Dyslipidaemia and cardiorenal disease: mechanisms, therapeutic opportunities and clinical trials

Dyslipidaemia is an important risk factor for the development of chronic kidney disease (CKD) and cardiovascular disease (CVD). CKD generates an atherogenic lipid profile, characterised by high triglycerides, low high-density lipoprotein (HDL) cholesterol and accumulation of small dense low-density lipoprotein (LDL) particles, comparable to that in the metabolic syndrome. These changes are due specifically to the effects of CKD on key enzymes, transfer proteins and receptors involved in lipid metabolism. Dyslipidaemia is further compounded by dialysis, immunosuppressive drugs, and concomitant diseases such as diabetes mellitus. Post hoc analyses from large intervention trials suggest the benefit of statins in patients with early CKD, but prospective clinical trials in haemodialysis (HD) and renal transplant recipients have not conclusively shown improvements in hard cardiovascular end-points. The lack of efficacy of statins in late-stage CKD could be a consequence of other disease processes, such as calcific arteriopathy and insulin resistance, which are not modified by lipid-lowering agents. Despite uncertainty and pending the results of ongoing statin trials such as Study of Heart and Renal Protection (SHARP) and AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events), major international guidelines continue to support statin therapy in CKD and renal transplant patients to reduce cardiovascular risk burden. Because of increased risk of toxicity, particularly myopathy, statins and other lipid-regulating agents should be used cautiously in CKD and renal transplant recipients.     

The response to intravenous glucose infusion in normal and diabetic subjects

Summary Data from single injection studies on 23 normal subjects led to development of an intravenous primed — constant infusion test. The plasma glucose response to this test was determined in 48 normal and 24 diabetic subjects. Variation in plasma glucose concentration at equilibrium was minimal in normal and marked in diabetic subjects — assessed by the difference between maximum and minimum glucose concentration over the final 25 min of a 50 min infusion. This parameter was used successfully in predicting the course of 16 pregnant women with clinical suspicion of prediabetes unresolved by oral glucose tolerance tests.Submitted as part fulfillment of the requirements for Doctor of Medicine, Monash University, Melbourne, 1967.     

Adenylate cyclase: Its probable localization in sarcoplasmic reticulum as well as sarcolemma of the canine heart

Cardiac microsomes prepared by two different methods were compared in terms of Ca-binding and Ca-uptake, believed to represent markers for fragmented sarcoplasmic reticulum, and the (Na⁺ + K⁺)-activated ATPase activity considered to be a marker for the plasma membrane. Microsomes prepared in dilute buffer (H₂O-microsomes) contain two to four times the activity of sarcoplasmic reticulum markers when compared to microsomes prepared in 10% sucrose (suc-microsomes). Conversely, the plasma membrane marker was present in greater amounts in the suc-microsomes. Basal, epinephrine-stimulated and NaF-stimulated adenylate cyclase activities were slightly higher in H₂O-microsomes, as was the degree of stimulation by the β-adrenergic agonist. These findings provide evidence that both β-receptor and adenylate cyclase activities may be present in the heart's sarcoplasmic reticulum, as well as in the sarcolemma.     

Effect of “Speak Up” educational tools to engage patients in advance care planning in outpatient healthcare settings: A prospective before-after study

BackgroundTools for advance care planning (ACP) are advocated to help ensure patient values guide healthcare decisions. Evaluation of the effect of tools introduced to patients in clinical settings is needed.ObjectiveTo evaluate the effect of the Canadian Speak Up Campaign tools on engagement in advance care planning (ACP), with patients attending outpatient clinics.Patient involvement: Patients were not involved in the problem definition or solution selection in this study but members of the public were involved in development of tools. The measurement of impacts involved patients.MethodsThis was a prospective pre-post study in 15 primary care and two outpatient cancer clinics. The outcome was scores on an Advance Care Planning Engagement Survey measuring Behavior Change Process on 5-point scales and Actions (0?21-point scale) administered before and six weeks after using a tool, with reminders at two or four weeks.Results177 of 220 patients (81%) completed the study (mean 68 years of age, 16% had cancer). Mean Behavior Change Process scores were 2.9 at baseline and 3.5 at follow-up (mean change 0.6, 95% confidence interval 0.5 to 0.7; large effect size of 0.8). Mean Action Measure score was 3.7 at baseline and 4.8 at follow-up (mean change 1.1, 95% confidence interval 0.6–1.5; small effect size of 0.2).Practical valuePublicly available ACP tools may have utility in clinical settings to initiate ACP among patients. More time and motivation may be required to stimulate changes in patient behaviors related to ACP.     

