Jan C.M. Hendriks

Definition dependent properties of the cortical silent period in upper-extremity muscles, a methodological study

BackgroundTo explore if stimulus–response (S-R) characteristics of the silent period (SP) after transcranial magnetic stimulation (TMS) are affected by changing the SP definition and by changing data presentation in healthy individuals. This information would be clinically relevant to predict motor recovery in patients with stroke using stimulus–response curves.MethodsDifferent landmarks to define the SP onset and offset were used to construct S-R curves from the biceps brachii (BB) and abductor digiti minimi (ADM) muscles in 15 healthy participants using rectified versus non-rectified surface electromyography (EMG). A non-linear mixed model fit to a sigmoid Boltzmann function described the S-R characteristics. Differences between S-R characteristics were compared using paired sample t-tests. The Bonferroni correction was used to adjust for multiple testing.ResultsFor the BB, no differences in S-R characteristics were observed between different SP onset and offset markers, while there was no influence of data presentation either. For the ADM, no differences were observed between different SP onset markers, whereas both the SP offset marker “the first return of any EMG-activity” and presenting non-rectified data showed lower active motor thresholds and less steep slopes.ConclusionsThe use of different landmarks to define the SP offset as well as data presentation affect SP S-R characteristics of the ADM in healthy individuals.

Results of the first international round robin for the quantification of urinary and plasma hepcidin assays: need for standardization

This study indicates that hepcidin levels reported by various methods vary considerably but analytical variance is generally low and similar for all methods. See related perspective article on page 1631. The recently discovered iron regulatory peptide hormone hepcidin holds promise as a novel biomarker in iron metabolism disorders. To date, various mass spectrometry and immunochemical methods have been developed for its quantification in plasma and urine. Differences in methodology and analytical performance hinder the comparability of data. As a first step towards method harmonization, several hepcidin assays were compared. Worldwide eight laboratories participated in a urinary and plasma round robin in which hepcidin was analyzed. For both urine and plasma: (i) the absolute hepcidin concentrations differed widely between methods, (ii) the between-sample variation and the analytical variation of the methods are similar. Importantly, the analytical variation as percentage of the total variance is low for all methods, indicating their suitability to distinguish hepcidin levels of different samples. Spearman correlations between methods were generally high. The round robin results inform the scientific and medical community on the status and agreement of the current hepcidin methods. Ongoing initiatives should facilitate standardization by exchanging calibrators and representative samples.

Identification of multiple dense LDL subfractions with enhanced susceptibility to in vitro oxidation among hypertriglyceridemic subjects. Normalization after clofibrate treatment.

The influence of different plasma triglyceride concentrations on the heterogeneity of low density lipoprotein (LDL) and on the susceptibility of LDL to copper oxidation was investigated. By density gradient ultracentrifugation, LDL subfractions were isolated from the plasma of 10 normolipidemic control subjects and 12 hypertriglyceridemic patients both before and after clofibrate treatment. In the plasma of control subjects three LDL subfractions were present: LDL1 (d = 1.030-1.033 g/mL), LDL2 (d = 1.033-1.040 g/mL), and LDL3 (d = 1.040-1.045 g/mL). In the plasma of nine moderately hypertriglyceridemic subjects up to five LDL subfractions could be detected: LDL1-LDL3, LDL4 (d = 1.045-1.049 g/mL), and LDL5 (d = 1.049-1.054 g/mL). This polydispersity of LDL was replaced by monodispersity with increasing plasma triglyceride concentrations in three subjects with chylomicronemia, in whom LDL was concentrated in the narrow LDL5 density range. Clofibrate treatment resulted in a lighter LDL subfraction pattern (LDL1-LDL4). In both the control and the moderately hypertriglyceridemic subjects, the small dense LDL subfractions appeared more prone to oxidative modification in vitro than the light LDL subfractions, as measured by the decreased lag time preceding the onset of lipid peroxidation. Furthermore, the dense LDL subfractions were more extensively modified over time, as shown by an increased oxidation rate and a greater number of dienes formed after 6 hours of oxidation. These results suggest an enhanced atherogenic potential of the small, dense LDL subfractions within each LDL subfraction profile. The hypertriglyceridemic LDL subfractions before therapy (LDL3-LDL5) were less resistant to in vitro oxidation than the light, control LDL subfractions (LDL1-LDL3).(ABSTRACT TRUNCATED AT 250 WORDS)

Nomogram to Diagnose Familial Combined Hyperlipidemia on the Basis of Results of a 5-Year Follow-Up Study

