The impact of COVID-19 on national hockey league players' return to play.

OBJECTIVE: Evaluate the on-ice performance and return to play (RTP) rate following COVID-19 for National Hockey League (NHL) players during the 2020-21 season. METHODS: Players with COVID-19 during the abbreviated 2020-21 season were identified using publicly accessible online sources. Demographics and on-ice metrics were accessed using the NHL's online statistics website. The length of time, rate of RTP, and games missed due to COVID-19 were analyzed. Primary outcomes included average time on ice (TOI) per game (TOI/G), average TOI per shift (TOI/S), and points per game (PPG) compared at different timepoints including pre- and post-COVID-19. RESULTS: A total of 73 players (47 forwards, 18 defensemen, 8 goalies) had a documented COVID-19 diagnosis during the abbreviated 2020-21 season. Players missed an average of 5.6 games (14.7 days) due to COVID-19. The post-COVID-19 RTP rate was 97.3%, including playoffs. No differences were found in TOI/G between the pre- (15.7 ± 3.9 min) and post-COVID-19 (15.8 ± 3.4 min, p = 0.874) or in the first (15.8 ± 4.0 min) and second week (15.9 ± 3.8 min, p = 0.925) returned. TOI/shift did not change from pre- (45.6 ± 5.3 sec) to post-COVID-19 (46.7 ± 4.6 sec, p = 0.035) or in first (46.2 ± 5.4 sec) and second week post-COVID-19 (46.2 ± 4.8 sec, p = .854). No differences were identified for PPG between career, pre-COVID-19, and post-COVID-19 (0.44 vs 0.38 vs 0.41; p = 0.274). CONCLUSION: RTP post-COVID was markedly high for NHL players. While the effects of COVID-19 on specific physiological measures remains to be elucidated, this study found NHL players do not have reduced performance following COVID-19.

Neuroactive steroids and Parkinson's disease: Review of human and animal studies.

The greater prevalence and incidence of Parkinson's disease (PD) in men suggest a beneficial effect of sex hormones. Neuroactive steroids have neuroprotective activities thus offering interesting option for disease-modifying therapy for PD. Neuroactive steroids are also neuromodulators of neurotransmitter systems and may thus help to control PD symptoms and side effect of dopamine medication. Here, we review the effect on sex hormones (estrogen, androgen, progesterone and its metabolites) as well as androstenediol, pregnenolone and dehydroepiandrosterone) in human studies and in animal models of PD. The effect of neuroactive steroids is reviewed by considering sex and hormonal status to help identify specifically for women and men with PD what might be a preventive approach or a symptomatic treatment. PD is a complex disease and the pathogenesis likely involves multiple cellular processes. Thus it might be useful to target different cellular mechanisms that contribute to neuronal loss and neuroactive steroids provide therapeutics options as they have multiple mechanisms of action.

Three-Dimensional Analysis of Sex- and Gonadal Status- Dependent Microglial Activation in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by neurodegeneration and neuroinflammation. PD prevalence and incidence are higher in men than in women and modulation of gonadal hormones could have an impact on the disease course. This was investigated in male and female gonadectomized (GDX) and SHAM operated (SHAM) mice. Dutasteride (DUT), a 5α-reductase inhibitor, was administered to these mice for 10 days to modulate their gonadal sex hormones. On the fifth day of DUT treatment, mice received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model PD. We have previously shown in these mice the toxic effect of MPTP in SHAM and GDX males and in GDX females on dopamine markers and astrogliosis whereas SHAM females were protected by their female sex hormones. In SHAM males, DUT protected against MPTP toxicity. In the present study, microglial density and the number of doublets, representative of a microglial proliferation, were increased by the MPTP lesion only in male mice and prevented by DUT in SHAM males. A three-dimensional morphological microglial analysis showed that MPTP changed microglial morphology from quiescent to activated only in male mice and was not prevented by DUT. In conclusion, microgliosis can be modulated by sex hormone-dependent and independent factors in a mice model of PD.

Sex and Age Differences in a Progressive Synucleinopathy Mouse Model.

