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.

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.

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.

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.

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].

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.

[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.

Respiratory viral infections aggravate airway damage caused by chronic rejection in rat lung allografts.

Airway damage resulting in bronchiolitis obliterans occurs frequently in patients after heart-lung and lung transplantation. Generally, chronic rejection is assumed to be the most important cause of bronchiolitis obliterans. However, viral infections might also be potential causes of airway damage after lung transplantation. In the present study, we investigated whether viral infections could induce airway damage in rat lung transplants in the absence or presence of chronic rejection. We compared the histopathology of the airways in 3 groups of rats: (1) nontransplanted LEW lungs, (2) LEW-to-LEW syngeneic lung transplants, and (3) BN-to-LEW allogeneic lung transplants. Nontransplanted and transplanted rats were treated with CsA to induce permanent graft acceptance of the allografts. Six months after transplantation, 4 noninfected rats of each group were killed for histological investigation (another 4 noninfected allografted rats were killed 56 days later). The remaining 16 rats in each group were infected with Sendai virus (parainfluenza type 1) intratracheally. These rats were killed for histological investigation 4, 7, 21, and 56 days after infection. In the lungs of the noninfected rats of the nontransplanted and syngeneically transplanted groups, airway changes were absent. After viral infection in these lungs, mild inflammation developed in the airways that was transient and completely resolved by day 56 after infection. In contrast, in the allogeneically transplanted lungs the viral infection caused severe and permanent damage of the airways. In the bronchioles and the large airways throughout the allogeneic lung transplants, inflammation with epithelial necrosis and formation of granulation tissue was present. On day 56 after infection, the bronchioles showed scarring in the submucosa and obliteration of the lumen, typical features of bronchiolitis obliterans. This study shows that a respiratory viral infection aggravates the airway damage in rat lung allografts with chronic rejection. The findings suggest that viral infections and chronic rejection play a synergistic role in the development of bronchiolitis obliterans after human heart-lung and lung transplantation: the virus infection may stimulate chronic rejection and rejection may hamper the local defense against the virus.

Inadequate antibody response against respiratory viral infection in long-surviving rat lung allografts.

Lung transplant recipients suffer from a high number of viral infections. It has been suggested that the defense against viral infections is impaired in lung transplants. Therefore, we investigated in rat lung transplants whether antibody responses against an intrapulmonary viral infection were impaired in 3 groups of rats with: (1) BN-to-LEW allogeneic lung transplants, (2) LEW-to-LEW syngeneic lung transplants, and (3) nontransplanted LEW lungs. All rats (including those with nontransplanted, normal lungs) were treated with cyclosporine on days 2 and 3 after operation; this treatment is adequate to induce permanent graft acceptance of the allografts. Six months after transplantation, viral infections with Sendai virus (parainfluenza type I) were induced intratracheally. At day 0, immediately before infection, and at days 4, 7, 21, and 56 after infection, 4 rats in each group were killed for histological evaluation of the lungs. The number of antibody-positive cells in the bronchus-associated lymphoid tissue (BALT) in the lungs and in the spleen, and presence of the virus in the lungs were determined by immunohistology. Serum antibody titers were followed for 56 days after infection. The allogeneically transplanted lungs failed to respond adequately against the virus: the number of antibody-positive cells in the BALT did not increase after infection, serum antibody titers were hardly detectable, and virus was present in the airways of the lungs up to day 21 after infection. In contrast, in the syngeneically and nontransplanted lungs, the number of antibody-forming cells in the BALT increased steeply until day 7, serum antibody titers rose until day 14, and virus could be detected only on day 4 after infection. This study shows that in rat lung allografts, both the local antibody production in the BALT and the systemic antibody response against a respiratory viral infection are inadequate. As a consequence, the virus is present longer in these allografted lungs and can exert its damaging effect over a longer period of time. These results may explain why lung transplants are so susceptible to viral infections.

Synthesis and organ distribution of [18F]fluoro-Org 6141 in the rat: a potential glucocorticoid receptor ligand for positron emission tomography.

