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Background & Aim: To assess consonant proficiency and velopharyngeal function in 10-year-old children born with unilateral cleft lip and palate (UCLP) within the Scandcleft project.Methods & Procedures: Three parallel group, randomized, clinical trials were undertaken as an international multicentre study by nine cleft teams in five countries. Three different surgical protocols for primary palate repair (Arm B–Lip and soft palate closure at 3–4 months, hard palate closure at 36 months, Arm C–Lip closure at 3–4 months, hard and soft palate closure at 12 months, and Arm D–Lip closure at 3–4 months combined with a single-layer closure of the hard palate using a vomer flap, soft palate closure at 12 months) were tested against a common procedure (Arm A–Lip and soft palate closure at 3–4 months followed by hard palate closure at 12 months) in the total cohort of 431 children born with a non-syndromic UCLP. Speech audio and video recordings of 399 children were available and perceptually analysed. Percentage of consonants correct (PCC) from a naming test, an overall rating of velopharyngeal competence (VPC) (VPC-Rate), and a composite measure (VPC-Sum) were reported.Outcomes & Results: The mean levels of consonant proficiency (PCC score) in the trial arms were 86–92% and between 58% and 83% of the children had VPC (VPC-Sum). Only 50–73% of the participants had a consonant proficiency level with their peers. Girls performed better throughout. Long delay of the hard palate repair (Arm B) indicated lower PCC and simultaneous hard and soft palate closure higher (Arm C). However, the proportion of participants with primary VPC (not including velopharyngeal surgeries) was highest in Arm B (68%) and lowest in Arm C (47%).Conclusions & Implications: The speech outcome in terms of PCC and VPC was low across the trials. The different protocols had their pros and cons and there is no obvious evidence to recommend any of the protocols as superior. Aspects other than primary surgical method, such as time after velopharyngeal surgery, surgical experience, hearing level, language difficulties and speech therapy, need to be thoroughly reviewed for a better understanding of what has affected speech outcome at 10 years.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The LOOP Study was funded by Innovation Fund Denmark [grant number 12-1352259], The Research Foundation for the Capital Region of Denmark, The Danish Heart Foundation [grant number 11-04-R83-A3363-22625], Aalborg University Talent Management Program, Arvid Nilssons Fond, Skibsreder Per Henriksen, R og Hustrus Fond, the European Union’s Horizon 2020 program [grant number 847770], Læge Sophus Carl Emil Friis og hustru Olga Doris Friis’ Legat, and an unrestricted grant from Medtronic. Background It is well known that atrial fibrillation (AF) confers a substantially increased risk of ischemic stroke, but data on health benefits from AF screening are scarce. The newly proposed MVP risk score combining the duration, voltage and morphology of P-wave has been demonstrated to be predictive of AF and might therefore also be useful in risk-stratifying individuals for AF screening and subsequent treatment. Purpose The present study sought to examine MVP risk score and its P-wave components for prediction of AF screening effects. Methods The LOOP Study randomized AF-naïve individuals aged 70-90 years with additional stroke risk factors to either continuous AF screening with implantable loop recorder (ILR) and subsequent anticoagulation initiation upon detection of AF episode ≥6 minutes, or usual care. In this secondary analysis, the LOOP participants with a baseline 12-lead electrocardiogram (ECG) suitable for P-wave measurement were included. Results Of 5759 participants included, 265 (4.6%) had had ischemic stroke during follow-up: 213 (4.9%) of 4311 in the control group versus 64 (3.6%) of 1448 in the ILR group. Among the participants in the control group, a significantly increased risk of ischemic stroke was observed for MVP score 5-6 versus score 0-2 (hazard ratio (HR) 1.66 [95% confidence interval (CI): 1.01-2.75]) and for the presence of interatrial block (IAB) versus no IAB (HR 1.85 [95% CI: 1.19-2.86]), whereas a P-wave voltage in lead I (PWVI) 110 versus ≤110 ms). Compared with usual care, ILR screening did not significantly reduce the stroke risk regardless of MVP risk score, PWD, PWVI, or IAB pattern at baseline. Conclusions In an elderly population with additional stroke risk factors, both the P-wave parameters and the combined MVP risk score based on 12-lead ECG were associated with ischemic stroke, but these did not successfully demonstrate an association with effects of AF screening on stroke prevention.

Background Cornell voltage criteria (CL) and Sokolow-Lyon criteria (SL) for electrocardiographic left ventricular hypertrophy (ECG-LVH) are well known predictors of cardiovascular outcome. However, their predictive value may differ according to patient type and remains to be further tested in diabetic mellitus (DM) patients. Purpose The present study aims to determine the prevalence of each ECG-LVH criteria and their respective predictive value in DM patients. Method A retrospective cohort study of individuals age >40 years with digital ECGs from primary care were collected during 2001 to 2011. Data on medication, comorbidity, and outcomes were collected from Danish nationwide registries. DM was defined if individuals were prescribed oral antidiabetics or insulin, if they were diagnosed with DM type I or II, or had a HbA1c>48 mmol/l. Cox multivariable analysis was used for estimating hazard ratio (HR) and 95% confidence intervals (95% CI) for all-cause mortality during follow-up of up to 17 years. Results Included were 183,749 individuals with a digital ECG collected in primary care. A total of 13,003 (7.1%) individuals had DM, they were older (65.8 vs. 61.3 years), had more myocardial infarction (16.1% vs. 5.2%), stroke (14.4% vs. 6.2%), hypertension (35.1% vs. 13.2%), CL LVH (8.0% vs. 5.6%) and more were males (53.3% vs. 45.3%) compared to the non-DM individuals (all p0.45). Conclusion Cornell Voltage Left Ventricular Hypertrophy is a strong predictor of mortality in patients with and without diabetes and an independent risk factor compared to hypertension and diabetes. The predictive value was substantially stronger than Sokolow-Lyon Voltage criteria for hypertrophy. Figure 1. LVH and all-cause mortality Funding Acknowledgement Type of funding source: None

