Idle central venous catheter-days pose infection risk for patients after discharge from intensive care

This prospective observational study measured idle central venous catheter (CVC)-days (no medical indication), and ward clinicians' adherence to evidence-based practices for preventing short-term central line-associated bloodstream infections (CLABSIs). In 340 patients discharged from ICU over a 1-year period, 208 of 794 CVC-days (26.2%) were idle. Interventions to prevent CLABSIs were poorly implemented. Ward clinicians need education regarding risk management strategies to prevent CLABSIs, and clear accountability processes for prompt catheter removal are recommended.

The PREPARE pilot RCT of home-based progressive resistance exercises for venous leg ulcers

OBJECTIVE: To establish the feasibility of conducting a home-based progressive resistance exercise programme to improve calf muscle pump function in community-based patients with venous leg ulcers. METHOD: Participants were randomised to receive a 12-week progressive resistance exercise programme using heel raises in addition to compression. The control was usual care in addition to compression. Randomisation was stratified by ulcer duration and ulcer size. Air plethysmography was used to determine changes in calf muscle pump function from baseline. Changes in ulcer parameters were measured using the SilhouetteMobile device. RESULTS: Forty participants were randomised. There were significantly greater improvements in ejection fraction of the calf muscle in the exercise group compared with the control (usual care) group (mean difference 18.5%, 95% CI 0.03 to 36.6%, p<0.05). Other parameters improved in the exercise group but the mean differences were not significant. Adherence with prescribed exercises was 81% and there was no significant difference in the numbers reporting adverse events. There were also no significant differences in ulcer healing parameters (change in area, percentage change in area, number healed at 12 weeks, time to healing). CONCLUSION: A community-based randomised trial of progressive resistance exercise is feasible. The prescribed exercises appeared to increase ejection fraction, but the effect of exercise on ulcer healing requires further investigation.

Role of the ATP-binding cassette drug transporters in the intestinal absorption of tanshinone IIB, one of the major active diterpenoids from the root of Salvia miltiorrhiza

There is an increasing use of herbal medicines worldwide, and the extracts from the root of Salvia miltiorrhiza are widely used in the treatment of angina and stroke. In this study, we investigated the mechanism for the intestinal absorption of tanshinone IIB (TSB), a major constituent of S. miltiorrhiza. The oral bioavailability of TSB was about 3% in rats with less proportional increase in its maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) with increasing dosage. The time to C_max (T_max) was prolonged at higher oral dosage. In a single pass rat intestinal perfusion model, the permeability coefficients (P_app) based on TSB disappearance from the lumen (P_lumen) were 6.2- to 7.2-fold higher (p < 0.01) than those based on drug appearance in mesenteric venous blood (P_blood). The uptake and efflux of TSB in Caco-2 cells were also significantly altered in the presence of an inhibitor for P-glycoprotein (PgP) or for multi-drug resistance associated protein (MRP1/2). TSB transport from the apical (AP) to basolateral (BL) side in Caco-2 monolayers was 3.3- to 5.7-fold lower than that from BL to AP side, but this polarized transport was attenuated by co-incubation of PgP or MRP1/2 inhibitors. The P_app values of TSB in the BL-AP direction were significantly higher in MDCKII cells over-expressing MDR1 or MRP1, but not in cells over-expressing MRP2-5, as compared with the wild-type cells. The plasma AUC_0-24hr in mdr1a and mrp1 gene-deficient mice was 10.2- to 1.7-fold higher than that in the wild-type mice. Furthermore, TSB significantly inhibited the uptake of digoxin and vinblastine in membrane vesicles containing PgP or MRP1. TSB also moderately stimulated PgP ATPase activity. Taken collectively, our findings indicate that TSB is a substrate for PgP and MRP1 and that drug resistance to TSB therapy and drug interactions may occur through PgP and MRP1 modulation.