The mutation and overexpression of the alpha-synuclein protein (αSyn), described as synucleinopathy, is associated with Parkinson's disease (PD)-like pathologies. A higher prevalence of PD is documented for men versus women, suggesting female hormones' implication in slowing PD progression. The nigrostriatal dopamine (DA) neurons in rodent males are more vulnerable to toxins than those in females. The effect of biological sex on synucleinopathy remains poorly described and was investigated using mice knocked out for murine αSyn (SNCA-/-) and also overexpressing human αSyn (SNCA-OVX) compared to wildtype (WT) mice. All the mice showed decreased locomotor activity with age, and more abruptly in the male than in the female SNCA-OVX mice; anxiety-like behavior increased with age. The SNCA-OVX mice had an age-dependent accumulation of αSyn. Older age was associated with the loss of nigral DA neurons and decreased striatal DA contents. The astrogliosis, microgliosis, and cytokine concentrations increased with aging. More abrupt nigrostriatal DA decreases and increased microgliosis were observed in the male SNCA-OVX mice. Human αSyn overexpression and murine αSyn knockout resulted in behavioral dysfunctions, while only human αSyn overexpression was toxic to DA neurons. At 18 months, neuroprotection was lost in the female SNCA-OVX mice, with a likely loss of estrus cycles. In conclusion, sex-dependent αSyn toxicity was observed, affecting the male mice more significantly.

Impact of sex on neuroimmune contributions to Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Inflammation has been observed in both the idiopathic and familial forms of PD. Importantly, PD is reported more often in men than in women, men having at least 1.5- fold higher risk to develop PD than women. This review summarizes the impact of biological sex and sex hormones on the neuroimmune contributions to PD and its investigation in animal models of PD. Innate and peripheral immune systems participate in the brain neuroinflammation of PD patients and is reproduced in neurotoxin, genetic and α-synuclein based models of PD. Microglia and astrocytes are the main cells of the innate immune system in the central nervous system and are the first to react to restore homeostasis in the brain. Analysis of serum immunoprofiles in female and male control and PD patients show that a great proportion of these markers differ between males and females. The relationship between cerebrospinal fluid inflammatory markers and PD clinical characteristics or PD biomarkers shows sex differences. Conversely, in animal models of PD, sex differences in inflammation are well documented and the beneficial effects of endogenous and exogenous estrogenic modulation in inflammation have been reported. Targeting neuroinflammation in PD is an emerging therapeutic option but gonadal drugs have not yet been investigated in this respect, thus offering new opportunities for sex specific treatments.

Foliglurax, a positive allosteric modulator of the metabotrophic glutamate receptor 4, protects dopaminergic neurons in MPTP-lesioned male mice.

Overactivity of the corticostriatal glutamatergic pathway is documented in Parkinson's disease (PD) and stimulation of presynaptic metabotropic glutamate (mGlu) receptors 4 on these striatal afferents inhibits glutamate release normalizing neuronal activity in the basal ganglia. Moreover, mGlu4 receptors are also expressed in glial cells and are able to modulate glial function making this receptor a potential target for neuroprotection. Hence, we investigated whether foliglurax, a positive allosteric modulator of mGlu4 receptors with high brain exposure after oral administration, has neuroprotective effects in MPTP mice to model early PD. Male mice were treated daily from day 1 to 10 with 1, 3 or 10 mg/kg of foliglurax and administered MPTP on the 5th day then euthanized on the 11th day. Dopamine neuron integrity was assessed with measures of striatal dopamine and its metabolites levels, striatal and nigral dopamine transporter (DAT) binding and inflammation with markers of striatal astrocytes (GFAP) and microglia (Iba1). MPTP lesion produced a decrease in dopamine, its metabolites and striatal DAT specific binding that was prevented by treatment with 3 mg/kg of foliglurax, whereas 1 and 10 mg/kg had no beneficial effect. MPTP mice had increased levels of GFAP; foliglurax treatment (3 mg/kg) prevented this increase. Iba1 levels were unchanged in MPTP mice compared to control mice. There was a negative correlation between dopamine content and GFAP levels. Our results show that positive allosteric modulation of mGlu4 receptors with foliglurax provided neuroprotective effects in the MPTP mouse model of PD.

Postoperative recovery comparisons of arthroscopic Bankart to open Latarjet for the treatment of anterior glenohumeral instability.

