Prophylactic Knee Bracing in Offensive Linemen of the National Football League: A Retrospective Analysis of Usage Trends, Player Performance, and Major Knee Injury.

Background: Offensive linemen in American football are prone to high-energy valgus forces to the knee, leading to associated injuries. Some offensive linemen in the National Football League (NFL) wear prophylactic knee braces (PKB) to prevent ligamentous injury. Purpose/Hypothesis: This purpose of the study was to compare injury rates and performance between NFL offensive linemen who wear PKB and those who do not. It was hypothesized that brace wear would be associated with fewer major knee injuries and no difference in gameplay performance. Study Design: Cohort study; Level of evidence, 3. Methods: For the 2014 through 2020 NFL seasons, offensive linemen with at least 200 game snaps per regular season were identified. Players were grouped by PKB status (bracers vs nonbracers) based on visualization of bilateral, dual-hinged metal knee braces as part of gameday uniforms on publicly available imaging databases and/or game videos. Major knee injuries, defined as those requiring the missing of games, were identified using publicly available data. Performance was assessed with Pro Football Focus grades for each season. Rates of major knee injury were compared between groups with the 2-sample Z test for proportions, and performance grades were compared with the unpaired t test. Results: For the cumulative study period, bracers demonstrated a significantly lower rate of major knee injuries than nonbracers (0.013 vs 0.049 injuries per player, respectively; P = .04). Isolated MCL injury was the most common injury for nonbracers. There was no group difference in performance for the cumulative study period or during most individual seasons. Yearly prevalence of PKB usage declined steadily from 16.3% in 2014 to 5.6% in 2020. A subgroup analysis of rookie players demonstrated an overall downtrend in usage during the study period as well. Conclusion: Results indicated that knee brace prophylaxis by NFL offensive linemen was associated with a reduced risk of major knee injury without a significant difference in performance when compared with nonbracers. Despite this, the prevalence of PKB declined over the study period.

Returning Athletes to Sports Following Anterior Cruciate Ligament Tears.

PURPOSE OF REVIEW: The purpose of this review is to discuss treatment options, rehabilitation protocols, return-to-play criteria, and expected outcomes after non-operative and operative treatment of anterior cruciate ligament (ACL) tears among an athletic population. RECENT FINDINGS: Non-operative treatment may be a viable option for some athletes with an ACL tears but can be difficult to predict "copers," and those that resume to sports return at lower performance level and/or less intense activities. Most studies assessing function after ACL reconstruction demonstrate favorable outcomes using patient-reported outcome studies. However, return-to-play and graft re-rupture rates vary substantially based on patient characteristics and level and type of athletic activity. Grafts used to reconstruct ACL produce similar objective outcomes and favorable patient-reported outcomes but have variable re-rupture rates depending on study and differ largely on morbidity associated with graft harvest. Various treatment methods including non-operative and operative techniques have been demonstrated to be efficacious in returning athletes to athletic activity depending on patient age and level of activity. Adherence to fundamental rehabilitation principles and accepted return-to-play guidelines can optimize outcomes and limit re-injury to the injured or contralateral limb.

Outcomes of Hardware Removal Surgery for Children.

Hardware removal is among the most common orthopedic procedures performed in the United States. The goal of this study was to report the outcomes of deep hardware removal for children. This study received institutional review board approval. Patients younger than 18 years who underwent deep hardware removal between 2007 and 2017 were studied. We reviewed 227 procedures involving 132 boys and 95 girls. Mean follow-up was 25 months (range, 14-36 months). Mean age at the time of surgery was 12.8 years (range, 2-17 years). Mean time from initial surgery to hardware removal was 8.4 months (range, 1-72 months). Of the 227 cases, 75 used a tourniquet. Mean tourniquet time was 30.1 minutes (range, 1-118 minutes). Mean length of surgery was 44.0 minutes (range, 4-173 minutes). Mean resident level performing the surgery was postgraduate year 3 (range, postgraduate year 2 to fellow). There were 3 complications. Locations of the implanted hardware included: femur, 85; humerus, 49; tibia, 46; hip/pelvis, 17; ulna, 11; miscellaneous foot, 10; radius, 6; and fibula, 3. Indications for surgery included surgeon recommendations in 122 cases; symptomatic hardware in 68 cases, and parent wishes in 37 cases. Hardware removal for children was safe, and the outcomes were excellent. Complications of hardware removal at a teaching hospital can be minimized when a more senior resident is the primary surgeon. Despite the challenging and historically troublesome nature of deep hardware removal, the current study shows that hardware removal for children is safe and effective. [Orthopedics. 2022;45(2):e91-e95.].

