Monocyte chemoattractant protein‐1 and CC‐chemokine receptor‐2 in severe hypercholesterolaemia

Objectives: To investigate whether plasma concentrations of monocyte chemoattractant protein‐1 (MCP‐1) and the gene expression of its receptor on the monocyte cell surface CCR‐2 were elevated above normal in subjects with asymptomatic, isolated hypercholesterolaemia and if statin treatment could influence this cytokine. Methods: The investigation was designed as a cross sectional study followed by a single, blind, treatment study of patients receiving pravastatin 80?mg/day for 8 weeks. The study included 23 patients with severe hypercholesterolaemia (LDL>5.2?mmol/L) and 39 normocholesterolaemic controls. Blood samples were obtained from patients and controls at baseline and from patients at end of the study and analysed for lipoproteins and inflammatory mediators: MCP‐1, high‐sensitivity C‐reactive protein (HS‐CRP). Isolated peripheral mononuclear cells were analysed for CCR‐2 gene expression. Results: Mean plasma LDL‐C was significantly higher in patients than in controls. No difference in plasma MCP‐1 levels or CCR‐2 gene expression was seen between the groups at baseline, nor were there any differences in plasma concentrations of CRP. After treatment with pravastatin, LDL‐C decreased by 31%. Treatment did not significantly affect the levels of MCP‐1 or CCR‐2 gene expression, nor was CRP affected by treatment with pravastatin. Conclusions: Our study does not support the view that MCP‐1 plasma levels and CCR‐2 gene expression in circulating monocytes are directly responsible for the monocyte recruitment into the arterial intima in patients with severe asymptomatic hypercholesterolaemia. In addition, the inflammatory response of a high concentration of LDL‐C in isolated asymptomatic hypercholesterolaemia is minute.     

INTRA‐RATER AND INTER‐RATER RELIABILITY OF THE FIVE IMAGE‐BASED CRITERIA OF THE FOOT POSTURE INDEX‐6

Purpose/Background:

The Foot Posture Index‐6 (FPI‐6) is considered a simple quantification tool to assess static foot alignment. Palpation of the foot is required for assessment of one of the six criteria that comprise the FPI‐6; the remaining five criteria may be evaluated using still‐frame photographs. Using only the image‐based criteria may allow multiple clinicians to evaluate large groups of patients quickly. Reliability using only these five image‐based criteria has not been established. The purposes of the current study were to establish the inter‐ and intra‐rater reliability using five image‐based criteria from the Foot Posture Index‐6 (FPI‐6) as well as to examine the agreement between the raters in identifying foot type using the composite five FPI scores.

Methods:

Forty participants (23 females, 17 males; 23.67 ± 8.49 years; 64.59 ± 14.43 kg; 166.07 ± 11.79 cm) volunteered for this study. An investigator took three photos with a digital camera of the medial longitudinal arch, posterior ankle, and of the talonavicular joint approximately 45° from the posterior calcaneus for both right and left feet. Two investigators assessed the five image‐based criteria of the FPI‐6 for both feet of 40 participants on three occasions separated by a day. Inter‐and intra‐rater reliability were assessed with Intraclass Correlation Coefficients (ICC_3,2). The amount of agreement for classification of foot posture type between the two raters was assessed with Cohen''s kappa coefficient. Significance was set a priori at P < 0.05.

Results:

The inter‐rater reliability was poor to moderate for all three sessions (ICC_3,2 = 0.334‐0.634). For the foot posture classification, the amount of agreement between two raters was poor for left (κ= 0.12) and right (κ= 0.19) feet. The intra‐rater reliability was excellent for left (ICC_3,2=0.956) and right feet (ICC_3,2=0.959).

Conclusions:

Excellent intra‐rater and poor to moderate inter‐rater reliability was found using only the five image‐based criteria of the FPI‐6. However, the classification of foot posture did not improve the amount of agreement between raters. Therefore, caution is needed when interpreting FPI scores from five image‐based criteria.

