Spatial Atlas for Mapping Vascular Microcalcification Using 18F-NaF PET/CT: Application in Hyperphosphatemic Familial Tumoral Calcinosis.

BACKGROUND: Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission tomography/computed tomography has emerged as a sensitive and specific method for detecting and quantifying active microcalcifications. We developed a novel technique to quantify and map total vasculature microcalcification to a common space, allowing simultaneous assessment of global disease burden and precise tracking of site-specific microcalcifications across time and individuals. METHODS: To develop this technique, 4 patients with hyperphosphatemic familial tumoral calcinosis, a monogenic disorder of FGF23 (fibroblast growth factor-23) deficiency with a high prevalence of vascular calcification, underwent radiolabeled sodium fluoride positron emission tomography/computed tomography imaging. One patient received serial imaging 1 year after treatment with an IL-1 (interleukin-1) antagonist. A radiolabeled sodium fluoride-based microcalcification score, as well as calcification volume, was computed at all perpendicular slices, which were then mapped onto a standardized vascular atlas. Segment-wise mCSmean and mCSmax were computed to compare microcalcification score levels at predefined vascular segments within subjects. RESULTS: Patients with hyperphosphatemic familial tumoral calcinosis had notable peaks in microcalcification score near the aortic bifurcation and distal femoral arteries, compared with a control subject who had uniform distribution of vascular radiolabeled sodium fluoride uptake. This technique also identified microcalcification in a 17-year-old patient, who had no computed tomography-defined calcification. This technique could not only detect a decrease in microcalcification score throughout the patient treated with an IL-1 antagonist but it also identified anatomic areas that had increased responsiveness while there was no change in computed tomography-defined macrocalcification after treatment. CONCLUSIONS: This technique affords the ability to visualize spatial patterns of the active microcalcification process in the peripheral vasculature. Further, this technique affords the ability to track microcalcifications at precise locations not only across time but also across subjects. This technique is readily adaptable to other diseases of vascular calcification and may represent a significant advance in the field of vascular biology.

Optoα1AR activation in astrocytes modulates basal hippocampal synaptic excitation and inhibition in a stimulation-specific manner.

Astrocytes play active roles at synapses and can monitor, respond, and adapt to local synaptic activity. While there is abundant evidence that astrocytes modulate excitatory transmission in the hippocampus, evidence for astrocytic modulation of hippocampal synaptic inhibition remains more limited. Furthermore, to better investigate roles for astrocytes in modulating synaptic transmission, more tools that can selectively activate native G protein signaling pathways in astrocytes with both spatial and temporal precision are needed. Here, we utilized AAV8-GFAP-Optoα1AR-eYFP (Optoα1AR), a viral vector that enables activation of Gq signaling in astrocytes via light-sensitive α1-adrenergic receptors. To determine if stimulating astrocytic Optoα1AR modulates hippocampal synaptic transmission, recordings were made in CA1 pyramidal cells with surrounding astrocytes expressing Optoα1AR, channelrhodopsin (ChR2), or GFP. Both high-frequency (20 Hz, 45-ms light pulses, 5 mW, 5 min) and low-frequency (0.5 Hz, 1-s pulses at increasing 1, 5, and 10 mW intensities, 90 s per intensity) blue light stimulation were tested. 20 Hz Optoα1AR stimulation increased both inhibitory and excitatory postsynaptic current (IPSC and EPSC) frequency, and the effect on miniature IPSCs (mIPSCs) was largely reversible within 20 min. However, low-frequency stimulation of Optoα1AR did not modulate either IPSCs or EPSCs, suggesting that astrocytic Gq -dependent modulation of basal synaptic transmission in the hippocampus is stimulation-dependent. By contrast, low-frequency stimulation of astrocytic ChR2 was effective in increasing both synaptic excitation and inhibition. Together, these data demonstrate that Optoα1AR activation in astrocytes changes basal GABAergic and glutamatergic transmission, but only following high-frequency stimulation, highlighting the importance of temporal dynamics when using optical tools to manipulate astrocyte function.

Emerging Role of 18F-NaF PET/Computed Tomographic Imaging in Osteoporosis: A Potential Upgrade to the Osteoporosis Toolbox.

Osteoporosis is a metabolic bone disorder that leads to a decline in bone microarchitecture, predisposing individuals to catastrophic fractures. The current standard of care relies on detecting bone structural change; however, these methods largely miss the complex biologic forces that drive these structural changes and response to treatment. This review introduces sodium fluoride (18F-NaF) positron emission tomography/computed tomography (PET/CT) as a powerful tool to quantify bone metabolism. Here, we discuss the methods of 18F-NaF PET/CT, with a special focus on dynamic scans to quantify parameters relevant to bone health, and how these markers are relevant to osteoporosis.

