Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil.

Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug-induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J-Tpeak) and late repolarization (global Tpeak-Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug-related cardiac electrophysiology.

Islet autoantibodies and residual beta cell function in type 1 diabetes children followed for 3-6 years.

AIMS: To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D. METHODS: T1D children (n=260, median age at diagnosis 9.4, range 0.9-14.7 years) were tested for GAD65, IA-2, ZnT8R, ZnT8W and ZnT8Q autoantibodies (A) at diagnosis, and 3-6 years after diagnosis when also fasting and stimulated RBF were determined. RESULTS: For every 1-year increase in age at diagnosis of TID, the odds of detectable C-peptide increased 1.21 (1.09, 1.34) times for fasting C-peptide and 1.28 (1.15, 1.42) times for stimulated C-peptide. Based on a linear model for subjects with no change in IA-2A levels, the odds of detectable C-peptide were 35% higher than for subjects whose IA-2A levels decreased by half (OR=1.35 (1.09, 1.67), p=0.006); similarly for ZnT8WA (OR=1.39 (1.09, 1.77), p=0.008) and ZnT8QA (OR=1.55 (1.06, 2.26) p=0.024). Such relationship was not detected for GADA or ZnT8RA. All OR adjusted for confounders. CONCLUSIONS: Age at diagnosis with T1D was the major predictor of detectable C-peptide 3-6 years post-diagnosis. Decreases in IA-2A, and possibly ZnT8A, levels between diagnosis and post-diagnosis were associated with a reduction in RBF post-diagnosis.

A De Novo Whole GCK Gene Deletion Not Detected by Gene Sequencing, in a Boy with Phenotypic GCK Insufficiency.

We report on a boy with diabetes mellitus and a phenotype indicating glucokinase (GCK) insufficiency, but a normal GCK gene examination applying direct gene sequencing. The boy was referred for diabetes mellitus at 7.5 years old. His father, grandfather and great grandfather suffered type 2 DM. Several blood glucose profiles showed (BG) of 6.5-10 mmol/L L. After three years on neutral insulin Hagedorn (NPH) in a dose of 0.3 IU/kg/day haemoglobin A1c (HbA1c) was 6.8%. Treatment was changed to sulphonylurea 750 mg a day, and after 4 years HbA1c was 7%. At that time a multiplex ligation-dependent amplification gene dosage assay (MLPA) was done, revealing a whole GCK gene deletion. Medical treatment was ceased, and after one year HbA1c was 6.8%. This case underscores the importance of a MLPA examination if the phenotype of a patient is strongly indicative of GCK insufficiency and no mutation is identified using direct sequencing.

The reproducibility of quantitative measurements in lumbar magnetic resonance imaging of children from the general population.

STUDY DESIGN: Quantitative lumbar magnetic resonance imaging (MRI) measurements in children were taken twice and analyzed for intra- and intertester reproducibility. OBJECTIVE: To evaluate the reproducibility of a variety of lumbar quantitative measurements taken from MRIs of children from the general population. SUMMARY OF BACKGROUND DATA: The reproducibility of lumbar quantitative measurements has never been tested on MRIs of children from the general population. This is a prerequisite for a reliable anatomic characterization of the immature spine in normal and pathologic conditions. METHODS: Lumbar quantitative measurements from 40 T2-weighted lumbar (L1-S1) MRIs of children from the general population were taken twice by 1 tester for intratester reproducibility and compared with the same measurements (L4-S1) of the same MRIs taken by a second tester for intertester reproducibility. The following parameters were measured using the iQ-VIEW system (IMAGE Information Systems Ltd., version 1.2.2, Plauen, Germany): Linear measurements--zygoappophyseal facets and interfacet widths, and vertebral body (VB), pedicle and intervertebral discs heights, widths, and lengths. Angular measurements--zygoappophyseal tranverse superior facet angles, sagittal VB, and disc wedging, lumbar lordosis, and sacral inclination. Statistical analysis included the concordance correlation coefficient (CCC), and Bland and Altman's limits of agreement (LOA). RESULTS: A total of 6160 measurements were analyzed. Good to excellent intratester reproducibility (0.75 < or =CCC < or =0.99) was indicated for all linear measurements (except for pedicle heights) (LOA: -4.76; 5.74 mm) and for angular measurements related to the facets orientation, lumbar lordosis, and sacral inclination (LOA: 11.22 degrees ; 12.34 degrees). VB and disc sagittal wedging manifested poor intratester reproducibility (CCC < 0.75). Good to excellent intertester reproducibility was indicated for 70% of all linear measurements (LOA: -5.83; 4.59 mm) and for all angular measurements in the lumbar spine (L4-S1) (LOA: -9.96 degrees ; 14.62 degrees) except for VB and disc sagittal wedging at L5 (CCC < 0.75). CONCLUSION: Quantitative lumbar MRI measurements in children from the general population were found to be reproducible indicating a good visualization of immature vertebral anatomic margins on MRIs and an accurate definition of the measurement protocol.

