Safety and feasibility of arterial wall targeting with robot-assisted high intensity focused ultrasound: a preclinical study.

PURPOSE: High-intensity focused ultrasound (HIFU) is a potential noninvasive thermal ablation method for the treatment of peripheral artery disease. Dual-mode ultrasound arrays (DMUA) offer the possibility of simultaneous imaging and treatment. In this study, safety and feasibility of femoral artery robot-assisted HIFU/DMUA therapy was assessed. METHODS: In 18 pigs (∼50kg), angiography and diagnostic ultrasound were used to visualize diameter and blood flow of the external femoral arteries (EFA). HIFU/DMUA-therapy was unilaterally applied to the EFA dorsal wall using a 3.5 MHz, 64-element transducer, closed-loop-control was used to automatically adjust energy delivery to control thermal lesion formation. A continuous lesion of at least 25 mm was created by delivering 6-8 HIFU shots per imaging plane perpendicular to the artery spaced 1 mm apart. Directly after HIFU/DMUA-therapy and after 0, 3 or 14 days follow up, diameter and blood flow were measured and the skin was macroscopically examined for thermal damage. The tissue was removed for histological analysis. RESULTS: No complications were observed. The most frequently observed treatment effect was formation of scar tissue, predominantly in the adventitia and the surrounding tissue. No damage to the endothelium or excessive damage of the surrounding tissue was observed. There was no significant decrease in the mean arterial diameter after HIFU/DMUA-therapy. CONCLUSION: HIFU/DMUA therapy successfully targeted the vessel walls of healthy porcine arteries, without causing endothelial damage or other vascular complications. Therefore, this therapy can be safely applied to healthy arterial walls in animals. Future studies should focus on safety and dose-finding in atherosclerotic diseased arteries.

Intravenous thrombolysis for large vessel or distal occlusions presenting with mild stroke severity.

BACKGROUND AND PURPOSE: We investigated the effectiveness of intravenous thrombolysis (IVT) in acute ischaemic stroke (AIS) patients with large vessel or distal occlusions and mild neurological deficits, defined as National Institutes of Health Stroke Scale scores < 6 points. METHODS: The primary efficacy outcome was 3-month functional independence (FI) [modified Rankin Scale (mRS) scores 0-2] that was compared between patients with and without IVT treatment. Other efficacy outcomes of interest included 3-month favorable functional outcome (mRS scores 0-1) and mRS score distribution at discharge and at 3 months. The safety outcomes comprised all-cause 3-month mortality, symptomatic intracranial hemorrhage (ICH), asymptomatic ICH and severe systemic bleeding. RESULTS: We evaluated 336 AIS patients with large vessel or distal occlusions and mild stroke severity (mean age 63 ± 15 years, 45% women). Patients treated with IVT (n = 162) had higher FI (85.6% vs. 74.8%, P = 0.027) with lower mRS scores at hospital discharge (P = 0.034) compared with the remaining patients. No differences were detected in any of the safety outcomes including symptomatic ICH, asymptomatic ICH, severe systemic bleeding and 3-month mortality. IVT was associated with higher likelihood of 3-month FI [odds ratio (OR), 2.19; 95% confidence intervals (CI), 1.09-4.42], 3-month favorable functional outcome (OR, 1.99; 95% CI, 1.10-3.57), functional improvement at discharge [common OR (per 1-point decrease in mRS score), 2.94; 95% CI, 1.67-5.26)] and at 3 months (common OR, 1.72; 95% CI, 1.06-2.86) on multivariable logistic regression models adjusting for potential confounders, including mechanical thrombectomy. CONCLUSIONS: Intravenous thrombolysis is independently associated with higher odds of improved discharge and 3-month functional outcomes in AIS patients with large vessel or distal occlusions and mild stroke severity. IVT appears not to increase the risk of systemic or symptomatic intracranial bleeding.

Post-treatment reading development in children with dyslexia: the challenge remains.