For the synthesis of [18F]Fluoro-Org 6141 via a nucleophilic substitution reaction with 18F-, the tosyl group was chosen as the leaving group because of its stability and excellent leaving group ability. The biodistribution of the high affinity and moderate lipophilicity (log P = 2.66, calculated value) ligand [18F]Fluoro-Org 6141 (specific activity 8.2 to 37 TBq/mmol, yield 10% at EOB) was examined in sham adrenalectomized (sADX) and adrenalectomized (ADX) male Wistar rats. Two days after ADX or sADX, the animals were anesthetized and 0.37 to 1.85 MBq of [18F]Fluoro-Org 6141 was administered intravenously. Kinetics of 18F activity uptake were monitored for 3 h using a stationary double-headed positron emission tomography (PET) camera, and the biodistribution was assessed by ex vivo determination of radioactivity in several tissues and different brain areas. One hour after injection of the radioligand, the bladder, kidney, liver, trachea, and bone of sADX animals contained more concentration on a wet weight basis than blood. Three hours post injection, radioactivity was retained in bladder, trachea, and bone. The accumulation of radioactivity in brain corresponded to the concentration of activity in the blood within the first hours after injection. ADX animals showed a higher uptake of 18F activity in spleen, testes, and brain areas (hippocampus and brainstem) but a lower uptake in bone than sADX rats. PET scans suggested that 18F activity uptake in the brain had not yet reached a maximum at this interval. Although [18F]Fluoro-Org 6141 is not useful for PET studies of glucocorticoid receptors (GRs), the results obtained with this compound indicate a synthetic strategy suitable for the synthesis of high-affinity radioligands for GRs.

Administration of an LHRH-antagonist to male mice: effects on in vivo secretion of hormones and on the growth of a transplantable human prostatic carcinoma.

The potent luteinizing hormone releasing hormone (LHRH) antagonist [N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]-LHRH was chronically administered to male nude mice bearing the transplantable human hormone-dependent prostatic adenocarcinoma PC-82. Treatment of tumor-bearing male mice with a daily dose of 100 micrograms (4 mg/kg b w.) for 21 days did not significantly affect the growth of the PC-82 tumor tissue, or the weights of ventral prostate, seminal vesicles and testes. At 24 hours after the last dose of the antagonist the mean plasma-testosterone (T) value in these animals was not different from the control level. Administration of similar doses of the antagonist to intact normal immunocompetent male mice significantly reduced plasma LH concentrations and suppressed plasma-T to near-castrate levels, when blood was taken 2 hours after the last injection. At 24 hours after the last dose, however, plasma concentrations of LH and T had returned to control levels. This time-dependent pattern of T suppression by the antagonist was confirmed by a time-course experiment in animals receiving a single dose of the compound. These data demonstrate that a daily high dose of this antagonist cannot effectively suppress plasma-T in male mice. Therefore, the mouse may not be a suitable model for the investigation of the "castration-like" effect of LHRH-antagonists on androgen-dependent prostate xenografts.

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.

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.

Synthetic approaches toward total synthesis of 12 beta-methyl- and 12-methylene-19-norpregnanes.

The effect of a substituent in the 12-position of progestagens was studied. To this end, various approaches toward the preparation of 12 beta-alkyl- and 12-alkylidenenorpregnanes were investigated. Eventually, the desired compounds 17 beta-hydroxy-12 beta-methyl-18a-homo-19-nor-17 alpha-pregn-4-en-20-yn-3-one (37) and 17 beta-hydroxy-12-methylene-18a-homo-19-nor-17 alpha-pregn-4-en-20-yn- 3-one (38) were obtained in racemic form by total synthesis; they were shown to lack progestagenic activity.

Ent-16 alpha-methylamino-3-methoxy-1,3,5(10)-estratrien-17 beta-ol hydrochloride, a selective anti-arrhytmic enantiosteroid.

The title compound and its antipode with natural steroid configuration were synthesized and tested. Both compounds showed equal potency as anti-arrhythmic compounds. An additional effect found for the steroid with natural configuration was its plasma cholesterol lowering activity in the rat. This suggests that enantiosteroids may have a more selective action than the steroids with natural configuration.

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.

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.