Antibiotic treatment in patients with low-back pain associated with Modic changes Type 1 (bone oedema): a pilot study.

OBJECTIVE: The aim of this study was to assess the clinical effect of antibiotic treatment in a cohort of patients with low-back pain (LBP) and Modic changes Type 1 (bone oedema) following a lumbar herniated disc. DESIGN: This was a prospective uncontrolled trial of 32 LBP patients who had Modic changes and were treated with Amoxicillin-clavulanate (500 mg/125 mg) 3 x day for 90 days. All patients had previously participated in a randomised controlled trial (RCT) that investigated active conservative treatment for a lumbar herniated disc (n = 166). All patients in that RCT who had Modic changes and LBP at 14 months follow-up (n = 37) were invited to participate in this subsequent antibiotic trial but five did not meet the inclusion criteria. RESULTS: 29 patients completed the treatment, as three patients dropped out due to severe diarrhoea. At the end of treatment and at long-term follow-up (mean 10.8 months) there was both clinically important and statistically significant (p

Modic changes, possible causes and relation to low back pain.

UNLABELLED: In patients with low back pain (LBP) it is only possible to diagnose a small proportion, (approximately 20%), on a patho-anatomical basis. Therefore, the identification of relevant LBP subgroups, preferably on a patho-anatomical basis, is strongly needed. Signal changes on MRI in the vertebral body marrow adjacent to the end plates also known as Modic changes (MC) are common in patients with LBP (18-58%) and is strongly associated with LBP. In asymptomatic persons the prevalence is 12-13%. MC are divided into three different types. Type 1 consists of fibro vascular tissue, type 2 is yellow fat, and type 3 is sclerotic bone. The temporal evolution of MC is uncertain, but the time span is years. Subchondral bone marrow signal changes associated with pain can be observed in different specific infectious, degenerative and immunological diseases such as osseous infections, osteoarthritis, ankylosing spondylitis and spondylarthritis. In the vertebrae, MC is seen in relation to vertebral fractures, spondylodiscitis, disc herniation, severe disc degeneration, injections with chymopapain, and acute Schmorl's impressions. The aim of this paper is to propose two possible pathogenetic mechanisms causing Modic changes. These are: A mechanical cause: Degeneration of the disc causes loss of soft nuclear material, reduced disc height and hydrostatic pressure, which increases the shear forces on the endplates and micro fractures may occur. The observed MC could represent oedema secondary to the fracture and subsequent inflammation, or a result of an inflammatory process from a toxic stimulus from the nucleus pulposus that seeps through the fractures. A bacterial cause: Following a tear in the outer fibres of the annulus e.g. disc herniation, new capilarisation and inflammation develop around the extruded nuclear material. Through this tissue it is possible for anaerobic bacteria to enter the anaerobic disc and in this environment cause a slowly developing low virulent infection. The MC could be the visible signs of the inflammation and oedema surrounding this infection, because the anaerobic bacteria cannot thrive in the highly aerobic environment of the MC type 1. PERSPECTIVES: One or both of the described mechanisms can - if proven - be of significant importance for this specific subgroup of patients with LBP. Hence, it would be possible to give a more precise and relevant diagnosis to 20-50% of patients with LBP and enable in the development of efficient treatments which might be antibiotics, special rehabilitation programmes, rest, stabilizing exercise, or surgical fixation, depending on the underlying cause for the MC.

Pharmacokinetics of 1,8-cineole, a dietary toxin, in the brushtail possum (Trichosurus vulpecula): significance for feeding.

