Effect of elevated lipid concentrations on human skeletal muscle gene expression

Dietary fatty acids regulate the abundance and activity of various proteins involved in the regulation of fat oxidation by functioning as regulators of gene transcription. To determine whether the transcription of key lipid metabolic proteins necessary for fat metabolism within human skeletal muscle are regulated by acute elevations in circulating free fatty acid (FFA) concentrations, 7 healthy men underwent 3 randomized resting infusions of Intralipid (20%) with heparin sodium, saline and heparin sodium, or saline only for 5 hours. These infusions significantly elevated plasma FFA concentrations by 15-fold (to 1.67 ± 0.13 mmol/L) in the Intralipid infusion trial, with modest elevations observed in the saline and heparin sodium and saline alone infusion groups (0.67 ± 0.09 and 0.49 ± 0.087 mmol/L, P < .01 both vs Intralipid infusion). Analysis of messenger RNA (mRNA) concentration demonstrated that pyruvate dehydrogenase kinase isoform 4 (PDK4) mRNA, a key negative regulator of glucose oxidation, was increased in all trials with a 24-fold response after Intralipid infusion, 15-fold after saline and heparin infusion, and 9-fold after saline alone. The PDK4 increases were not significantly different between the 3 trials. The mRNA concentration of the major uncoupling protein within skeletal muscle, uncoupling protein 3, was not elevated in parallel to the increased plasma FFA as similar (not, vert, similar2-fold) increases were evident in all trials. Additional genes involved in lipid transport (fatty acid translocase/CD36), oxidation (carnitine palmitoyltransferase I), and metabolism (1-acylglycerol-3-phosphate O-acyltransferase 1, hormone-sensitive lipase, and peroxisomal proliferator-activated receptor-γ coactivator-1α) were not altered by increased circulating FFA concentrations. The present data demonstrate that of the genes analyzed that encode proteins that are key regulators of lipid homeostasis within skeletal muscle, only the PDK4 gene is uniquely sensitive to increasing FFA concentrations after increased plasma FFA achieved by intravenous lipid infusion.

Development and application of model of resource utilization, costs, and outcomes for stroke (MORUCOS): an Australian economic model for stroke.

Objectives: To outline the development, structure, data assumptions, and application of an Australian economic model for stroke (Model of Resource Utilization, Costs, and Outcomes for Stroke [MORUCOS]). Methods: The model has a linked spreadsheet format with four modules to describe the disease burden and treatment pathways, estimate prevalence-based and incidence-based costs, and derive life expectancy and quality of life consequences. The model uses patient-level, community-based, stroke cohort data and macro-level simulations. An interventions module allows options for change to be consistently evaluated by modifying aspects of the other modules. To date, model validation has included sensitivity testing, face validity, and peer review. Further validation of technical and predictive accuracy is needed. The generic pathway model was assessed by comparison with a stroke subtypes (ischemic, hemorrhagic, or undetermined) approach and used to determine the relative cost-effectiveness of four interventions. Results: The generic pathway model produced lower costs compared with a subtypes version (total average first-year costs/case AUD$15,117 versus AUD$17,786, respectively). Optimal evidence-based uptake of anticoagulation therapy for primary and secondary stroke prevention and intravenous thrombolytic therapy within 3 hours of stroke were more cost-effective than current practice (base year, 1997). Conclusions: MORUCOS is transparent and flexible in describing Australian stroke care and can effectively be used to systematically evaluate a range of different interventions. Adjusting results to account for stroke subtypes, as they influence cost estimates, could enhance the generic model.

Why invest in a national public health program for stroke? An example using Australian data to estimate the potential benefits and cost implications

Objectives: Stroke is the world’s second leading cause of death in people aged over 60 years. Approximately 50,000 strokes occur annually in Australia with numbers predicted to increase by about one third over 10-years. Our objectives were to assess the economic implications of a public health program for stroke by: (1) predicting what potential health-gains and cost-offsets could be achieved; and (2) determining the net level of annual investment that would offer value-for-money.

