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Topical 17-beta-estradiol (E2) regulates the hair cycle, hair shaft differentiation, and sebum production. Vitamin A also regulates sebum production. Vitamin A metabolism proteins localized to the pilosebaceous unit (PSU; hair follicle and sebaceous gland); and were regulated by E2 in other tissues. This study tests the hypothesis that E2 also regulates vitamin A metabolism in the PSU. First, aromatase and estrogen receptors localized to similar sites as retinoid metabolism proteins during mid-anagen. Next, female and male wax stripped C57BL/6J mice were topically treated with E2, the estrogen receptor antagonist ICI 182,780 (ICI), letrozole, E2 plus letrozole, or vehicle control (acetone) during mid-anagen. E2 or one of its inhibitors regulated most of the vitamin A metabolism genes and proteins examined in a sex-dependent manner. Most components were higher in females and reduced with ICI in females. ICI reductions occurred in the premedulla, sebaceous gland, and epidermis. Reduced E2 also reduced RA receptors in the sebaceous gland and bulge in females. However, reduced E2 increased the number of retinal dehydrogenase 2 positive hair follicle associated dermal dendritic cells in males. These results suggest that estrogen regulates vitamin A metabolism in the skin. Interactions between E2 and vitamin A have implications in acne treatment, hair loss, and skin immunity.

Purpose Limited data exist regarding the role of perineural blockade of the distal median, ulnar, and radial nerves as a primary anesthetic in patients undergoing hand surgery. We conducted a prospective and randomized pilot study to compare these techniques to brachial plexus blocks as a primary anesthetic in this patient population. Methods Sixty patients scheduled for hand surgery were randomized to receive either an ultrasound-guided supraclavicular, infraclavicular, or axillary nerve block (brachial plexus blocks) or ultrasound-guided median, ulnar, and radial nerve blocks performed at the level of the mid to proximal forearm (forearm blocks). The ability to undergo surgery without analgesic or local anesthetic supplementation was the primary outcome. Block procedure times, postanesthesia care unit length of stay, instances of nausea/vomiting, and need for narcotic administration were also assessed. Results The 2 groups were similar in terms of the need for conversion to general anesthesia or analgesic or local anesthetic supplementation, with only 1 patient in the forearm block group and 2 in the brachial plexus block group requiring local anesthetic supplementation or conversion to general anesthesia. Similar durations in surgical and tourniquet times were also observed. Both groups reported similarly low numerical rating scale pain scores as well as the need for postoperative analgesic administration (2 patients in the forearm block group and 1 in the brachial plexus block group reported numerical rating scale pain scores > 0 and required opioid administration in the postanesthesia care unit). Block procedure characteristics were similar between the 2 groups. Conclusions Forearm blocks may be used as a primary anesthetic in patients undergoing hand surgery. Further research is warranted to determine the appropriateness of these techniques in patients undergoing surgery in the thumb or proximal to the hand. Type of study/level of evidence Therapeutic II.

No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease due to defect in α-N-acetylglucosaminidase (NAGLU). In preparation for a clinical trial, we performed an IND-enabling GLP-toxicology study to assess systemic rAAV9-CMV-hNAGLU gene delivery in WT C57BL/6 mice at 1 × 10(14) vg/kg and 2 × 10(14) vg/kg (n = 30/group, M:F = 1:1), and non-GLP testing in MPS IIIB mice at 2 × 10(14) vg/kg. Importantly, no adverse clinical signs or chronic toxicity were observed through the 6 month study duration. The rAAV9-mediated rNAGLU expression was rapid and persistent in virtually all tested CNS and somatic tissues. However, acute liver toxicity occurred in 33% (5/15) WT males in the 2 × 10(14) vg/kg cohort, which was dose-dependent, sex-associated, and genotype-specific, likely due to hepatic rNAGLU overexpression. Interestingly, a significant dose response was observed only in the brain and spinal cord, whereas in the liver at 24 weeks postinfection (pi), NAGLU activity was reduced to endogenous levels in the high dose cohort but remained at supranormal levels in the low dose group. The possibility of rAAV9 germline transmission appears to be minimal. The vector delivery resulted in transient T-cell responses and characteristic acute antibody responses to both AAV9 and rNAGLU in all rAAV9-treated animals, with no detectable impacts on tissue transgene expression. This study demonstrates a generally safe and effective profile, and may have identified the upper dosing limit of rAAV9-CMV-hNAGLU via systemic delivery for the treatment of MPS IIIB.