1,8-Cineole (cineole) is a Eucalyptus leaf toxin that defends against predation by herbivores such as the brushtail possum (Trichosurus vulpecula). The aim of the current study was to characterize the pharmacokinetics of cineole in the possum to improve understanding about how possums can avoid cineole toxicity when eating a Eucalyptus diet. Nine male possums were trapped in the wild and acclimated to captivity; a subcutaneous port was then implanted for venous blood sampling. Cineole was administered intravenously (10 and 15 mg kg(-1)) via a lateral tail vein and orally (30, 100 and 300 mg kg(-1)) by gavage, and blood concentrations of cineole and its metabolites were determined by gas chromatography. Cineole had a large terminal volume of distribution (V(z) = 27 l kg(-1)) and a high clearance (43 ml min(-1) kg(-1)), equal to hepatic blood flow. The terminal half-life was approximately 7 h. Oral bioavailability was low (F = 0.05) after low doses, but increased tenfold with dose, probably due to saturable first-pass metabolism. These findings indicate that when possums feed on a cineole diet, they eat until the cineole consumed is sufficient to saturate pre-systemic metabolism, leading to a rapid rise in bioavailability and cineole blood levels, and a cessation of the feeding bout. This is the first report on the pharmacokinetics of a dietary toxin in a wild herbivore, and provides insights into the interactions between the blood concentration of a plant secondary metabolite and the browsing behaviour of a herbivore.

Intra- and interobserver reproducibility of vertebral endplate signal (modic) changes in the lumbar spine: the Nordic Modic Consensus Group classification.

BACKGROUND: The lumbar vertebral endplate is considered a potential cause of specific low back pain. However, in relation to future research, there is need for a reliable and detailed magnetic resonance imaging (MRI) protocol to be used in the evaluation of vertebral endplate signal changes. PURPOSE: To assess the intra- and interobserver reliability of the "Nordic Modic classification" protocol. MATERIAL AND METHODS: MRI scans of 50 individuals representative of the general Danish population aged 40 were evaluated by two observers. Criteria for grading the changes were developed by the Nordic Modic Consensus Group. After consensus was established, all 50 MRI examinations were evaluated independently by each observer. Intraobserver reliability was assessed by re-evaluation of the 50 examinations by one of the observers. Kappa statistics were used to calculate agreement. RESULTS: Intra- and interobserver agreement of the evaluation of variables describing vertebral signal changes, i.e. Modic type, location, volume, maximum height, and endplate area, were all found to have substantial to almost perfect agreement. The evaluation of osteophytes was found to be reliable, whereas the evaluation of localized endplate defects and irregular endplates had only moderate agreement. The evaluation of development over time was found to have substantial intraobserver agreement but only moderate interobserver agreement. As expected, intraobserver agreement was generally better than interobserver agreement. CONCLUSION: In this study, we found convincing reproducibility of a detailed evaluation protocol of vertebral endplate signal changes, the "Nordic Modic Classification." The authors recommend that the evaluation protocol should be used in future studies investigating vertebral endplate signal changes.

A specialist herbivore (Neotoma stephensi) absorbs fewer plant toxins than does a generalist (Neotoma albigula).

Detoxification capacity of enzymes in the liver is thought to be the primary factor governing dietary toxin intake by mammalian herbivores. Recently, toxin absorption in the gut was proposed as an alternative process that also influences toxin intake. We examined the role of the gut in regulating toxin absorption by quantifying excretion of a plant secondary compound in the feces. We hypothesized that specialists have a greater capacity to reduce intestinal absorption of toxins than do generalists. To test this hypothesis, we compared fecal excretion of alpha-pinene in specialist (Neotoma stephensi) and generalist (Neotoma albigula) woodrats. Alpha-pinene is the most abundant monoterpene in Juniperus monosperma, which occurs in the natural diet of both woodrat species. Woodrats were fed alpha-pinene in diets containing juniper foliage for 3 wk and, in a separate experiment, were given a single oral dose of alpha-pinene. Feces were collected from animals at the end of each experiment and analyzed for alpha-pinene concentration using gas chromatography. Both woodrat species excreted unchanged alpha-pinene in the feces. However, specialist woodrats excreted 40% more alpha-pinene per unit ingested from a juniper diet and excreted nearly four times a greater percentage of an oral dose of alpha-pinene compared with generalists.

Elimination of plant toxins by herbivorous woodrats: revisiting an explanation for dietary specialization in mammalian herbivores.

