The influence of posterior acromial morphology on outcomes and return to pushups in young patients undergoing arthroscopic posterior capsulolabral repair.

Background: Prior evidence has identified specific posterior acromial morphology as significantly associated with unidirectional posterior shoulder instability. The purpose of this study is to determine the influence of posterior acromial morphology on the outcomes of arthroscopic posterior capsulolabral repair (APCLR) for unidirectional posterior shoulder instability. Additionally, we sought to determine the influence of posterior acromial morphology on the rate and time to return to pushups following APCLR. Methods: We performed a retrospective review of prospectively collected data. The study included consecutive patients undergoing APCLR. Data collected included demographics, radiographic measurements including posterior acromial height (PAH) and posterior acromial tilt on preoperative scapular-Y radiographs, and patient-reported outcome measures at the preoperative and postoperative visits. In addition, starting at 6 months postoperative, patients were asked if they could perform pushups defined as at least 10 repetitions. At the final follow-up, we collected the number of pushups patients were able to perform. Results: Thirty-two consecutive patients underwent APCLR with a mean follow-up of 26 months (range, 12-41). Significant improvement from preoperative to 2 years postoperative was demonstrated in Subjective Shoulder Value (50-85), VAS (6-2.5), American Shoulder and Elbow Surgeons (48 to 83), and Western Ontario Shoulder Instability (WOSI) (1437-777), P = .001. The recurrent instability rate was 3/32 (9%). Patients with PAH > 23 (N = 17) had a recurrent instability rate of 18% (3/17) versus PAH ≤ 23 (N = 15) 0% (0/15), worse WOSI scores (P = .41), and a lower number of pushups (P = .48). The percentage of patients reporting the ability to perform pushups was (6 months/1 year/2 years) (50%/78%/95%). The mean number of pushups reported at the final follow-up was 33 (range, 1-60). Discussion: Following APCLR, approximately 50% of patients resume pushups at 6 months postoperatively, and 80% return at 1 year. Patients reported performing a mean of 33 pushups following APCLR at the final follow-up. Patients with a PAH greater than 23 on preoperative scapular-Y radiographs had a higher rate of recurrent posterior instability, worse WOSI scores, and lower return to pushups; however, the results did not meet statistical significance. Therefore, future larger studies are needed to determine if posterior acromial morphology is independently associated with worse outcomes and increased recurrent instability rates following APCLR.

A High Rate of Return to Running Is Seen After Both Arthroscopic and Open Shoulder Surgery.

Purpose: To determine the percentage of patients who report the ability to run 1 mile at various time points after arthroscopic and open shoulder surgery. Methods: We performed a retrospective review of prospectively collected data for all active-duty military patients aged 18 to 45 years who underwent shoulder surgery at a single institution over a 2-year period. The rehabilitation protocol discouraged running before 3 months, but all patients were able to return to unrestricted running at 3 months postoperatively. Patients were excluded if they lacked 1-year follow-up data. Parameters collected included demographic information and validated patient-reported outcome measures at the preoperative and short-term postoperative visits, as well as patients' ability to run at least 1 mile postoperatively. Results: A total of 126 patients were identified who underwent shoulder surgery with return-to-running data. Compared with baseline, significant improvements in patient-reported outcomes were shown at 1 and 2 years postoperatively (P = .001). The percentage of patients reporting the ability to run 1 mile postoperatively was 59% at 3 months, 74% at 4.5 months, 79% at 6 months, 83% at 12 months, and 91% at 24 months. There was no significant difference in patients undergoing shoulder surgery for instability versus non-instability diagnoses or in patients undergoing open versus arthroscopic anterior stabilization. All 11 patients unable to return to running at final follow-up had chronic lower-extremity diagnoses limiting their running ability. Conclusions: Young military athletes undergoing arthroscopic and open shoulder surgery have a high rate of early return to running. Approximately 60% of patients report the ability to run 1 mile at 3 months postoperatively, and three-quarters of patients do so at 4.5 months. Age, sex, military occupation, underlying diagnosis or type of surgery did not influence the rate of return to running after shoulder surgery. Level of Evidence: Level IV, therapeutic case series.

