Perspectives in football medicine.

The high injury rate among men's professional football players is well-known. Therefore, the Union of European Football Associations (UEFA) launched an injury study already in 2001. This study, the UEFA Elite Club Injury Study (ECIS), currently includes data from a total of 51 clubs from 18 European countries with more than 14,000 registered injuries. With the 21st World Cup (WC) in Russia just around the corner, we have from our study identified a higher match injury rate and a higher proportion of severe injuries in the European Championships compared to the preceding club competitive seasons. Moreover, we have also recently showed that the muscle injury rate is higher when players are given a recovery window of five days or less between two matches. Considering the congested match schedule of the upcoming WC, it is therefore likely that injuries and fatigue once again will be a topic of discussion this summer.

A predictive model for alternative admission to dental education.

AIM: To compare academic progress and performance of students admitted through two admission systems and to analyse the predictive power of different components in an alternative admission. SAMPLE AND METHODS: The subjects were students admitted to the dental programme at Malmö University, Sweden. The grade admission group was admitted on grades from secondary school (n = 126) and the alternative admission group via an alternative admission procedure (n = 157). The alternative admission procedure consisted of the following components: problem-solving matrices, spatial capacity tested with folding and tin models, manual dexterity, capacity for empathy and interview. Comparisons were made for academic progress (dropouts from the programme and study rate) and academic performance (examinations failed and outcomes of a comprehensive clinical examination). Spearman correlation was calculated for each component of the alternative admission procedure and academic progress as well as academic performance. Multivariate analyses were also carried out. RESULTS: Compared to the grade admission group, the alternative admission group presented lower rate of dropouts (3% vs. 20%, P < 0.001) and a larger proportion graduated within the expected time (88% vs. 60%, P < 0.01). There was no difference between the groups concerning academic performance. Capacity of empathy was correlated with study rate and outcomes of the clinical examination. The matrices predicted low proportion failed examinations and high students' self-assessments in the clinical examination. Predictive power of folding was limited and so was that of the interview. Manual dexterity was not correlated with academic progress or performance. CONCLUSIONS: Results support further development of admission selection criteria, particularly emphatic capacity that predicts important student academic achievements.

Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial.

The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double-blind, randomized, placebo-controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose-dependent almorexant effects were observed on SE , LPS , and WASO . SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (­18 min (P = 0.02)) and WASO (­54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse-event incidence was dose-related. Almorexant consistently and dose-dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia.

The effect of extremely preterm birth on attachment organization in late adolescence.

BACKGROUND: Prior studies have examined the impact of preterm birth on the quality of the attachment relationship to the mother in infancy, but few have examined extremely preterm born infants and almost no data have been reported on prematurity and its impact on the attachment organization attained after childhood. METHODS: Thirty-nine adolescents born extremely preterm and 39 full-term born control participants were assessed with the Adult Attachment Interview. RESULTS: The prematurely born showed lower scores regarding measures of attachment security and, in particular, a higher proportion of insecure dismissive patterns. This difference seemed to be clear and persistent even when controlled for intelligence and socio-economic variables. CONCLUSIONS: Because insecure attachment as well as prematurity may be considered as significant risk factors for developing psychopathology, they deserve careful attention in future research and clinical follow-ups.

Estimation and assessment of raw copy numbers at the single locus level.

MOTIVATION: Although copy-number aberrations are known to contribute to the diversity of the human DNA and cause various diseases, many aberrations and their phenotypes are still to be explored. The recent development of single-nucleotide polymorphism (SNP) arrays provides researchers with tools for calling genotypes and identifying chromosomal aberrations at an order-of-magnitude greater resolution than possible a few years ago. The fundamental problem in array-based copy-number (CN) analysis is to obtain CN estimates at a single-locus resolution with high accuracy and precision such that downstream segmentation methods are more likely to succeed. RESULTS: We propose a preprocessing method for estimating raw CNs from Affymetrix SNP arrays. Its core utilizes a multichip probe-level model analogous to that for high-density oligonucleotide expression arrays. We extend this model by adding an adjustment for sequence-specific allelic imbalances such as cross-hybridization between allele A and allele B probes. We focus on total CN estimates, which allows us to further constrain the probe-level model to increase the signal-to-noise ratio of CN estimates. Further improvement is obtained by controlling for PCR effects. Each part of the model is fitted robustly. The performance is assessed by quantifying how well raw CNs alone differentiate between one and two copies on Chromosome X (ChrX) at a single-locus resolution (27kb) up to a 200kb resolution. The evaluation is done with publicly available HapMap data. AVAILABILITY: The proposed method is available as part of an open-source R package named aroma.affymetrix. Because it is a bounded-memory algorithm, any number of arrays can be analyzed.