Background: Stroke is an increasing health problem worldwide. Atrial fibrillation (AF) is a major risk factor for stroke, and the attention given to AF screening is rising, as new monitoring technologies emerge. We aimed to evaluate the performance of a large panel of screening strategies and to assess population characteristics associated with diagnostic yield. Methods: Individuals with stroke risk factors but without AF were recruited from the general population to undergo screening with an implantable loop recorder. New-onset AF lasting ≥6 minutes was adjudicated by senior cardiologists. After continuous monitoring for >3 years, complete day-to-day heart rhythm data sets were reconstructed for every participant, including exact time of onset and termination of all AF episodes. Random sampling was applied to assess the sensitivity and negative predictive value of screening with various simulated screening strategies compared with the implantable loop recorder. The diagnostic yield across strategies and population subgroups was compared by use of nonparametric tests. Results: The rhythm data sets comprised 590 participants enduring a total of 659 758 days of continuous monitoring and 20 110 AF episodes. In these data, a single 10-second ECG yielded a sensitivity (and negative predictive value) of 1.5% (66%) for AF detection, increasing to 8.3% (67%) for twice-daily 30-second ECGs during 14 days and to 11% (68%), 13% (68%), 15% (69%), 21% (70%), and 34% (74%) for a single 24-hour, 48-hour, 72-hour, 7-day, or 30-day continuous monitoring, respectively. AF detection further improved when subsequent screenings were performed or when the same monitoring duration was spread over several periods compared with a single period (eg, three 24-hour monitorings versus one 72-hour monitoring; P 2 score >2, or NT-proBNP (N-terminal pro-B-type natriuretic peptide) ≥40 pmol/L and among participants with underlying ≥24-hour AF episodes compared with shorter AF ( P Conclusions: In screening for AF among participants with stroke risk factors, the diagnostic yield increased with duration, dispersion, and number of screenings, although all strategies had low yield compared with the implantable loop recorder. The sensitivity was higher among participants who were older, were male, or had higher NT-proBNP. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02036450 .

Aims Potassium disturbances are common and associated with increased morbidity and mortality, even in patients without prior cardiovascular disease. We examined six electrocardiographic (ECG) measures and their association to serum potassium levels. Methods and results From the Copenhagen General Practitioners' Laboratory, we identified 163,547 individuals aged ≥16 years with a first available ECG and a concomitant serum potassium measurement during 2001–2011. Restricted cubic splines curves showed a non-linear relationship between potassium and the Fridericia corrected QT (QTcF) interval, T-wave amplitude, morphology combination score (MCS), PR interval, P-wave amplitude and duration. Therefore, potassium was stratified in two intervals K: 2.0–4.1 mmol/L and 4.2–6.0 mmol/L for further analyses. Within the low potassium range, we observed: QTcF was 12.5 ms longer for each mmol/L decrease in potassium (p Restricted cubic splines on adjusted lin Conclusion The association of potassium with six commonly measured ECG parameters was non-linear. Strong associations between ECG abnormalities and potassium were seen among individuals with lower potassium levels (≤4.1 mmol/L). Acknowledgement/Funding None

The output from a motor nucleus is determined by the synaptic input to the motor neurons and their intrinsic properties. Here, we explore whether the source of synaptic inputs to the motor neurons (cats) and the age or post-stroke conditions (humans) may change the recruitment gain of the motor neuron pool. In cats, the size of Ia EPSPs in triceps surae motor neurons (input) and monosynaptic reflexes (MSRs; output) was recorded in the soleus and medial gastrocnemius motor nerves following graded stimulation of dorsal roots. The MSR was plotted against the EPSP thereby obtaining a measure of the recruitment gain. Conditioning stimulation of sural and peroneal cutaneous afferents caused significant increase in the recruitment gain of the medial gastrocnemius, but not the soleus motor neuron pool. In humans, the discharge probability of individual soleus motor units (input) and soleus H-reflexes (output) was performed. With graded stimulation of the tibial nerve, the gain of the motor neuron pool was assessed as the slope of the relation between probability of firing and the reflex size. The gain in young subjects was higher than in elderly subjects. The gain in post-stroke survivors was higher than in age-matched neurologically intact subjects. These findings provide experimental evidence that recruitment gain of a motor neuron pool contributes to the regulation of movement at the final output stage from the spinal cord and should be considered when interpreting changes in reflex excitability in relation to movement or injuries of the nervous system.

With the availability of large-scale biobanks, genome-wide scale phenome-wide association studies are being instrumental in discovering novel genetic variants associated with clinical phenotypes. As increasing number of such association results from different biobanks become available, methods to meta-analyse those association results is of great interest. Because the binary phenotypes in biobank-based studies are mostly unbalanced in their case-control ratios, very few methods can provide well-calibrated tests for associations. For example, traditional Z score-based meta-analysis often results in conservative or anti-conservative type I error rates in such unbalanced scenarios. We propose two meta-analysis strategies that can efficiently combine association results from biobank-based studies with such unbalanced phenotypes, using the saddlepoint approximation-based score test method (SPA). Our first method involves sharing the overall genotype counts from each study, and the second method involves sharing an approximation of the distribution of the score test statistic from each study using cubic Hermite splines. We compare our proposed methods with a traditional Z score-based meta-analysis strategy using numerical simulations and real data applications, and demonstrate the superior performance of our proposed methods in terms of type I error control.