Intraoperative Imaging in Total Hip Arthroplasty Is Cost-Effective Regardless of Surgical Approach.

BACKGROUND: Component positioning in total hip arthroplasty (THA) may be improved with utilization of intraoperative imaging. The purpose of this study is to determine if intraoperative imaging during THA is cost-effective. METHODS: A break-even analysis was used as a model for cost-effectiveness, which incorporates cost of imaging (including direct charges and the additional time required for imaging), rate of revision surgery, and cost of revision surgery, yielding a final revision rate that needs to be achieved with use of intraoperative imaging in order for its use to be cost-effective. Absolute risk reduction (ARR) is determined by the difference between the initial revision rate and final revision rate. RESULTS: At an anticipated institutional cost of $120 and requiring 4 additional minutes, intraoperative fluoroscopy would be cost-effective if the baseline rate of revision due to component mispositioning (0.62%) is reduced to 0.46%. Intraoperative flat plate radiographs ($127) are cost-effective at an ARR of 0.16%. Cost-effectiveness is achieved with lower ARR in the setting of lower imaging costs ($15, ARR 0.02%), and higher ARR with higher imaging costs ($225, ARR 0.29%). ARR for cost-effectiveness is independent of baseline revision rate, but varies with the cost of revision procedures. CONCLUSION: At current revision rates for component malpositioning, only 1 revision among 400 THAs needs to be prevented for the utilization of fluoroscopy (or 1 in 385 THAs with flat plate imaging), to achieve cost-effectiveness.

Morphological Analysis of Metacarpal Shafts With Respect to Retrograde Intramedullary Headless Screw Fixation.

Background: The use of retrograde intramedullary headless compression screw fixation for metacarpal neck and shaft fractures has been described in the literature. The purpose of this study was to perform a computed tomography (CT)-based morphological analysis of metacarpal size to help surgeons anticipate expected hardware needs. Methods: In all, 108 consecutive hand CT scans were evaluated for the medullary diameter in the volar-dorsal and radial-ulnar planes at the narrowest point of the canal, as well as for the distance from the articular surface to this point. Results were then analyzed by finger and by sex. Results: The ring finger had the smallest average medullary canal diameter for both men and women (2.7 and 2.6 mm, respectively); the small finger had the largest average diameter (3.9 mm) for men and the middle finger (3.6 mm) for women. Radial-ulnar was the rate-limiting dimension in the index, middle, and ring fingers, whereas volar-dorsal was the smallest dimension in the small finger, regardless of sex. Medullary diameter tended to be larger in patients aged more than 50 years. More than 50% of fingers have diameters >3.0 mm, and at least 40% of index, middle, and small fingers have diameters >3.5 mm, which are common diameters of commercially available headless compression screws. Conclusions: When preparing to perform open reduction internal fixation of a metacarpal using retrograde intramedullary headless compression screws, the surgeon needs to be prepared with screws of larger diameters to optimize fixation. Screws of larger diameters are needed to achieve endosteal purchase, regardless of sex.

The outcomes of quadriceps tendon autograft for anterior cruciate ligament reconstruction in adolescent athletes: a retrospective case series.