Assessment and evaluation of individual prerequisites for dental education.

Since 2001 the School of Dentistry of Malmo University in Sweden has used an alternative admissions procedure based on results of an investigation supported by the Swedish Council for the Renewal of Undergraduate Education. The investigation concerned possibilities of predicting dental school performance on the basis of an interview, as well as tests of general intelligence, spatial ability, manual dexterity, empathy and social competence. Two groups of incoming students were followed from start to completion of their training. Significant relationships were found between (i) number of course examinations failed and poor results on interviews, as well as low scores on intelligence, spatial ability, and a test of spatial-manual ability, (ii) good results in a pre-clinical course in cavity preparation and high scores on spatial ability, (iii) assessments of high social competence during training and good results on interviews, as well as high scores on empathy and non-verbal intelligence. Dropout from the study programme could not be predicted, possibly due to the varying reasons for it.

Interaction of the antidepressant mirtazapine with alpha2-adrenoceptors modulating the release of 5-HT in different rat brain regions in vivo.

Mirtazapine (MIR) is a novel antidepressant, reported to raise extracellular noradrenaline (NA) through blockade of alpha2-autoreceptors and serotonin (5-HT) output via (1) indirect activation of facilitatory alpha1-adrenoceptors on the cell bodies of ascending 5-HT neurones and (2) blockade of presynaptic release-modulating alpha2-heteroreceptors on 5-HT terminals in the forebrain. To further assess the effect of MIR on NA/5-HT system interplay, including putative regional differences in the effects of the drug on 5-HT release in rat forebrain, we used in vivo microdialysis in anaesthetised rats. Probes were implanted in the dorsal hippocampus (DH) and frontal cortex (FCx), representing median and dorsal raphe 5-HT projection areas, respectively. In the DH, MIR (10 mg/kg s.c.) completely blocked the 5-HT release-suppressing action of the selective alpha2-adrenoceptor agonist clonidine (0.1 mg/kg s.c.), but had no effect per se on the 5-HT output. Neither drug significantly changed the 5-HT levels in the FCx. MIR perfused locally (10 microM via reverse-dialysis) also failed to significantly elevate 5-HT output, and did not affect the clonidine response in either brain area. Thus, the data confirm the basic alpha2-adrenoceptor-blocking properties of MIR, but are only partly concordant with previous studies reporting an increase of 5-HT output after MIR alone. Moreover, we find no elevation in 5-HT by the reference alpha2-adrenoceptor antagonist idazoxan (0.3-1.0 mg/kg s.c.). The discrepancies encountered, and the potential ability of alpha2-adrenoceptor antagonists in general to raise the output of 5-HT, are discussed with particular reference to methodological and other factors that may influence the experimental outcome (e.g., brain regional aspects, different alpha2-adrenoceptor subtypes, potential differences in adrenoceptor tone under varying experimental conditions).

Serotonin autoreceptor function and antidepressant drug action.

