Epidemiology of hip and groin injuries in Swedish male first football league.

PURPOSE: This study aimed to investigate the incidence, pattern, and burden of hip/groin injuries in Swedish professional male football players over five consecutive seasons. METHODS: Injury history from 16 football teams in the Swedish male first football league was evaluated during five consecutive seasons. The team's medical staff recorded team exposure and time-loss injuries prospectively between 2012 and 2016. RESULTS: In total, 467 time-loss injuries located in the hip/groin area were recorded among 1,687 professional male football players, with an overall incidence and burden of 0.82/1,000 h and 15.6/1,000 h, respectively. There appeared to be an increased risk of hip/groin injuries during the last two seasons (2015-2016); however, the difference was not statistically significant (n.s). Recurrent injury rate was relatively low (14%), and overuse injuries accounted for the majority of injuries and absence days. Muscle injuries were the main injury type, while kicking and sprinting/running were the primary causes of injury. Goalkeepers had the lowest percentage of injuries and absence days. CONCLUSION: Hip/groin injuries are a substantial problem in football, but does not seem to be an increasing phenomenon in the Swedish male first football league. Index and overuse injuries accounted for the majority of injuries and absence days. Thus, the focus should be on preventing hip/groin injuries to lower the injury rate. These new findings should be taken into consideration when designing and implementing preventive training interventions. LEVEL OF EVIDENCE: II.

Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1-((1S,3R)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor.

Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.

Muscle injuries of the dominant or non-dominant leg in male football players at elite level.

PURPOSE: The aim was to study possible differences of muscle injuries regarding type, localization and the extent of injury between the dominant and non-dominant leg in elite male football players. Another aim was to study the injury incidence of muscle injuries of the lower extremity during match and training. METHODS: Data were consecutively collected between 2007 and 2013 in a prospective cohort study based on 54 football players from one team of the Swedish first league. The injury incidence was calculated for both match and training, injuries to the hip adductors, quadriceps, hamstrings and triceps surae were diagnosed and evaluated with ultrasonography, and their length, depth and width were measured to determine the extent of structural muscle injuries. RESULTS: Fifty-four players suffered totally 105 of the studied muscle injuries. Out of these 105 injuries, the dominant leg was affected in 53 % (n = 56) of the cases. A significantly greater extent of the injury was found in the dominant leg when compared with the non-dominant leg with regard to structural injuries of the hamstrings. No other significant differences were found. CONCLUSIONS: Structural hamstring muscle injuries were found to be of greater extent in the dominant leg when compared with the non-dominant leg. This new finding should be taken into consideration when allowing the football player to return to play after leg muscle injuries. LEVEL OF EVIDENCE: IV.

Muscle injuries of the lower extremity: a comparison between young and old male elite soccer players.

PURPOSE: The aim of this study was to make a comparison between players in two age groups in an elite male soccer team regarding injury localisation within the muscle-tendon unit, injury size and muscle group in terms of muscle injuries of the lower extremity. METHODS: Cohort study based on data collected from a Swedish elite male soccer team during the seasons 2007-2012. In total, 145 muscle injuries were included. Injury localisation to the tendon or muscle, the size of haematoma and the affected muscle group were assessed using ultrasound. Age comparison was made between younger players (≤23 years) and older players (>23 years). RESULTS: No difference regarding injury localisation to either the tendon or the muscle, or the size of haematoma between the two age groups was found. However, the older group of players suffered a significantly higher number of injuries to the triceps surae than the younger players (p = 0.012). CONCLUSIONS: In a Swedish team of male soccer players at elite level, there was no difference between players 23 years or younger and players older than 23 years, in terms of injury distribution to muscles or tendons. Players older than 23 years sustained more injuries to triceps surae when compared with players 23 years or younger. The clinical relevance is to pay attention to muscle function of triceps surae in older players and to screen those players who may need an injury prevention programme. LEVEL OF EVIDENCE: II.

Effects of the dopamine stabilizers (S)-(-)-OSU6162 and ACR16 on prolactin secretion in drug-naive and monoamine-depleted rats.

Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus α-methyl-DL: -p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion.

Allosteric modulation of NMDA receptor via elevation of brain glycine and D-serine: the therapeutic potentials for schizophrenia.