Effect of stimulants on final adult height.

BACKGROUND: The use of stimulant medications for treatment of ADHD has raised concern as to whether they adversely impact linear growth. Previous studies have indicated that stimulant medications may suppress growth for a short period after treatment initiation; however, more information is needed to evaluate the long-term effects on final adult stature. This mini review aims to evaluate the effect of stimulant medications on final adult height in children with ADHD. CONTENTS: We performed a literature review across PubMed/MEDLINE database. Only articles that included data on final adult height or near final adult height (age≥16 or 17 years) were included. SUMMARY: Early studies investigating the long-term impacts of stimulant medications observed growth suppression during the active treatment period, but when comparing final adult height, there was no difference between the control and ADHD groups. A recent larger comprehensive study (Multimodal Treatment of ADHD study) has suggested that the long-term use of significant doses of stimulants during childhood may compromise final adult height to a clinically significant degree when comparing adult height across three long-term patterns of stimulant treatment (Consistent, Intermittent, Negligible). The consistent use subgroup was significantly shorter than other subgroups. OUTLOOK: For children with ADHD, a significant long-term dose of stimulant treatment should be used with caution to avoid diminishing adult height potential. Pediatric endocrinologists should consider chronic use of stimulants as a factor contributing to reduced adult height.

Patellar Tendon Reconstruction for a Chronic Extensor Mechanism Deficit Using an Achilles Tendon Allograft With Hamstring Autograft and Suture Augmentation.

Patellar tendon ruptures are the third most common injury to the extensor mechanism. These injuries are debilitating to the patient, and delays in treatment can present a challenge to the treating surgeon. Chronic patellar tendon injuries are rare and are more difficult to manage given proximal patellar retraction, scarring, and atrophy of surrounding tissues. There is no consensus on the optimal approach for treatment, and numerous reconstruction techniques have been described using a variety of graft choices and fixation methods. We describe our surgical technique for a 3-fold reconstruction of a chronic patellar tendon rupture using an Achilles tendon allograft augmented with a vascularized ipsilateral hamstring tendon autograft and additional FiberTape augmentation. The aim of this procedure is to restore patellar height and prevent extensor lag.

Can Radiographic Joint Space Accurately Predict Chondral Damage During Hip Arthroscopy? A Cross-Sectional Analysis.

PURPOSE: To examine how preoperative radiographic joint space correlated with intraoperative chondral damage as diagnosed during hip arthroscopy, in patients without radiographic evidence of osteoarthritis or joint space <2 mm. METHODS: Patients younger than the age of 50 years without previous hip conditions who underwent hip primary arthroscopy had their joint space and intraoperative chondral damage compared. A narrow joint space group was defined as those in the lowest decile of the average joint space. The demographics and presence of intra-articular findings of chondral damage were compared. In addition, receiver operator characteristic (ROC) curves were used to assess joint space as a predictor of intraarticular damage. RESULTS: There were 1892 in this analysis. The incidence of severe cartilage damage (Outerbridge III and IV) was not significantly different between the narrow and non-narrow groups. The ROC analysis for joint space at detecting chondral damage was poor. The ROC area under the curve for joint space detecting any chondral defect (acetabular or femoral head) was 0.536 (confidence interval 0.506-0.565), with low sensitivity (0.492), specificity (0.582), negative predictive value (0.720), and positive predictive value (0.340). Spearman correlation could not demonstrate a correlation between joint space and cartilage damage (⍴Acetabular = 0.10, ⍴Femoral Head = 0.04). Interestingly, a gradual widening was observed between the medial and lateral joint spaces, with more pronounced findings in hips without damage. CONCLUSIONS: The results of this study demonstrate that in patients with Tönnis 0 and 1, narrower joint space may be an anatomic variant and cannot predict actual intraoperative cartilage damage. However, if the lateral joint space has relative narrowing compared with the medial joint space, this may indicate acetabular cartilage damage. LEVEL OF EVIDENCE: III, retrospective diagnostic comparative study.

Platelet-Rich Plasma Versus Surgery for the Management of Recalcitrant Greater Trochanteric Pain Syndrome: A Systematic Review.