The goal of this study was to examine the post-treatment development of word and pseudoword accuracy and fluency and its cognitive and linguistic predictors in Dutch children with dyslexia compared with typical readers in the upper primary grades. Word and pseudoword reading accuracy and fluency were assessed at the start and end of grade 5 and at the end of grade 6. Phonological awareness, rapid naming, verbal short-term memory, vocabulary, and visual attention span were assessed at the start of grade 5. Repeated measures ANOVAs revealed that children with dyslexia were less accurate than typical readers and showed very little improvements in accuracy over time. They were also less fluent and showed less growth in reading fluency than typical readers. The children with dyslexia did improve more in word reading fluency than in pseudoword reading fluency over time. Visual attention span and phonological awareness predicted reading accuracy development in typical readers, while rapid naming predicted individual differences in reading fluency in children with dyslexia. It can be concluded that in the upper grades, children with dyslexia not only struggled with fluent reading, but they also still struggled with accurate reading in a relatively transparent orthography like Dutch, even after they had received a reading intervention to remediate their reading difficulties.

Deficient Response to Altered Auditory Feedback in Dyslexia.

Although dyslexia is characterized by a deficit in phonological representations, the nature of this deficit is debated. Previously, it was shown that adults with dyslexia respond differently to online manipulations of auditory feedback. In the present study, we found that individual differences in reading and reading-related skills within a group of 30 children (10-13 years old) with dyslexia were associated with the response to altered feedback. The fractional anisotropy of the arcuate fasciculus/superior longitudinal fasciculus was not directly related to the response to altered feedback. This study corroborates that speech perception-production communication is important for phonological representations and reading.

[Preventive contralateral mastectomy despite absence of gene mutation; management and treatment of women with no medical indication]. / Geen aangetoonde genmutatie, maar toch preventieve contralaterale mastectomie.

Recently, there has been an increase in the rate of contralateral prophylactic mastectomies (CPM) as a therapy for breast cancer. The CPM is performed to achieve a reduction in the risk of developing asecond breast cancer. However, evidence is lacking for beneficial survival outcomes after a CPM in patients without a gene mutation, and complications of surgery are inevitable. Currently there are no evidence-based clinical practice guidelines available for clinicians to decide upon the right treatment for patients without a gene mutation. Our hospitals have therefore implemented their own clinical pathway to achieve a comprehensive treatment for this group of patients. In this article we will provide an overview of the existing literature and illustrate our clinical pathway by presenting three patients treated in our hospitals in the last two years.

Short communication: Effect of straw inclusion rate in a dry total mixed ration on the behavior of weaned dairy calves.

The primary objective of this study was to determine the effect of straw inclusion levels on the feeding behavior of young, weaned calves adapted to a dry total mixed ration (TMR) composed of a multitextured concentrate and chopped straw. A secondary objective was to determine how developed feeding patterns persist after calves were switched to a conventional silage-based diet. Ten Holstein bull calves (91 ± 2.4d of age, weighing 136 ± 12.3 kg) were assigned to 1 of 2 treatments: a TMR containing [dry matter (DM) basis] either (1) 85% concentrate and 15% chopped straw for 10 wk (wk 1 to 10) or (2) 85% concentrate and 15% chopped straw for 5 wk (wk 1 to 5), then 70% concentrate and 30% chopped straw for 5 wk (wk 6 to 10). After 10 wk, all animals were transitioned to a TMR containing (DM basis) 42.3% corn silage and 57.7% haylage for 2 wk (wk 11 to 12). During wk 1 to 5, all calves had similar DMI (5.5 kg/d), average daily gain (1.7 kg/d), feed efficiency (3.5 kg of DM/kg of gain), and eating time (151.9 min/d). During wk 6 to 10, calves transitioned to the 70% diet ate less DM (5.5 vs. 7.4 kg/d), grew more slowly (1.3 vs. 1.6 kg/d), sorted more against long forage particles (62.8 vs. 103.8%), and had greater feeding times (194.9 vs. 102.6 min/d). The difference in feeding time occurred only during the first 8 h after feed delivery. Despite similar DMI (5.2 kg/d) and average daily gain (1.1 kg/d) in wk 11 to 12, differences in behavior were observed resulting from previous diets. In wk 11 to 12, calves previously fed the 70% diet continued to have a longer meal immediately after feed delivery. Overall, the results indicate that diluting a dry TMR containing a multitextured concentrate and chopped straw with more straw resulted in calves spending more time feeding and having longer meals immediately after feed delivery; this feeding pattern carried over after calves were transitioned to a silage-based ration.