This article briefly summarizes, within the context of a brief review of the relevant literature, the outcome of our recent rat microdialysis studies on (1) the relative importance of serotonin (5-HT)1A versus 5-HT1B autoreceptors in the mechanism of action of 5-HT reuptake blocking agents, including putative regional differences in this regard, and (2) autoreceptor responsiveness following chronic SSRI administration. First, our data are consistent with the primacy of 5-HT1A autoreceptors in restraining the elevation of 5-HT levels induced by SSRIs, whereas nerve terminal 5-HT1B autoreceptors appear to have an accessory role in this regard. Second, there is an important interplay between cell body and nerve terminal 5-HT autoreceptors, and recent findings suggest that this interplay may potentially be exploited to obtain regionally preferential effects on 5-HT neurotransmission in the central nervous system, even upon systemic drug administration. In particular, emerging data suggest that somatodendritic 5-HT1A autoreceptor- and nerve terminal 5-HT1B autoreceptor-mediated feedback may be relatively more important in the control of 5-HT output in dorsal raphe-frontal cortex and median raphe-dorsal hippocampus systems, respectively. Third, 5-HT autoreceptors evidently retain the capability to limit the 5-HT transmission-promoting effect of SSRIs after chronic treatment. Thus, although the responsiveness of these sites is probably somewhat reduced, residual autoreceptor capacity still remains an effective restraint on large increases in extracellular 5-HT, even after prolonged treatment. If a further increase in extracellular 5-HT is crucial to the remission of depression in patients responding only partially to prolonged administration of antidepressants, then sustained adjunctive treatment with autoreceptor-blocking drugs may consequently prove useful in the long term.

Evolution of sleep apnea syndrome in sleepy snorers: a population-based prospective study.

This study followed a small number of men previously studied polysomnographically 10 yr earlier to investigate the relationship between the development of sleep-disordered breathing and age, weight gain, and smoking. In 1984, 3,201 men answered a questionnaire including questions about snoring and excessive daytime sleepiness (EDS). Of those reporting symptoms related to obstructive sleep apnea syndrome (OSAS), a random sample of 61 men was investigated using whole-night polysomnography in 1985. Ten years later, 38 men participated in the present follow-up, which included a structured interview and polysomnography. During the 10-yr period, nine men had been treated for OSAS. Of the 29 untreated subjects, the number of men with OSAS, defined as an apnea-hypopnea index (AHI) of >/= 5/h, increased from four in 1985 to 13 in 1995 (p < 0.01). In this small sample, no significant associations were found between DeltaAHI (i.e., AHI 1995 - AHI 1985) and age, weight gain, or smoking. We conclude that, among this small group of individuals who were selected for original polysomnographic study and follow-up because they were thought to have symptoms of sleep apnea, sleep-disordered breathing became significantly worse over time.

A descriptive study of how dentists view their profession and the doctor-patient relationship.

In this article we report on how 64 dentists working in a big city in southern Sweden view their profession. The dentists ranged in age from 30 to 70 years (as it was indicated in intervals of 10 years). Their professional experience ranged from 2 to 44 years (mean, 23 years). We collected their views on the ideal skills of a good dentist by means of a questionnaire. From this material we identified three categories: 1) interpersonal skills; 2) clinical skills; and 3) others, such as self-confidence, stress tolerance, and managerial and administrative skills. Next, they rated the relative importance of a number of listed attributes in dentistry in this order: contact with patients, communication skills, empathy, manual skills, and theory. Finally, they described a number of aspects of their profession. We conclude that the importance of interpersonal skills, as well as stress tolerance and administrative skills, is emphasized by experienced practitioners but that these skills are not focused on in the dental curriculum.

Potentiating interactions between morphogenetic protein and neurotrophic factors in developing neurons.

mRNA for bone morphogenetic protein receptor type II (BMPR-II) was mapped to different neurons in peripheral ganglia and spinal cord of the chicken embryo. The expression of this serine/threonine kinase receptor partially overlaps with that of tyrosine kinase receptors Trk and Ret. Biological activities of osteogenic protein-1 (OP-1), a documented ligand for BMPR-II, were tested in explanted embryonic chicken ganglia and dissociated ganglionic neurons. OP-1 had only a limited stimulatory effect on neuronal survival. However, OP-1 combined with either neurotrophin-3 (NT-3, a relative of nerve growth factor) or glial cell line-derived neurotrophic factor (GDNF) potentiated neuronal survival three- to fourfold. We also show that OP-1 strongly potentiates nerve fiber outgrowth from ganglia stimulated with NT-3 or GDNF. Signaling by BMPR-II in neurons may potentiate the tyrosine kinase pathway activated by NT-3 and GDNF. The data suggest that morphogenetic proteins may modulate neurotrophic activities during neuronal development and plasticity.