Methods: Lifetime costs and outcomes were calculated for additional cases that would benefit if ‘current practice’ was feasibly improved, estimated for one indicative year using: (i) local epidemiological data, coverage rates and costs; and (ii) pooled effect sizes from systematic reviews.

Interventions: blood pressure lowering; warfarin for atrial fibrillation; increased access to stroke units; intravenous thrombolysis and aspirin for ischemic events; and carotid endarterectomy. Value-for-money threshold: AUD$30,000/DALY recovered.

Results: Improved, prevention and management could prevent about 27,000 (38%) strokes in 2015. In present terms (2004), about 85,000 DALYs and AUD$1.06 billion in lifetime cost-offsets could be recovered. The net level of annual warranted investment was AUD$3.63 billion.

Conclusions: Primary prevention, in particular blood pressure lowering, was most effective. A public health program for stroke
is warranted

Dietary omega 3 fatty acids decrease intraocular pressure with age by increasing Aqueous outflow

Purpose: To determine whether there is an association between dietary omega-3 (ω-3) fatty acid intake, age, and intraocular pressure (IOP) caused by altered aqueous outflow. Methods: Sprague–Dawley rats were fed either ω-3–sufficient (ω-3⁺) or ω-3–deficient (ω-3^–) diets from conception. The diets had 7% lipid content. The ω-3⁺ diet contained safflower, flaxseed, and tuna oils (5.5:1.0:0.5), and the ω-3^– diet contained safflower oil only. Intraocular pressure was measured at 5 to 40 weeks of age under light anesthesia (ω-3⁺, n = 39; ω-3^–, n = 48). Aqueous outflow was determined at 45 weeks in a subgroup of animals (ω-3⁺, n = 15;ω-3^–, n = 22) using pulsed infusion. Ciliary body tissues (n = 6 per group) were assayed for fatty acid content by thin-layer and gas-liquid chromatography in both diet groups. Results: Animals raised on ω-3⁺ diets had a 13% decrease in IOP at 40 weeks of age (13.48 ± 0.32 mm Hg vs. 15.46 ± 0.29 mm Hg; P < 0.01). When considered as a change in IOP relative to 5 weeks of age, the ω-3⁺ group showed a 23% decrease (P < 0.001). This lower IOP in the ω-3⁺ diet group was associated with a significant increase (+56%; P < 0.001) in outflow facility and a decrease in ocular rigidity (–59%; P < 0.001). The ω-3⁺ group showed a 3.3 times increase in ciliary body docosahexaenoic acid (P < 0.001). Conclusions: Increasing dietary ω-3 reduces IOP with age because of increased outflow facility, likely resulting from an increase in docosanoids. This indicates that dietary manipulation may provide a modifiable factor for IOP regulation. However, further studies are needed to consider whether this can modify the risk for glaucoma and can play a role in treatment of the disease.

Bypassing luminal barriers, delivery to a gut addressin by parenteral targeting elicits local IgA responses

Induction of mucosal immunity, particularly to subunit vaccines, has been problematic. The primary hurdle to successful mucosal vaccination is the effective delivery of vaccine antigen to the mucosal associated lymphoid tissue. Physical and chemical barriers restrict antigen access and, moreover, immune responses induced in the mucosa can be biased towards tolerance or non-reactivity. We proposed that these difficulties could be circumvented by targeting antigen to the gastrointestinal associated lymphoid tissue via systemic (parenteral) rather than alimentary routes, using antibodies specific for the mucosal addressin cellular adhesion molecule-1 (MAdCAM). After intravenous or intramuscular injection of such rat antibodies in mice, we found a greatly enhanced (up to 3 logs) anti-rat antibody response. MAdCAM targeting induces a rapid IgA antibody response in the gut and vastly improves the systemic antibody response. Targeting also enhanced T cell proliferation and cytokine responses. Parenteral targeting of mucosal addressins may represent a generic technique for bypassing mucosal barriers and eliminating the need for adjuvants in the induction of proximal and systemic immunity.