Effects of dietary fat and conjugated linoleic acid on plasma metabolite concentrations and metabolic responses to homeostatic signals in pigs

Sixteen female cross-bred (Large White × Landrace) pigs (initial weight 65 kg) with venous catheters were randomly allocated to four treatment groups in a 2×2 factorial design. The respective factors were dietary fat (25 or 100 g/kg) and dietary conjugated linoleic acid (CLA; 0 or 10 g CLA-55/kg). Pigs were fed every 3 h (close to ad libitum digestible energy intake) for 8 d and were bled frequently. Plasma glucose and non-esterified fatty acid (NEFA) responses to insulin and adrenaline challenges were determined on day 8. Plasma concentrations of NEFA were significantly increased (10·5 and 5·4 % for low- and high-fat diets respectively, P=0·015) throughout the experiment, suggesting that there was a possible increase in fat mobilisation. The increase in lipolysis, an indicator of ß-adrenergic stimulated lipolysis, was also evident in the NEFA response to adrenaline. However, the increase in plasma triacylglycerol (11·0 and 7·1 % for low- and high-fat diets respectively, P=0·008) indicated that CLA could have reduced fat accretion via decreased adipose tissue triacylglycerol synthesis from preformed fatty acids, possibly through reduced lipoprotein lipase activity. Plasma glucose, the primary substrate for de novo lipid synthesis, and plasma insulin levels were unaffected by dietary CLA suggesting that de novo lipid synthesis was largely unaffected (P=0·24 and P=0·30 respectively). In addition, the dietary CLA had no effect upon the ability of insulin to stimulate glucose removal.

Effect of sodium bicarbonate on muscle metabolism during intense endurance cycling

Introduction: Sodium bicarbonate (NaHCO₃) ingestion has been shown to increase both muscle glycogenolysis and glycolysis during brief submaximal exercise. These changes may be detrimental to performance during more prolonged, exhaustive exercise. This study examined the effect of NaHCO₃ ingestion on muscle metabolism and performance during intense endurance exercise of ~60 min in seven endurance-trained men. Methods: Subjects ingested 0.3 g·kg^-1 body mass of either NaHCO₃ or CaCO₃ (CON) 2 h before performing 30 min of cycling exercise at 77 ± 1% [latin capital V with dot above]O_2peak followed by completion of 469 ± 21 kJ as quickly as possible (~30 min, ~80% [latin capital V with dot above]O_2peak). Results: Immediately before, and throughout exercise, arterialized-venous plasma HCO₃- concentrations were higher (P < 0.05) whereas plasma and muscle H⁺ concentrations were lower (P < 0.05) in NaHCO₃ compared with CON. Blood lactate concentrations were higher (P < 0.05) during exercise in NaHCO₃, but there was no difference between trials in muscle glycogen utilization or muscle lactate content during exercise. Reductions in PCr and ATP and increases in muscle Cr during exercise were also unaffected by NaHCO₃ ingestion. Accordingly, exercise performance time was not different between treatments. Conclusion: NaHCO₃ ingestion resulted in a small muscle alkalosis but had no effect on muscle metabolism or intense endurance exercise performance in well-trained men.

The influence of allopurinol on urinary purine loss after repeated sprint exercise in man

The influence of allopurinol on urinary purine loss was examined in 7 active male subjects (age 24.9 ± 3.0 years, weight 82.8 ± 8.3 kg, V˙o₂peak 48.1 ± 6.9 mL · kg⁻¹ · min⁻¹). These subjects performed, in random order, a trial with 5 days of prior ingestion of a placebo or allopurinol. Each trial consisted of eight 10-second sprints on an air-braked cycle ergometer and was separated by at least a week. A rest period of 50 seconds separated each repeated sprint. Forearm venous plasma inosine, hypoxanthine (Hx) and uric acid concentrations were measured at rest and during 120 minutes of recovery from exercise. Urinary inosine, Hx, xanthine, and uric acid excretion were also measured before and for 24 hours after exercise. During the first 120 minutes of recovery, plasma Hx concentrations, as well as the urinary Hx and xanthine excretion rates, were higher (P < .05) with allopurinol compared with the placebo trial. In contrast, plasma uric acid concentration and urinary uric acid excretion rates were lower (P < .05) with allopurinol. The total urinary excretion of purines (inosine + Hx + xanthine + uric acid) above basal levels was higher in the allopurinol trial compared with placebo. These results indicate that the total urinary purine excretion after intermittent sprint exercise was enhanced with allopurinol treatment. Furthermore, the composition of urinary purines was markedly affected by this drug.

Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue

Hormone-sensitive lipase (HSL) is important for the degradation of triacylglycerol in adipose and muscle tissue, but the tissue-specific regulation of this enzyme is not fully understood. We investigated the effects of adrenergic stimulation and AMPK activation in vitro and in circumstances where AMPK activity and catecholamines are physiologically elevated in humans in vivo (during physical exercise) on HSL activity and phosphorylation at Ser⁵⁶³ and Ser⁶⁶⁰, the PKA regulatory sites, and Ser⁵⁶⁵, the AMPK regulatory site. In human experiments, skeletal muscle, subcutaneous adipose and venous blood samples were obtained before, at 15 and 90 min during, and 120 min after exercise. Skeletal muscle HSL activity was increased by ~80% at 15 min compared with rest and returned to resting rates at the cessation of and 120 min after exercise. Consistent with changes in plasma epinephrine, skeletal muscle HSL Ser⁵⁶³ and Ser⁶⁶⁰ phosphorylation were increased by 27% at 15 min (P < 0.05), remained elevated at 90 min, and returned to preexercise values postexercise. Skeletal muscle HSL Ser⁵⁶⁵ phosphorylation and AMPK signaling were increased at 90 min during, and after, exercise. Phosphorylation of adipose tissue HSL paralleled changes in skeletal muscle in vivo, except HSL Ser⁶⁶⁰ was elevated 80% in adipose compared with 35% in skeletal muscle during exercise. Studies in L6 myotubes and 3T3-L1 adipocytes revealed important tissue differences in the regulation of HSL. AMPK inhibited epinephrine-induced HSL activity in L6 myotubes and was associated with reduced HSL Ser660 but not Ser563 phosphorylation. HSL activity was reduced in L6 myotubes expressing constitutively active AMPK, confirming the inhibitory effects of AMPK on HSL activity. Conversely, in 3T3-L1 adipocytes, AMPK activation after epinephrine stimulation did not prevent HSL activity or glycerol release, which coincided with maintenance of HSL Ser660 phosphorylation. Taken together, these data indicate that HSL activity is maintained in the face of AMPK activation as a result of elevated HSL Ser660 phosphorylation in adipose tissue but not skeletal muscle.

Splanchnic blood flow and hepatic glucose production in exercising humans : role of renin-angiotensin system

The study examined the implication of the renin-angiotensin system (RAS) in regulation of splanchnic blood flow and glucose production in exercising humans. Subjects cycled for 40 min at 50% maximal O2 consumption (VO2 max) followed by 30 min at 70% VO2 max either with [angiotensin-converting enzyme (ACE) blockade] or without (control) administration of the ACE inhibitor enalapril (10 mg iv). Splanchnic blood flow was estimated by indocyanine green, and splanchnic substrate exchange was determined by the arteriohepatic venous difference. Exercise led to an ~20-fold increase (P < 0.001) in ANG II levels in the control group (5.4 ± 1.0 to 102.0 ± 25.1 pg/ml), whereas this response was blunted during ACE blockade (8.1 ± 1.2 to 13.2 ± 2.4 pg/ml) and in response to an orthostatic challenge performed postexercise. Apart from lactate and cortisol, which were higher in the ACE-blockade group vs. the control group, hormones, metabolites, VO2, and RER followed the same pattern of changes in ACE-blockade and control groups during exercise. Splanchnic blood flow (at rest: 1.67 ± 0.12, ACE blockade; 1.59 ± 0.18 l/min, control) decreased during moderate exercise (0.78 ± 0.07, ACE blockade; 0.74 ± 0.14 l/min, control), whereas splanchnic glucose production (at rest: 0.50 ± 0.06, ACE blockade; 0.68 ± 0.10 mmol/min, control) increased during moderate exercise (1.97 ± 0.29, ACE blockade; 1.91 ± 0.41 mmol/min, control). Refuting a major role of the RAS for these responses, no differences in the pattern of change of splanchnic blood flow and splanchnic glucose production were observed during ACE blockade compared with controls. This study demonstrates that the normal increase in ANG II levels observed during prolonged exercise in humans does not play a major role in the regulation of splanchnic blood flow and glucose production.