BACKGROUND: Multiple graft options exist for anterior cruciate ligament (ACL) reconstruction in an adolescent athlete. Patellar tendon harvest can lead to anterior knee pain, while hamstring tendon harvest can affect knee flexion strength and alter mechanics. Allograft is less desirable in pediatric patients due to the higher failure rate and slight risk of disease transmission. Quadriceps tendon autograft has rarely been reported for adolescent ACL reconstruction in the USA, but is an excellent option due to its large size, low donor site morbidity, and versatility. The purpose of this study is to report the outcomes of adolescents who have undergone ACL reconstruction using quadriceps tendon autograft. METHODS: Twenty-two ACL reconstructions using the quadriceps autograft were performed on 21 pediatric patients by the senior author between 2010 and 2017. The patient's demographics, injury characteristics, imaging, physical examination findings, operative findings, outcomes and sports were recorded. RESULTS: The average age at the time of surgery was 15 years. Two patients had open physes; the remainder had closing physes. 64% of patients had additional meniscal tears and 76% had bony contusions. The average duration of follow-up was 2.8 years (range 2-5 years). At final follow-up, there were no angular deformities or leg length discrepancies. The average quadriceps atrophy of the operative leg was 4 mm. The average Lysholm score was 98. 86% of patients returned to sports. No patients had re-rupture of their operative ACL. No incidences of infections, numbness, or anterior knee pain were reported. Two patients had a second arthroscopy for re-injury, revealing new meniscal tears but intact ACL grafts. CONCLUSIONS: Use of quadriceps tendon autograft for ACL reconstruction in adolescent patients allows reliable return to sport with minimal complications. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Impaction Bone Grafting for Treatment of Unstable Osteochondritis Dissecans (OCD) Lesions.

Although treatment options for unstable and unsalvageable large osteochondral lesions have largely been limited to autologous chondrocyte implantation (ACI) and osteochondral allografts, isolated impaction bone grafting represents a cost-friendly alternative, with predictable outcomes comparable to other options. Furthermore, the procedure can be completed in a single stage on an elective basis. We present our technique for impaction bone grafting of unstable osteochondritis dissecans (OCD) using either cancellous autograft or allograft.

The Vacuum-Assisted Closure Device Increases Value in the Treatment of Gustilo Grade IIIb Open Tibia Fractures in Children.

Background Wound management associated with Gustilo grade IIIb open tibia fractures in children often requires muscle flaps, skin grafts, and amputations. The purpose of this study is to report the outcomes and complications of vacuum-assisted closure (VAC) treatment, as well as discuss its role in optimizing value when treating these injuries. Methods A retrospective review of medical records and imaging studies was performed from 2008-2015. Six pediatric patients with Gustilo grade IIIb fractures managed with the VAC were identified. The time to treatment, frequency of VAC changes, VAC size, and closure attempts, including muscle flaps and skin grafts, were documented. Fracture fixation methods, the incidence of delayed union or nonunion, as well as the occurrence of deep tissue infection and compartment syndrome were detailed. Results Five patients were male and one was female with an average age of 12 years (range 8-15 years). All patients sustained a Gustilo IIIb open tibia fracture and were treated with irrigation, debridement, intravenous (IV) antibiotics, fixation, and a VAC as a wound care adjunct. Three patients required both a muscle flap and a skin graft. One patient required a skin graft. There was one case of deep tissue infection. Three patients were treated successfully with the VAC alone and did not require any flap procedures. Conclusions Wound care for Gustilo grade IIIb open tibia fractures in children traditionally involved potentially painful twice-daily dressing changes with solutions such as dilute bleach or iodine. The implementation of VAC markedly reduced the frequency of dressing changes every three days. In the current study, the open wound gradually closed with only a VAC in 50% of Gustilo grade IIIb open pediatric tibia fractures. In summary, the VAC is an adjunct that increases value in the care of pediatric patients with Gustilo grade IIIb open tibia fractures (Value = Outcomes/Cost). Level of evidence Therapeutic level IV.

Surgical management of angulated femoral intramedullary nails associated with closed fractures: A systematic review of the literature.