Background—Familial combined hyperlipidemia (FCH) is traditionally diagnosed by total plasma cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender. In a recent study, we showed that the diagnosis of FCH on the basis of these diagnostic criteria was inconsistent in 26% of the subjects over a 5-year period. This result emphasizes the need for reevaluation of the diagnostic criteria for FCH. Methods and Results—A total of 32 families (299 subjects) were studied in 1994 and 1999. A subject was defined “truly” FCH when diagnosed FCH in 1994 and/or 1999 on the basis of traditional plasma lipid criteria. Additional lipid and lipoprotein parameters, including apolipoprotein B (apoB) and small, dense LDL, were measured at both time points. In total, 121 subjects (40%) were defined as truly FCH. Multivariate analysis revealed that absolute apoB values combined with triglyceride and total cholesterol levels adjusted for age and gender best predicted truly FCH. A nomogram including these parameters is provided to simply and accurately calculate the probability to be affected by FCH. Furthermore, it is shown that when percentiles of triglyceride and total cholesterol adjusted for age and gender are not available in a population, the definition of FCH can be established on the basis of hypertriglyceridemia (>1.5 mmol/L) and hyper-apoB (>1200 mg/L). Conclusions—The diagnosis of FCH is best predicted by absolute apoB levels combined with triglyceride and total cholesterol levels adjusted for age and gender and can accurately be calculated by a nomogram. This definition is also a good predictor of cardiovascular risk in FCH.

Strength training and albuterol in facioscapulohumeral muscular dystrophy

Background: In animals and healthy volunteers β2-adrenergic agonists increase muscle strength and mass, in particular when combined with strength training. In patients with facioscapulohumeral muscular dystrophy (FSHD) albuterol may exert anabolic effects. The authors evaluated the effect of strength training and albuterol on muscle strength and volume in FSHD. Methods: Sixty-five patients were randomized to strength training of elbow flexors and ankle dorsiflexors or non-training. After 26 weeks albuterol (sustained-release, 8 mg BID) was added in a randomized, double-blind, placebo-controlled design. Primary outcome was maximum voluntary isometric strength (MVIC) at 52 weeks. Secondary outcomes comprised dynamic strength and muscle volume. Results: Training and albuterol were well tolerated. Training of elbow flexors did not result in a significant effect on MVIC, but dynamic strength improved significantly. Elbow flexor MVIC strength increased significantly in albuterol vs placebo treated patients. Ankle dorsiflexor strength decreased in all groups. Eleven out of twelve non-trained muscles in the albuterol group showed a positive effect on MVIC compared to the placebo group (p < 0.05 in seven muscle groups). Muscle volume decreased in the placebo-treated, and increased in the albuterol-treated patients. No synergistic or antagonistic effects were observed between training and albuterol. Conclusions: In FSHD strength training and albuterol appear safe interventions with limited positive effect on muscle strength and volume. Consequences of prolonged use are presently unclear, which precludes routine prescription.

Low density lipoprotein subfractions and relationship to other risk factors for coronary artery disease in healthy individuals.

By a recently developed sensitive density gradient ultracentrifugation method, the distribution of low density lipoprotein (LDL) subfractions was studied in the serum of healthy blood donors (20 to 62 years old). For each subject, we observed a specific LDL subfraction distribution characterized by the relative contribution of the three major LDL subfractions, LDL-1 (1.020 to 1.028 g/ml), LDL-2 (1.027 to 1.034 g/ml), and LDL-3 (1.033 to 1.039 g/ml), to total LDL. Statistical analysis was performed by using the LDL density variable defined as: (% of LDL-1) x 1.024 + (% of LDL-2) x 1.0305 + (% of LDL-3) x 1.036 as a continuous variable. Controlling for age, smoking habits, relative body weight and, when appropriate, for gender, it appeared that: 1) dense LDL subfraction patterns characterized by a predominant LDL-3 subfraction and a decreased LDL particle size were more likely to be found among men than among women, 2) with increasing density of LDL, the levels of serum triglycerides increased, whereas the concentration of HDL cholesterol and the ratio of LDL cholesterol to LDL apolipoprotein (apo) B decreased, and 3) the best model with significant contribution in the prediction of the LDL subfraction distribution was the three-variable model: total cholesterol, serum triglycerides, and LDL apo B (R2 = 0.40), whereas the best two-variable model consisted of serum triglycerides and high density lipoprotein cholesterol (R2 = 0.37). These data are consistent with results from a study described previously in which a different approach based on LDL subfraction quantification by gradient gel electrophoresis of whole plasma was used.

(Pre)analytical imprecision, between-subject variability, and daily variations in serum and urine hepcidin: implications for clinical studies.