We describe the genotypes of the complete cohort, from 1967 to 2014, of phenylketonuria (PKU) patients in Denmark, in total 376 patients. A total of 752 independent alleles were investigated. Mutations were identified on 744 PKU alleles (98.9%). In total, 82 different mutations were present in the cohort. The most frequent mutation c.1315+1GA (IVS12+1GA) was found on 25.80% of the 744 alleles. Other very frequent mutations were c.1222CT (p.R408W) (16.93%) and c.1241AG (p.Y414C) (11.15%). Among the identified mutations, five mutations; c.532GA (p.E178K), c.730CT (p.P244S), c.925GA (p.A309T), c.1228TA (p.F410I), and c.1199+4AG (IVS11+4AG) have not been reported previously. The metabolic phenotypes of PKU are classified into four categories; 'classical PKU', 'moderate PKU', 'mild PKU' and 'mild hyperphenylalaninemia'. In this study, we assigned the phenotypic outcome of three of the five novel mutations and furthermore six not previously classified mutations to one of the four PKU categories.

Phenylketonuria (PKU) is caused by an autosomal recessive deficiency of the enzyme phelnylalanine hydroxylase leading to a failure to convert phenylalanine to tyrosine. To avoid irreversible neurological damage because of increased phenylalanine, treatment is instituted rapidly after birth. We examined 31 adult PKU patients living on a less protein-restricted diet. Theoretically, these PKU patients had an increased risk of developing vitamin B(12) and B(6) deficiency because of a limited intake of animal products. Besides laboratory tests (n = 31) we obtained clinical information (n = 30) and detailed information on food consumption (n = 28). Three-quarters of the patients had early biochemical signs of vitamin B(12) deficiency. In spite of a normal folate status, 9 (29%) had a plasma homocysteine above 12 micromol/L. In accord with these findings, the food questionnaires indicated that 11 (39%) patients received less than the recommended daily vitamin B(12), and 20 (71%) received less vitamin B(6) than recommended. A significant association was found between reduced vitamin B(12) intake and both reduced serum cobalamins (p = 0.04) and reduced serum transcobalamin saturation (p = 0.03). Eleven patients took a vitamin pill daily, and these patients had a significantly lower plasma homocysteine compared to the rest. The present study suggests that adult PKU patients were at increased risk of developing vitamin B(12) deficiency, and their intake of vitamin B(6) was below the recommended daily intake. In conclusion PKU patients need continuing dietary guidance throughout adult life, and considering the risks, costs and potential benefits, daily vitamin supplementation seems justified in these patients.

In the emerging paradigm of urban forestry objectives are often to develop mixed stands with complex structures. Such stands cannot easily be described in words and numbers. A logical alternative would seem to describe the structure of such mixed stands by use of image-based management tools. However implementing new management goals and using image-based tools challenges professionals, educated and trained within the age-class forestry tradition, to use their knowledge in a creative way. This paper describes how professionals contextualise from hand drawn profile diagrams when planning the management of mixed stands. The appropriateness of profile diagrams in this context is further discussed. The study was carried out as a case study focusing on the planning and development of long-term management goals for two young mixed stands for recreational use. We used explorative, in-depth interviews to identify the perspective on profile diagrams, as experienced by five individuals with different academic backgrounds as well as years of experience. The interviewees revealed that personal experiences and mental images played a key role in order to display an intuitive understanding of the subject stands through the profile diagrams. Further, they recognised this approach themselves often referring to other stands to make comparisons. The types of references used could be divided into three distinct categories: specific, generic and metaphoric. With regard to the ongoing move from age-class forestry to multifunctional management of mixed stands, this aid to dialogue might be the most relevant way in which profile diagrams can contribute to the implementation of new management paradigms.

This article reports a measurement of the production cross section of prompt isolated photon pairs in proton-antiproton collisions at √s=1.96TeV using the CDF II detector at the Fermilab Tevatron collider. The data correspond to an integrated luminosity of 5.36fb -1. The cross section is presented as a function of kinematic variables sensitive to the reaction mechanisms. The results are compared with three perturbative QCD calculations: (1) a leading-order parton shower Monte Carlo, (2) a fixed next-to-leading-order calculation and (3) a next-to-leading-order/next-to-next-to-leading-log resummed calculation. The comparisons show that, within their known limitations, all calculations predict the main features of the data, but no calculation adequately describes all aspects of the data. © 2011 American Physical Society.

In this study, an animal model was developed for the examination of urethral strictures (US). Through a resectoscope, a resection was made in the urethras of 15 male rabbits. After 30 days, the rabbits were evaluated with urethrography, impedance planimetry and either histology or the determination of collagen content. Fifteen rabbits serving as controls were evaluated in the same way. Three rabbits in the resection group and one in the control group died before evaluation. Urethrography demonstrated a stricture in the remaining 12 animals in the resection group. The urethras of the control animals were all normal. Impedance planimetry confirmed that the luminal cross sectional area (CSA) of the strictures was significantly smaller than the CSA of the corresponding part of the urethra in the control group. No difference in CSA was found 1 cm proximal to the stricture. The strictures consisted of densely woven collagen which sent tongues into the adjacent normal parts of the urethra. No difference in collagen content was found between the two groups either at the stricture site or 1 cm proximally. The described method of producing US in the rabbit model was very consistent with all operated animals developing a stricture. The model might prove valuable in evaluating new methods for the treatment of US.

We evaluated the effect of the somatostatin analogue lanreotide on the development of surgically induced experimental strictures in the anterior urethra of the male rabbit. A total of 74 male rabbits were randomly allocated into four groups. Lanreotide was administered to the rabbits in groups 2 and 4 from day 0 to 14. To create a stricture, a resection was made in the urethra of the rabbits in groups 3 and 4 on day 2. On day 30, all rabbits were examined with urethrography, impedance planimetry and either histology or for collagen content. Urethrography and impedance planimetry demonstrated a urethral stricture in all operated animals. No difference was found between the two stricture groups, regardless of lanreotide administration, with respect to luminal cross-sectional area (CSA), circumferential tension-strain relation, histology or collagen content. The CSA of the urethra of the normal controls treated with lanreotide was smaller than the CSA of the normal controls not treated with lanreotide, however, no difference was found in histology or collagen content. Lanreotide had no measurable effect on the development of a surgically induced stricture in the male rabbit anterior urethra, however, lanreotide seems to exert an inhibitory effect on the normal growth of the urethra.