Levels of Evidence:

3b     

Sunitinib‐Induced Cardiotoxicity Is Mediated by Off‐Target Inhibition of AMP‐Activated Protein Kinase

Tyrosine kinase inhibitors (TKIs) are transforming the treatment of patients with malignancies. One such agent, sunitinib (Sutent, Pfizer, New York, NY, USA), has demonstrated activity against a variety of solid tumors. Sunitinib is “multitargeted,” inhibiting growth factor receptors that regulate both tumor angiogenesis and tumor cell survival. However, cardiac dysfunction has been associated with its use. Identification of the target of sunitinib‐associated cardiac dysfunction could guide future drug design to reduce toxicity while preserving anticancer activity. Herein we identify severe mitochondrial structural abnormalities in the heart of a patient with sunitinib‐induced heart failure. In cultured cardiomyocytes, sunitinib induces loss of mitochondrial membrane potential and energy rundown. Despite the latter, 5′ adenosine monophosphate‐activated protein kinase (AMPK) activity, which should be increased in the setting of energy compromise, is reduced in hearts of sunitinib‐treated mice and cardiomyocytes in culture, and this is due to direct inhibition of AMPK by sunitinib. Critically, we find that adenovirus‐mediated gene transfer of an activated mutant of AMPK reduces sunitinib‐induced cell death. Our findings suggest AMPK inhibition plays a central role in sunitinib cardiomyocyte toxicity, highlighting the potential of off‐target effects of TKIs contributing to cardiotoxicity. While multitargeting can enhance tumor cell killing, this must be balanced against the potential increased risk of cardiac dysfunction.     

A memory‐shape temperature‐dependent nickel‐titanium device for colonic anastomosis in laparoscopic surgery

Minimally invasive surgery is a growing issue in medicine and is also increasingly being used for colonic surgery. With this procedure, the involved colon is dissected laparoscopically, exteriorized through a small incision and the segment containing the tumor is resected. The anastomosis is done extraperitoneally either by hand suture or with a stapler. Our study was designed to evaluate the feasibility of using a memory‐shape compression anastomosis clip (CAC) to perform colonic anastomosis in laparoscopy. Ten patients who were scheduled for laparoscopic colonic surgery entered the study. In five patients, the anastomosis was performed with the CAC and in five patients, with a stapler. To perform anastomosis with CAC, the two edges of the resected colon are placed parallel. Two 5‐mm incisions are made close to the edges, where the CAC is introduced in an open position after being cooled in ice water at 0°C, using a special applier. The applier introduces the clip which clamps the two bowel loops together, creating a small incision through the clamped walls, and then releasing the clip inside the intestine. The two 5‐mm incisions are then sutured. The clip is expelled with the stool within five to seven days after the operation, creating a perfect uniform anastomosis. Neither group had complications related to the anastomosis. Our study shows that the use of the CAC for colonic laparoscopic surgery is simple, very efficient and shortens operation time. It creates a uniform anastomosis, coming close to the no‐touch concept in surgery, may prevent infection, and is low in cost compared to the stapler.     

Normal S‐cholesterol indicates unchanged S‐LDL,S‐HDL and S‐triglycerides in patients with previously acceptable blood lipids

Background. Analysis of blood lipids should be repeated routinely in many patients, and limiting testing to total cholesterol may eliminate the need for fasting prior to sampling, thereby saving time and money. The primary aim was to investigate the sufficiency of S‐cholesterol analysis (TC) in monitoring all blood lipids. Material and Methods. The results of blood lipid measurement in blood samples taken at a primary care unit over a 10‐year period were studied retrospectively, and the probability of TC predicting acceptable levels of LDL, HDL and TG was calculated. Results. Blood lipid levels from two samples in 518 patients taken within an interval of 0.5 to 3 years were accessible for study. If TC, LDL, HDL and TG levels were previously acceptable within this interval, a single acceptable TC was a predictor of acceptable LDL (97?%), HDL (94–97?%) and TG levels (96?%). Conclusions. In patients requiring blood lipid monitoring, it may be concluded that if TC, LDL, HDL and TG levels are acceptable in one blood sample, this is sufficient to monitor TC levels. If TC levels remain acceptable, there is no need to analyse LDL, HDL and TG levels more than every second year.     