The role of 5-HT1A autoreceptors and alpha1-adrenoceptors in the modulation of 5-HT release--III. Clozapine and the novel putative antipsychotic S 16924.

Clozapine and the novel putative, antipsychotic S 16924 ((1-(benzodioxane-5-yl)-3-[3-(4-fluorophenacyl)pyrrolidine]-1-o xapropane HCl) share significant affinity for alpha1-adrenoceptors and 5-HT1A autoreceptors in vitro and display an 'atypical' behavioural profile in in vivo models used for detecting potential neuroleptic effects. In the present study, in vivo microdialysis was used to examine the effect of clozapine and S 16924 on 5-HT overflow in the rat ventral hippocampus, and to assess the relative role of putative alpha1-adrenoceptor antagonist and 5-HT1A autoreceptor agonist properties of the drugs in this regard. S 16924 (0.1-3 mg/kg, s.c.) reduced dialysate 5-HT in a dose- and time-dependent fashion by maximally approximately 70% from baseline 40-60 min after injection. Clozapine (0.1-10 mg/kg, s.c.) reduced 5-HT overflow in the same manner, with a maximum effect of approximately 60% from baseline, obtained after 60-80 min. The 5-HT decrease elicited by S 16924 (1.0 mg/kg, s.c.) was significantly, though only partially, antagonized by pretreatment with the selective 5-HT1A receptor antagonist WAY 100635 (0.3 mg/kg, s.c.). The selective alpha1-adrenoceptor agonist cirazoline (0.02 mg/kg, i.p.) alone did not significantly attenuate the effect of S 16924 (1.0 mg/kg, s.c.) on 5-HT overflow. Combined treatment with both WAY 100635 and cirazoline, however, totally reversed the 5-HT-suppressing effect of S 16924 (1.0 mg/kg, s.c.). By comparison, when given separately, neither WAY 100635 (0.3 mg/kg, s.c.) nor cirazoline (0.02 mg/kg, i.p.) antagonized the clozapine (0.3 mg/kg, s.c.)-induced decrease of 5-HT in ventral hippocampus dialysates. In the presence of both WAY 100635 and cirazoline, the response to this dose of clozapine was however significantly, though modestly, attenuated. In contrast, the WAY 100635/cirazoline combination failed to antagonise the 5-HT decrease resulting from a higher dose (3.0 mg/kg, s.c.) of clozapine. We conclude that both alpha1-adrenoceptor antagonist and 5-HT1A receptor agonist properties of clozapine and S 16924 contribute to the 5-HT release-reducing action of these drugs. Whereas these factors apparently explain the effect of S 16924 fully, additional mechanism(s) appear to be involved in the case of clozapine. With regard to the interplay between alpha1-adrenoceptor and 5-HT1A (auto)receptor mechanisms in the control of 5-HT release in the rat forebrain, the present data suggest that an excitation mediated by the former is outweighed by the simultaneous activation of the latter-inhibitory-receptors.

BMPR-II expression and OP-1 effects in developing chicken retinal explants.

Low-stringency PCR was used to isolate the chicken homologue of the human bone morphogenetic protein receptor type II (BMPR-II). In situ hybridization localized mRNA expression for this serine/threonine kinase receptor. It was weakly expressed in the vitreal side of the neural retina at E6. In the E7 chicken, fairly strong labelling was found in cells of the internal part of the neural retina. At E9, strong labelling was found in the region of the retinal ganglion cells. Explants of E6 retina exposed to osteogenic protein-1 (OP-1/BMP-7), exhibited dense retinal fibre outgrowth. This suggests that BMPR-II may form a signalling receptor complex important for retinal development. OP-1 and related ligands may serve functions supplementary to those of neurotrophins.

Bone morphogenetic proteins and their receptors: potential functions in the brain.

