1: 82% predicted vs. 83% predicted; P = 0·73), sputum neutrophil ratios (29·9% vs. 46·8%; P = 0·20), TNF‐α (58 pg/mL vs. 44·5 pg/mL; P = 0·55) and IL‐8 (2·7 ng/mL vs. 2·4 ng/mL; P = 0·82) levels in induced sputum were similar before and after 12‐week withdrawal of inhaled steroids. However, the number of patients with bronchial hyperreactivity increased (37% vs. 63% of patients; P = 0·016) and neutrophilic apoptosis in induced sputum decreased (42·8% vs. 20·2%; P = 0·03) after withdrawal. Conclusion: In this study, 12 week‐withdrawal of inhaled steroid treatment resulted in a significant increase in bronchial hyperreactivity and decrease in neutrophil apoptosis, but no change in sputum inflammatory markers in children with non‐CF bronchiectasis was observed.     

Circulatory response to single circuit weight and walking training sessions of similar energy cost in middle‐aged overweight females

The aim of this study was to compare circulatory responses to circuit weight (CWT) and aerobic walking training sessions of similar energy cost in middle‐aged overweight females. Thirty‐three middle‐aged pre‐menopausal females participated in the experiment. They were divided into overweight (n=18, 36·2 ± 6·3 years, 166·3 ± 8·0 cm, 83·5 ± 9·7 kg, BMI 30·2 ± 3·1 kg m^–2) and non‐overweight control (n=15, 34·1 ± 6·3 years, 165·0 ± 5·6 cm, 61·6 ± 5·0 kg, BMI 22·7 ± 1·5 kg m^–2) groups. Individual physical working capacity (PWC) was measured using the cycle ergometer test (calculated at the level of predicted HR_max (205 – ½ age). A CWT session consisted of leg extension, bench press, sit‐ups and leg press exercises. The subjects performed four circuits at the maximal possible speed, using a work‐to‐rest ratio of 60 s. Blood pressure (BP) was measured during every rest period between the exercises, and the heart rate (HR) was recorded continuously during the whole CWT programme. During the walking training session, the subjects walked as fast as possible on the indoor track. The total energy cost of the walking training session was the same as during the CWT session, approximately 270 kcal, and was controlled by a CALTRAC accelerometer. HR and BP were measured every 5 min during the walking training session. The PWC index was significantly (P<0·05) higher in the overweight group in comparison with the control females (215·4 ± 76·1 and 187·9 ± 42·4 W, respectively). The resting BP was normal in both groups (<140/90 mmHg). HR was between 120 and 140 beats min^–1 during CWT and walking sessions. There were no differences in BP during both training sessions in overweight and control subjects. It was concluded that both CWT and walking training sessions were acceptable forms of physical activity to increase cardiovascular fitness in middle‐aged overweight and normal body weight females.     

Reproducibility of orthostatic changes in cerebral oxygenation in healthy subjects aged 70 years or older

In the elderly, standing can frequently be accompanied by blood pressure (BP) changes and cerebral symptoms such as dizziness, fall, or even syncope, but this may vary from day‐to‐day. Therefore, we aimed to investigate the reproducibility of orthostatic responses of cerebral cortical oxygenation and systemic haemodynamics in elderly subjects. In 27 healthy elderly subjects (age 70–84 years), changes in systolic BP (SBP), diastolic BP (DBP), heart rate (HR) and stroke volume (SV) were continuously monitored by Finapres (Finger Arterial Pressure), and changes in oxyhaemoglobin ([O₂Hb]) and deoxyhaemoglobin ([HHb]) concentrations were continuously measured over the right frontal cortex by near infrared spectroscopy (NIRS) during supine rest and 10 min of active standing on two separate occasions. SBP and DBP increased by 6·7 ± 15·4 mmHg (P<0·05, mean ± SD) and 8·2 ± 6·4 mmHg (P<0·01), respectively, whereas HR increased by 9·5 ± 5·0 bpm (P<0·01) and SV decreased by –8·3 ± 7·4 ml (P<0·01) during standing on the first occasion. [O₂Hb] decreased by –3·9 ± 2·9 μmol l^–1 (P<0·01), while [HHb] increased by 1·8 ± 2·2 μmol l^–1 (P<0·01). Group‐averaged orthostatic changes in cortical oxygenation and systemic haemodynamics were very similar on the two occasions, although an intraindividual variation was found. Cortical oxygenation changes were not accompanied by severe cerebral symptoms. Active standing induced reproducible group‐averaged frontal cortical oxygenation declines in healthy elderly subjects, although an intraindividual day‐to‐day variability was present, possibly related to the variability of orthostatic BP responses. These findings indicate that cerebral autoregulation fails to compensate completely for postural changes in elderly subjects, which might predispose elderly subjects to ischaemic cerebral symptoms.     

N-acetylcysteine versus N-acetylcysteine + theophylline for the prevention of contrast nephropathy

Background The use of N‐acetylcysteine or theophylline in specific subgroups of patients has been suggested to reduce the incidence of contrast‐induced nephropathy (CIN) in patients undergoing angiographic procedures. Our purpose was to compare the use of N‐acetylcysteine versus N‐acetylcysteine + theophylline for the prevention of CIN. Materials and methods We randomized 217 patients with estimated glomerular filtration rate (eGFR) (calculated by Modification of Diet in Renal Disease formula) between 30 and 60 mL min^?1 1·73 m^?2 who were undergoing coronary angiography to three prophylactic treatment groups: Group 1: Intravenous hydration with isotonic saline (1 mL kg^?1 h^?1 for 12 h before and after contrast, n = 72). Group 2: Intravenous hydration with isotonic saline (1 mL kg^?1 h^?1 for 12 h before and after contrast)+ N‐acetylcysteine (600 mg p.o. twice daily the preceding day and the day of angiography, n = 73). Group 3: Intravenous hydration with isotonic saline (1 mL kg^?1 h^?1 for 12 h before and after contrast)+ N‐acetylcysteine + theophylline (600 mg N‐acetylcysteine p.o. and 200 mg theophylline p.o. twice daily for the preceding day and the day of angiography, n = 72). The incidence of CIN (0·5 mg dL^?1 increase in serum creatinine from the baseline value 48 h after intravascular injection of contrast) was compared in three groups. Results Of the 217 patients, 12 patients (5·5%) experienced CIN. Five patients (6·9%) in group 1, seven patients (9·6%) in group 2 and zero (0%) patients in group 3 experienced CIN (P < 0·033). Conclusion Among patients with eGFR between 30 and 60 mL min^?1 1·73 m^?2 undergoing coronary angiography, oral administration of N‐acetylcysteine + theophylline in addition to saline hydration has a beneficial effect in the prevention of CIN.