Ionotropic AMPA and NMDA glutamate receptors are ligand-gated ion channels that mediate fast synaptic transmission in the brain and play a crucial role in learning and memory. Dysfunction of these receptors is believed to be associated with a number of neuropsychiatric disorders, including schizophrenia. As direct activation of these ionotropic receptors can lead to excitoxicity, allosteric modulation of these receptors could minimize side-effects to achieve better therapeutic efficacy. Our review here focuses on the allosteric modulation of the NMDA receptor. Endogenous glycine and D-serine both act as co-agonists on the strychnine-insensitive GlyB site on the NMDA receptor, and along with glutamate, co-activate the NMDA receptor. Forebrain synaptic glycine and d-serine levels are regulated by the Glycine Transporter-1 (GlyT1) and the arginine-serine-cysteine transporter-1 (Asc-1), respectively; in addition to D-serine metabolism by D-Amino Acid Oxidase (DAAO). Together, these processes prevent the GlyB site from being saturated by the high extracellular levels of brain glycine, and perhaps d-serine, in vivo. Blockade of NMDA receptors by phencyclidine induces schizophrenia-like symptoms with the associated cognitive deficits. It was proposed that: a) blockade of GlyT1 mediated reuptake of glycine, or b) inhibition of D-amino Acid Oxidase, or Asc-1 will elevate brain glycine, and D-serine to upregulate NMDA receptor functions via glycine and D-serine co-agonistic allosteric modulation of the GlyB sites on the NMDA receptor. These approaches may provide novel treatments to schizophrenia, provided that some of the known adverse effects associated with existing GlyT1 agents can be safely and adequately dealt with.

Neurochemical and behavioral profiling of the selective GlyT1 inhibitors ALX5407 and LY2365109 indicate a preferential action in caudal vs. cortical brain areas.

Selective inhibitors of the glycine transporter 1 (GlyT1) have been implicated in central nervous system disorders related to hypoglutamatergic function such as schizophrenia. The selective GlyT1 inhibitors ALX5407 (NFPS) and LY2365109 {[2-(4-benzo[1,3]dioxol-5-yl-2-tert-butylphenoxy)ethyl]-methylamino}-acetic acid increased cerebrospinal fluid levels of glycine and potentiated NMDA-induced increases in dialysate levels of neurotransmitters in the prefrontal cortex (PFC) and the striatum. However, higher doses produced both stimulatory and inhibitory effects on motor performance and impaired respiration, suggesting significant involvement of cerebellar and brain stem areas. A dual probe microdialysis study showed that ALX5407 transiently elevated extracellular levels of glycine in the PFC with more sustained increases in the cerebellum. In support of these findings, immuno-staining with pan-GlyT1 and GlyT1a antibodies showed a higher abundance of immunoreactivity in the brain stem/cerebellum as compared to the frontal cortical/hippocampal brain areas in four different species studied, including the mouse, rat, monkey and human. In addition, the inhibitory effects of ALX5407 on cerebellar levels of cGMP in the mouse could be reversed by the glycine A receptor antagonist strychnine but not the glycine B receptor antagonist L-701324. We propose that the adverse events seen with higher doses of ALX5407 and LY2365109 are the result of high GlyT1 inhibitory activity in caudal areas of the brain with sustained elevations of extracellular glycine. High levels of glycine in these brain areas may result in activation of strychnine-sensitive glycine A receptors that are inhibitory on both motor activity and critical brain stem functions such as respiration.

The dopamine stabilizers (S)-(-)-(3-methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-methanesulfonylphenyl)-1-propyl-piperidine (ACR16) show high in vivo D2 receptor occupancy, antipsychotic-like efficacy, and low potential for motor side effects in the rat.

"Dopamine stabilizers" are a new class of compounds that have the ability to reverse both hypo- as well as hyperdopaminergia in vivo. This class, exemplified by the phenylpiperidines (S)-(-)-3-(3-methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-methanesulfonyl-phenyl)-1-propyl)-piperidine [ACR16] although lacking high in vitro binding affinity for dopamine D2 receptor [(-)-OSU6162, Ki = 447 nM; ACR16, Ki > 1 microM], shows functional actions, suggestive of their interaction. Hence, we evaluated in vivo D2 occupancy of these agents in rats and correlated it to observed effects in a series of behavioral, neurochemical, and endocrine models relevant to the dopamine system and antipsychotic effect. Both (-)-OSU6162 and ACR16 showed robust dose-dependent striatal D2 occupancy with ED50 values of 5.27 and 18.99 mg/kg s.c., respectively, and functional assays showed no partial agonism. Over an occupancy range of 37 to 87% (3-60 mg/kg) for (-)-OSU6162 and 35 to 74% (10-60 mg/kg) for ACR16, we observed both inhibitory (amphetamine-induced locomotor activity) and stimulatory effects (in habituated rats). Haloperidol, over a similar occupancy range (33-78%), potently inhibited psychostimulant activity and induced catalepsy, but it failed to activate habituated animals. In the conditioned avoidance response assay, ACR16 was clearly more efficacious than (-)-OSU6162. In addition, both these compounds demonstrated significant preferential Fos induction in the nucleus accumbens compared with the dorsolateral striatum, a strong predictor of atypical antipsychotic efficacy. The results suggest that dopamine stabilizers exhibit locomotor stabilizing as well as antipsychotic-like effects, with low motor side effect liability, in a dose range that corresponds to high D2 in vivo occupancy.