The aim of this study was to determine whether intravesical treatment with capsaicin could block detrusor hyper-reflexia (DH) and alter the substance P content, nerve fibres and mucosa of the bladder. Twelve patients with spinal cord disease with DH and urinary incontinence resistant to anticholinergic treatment underwent intravesical administration of 50 ml 2% lignocaine. followed by either 100 ml 1 mmol/l capsaicin or 100 ml physiological saline for 30 min. Cross-over to the alternative treatment took place after 4 weeks. Varying degrees of burning sensation were experienced by all but one patient during the capsaicin treatment and precluded the possibility of conducting studies of this type in a blind manner. No preference for capsaicin treatment was found, and micturition and VAS scores were unchanged after treatment with capsaicin. The mean volume of the contents of the bladder at which DH first appeared was 175 ml after saline and 195 ml after capsaicin (mean difference 20 ml with a 5% confidence interval from -25 to 65). Bladder biopsies taken 2 weeks after treatment with capsaicin showed more pronounced inflammation, superficial haemorrhage, squamous epithelial metaplasia and a more condensed bladder stroma. Immunohistochemical staining for substance P and neuronal cell adhesive molecule revealed the presence of small terminal axons and small nerve bundles in all of the biopsies. Intravesical treatment with capsaicin did not have a beneficial effect on DH or a destructive effect on nerve fibres. It did, however, produce significant reactive changes in the mucosa of the bladder.

Prolongation of inspiratory time is used to reduce lung injury in mechanical ventilation. The aim of this study was to isolate the effects of inspiratory time on airway pressure, gas exchange, and hemodynamics, while ventilatory frequency, tidal volume, and mean airway pressure were kept constant.Randomized experimental trial.Experimental laboratory of a University Department of Anesthesiology and Intensive Care.Twelve anesthetised piglets.After lavage the reference setting was pressure-controlled ventilation with a decelerating flow; I:E was 1:1, and PEEP was set to 75% of the inflection point pressure level. The I:E ratios of 1.5:1, 2.3:1, and 4:1 were applied randomly. Under open lung conditions, mean airway pressure was kept constant by reduction of external PEEP.Gas exchange, airway pressures, hemodynamics, functional residual capacity (SF6 tracer), and intrathoracic fluid volumes (double indicator dilution) were measured. Compared to the I:E of 1:1, PaCO2 was 8% lower, with I:E 2.3:1 and 4:1 (por = 0.01) while PaO2 remained unchanged. The decrease in inspiratory airway pressure with increased inspiratory time was due to the response of the pressure-regulated volume-controlled mode to an increased I:E ratio. Stroke index and right ventricular ejection fraction were depressed at higher I:E ratios (SI by 18% at 2.3:1, 20% at 4:1; RVEF by 10% at 2.3:1, 13% at 4:1; por = 0.05).Under open lung conditions with an increased I:E ratio, oxygenation remained unaffected while hemodynamics were impaired.

Indirect evidence that the motor cortex and the corticospinal tract contribute to the control of walking in human subjects has been provided in previous studies. In the present study we used coherence analysis of the coupling between EEG and EMG from active leg muscles during human walking to address if activity arising in the motor cortex contributes to the muscle activity during gait. Nine healthy human subjects walked on a treadmill at a speed of 3.5–4 km h(-1). Seven of the subjects in addition walked at a speed of 1 km h(-1). Significant coupling between EEG recordings over the leg motor area and EMG from the anterior tibial muscle was found in the frequency band 24–40 Hz prior to heel strike during the swing phase of walking. This signifies that rhythmic cortical activity in the 24–40 Hz frequency band is transmitted via the corticospinal tract to the active muscles during walking. These findings demonstrate that the motor cortex and corticospinal tract contribute directly to the muscle activity observed in steady-state treadmill walking.

Congestive heart failure (CHF) is associated with increased renal sympathetic nerve activity and renal sodium retention. Rats with CHF display increased expression of the Na-K-2Cl cotransporter (NKCC2) in the renal medullary thick ascending limb of the loop of Henle (mTAL), and arginine vasopressin (AVP)-stimulated cAMP formation in mTAL segments is increased in rats with CHF. The aim of the study was to investigate the role of RSNA on cAMP formation and NKCC2 expression in mTAL in rats with CHF.Congestive heart failure was induced in male Wistar rats by ligation of the left anterior descending coronary artery. Bilateral surgical renal denervation (DNX) was performed 3 weeks later. Two weeks after DNX, mTAL segments were isolated and stimulated with AVP.Congestive heart failure rats displayed increased mTAL NKCC2 expression (2.5 ± 0.5 vs. 1 ± 0.2 in Sham rats), which was abolished by DNX. Bilateral denervation decreased basal cAMP levels in unstimulated tubules from CHF rats (CHF: 12.56 ± 7.73 fmol μg(-1) protein vs. DNX-CHF: 7.94 ± 4.33; P0.05), as well as from Sham rats (SHAM: 4.70 ± 1.38 vs. DNX-SHAM: 2.36 ± 1.52; P0.05). mTAL segments from DNX-CHF and DNX-Sham rats showed decreased AVP (10(-6) M)-stimulated cAMP formation, compared with CHF (CHF: 11.92 ± 4.89 fmol μg(-1) protein vs. DNX-CHF: 4.68 ± 2.47; P0.05) and Sham (SHAM: 10.78 ± 5.59 vs. DNX-SHAM: 4.89 ± 2.62; P0.05).These results indicate that the renal sympathetic nerves have an effect on NKCC2 expression in the mTAL and might have an effect on cAMP formation in the TAL in CHF.