PURPOSE: To perform a systematic review of the outcomes of platelet-rich plasma (PRP) injections as an in-office procedure versus surgical treatment for recalcitrant greater trochanteric pain syndrome (GTPS). METHODS: The MEDLINE and Embase databases were searched in June 2019 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Clinical studies on patients with recalcitrant GTPS treated with PRP or surgery were included. Demographic characteristics, patient-reported outcomes (PROs), and complications were compared. A qualitative analysis using the Methodological Index for Non-randomized Studies and Cochrane Risk of Bias Tool scores was performed. RESULTS: A total of 5 PRP and 5 surgery studies met the inclusion criteria, contributing 94 and 185 patients, respectively. The mean follow-up time was shorter for the PRP studies (range, 2-26 months) than with surgery (range, 12-70 months). The mean Methodological Index for Non-randomized Studies scores for the PRP and surgery groups were 11.25 and 11.4, respectively, and the only randomized trial had a low risk of bias. Two studies in the PRP group (n = 56) reported improvements in the modified Harris Hip Score at final follow-up (from 53.8 to 82.6 and from 56.7 to 74.2). The other PRP studies reported improvements using other measures. In the surgery group, 2 studies reported improvements in the Harris Hip Score (from 53.0 to 80 and from 53.3 to 88) whereas 3 used unique PROs (Oxford score, from 20.4 to 37.3; modified Harris Hip Score, from 54.9 to 76.2; and Merle d'Aubigné and Postel score, from 10.9 to 16.7). Although significant improvement was reported in all studies included, PRP showed a large effect size whereas surgery showed a moderate to large effect size. No major complications were associated with PRP treatment; however, the surgery group reported a higher rate of complications including recurrent external snapping hip, retears resulting from falls, trochanteric fracture, venous thrombosis, and wound-related problems. CONCLUSIONS: Both PRP and surgical intervention for the treatment of recalcitrant GTPS showed statistically and clinically significant improvements based on PROs. Although not covered by most medical insurance companies, PRP injections for recalcitrant GTPS provides an effective and safe alternative after failed physical therapy. If surgery is indicated, endoscopy is safer than the open technique. LEVEL OF EVIDENCE: Level IV, systematic review of Level I to IV studies.

Hip Arthroscopy Successfully Treats Femoroacetabular Impingement in Adolescent Athletes.

BACKGROUND: There is evidence that femoroacetabular impingement (FAI) is increasingly prevalent among adolescent athletes. Abnormal contact forces across the hip and alterations in bony morphology characteristic of FAI may be especially detrimental in this group, given their young age and active lifestyle. PURPOSE: The purpose of this study was to report the findings, outcomes, and return to sport percentage among adolescent athletes with FAI treated with hip arthroscopy. METHODS: A retrospective review of all patients younger than 18 years who underwent hip arthroscopy for FAI at a single institution was performed. All athletes who were attempting to return to sport and underwent hip arthroscopy were included. Patients with previous hip surgery and/or hip conditions were excluded. Arthroscopic procedures and an assessment of intra-articular findings were recorded. Patient-reported outcome measures were recorded at 3 months, 1 year, and 2 years postoperatively, and included the modified Harris hip score, the nonarthritic hip score, hip outcome score-sports subscale, visual analogue scale for pain, and patient satisfaction. Return to sport percentage and ability levels were also noted. RESULTS: There were 96 eligible cases of adolescent athletes treated with hip arthroscopy; 81 (84.4%) hips in 69 patients had 2-year follow-up. Running/track and field was the most common sport (25), followed by soccer (12), dance (10), baseball/softball (9), and basketball (6). There were 61 females and 20 males, whose average age was 15.9±1.2 y (range: 13.1 to 18.0 y). The most common procedures were labral repair (81.5%), iliopsoas fractional lengthening (72.8%), femoroplasty (69.1%), and acetabuloplasty (66.7%). Capsular repair or plication was performed in most patients (81.5%). Cartilage damage was more common on the acetabulum than the femur, with Outerbridge grade 2 or higher occurring in 23.5% and 4.9% of hips, respectively. Statistically significant improvements were seen in all patient-reported outcomes from preoperative to minimum 2-year follow-up. A total of 84.0% of patients had returned to their sport at latest follow-up. There were 6 (7.4%) patients who underwent revision arthroscopy at a mean of 37.3 months postoperatively. CONCLUSION: Symptomatic FAI in adolescent athletes can be successfully treated with hip arthroscopy, with a higher return to sport rate and low complications and reoperation rate at minimum 2-year follow-up.