Constraints on rates of detoxification and elimination of plant toxins are thought to be responsible for limiting dietary specialization in mammalian herbivores. This hypothesis, known as the detoxification limitations hypothesis, suggests that most mammalian herbivores are generalists to avoid overdosing on toxins from a single plant species. The hypothesis also predicts that the few mammalian specialists that exist should have adaptations for rapid detoxification and elimination of plant secondary compounds. We took a pharmacological approach to test whether specialists eliminate toxins from the bloodstream faster than generalists. We compared elimination rate and total exposure of alpha-pinene in closely related dietary specialist and generalist woodrats, Neotoma stephensi and N. albigula, respectively. Animals were orally gavaged with alpha-pinene, a plant secondary compound present in the natural diets of both woodrat species. We collected venous blood at 3, 6, 10, 15, and 20 min post-ingestion of alpha-pinene. Blood was analyzed for alpha-pinene concentration using gas chromatography. We found that specialist and generalist woodrats did not differ in elimination rates of alpha-pinene. However, specialists had lower exposure levels of alpha-pinene than generalists due to lower initial delivery of alpha-pinene to the general circulation. The levels of alpha-pinene detected in the bloodstream of specialists were 4.7-5.3x lower over all time intervals than generalists. Thus, specialists encounter a functionally lower dose of toxin than generalists. We suggest that the lower exposure level of specialist woodrats may be due to mechanisms in the gut that decrease toxin absorption. Regardless of mechanism, lower exposure to plant toxins may allow specialists to forage on diets with high toxin concentrations thereby facilitating dietary specialization.

[Is visual assessment of MRI adequate in the investigation of patients with temporal lobe epilepsy? Evaluation of the diagnostic accuracy of the visual assessment of MRI in mesial temporal sclerosis]. / Er visuel bedømmelse af MR-scanning tilstraekkelig ved udredning af patienter med temporallapsepilepsi? Vurdering af den diagnostiske sikkerhed ved visuel bedømmelse af mesial temporal sklerose på MR-scanninger.

INTRODUCTION: Is visual assessment of MRI adequate in patients with temporal lobe epilepsy? Visual versus quantitative MRI assessment of mesial temporal sclerosis (hippocampal gliosis (HG) and hippocampal atrophy (HA)). MATERIAL AND METHODS: The MRIs of 25 patients with temporal lobe epilepsy were assessed visually by three radiologists with different levels of neuroradiological MRI experience (expert, trained, and inexperienced). Diagnosis obtained earlier by T2-relaxometry and volume measurements were considered to be the gold standard. RESULTS: The diagnostic accuracy of visual assessment was high for unilateral HA, but low for bilateral HA and unilateral and bilateral HG, and it was not better for the expert eye than for the inexperienced. Interobserver agreement on the visual diagnosis of HG and HA (Cohen's Kappa coefficient): 0.49 (HG) and 0.84 (HA). Intraobserver reliability for the expert/trained/inexperienced observer for visual diagnosis (Kappa): 0.83/0.64/0.47 (HG) and 0.88/0.69/0.73 (HA). DISCUSSION: Reproducibility and diagnostic accuracy of visual assessment varied unacceptably from the quantitative MRI-based diagnosis. Quantitative measurements are recommended in patients suspected of MTS.

Magnetic resonance imaging and transvaginal ultrasonography for the diagnosis of adenomyosis.

OBJECTIVE: To compare the diagnostic potential of magnetic resonance imaging (MRI) and transvaginal ultrasonography (TVS) in the diagnosis of adenomyosis. DESIGN: Double blind set-up. SETTING: University medical school. PATIENT(S): We studied 106 consecutive premenopausal women who underwent hysterectomy for benign reasons. INTERVENTION(S): Transvaginal ultrasonography and MRI were compared with histopathologic examination as the golden standard. MAIN OUTCOME MEASURE(S): Adenomyosis. RESULT(S): Twenty-two (21%) patients had adenomyosis. The sensitivity and specificity were as follows: sensitivity: MRI 0.70 (0.46-0.87) and TVS 0.68 (0.44-0.86) (P=.66); specificity: MRI 0.86 (0.76-0.93) and TVS 0.65 (0.50-0.77) (P=.03). The combination of MRI and TVS was most sensitive (0.89 [0.64-0.98]), but produced the lowest specificity (0.60 [0.44-0.73]). Adenomyosis was not detected by either MRI or TVS at uterine volumes >400 mL. Exclusion of uteri >400 mL from the analysis improved the diagnostic precision of MRI, but not that of TVS. The diagnostic accuracy at MRI was improved by calculating the maximum difference between the thinnest and thickest junctional zone (JZdif) (i.e., > or =5-7 mm). CONCLUSION(S): Magnetic resonance imaging was superior to TVS for the diagnosis of adenomyosis. Magnetic resonance imaging had a higher specificity than TVS, but their sensitivities were in line. The diagnostic accuracy of MRI, as that of TVS, was at an intermediate level, but the diagnostic accuracy of the former improved by exclusion of uteri >400 mL. The combination of MRI and TVS produced the highest level of accuracy for exclusion of adenomyosis, but the low specificity may necessitate further investigation of positive findings. Measurement of the difference in junctional zone thickness may optimize the diagnosis of adenomyosis at MRI.