IMMEDIATE EFFECTS OF A DYNAMIC ROTATION‐SPECIFIC WARM‐UP ON X‐FACTOR AND X‐FACTOR STRETCH IN THE AMATEUR GOLFER

Background

Recent evidence suggests performing a warm‐up prior to golf can improve performance and reduce injuries. While some characteristics of effective golf warm‐ups have been determined, no studies have explored the immediate effects of a rotational‐specific warm‐up with elements of motor control on the biomechanical aspects of the full X‐Factor and X‐Factor Stretch during the golf swing.

Methods

Thirty‐six amateur golfers (mean ± SD age: 64 ± 8 years old; 75% male) were randomized into a Dynamic Rotation‐Specific Warm‐up group (n=20), or a Sham Warm‐up group (n=16). X‐Factor and X‐Factor Stretch were measured at baseline and immediately following the warm‐up. Mixed model ANCOVAs were used to determine if a Group*Time interaction existed for each variable with group as the between‐subjects variable and time as the within‐subjects variable.

Results

The mixed model ANCOVAs did not reveal a statistically significant group*time interaction for X‐Factor or X‐Factor Stretch. There was not a significant main effect for time for X‐Factor but there was for X‐Factor Stretch. These results indicate that neither group had a significant effect on improving X‐Factor, however performing either warm‐up increased X‐Factor Stretch without significant difference between the two.

Conclusions

The results of this study suggest that performing the Dynamic Rotation‐Specific Warm‐up did not increase X‐Factor or X‐Factor Stretch when controlled for age compared to the Sham Warm‐up. Further study is needed to determine the long‐term effects of the Dynamic Rotation‐Specific Warm‐up on performance factors of the golf swing while examining across all ages.

Level of Evidence

2b     

Accuracy of N‐terminal‐pro‐atrial natriuretic peptide in patients admitted to emergency department

Objective. B‐type natriuretic peptide (BNP) and N‐terminal‐pro‐BNP (Nt‐proBNP) are commonly used for the triage of patients in the emergency department (ED) with dyspnoea and/or chest pain. The aim of our study was to determine the accuracy of N‐terminal‐pro‐ANP (Nt‐proANP) in such patients. Material and methods. Nt‐proANP was measured by home‐made radioimmunoassay in 137 ED patients admitted with cardiovascular and/or pulmonary disorders. BNP and Nt‐pro‐BNP were determined with automated assays. Final diagnosis was confirmed at discharge or after follow‐up. Results. Nt‐proANP levels were significantly influenced by the diagnostic subgroups (ANOVA: p<0.001) and were [geometric mean (range)]: 19727?ng/L (5260–45200) in congestive heart failure (CHF, n = 31), 6575?ng/L (1350–36000) in coronary artery disease (CAD, n = 19), 5324?ng/L (1710–13150) in pulmonary embolism (PE, n = 20), 5035?ng/L (1510–16600) in pulmonary diseases (PD, n = 24) and 3001?ng/L (750–11860) in patients without cardiopulmonary diseases (n = 43). Pairwise comparisons demonstrated that CHF patients had Nt‐pro‐ANP values higher than all other groups (p<0.05) and that patients without cardiopulmonary diseases had the lowest values (p<0.05). For diagnosis of CHF, the area under the ROC curve of Nt‐proANP was 0.94 (95?% CI: 0.89–0.98) and was equivalent to Nt‐proBNP (0.91; p = 0.284) and BNP (0.93; p = 0.572). Conclusions. The diagnostic accuracy of Nt‐proANP was equivalent to BNP and Nt‐proBNP in the present cohort of patients admitted to ED with dyspnoea and/or chest pain.     