Transforming growth factors-beta (TGF-betas), activins, and bone morphogenetic proteins (BMPs) comprise an evolutionarily well-conserved group of proteins controlling a number of cell differentiation, cell growth, and morphogentic processes during development. The superfamily of TGFbeta-related genes include over 25 members in mammals several of which are expressed in the growing nervous system and serve important functions in regionalizing the early CNS. Cultured nerve cells show different responses to these factors. Recent developments have revealed that TGFbetas, activins, and BMPs selectively signal to the responding cells via different hetero-oligomeric complexes of type I and type II serine/threonine kinase receptors. The adult brain exhibits specific expression patterns of some of these receptors suggesting neuronal functions not only during development but also in the mature brain. In particular, the brain is expressing high levels of bone morphogenetic protein receptor type II (BMPR-II), activin receptor type I (ActR-I), and activin receptor type IIA (ActR-II). This indicates that osteogenic protein-1 (OP-1/BMP-7), BMP-2, and BMP-4 as well as activins may serve functions for brain neurons. Expression of the receptors partially overlaps in populations of neurons and has been shown to be regulated by brain lesions. This suggests that brain neurons may use receptors BMPR-II and ActR-I to sense the presence of BMPs. This may form a system parallel to the neurotrophin Trk tyrosine kinase receptors regulating neuroplasticity and brain repair. The presence of BMPs in brain is not well studied, but preliminary in situ data indicate that the BMP relatives growth/differentiation factor (GDF)-1 and GDF-10 are distinctly but differentially expressed at high levels in neurons expressing BMPR-II and ActR-I. The receptors mediating responses to these two GDFs remain, however, to be defined. Finally, recent data show that the signal from the activated type I serine/threonine kinase receptor is directly transduced to the nucleus by Smad proteins that become incorporated into transcriptional complexes. Preliminary in situ hybridization observations demonstrate the existence of different Smad mRNAs. It is concluded that BMPs and their signaling systems may comprise a novel pathway for control of neural activity and offer means for pharmacological interventions rescuing brain neurons.

No effect of diclofenac on the pharmacokinetics of cloxacillin.

We studied the influence of diclofenac on the pharmacokinetics of cloxacillin in healthy volunteers, 60 years or older, as well as the possible effect of cloxacillin and diclofenac on urinary protein excretion. In a randomized, double-blind, cross-over study 15 subjects were given 1 g cloxacillin, and placebo or 75 mg diclofenac, as single intravenous doses. Plasma concentrations of cloxacillin were followed over 10.5 hr, and urine excretion of cloxacillin over 24 hr. The effect of the drugs on urinary excretion of protein indicators of glomerular (albumin, IgG) and tubular (protein HC) function was also studied. Total plasma clearance of cloxacillin was with placebo 219 +/- 51 (mean +/- S.D.), and with diclofenac 212 +/- 39 ml/min./1.73 m2 (ns); renal clearance was 97 +/- 21 and 96 +/- 24 ml/min./1.73 m2, respectively (ns). The terminal t1/2 of cloxacillin was 1.03 +/- 0.42 hr with placebo, and 1.12 +/- 0.37 with diclofenac (ns). The mean ratio of AUC0-infinity's (cloxacillin plus diclofenac/cloxacillin plus placebo) was 1.03 (90% CI: 0.99, 1.08). Urinary excretion of the proteins was low and was not increased by cloxacillin or diclofenac. In healthy volunteers, 60 years or older, diclofenac does not alter cloxacillin pharmacokinetics, and neither cloxacillin nor diclofenac in single intravenous doses cause renal dysfunction.

WAY100635-induced augmentation of the 5-HT-elevating action of citalopram: relative importance of the dose of the 5-HT1A (auto)receptor blocker versus that of the 5-HT reuptake inhibitor.

