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.

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.

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.

Adverse events associated with robotic-assistance in total hip arthroplasty: an analysis based on the FDA MAUDE database.

BACKGROUND: The Food and Drug Administration (FDA) maintains the Manufacturer and User Facility Device Experience (MAUDE) database for reporting adverse events associated with medical devices, including emerging technologies, such as robotic-assisted total hip arthroplasty (THA). Aim of this study was to evaluate the variation of adverse events associated with robotics in THA. METHODS: Medical device reports (MDRs) within the MAUDE database were identified between 2017 and 2021. For MDR identification the product class "orthopaedic stereotaxic equipment" and terms associated with THA were used. Individual adverse events were identified and organised by type and consequences, such as patient injury, surgical delay, or conversion to the manual technique. RESULTS: 521 MDRs constituting 546 discrete events were found. The most common reported complication was intraoperative hardware failure (304/546, 55.7%), among which the most common failure was a broken impaction handle/platform (110, 20.1%). Inaccurate cup placement was the second most common reported complication (63, 11.5%). Abandoning the robot occurred in 13.0% (71/521) of reports. A surgical delay was noted in 28% (146/521) of reports, with an average delay of 17.9 (range 1-60) minutes. CONCLUSIONS: Identifying complications that may occur with robotics in THA is an important first step in preventing adverse events and surgical delays. Database analysis provide an overview of the range of complications.

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.

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.

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.].

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.

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.

Experimental neonatal status epilepticus and the development of temporal lobe epilepsy with unilateral hippocampal sclerosis.

Hippocampal sclerosis is a common pathological finding in patients with temporal lobe epilepsy, including children, but a causal relationship to early-life seizures remains in question. Neonatal status epilepticus in animals can result in neuronal death within the hippocampus, although macroscopic features of hippocampal shrinkage are not evident at adulthood. Here, we examined electrophysiological and pathological consequences of focally evoked status epilepticus triggered by intra-amygdala microinjection of kainic acid in postnatal day 10 rat pups. Neonatal status epilepticus resulted in extensive neuronal death in the ipsilateral hippocampal CA1 and CA3 subfields and hilus, as assessed by DNA fragmentation and Fluoro-Jade B staining 72 hours later. The contralateral hippocampus was not significantly damaged. Histopathology at P55/P65 revealed unilateral hippocampal sclerosis (grade IV, modified Wyler/Watson scale) comprising >50% CA1 and CA3 neuron loss and astrogliosis. Additional features included hydrocephalus ex vacuo, modest dentate granule cell layer widening, and altered neuropeptide Y immunoreactivity indicative of synaptic rearrangement. Hippocampal atrophy was also evident on magnetic resonance imaging. Depth electrode recordings at adulthood detected spontaneous seizures that involved the ipsilateral hippocampus and amygdala. A significant positive correlation was found between hippocampal pathology grade and both frequency and duration of epileptic seizures at adulthood. The current study demonstrates that experimental neonatal status epilepticus can result in classical unilateral hippocampal sclerosis and temporal lobe epilepsy.

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.

Dopamine D1 vs D5 receptor-dependent induction of seizures in relation to DARPP-32, ERK1/2 and GluR1-AMPA signalling.

Recent reports have shown that the selective dopamine D(1)-like agonist SKF 83822 [which stimulates adenylate cyclase, but not phospholipase C] induces prominent behavioral seizures in mice, whereas its benzazepine congener SKF 83959 [which stimulates phospholipase C, but not adenylate cyclase] does not. To investigate the relative involvement of D(1) vs D(5) receptors in mediating seizures, ethological behavioral topography and cortical EEGs were recorded in D(1), D(5) and DARPP-32 knockout mice in response to a convulsant dose of SKF 83822. SKF 83822-induced behavioral and EEG seizures were gene dose-dependently abolished in D(1) knockouts. In both heterozygous and homozygous D(5) knockouts, the latency to first seizure was significantly increased and total EEG seizures were reduced relative to wild-types. The majority (60%) of homozygous DARPP-32 knockouts did not have seizures; of those having seizures (40%), the latency to first seizure was significantly increased and the number of high amplitude, high frequency polyspike EEG events was reduced. In addition, immunoblotting was performed to investigate downstream intracellular signalling mechanisms at D(1)-like receptors following challenge with SKF 83822 and SKF 83959. In wild-types administered SKF 83822, levels of ERK1/2 and GluR1 AMPA receptor phosphorylation increased two-fold in both the striatum and hippocampus; in striatal slices DARPP-32 phosphorylation at Thr34 increased five-fold relative to vehicle-treated controls. These findings indicate that D(1), and to a lesser extent D(5), receptor coupling to DARPP-32, ERK1/2 and glutamatergic signalling is involved in mediating the convulsant effects of SKF 83822.