Rate and time to return to shooting following arthroscopic and open shoulder surgery.

Background: There is limited information on return to shooting following shoulder surgery. The purpose of this study is to determine the rate and timing for resuming shooting a rifle following shoulder surgery. Methods: We performed a retrospective review of prospectively collected data. The study included patients undergoing arthroscopic and open shoulder stabilization for unidirectional shoulder instability, and arthroscopic surgery for rotator cuff tears, SLAP lesions, biceps tendinopathy, and acromioclavicular pathology. Data collected included the laterality of surgery, shooting dominance, and patient-reported outcome measures at the preoperative and postoperative visits. Starting at the 4.5-month clinic visit, patients were asked if they could shoot a military rifle. Results: One hundred patients were identified with arthroscopic and open shoulder surgery with a mean age of 30 years (range, 18-45) and a mean follow-up of 24 months (range, 12-32). The cohort consisted of patients undergoing arthroscopic Bankart repair (n = 23), arthroscopic posterior labral repair (n = 18), open Latarjet (n = 16), mini-open subpectoral biceps tenodesis (OBT) (n = 25), OBT with open distal clavicle resection (DCR) (n = 10), open DCR (n = 4), and arthroscopic rotator cuff repair with concomitant OBT (n = 4). Significant improvement in SSV, VAS, ASES, and WOSI was shown at 1-year postoperative, SSV 85, VAS 2, ASES 85, WOSI 239, P = .001. The percentage of patients reporting the ability to shoot a military rifle postoperatively were 47%, 63%, 85%, and 94% at 4.5 months, 6 months, 1 year, and 2 years, respectively. At 4.5 months postoperatively, patients who underwent surgery ipsilateral to their shooting dominance (n = 59) had a rate of return to shooting (33%) versus shoulder surgery on the contralateral side of shooting dominance (n = 41) (60%), P = .04. However, there was no significant difference in the groups at 6 months and 1 year. Additionally, there was a significant difference in the rate of return to shooting at 6 months in patients undergoing arthroscopic posterior labral repair versus the remainder of the cohort (posterior instability (33%) vs. (69%), P = .016), and a significant difference between posterior shoulder stabilization and anterior shoulder stabilization (70%), P = .03. Conclusion: Patients undergoing arthroscopic and open shoulder surgery have a high rate of return to shooting. Approximately 60% of patients resume shooting at 6 months postoperatively and 85% return at 1 year. Patients undergoing shoulder surgery on the contralateral side of their shooting dominance return to shooting significantly faster than those with shoulder surgery ipsilateral to their shooting dominance. Additionally, those undergoing arthroscopic posterior shoulder stabilization return to shooting at a slower rate than anterior stabilization surgery.

Direct delivery of an investigational cell therapy in patients with Parkinson's disease: an interim analysis of feasibility and safety of an open-label study using DBS-Plus clinical trial design.

Objective: To evaluate the interim feasibility, safety and clinical measures data of direct delivery of regenerating peripheral nerve tissue (PNT) to the substantia nigra (SN) in participants with Parkinson's disease (PD). Methods: Eighteen (13 men/5 women) participants were unilaterally implanted with PNT to the SN, contralateral to the most affected side during the same surgery they were receiving deep brain stimulation (DBS) surgery. Autologous PNT was collected from the sural nerve. Participants were followed for safety and clinical outcomes for 2 years (including off-state Unified Parkinson's Disease Rating Scale (UPDRS) Part III assessments) with study visits every 6 months. Results: All 18 participants scheduled to receive PNT implantation received targeted delivery to the SN in addition to their DBS. All subjects were discharged the following day except for two: post-op day 2; post-op day 3. The most common study-related adverse events were hypoaesthesia and hyperaesthesias to the lateral aspect of the foot and ankle of the biopsied nerve (6 of 18 participants experienced). Clinical measures did not identify any hastening of PD measures providing evidence of safety and tolerability. Off-state UPDRS Part III mean difference scores were reduced at 12 months compared with baseline (difference=-8.1, 95% CI -2.4 to -13.9 points, p=0.005). No complications involving dyskinesias were observed. Conclusions: Targeting the SN for direct delivery of PNT was feasible with no serious adverse events related to the study intervention. Interim clinical outcomes show promising results meriting continued examination of this investigational approach. Trial registration number: NCT02369003.