Effect of Glucocorticoid pretreatment on oxidative liver injury and survival in jaundiced rats with Endotoxing Cholangitis

Introduction: Biliary tract infection is associated with high mortality. This study investigated the effect of glucocorticoid pretreatment on lipopolysaccharide (LPS)-induced cholangitis. Methods: Rats undergoing either sham operation or ligation of the extrahepatic bile duct (BDL) for 2 weeks were randomly assigned to receive intravenous injections of dexamethasone (DX) or normal saline (NS) prior to infusing LPS into the biliary tract. The plasma levels of tumor necrosis factor-α (TNFα), chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) as well as liver mRNA expression of MCP-1 and MIP-2 were determined. Infiltration of monocytes, Kupffer cells, and neutrophils in rat liver were studied with immunohistochemistry. Oxidative liver injury was measured by the malondialdehyde (MDA) content. Results: Dexamethasone pretreatment resulted in significantly decreased plasma levels of TNFα at 1 hour, MCP-1 and MIP-2 at 2 and 3 hours, and decreased liver MCP-1 mRNA expression at 3 hours following LPS infusion in BDL-DX rats than in BDL-NS rats. The number of inflammatory cells in the liver was significantly different between sham- and BDL-treated rats but was not affected by DX pretreatment. Pretreatment with DX resulted in significantly decreased liver MDA contents in the BDL-DX group than that in the BDL-NS group. Jaundiced rats pretreated with 5 mg DX prior to infusion of 1 g of LPS were 6.8 times more likely to survive than those that were not pretreated. Conclusions: Pretreatment of jaundiced, LPS-treated rats with a  supraphysiological dose of dexamethasone may rescue their lives by suppression of chemokine expression and alleviation of oxidative liver injury.

Pharmacokinetics of recombinant human endostatin in rats

The pharmacokinetics of recombinant human endostatin (rh-Endo) has not been established in the rat, although this species of animal is commonly used in the pharmacological studies of rh-Endo. This study aimed to investigate the pharmacokinetics, tissue distribution, and excretion of rh-Endo in rats. 125I-radiolabeled rh-Endo was administered to healthy rats by intravenous (i.v) bolus injection at 1.5, 4.5 and 13.5 mg/kg. The maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) of rh-Endo increased proportionally with the increase of the dosage. There were no significant differences in total body clearance (CL) and elimination half-life (t1/2beta) of rh-Endo among the three dosages used. A 93.5% and 2.2% of the radioactivity was recovered in the urine and feces, respectively, in bile-duct intact rats; whereas only 0.1% of the total radioactivity was excreted into the bile in bile-duct cannulated rats. rh-Endo was rapidly and widely distributed in the liver, kidneys, spleen and lungs. Furthermore, a significant allometric relationship between CL, but not volume of distribution (Vd) and t1/2beta of rh-Endo, and the body weight was observed across mouse, rat and monkey, with the predicted values in humans significantly lower than those observed in cancer patients. rh-Endo exhibited a linear pharmacokinetics in rats and it is mainly excreted through the urine.

Pharmacokinetic mechanisms for reduced toxicity of irinotecan by coadministered Thalidomide