Maternal Apical Periodontitis Increases Insulin Resistance and Modulates the Antioxidant Defense System in the Gastrocnemius Muscle of Adult Offspring

IntroductionMaternal apical periodontitis (AP) is associated with insulin resistance (IR) in adult offspring. Oxidative stress has been linked to IR. This study investigated insulin sensitivity (IS) and oxidative stress in the gastrocnemius muscle (GM) of adult offspring of rats with AP.MethodsFifteen female Wistar rats were distributed into a control group, a group with 1 tooth with AP, and a group with 4 teeth with AP. Thirty days after AP induction, female rats were mated with healthy male rats. When male offspring reached 75 days of age, glycemia, insulinemia, and IS were determined. In the GM, the oxidative damage products (thiobarbituric acid reactive substances and carbonyl protein) and activities of enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) and nonenzymatic (glutathione and total antioxidant capacity) antioxidants were quantified. Analysis of variance was performed followed by the Tukey post hoc test (P < .05).ResultsMaternal AP was associated with decreased IS and changes in antioxidant activities (reduced superoxide dismutase and increased catalase, glutathione peroxidase, and glutathione) and decreased thiobarbituric acid reactive substance concentration in the GM of their adult offspring. However, maternal AP does not appear to affect glycemia, carbonyl protein concentration, and the nonenzymatic total antioxidant capacity in the GM of this offspring.ConclusionsMaternal AP modulates the antioxidant defense system in the GM of their adult offspring, attenuating lipid peroxidation in this tissue. This reflects part of an adaptive response of the offspring to the stimulation of the maternal chronic oral inflammatory process in which the organism acts by decreasing oxidative tissue damage in the postnatal stage. The present study improves knowledge about the impact of maternal oral inflammation on healthy offspring.     

The predictive effect of anatomic femoral and tibial graft tunnel placement in posterior cruciate ligament reconstruction on functional and radiological outcome

Purpose

Biomechanical reports have advocated anatomic graft tunnel placement for reconstruction of the posterior cruciate ligament (PCL) to restore knee joint stability and facilitate optimal functional outcome. However, in vivo investigations that correlate tunnel position to functional results are lacking so far. This study evaluates the anatomic accuracy of femoral and tibial tunnel apertures on postoperative computed tomography (CT) scans and compares these findings to subjective and objective clinical outcome parameters.

Methods

After single-bundle PCL reconstruction, 29 patients were stratified into several subgroups according to the anatomic accuracy of femoral and tibial tunnel apertures measured on postoperative CT scans. A threshold value for the centres of the tunnel apertures was determined using a measurement grid system as a radiographic reference. To evaluate the functional and radiological results, visual analogue scale, International Knee Documentation Committee (IKDC), Tegner, Lysholm, Knee Injury and Osteoarthritis Outcome Score and osteoarthritis scores were obtained.

Results

Comparison between functional outcome and tunnel position yielded a statistically significant difference for subjective IKDC score and angle segment α and for objective stability and tunnel position P3 but no statistically significant difference with respect to intercondylar depth, intercondylar height and tibial tunnel position P2. No correlation was found between anatomic tunnel position and present or progressive osteoarthritis on follow-up. Of the patients, 72 % classified their result as excellent and good and 90 % would repeat surgical treatment.

Conclusions

Despite a small sample size and subject to the threshold values we used, our data indicate a potentially minor effect of anatomic tunnel placement on midterm functional outcome following PCL reconstruction.