Insulin‐like growth factor (IGF)‐I,IGF‐II and IGF‐binding protein (IGFBP)‐3 levels in Arab subjects with coronary heart disease

Objective. Insulin‐like growth factors (IGF‐I, IGF‐II) and their binding protein (IGFBP‐3) may be risk markers for coronary heart disease (CHD). This study aimed to assess the levels and determinants of the serum levels of IGF‐I, IGF‐II and IGFBP‐3 in Arab patients with established CHD. Material and methods. Two groups of subjects were matched for age, gender, BMI and waist–hip ratio (WHR): (i) CHD (n = 105), median age 51.0 (range 40.0–60.0) years; (ii) controls (n = 97) aged 49.0 (range 37.0–60.0) years. We measured fasting serum levels of glucose and lipoproteins (total cholesterol, triglycerides, LDL, HDL, apo B), insulin, HOMA‐IR, IGF‐I, IGF‐II and IGFBP‐3 and compared the results between groups. The effects of body mass and the metabolic syndrome (MS) on IGF levels were also examined, and linear correlations were sought between the various parameters. Results. The levels of IGF‐I, IGF‐II and IGFBP‐3 were significantly lower (all p<0.01) for the CHD group than for the control group. These differences were not influenced by BMI or with the presence of MS. In CHD, there were no significant correlations between levels of IGF‐I and IGF‐II and age, BMI, WHR, lipoprotein concentrations and insulin sensitivity, although IGFBP‐3 had weakly significant relationships with some of the lipoproteins. Conclusions. Levels of IGF‐I, IGF‐II and IGFBP3 are reduced in male Arab patients with CHD, and did not appear influenced by traditional CHD risk factors such as age, BMI, insulin sensitivity and presence of MS. Perturbations in the IGF/IGFBP‐3 axis may be potential additional targets for pharmacological manipulation in CHD.     

Development of self‐directed learning behaviors in a partially teacher‐directed problem‐based learning curriculum

Data from three sources (self‐reports of students, review of accreditation and program evaluation documents, and library circulation statistics) supported the hypothesis that students in a problem‐based learning (PBL) curriculum with significant teacher‐centered components nevertheless acquire behaviors reflecting self‐directed learning skills. These PBL students exhibited differences in the extent to which their learning was self‐directed when compared to lecture‐based students. The learning process and features of this partially teacher‐directed, PBL program that fostered the development of self‐directed learning are discussed. Development of these skills depended on the curriculum's adherence to the use of student‐generated learning issues as a guide for defining content to be learned, but also on several other factors.     

Problem‐based learning in a third‐year pediatric clerkship

A randomized treatment‐control study of third‐year clerks during their pediatrics rotation was performed to assess whether a problem‐based learning (PBL) curriculum assures adequate exposure to pediatric concepts while enhancing the quality of students’ experience. Forty‐five out of 202 medical students were randomly selected to participate in the PBL track. These students attended PBL rounds covering predesigned cases, whereas the control group attended traditional rounds. Curricular content, exam performance, and student satisfaction were evaluated. Correlation of learning issues and essential course objectives was greater than 90%. There was no difference between groups on standardized exam performance. PBL students were more satisfied with the amount of observation by attendings and with evaluations by residents and attendings. We conclude that the PBL curriculum was successfully introduced, curricular content controlled, whereas test performance was preserved and satisfaction with evaluation increased.     