BACKGROUND: Femoral nail bending is a rare complication of intramedullary (IM) fixation of femoral diaphyseal fractures. Published literature regarding this injury pattern has thus far been limited to case reports or case series, thus no universally accepted surgical treatment strategy has been developed. METHODS: A systematic review was conducted using the Pubmed/MEDLINE and Scopus/EMBASE databases. A standardized template was used to extract data including author, year of publication, patient demographics, degree of angulation, mechanism of injury, time since initial procedure to reinjury, surgical treatment, and clinical outcomes. A case report from our institution was described as well. RESULTS: 27 cases in 25 reports were included in the qualitative analysis. All of the patients were males, and the ages ranged from 17 to 66 (mean age = 27.8). The degree of deformity ranged from 18 to 85° (mean 35.6), most commonly in a varus or apex anterior orientation. The nail deformities were corrected via one of six general surgical techniques: full transection of the nail, partial sectioning and manual straightening, limited corticotomy or longitudinal bone window, straightening with the assistance of a plate and reduction clamps, closed manipulation, or extraction without the need for manipulation. The fractures were then most commonly treated with revision IM nail. CONCLUSIONS: The bent IM nail is a rare and challenging injury to treat. No one technique has been identified as "the gold standard" and each case must be approached with its unique characteristics in mind.

Outcomes Following ACL Reconstruction Based on Graft Type: Are all Grafts Equivalent?

PURPOSE OF REVIEW: Anterior cruciate ligament reconstruction is one of the most common orthopedic procedures performed, accounting for over 200,000 cases annually. Despite the high prevalence, there is still much debate as to the optimal graft choice. The purpose of this review is to evaluate the current literature and discuss the reported outcomes for the most common graft choices. RECENT FINDINGS: The most common autografts being used include bone-patellar tendon-bone (BPTB), hamstring tendon (HT), and quadriceps tendon (QT). Hamstring tendon might have a slightly higher re-tear rate when compared with BPTB (2.84 versus 2.80). However, BPTB has a higher rate of anterior knee and kneeling pain in the short- and mid-term follow-up. This has not been shown to be the case in long-term follow-up. Allograft is a viable option for revisions and primaries in patients greater than 35 years old; however, re-tear rate increases significantly in younger patients. ACL reconstruction graft choice is a highly studied and yet still exceedingly debated topic. Most large studies report either no significant difference or a small difference in failure rate and outcome scores between the different autograft choices. Allografts have been demonstrated to have an increased risk of failure in younger athletes and should be reserved for revision cases and those aged 35 years and older. Graft choice should ultimately be decided upon based on surgeon comfort and experience and individual patient characteristics.

Bi-directional genetic modulation of GSK-3ß exacerbates hippocampal neuropathology in experimental status epilepticus.

Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed throughout the brain and involved in vital molecular pathways such as cell survival and synaptic reorganization and has emerged as a potential drug target for brain diseases. A causal role for GSK-3, in particular the brain-enriched GSK-3ß isoform, has been demonstrated in neurodegenerative diseases such as Alzheimer's and Huntington's, and in psychiatric diseases. Recent studies have also linked GSK-3 dysregulation to neuropathological outcomes in epilepsy. To date, however, there has been no genetic evidence for the involvement of GSK-3 in seizure-induced pathology. Status epilepticus (prolonged, damaging seizure) was induced via a microinjection of kainic acid into the amygdala of mice. Studies were conducted using two transgenic mouse lines: a neuron-specific GSK-3ß overexpression and a neuron-specific dominant-negative GSK-3ß (GSK-3ß-DN) expression in order to determine the effects of increased or decreased GSK-3ß activity, respectively, on seizures and attendant pathological changes in the hippocampus. GSK-3 inhibitors were also employed to support the genetic approach. Status epilepticus resulted in a spatiotemporal regulation of GSK-3 expression and activity in the hippocampus, with decreased GSK-3 activity evident in non-damaged hippocampal areas. Consistent with this, overexpression of GSK-3ß exacerbated status epilepticus-induced neurodegeneration in mice. Surprisingly, decreasing GSK-3 activity, either via overexpression of GSK-3ß-DN or through the use of specific GSK-3 inhibitors, also exacerbated hippocampal damage and increased seizure severity during status epilepticus. In conclusion, our results demonstrate that the brain has limited tolerance for modulation of GSK-3 activity in the setting of epileptic brain injury. These findings caution against targeting GSK-3 as a treatment strategy for epilepsy or other neurologic disorders where neuronal hyperexcitability is an underlying pathomechanism.

A Cost-Utility Analysis of 5 Strategies for the Management of Acute Otitis Media in Children.