The clinical use of irinotecan (CPT-11) is hindered by dose-limiting diarrhea and myelosuppression. Recent clinical studies indicate that thalidomide, a known tumor necrosis factor-alpha inhibitor, ameliorated the toxicities induced by CPT-11. However, the mechanisms for this are unknown. This study aimed to investigate whether combination of thalidomide modulated the toxicities of CPT-11 using a rat model and the possible role of the altered pharmacokinetic component in the toxicity modulation using in vitro models. The toxicity model was constructed by treatment of healthy rats with CPT-11 at 60 mg/kg per day by intravenous (i.v.) injection. Body weight, acute and delayed-onset diarrhea, blood cell counts, and macroscopic and microscopic intestinal damages were monitored in rats treated with CPT-11 alone or combined therapy with thalidomide at 100 mg/kg administered by intraperitoneal (i.p.) injection. Single dose and 5-day multiple-dose studies were conducted in rats to examine the effects of concomitant thalidomide on the plasma pharmacokinetics of CPT-11 and its major metabolites SN-38 and SN-38 glucuronide (SN-38G). The effect of CPT-11 on thalidomide's pharmacokinetics was also checked. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were used to study the in vitro metabolic interactions between these two drugs. H4-II-E cells were also used to investigate the effect of thalidomide and its hydrolytic products on the transport of CPT-11 and SN-38. In addition, the effect of thalidomide and its hydrolytic products on rat plasma protein binding of CPT-11 and SN-38 was examined. Administration of CPT-11 by i.v. for 4 consecutive days to rats induced significant body weight loss, decrease in neutrophil and lymphocyte counts, severe acute- and delayed-onset diarrhea, and intestinal damages. These toxicities were alleviated when CPT-11 was combined with thalidomide. In both single-dose and 5-day multiple-dose pharmacokinetic study, coadministered thalidomide significantly increased the area under the plasma concentration-time curve (AUC) of CPT-11, but the AUC and elimination half-life (t(1/2)) of SN-38 were significantly decreased. However, CPT-11 did not significantly alter the pharmacokinetics of thalidomide. Thalidomide at 25 and 250 microM and its hydrolytic products at a total concentration of 10 microM had no significant effect on the plasma protein binding of CPT-11 and SN-38, except for that thalidomide at 250 microM caused a significant increase in the unbound fraction (f(u)) of CPT-11 by 6.7% (P < 0.05). The hydrolytic products of thalidomide (total concentration of 10 microM), but not thalidomide, significantly decreased CPT-11 hydrolysis by 16% in rat liver microsomes (P < 0.01). The formation of both SN-38 and SN-38G from CPT-11, SN-38 glucuronidation, or intracellular accumulation of both CPT-11 and SN-38 in H4-II-E cells followed Michaelis-Menten kinetics with the one-binding site model being the best fit for the kinetic data. Coincubation or 2-hr preincubation of thalidomide at 25 microM and 250 microM and its hydrolytic products at 10 microM did not show any significant effects on CPT-11 hydrolysis and SN-38 glucuronidation. However, preincubation of H4-II-E cells with thalidomide (250 microM), its hydrolytic products (total concentration of 10 microM), or phthaloyl glutamic acid (one major thalidomide hydrolytic product, 10 microM) significantly increased the intracellular accumulation of SN-38, but not CPT-11 (P < 0.01). The dose-limiting toxicities of CPT-11 were alleviated by combination with thalidomide in rats and the pharmacokinetic modulation by thalidomide may partially explain its antagonizing effects on the toxicities of CPT-11. The hydrolytic products of thalidomide, instead of the parental drug, modulated the hepatic hydrolysis of CPT-11 and intracellular accumulation of SN-38, probably contributing to the altered plasma pharmacokinetics of CPT-11 and SN-38. Further studies are needed to explore the role of both pharmacokinetics and pharmacodynamic components in the protective effect of thalidomide against the toxicities of CPT-11.

Alteration of the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, due to actue gastrointestinal tosicity of doxorubicin

Purpose Combination of COL-3, a matrix metalloproteinase inhibitor, and doxorubicin (DOX) might be a promising anticancer regimen. The present study was to examine the potential pharmacokinetic interactions and toxicity profile following their coadministration in rats.
Methods Normal rats were treated with single agent or different combinations with oral or intravenous COL-3 and DOX, and the bile-duct cannulated (BDC) rats received oral COL-3 plus DOX. In a separate disposition study, the effects of DOX on the biliary, urinary, and fecal excretion of COL-3 were examined. In addition, the effects of DOX on in vitro protein binding, metabolism, and transport of COL-3 across Caco-2 monolayers were investigated.
Results COL-3 did not affect the pharmacokinetics of DOX in rats. However, treatment with DOX significantly decreased the oral absorption, and prolonged the elimination, of COL-3 in the normal rats, but not in the BDC rats. DOX did not alter the biliary and urinary excretion of COL-3, but significantly decreased the fecal excretion of COL-3. DOX significantly enhanced the basolateral to apical flux of COL-3 across Caco-2 monolayers, but had no apparent effects on the protein binding and metabolism of COL-3. The combination of DOX with oral COL-3 did not significantly (p > 0.05) increase the acute diarrhea score and intestinal damage compared to rats receiving DOX alone.
Conclusions These results indicated that DOX altered the oral absorption and elimination of COL-3, largely resulting from gastrointestinal toxicity caused by biliary excretion of DOX. Further studies are required to explore the efficacy and optimized dosage regimen of this promising combination.