We present a model suggesting high chemical activity of electronically-excited molecules colliding with an isolator surface. Initial photochemical event is accounted for as the result of molecular evolution on the electronically-excited potential energy surface (PES), where acceleration and alignment are taking place, guiding all the molecules towards the intersections with the ground state PES, where transitions to the ground state PES will occur with minimum energy dissipation. The accumulated kinetic energy may be used to overcome the chemical reaction barrier. While recombination chemical reactions in a gas phase require participation of a third body, this strong limitation on the reaction rates is removed upon interaction with a surface. To observe the predicted phenomenon, we suggested a new experimental approach, Evanescent Wave Photocatalysis1, based on application of total internal reflection on an insulator surface. Laser photoexcitation is localized in a narrow boundary gas layer just above the interface; majority of the excited molecules can reach the surface before the relaxation. The experiments are performed at high gas pressures, so that dense fluxes of the excited reagents can be readily produced. Products of chemical adsorption and/or chemical reactions induced within adsorbates are aggregated on the surface and observed by light scattering. We will demonstrate how pressure and spectral dependencies of the chemical outcomes, polarization of the light and interference of two laser beams inducing the reaction can be used to distinguish the new process we try to investigate from chemical reactions induced by photoexcitation within adsorbed molecules and/or gas phase photolysis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a preferential loss of motor neurones. Previous publications using in vitro neonatal preparations suggest an increased excitability of motor neurones in various superoxide dismutase-1 (SOD1) mutant mice models of ALS which may contribute to excitotoxicity of the motor neurones.Using intracellular recording, we tested this hypothesis in vivo in the adult presymptomatic G127insTGGG (G127X) SOD1 mutant mouse model of ALS.At resting membrane potentials the basic intrinsic properties of lumbar motor neurones in the adult presymptomatic G127X mutant are not significantly different from those of wild type. However, at more depolarized membrane potentials, motor neurones in the G127X SOD1 mutants can sustain higher frequency firing, showing less spike frequency adaption (SFA) and with persistent inward currents (PICs) being activated at lower firing frequencies and being more pronounced.We demonstrated that, in vivo, at resting membrane potential, spinal motor neurones of the adult G127X mice do not show an increased excitability. However, when depolarized they show evidence of an increased PIC and less SFA which may contribute to excitotoxicity of these neurones as the disease progresses.

A series of 3-(4-fluorophenyl)-1H-indoles substituted in the 1-position with 4-piperidinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperazinyl was synthesized. By variation of the substituents in the benzene part of the indole nucleus in 1-[2-[4-[3-4-fluorophenyl)-1H-indol-1-yl]-1-piperidinyl]-ethyl]-2- imidazolidinones, the highest 5-HT2 receptor affinity and selectivity with respect to dopamine D2 receptors and alpha 1 adrenoceptors were obtained by 5-methyl substitution. Different substituents were introduced in the 1-position of the piperidine ring in the 5-methyl-substituted derivative. Thus replacement of the 2-(2-imidazolidinon-1-yl)ethyl side chain with a 2-(1,3-dimethyl-1-ureido)ethyl or methyl substituent resulted in unchanged affinity and selectivity for 5-HT2 receptors. Replacement with a 2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl side chain reduced binding to alpha 1 adrenoceptors with a factor of four, while affinities for 5-HT2 and D2 receptors were retained, compared to the 3-unsubstituted imidazolidinone. Indoles substituted in the 1-position with 4-piperazinyl had generally weaker affinity for both 5-HT2 and D2 receptors compared to corresponding 4-piperidinyl- and 1,2,3,6-tetrahydro-4-pyridinyl-substituted indoles. Introduction of a methyl group in the 2-position of the 5-methyl-substituted indole resulted in further increase of selectivity for the 5-HT2 receptor. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and showed a long duration of action (> 24 h). In general, the derivatives were found to be considerably more potent at 24 h than at 2 h after the administration. The compounds within this series were prepared as analogues of the previously described 1-(4-fluorophenyl)-3-(4-piperidyl)-1H-indoles by interchange of the C-3 carbon atom and the nitrogen atom in the indole nucleus. The pharmacological results indicate that this isosteric replacement results in higher selectivity for 5-HT2 receptors compared to the former series. The 1-[2-[4-[2,5-dimethyl-3-(4-fluorophenyl)-1H-indol-1-yl]-1- piperidinyl]ethyl]-2-imidazolidinone has high affinity for 5-HT2 receptors (IC50 = 3.4 nM) and extremely low affinity for both dopamine D2 receptors (IC50 = 6900 nM) and alpha 1 adrenoceptors (IC50 = 2300 nM).

Previous studies have indicated that rat neurofilament protein may contain an endogenous MSH-like epitope with neuroregenerative properties. The presence of such an epitope has now been studied in nerve tissue from Xenopus laevis. Western blot analyses of sciatic nerve tissue using an assortment of sequence-specific MSH/ACTH antisera revealed the presence of two major immunoreactive protein bands of 52 and 50 kDa, which contained a mid-region MSH-like epitope. Weaker staining occurred in another protein band at 135 kDa. Immunocytochemistry revealed the immunoreactivity to reside in the axis cylinders of the nerve fibers. Other antisera, recognizing other regions of MSH/ACTH produced strong staining of Xenopus intermediate lobes, but failed to stain sciatic nerves. Thus, the proteins detected have no clear relation to either Xenopus neurofilament proteins or proopiomelanocortin.