OBJECTIVE: To assess whether antimicrobial therapy in young children with acute otitis media reduces time to resolution of symptoms, overall symptom burden, and persistence of otoscopic evidence of infection. We used a cost-utility model to evaluate whether immediate antimicrobial treatment seems to be worthwhile, and if so, which antimicrobial agent is most cost effective. STUDY DESIGN: We compared the cost per quality-adjusted life-day of 5 treatment regimens in children younger than 2 years of age with acute otitis media: immediate amoxicillin/clavulanate, immediate amoxicillin, immediate cefdinir, watchful waiting, and delayed prescription (DP) for antibiotic. RESULTS: The 5 treatment regimens, listed in order from least effective to most effective were DP, watchful waiting, immediate cefdinir, immediate amoxicillin, and immediate amoxicillin/clavulanate. Listed in order from least costly to most costly, the regimens were DP, immediate amoxicillin, watchful waiting, immediate amoxicillin/clavulanate, and immediate cefdinir. The incremental cost-utility ratio of immediate amoxicillin compared with DP was $101.07 per quality-adjusted life-day gained. The incremental cost-utility ratio of immediate amoxicillin/clavulanate compared with amoxicillin was $2331.28 per quality-adjusted life-day gained. CONCLUSIONS: In children younger than 2 years of age with acute otitis media and no recent antibiotic exposure, immediate amoxicillin seems to be the most cost-effective initial treatment.

Effects of hypoxia-induced neonatal seizures on acute hippocampal injury and later-life seizure susceptibility and anxiety-related behavior in mice.

Seizures are common during the neonatal period, often due to hypoxic-ischemic encephalopathy and may contribute to acute brain injury and the subsequent development of cognitive deficits and childhood epilepsy. Here we explored short- and long-term consequences of neonatal hypoxia-induced seizures in 7 day old C57BL/6J mice. Seizure activity, molecular markers of hypoxia and histological injury were investigated acutely after hypoxia and response to chemoconvulsants and animal behaviour was explored at adulthood. Hypoxia was induced by exposing pups to 5% oxygen for 15 min (global hypoxia). Electrographically defined seizures with behavioral correlates occurred in 95% of these animals and seizures persisted for many minutes after restitution of normoxia. There was minimal morbidity or mortality. Pre- or post-hypoxia injection of phenobarbital (50mg/kg) had limited efficacy at suppressing seizures. The hippocampus from neonatal hypoxia-seizure mice displayed increased expression of vascular endothelial growth factor and the immediate early gene c-fos, minimal histological evidence of cell injury and activation of caspase-3 in scattered neurons. Behavioral analysis of mice five weeks after hypoxia-induced seizures detected novel anxiety-related and other behaviors, while performance in a spatial memory test was similar to controls. Seizure threshold tests with kainic acid at six weeks revealed that mice previously subject to neonatal hypoxia-induced seizures developed earlier, more frequent and longer-duration seizures. This study defines a set of electro-clinical, molecular, pharmacological and behavioral consequences of hypoxia-induced seizures that indicate short- and long-term deleterious outcomes and may be a useful model to investigate the pathophysiology and treatment of neonatal seizures in humans.

Neurogenic function in rats with unilateral hippocampal sclerosis that experienced early-life status epilepticus.

Status epilepticus in the adult brain invariably causes an increase in hippocampal neurogenesis and the appearance of ectopic cells and this has been implicated as a causal factor in epileptogenesis. The effect of status epilepticus on neurogenesis in the developing brain is less well characterized and models of early-life seizures typically do not reproduce the hippocampal damage common to human mesial temporal sclerosis. We recently reported that evoking status epilepticus by intra-amygdala microinjection of kainic acid in post-natal (P) day 10 rats caused substantial acute neuronal death within the ipsilateral hippocampus and rats later developed unilateral hippocampal sclerosis and spontaneous recurrent seizures. Here, we examined the expression of a selection of genes associated with neurogenesis and assessed neurogenic function in this model. Protein levels of several markers of neurogenesis including polysialic acid neural cell adhesion molecule, neuroD and doublecortin were reduced in the hippocampus three days after status epilepticus in P10 rats. In contrast, protein levels of neurogenesis markers were similar to control in rats at P55. Pulse-chase experiments using thymidine analogues suggested there was a reduction in new neurons at 72 h after status epilepticus in P10 rats, whereas numbers of new neurons labelled in epileptic rats at P55 with hippocampal sclerosis were similar to controls. The present study suggests that status epilepticus in the immature brain suppresses neurogenesis but the neurogenic potential is retained in animals that later develop hippocampal sclerosis.