Gait and Balance Changes with Investigational Peripheral Nerve Cell Therapy during Deep Brain Stimulation in People with Parkinson's Disease.

BACKGROUND: The efficacy of deep brain stimulation (DBS) and dopaminergic therapy is known to decrease over time. Hence, a new investigational approach combines implanting autologous injury-activated peripheral nerve grafts (APNG) at the time of bilateral DBS surgery to the globus pallidus interna. OBJECTIVES: In a study where APNG was unilaterally implanted into the substantia nigra, we explored the effects on clinical gait and balance assessments over two years in 14 individuals with Parkinson's disease. METHODS: Computerized gait and balance evaluations were performed without medication, and stimulation was in the off state for at least 12 h to best assess the role of APNG implantation alone. We hypothesized that APNG might improve gait and balance deficits associated with PD. RESULTS: While people with a degenerative movement disorder typically worsen with time, none of the gait parameters significantly changed across visits in this 24 month study. The postural stability item in the UPDRS did not worsen from baseline to the 24-month follow-up. However, we measured gait and balance improvements in the two most affected individuals, who had moderate PD. In these two individuals, we observed an increase in gait velocity and step length that persisted over 6 and 24 months. CONCLUSIONS: Participants did not show worsening of gait and balance performance in the off therapy state two years after surgery, while the two most severely affected participants showed improved performance. Further studies may better address the long-term maintanenace of these results.

Ultrasound-Guided Biceps Tendon Sheath Injections Frequently Extravasate Into the Glenohumeral Joint.

PURPOSE: To evaluate the frequency of glenohumeral joint extravasation of ultrasound (US)-guided biceps tendon sheath injections. METHODS: Fifty shoulders with a clinical diagnosis of bicipital tenosynovitis pain received a US-guided biceps sheath injection with anesthetic, steroid, and contrast (5.0 mL mixture) followed immediately by orthogonal radiographs to localize the anatomic distribution of the injection. Radiographic evaluation of contrast localization was determined and interobserver reliability calculated. RESULTS: All 50 postinjection radiographs (100%) demonstrated contrast within the biceps tendon sheath. In addition, 30 of 50 (60%) radiographs also revealed contrast in the glenohumeral joint. Interobserver reliability for determination of intraarticular contrast was good (kappa value 0.87). CONCLUSIONS: US-guided bicipital sheath injections reproducibly result in intrasheath placement of injection fluid. Bicipital sheath injections performed with 5 mL of volume result in partial extravasation into the joint 60% of the time. These data may be useful for surgeons who use the results of diagnostic biceps injections for diagnosis and surgical decision-making. LEVEL OF EVIDENCE: III, prospective cohort study, diagnosis.

Arthroscopic Surgery or Physical Therapy for Patients With Femoroacetabular Impingement Syndrome: A Randomized Controlled Trial With 2-Year Follow-up.

BACKGROUND: Arthroscopic hip surgery has risen 18-fold in the past decade; however, there is a dearth of clinical trials comparing surgery with nonoperative management. PURPOSE: To determine the comparative effectiveness of surgery and physical therapy for femoroacetabular impingement syndrome. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients were recruited from a large military hospital after referral to the orthopaedic surgery clinic and were eligible for surgery. Of 104 eligible patients, 80 elected to participate, and the majority were active-duty service members (91.3%). No patients withdrew because of adverse events. The authors randomly selected patients to undergo either arthroscopic hip surgery (surgery group) or physical therapy (rehabilitation group). Patients in the rehabilitation group began a 12-session supervised clinic program within 3 weeks, and patients in the surgery group were scheduled for the next available surgery at a mean of 4 months after enrollment. Patient-reported outcomes of pain, disability, and perception of improvement over a 2-year period were collected. The primary outcome was the Hip Outcome Score (HOS; range, 0-100 [lower scores indicating greater disability]; 2 subscales: activities of daily living and sport). Secondary measures included the International Hip Outcome Tool (iHOT-33), Global Rating of Change (GRC), and return to work at 2 years. The primary analysis was on patients within their original randomization group. RESULTS: Statistically significant improvements were seen in both groups on the HOS and iHOT-33, but the mean difference was not significant between the groups at 2 years (HOS activities of daily living, 3.8 [95% CI, -6.0 to 13.6]; HOS sport, 1.8 [95% CI, -11.2 to 14.7]; iHOT-33, 6.3 [95% CI, -6.1 to 18.7]). The median GRC across all patients was that they "felt about the same" (GRC = 0). Two patients assigned to the surgery group did not undergo surgery, and 28 patients in the rehabilitation group ended up undergoing surgery. A sensitivity analysis of "actual surgery" to "no surgery" did not change the outcome. Twenty (33.3%) patients who underwent surgery and 4 (33.3%) who did not undergo surgery were medically separated from military service at 2 years. CONCLUSION: There was no significant difference between the groups at 2 years. Most patients perceived little to no change in status at 2 years, and one-third of military patients were not medically fit for duty at 2 years. Limitations include a single hospital, a single surgeon, and a high rate of crossover. Registration: NCT01993615 ( ClinicalTrials.gov identifier).