A survey is given of literature reports on the effect of performance in offspring from 26 maternal PKU pregnancies treated prior to conception. The survey includes two women who were referred to us for genetic counselling because they had both given birth to microcephalic, mentally retarded children. The women were discovered to suffer from unrecognized maternal PKU with fasting phenylalanine concentration of 1.1-1.5 mmol/L. A strict diet was introduced prior to planned pregnancy and after some months on diet (phenylalanine concentrations less than 0.6 mmol/L) they became pregnant again. Serum phenylalanine levels were monitored weekly throughout pregnancy, and adjustments in the diet were made to keep serum phenylalanine concentration within the range of 0.18-0.42 mmol/L. The outcome of the pregnancies were healthy children who have developed normally. Their IQs are 105 and 119 at ten and four years of age, respectively and their head circumferences are normal. Our data show that the effect of preconceptional dietary treatment was children with a normal performance, contrary to their older siblings born following untreated pregnancies. These results are in agreement with the survey of ten years' promising experiences with preconceptional treatment in maternal PKU. The data may help to motivate young PKU women to accept planned pregnancies and to encourage them to return to the strict diet, which has prevented them from being retarded.

The plasma amino acid concentrations were measured in 12 neonates with phenylketonuria (PKU). Blood samples were taken when fasting and two hours after a meal. The individual amino acid concentrations, the glycine/valine ratios, and the total amino acid concentrations were mutually compared and also compared to reference intervals. When the diet was instituted and plasma phenylalanine decreased, we observed a normalization of the postprandial response of isoleucine, leucine, tyrosine, and valine.

The plasma amino acid concentrations were measured in 10 children with phenylketonuria (PKU) on the phenylalanine-free amino acid mixture Phenyldon and 9 PKU children on the phenylalanine-free protein hydrolysate Albumaid. The blood samples were taken fasting and two hours after the meal. The individual amino acid concentrations, the glycine/valine ratios, and the total amino acid concentrations were mutually compared and also compared to reference intervals. No differences of the concentration of phenylalanine on the two diet formulas were observed. Children on Phenyldon showed fasting and postprandial isoleucine higher than the reference intervals. Furthermore, a postprandial increase of several amino acids was observed on both diet formulas. This response was statistically significant in children on Phenyldon.

In the rat, non-invasive transcranial magnetic stimulation (TMS) has shown promise for evaluation of transmission through the spinal cord before and after repair strategies, but it is still unclear which pathways are activated by TMS. The aim of the present study was therefore to identify these pathways and to analyse the effect of TMS on spinal neurons. In 19 rats, TMS evoked responses bilaterally in forelimb (biceps brachii; BB) and hindlimb muscles (tibialis anterior). The latency and amplitude of these motor-evoked responses (MEPs) were highly variable and depended strongly on the coil position and the stimulation intensity. The most frequently observed latencies for the BB MEPs could be divided into three groups: 3-6 ms, 8-12 ms and 14-18 ms. Lesions in the dorsal columns, which destroyed the corticospinal tract at C2 and C5, significantly depressed MEPs in the mid- and high-latency ranges, but not those in the low-latency range. Lesions in the dorsolateral funiculus, which interrupted the rubrospinal tract, had no effect on MEPs in any of the latency ranges. By contrast, bilateral lesion of the reticulospinal tract and other ventro-laterally located descending pathways abolished all responses. Intracellular recordings from 54 cervical motoneurons in five rats revealed that TMS evoked excitatory postsynaptic potentials (EPSPs) at latencies that corresponded well with those of the BB MEPs. The short-latency EPSPs had rise times of around 1 ms, suggesting that they were mediated by a monosynaptic pathway. EPSPs with longer latencies had considerably longer rise times, which indicated conduction through polysynaptic pathways. Selective electrical stimulation of the pyramidal tract in the brainstem was performed in seven rats, where intracellular recordings from 70 motoneurons revealed that the earliest EPSPs and MEPs evoked by TMS were not mediated by the corticospinal tract, but by other descending motor pathways. Together, these results showed that in the rat TMS activates several descending pathways that converge on common spinal interneurons and motoneurons. Our observations confirm that the corticospinal tract has weak (and indirect) projections to cervical spinal motoneurons.

The basic locomotor rhythm in the cat is generated by a neuronal network in the spinal cord. The exact organization of this network and its drive to the spinal motoneurones is unknown. The purpose of the present study was to use time (cumulant density) and frequency domain (coherence) analysis to examine the organization of the last order drive to motoneurones during fictive locomotion (evoked by application of nialamide and dihydroxyphenylalanine (DOPA)) in the spinal cat. In all cats, narrow central synchronization peaks (half-width < 3 ms) were observed in cumulants estimated between electroneurograms (ENGs) of close synergists, but not between nerves belonging to muscles acting on different joints or to antagonistic muscles. Coherence was not observed at frequencies above 100 Hz and was mainly observed between synergists. Intracellular recording was obtained from a population of 70 lumbar motoneurones. Significant short-term synchronization was observed between the individual intracellular recordings and the ENGs recorded from nerves of the same pool and of close synergists. Recordings from 34 pairs of motoneurones (10 pairs belonged to the same motor pool, 11 pairs to close synergists and 13 pairs to antagonistic pools) failed to reveal any short-lasting synchronization. These data demonstrate that short-term synchronization during fictive locomotion is relatively weak and is restricted to close synergists. In addition, coherence analysis failed to identify any specific rhythmic component in the locomotor drive that could be associated with this synchronization. These results resemble findings obtained during human treadmill walking and imply that the spinal interneurones participating in the generation of the locomotor rhythm are themselves weakly synchronized. The restricted synchronization within the locomotor drive to motoneuronal pools may be a feature of the locomotor generating networks that is related to the ability of these networks to produce highly adaptive patterns of muscle activity during locomotion.