The elevation of extracellular 5-HT after systemic administration of 5-HT reuptake inhibiting drugs is strongly potentiated by agents capable of blocking 5-HT1A autoreceptors in the midbrain raphe. The present in vivo microdialysis study was aimed at assessing the relative importance of 5-HT reuptake inhibition versus 5-HT1A autoreceptor blockade in this interaction. Citalopram (0.5 or 5.0 mg/kg s.c.) dose-dependently increased dialysate 5-HT in the rat ventral hippocampus, maximally doubling the initial baseline values within 60 min after injection. The selective 5-HT1A receptor blocker, WAY100635 (0.01-0.3 mg/kg s.c.), further augmented, in a dose-dependent manner, the high-dose citalopram response (to approximately 4-5 x the pre-citalopram baseline). For comparison, the effect of low-dose (0.5 mg/kg s.c.) citalopram was mildly, but not significantly, potentiated by WAY100635 (0.3 mg/kg). WAY100635 given alone does not alter 5-HT under these conditions. The data confirm previous findings that 5-HT1A autoreceptor blockade enhances the citalopram-induced increase of extracellular 5-HT in the forebrain. To the extent the extracellular levels of 5-HT is a valid index, through 5-HT reuptake blockade appears to be the primary prerequisite for this interaction to occur. New drugs and/or treatment regimes based on the SSRI/5-HT1A autoreceptor blocker combination concept should, therefore, emphasize the former property.

Long-term follow-up of patients with obstructive sleep apnea treated with uvulopalatopharyngoplasty.

OBJECTIVE: To study the long-term outcome after treatment with uvulopalatopharyngoplasty (UPPP). DESIGN: Long-term follow-up (4-8 years) with polysomnography. SETTING: Referral center for patients with sleep-disordered breathing. PATIENTS: Thirty-four consecutive patients of whom 25 (22 men and 3 women; mean age, 49 years) participated in the follow-up. All patients had obstructive sleep apnea syndrome. INTERVENTION: Uvulopalatopharyngoplasty. MAIN OUTCOME MEASURES: Symptoms and apnea-hypopnea index (AHI) before and after UPPP. Response to treatment defined as a 50% or more reduction in AHI and a postoperative AHI of 10 or less. RESULTS: Reduced prevalence of snoring and daytime sleepiness and reduction in AHI (mean [+/-SD], 40 +/- 26 to 21 +/- 21) at follow-up (P < .001). Sixteen patients (64%) were responders after 6 months and 12 (48%) at the long-term follow-up. Responders had a lower preoperative AHI (25 +/- 7) than did nonresponders (48 +/- 29) (P < .05). None of the 7 patients with preoperative AHI of more than 40 were responders (P < .01). No difference was seen in preoperative body mass index, lung function, ventilatory response to carbon dioxide, computed tomography scan of upper airways, or change in body mass index between responders and nonresponders. CONCLUSIONS: Four to 8 years after UPPP, about half of our patients were clinically and objectively improved. Uvulopalatopharyngoplasty should be reserved for patients with mild or moderate obstructive sleep apnea. After UPPP, long-term follow-up is recommended because some initially successfully treated patients will relapse in the long term.

Raphe 5-HT1A autoreceptors, but not postsynaptic 5-HT1A receptors or beta-adrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo.

In vivo microdialysis in rat ventral hippocampus was used (i) to verify the importance of 5-HT1A autoreceptors in the raphe as targets for drugs that enhance the citalopram-induced elevation of forebrain 5-hydroxytryptamine (5-HT), and (ii) to further examine the specificity of (-)-penbutolol in this regard. The selective 5-HT1A receptor antagonist WAY100635 (s.c., or intra-raphe) or the mixed 5-HT1A/1B/beta-adrenoceptor antagonist (-)-penbutolol (s.c.), potentiated the citalopram-induced 5-HT rise, whereas local "reverse' dialysis of WAY100635 into the ventral hippocampus did not. Furthermore, the (-)-penbutolol-induced augmentation proved stereoselective and not mediated by beta-adrenoceptors (no effect of s.c. (+)-penbutolol, or beta 1- and beta 2-adrenoceptor blockers (betaxolol, ICI118.551)). These data provide direct evidence that increased stimulation of 5-HT1A autoreceptors in the midbrain raphe impedes the effect of citalopram on forebrain extracellular 5-HT, whereas neither postsynaptic 5-HT1A receptors nor beta-adrenoceptors appear to be involved.