Mitochondrial localization of the forkhead box class O transcription factor FOXO3a in brain.

FOXO3a is member of the Forkhead box class O transcription factors, which functions in diverse pathways to regulate cellular metabolism, differentiation, and apoptosis. FOXO3a shuttles between the cytoplasm and nucleus and may be activated in neurons by stressors, including seizures. A subset of nuclear transcription factors may localize to mitochondria, but whether FOXO3a is present within brain mitochondria is unknown. Here, we report that purified mitochondrial fractions from rat, mouse, and human hippocampus, as well as HT22 hippocampal cells, contain FOXO3a protein. Immunogold electron microscopy supported the presence of FOXO3a within brain mitochondria, and chromatin immunoprecipitation analysis suggested FOXO3a was associated with mitochondrial DNA. Over-expression of a mitochondrially targeted FOXO3a fusion protein in HT22 cells, but not primary hippocampal neurons, conferred superior protection against glutamate toxicity than FOXO3a alone. Mitochondrial FOXO3a levels were reduced in the damaged region of the mouse hippocampus after status epilepticus, while mitochondrial fractions from the hippocampus of patients with temporal lobe epilepsy displayed higher levels of FOXO3a than controls. These results support mitochondria as a site of FOXO3a localization, which may contribute to the overall physiological and pathophysiological functions of this transcription factor.

Kainic acid-induced seizures modulate Akt (SER473) phosphorylation in the hippocampus of dopamine D2 receptor knockout mice.

Dopamine D2 receptor (D2R) signalling has been shown to modulate seizure-induced hippocampal cell death. D2R knockout (D2R-/-) mice are more susceptible to kainic acid (KA)-induced excitotoxicity, displaying cell death in the CA3 subfield of the hippocampus at KA doses not damaging in wild-type (WT) animals. Absence of D2R signalling in the hippocampus leads to activation (dephosphorylation) of glycogen synthase kinase 3ß (GSK-3ß) after KA (20 mg/kg), which is not associated with a change in the phosphorylation of the GSK-3ß regulator Akt at the canonical threonine 308 residue. In the present study, we investigated alternative pathways responsible for the activation of GSK-3ß in the hippocampus of the D2R-/- mice 24 h following KA-induced seizures. Here, we show that phosphorylation of Akt occurs at serine 473 (Ser473) in the CA3 region of WT but not D2R-/- mice following KA. Moreover, the CA1 subregion, which does not undergo neurodegeneration in either WT or D2R-/- mice, displays a strong induction of Akt (Ser473) phosphorylation after KA. Additionally, the vulnerability in the CA3 is not associated with changes to p38MAPK and Dishevelled activation, and ß-catenin does not appear to be a downstream target of the GSK-3ß. Thus, we propose that GSK-3ß phosphorylation-mediated hippocampal cell survival may depend on Akt (Ser473) phosphorylation; loss of D2R-mediated signalling in the CA3 region of D2R-/- mice leads to reduced Akt (Ser473) phosphorylation rendering neurons more vulnerable to apoptosis. Further investigation is required to fully elucidate the GSK-3ß targets involved in D2R-dependent response to excitotoxicity.

Mutation of Semaphorin-6A disrupts limbic and cortical connectivity and models neurodevelopmental psychopathology.