Peripheral nerve grafts implanted into the substantia nigra in patients with Parkinson's disease during deep brain stimulation surgery: 1-year follow-up study of safety, feasibility, and clinical outcome.

OBJECTIVECurrently, there is no treatment that slows or halts the progression of Parkinson's disease. Delivery of various neurotrophic factors to restore dopaminergic function has become a focus of study in an effort to fill this unmet need for patients with Parkinson's disease. Schwann cells provide a readily available source of such factors. This study presents a 12-month evaluation of safety and feasibility, as well as the clinical response, of implanting autologous peripheral nerve grafts into the substantia nigra of patients with Parkinson's disease at the time of deep brain stimulation (DBS) surgery.METHODSStandard DBS surgery targeting the subthalamic nucleus was performed in 8 study participants. After DBS lead implantation, a section of the sural nerve containing Schwann cells was harvested and unilaterally grafted to the substantia nigra. Adverse events were continually monitored. Baseline clinical data were obtained during standard preoperative evaluations. Clinical outcome data were obtained with postoperative clinical evaluations, neuropsychological testing, and MRI at 1 year after surgery.RESULTSAll 8 participants were implanted with DBS systems and grafts. Adverse event profiles were comparable to those of standard DBS surgery with the exception of 1 superficial infection at the sural nerve harvest site. Three participants also reported numbness in the distribution of the sural nerve distal to the harvest site. Motor scores on Unified Parkinson's Disease Rating Scale (UPDRS) part III while the participant was off therapy at 12 months improved from baseline (mean ± SD 25.1 ± 15.9 points at 12 months vs 32.5 ± 9.7 points at baseline). An analysis of the lateralized UPDRS scores also showed a greater overall reduction in scores on the side contralateral to the graft.CONCLUSIONSPeripheral nerve graft delivery to the substantia nigra at the time of DBS surgery is feasible and safe based on the results of this initial pilot study. Clinical outcome data from this phase I trial suggests that grafting may have some clinical benefit and certainly warrants further study to determine if this is an efficacious and neurorestorative therapy.Clinical trial registration no.: NCT01833364 (clinicaltrials.gov).

Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia.

OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins. METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells ex vivo. RESULTS: Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type 2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury, and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats. INTERPRETATION: These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke. Ann Neurol 2017;82:208-222.

Accuracy of Ultrasound-Guided Intra-articular Hip Injections Performed in the Orthopedic Clinic.