Design, aerodynamics and autonomy of the DelFly.

One of the major challenges in robotics is to develop a fly-like robot that can autonomously fly around in unknown environments. In this paper, we discuss the current state of the DelFly project, in which we follow a top-down approach to ever smaller and more autonomous ornithopters. The presented findings concerning the design, aerodynamics and autonomy of the DelFly illustrate some of the properties of the top-down approach, which allows the identification and resolution of issues that also play a role at smaller scales. A parametric variation of the wing stiffener layout produced a 5% more power-efficient wing. An experimental aerodynamic investigation revealed that this could be associated with an improved stiffness of the wing, while further providing evidence of the vortex development during the flap cycle. The presented experiments resulted in an improvement in the generated lift, allowing the inclusion of a yaw rate gyro, pressure sensor and microcontroller onboard the DelFly. The autonomy of the DelFly is expanded by achieving (1) an improved turning logic to obtain better vision-based obstacle avoidance performance in environments with varying texture and (2) successful onboard height control based on the pressure sensor.

Weak hand preference in children with down syndrome is associated with language deficits.

This study explores associations between language ability and hand preference in children with Down syndrome. Compared to typically developing children of the same age, children with Down syndrome showed weaker hand preference, were less consistent in the hand they used and also less willing to reach to extreme positions in contralateral space. Within the group of children with Down syndrome, those who showed a stronger or more consistent hand preference had better language and memory skills. This association could not be explained by differences in non-verbal cognitive ability or hearing loss. These findings are discussed within the theory of neurolinguistic development proposed by Locke [Locke (1997). Brain & Language, 58, 265-326].

Proposal for a multidisciplinary approach to the patient with morbid obesity: the St. Franciscus Hospital morbid obesity program.

Morbid obesity is a serious disease as it is accompanied by substantial co-morbidity and mortality. The prevalence is increasing to an alarming extent, in Europe as well as in the United States. In the past few decades, bariatric surgery has developed and gained importance. It currently represents the only long-lasting therapy for this group of patients, resulting in an efficient reduction in body weight and obesity-related medical conditions, mostly cardiovascular in nature. The importance of a standardized protocol, the use of selection criteria, and a multidisciplinary approach have been stressed but not yet described in detail. Therefore, in this article, the multidisciplinary approach and the treatment protocol that have been applied in our hospital for more than 20 years are set out in a detailed manner. The application of a strict protocol may help to select and follow-up motivated patients and to organize multidisciplinary research activities.

Efficient library synthesis of imidazoles using a multicomponent reaction and microwave irradiation.

Optimization of Radziszewski's four-component reaction employing a microwave-assisted protocol, led to a small library of 48 imidazoles with a success rate of 65% (conversion > 45%). All three diversity points of the four-component reaction were varied. Aromatic and aliphatic inputs were successfully implemented and mono-, di-, tri- and tetrasubstituted imidazoles with various substitution patterns were synthesized. Furthermore, unsymmetrical diketones could successfully be used which improved the intrinsic diversity of the method significantly. If the unsymmetrical diketone 1,2-phenylpropanedione (R1 and R2) was used two regioisomers were formed. Depending on the type of amine (R4) and aldehyde (R3) applied, regioselectivity was modest to good. Based on these results, a reaction mechanism is proposed.