Background: The radiographic appearance of osteochondritis dissecans (OCD) of the humeral capitellum varies according to the stage of the lesion. It is important to evaluate the stage of OCD lesion carefully to guide treatment. We compared the interobserver reliability of currently used classification systems for OCD of the humeral capitellum to identify the most reliable classification system. Methods: Thirty-two musculoskeletal radiologists and orthopaedic surgeons specialized in elbow surgery from several countries evaluated anteroposterior and lateral radiographs and corresponding computed tomography (CT) scans of 22 patients to classify the stage of OCD of the humeral capitellum according to the classification systems developed by (1) Minami, (2) Berndt and Harty, (3) Ferkel and Sgaglione, and (4) Anderson on a Web-based study platform including a Digital Imaging and Communications in Medicine viewer. Magnetic resonance imaging was not evaluated as part of this study. We measured agreement among observers using the Siegel and Castellan multirater kappa. Results: All OCD classification systems, except for Berndt and Harty, which had poor agreement among observers (kappa = 0.20), had fair interobserver agreement: k was 0.27 for the Minami, 0.23 for Anderson, and 0.22 for Ferkel and Sgaglione classifications. The Minami Classification was significantly more reliable than the other classifications (P

Extraskeletal osteosarcoma is a rare disease that uncommonly affects the upper extremity. A 46-year-old African American man presented for evaluation of a right middle finger mass. Excisional biopsy demonstrated extraskeletal osteosarcoma of the soft tissues. We performed a transmetacarpal ray resection.

The reverse radial forearm fascial flap can be used to provide coverage for the median nerve in a variety of circumstances. This flap has utility for trauma coverage, recurrent carpal tunnel syndrome, as well as numerous other scenarios. The advantage of this flap is that it preserves the radial artery and has an overall more tolerable aesthetic appearance compared to the traditional reverse radial forearm flap.

Carpal tunnel syndrome is now a well-understood clinical phenomenon in which neuropathic symptoms are secondary to median nerve compression within the carpal tunnel. Prior to this understanding, the symptoms of carpal tunnel syndrome were attributed to several different etiologies: (1) post-traumatic median neuropathy, (2) brachial plexus compression, and (3) thenar neuritis. However it was not until the mid-1900s that the pathophysiology was elucidated to provide a means for clinical care. Herbert Galloway performed the first carpal tunnel release in 1924, and the term “carpal tunnel syndrome” was first used in print by Kremer in 1953.

Item does not contain fulltext PURPOSE: Surgical costs are under scrutiny and surgeons are being held increasingly responsible for cost containment. In some instances, implants are the largest component of total procedure cost, yet previous studies reveal that surgeons' knowledge of implant prices is poor. Our study aims to (1) understand drivers behind implant selection and (2) assess whether educating surgeons about implant costs affects implant selection. METHODS: We surveyed 226 orthopedic surgeons across 6 continents. The survey presented 8 clinical cases of upper extremity fractures with history, radiographs, and implant options. Surgeons were randomized to receive either a version with each implant's average selling price ("price-aware" group), or a version without prices ("price-naive" group). Surgeons selected a surgical implant and ranked factors affecting implant choice. Descriptive statistics and univariate, multivariable, and subgroup analyses were performed. RESULTS: For cases offering implants within the same class (eg, volar locking plates), price-awareness reduced implant cost by 9% to 11%. When offered different models of distal radius volar locking plates, 25% of price-naive surgeons selected the most expensive plate compared with only 7% of price-aware surgeons. For cases offering different classes of implants (eg, plate vs external fixator), there was no difference in implant choice between price-aware and price-naive surgeons. Familiarity with the implant was the most common reason for choosing an implant in both groups (35% vs 46%). Price-aware surgeons were more likely to rank cost as a factor (29% vs 21%). CONCLUSIONS: Price awareness significantly influences surgeons' choice of a specific model within the same implant class. Merely including prices with a list of implants leads surgeons to select less expensive implants. This implies that an untapped opportunity exists to reduce surgical expenditures simply by enhancing surgeons' cost awareness. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic/Decision Analyses I.

This chapter discusses the pathophysiological mechanisms and contributing factors underlying the etiology of carpal tunnel syndrome. The etiology of carpal tunnel syndrome is complex and still has not been fully elucidated. Many factors have been implicated in the development and progression of carpal tunnel syndrome. Injury due to repetitive mechanical stress and resulting nerve injury has been historically thought to be the cause of carpal tunnel syndrome. Additionally, systemic disease states including diabetes, acromegaly, thyroid dysfunction, and rheumatoid arthritis among others have been linked to carpal tunnel syndrome. Age, gender, and genetic factors have also been associated with the development of carpal tunnel syndrome. The various elements that may predispose to carpal tunnel syndrome have been explored in depth in this chapter.