Intra-articular hip injections have proven clinical value for both diagnostic and therapeutic purposes. Historically, these injections have been performed by radiologists using fluoroscopic guidance. This necessitates a radiology referral, delays the injection, and represents lost productivity for the orthopedist. Ultrasound-guided intra-articular hip injections have been described in the radiology literature with excellent accuracy. These injections were performed by radiologists. The purpose of this study was to determine the accuracy of ultrasound-guided hip injections performed in the orthopedic clinic by orthopedic surgeons and orthopedic physician assistants. Fifty ultrasound-guided hip injections were performed using a standard technique. Contrast was included, and an anteroposterior pelvis radiograph was obtained immediately following injection. Diagnosis, body mass index, procedure time, and visual analog scale scores were recorded. Radiographs were reviewed independently by a musculoskeletal radiologist and an orthopedic surgeon to determine intra-articular placement of the injection. A total of 50 hips were injected. There was no identifiable contrast in 2 patients, leaving 48 hips for analysis. Of these, contrast was injected intra-articularly in 46 hips for an accuracy of 96%. Average procedural time was 2.6 minutes, and the average visual analog scale score was 1.9 during the procedure. Revenue value units ranged from 1.72-2.55 for ultrasound-guided hip injections. These findings indicate ultrasound-guided intra-articular hip injections performed in the orthopedic clinic by surgeons or physician assistants are accurate, efficient, and patient-friendly. Additionally, they preserve patient continuity and maintain productivity within the orthopedic clinic. [Orthopedics. 2017; 40(2):96-100.].

Bilateral Radiation Optic Neuropathy Following Concurrent Chemotherapy and Radiation in Glioblastoma.

Radiation optic neuropathy (RON) is an iatrogenic complication that causes severe, irreversible vision loss within months to years following radiation to lesions close to the visual pathway. The authors describe a case of RON in glioblastoma after radio-sensitisation with temozolomide with sequential involvement of both optic nerves. This case provides a timeline for clinical and imaging findings with RON and specifically resolution of nerve enhancement. The authors also highlight the potential of an increase in incidence of RON in glioblastoma with advances in survival seen with greater use of second-line chemotherapy and even re-radiation.

Implantation of autologous peripheral nerve grafts into the substantia nigra of subjects with idiopathic Parkinson's disease treated with bilateral STN DBS: a report of safety and feasibility.

OBJECTIVE One avenue of intense efforts to treat Parkinson's disease (PD) involves the delivery of neurotrophic factors to restore dopaminergic cell function. A source of neurotrophic factors that could be used is the Schwann cell from the peripheral nervous system. The authors have begun an open-label safety study to examine the safety and feasibility of implanting an autologous peripheral nerve graft into the substantia nigra of PD patients undergoing deep brain stimulation (DBS) surgery. METHODS Multistage DBS surgery targeting the subthalamic nucleus was performed using standard procedures in 8 study participants. After the DBS leads were implanted, a section of sural nerve containing Schwann cells was excised and unilaterally delivered into the area of the substantia nigra. Adverse events were continuously monitored. RESULTS Eight of 8 participants were implanted with DBS systems and grafts. Adverse event profiles were comparable to those of standard DBS surgery. Postoperative MR images did not reveal edema, hemorrhage, or significant signal changes in the graft target region. Three participants reported a patch of numbness on the outside of the foot below the sural nerve harvest site. CONCLUSIONS Based on the safety outcome of the procedure, targeted peripheral nerve graft delivery to the substantia nigra at the time of DBS surgery is feasible and may provide a means to deliver neurorestorative therapy. Clinical trial registration no.: NCT01833364 ( clinicaltrials.gov ).

Two-year outcomes after arthroscopic surgery compared to physical therapy for femoracetabular impingement: A protocol for a randomized clinical trial.

BACKGROUND: As the prevalence of hip pathology in the younger athletic population rises, the medical community continues to investigate effective intervention options. Femoracetabular impingement is the morphologically abnormal articulation of the femoral head against the acetabulum, and often implicated in pre-arthritic hip conditions of musculoskeletal nature. Arthroscopic surgical decompression and non-surgical rehabilitation programs focused on strengthening and stability are common interventions. However, they have never been directly compared in clinical trials. The primary purpose of this study will be to assess the difference in outcomes between these 2 commonly utilized interventions for femoracetabular impingement. METHODS: The study will be a single site, non-inferiority, randomized controlled trial comparing two different treatment approaches (surgical and nonsurgical) for FAI. The enrollment goal is for a total of 80 subjects with a diagnosis of Femoracetabular impingement that are surgical candidates and have failed 6 weeks of conservative treatment. This will be a convenience sample of consecutive patients that are Tricare beneficiaries and seeking care at Madigan Army Medical Center. Patients that meet the criteria will be screened, provide written consent before enrollment, and then randomized into one of two arms (Group I = hip arthroscopy, Group II = physical therapy). Group I will undergo hip arthroscopy with or without labral repair. Group II will follow an impairment based physical therapy program consisting of 2 sessions per week for 6 weeks. The primary outcome will be the Hip Outcome Score and secondary measures will include the International Hip Outcome Tool and the Global Rating of Change. Measures will be taken at baseline, 6 months, 1 and 2 years. Hip-related healthcare utilization between both groups will also be assessed at the end of 2 years. DISCUSSION: The current evidence to support both surgical and conservative interventions for femoroacetabular impingement is based on low-level research. To date, none of these interventions have been directly compared in a randomized clinical trial. Clinical trials are needed to help establish the value of these interventions in the management of femoracetabular impingement and to help define appropriate clinical pathways. TRIAL REGISTRATION: NCT01993615 30 October 2013.