[Favourable short-term effects of a multidisciplinary, behavioural therapy, group treatment for overweight or obese children]. / Gunstige kortetermijneffecten van een multidisciplinaire gedragstherapeutische groepsbehandeling voor kinderen met overgewicht of obesitas.

OBJECTIVE: Evaluate the effect of a multidisciplinary, behavioural therapy, group therapy for obese children. DESIGN: Descriptive. METHOD: The treatment consisted of 8 child and 2 parent sessions over a period of 10 weeks, in the Sint Franciscus Gasthuis Hospital in Rotterdam, the Netherlands. Attention was devoted to eating behaviour, physical exercise and psychosocial aspects. Data were collected about children treated in the period 1999-2002. Inclusion criteria were: age 7-14 years, body-mass index (BMI) > or = 25 kg/m2, spoke Dutch, and no problematic behaviour according to the CBCL (total score < 70). Outcome measures were BMI, energy uptake, treadmill endurance time in the Bruce test, and problematic behaviour. There were three measurement points: 3 months before the treatment, immediately before the treatment and immediately after the treatment. RESULTS: 7 of the 78 children who were to participate dropped out. The study cohort consisted of 52 girls and 19 boys with an average age of 10.5 years. In the months prior to the treatment there was no statistically significant change in the outcomes. During the treatment period all of the children lost weight. The mean BMI decreased by 1.7 kg/m2 (-0.3 SDS), the mean daily energy uptake decreased by 1242 kJ and the maximal endurance time increased by 0.8 min (all: p < 0.001). There was no significant decrease in the score for problematic behaviour. CONCLUSION: For the overweight or obese children who followed the treatment programme the BMI and energy intake decreased during the programme and the fitness increased.

Glucocorticoid receptor antagonists: new tools to investigate disorders characterized by cortisol hypersecretion.

Increased cortisol levels have been observed in patients suffering from a number of metabolic and psychiatric disorders. In some of these disorders a causal relationship has been suggested between the increased cortisol secretion and the observed clinical phenomena. Glucocorticoid receptor antagonists which block cortisol effects might have a benefit in both the diagnosis and treatment of these disorders. Selective glucocorticoid receptor antagonists with in vivo potency have not been described thus far, partly due to the similarity between the glucocorticoid and progesterone receptors. In the present studies, we report on three different chemical classes derived from the glucocorticoid/progestagen antagonist RU486. Selected compounds from the classes 11-monoaryl steroids, 11,21-bisaryl steroids and 11-aryl, 16-hydroxy steroids proved to be selective glucocorticoid receptor binders with in vivo antagonistic activity. Most compounds were able to pass the blood-brain barrier. These compounds offer the opportunity to investigate and possibly treat patients with a disturbed hypothalamus-pituitary-adrenal axis without side effects caused by an antiprogestagenic action.

Conformational comparison of five follicular fluid meiosis-activating sterol-related active and inactive compounds.

The crystal structures of five follicular fluid meiosis-activating sterol-related Delta(8,14)-sterol compounds are presented. These are 4,4-dimethyl-23-phenyl-24-nor-5alpha-chola-8,14-dien-3beta-ol, C(31)H(44)O, 4,4-dimethyl-22-phenyl-23,24-dinor-5alpha-chola-8,14-dien-3beta-ol, C(30)H(42)O, (20R)-4,4-dimethyl-22-oxa-5alpha,20-cholesta-8,14,24-trien-3beta-ol, C(28)H(44)O(2), 4,4-dimethyl-23-phenyl-22-oxa-24-nor-5alpha-chola-8,14-dien-3beta-ol-water (4/1), 4C(30)H(42)O(2).H(2)O, and 4,4-dimethyl-5alpha-cholesta-8,14-dien-3-one, C(29)H(46)O. Two of the derivatives are inactive and three are active as agonists. Preliminary structure-activity relationship studies showed that the positions of the double bonds in the skeleton and the structures of the side chains are important determinants for activity. The conformations of the skeletons were compared with double-bond isomers retrieved from the Cambridge Structural Database [Allen & Kennard (1993). Chem. Des. Autom. News, 8, 1, 31-37]; no significant differences were found. Thus, conformational changes induced by the double bonds are not discriminative with respect to the activity of the compounds. Comparisons of the side-chain conformations of active and inactive structures revealed that the crystal structures were not conclusive as far as correlation of conformation and activity of the side chains were concerned.