Background Data are limited regarding the use of peripheral nerve blockade at the level of the forearm, and most studies regard these procedures as rescue techniques for failed or incomplete blocks. The purpose of the study was to investigate patients undergoing hand surgery with distal peripheral nerve (forearm) blocks and compare them with patients having similar procedures under more proximal brachial plexus blockade. No investigations comparing distal nerve blockade to proximal approaches are currently reported in the literature. Methods Medical records were retrospectively reviewed for patients who had undergone hand surgery with a peripheral nerve block between November 2012 and October 2013. The primary outcome was the ability to provide a primary anesthetic without the need for general anesthesia or local anesthetic supplementation by the surgical team. Secondary outcome measures included narcotic administration during the block and intraoperative procedures, block performance times, and the need for rescue analgesics in the post anesthesia care unit (PACU). Results No statistical difference in conversion rates to general anesthesia was observed between the two groups. Total opiate administration for the block and surgical procedure was lower in the forearm block group. There was no difference in block performance times or need for rescue analgesics in the PACU. Conclusions Forearm blocks are viable alternatives to proximal blockade and are effective as a primary anesthetic technique in patients undergoing hand surgery. Compared to the more proximal approaches, these blocks have the benefits of not causing respiratory compromise, the ability to be performed bilaterally, and may be safer in anticoagulated patients.

Loss of contact between radial head fracture fragments is strongly associated with other elbow or forearm injuries. If this finding has adequate interobserver reliability, it could help examiners identify and treat associated ligament injuries and fractures (eg, forearm interosseous ligament injury or elbow dislocation). (1) What is the interobserver agreement on radiographic loss of contact between radial head fracture fragments? (2) Are there factors associated with the observer such as location of practice or subspecialization that increase interobserver reliability? Fully trained practicing orthopaedic and trauma surgeons from around the world evaluated 27 anteroposterior and lateral radiographs of radial head fractures on a web-based platform for the following characteristics: (1) loss of contact between at least one radial head fracture fragment and the remaining radial head and neck; (2) a gap between fragments of 2 mm or greater; (3) anticipated fracture instability (mobility) on operative exposure; (4) anticipated associated ligament injuries; and (5) recommendation for treatment. Agreement among observers was measured using the multirater kappa measure. Kappas for various observer characteristics were compared using 95% confidence intervals. The overall interobserver agreement was moderate (range, 0.49-0.55) for each question except associated ligament injury, which was fair (0.33). Shoulder and elbow surgeons had substantial agreement (range, 0.51-0.61) in many areas, but kappas were generally in the moderate range (0.41-0.59) based on number of years in practice, radial head fractures treated per year, and trainee supervision. Radiographic signs of radial head fracture instability such as loss of contact have moderate reliability. This characteristic seems clinically useful, because loss of contact between at least one radial head fracture fragment and the remaining radial head and neck is strongly associated with associated ligament injury or other fractures. Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence

Background Forequarter amputation (FQA) is reserved for large, multifocal, or recurrent tumors affecting the shoulder and upper extremity. Although it is performed less frequently with the advancement of limb salvage surgery, FQA remains an important treatment in select patients. The purpose of this study is to illustrate the surgical technique in a case series of 4 patients. Methods Between 2010 and 2012, 4 patients (mean age, 61 years; range, 36-78 years) presented with malignant disease of the upper extremity that was not amenable to or had failed limb salvage. All patients had FQA by the illustrated anterior clavicular osteotomy technique. Patient data were retrospectively reviewed from preoperative workup until last follow-up or death. Results All patients had tumors that involved major neurovascular structures of the upper extremity and shoulder girdle. One presented with neuroendocrine carcinoma and has achieved local control after FQA. Three presented with high-grade sarcoma. One of these had recurrence after prior limb salvage and neoadjuvant radiation and unfortunately succumbed to metastatic disease 6 months after FQA. An additional sarcoma patient who presented after shoulder arthroscopy for a “labral cyst” with recurrent and fulminant synovial sarcoma succumbed to her disease. The remaining sarcoma patient has had no recurrence and minimal phantom pain at last follow-up. Discussion Obtaining vascular control early in the procedure is crucial to minimize blood loss. When it is indicated, FQA is a relatively safe and reliable procedure for dealing with otherwise challenging tumors of the shoulder girdle and upper extremity.