BACKGROUND: Recurrent anterior glenohumeral instability is a disabling pathology that can be successfully treated by arthroscopic Bankart repair or open Latarjet. However, there is a paucity of studies comparing the postoperative recovery. The purpose of this study is to evaluate the postoperative pain and functional recovery following arthroscopic Bankart versus open Latarjet. METHODS: This is a retrospective analysis of a multicenter prospective outcomes registry database. Postoperative recovery outcomes of either a primary or revision arthroscopic Bankart and open Latarjet procedures were compared. A minimum of 1-year follow-up was required. Outcomes measures included pain visual analog scale (VAS), American Shoulder and Elbow Surgeons (ASES) function score, ASES index score, and single assessment numeric evaluation (SANE) score. Overall, 787 patients underwent primary arthroscopic Bankart, 36 underwent revision arthroscopic Bankart and 75 underwent an open Latarjet procedure. RESULTS: When compared to primary arthroscopic Bankart, open Latarjet demonstrated significantly lower VAS scores at 6 weeks (p = 0.03), 3 months (p = 0.01), and 2 years (p < 0.05). Medium-term outcomes for ASES scores and SANE score, at 1 and 2 years showed no difference. Latarjet demonstrated significantly lower (p < 0.05) preoperative early postoperative VAS pain scores with no difference at 1 year or 2 years when compared to primary Bankart. There was no difference in ASES function or index between Bankart and Latarjet. Revision Bankart provided inferior outcomes for VAS, ASES function, and ASES index when compared to primary Bankart and Latarjet at 1 year and 2 years. CONCLUSIONS: Primary arthroscopic Bankart repair and open Latarjet provided nearly equivalent improvements in pain (VAS) and functional outcomes (ASES, SANE, VR-12) during the early recovery phase (2 years). This study supports the use of either procedure in the primary treatment of anterior glenohumeral instability. Revision arthroscopic Bankart repair demonstrated deteriorating outcomes at 1 and 2 years postoperatively.

Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson's Disease Models.

Gastrointestinal disorders in Parkinson's disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the immunomodulatory effect of female hormones to treat enteric neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. This study made the hypothesis of obtaining similar neuroprotection as with hormone treatments by affecting steroidogenesis with two 5α-reductase inhibitors, finasteride and dutasteride. These drugs are approved to treat benign prostatic hyperplasia and alopecia and display mitochondrial effects. In MPTP-treated mice, the dopaminergic and vasoactive intestinal peptide (VIP) neurons alteration was prevented by finasteride and dutasteride, while the increase in proinflammatory macrophages density was inhibited by dutasteride treatment but not finasteride. NF-κB response, oxidative stress, and nitric oxide and proinflammatory cytokines production in vitro were only prevented by dutasteride. In addition, mitochondrial production of free radicals, membrane depolarization, decreased basal respiration, and ATP production were inhibited by dutasteride, while finasteride had no effect. In conclusion, the present results indicate that dutasteride treatment prevents enteric neuronal damages in the MPTP mouse model, at least in part through anti-inflammatory and mitochondrial effects. This suggests that drug repurposing of dutasteride might be a promising avenue to treat enteric neuroinflammation in early PD.

Partial Rotator Cuff Repair Provides Improved Patient-Reported Outcome Measures Following Superior Capsule Reconstruction (SCR).

Purpose: To evaluate the role of concomitant partial rotator cuff repair (RCR) (i.e., infraspinatus) on patient-reported clinical outcomes following superior capsule reconstruction (SCR). Methods: Postoperative recovery outcomes of SCR alone were compared with SCR with concomitant infraspinatus rotator cuff repair (SCR+RCR) at 3, 6, 12, and 24 months. Patients were included if they had an SCR surgery with or without a concomitant infraspinatus repair. Patients were excluded if they did not have a minimum of 6 months' follow-up or if a preoperative baseline questionnaire was not performed. Outcome measures included pain visual analog scale, American Shoulder and Elbow Surgeons (ASES) Shoulder Function, ASES Shoulder Index, and Single Assessment Numeric Evaluation (SANE) score. Results: Overall, 180 patients were evaluated, including 163 patients who underwent SCR alone and 17 patients who underwent concomitant infraspinatus repair (SCR+RCR). There was no difference in demographic data including age, sex, and body mass index. The postoperative recovery curves demonstrated SCR alone and SCR+RCR both provide significantly improved pain and functional scores at 2 years postoperatively (P < .001). When we compared the 2 groups, SCR+RCR provided significantly improved ASES Index (87.6 vs 78.2, P = .048) and ASES Function (25.5 vs 21.7, P = .02). There was no statistically significant difference in SANE scores (75.5 vs 64.2, P = .07) at 24 months' follow-up. Conclusions: SCR provides modest improvements in pain and function at 2 years postoperatively in patients with irreparable rotator cuff tears. Patients who underwent SCR and concomitant infraspinatus repair demonstrated significantly improved ASES Index and ASES Function scores and statistically nonsignificant improvement in SANE scores at 24 months postoperatively when compared with SCR alone. Level of Evidence: III, retrospective cohort study.