Initiation and dose optimization for levodopa-carbidopa intestinal gel: Insights from phase 3 clinical trials.

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) provides continuous infusion and reduces "off" time in advanced Parkinson's disease (PD) patients with motor fluctuations despite optimized pharmacotherapy. METHODS: Clinical experience with 2 LCIG dosing paradigms from phase 3 studies was examined. In an open-label, 54-week study, LCIG was initiated as daytime monotherapy via nasojejunal (NJ) tube then switched to percutaneous endoscopic gastrojejunostomy (PEG-J) tube; adjunctive therapy was permitted 28 days postPEG-J. In a 12-week, double-blind, placebo-controlled, double-dummy trial, patients continued stable doses of existing anti-PD medications, but LCIG replaced daytime oral levodopa-carbidopa and was initiated directly via PEG-J. RESULTS: In the open-label study, 92% of 354 patients received monotherapy at post-PEG-J week 4; mean titration duration was 7.6 days; dosing remained stable post-titration (mean total daily dose [TDD] was 1572 mg at last visit). In the double-blind trial, 84% received polypharmacy; mean titration took 7.1 days for the LCIG arm (TDD post-titration: 1181 mg; n = 37). At post-PEG-J week 4, mean "off" time with LCIG was reduced by 3.9 h (open-label/monotherapy study) and 3.7 h (double-blind/polypharmacy trial). NJ treatment (open-label study only) required an additional procedure with related adverse events (AEs) and withdrawals. The most common AEs during PEG-J weeks 1-4 in the open-label/monotherapy and double-blind/polypharmacy trials, respectively, were complication of device insertion (35%, 57%) and abdominal pain (26%, 51%). Discontinuations due to nonprocedure/nondevice AEs were low (2.2%, 2.7%). CONCLUSION: These results support the option of initiating LCIG with or without NJ and as either monotherapy or polypharmacy.

Intrasubstance ruptures of the biceps brachii: diagnosis and management.

Traumatic intrasubstance ruptures of the biceps brachii are rare and historically specific to military static line parachute jumps; however, these injuries have recently been reported in the civilian literature. Diagnosis is made by history, clinical weakness in supination and elbow flexion, extensive ecchymosis and edema, and a palpable defect. Ultrasound and magnetic resonance imaging are useful to confirm the diagnosis and injury severity. Nonoperative treatment involves splinting in acute flexion. Percutaneous hematoma aspiration has been described. Early surgical intervention with primary repair has been shown to be more successful than late reconstruction. Studies comparing operative and nonoperative treatment are lacking.

Replication of association between ELAVL4 and Parkinson disease: the GenePD study.

Genetic variants in embryonic lethal, abnormal vision, Drosophila-like 4 (ELAVL4) have been reported to be associated with onset age of Parkinson disease (PD) or risk for PD affection in Caucasian populations. In the current study we genotyped three single nucleotide polymorphisms in ELAVL4 in a Caucasian study sample consisting of 712 PD patients and 312 unrelated controls from the GenePD study. The minor allele of rs967582 was associated with increased risk of PD (odds ratio = 1.46, nominal P value = 0.011) in the GenePD population. The minor allele of rs967582 was also the risk allele for PD affection or earlier onset age in the previously studied populations. This replication of association with rs967582 in a third cohort further implicates ELAVL4 as a PD susceptibility gene.

Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress.

The high-metabolic demand of neurons and their reliance on glucose as an energy source places them at risk for dysfunction and death under conditions of metabolic and oxidative stress. Uncoupling proteins (UCPs) are mitochondrial inner membrane proteins implicated in the regulation of mitochondrial membrane potential (Deltapsim) and cellular energy metabolism. The authors cloned UCP4 cDNA from mouse and rat brain, and demonstrate that UCP4 mRNA is expressed abundantly in brain and at particularly high levels in populations of neurons believed to have high-energy requirements. Neural cells with increased levels of UCP4 exhibit decreased Deltapsim, reduced reactive oxygen species (ROS) production and decreased mitochondrial calcium accumulation. UCP4 expressing cells also exhibited changes of oxygen-consumption rate, GDP sensitivity, and response of Deltapsim to oligomycin that were consistent with mitochondrial uncoupling. UCP4 modulates neuronal energy metabolism by increasing glucose uptake and shifting the mode of ATP production from mitochondrial respiration to glycolysis, thereby maintaining cellular ATP levels. The UCP4-mediated shift in energy metabolism reduces ROS production and increases the resistance of neurons to oxidative and mitochondrial stress. Knockdown of UCP4 expression by RNA interference in primary hippocampal neurons results in mitochondrial calcium overload and cell death. UCP4-mRNA expression is increased in neurons exposed to cold temperatures and in brain cells of rats maintained on caloric restriction, suggesting a role for UCP4 in the previously reported antiageing and neuroprotective effects of caloric restriction. By shifting energy metabolism to reduce ROS production and cellular reliance on mitochondrial respiration, UCP4 can protect neurons against oxidative stress and calcium overload.

High resolution ultrasound-guided microinjection for interventional studies of early embryonic and placental development in vivo in mice.

BACKGROUND: In utero microinjection has proven valuable for exploring the developmental consequences of altering gene expression, and for studying cell lineage or migration during the latter half of embryonic mouse development (from embryonic day 9.5 of gestation (E9.5)). In the current study, we use ultrasound guidance to accurately target microinjections in the conceptus at E6.5-E7.5, which is prior to cardiovascular or placental dependence. This method may be useful for determining the developmental effects of targeted genetic or cellular interventions at critical stages of placentation, gastrulation, axis formation, and neural tube closure. RESULTS: In 40 MHz ultrasound images at E6.5, the ectoplacental cone region and proamniotic cavity could be visualized. The ectoplacental cone region was successfully targeted with 13.8 nL of a fluorescent bead suspension with few or no beads off-target in 51% of concepti microinjected at E6.5 (28/55 injected). Seventy eight percent of the embryos survived 2 to 12 days post injection (93/119), 73% (41/56) survived to term of which 68% (38/56) survived and appeared normal one week after birth. At E7.5, the amniotic and exocoelomic cavities, and ectoplacental cone region were discernable. Our success at targeting with few or no beads off-target was 90% (36/40) for the ectoplacental cone region and 81% (35/43) for the exocoelomic cavity but tended to be less, 68% (34/50), for the smaller amniotic cavity. At E11.5, beads microinjected at E7.5 into the ectoplacental cone region were found in the placental spongiotrophoblast layer, those injected into the exocoelomic cavity were found on the surface or within the placental labyrinth, and those injected into the amniotic cavity were found on the surface or within the embryo. Following microinjection at E7.5, survival one week after birth was 60% (26/43) when the amniotic cavity was the target and 66% (19/29) when the target was the ectoplacental cone region. The survival rate was similar in sham experiments, 54% (33/61), for which procedures were identical but no microinjection was performed, suggesting that surgery and manipulation of the uterus were the main causes of embryonic death. CONCLUSION: Ultrasound-guided microinjection into the ectoplacental cone region at E6.5 or E7.5 and the amniotic cavity at E7.5 was achieved with a 7 day postnatal survival of >/=60%. Target accuracy of these sites and of the exocoelomic cavity at E7.5 was > or =51%. We suggest that this approach may be useful for exploring gene function during early placental and embryonic development.