This paper presents several aspects of the dynamics of a cylindrical shell with and without heavy internal fluid loading, which have not been studied before in detail. Firstly, a consistent formulation of boundary integral equations for a shell of finite length is derived based on the energy conservation principle and the reciprocity theorem. This derivation naturally leads to identification of principal components of the energy flux through an arbitrary cross-section of a shell and to formulation of Green's matrix for an infinitely long shell at each individual circumferential wave number. Secondly, an inspection into the energy re-distribution between several transmission paths in a near field (in a boundary layer at the vicinity of a loaded cross-section) is performed, which sheds light on the role of evanescent waves in motions of a driven shell. Thirdly, the influence of excitation conditions on steady fluctuations of the overall energy flow between transmission paths in a far field is explored for the case, when several propagating waves exist in a shell both with and without internal fluid loading. Besides, a systematic verification of the solution offered by the boundary equations method is given through comparison of eigenfrequencies with those computed in finite element modelling for various boundary conditions. Analysis of dispersion curves and input mobilities is also presented.

Rett syndrome (RS, MIM 312750) is an X linked dominant neurodevelopmental disorder, which has been considered to affect girls only.1 Males were thought to be aborted spontaneously or to have a different phenotype.2 The disease is caused by mutations in MECP2 , encoding a methyl-CpG binding protein MeCP2.3 MeCP2 is an abundantly expressed protein acting as a global transcription repressor.4 The protein contains two domains, the 85 amino acid methyl-CpG binding domain (MBD) and the 102 amino acid transcriptional repression domain (TRD).4,5 Furthermore, a domain in the C terminal part of the protein, facilitating DNA binding and harbouring the nuclear localising signal (NLS), has been described.6 The mutation responsible for RS has now been found in the majority of RS patients and more than 100 different mutations have been published. Although some association between phenotype and genotype has been shown, their correlation is not predictive of the clinical manifestations in the individual case.7,8 Since 1999, when mutations in MECP2 were first reported in patients with RS,3 it has been possible to analyse boys for mutations resulting in a confirmation of the diagnosis in some of the earlier reported cases.9,10 Screening of groups of patients with mental retardation of different types has further identified MECP2 mutations in males. So far, 17 cases of males with a disease causing mutation in MECP2 have been found. However, six of them were found to have Klinefelter syndrome or were mosaics for the mutation in question.8–15 The latter can roughly be divided into two groups, the severe neonatal cases, who die within the first years of life, all caused by an MECP2 mutation that in females causes classical RS,8–10 and the non-specific mental retardation type with mutations that, if …

An intervention study was performed in a mechanically ventilated office building in which there were severe indoor climate complaints among the occupants. In one part of the building a new heating and ventilation strategy was implemented by renovating the HVAC system, and a carpet was replaced with a low-emitting vinyl floor material; the other part of the building was kept unchanged, serving as a control. A comprehensive indoor climate investigation was performed before and after the intervention. Over a 2-week period, the occupants completed a daily questionnaire regarding their comfort and health. Physiological examinations of eyes, nose and lungs were performed on each occupant. Physical, chemical and sensory measurements were performed before and after the intervention. The renewal of the flooring material was performed after a sensory test of alternative solutions in the laboratory. Before the floor material was installed in the office building, a full-scale exposure experiment was performed in the laboratory. The new ventilation strategy and renovation of the HVAC system were selected on the basis of laboratory experiments on a full-scale mock-up of a cellular office. The severity of occupants' environmental perceptions and symptoms was significantly reduced by the intervention.

The paper addresses the analysis of in-plane coupled flexural and longitudinal vibrations of a structure composed of elastic tubular beams. Emphasis is put on optimization of structural performance in terms of minimization of total power flow over a broad-banded frequency range, i.e. minimization of the emitted/trans- mitted energy of vibrations. The objective function is chosen as an energy outflow (a structural intensity) integrated within the given frequency range at a given remote point (cross-section) of the tubular structure. To gain insight into the physical mechanisms of energy transportation, the structure is decomposed into a set of elementary dynamical systems. These elementary dynamical systems (subsystems) are chosen as one-dimensional wave-guides carrying either longitudinal or flexural waves. Vibrations of each dynamical subsystem are described by a boundary equation method, a novel method in structural dynamics which ideally fits the substructuring concept since it deals with physical variables at boundaries between substructures, no matter what type of excitation is applied at individual substructures. A system of boundary integral equations is accomplished by continuity conditions at interfaces between subsystems and by boundary conditions. Since Green's functions used in the boundary integral formulation satisfy the radiation principle, the governing system of equations is equally applicable for analysis of vibrations of both finite-length structures and the structures having infinitely long elements jointed with elements of finite length.

This paper addresses analysis and optimization of in-plane coupled flexural and longitudinal vibrations within the framework of a theory outlined in a companion paper. An optimization problem is posed for a model structure consisting of two elements of a finite length and one semi-infinite element. This model structure has four terminal points. Parameters of design are chosen as stiffness, mass and the location of two of the terminal points. A parametric study of vibrations of the structure is performed and optimal locations of terminal points are detected. Analysis of energy flows between elementary dynamical systems is done and the dynamics of a structure with the optimized design shape is compared with the dynamics associated with the initial design shape. The formulation of the optimization problem is also extended to include amplitudes of "secondary forces" as design variables. Possibilities of active control of energy flows by usage of "secondary" sources of excitation are discussed.