Comparison of detoxification enzyme mRNAs in woodrats (Neotoma lepida) and laboratory rats.

To understand how mammalian herbivores process plant secondary compounds, we examined differences in expression of biotransformation enzyme mRNAs among populations of wild woodrats (Neotoma lepida) and laboratory rats. We compared expression of mRNAs for 10 biotransforming enzymes in five families (CYP, mEH, QOR, GST, and UGT) by using Northern blot analysis. We found significant differences in eight of 10 mRNAs tested. We suggest that the differences in mRNA expression among populations of woodrats and laboratory rats may be due to differences in the secondary compound composition of their diets. Our results provide background for future studies of detoxification strategies in mammalian herbivores that combine pharmacological techniques with an ecological perspective.

[MR-cholangiography in patients suspected with choledochus calculi]. / MR-kolangiografi hos patienter mistaenkt for choledochussten.

To test a new non-invasive imaging method, magnetic resonance cholangiography (MRCP), we compared MRCP with intraoperative cholangiography (IOC) or endoscopic retrograde cholangiography (ERC). In 55 patients with 11 common bile duct stones MRCP identified all 11 stones and incorrectly found stones in seven additional patients. Predictive value of positive test was 61%, predictive value of negative test was 100%. As a consequence of MRCP, ERC or IOC can be avoided in 67% of the patients.

Volvulus of the transverse colon in children.

Volvulus of the transverse colon is extremely rare in children. A case report of this unusual condition in a 9-year-old girl is presented together with a review of the literature. The transverse colon volvulus was managed operatively by detorsion. Four and half months later, she had a similar attack. Colonoscopic detorsion was performed with elective resection of the transverse colon and primary anastomosis. Recovery was uneventful. Possible factors of pathogenesis are discussed, and an outline of diagnostic and therapeutic measures are included.

[Prevalence of risk factors in cerebral ischemia]. / Forekomst af risikofaktorer ved cerebral iskaemi.

The prevalence of risk factors for ischaemic stroke is described in 270 patients with transient ischaemic attacks or ischaemic stroke. Smoking was the most common risk factor (46%) followed by hypertension (30%) and increased levels of serum cholesterol (26%). Diabetes mellitus, atrial fibrillation and earlier myocardial infarction were less common risk factors. Ninety-one patients (34%) had two or more risk factors. In conclusion, vascular risk factors are frequently present in patients with transient ischaemic attacks or ischaemic stroke. It is still not yet clarified if risk factor modification is of any value in prevention of stroke recurrence.

Functional fracture bracing in metacarpal fractures: the Galveston metacarpal brace versus a plaster-of-Paris bandage in a prospective study.

A total of 133 patients with fractures of the second through the fifth metacarpal bones were randomized to receive either a functional brace (the Galveston metacarpal brace) or a dorsal/ulnar plaster cast. Only 42% of the patients in the metacarpal-brace group completed the treatment, in contrast to 81% of the patients in the plaster-cast group. Complications with the brace were due to 60% of the exclusion. No difference according to gender, age, fracture type, hand affected (right/left), or mechanism of injury was observed between the patients who completed the treatment and those who were excluded. Reduction of fractures could not be demonstrated. Reduction of mobility was more frequent in the plaster-cast group, but three months postinjury no reduction of mobility was observed in either group.

[Surgical treatment of forearm fractures]. / Operativ behandling af antebrachiumfrakturer.

A retrospective investigation was undertaken on 62 patients with 103 fractures. Of these, 61 fractures were treated with Rush pin, ten with plate osteosynthesis and three with cerclage. Fifty-three patients were followed up. This revealed that 50% of the patients achieved excellent or satisfactory results. 39% did not have satisfactory results while six patients (9.7%) developed pseudoarthrosis and thus unacceptable results. The healing percentage was 92.3 and the infection rate 3.1. These results are considerably better than previously reported series of forearm fractures treated with medullary osteosynthesis and they are comparable with the results of plate osteosynthesis. Rush pin osteosynthesis appears to be as good as plate osteosynthesis but this should be illustrated by means of a controlled investigation.