The utility of urine and serum hepcidin measurements in the clinic depends on their reproducibility. We sought to expand our previous work on the within-subject variability and between-subject variability of this novel iron parameter in the serum and urine of 24 healthy controls by time-of-flight mass spectrometry at four different time points during the day. A linear mixed model for repeated data was used to distinguish three components of the total variability in the measurements: within-day/within-subject variability, between-subject variability, and additional residual or (pre)analytical variability. Differences in diurnal hepcidin patterns were observed between urine and serum. Urine levels remained similar during the course of the morning and increased significantly during the afternoon, whereas serum levels increased significantly throughout both the morning and afternoon. Furthermore, in serum the (pre)analytical variability (28.6%) was smaller than the between-subject (48.1%) and within-day/within-subject variability (30.3%) compared with urine variability (97.2% vs. 67.7 and 77.3%, respectively). High serum ferritin levels were associated with higher serum hepcidin levels but not with urine levels. Transferrin saturation did not correlate with hepcidin levels. To minimize variability, we recommend (i) standardizing for sampling time and (ii) measuring serum hepcidin levels.

Taurolidine lock is highly effective in preventing catheter-related bloodstream infections in patients on home parenteral nutrition: a heparin-controlled prospective trial.

BACKGROUND & AIMS Catheter-related bloodstream infections remain the major threat for Home Parenteral Nutrition programs. Taurolidine, a potent antimicrobial agent, holds promise as an effective catheter lock to prevent such infections. Aim of the present study was to compare taurolidine with heparin, the most frequently used lock, in this respect in these high-risk patients. METHODS Thirty patients from one referral centre for intestinal failure were enrolled after developing a catheter-related bloodstream infection. Following adequate treatment, either with or without a new access device (tunneled catheter or subcutaneous port), these patients were randomized to continue Home Parenteral Nutrition using heparin (n = 14) or taurolidine (n = 16) as catheter lock. RESULTS Whereas in controls 10 re-infections were observed, in the taurolidine group during 5370 catheter days only 1 re-infection occurred (mean infection-free survival 175 (95% CI 85-266; heparin) versus 641 (95% CI 556-727; taurolidine) days; log-rank p < 0.0001). No side effects or catheter occlusions were reported in either group. Moreover, after crossing-over of 10 patients with infections on heparin to taurolidine, only 1 new infection was observed. CONCLUSION Taurolidine lock dramatically decreased catheter-related bloodstream infections when compared with heparin in this high-risk group of Home Parenteral Nutrition patients.

Risk Factors for Exposure, Pain, and Dyspareunia After Tension-Free Vaginal Mesh Procedure

OBJECTIVE: To identify possible risk factors for exposure, dyspareunia, and pain after insertion of tension-free vaginal mesh in pelvic organ prolapse surgery. METHODS: This was a prospective observational cohort study. Consecutive women who underwent surgery with a trocar-guided tension-free vaginal mesh kit were included and evaluated at 6 weeks and at 6 and 12 months after surgery with respect to anatomy and complications. Logistic regression analysis was performed to identify risk factors for exposure, dyspareunia, and pain. RESULTS: Two hundred ninety-four patients were included. Exposure was found in 34 patients (12%). Smoking and total mesh were risk factors for exposure (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.1–8.7 and OR 3.0, 95% CI 1.2–7.0, respectively). Clinical and surgical experience were inversely related to the risk of exposure (OR 0.5, 95% CI 0.3–0.8 per decade). Pain (OR 3.2, 95% CI 1.2–8.4) and dyspareunia (OR 4.7, 95% CI 1.7–12.8) before surgery were predictive for pain and dyspareunia after surgery, respectively. Pain after surgery was found in 35 out of 275 (13%) patients and dyspareunia was found in 77 out of 171 (45%) patients. CONCLUSION: Smoking, total tension-free vaginal mesh, and experience were predictive factors for mesh exposure. LEVEL OF EVIDENCE: II

Robot-assisted versus total laparoscopic radical hysterectomy in early cervical cancer, a review

OBJECTIVE The aim of this study was to review current literature on total laparoscopic (TLRH) and robot-assisted radical hysterectomy (RRH) with pelvic lymphadenectomy in the treatment of early stage cervical cancer by analyzing data published in individual case series in order to compare surgical and oncological outcomes. METHODS Up to January 2010, 27 studies were identified that met the inclusion criteria, together with our own unpublished data of patients, accounted for 342 RRH patients and 914 TLRH patients. RESULTS There was no statistical difference between the methods in terms of age, BMI or prior abdominal surgery. Estimated mean operative time, blood loss and number of lymph nodes retrieved did not statistically differ between the RRH and TLRH method. Less blood transfusions were needed in patients treated by RRH (5.4%) versus TLRH (9.7%, p<0.05). Both methods were similar in respect to adjuvant chemo- or (chemo)radiation and recurrence rate. When complications were prioritized to severity, major post-operative complications where more frequent in RRH patients (9.6%) than in TLRH patients (5.5%, p<0.05). The length of hospital stay was significantly shorter in RRH compared to TLRH treatment (3.3 versus 6.2days respectively; p:0.04). CONCLUSIONS Robot-assisted and total laparoscopic radical hysterectomy appears to be equally adequate and feasible. RRH studies had small patient populations and further experience beyond the learning curve phase may improve operative time and complication rate. Both minimal invasive techniques should be investigated in a randomized manner.