Psychiatric disorders such as schizophrenia and autism are characterised by cellular disorganisation and dysconnectivity across the brain and can be caused by mutations in genes that control neurodevelopmental processes. To examine how neurodevelopmental defects can affect brain function and behaviour, we have comprehensively investigated the consequences of mutation of one such gene, Semaphorin-6A, on cellular organisation, axonal projection patterns, behaviour and physiology in mice. These analyses reveal a spectrum of widespread but subtle anatomical defects in Sema6A mutants, notably in limbic and cortical cellular organisation, lamination and connectivity. These mutants display concomitant alterations in the electroencephalogram and hyper-exploratory behaviour, which are characteristic of models of psychosis and reversible by the antipsychotic clozapine. They also show altered social interaction and deficits in object recognition and working memory. Mice with mutations in Sema6A or the interacting genes may thus represent a highly informative model for how neurodevelopmental defects can lead to anatomical dysconnectivity, resulting, either directly or through reactive mechanisms, in dysfunction at the level of neuronal networks with associated behavioural phenotypes of relevance to psychiatric disorders. The biological data presented here also make these genes plausible candidates to explain human linkage findings for schizophrenia and autism.

The role of GABAergic system in neurodevelopmental disorders: a focus on autism and epilepsy.

Autism spectrum disorders (ASD) and epilepsy are very common neurological disorders of childhood, with an estimated incidence of about 0.5 - 1 % in worldwide population. ASD and epilepsy are often associated, suggesting that common neurodevelopmental bases may exist for these two disorders. The neurodevelopmental bases of both ASD and epilepsy have been clearly showed by a number of genetic, neuroimaging and neuropathological studies. In recent years, dysfunction of inhibitory GABAergic circuits has been proposed as a cause for both disorders. Several studies performed on both animal models and postmortem human samples indicate that GABAergic neurons and circuits are altered in both ASD and epilepsy, suggesting that the excitation/inhibition imbalance resulting from neurodevelopmental defects in GABAergic circuitry might represent a common pathogenetic mechanism for these disorders. Here, we will review the most significant studies supporting this hypothesis.

Cell signaling underlying epileptic behavior.

Epilepsy is a complex disease, characterized by the repeated occurrence of bursts of electrical activity (seizures) in specific brain areas. The behavioral outcome of seizure events strongly depends on the brain regions that are affected by overactivity. Here we review the intracellular signaling pathways involved in the generation of seizures in epileptogenic areas. Pathways activated by modulatory neurotransmitters (dopamine, norepinephrine, and serotonin), involving the activation of extracellular-regulated kinases and the induction of immediate early genes (IEGs) will be first discussed in relation to the occurrence of acute seizure events. Activation of IEGs has been proposed to lead to long-term molecular and behavioral responses induced by acute seizures. We also review deleterious consequences of seizure activity, focusing on the contribution of apoptosis-associated signaling pathways to the progression of the disease. A deep understanding of signaling pathways involved in both acute- and long-term responses to seizures continues to be crucial to unravel the origins of epileptic behaviors and ultimately identify novel therapeutic targets for the cure of epilepsy.

Convulsant doses of a dopamine D1 receptor agonist result in Erk-dependent increases in Zif268 and Arc/Arg3.1 expression in mouse dentate gyrus.

Activation of dopamine D1 receptors (D1Rs) has been shown to induce epileptiform activity. We studied the molecular changes occurring in the hippocampus in response to the administration of the D1-type receptor agonist, SKF 81297. SKF 81297 at 2.5 and 5.0 mg/kg induced behavioural seizures. Electrophysiological recordings in the dentate gyrus revealed the presence of epileptiform discharges peaking at 30-45 min post-injection and declining by 60 min. Seizures were prevented by the D1-type receptor antagonist, SCH 23390, or the cannabinoid CB1 receptor agonist, CP 55,940. The effect of SKF 81297 was accompanied by increased phosphorylation of the extracellular signal-regulated protein kinases 1 and 2 (ERK), in the granule cells of the dentate gyrus. This effect was also observed in response to administration of other D1-type receptor agonists, such as SKF83822 and SKF83959. In addition, SKF 81297 increased the phosphorylation of the ribosomal protein S6 and histone H3, two downstream targets of ERK. These effects were prevented by genetic inactivation of D1Rs, or by pharmacological inhibition of ERK. SKF 81297 was also able to enhance the levels of Zif268 and Arc/Arg3.1, two immediate early genes involved in transcriptional regulation and synaptic plasticity. These changes may be involved in forms of activity-dependent plasticity linked to the manifestation of seizures and to the ability of dopamine to affect learning and memory.