Accumulation of Bisphosphonates in Human Artery and their Effects on Human and Rat Arterial Function in vitro

Abstract: Clodronate, etidronate and pamidronate are bisphosphonates introduced in the treatment of hypercalcaemia and osteoporosis. Interestingly, they also inhibit development of experimental atherosclerosis and affect smooth muscle tone of isolated rat tail artery. We have studied in vitro whether these hydrophilic compounds 1) accumulate in the wall of the human artery, 2) influence human arterial tone, and 3) interfere with the vascular action of L-type Ca²⁺ antagonists. Human internal mammary artery rings were incubated with ¹⁴C-labelled bisphosphonates. After a 2-hr incubation, the ratios of artery-to-incubate concentrations with 4 and 40 μmol/1 of clodronate were, respectively, 3.0+0.5 (mean+S.E.M.) and 1.3+0.2, with 4 and 40 μmol/1 of etidronate 7.4+0.9 and 3.2+0.4, and with 0.4 and 4 μmol/1 of pamidronate 4.7+0.7 and 3.9+0.8. Both tested bisphosphonates, clodronate and pamidronate, reduced the arterial contractile force induced by α-adrenergic stimulation with noradrenaline and membrane depolarization with high concentration of KCl. Clodronate also decreased the arterial contraction induced by cumulative addition of Ca²⁺ with KCl as the agonist, and had an additive inhibitory effect on this response with the L-type Ca²⁺-channel blocker nifedipine. The results demostrate that 1) bisphosphonates accumulate markedly in human artery, 2) clodronate and pamidronate reduce human arterial contactile force to α-adrenergic and depolarizing stimuli, and 3) as shown with clodronate, bisphosphonates may exert an additive inhibitory effect on human arterial contractions with an L-type Ca²⁺-channel blocker.     

Effect of ultrasound therapy on bone healing of lateral malleolar fractures of the ankle joint fixed with bioabsorbable screws

Background We investigated the effect of low-intensity ultrasound on bone healing in bioabsorbable self-reinforced poly-l-lactic acid (SR-PLLA) screw-fixed lateral malleolar fractures. The study design was prospective, randomized, double-blind, and placebo-controlled.Methods A total of 22 fractures were fixed with one SR-PLLA screw. All the patients were instructed to use an ultrasound device 20 min daily for 42 days without knowing whether it was active or inactive. Eleven patients had active and eleven sham ultrasound devices. The causes of error during treatment with head module placement and attachment to the convex surface of the lateral distal fibula were minimized by careful targeting and using coupling gel. Radiological fracture healing was assessed by radiographs and multidetector computed tomography (CT) scans in a blinded manner by a radiologist and orthopedic surgeons.Results The overall compliance to the daily ultrasound treatments was good. All wounds healed uneventfully, and no foreign body reactions were observed. No difference was observed between the groups regarding either fracture line visualization or callus formation assessed by plain radiographs. In the CT images at 9 weeks, the share of the endosteal united fracture line compared to the non-united fracture line was slightly higher in the active ultrasound device group than in the sham ultrasound device group, but the difference was not statistically significant.Conclusion The study indicates that the biocompatibility of ultrasound therapy and bioabsorbable SR-PLLA screw fixation is good. There was no obvious effect of low-intensity ultrasound on lateral malleolar fracture healing. However, the relatively small number of patients must be kept in mind when interpreting our results. It is also important to limit any conclusions based on the present study to malleolar fractures fixed with the SR-PLLA screw.     

Preoperative hyperglycemia predicts infected total knee replacement

BackgroundDiabetes increases the risk of surgical site infections. In many patients undergoing total knee replacement, however, diabetes has not been diagnosed. The purpose of this study was to analyze the applicability of preoperative screening for hyperglycemia in identifying patients predisposed to infected knee replacement.MethodsA recent series of 1565 primary total knee replacements performed due to osteoarthritis in a specialized, publicly funded hospital for joint replacement was reviewed.ResultsPreoperative hyperglycemia was significantly associated with infected knee replacement: during the 1-year follow-up infection occurred in 0.44%, 0.93% and 2.42% of patients with preoperative plasma glucose < 6.1 mmol/l (< 110 mg/dl), 6.1–6.9 mmol/l (110–125 mg/dl) and ≥ 7.0 mmol/l (≥ 126 mg/dl). In age- and gender-adjusted analysis the patients with the highest glucose levels had a 4-fold risk for infected knee replacement compared to the patients with the lowest glucose. Obesity increased the risk of infected knee replacement, but the effect of hyperglycemia on the infection rates remained significant also after adjustment for body mass index. None of the patients with normal but 2.8% of patients with increased glycosylated hemoglobin (> 6.5%) experienced infected knee replacement.ConclusionObesity and hyperglycemia associate with a higher risk of infected knee replacement. Preoperative screening of plasma glucose is an efficient way to identify patients in increased risk of infection following primary total knee replacement.     