A mechanistic study of the intestinal absorption of crypotanshinone, the major active constituent of Saliva miltiorrhiza

The nature of intestinal absorption of most herbal medicine is unknown. Cryptotanshinone (CTS) is the principal active constituent of the widely used cardiovascular herb Salvia miltiorrhiza (Danshen). We investigated the oral bioavailability of CTS in rats and the mechanism for its intestinal absorption using several in vitro and in vivo models:1) Caco-2 cell monolayers; 2) monolayers of MDCKII cells overexpressing P-glycoprotein
(PgP); and 3) single-pass rat intestinal perfusion with mesenteric vein cannulation. The systemic bioavailabilities of CTS after oral and intraperitoneal administration at 100 mg/kg were 2.05 and 10.60%, respectively. In the perfused rat intestinal model, permeability coefficients based on CTS disappearance from the luminal perfusate (P_lumen) were 6.7- to 10.3-fold higher than permeability coefficients based on drug appearance in venous blood (P_blood). P_blood significantly increased in the presence of the P-gP inhibitor, verapamil. CTS transport across Caco-2 monolayers was pH-, temperature- and ATP-dependent. The transport from the apical (AP) to the basolateral (BL) side was 3- to 9-fold lower than that from the BL to the AP side. Inclusion of verapamil (50 µM) in both AP and BL sides abolished the polarized CTS transport across Caco-2 cells. Moreover, CTS was significantly more permeable in the BL to AP than in the AP to BL direction in MDCKII and MDR1-MDCKII cells. The permeability coefficients in the BL to AP direction were significantly higher in MDCKII cells overexpressing PgP. These findings indicate that CTS is a substrate for PgP that can pump CTS into the luminal side.

Adiponectin in umbillcal cord blood is inversely related to low-density lipoprotein cholesteril but not ethnicity

Context: Adiponectin is a recognized protective risk marker for cardiovascular disease in adults and is associated with an optimal lipid profile. The role of adiponectin at birth is not well understood, and its relationship with the neonatal lipid profile is unknown. Because ethnic disparities in cardiovascular risk have been attributed to low adiponectin and its associated low high-density lipoprotein cholesterol (HDL-C), investigation at birth may help determine the etiology of these risk patterns.

Objective: Our objective was to investigate the relationship between neonatal adiponectin and lipid profile at birth in two ethnic groups in cord blood.

Design, Setting, and Participants: Seventy-four healthy mothers and their newborns of South Asian and White European origin were studied in this cross-sectional study at St. Mary’s Hospital, Manchester, United Kingdom.

Main Outcome Measures: Serum adiponectin, total cholesterol, HDL-C, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels were measured in umbilical venous blood at birth and in maternal blood collected at 28 wk gestation.

Results: Cord adiponectin was significantly inversely associated with cord LDL-C (r = –0.32; P = 0.005) but not HDL-C. In a multiple regression analysis, cord LDL-C remained the most significant association of cord adiponectin (ß = –0.13; P < 0.001). We did not find any significant ethnic differences in cord adiponectin or lipids with the exception of triglycerides, which were significantly lower in South Asian newborns (P < 0.05).

Conclusion: This is the first report of an inverse relationship between cord adiponectin and LDL-C at birth. In contrast to adult studies, we found no significant association between adiponectin and HDL-C in cord blood. Our results and the strong independent association between adiponectin and HDL-C observed in adult studies suggest a role for adiponectin in lipid metabolism. Ethnic differences in adiponectin may arise after birth.

The fine line between harm reduction and harm production - development of a clinical policy on femoral (groin) injecting

The femoral region ('groin') appears to be increasingly commonly used by injecting drug users in the UK. With the advent of Britain's first supervised prescribed injectable opioid treatment clinic, unprecedented decisions and judgements were required about the safe supervision of this practice, or whether to permit this behaviour on site at all. This paper reports the reasons for, and outcome of, development of a clinical policy on injecting into the deep femoral vein (groin injecting)

Adrenergic regulation of carbohydrate metabolism during exercise

1. This series of studies was undertaken to examine the adrenergic regulation of carbohydrate metabolism during exercise. Recreationally active males were tested during moderate to intense exercise on a stationary cycle ergometer. Venous and arterial plasma obtained from indwelling catheters was analysed for hormonal and metabolite responses, and hepatic glucose production and glucose uptake were measured using the tracer-dilution method with stable isotopes. Muscle samples were obtained by the needle biopsy technique to examine muscle glycogen utilisation and the flux of related muscle metabolites using enzymatic, fluorometric and radioisotopic techniques. 2. During moderate exercise adrenaline infusion induced a marked hyperglycemia and this was due to reduced glucose uptake rather than enhanced hepatic glucose production. The reduction in glucose uptake was most likely mediated by a decrease in glucose phosphorylation, as indicated by the accumulation of glucose 6-phosphate with adrenaline infusion. 3. The hyperglycemic response to intense exercise was prevented by the administration of α- and β-adrenergic antagonists. Adrenergic blockade was without effect on hepatic glucose production whereas glucose uptake was enhanced when compared with control subjects. These data support the notion that adrenergic mechanisms are more important in restraining glucose uptake than enhancing hepatic glucose production during intense exercise. Other glucoregulatory factors are responsible for the increase in glucose production during intense exercise. 4. Elevated plasma adrenaline levels during moderate exercise in untrained men increases skeletal muscle glycogen breakdown and PDH activation which results