Cerebrospinal fluid neuron‐specific enolase in non‐selected patients

The degree to which cerebrospinal fluid (CSF) neuron‐specific enolase (NSE) contributes to the diagnosis and prognosis of disorders of the central nervous system (CNS) or peripheral nervous system (PNS) is still under debate. The aim of the study was thus to assess the validity of CSF‐NSE levels in the diagnostic work‐up of these conditions. The study consecutively included 106 adult patients who had undergone a diagnostic spinal tap or myelography during the diagnostic work‐up for various CNS or PNS disorders. Thirty‐five of these patients (16 F, 19 M, aged 24–88 years) without indication of a CNS disorder and with normal routine CSF investigations served as controls. The remaining 71 patients (31 F, 40 M, aged 28–87 years) constituted the disease group. CSF‐NSE was independent of sex and age. The upper reference limit of CSF‐NSE was 0.01536?ng/L. CSF‐NSE was elevated in 13 of the 71 patients (18%): 6 with metabolic myopathy, 4 with polyneuropathy and 3 with hepatic encephalopathy, multiple sclerosis and paraspasticity, respectively. Only 6 of the 13 patients (46%) showed CNS involvement. The study shows that CSF‐NSE is elevated in only one‐fifth of unselected patients who consecutively undergo a spinal tap. CSF‐NSE is elevated most frequently in patients with metabolic myopathy and polyneuropathy, even in cases without CNS abnormalities.     

Hydrocortisone‐Induced Convulsions

Abstract

Glucocorticoids may indirectly cause convulsions by the induction of electrolytes abnormalities, severe hypertension, or severe hyperglycemia. These agents may rarely cause convulsions by a direct toxicity to the central nervous system (CNS). We describe a 23‐yr‐old patient with Crohn's disease in whom generalized convulsions developed on two occasions while receiving intravenous hydrocortisone.     

Twelve‐month maintenance treatment of heroin‐dependent outpatients with buprenorphine

The aim of this study was to assess the efficacy of 1‐mg, 3‐mg, and 8‐mg/day doses of buprenorphine in the maintenance treatment of heroin‐dependent patients over a 12‐month treatment period. Subjects were allocated randomly to three dosage groups. Participants consisted of 123 male heroin dependents who met the DSM‐IV criteria for opioid dependence and were seeking treatment. Their mean age was 31.4 years ranging from 16 to 64 (SD=9.4). Subjects received buprenorphine at a dose of 1?mg, 3?mg, or 8?mg/day and were treated in an urban outpatient clinic, offering a 1‐h weekly individual counselling session. Days retained in treatment were measured. Overall, 49 patients (39.8%) completed the 12‐month study. Completion rates by dosage group were 7 (17.1)% for the 1‐mg dose group, 16 (39%) for the 3‐mg dose group, and 26 (63.4%) for the 8‐mg dose group. Retention in the 8‐mg dose group was significantly better than in the 1‐mg dose group (p=0.00002) and in the 3‐mg dose group (p=0.027); other comparison (1‐mg dose with 3‐mg dose) was also significant (p=0.027). The results support the efficacy and safety of buprenorphine for outpatient treatment of heroin dependence and seem to indicate that the highest dose (8?mg) of buprenorphine was the best of the three doses for Iranian heroin dependents to increase their retention in treatment.     

Confocal dual‐frequency enhances the damaging effect of high‐intensity focused ultrasound in tissue‐mimicking phantom

The volume of the lesions created by conventional single‐frequency high‐intensity focused ultrasound (HIFU) is small, which leads to long treatment duration in patients who are undergoing tumor ablation. In this study, the lesions induced by confocal dual‐frequency HIFU in an optically transparent tissue‐mimicking phantom were investigated and compared with the lesions created by conventional single‐frequency HIFU. The results show that using different exposure times resulted in lesions of different sizes in both dual‐frequency and single‐frequency HIFU modes at the same spatially averaged intensity level (ISAL = 4900?W?cm^?2), but the lesion dimensions made in dual‐frequency mode were significantly larger than those made in single‐frequency mode. Difference frequency acoustic fields that exist in the confocal region of dual‐frequency HIFU may be the reason for the enlargement of the lesions' dimensions. The dual‐frequency HIFU mode may represent a new technique to improve the ablation efficiency of HIFU. The total time for the ablation of a tumor can be reduced, thus requiring less therapy time and reducing possible patient complications.