Differential contribution of estrogen receptors to the intestinal therapeutic effects of 17ß-estradiol in a murine model of Parkinson's disease.

Beneficial effects of estrogens have been reported in Parkinson's disease (PD) for many years. We previously reported their neuroprotective and anti-inflammatory potentials in the enteric nervous system of the intestine, a region possibly affected during the early stages of the disease according to Braak's hypothesis. Three different estrogen receptors have been characterized to date: the estrogen receptor alpha (ERα), the estrogen receptor beta (ERß) and the G protein coupled estrogen receptor 1 (GPER1). The aim of the present study was to decipher the individual contribution of each estrogen receptor to the therapeutic properties of 17ß-estradiol (E2) in the myenteric plexus of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Different agonists, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT; ERα), 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; ERß), G1 (GPER1), and antagonists, ICI 182,780 (ERα and ERß), G15 (GPER1), were used to analyze the involvement of each receptor. We confirmed that G1 protects dopamine (DA) neurons to a similar extent as E2. An anti-inflammatory effect on proinflammatory macrophages and cultured human monocytes was also demonstrated with E2 and G1. The effects of PPT and DPN were less potent than G1 with only a partial neuroprotection of DA neurons by PPT and a partial reduction of interleukin (IL)- 1ß production in monocytes by PPT and DPN. Overall, the present results indicate that the positive outcomes of estrogens are mainly through activation of GPER1. Therefore, this suggests that targeting GPER1 could be a promising approach for future estrogen-based hormone therapies during early PD.

Prevention of L-Dopa-Induced Dyskinesias by MPEP Blockade of Metabotropic Glutamate Receptor 5 Is Associated with Reduced Inflammation in the Brain of Parkinsonian Monkeys.

Proinflammatory markers were found in brains of Parkinson's disease (PD) patients. After years of L-Dopa symptomatic treatment, most PD patients develop dyskinesias. The relationship between inflammation and L-Dopa-induced dyskinesias (LID) is still unclear. We previously reported that MPEP (a metabotropic glutamate receptor 5 antagonist) reduced the development of LID in de novo MPTP-lesioned monkeys. We thus investigated if MPEP reduced the brain inflammatory response in these MPTP-lesioned monkeys and the relationship to LID. The panmacrophage/microglia marker Iba1, the phagocytosis-related receptor CD68, and the astroglial protein GFAP were measured by Western blots. The L-Dopa-treated dyskinetic MPTP monkeys had increased Iba1 content in the putamen, substantia nigra, and globus pallidus, which was prevented by MPEP cotreatment; similar findings were observed for CD68 contents in the putamen and globus pallidus. There was a strong positive correlation between dyskinesia scores and microglial markers in these regions. GFAP contents were elevated in MPTP + L-Dopa-treated monkeys among these brain regions and prevented by MPEP in the putamen and subthalamic nucleus. In conclusion, these results showed increased inflammatory markers in the basal ganglia associated with LID and revealed that MPEP inhibition of glutamate activity reduced LID and levels of inflammatory markers.

Effect of sex and gonadectomy on brain MPTP toxicity and response to dutasteride treatment in mice.

The main neuropathological feature of Parkinson's disease (PD) is degeneration of dopamine (DA) neurons in the substantia nigra (SN); PD prevalence is higher in men, suggesting a role of sex hormones in neuroprotection. This study sought the effects of sex hormones in the brain in a mouse model of PD and modulation of steroid metabolism/synthesis with the 5α-reductase inhibitor dutasteride shown to protect 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) male mice. Male and female mice were gonadectomized (GDX) or SHAM operated. They were treated with vehicle or dutasteride (5 mg/kg) for 10 days and administered a low dose of MPTP (5.5 mg/kg) or saline on the 5th day to model early PD; brains were collected thereafter. Striatal measures of the active metabolite 1-methyl-4-phenylpyridinium (MPP+) contents showed no difference supporting an effect of the experimental conditions investigated. In SHAM MPTP male mice loss of striatal DA and metabolites, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding in the striatum and SN was prevented by dutasteride treatment; these changes were inversely correlated with glial fibrillary acidic protein (GFAP, an astrogliosis marker) levels. In SHAM female mice MPTP treatment had little or no effect on striatal and SN DA markers and GFAP levels whereas GDX male and female mice showed a similar loss of striatal DA markers and increase of GFAP. No effect of dutasteride treatment was observed in GDX male and female mice. In conclusion, sex differences in mice MPTP toxicity and response to dutasteride were observed that were lost upon gonadectomy implicating neuroinflammation.