Metabolic and cardiac outcomes after acute myocardial infarction

The original DIGAMI protocol recommended using intravenous insulin to manage myocardial infarction from first presentation followed by subcutaneous insulin for 3 months in patients with diabetes. This paper describes the metabolic and cardiac outcomes and barriers to implementing a protocol designed to match the DIGAMI principles across our emergency and cardiology departments. Patients managed using the revised DIGAMI protocol achieved better blood glucose control and had fewer reinfarcts than those managed without insulin. The major barrier to using the protocol appeared to be staff fear of causing hypoglycaemia.

Dancing with death : risk, health promotion and injecting drug users

The thesis investigated ambivalent attitudes towards death in injecting drug users, factors that may lead to such ambivalent attitudes and implications for health promotion campaigns. It was found that this relationship with death was principally attributable to government drug policy in Australia.

Ritual and nursing

The literature reveals that much of nursing comprises ritualized activity and behaviour and that these rituals have a significant impact on nursing practice. This study uses an ethnographic approach to uncover the meaning of ritual and its impact on nursing practice by examining the rituals embedded in Intravenous therapy management of four registered nurses working in two surgical wards in South Australia.

Renal and gastrointestinal amyloidosis in an HIV-infected injection drug user

A 30-year-old HIV-infected intravenous drug user presented with sepsis, acute renal failure, oedema, proteinuria and iron deficiency anaemia. After extensive investigation, a diagnosis of reactive systemic AA (amyloid, serum amyloid A protein) amyloidosis was made on the basis of renal, gastric and duodenal biopsies.

Pain relief for the removal of femoral sheath in interventional cardiology adult patients (Review)

Pain relief for removal of femoral sheath after cardiac procedures
Procedures for the non-surgical management of coronary heart disease include balloon angioplasty and intracoronary stenting. At the start of each procedure an introducer sheath is inserted through the skin (percutaneously) into an artery, frequently a femoral artery in the groin. This allows the different catheters used for the procedure to be exchanged easily without causing trauma to the skin. At the end of the procedure the sheath is removed and, if the puncture site isn't "sealed" using a device closure, firm pressure is required over the site for 30 minutes or more to control any bleeding and reduce vascular complications. Removing the sheath and the firm pressure required to control bleeding can cause pain, although this is generally mild. Some centres routinely give pain relief before removal such as intravenous morphine, or an injection of a local anaesthetic in the soft tissue around the sheath (called a subcutaneous injection). Adequate pain control during sheath removal is also associated with a reduced incidence of a vasovagal reaction, a potentially serious complication involving a sudden drop of blood pressure and a slowed heart rate. Four studies were reviewed in total. Three trials involving 498 participants compared subcutaneous lignocaine, a short acting local anaesthetic, with a control group (participants received either no pain relief or an inactive substance known as a placebo). Two trials involving 399 people compared intravenous opioids (fentanyl or morphine) and an anxiolytic (midazolam) with a control group. One trial involving 60 people compared subcutaneous levobupivacaine, a long acting local anaesthetic, with a control group. Intravenous pain regimens and subcutaneous levobupivacaine appear to reduce the pain experienced during femoral sheath removal. However, the size of the reduction was small. A significant reduction in pain was not experienced by participants who received subcutaneous lignocaine or who were in the control group. There was insufficient data to determine a correlation between pain relief administration and either adverse events or complications. Some patients may benefit from routine pain relief using levobupivacaine or intravenous pain regimens. Identifying who may potentially benefit from pain relief requires clinical judgement and consideration of patient preference. The mild level of pain generally experienced during this procedure should not influence the decision as some people can experience moderate levels of pain.