Outcomes of Nonoperative Management, Iliopsoas Tenotomy, and Revision Arthroplasty for Iliopsoas Impingement after Total Hip Arthroplasty: A Systematic Review.

BACKGROUND: Nonoperative and operative management of iliopsoas impingement (IPI) is commonly performed following total hip arthroplasty (THA). The purpose of this systematic review is to compare patient-reported outcomes (PROs) following conservative treatment, iliopsoas (IP) tenotomy, and revision arthroplasty in patients presenting with IPI after THA. METHODS: The PubMed and Embase databases were searched for articles regarding IPI following THA. Studies were included if (1) IPI after THA was treated with conservative management, an IP tenotomy, or acetabular component revision and (2) included PROs. RESULTS: Eleven articles were selected for review and there were 280 hips treated for IPI following THA. Harris Hip Scores reported for the conservative group, the IP tenotomy group, and the cup revision group were 59.0 preoperatively to 77.8, 58.0 preoperatively to 85.4, and 58.1 preoperatively to 82.4 at latest follow-up, respectively. The IP tenotomy cohort also demonstrated superior postoperative functional outcomes using the Western Ontario and McMaster Universities Index, Medical Research Council score, Oxford Hip Score, and Merle d'Aubigné-Postel Pain Score. Patients who had a revision exhibited higher Oxford Hip Scores, higher Medical Research Council scores, and lower Visual Analog Scale Pain scores postoperatively. CONCLUSION: Management of IPI following THA includes nonoperative measures, IP tenotomy, or acetabular component revision. Patients have been shown to experience favorable PROs at latest follow-up, with an apparent advantage for surgical treatment. Compared to revision arthroplasty, IP tenotomy resulted in a lower overall rate of complications with less severe complication types. Therefore, IP tenotomy should be considered as a second line of treatment for patients who failed conservative measures. Revision arthroplasty should be reserved for recalcitrant cases. LEVEL OF EVIDENCE: IV.

The Modified Resisted Internal Rotation Test for Detection of Gluteal Tendon Tears.

Greater trochanteric pain syndrome (GTPS) has received increasing attention in recent years. Most patients with GTPS present with trochanteric bursitis and respond to nonoperative treatment. However, a subset of patients may have persistent lateral hip pain or recalcitrant GTPS resulting from an undiagnosed gluteal tendon tear. Recalcitrant GTPS may be a debilitating condition in this patient subset. There is a need for an accurate and evidence-based physical examination maneuver to aid in earlier diagnosis of gluteal tendon tears and timely intervention in these patients. Most studies evaluating gluteal tendinopathy fail to assess surgical indications and instead focus on identifying trochanteric bursitis, which may or may not require surgical treatment. The modified resisted internal rotation test has been used in our practice to detect gluteus medius tendon tears in the recalcitrant GTPS patient population. Fundamental anatomic, biomechanical, electromyographic, and clinical data have been reviewed to make this an evidence-based clinical test for early detection of this pathology.

Differential impacts on multiple forms of spatial and contextual memory in diazepam binding inhibitor knockout mice.

Learning and memory are fundamental processes that are disrupted in many neurological disorders including Alzheimer's disease and epilepsy. The hippocampus plays an integral role in these functions, and modulation of synaptic transmission mediated by γ-aminobutyric acid (GABA) type-A receptors (GABAA Rs) impacts hippocampus-dependent learning and memory. The protein diazepam binding inhibitor (DBI) differentially modulates GABAA Rs in various brain regions, including hippocampus, and changes in DBI levels may be linked to altered learning and memory. The effects of genetic loss of DBI signaling on these processes, however, have not been determined. In these studies, we examined male and female constitutive DBI knockout mice and wild-type littermates to investigate the role of DBI signaling in modulating multiple forms of hippocampus-dependent spatial learning and memory. DBI knockout mice did not show impaired discrimination of objects in familiar and novel locations in an object location memory test, but did exhibit reduced time spent exploring the objects. Multiple parameters of Barnes maze performance, testing the capability to utilize spatial reference cues, were disrupted in DBI knockout mice. Furthermore, whereas most wild-type mice adopted a direct search strategy upon learning the location of the target hole, knockout mice showed higher rates of using an inefficient random strategy. In addition, DBI knockout mice displayed typical levels of contextual fear conditioning, but lacked a sex difference observed in wild-type mice. Together, these data suggest that DBI selectively influences certain forms of spatial learning and memory, indicating novel roles for DBI signaling in modulating hippocampus-dependent behavior in a task-specific manner.