Associations between concussion and risk of diagnosis of psychological and neurological disorders: a retrospective population-based cohort study.

OBJECTIVE: To investigate associations between concussion and the risk of follow-up diagnoses of attention-deficit hyperactivity disorder (ADHD), mood and anxiety disorders (MADs), dementia and Parkinson's disease. DESIGN: A retrospective population-based cohort study. SETTING: Administrative health data for the Province of Manitoba between 1990-1991 and 2014-2015. PARTICIPANTS: A total of 47 483 individuals were diagnosed with a concussion using International Classification of Diseases (ICD) codes (ICD-9-CM: 850; ICD-10-CA: S06.0). All concussed subjects were matched with healthy controls at a 3:1 ratio based on age, sex and geographical location. Associations between concussion and conditions of interest diagnosed later in life were assessed using a stratified Cox proportional hazards regression model, with adjustments for socioeconomic status and pre-existing medical conditions. RESULTS: 28 021 men (mean age ±SD, 25±18 years) and 19 462 women (30±21 years) were included in the concussion group, while 81 871 men (25±18 years) and 57 159 women (30±21 years) were included in the matched control group. Concussion was associated with adjusted hazard ratios of 1.39 (95% CI 1.32 to 1.46, p<0.001) for ADHD, 1.72 (95% CI 1.69 to 1.76; p<0.001) for MADs, 1.72 (95% CI 1.61 to 1.84; p<0.001) for dementia and 1.57 (95% CI 1.41 to 1.75; p<0.001) for Parkinson's disease. CONCLUSION: Concussion was associated with an increased risk of diagnosis for all four conditions of interest later in life.

The Effects of Acute Anaerobic Exercise on the Cardiovascular and Metabolic Response to the Cold Pressor Test in Healthy Adult Males.

Little is known about the physiological response to the cold pressor test (CPT) when in a clinically-induced state of autonomic nervous system (ANS) imbalance, despite its utility in various disease- and injury-states. To date, research in this area is limited to acute aerobic and isometric exercise, with a paucity of research investigating the effects of anaerobic exercise on the physiological response to the CPT. Therefore, the purpose of our study was to assess the effects of the Wingate anaerobic cycle test (WAT) on cardiovascular (CV) and metabolic recovery following the CPT in a group of healthy adult males. A pre-post intervention study was conducted, whereby 10 healthy adult males (age = 29 ± 4 years, height = 182 ± 7 cm, mass = 83 ± 9 kg) completed a baseline cold pressor test (CPT-only) and a follow-up cold pressor test preceded by a Wingate anaerobic exercise test (WAT+CPT). Recovery slopes for various CV and metabolic variables, including heart rate (HR), blood pressure (BP), and relative oxygen consumption (V̇O2) were analyzed using single-subject analysis, with celeration line slopes calculated for all participants in the CPT-only and WAT+CPT testing sessions. Celeration line slopes were compared between testing sessions using paired t-tests. No differences were identified for recovery slopes for HR (p = .295), diastolic BP (p = .300), and relative V̇O2 (p = .176) when comparing CPT-only and WAT+CPT testing sessions. Our results suggest that the CPT elicits a CV and metabolic response beyond that elicited solely by an acute bout of anaerobic exercise. As such, the CPT may be able to serve as a surrogate test for anaerobic exercise for individuals where high-intensity exercise may be contraindicated. Future research is warranted however, as the specific physiological mechanisms governing the observed responses have yet to be elucidated.

Neuroprotection and immunomodulation of progesterone in the gut of a mouse model of Parkinson's disease.