Relation between the molecular electrostatic potential and activity of some FF-MAS related sterol compounds.

Follicular Fluid-Meiosis Activating Sterol (FF-MAS) is a compound important for maturation of gametes in mammals. Therefore, it may serve as a lead compound for a novel method of contraception. We studied the Molecular Electrostatic Potential of a series of active and inactive analogues of FF-MAS. We find that double bond configurations required for activity result in a local negative electrostatic potential which is larger as well as more dense compared to those of inactive molecules. We therefore hypothesize that the interaction energy of the double bond system of the MAS compounds with its receptor substantially contributes to the overall interaction energy. This notion is supported by interaction studies of the electrostatic potential originating from the double bonds in crystal structures of cholesterol and four MAS-derived Delta(8,14) structures synthesized and crystallized by us. In addition, we were able to derive a pharmacophore model that relates the local average ESP and its distance to the 3beta-OH oxygen atom to the activity of the molecules.

Synthesis of C-5'-alkyl substituted 17-spirofuran 19-norsteroids.

A number of new steroidal 17-spirofuran derivatives of the 19-nor series containing Me, Et or (i)Pr-substituents in the heterocyclic moiety has been prepared, which are expected to have a strong progestagenic activity. The proposed approach made use of the 1-3-dipolar cycloaddition of low-molecular nitrile oxides with steroidal acetylenic alcohols followed by transformation of the isoxazole side chain.

Synthesis of (3alpha,7beta,17alpha)-7-methyl-19-norpregn-5(10)-en-20-yne-3,7,17-triol, a metabolite of ORG OD14, and its 7-epimer.

The syntheses of the 7beta-hydroxy metabolite of ORG OD14 (Livial((R))), (3alpha,7beta,17alpha)-7-methyl-19-norpregn-5(10)-en-20-yne-3,7,17-triol (35), and its 7-epimer, (3alpha,7alpha,17alpha)-7-methyl-19-norpregn-5(10)-en-20-yne-3,7,17-triol (11), are described.

Application of (quantitative) structure-activity relationships to progestagens: from serendipity to structure-based design.

Progestagens are drugs, which are widely used in hormonal contraception and in hormone-replacement therapy. Since the natural hormone, progesterone, lacks oral activity, much effort has been devoted to finding analogues with improved oral activity and, preferably, higher potency and selectivity. A crystal structure of the hormone binding domain (HBD) region of the progesterone receptor (PR) could only be obtained recently. For more than forty years the process of designing new progestagens could therefore only be guided by the knowledge of the structure of the ligand and its corresponding in vitro/in vivo activities. While in early days chemical intuition and simple statistics (structure-activity relationship - SAR) were leading the drug design process, in later days more complex statistics and visualization tools have become routinely part of quantitative structure-activity relationship (QSAR) studies. The present review aims to provide a general overview of the strategies, efforts and achievements of synthetic and computational chemists in more than forty years of development of progestagens.

Synthesis of (3alpha,7beta, 17alpha)-7-methyl-19-norpregn-5(10)-en-20-yne-3,7,17-triol, a metabolite of ORG OD14, and its 7-epimer.

The syntheses of the 7beta-hydroxy metabolite of ORG OD14 (Livial), (3alpha,7beta, 17alpha)-7-methyl-19-norpregn-5(10)-en-20-yne-3,7,17-t riol (35), and its 7-epimer, (3alpha,7alpha, 17alpha)-7-methyl-19-norpregn-5(10)-en-20-yne-3,7,17-t riol (11), are described.