Determinants of left ventricular diastolic function—The Cardiovascular Risk in Young Finns Study

Decreased left ventricular (LV) diastolic function is associated with increased all‐cause mortality and risk for a heart failure. The determinants of LV diastolic function have been mainly studied in elderly populations; however, the origin of LV heart failure may relate to the lifestyle factors acquired during the life course. Therefore, we examined biochemical, physiological, and lifestyle determinants of LV diastolic function in 34–49‐year‐old participants of the Cardiovascular Risk in Young Finns Study (Young Finns Study). In 2011, clinical examination and echocardiography were performed for 1928 participants (880 men and 1048 women; aged 34–49 years). LV diastolic function was primarily defined using E/é‐ratio (population mean 4.8, range 2.1–9.0). In a multivariate model, systolic blood pressure (P < 0.005), female sex (P < 0.005), age (P < 0.005), waist circumference (P = 0.024), smoking (P = 0.028), serum alanine aminotransferase (P = 0.032) were directly associated with E/é‐ratio, while an inverse association was found for height (P < 0.005). Additionally, a higher E/é‐ratio was found in participants with concentric hypertrophy compared to normal cardiac geometry (P < 0.005). Other indicators of the LV diastolic function including E/A‐ratio and left atrial volume index showed similarly strong associations with systolic blood pressure and age. In conclusion, we identified systolic blood pressure, waist circumference and smoking as modifiable determinants of the LV diastolic function in the 34–49‐year‐old participants of the Young Finns Study.     

Serum sialic acid as a marker of alcohol consumption: effect of liver disease and heavy drinking

BACKGROUND: Serum sialic acid (SA) has been suggested as a new marker of alcohol consumption. There are, however, only a few studies on the clinical value of such measurements. The relationship between serum SA and liver disease is also unknown. METHODS: We determined serum SA concentrations in a sample of 51 alcoholics and 20 healthy controls by using high-performance liquid chromatography with an anion-exchange column and pulsed amperometric detection. The alcoholic sample included 32 patients with liver disease, the severity of which was assessed by previously established combined clinical, laboratory, and morphological indices. In addition, there were 19 heavy drinkers without significant liver disease despite a well documented history of excessive alcohol consumption. RESULTS: The (mean +/- SD) SA concentrations (1.449 +/- 0.3019 mmol/liter) were significantly higher in the alcoholics than in the healthy controls (1.154 +/- 0.1702 mmol/liter). With the optimal cutoff limit for serum SA (1.425 mmol/liter), a specificity of 1.00 and sensitivity of 0.51 were obtained. The diagnostic accuracy of serum SA according to receiver operating characteristic analysis was good, with the area under the curve being 0.805 (0.052). Unlike the traditional serum markers of alcohol consumption (gamma-glutamyl transferase, carbohydrate-deficient transferrin, and aspartate amino transferase), serum SA was not found to be different between the alcoholics with or without liver disease. CONCLUSIONS: Our study suggests that serum SA is a sensitive marker of excessive alcohol consumption. Such measurements may also prove to be of value in conditions in which the results of the traditional markers reflect the severity of liver disease rather than alcohol consumption.     

Testing Genetic Susceptibility Loci for Alcoholic Heart Muscle Disease

BACKGROUND: Although many heavy alcohol users have subclinical alcoholic heart muscle disease, only a very few develop severe dilated cardiomyopathy. Therefore, and because cardiac abnormalities correlate only weakly with the duration or quantity of drinking, individual susceptibility differences may exist. In this work we examined whether common gene variants previously associated with cardiac hypertrophy or altered alcohol metabolism could modify the effects of alcohol on the heart. METHODS: We studied 700 middle-aged male victims of sudden death who underwent a medicolegal autopsy. In addition to routine postmortem examination, the weights and the cavity and wall dimensions of the left and right ventricle were measured. Coronary artery stenoses were determined from a silicone rubber cast of the arteries. Alcohol consumption and cardiovascular risk factors were assessed by a structured interview of the spouse. The following gene polymorphisms were determined by using polymerase chain reaction restriction fragment length polymorphism and solid-phase minisequencing techniques: angiotensin converting enzyme I/D, angiotensin II type 1 receptor 1166A/C, aldosterone synthase -344C/T, alcohol dehydrogenases 2 and 3, acetaldehyde dehydrogenase 2, and cytochrome P-450 2E1 DraI, PstI, RsaI, and MspI. RESULTS: The most consistent effects of alcohol (p < 0.05) were a higher total heart weight and a larger right ventricle size with increasing daily drinking. However, these and other effects of alcohol were statistically fully independent of the studied genotypes. CONCLUSIONS: The gene polymorphisms selected for and analyzed in our study are unlikely to modify the effects of alcohol on the heart. Other unknown factors determine the individual susceptibility to alcoholic heart muscle disease.     

Automated reference region extraction and population-based input function for brain [11C]TMSX PET image analyses

[¹¹C]TMSX ([7-N-methyl-¹¹C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine) is a selective adenosine A2A receptor (A_2AR) radioligand. In the central nervous system (CNS), A_2AR are linked to dopamine D₂ receptor function in striatum, but they are also important modulators of inflammation. The golden standard for kinetic modeling of brain [¹¹C]TMSX positron emission tomography (PET) is to obtain arterial input function via arterial blood sampling. However, this method is laborious, prone to errors and unpleasant for study subjects. The aim of this work was to evaluate alternative input function acquisition methods for brain [¹¹C]TMSX PET imaging. First, a noninvasive, automated method for the extraction of gray matter reference region using supervised clustering (SCgm) was developed. Second, a method for obtaining a population-based arterial input function (PBIF) was implemented. These methods were created using data from 28 study subjects (7 healthy controls, 12 multiple sclerosis patients, and 9 patients with Parkinson''s disease). The results with PBIF correlated well with original plasma input, and the SCgm yielded similar results compared with cerebellum as a reference region. The clustering method for extracting reference region and the population-based approach for acquiring input for dynamic [¹¹C]TMSX brain PET image analyses appear to be feasible and robust methods, that can be applied in patients with CNS pathology.