Objective. This report describes a case in which the off-label use of liposomal bupivacaine (Exparel) in a peripheral nerve block resulted in marked improvement of a patient’s vasoocclusive symptoms. The vasodilating and analgesic properties of liposomal bupivacaine in patients with ischemic symptoms are unknown, but our clinical experience suggests a role in the management of patients suffering from vasoocclusive disease.Case Report. A 45-year-old African American female was admitted to the hospital with severe digital ischemic pain. She was not a candidate for any vascular surgical or procedural interventions. Two continuous supraclavicular nerve blocks were placed with modest clinical improvement. These effects were also short-lived, with the benefits resolving after the discontinuation of the peripheral nerve blocks. She continued to report severe pain and was on multiple anticoagulant medications, so a decision was made to perform an axillary nerve block using liposomal bupivacaine (Exparel) given the compressibility of the site as well as the superficial nature of the target structures.Conclusions. This case report describes the successful off-label usage of liposomal bupivacaine (Exparel) in a patient with digital ischemia. Liposomal bupivacaine (Exparel) is currently FDA approved only for wound infiltration use at this time.

Alopecia areata (AA) is an autoimmune disease that attacks anagen hair follicles. Gene array in graft-induced C3H/HeJ mice revealed that genes involved in retinoic acid (RA) synthesis were increased, whereas RA degradation genes were decreased in AA compared with sham controls. This was confirmed by immunohistochemistry in biopsies from patients with AA and both mouse and rat AA models. RA levels were also increased in C3H/HeJ mice with AA. C3H/HeJ mice were fed a purified diet containing one of the four levels of dietary vitamin A or an unpurified diet 2 weeks before grafting and disease progression followed. High vitamin A accelerated AA, whereas mice that were not fed vitamin A had more severe disease by the end of the study. More hair follicles were in anagen in mice fed high vitamin A. Both the number and localization of granzyme B–positive cells were altered by vitamin A. IFNγ was also the lowest and IL13 highest in mice fed high vitamin A. Other cytokines were reduced and chemokines increased as the disease progressed, but no additional effects of vitamin A were seen. Combined, these results suggest that vitamin A regulates both the hair cycle and immune response to alter the progression of AA.

Purpose It is our impression that there is substantial, unexplained variation in hand surgeon recommendations for treatment of peripheral mononeuropathy. We tested the null hypothesis that specific patient and provider factors do not influence recommendations for surgery. Methods Using a web-based survey, hand surgeons recommended surgical or nonsurgical treatment for patients in 2 different scenarios. Six elements of the first scenario (symptoms, circumstances, mindset, diagnosis, objective testing, and expectations) had 2 possibilities that were each independently and randomly assigned to each rater. For the second scenario, 2 different scenarios were randomly assigned to each rater. Multivariable logistic regression sought factors associated with a recommendation for surgery. Results A total of 186 surgeons of the Science of Variation Group completed a survey regarding recommendation of surgery for 2 different patients based on clinical scenarios. Recommendations for surgery did not vary significantly according to provider characteristics. For the various elements in scenario 1, recommendation for surgery was more likely for patients who were self-employed and continued to work and who had objective electrodiagnostic abnormalities. For the 2 vignettes used in scenario 2, a recommendation for surgery was associated with abnormal electrophysiology. Conclusions The findings of this study suggest that—at least in a survey setting—surgeons prefer to offer peripheral nerve decompression to patients with abnormal electrophysiology, particularly those with effective coping strategies. Clinical relevance The role of objective verification of pathophysiology is debated, but it is an influential factor in recommendations for hand surgery.

Purpose: To report the outcomes of mallet fractures treated with our modified tension band wiring technique.Methods: Eleven men and two women (mean age; 33 years) with mallet fractures in which happened more than five weeks before surgery, or with fracture fragments involving more than 2/3 or less than 1/3 of the distal phalanx articular surface or with previous surgical intervention, were subjected to this study. The fracture fragment was fixed with a modified tension band wiring technique using a stainless steel wire and an injection needle.Results: All patients achieved bone union in nine weeks in average. All patients had no pain except one with mild pain. No patient showed a gap or step-off greater than 1 mm.Conclusions: Our tension band wiring technique can be used regardless of the size of the dorsal fracture fragment or the interval between injury and surgery.