Gastrointestinal symptoms appear in Parkinson's disease patients many years before motor symptoms, suggesting the implication of dopaminergic neurones of the gut myenteric plexus. Inflammation is also known to be increased in PD. We previously reported neuroprotection with progesterone in the brain of mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and hypothesised that it also has neuroprotective and immunomodulatory activities in the gut. To test this hypothesis, we investigated progesterone administered to adult male C57BL/6 mice for 10 days and treated with MPTP on day 5. In an additional experiment, progesterone was administered for 5 days following MPTP treatment. Ilea were collected on day 10 of treatment and microdissected to isolate the myenteric plexus. Dopaminergic neurones were reduced by approximately 60% and pro-inflammatory macrophages were increased by approximately 50% in MPTP mice compared to intact controls. These changes were completely prevented by progesterone administered before and after MPTP treatment and were normalised by 8 mg kg-1 progesterone administered after MPTP. In the brain of MPTP mice, brain-derived neurotrophic peptide (BDNF) and glial fibrillary acidic protein (GFAP) were associated with progesterone neuroprotection. In the myenteric plexus, increased BDNF levels compared to controls were measured in MPTP mice treated with 8 mg kg-1 progesterone started post MPTP, whereas GFAP levels remained unchanged. In conclusion, the results obtained in the present study show neuroprotective and anti-inflammatory effects of progesterone in the myenteric plexus of MPTP mice that are similar to our previous findings in the brain. Progesterone is non-feminising and could be used for both men and women in the pre-symptomatic stages of the disease.

Evaluation of Early Submaximal Exercise Tolerance in Adolescents with Symptomatic Sport-related Concussion.

PURPOSE: This study aimed to compare cardiorespiratory response to a graded aerobic exercise challenge between adolescents with symptomatic sport-related concussion (SSRC) and healthy control subjects. METHODS: A quasiexperimental nonrandomized study at a multidisciplinary pediatric concussion program was conducted. Thirty-four adolescents with SSRC (19 males and 15 females) and 40 healthy control subjects (13 males and 27 females) completed the Buffalo Concussion Treadmill Testing (BCTT) until either symptom exacerbation or volitional fatigue. Main outcome measures included heart rate (HR), oxygen consumption (V˙O2), carbon dioxide production (V˙CO2), and minute ventilation (V˙E) at rest and at test termination, and change from rest in variables (ΔHR, ΔV˙O2, ΔV˙CO2, and ΔV˙E) during the first five stages of the BCTT. Main outcomes were analyzed using three-way mixed-model ANOVA, with group status (control vs SSRC) and sex (male vs female) as between-subject factors, and time (BCTT stage) as the within-subject factor. RESULTS: No group differences in resting HR, systolic and diastolic blood pressure, ΔV˙O2, V˙CO2, and V˙E were observed. During the first five stages of the BCTT, no group differences in ΔV˙O2, V˙CO2, and V˙E were observed; however, SSRC patients demonstrated higher RPE (P < 0.0005) compared with control subjects. No sex-based differences were observed among SSRC patients on measures collected at rest and during early stages of BCTT. CONCLUSIONS: Although SSRC patients exhibited higher RPE during a graded aerobic exercise challenge, no differences in cardiorespiratory response were observed compared with control subjects exercising at equivalent workloads. Further work is needed to elucidate the physiological mechanisms underlying exercise intolerance after SSRC.

Exercise-induced increases in the expression and activity of cardiac sarcoplasmic reticulum calcium ATPase 2 is attenuated in AMPKα2 kinase-dead mice.

Exercise enhances cardiac sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) function through unknown mechanisms. The present study tested the hypothesis that the positive effects of exercise on SERCA2a expression and function in the left ventricle is dependent on adenosine-monophosphate-activated protein kinase (AMPK) α2 function. AMPKα2 kinase-dead (KD) transgenic mice, which overexpress inactivated AMPKα2 subunit, and wild-type C57Bl/6 (WT) mice were randomized into sedentary groups or groups with access to running wheels. After 5 months, exercised KD mice exhibited shortened deceleration time compared with sedentary KD mice. In left ventricular tissue, the ratio of phosphorylated AMPKαThr172:total AMPKα was 65% lower (P < 0.05) in KD mice compared with WT mice. The left ventricle of KD mice had 37% lower levels of SERCA2a compared with WT mice. Although exercise increased SERCA2a protein levels in WT mice by 53%, this response of exercise was abolished in exercised KD mice. Exercise training reduced total phospholamban protein content by 23% in both the WT and KD mice but remained 20% higher overall in KD mice. Collectively, these data suggest that AMPKα influences SERCA2a and phospholamban protein content in the sedentary and exercised heart, and that exercise-induced changes in SERCA2a protein are dependent on AMPKα function.