Interrelations between ceruloplasmin and Fe status during human pregnancy

It is well established that Fe and ceruloplasmin interact in animals and in in vitro models. However, Fe-mediated regulation of ceruloplasmin has never been investigated in humans. In an observational study, 53 pregnant women aged 19-39 yr (29.8±0.7 yr, mean ± SEM) were recruited at the Aberdeen Antenatal Clinic, Aberdeen Maternity Hospital, UK. All requirements for local ethical committees were followed. Venous blood samples were taken from each woman at 34 wk gestation for measurement of Fe status and ceruloplasmin. Various parameters were used to test for Fe status. The most sensitive one appeared to be soluble transferrin receptor, which increased with parity. In the population studied, there was no relationship between hemoglobin or ferritin and serum ceruloplasmin. However, using soluble transferrin receptor (sTfR) levels, we were able to demonstrate an inverse linear relationship (r=0.37, p=0.021, n=41) between Fe status and ceruloplasmin. Fe supplementation, number of previous pregnancies, and smoking habits did not affect this relationship. Our data support in vitro results showing regulation of ceruloplasmin by Fe and also suggest that the interactions between Fe and ceruloplasmin should be considered when Fe supplementation is given.

Chronic disease risk factors in rural Australia : results from the Greater Green Triangle risk factor surveys

The aim of this article was to assess the level and prevalence of major chronic disease risk factors among rural adults. Two cross-sectional surveys were carried out in 2004 and 2005 in the southeast of South Australia and the southwest of Victoria. Altogether 891 randomly selected persons aged 25 to 74 years participated in the studies. Surveys included a self-administered questionnaire, physical measurements, and a venous blood specimen for lipid analyses. Two thirds of participants had cholesterol levels ≥5.0 mmol/L. The prevalence of high diastolic blood pressure (≥90 mm Hg) was 22% for men and 10% for women in southeast of South Australia, and less than 10% for both sexes in southwest of Victoria. Two thirds of participants were overweight or obese (body mass index ≥25 kg/m2). About 15% of men and slightly less women were daily smokers. The abnormal risk factor levels underline the need for targeted prevention activities in the Greater Green Triangle region. Continuing surveillance of levels and patterns of risk factors is fundamentally important for planning and evaluating preventive activities.

Impaired muscle Ca2+ and K+ regulation contribute to poor exercise performance post-lung transplantation

Lung transplant recipients (LTx) exhibit marked peripheral limitations to exercise. We investigated whether skeletal muscle Ca2+ and K+ regulation might be abnormal in eight LTx and eight healthy controls. Peak oxygen consumption and arterialized venous plasma [K+] (where brackets denote concentration) were measured during incremental exercise. Vastus lateralis muscle was biopsied at rest and analyzed for sarcoplasmic reticulum Ca2+ release, Ca2+ uptake, and Ca2+-ATPase activity rates; fiber composition; Na+-K+-ATPase (K+-stimulated 3-O-methylfluorescein phosphatase) activity and content ([3H]ouabain binding sites); as well as for [H+] and H+-buffering capacity. Peak oxygen consumption was 47% less in LTx (P < 0.05). LTx had lower Ca2+ release (34%), Ca2+ uptake (31%), and Ca2+-ATPase activity (25%) than controls (P < 0.05), despite their higher type II fiber proportion (LTx, 75.0 ± 5.8%; controls, 43.5 ± 2.1%). Muscle [H+] was elevated in LTx (P < 0.01), but buffering capacity was similar to controls. Muscle 3-O-methylfluorescein phosphatase activity was 31% higher in LTx (P < 0.05), but [3H]ouabain binding content did not differ significantly. However, during exercise, the rise in plasma [K+]-to-work ratio was 2.6-fold greater in LTx (P < 0.05), indicating impaired K+ regulation. Thus grossly subnormal muscle calcium regulation, with impaired potassium regulation, may contribute to poor muscular performance in LTx.