Unilateral hippocampal CA3-predominant damage and short latency epileptogenesis after intra-amygdala microinjection of kainic acid in mice.

Mesial temporal lobe epilepsy is the most common, intractable seizure disorder in adults. It is associated with an asymmetric pattern of hippocampal neuron loss within the endfolium (hilus and CA3) and CA1, with limited pathology in extra-hippocampal regions. We previously developed a model of focally-evoked seizure-induced neuronal death using intra-amygdala kainic acid (KA) microinjection and characterized the acute hippocampal pathology. Here, we sought to characterize the full extent of hippocampal and potential extra-hippocampal damage in this model, and the temporal onset of epileptic seizures. Seizure damage assessed at four stereotaxic levels by FluoroJade B staining was most prominent in ipsilateral hippocampal CA3 where it extended from septal to temporal pole. Minor but significant neuronal injury was present in ipsilateral CA1. Extra-hippocampal neuronal damage was generally limited in extent and restricted to the lateral septal nucleus, injected amygdala and select regions of neocortex ipsilateral to the seizure elicitation side. Continuous surface EEG recorded with implanted telemetry units in freely-moving mice detected spontaneous, epileptic seizures by five days post-KA in all mice. Epileptic seizure number averaged 1-4 per day. Hippocampi from epileptic mice 15 days post-KA displayed unilateral CA3 lesions, astrogliosis and increased neuropeptide Y immunoreactivity suggestive of mossy fiber rearrangement. These studies characterize a mouse model of unilateral hippocampal-dominant neuronal damage and short latency epileptogenesis that may be suitable for studying the cell and molecular pathogenesis of human mesial temporal lobe epilepsy.

Oxidative stress impairs upper airway muscle endurance in an animal model of sleep-disordered breathing.

Obstructive sleep apnoea is characterised by intermittent hypoxia due to recurrent obstructions of the pharyngeal airway during sleep. We have shown that chronic intermittent hypoxia impairs respiratory muscle function and CNS control of upper airway patency. In this study, we tested the hypothesis that disruption of an endogenous antioxidant defence system exacerbates the effects of intermittent hypoxia on upper airway muscle contractile function. Thirty-two male Wistar rats were placed in restrainers with their heads in hoods in which the ambient oxygen concentration could be modified by controlling the gas supply to the hoods. Sixteen rats were exposed to alternating equal periods of hypoxia and normoxia, twice per minute, 8 hours per day for 1 week. The remaining 16 animals were exposed to normoxia continuously under identical experimental conditions. In both groups, half the animals received daily injections of buthionine sulfoxamine (BSO), an inhibitor of the rate-limiting enzyme in glutathione synthesis. The other half received daily vehicle injections. At the end of the 1-week treatment period, the sternohyoid muscles were removed and fatigue characteristics were determined in vitro. Intermittent hypoxia was associated with a decrease in sternohyoid muscle endurance, an effect that was exacerbated by treatment with BSO. In separate experiments, daily treatment with the antioxidant N-acetyl cysteine blocked the deleterious effects of intermittent hypoxia on respiratory muscle function. We suggest that oxidative stress contributes to impaired upper airway muscle endurance in our animal model and that endogenous glutathione may be especially important in limiting free radical-induced muscle dysfunction. Our results may have particular relevance to respiratory disorders associated with recurrent hypoxia, such as the sleep apnoea/hypopnoea syndrome.

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.

Simultaneous recording of breathing and respiratory related neuronal activity in the brainstem of conscious rats.

One aim of integrative neurophysiology is to understand the relationship between neuronal activity and normal evolution of other physiological parameters. In this respect, anaesthetics or paralyzing agents, that have been shown to have a significant effect on several vital physiological processes, can be seen as a real problem for the interpretation of observations. Eletrophysiological recording in awake animals avoids this problem. Recordings in forebrain areas are now used routinely but a number of specific difficulties have limited their application to the medullary areas. In this paper, we describe a preparation that allows us to simultaneously record neuronal activity in the dorsal brainstem and respiratory activity in awake rats, while applying different types of respiratory challenges.