A boy was born with a right duplicated thumb (Wassel type 6) and a left radial club hand (type 3) associated with a hypoplastic thumb (type 3B). He underwent surgical centralization of the left wrist when he was 13 months old. At age 38 months, he underwent reconstruction of the carpometacarpal joint of the hypoplastic left thumb. This procedure involved transplantation of the radial ray of the right duplicated thumb to the base of the left thumb. When he was 6 years old, the patient underwent an abductor digiti minimi muscle transfer to create opposition for the left thumb and deepening of the first web. At the final follow-up, he could grasp items in the first web space and pick up small items between the thumb and other digits of the left hand. The treatment represents a method of using otherwise discarded tissues for effective reconstruction.

In immunocompromised individuals, such as organ transplant recipients, the risk of cutaneous squamous cell carcinoma (SCC) is increased 60-250 fold, and there is an increased likelihood to develop aggressive, metastatic SCC. An understanding of the genes involved in SCC tumorigenesis is critical to prevent SCC-associated morbidity and mortality. Mouse models show that different immunosuppressive drugs lead to SCCs varying in size, number, and malignant potential. In this study we utilized mouse models that mimic adult transplant recipients to study the effect of immunosuppressive drugs and UV light on SCC development. UV-induced tumors from six treatment groups, control, tacrolimus (Tac), rapamycin (Rap), cyclosporin (CsA), mycophenolate mofetil (MMF), and Rap plus CsA, were evaluated by array comparative genomic hybridication. Mouse SCCs appear to show similar genomic aberrations as those reported in human SCCs and offer the ability to identify genomic changes associated with specific and combinatorial effects of drugs. Fewer aberrations were seen in tumors of mice treated with MMF or Rap. Tumors from Tac treated animals showed the highest number of changes. Calcineurin inhibitors (Tac and CsA) did not cluster together by their genomic aberrations, indicating their contribution to UV mediated carcinogenesis may be through different pathways. The combination treatment (Rap plus CsA) did not cluster with either treatment individually, suggesting it may influence SCC tumorigenesis via a different mechanism. Future studies will identify specific genes mapping to regions of aberration that are different between treatment groups to identify target pathways that may be affected by these drugs.

No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease due to autosomal recessive defect in α-N-acetylglucosaminidase (NAGLU). In preparation for a clinical trial, we performed an IND-enabling GLP-toxicology study to assess systemic rAAV9-CMV-hNAGLU administration in wt C57BL/6 mice (6-8wk-old), at 1e14 vg/kg or 2e14 vg/kg (n=30/group, M:F=1:1). These were 2 and 4-fold higher, respectively, than our proposed clinical high dose. No adverse clinical signs were observed during the entire 6mo study duration. NAGLU activity above wt levels and vector genomes were detected in all tested CNS and somatic tissues in rAAV-treated mice through 6mo. However, acute mortality was observed in 5 male mice at 2e14 vg/kg dose on Days 6 and 8 pi. All 5 animals exhibited liver discoloration correlating with severe hepatic necrosis and vacuolation, without detectable leukocyte infiltration. At 6, 12 and 24wk pi, minimal single cell hepatocyte necrosis and/or vacuolation, and minimal cardiomyopathy were noted in a dose-dependent manner, with slight transient elevation of ALT or AST at 6wk pi. T-cell responses to AAV9 capsid and rNAGLU were detected at 6wk pi, but partially and completely diminished at 12wk pi, respectively. ELISA showed antibody responses to both AAV9 and rNAGLU in treated animals. In response to the acute mortality in the GLP-tox test, we performed a 6-wk non-GLP study mimicking the GLP-tox study conditions in male MPS IIIB and wt littermates, to further assess the approach and obtain data prior to early mortality. We treated the mice with the same batch of rAAV9-CMV-hNAGLU at the high dose, 2e14 vg/kg, and performed necropsy at 5 days and 6wk pi (n=4/group). No mortality or clinical signs were observed in either rAAV9-treated MPS IIIB or wt mice. At Day 5 pi necropsy, of 4 rAAV9-treated male wt mice, 1 exhibited liver discoloration, correlating with multifocal, periportal and midzonal hepatocyte necrosis, and 2 showed minimal single cell hepatocyte necrosis. Minimal liver damage and elevation of ALT/AST in wt mice persisted to 6wk pi. However, no abnormal changes attributed to vector treatment were detected in the liver in MPS IIIB mice. Therefore, we have identified genotype- and sex-specific dose-limiting toxicity of systemic rAAV9-hNAGLU delivery, supporting a safe profile for our proposed approach for treating MPS IIIB in patients.

Note: This procedure may often be performed in conjunction with other reconstructive procedures for the rheumatoid arthritis.