Repurposing sex steroids and related drugs as potential treatment for Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder for which a greater prevalence and incidence is described in men. This suggests a protective effect of sex hormones in the brain. Therefore, steroids and drugs to treat endocrine conditions could have additional application for PD. Here, we review the protective effect of sex hormones, particularly estrogens, progesterone, androgens and dehydroepiandrosterone, in animal models of PD and also in human studies. Data also support that drugs affecting estrogen neurotransmission such as selective estrogen receptor modulators or affecting steroid metabolism with 5α-reductase inhibitors could be repositioned for treatment of PD. Sex steroids are also modulator of neurotransmission, thus they could repurposed to treat PD motor symptoms and to modulate the response to PD medication. No drug is yet available to limit PD progression. PD is a complex disease implicating multiple pathological processes and a therapeutic strategy using drugs with several mechanisms of action, such as sex steroids and endocrine drugs are interesting repositioning options for symptomatic treatment and disease-modifying activity for PD. This article is part of the Special Issue entitled 'Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders'.

Steroid 5α-reductase 2 deficiency leads to reduced dominance-related and impulse-control behaviors.

The enzyme steroid 5α-reductase 2 (5αR2) catalyzes the conversion of testosterone into the potent androgen 5α-dihydrotestosterone. Previous investigations showed that 5αR2 is expressed in key brain areas for emotional and socio-affective reactivity, yet the role of this enzyme in behavioral regulation remains mostly unknown. Here, we profiled the behavioral characteristics of 5αR2 heterozygous (HZ) and knockout (KO) mice, as compared with their wild-type (WT) littermates. While male 5αR2 KO mice displayed no overt alterations in motoric, sensory, information-processing and anxiety-related behaviors, they exhibited deficits in neurobehavioral correlates of dominance (including aggression against intruders, mating, and tube dominance) as well as novelty-seeking and risk-taking responses. Furthermore, male 5αR2 KO mice exhibited reduced D2-like dopamine receptor binding in the shell of the nucleus accumbens - a well-recognized molecular signature of social dominance. Collectively, these results suggest that 5αR2 is involved in the establishment of social dominance and its behavioral manifestations. Further studies are warranted to understand how the metabolic actions of 5αR2 on steroid profile may be implicated in social ranking, impulse control, and the modulation of dopamine receptor expression in the nucleus accumbens.

Patient-Specific Alterations in CO2 Cerebrovascular Responsiveness in Acute and Sub-Acute Sports-Related Concussion.

BACKGROUND: Preliminary studies suggest that sports-related concussion (SRC) is associated with alterations in cerebral blood flow (CBF) regulation. Here, we use advanced magnetic resonance imaging (MRI) techniques to measure CBF and cerebrovascular responsiveness (CVR) in individual SRC patients and healthy control subjects. METHODS: 15 SRC patients (mean age = 16.3, range 14-20 years) and 27 healthy control subjects (mean age = 17.6, range 13-21 years) underwent anatomical MRI, pseudo-continuous arterial spin labeling (pCASL) MRI and model-based prospective end-tidal targeting (MPET) of CO2 during blood oxygenation level-dependent (BOLD) MRI. Group differences in global mean resting CBF were examined. Voxel-by-voxel group and individual differences in regional CVR were examined using statistical parametric mapping (SPM). Leave-one-out receiver operating characteristic curve analysis was used to evaluate the utility of brain MRI CO2 stress testing biomarkers to correctly discriminate between SRC patients and healthy control subjects. RESULTS: All studies were tolerated with no complications. Traumatic structural findings were identified in one SRC patient. No significant group differences in global mean resting CBF were observed. There were no significant differences in the CO2 stimulus and O2 targeting during BOLD MRI. Significant group and patient-specific differences in CVR were observed with SRC patients demonstrating a predominant pattern of increased CVR. Leave-one-out ROC analysis for voxels demonstrating a significant increase in CVR was found to reliably discriminate between SRC patients and healthy control subjects (AUC of 0.879, p = 0.0001). The optimal cutoff for increased CVR declarative for SRC was 1,899 voxels resulting in a sensitivity of 0.867 and a specificity of 0.778 for this specific ROC analysis. There was no correlation between abnormal voxel counts and Postconcussion Symptom Scale scores among SRC patients. CONCLUSION: Acute and subacute SRCs are associated with alterations in CVR that can be reliably detected by brain MRI CO2 stress testing in individual patients.