Motor-evoked potentials (MEPs) were recorded in the tibialis anterior and soleus muscles following transcranial magnetic stimulation (TMS) of the motor cortex. In the soleus, the H-reflex amplitude increased with the contraction level to the same extent as that of MEPs, whereas in the tibialis anterior, the H-reflex amplitude increased significantly less than that of MEPs. The latency of the MEPs decreased with contraction, whereas this was not the case of the H-reflexes. In the tibialis anterior, the response probability of single-motor units (SMU) to TMS increased more substantially during voluntary contraction than following stimulation of the peroneal nerve. In the tibialis anterior, the response probability of SMU increased more substantially during voluntary contraction than following stimulation of the peroneal nerve. The short-latency facilitation, presumably monosynaptic of origin, of the soleus H-reflex evoked by subthreshold TMS increased as a function of the plantarflexion force. This was not the case for the heteronymous Ia facilitation of the soleus H-reflex following stimulation of the femoral nerve. It is concluded that the corticospinal input to lower limb motor neurones generated by TMS increases with the level of voluntary contraction, whereas this is true only to a limited extent for the synaptic input from Ia afferents. It is suggested that this reflects changes in the susceptibility of corticospinal cells to TMS during voluntary contraction.

To determine renal function in patients with vesico-ureteric reflux (VUR) during 14 years of conservative treatment (no surgery).Sixty patients with VUR were consecutively included between 1981 and 1982. The degree of VUR was determined by conventional voiding cysto-uretherography (VCUG) after 3 months of prophylactic antibiotics. The VUR was grade I-IV, with grades III and IV characterized as high-grade VUR. In all patients, any urinary tract infections and bladder-urethral dysfunction were treated. Renal function and reflux were monitored by renal and bladder scintigraphy using 123I-hippuran and the glomerular filtration rate (GFR) was determined using the plasma clearance of 51Cr-ethylaminediamine tetra-acetic acid.Of the 60 patients who entered the study, 51 were followed for a mean of 13.7 years; nine patients were lost to follow-up. None of the patients underwent antireflux surgery. All patients were in good health and normotensive (except two with borderline hypertension). Of the 51 patients 21 had low-grade, 21 unilateral high-grade and nine bilateral high-grade reflux. In those with low-grade reflux both the mean renal split function on the most refluxing kidney and the GFR remained stable during the whole monitoring period. Eighteen patients who had a persistent reduction in renal split function or initially had had a significantly reduced functional share to the most refluxing kidney had their GFR re-assessed in adolescence. However, the body surface-corrected GFR remained constant. Total GFR and single kidney GFR increased significantly.A conservative treatment regimen in patients with VUR can ensure stable kidney function, although kidneys with a lower renal function at referral seem to have an impaired functional growth potential.

We here describe a patient where a process in the ureter initially suspected to be potentially malignant turned out to be a fibroepithelial polyp, diagnosed and treated endoscopically. The kidney function and the excretory urogram three years after the treatment were normal.

Blood lead concentrations in a Danish reference population were related to information from an extensive questionnaire on work, environment and life style. The mean concentration of lead in blood was 0.167 mumol/L, i.e. significantly lower than in previous studies. This finding is in accordance with the fact that less than 10% of petrol used in Denmark contained lead additives (up to 0.15 g/L). An important finding was that the well-documented predictors for lead in blood at higher concentration levels, such as age, gender, menopausal status, and intake of alcohol, are still valid in a low-level exposure situation. In addition, a strong and negative correlation was found between blood lead concentrations and dietary supplementation with vitamins and minerals. The present data indicate that lead exposure may still constitute a health risk in a small proportion of adult males and postmenopausal women.

In a multicentre study of 635 consecutive newly diagnosed patients with B-CLL, the histological bone marrow (BM) specimens were reviewed independently by each of 3 pathologists and found evaluable for BM infiltration pattern in 575 patients, 404 of whom had a CD5+, mainly FMC7-, faint surface-membrane immunoglobulin (SIg) fluorescence-intensity ppenotype. In these 404 patients the following BM infiltration patterns were found: mixed nodular-interstitial (30%), moderate interstitial (44%), heavy interstitial (20%) and diffuse packed (6%). In univariate survival analysis, significant differences were found according to BM pattern (p0.05), the presence of nodules being a favorable prognostic sign. In multivariate survival analysis in a model including age, clinical stage, BM pattern, BM lymphocytosis, WBC and sex, only age and stage but not BM pattern or BM lymphocytosis had independent prognostic significance. In stage A, progression-free survival was significantly longer in patients with nodular than in patients with non-nodular bone-marrow pattern. The overall survival of these patients, however, did not differ, possibly owing to the prompt and prolonged treatment given to most patients at the time of progression to stage B or C. We conclude that in CD5+, SIg(faint), mainly FMC7-B-CLL, bone-marrow histology may predict unstable disease in early clinical stage but is not important for treatment decisions, when these are based on clinical stage.

Evaluation of environmental risks involves several subjective elements, including the individual reaction to the mere presence of such risks. We have carried out a study of students participating in postgraduate courses in environmental and occupational medicine and of medical students. They received a form that contained twelve statements and were asked to indicate whether they agreed or disagreed with these statements. Almost half of the medical students agreed that one must count on developing cancer if one is exposed to a carcinogenic chemical. Responses to other statements were also contrary to the basic principle of the dose-response relationship. A majority in both groups disagreed with the statement that people are unnecessarily concerned about small amounts of pesticides in the environment. Compared to the medical students, the postgraduate students were more sceptical and less concerned regarding environmental risks. These results are in general agreement with a study carried out in the US using the same statements. The results are an indication that we do not necessarily react the same way with regard to information on risks. When communicating such information, the needs and the background of the audience must be appreciated.

Magnetic stimulation of the brain in awake human subjects was introduced ten years ago and has since then been used extensively both in the clinic and for research purposes. So far the method has been shown to be of importance as a supplement to other methods in the diagnosis and monitoring of multiple sclerosis. It may also achieve importance as a prognostic tool in early cerebral haemorrhage. It is yet unclear whether the method will achieve any importance in the diagnosis of other diseases such as Parkinsons disease, migraine and epilepsy. The method has caused a major breakthrough in the investigation of the central control of voluntary movement in man. The method thus provides a possibility of monitoring the activity of defined corticospinal pathways during voluntary movements.