First clinical experience with a new injectable recombinant human collagen scaffold combined with autologous platelet-rich plasma for the treatment of lateral epicondylar tendinopathy (tennis elbow).

BACKGROUND: Lateral epicondylitis is a tendinopathy of the common extensor origin at the elbow. When traditional conservative treatment fails, more effective therapies are needed. Vergenix Soft Tissue Repair (STR) Matrix (CollPlant Ltd., Ness-Ziona, Israel) is an injectable gel composed of cross-linked bioengineered recombinant human type I collagen combined with autologous platelet-rich plasma (STR/PRP). The complex forms a collagen-fibrin matrix that promotes cell migration and tissue repair. Based on positive outcomes from preclinical trials, this study is the first clinical trial of STR/PRP on tendinopathy. We hypothesized that STR/PRP would be a safe and effective treatment for lateral epicondylar tendinopathy. METHODS: Patients with chronic lateral epicondylitis underwent treatment with STR/PRP. Outcome assessment included grip strength, functional disability, and changes in sonographic tendon appearance for up to 6 months after treatment. RESULTS: The study enrolled 40 patients. No systemic or local severe adverse events were reported. Clinical evaluation revealed an improvement in the mean Patient-Rated Tennis Elbow Evaluation score from 64.8 before treatment and showed a 59% reduction at 6 months. The 12-Item Short-Form Health Survey questionnaire showed improvement from a mean score of 30.7 to 37.7 at the final follow-up. Grip strength increased from 28.8 kg at baseline to 36.8 kg at 6 months. Improvements in sonographic tendon appearance were evident among 68% of patients. CONCLUSION: STR/PRP is a safe treatment that effectively induces clinically significant improvements in elbow symptoms and general well-being as well as objective measures of strength and imaging of the common extensor tendon within 6 months of treatment of elbow tendinopathy recalcitrant to standard treatments.

Rare Median Nerve and Digital Nerve Tumor Resection and Distal Nerve Transfers: A Report of 2 Cases.

CASES: We present 2 cases of median nerve reconstruction using distal nerve transfers after resection of unusual benign median nerve tumors. Critical sensation was restored in case 1 by transferring the fourth common digital nerve to first web digital nerves. Thumb opposition was regained by transferring the abductor digiti minimi ulnar motor nerve branch to the recurrent median motor nerve branch. Critical sensation was restored in case 2 by transferring the long finger ulnar digital nerve to the index finger radial digital nerve. CONCLUSION: Distal nerve transfers, even with short grafts, are reliable median nerve deficit treatments, sparing the need for larger autologous nerve grafts and late tendon opponensplasties.

Association of Concave Deformity of the Anterior Scalene on Magnetic Resonance Imaging with Vascular Variant of Neurogenic Thoracic Outlet Syndrome.

Background: Neurogenic thoracic outlet syndrome (NTOS) is a dynamic compression of the brachial plexus. This study aimed to evaluate the correlation between the concave deformity of the posterior edge of the anterior scalene muscle (CDAS) on sagittal T1 with intraoperative findings of vascular compression. The second aim was to define the NTOS vascular subtypes and establish possible treatments. Methods: We retrospectively reviewed patients who met the Consortium for Research and Education on Thoracic Outlet Syndrome criteria for NTOS and were operated on after a failed rehabilitation program. Results: Forty-four patients were included; mean age was 29.51 years (range: 13-55 years), and 24 (54.5%) were women. CDAS on sagittal T1 magnetic resonance imaging (MRI) was identified in 20 of 44. Patients were divided into two categories: type A (pure NTOS) (20 of 44); and type B (mixed neurogenic-vascular variants) (24 of 44). Type B was divided into B1, B2, and B3, corresponding to subclavian artery (SCA) compression (seven of 44), subclavian vein compression (SCV) (five of 44), and both SCA and SCV compression (12 of 44), respectively. All patients with B1 had CDAS on MRI T1 sagittal, whereas CDAS was found on 5%, 60%, and 58.3% in types A, B2, and B3, respectively. Intraoperatively, all patients had at least one structural anomaly. Preoperative symptoms of lower or middle-lower brachial plexus trunk compressions were more prominent in patients with the vascular variant (B1: 85%, B2: 83%, and B3: 83%) than the pure NTOS (type A) (40%). Conclusions: NTOS presents as four subtypes: pure neurogenic (A) and vascular (B1, B2, and B3). Preoperative middle/lower trunk symptoms combined with positive upper limb duplex ultrasound of the SCA, SCV, and sagittal MRI show that a CDAS is correlated with the vascular form of NTOS and predicts failure of preoperative rehabilitation program.

Radial Nerve Palsy: Nerve Transfer Versus Tendon Transfer to Restore Function.

BACKGROUND: Radial nerve injuries cause profound disability, and a variety of reconstruction options exist. This study aimed to compare outcomes of tendon transfers versus nerve transfers for the management of isolated radial nerve injuries. METHODS: A retrospective chart review of 30 patients with isolated radial nerve injuries treated with tendon transfers and 16 patients managed with nerve transfers was performed. Fifteen of the 16 patients treated with nerve transfer had concomitant pronator teres to extensor carpi radialis brevis tendon transfer for wrist extension. Preoperative and postoperative strength data, Disabilities of the Arm, Shoulder, and Hand (DASH) scores, and quality-of-life (QOL) scores were compared before and after surgery and compared between groups. RESULTS: For the nerve transfer group, patients were significantly younger, time from injury to surgery was significantly shorter, and follow-up time was significantly longer. Both groups demonstrated significant improvements in grip and pinch strength after surgery. Postoperative grip strength was significantly higher in the nerve transfer group. Postoperative pinch strength did not differ between groups. Similarly, both groups showed an improvement in DASH and QOL scores after surgery with no significant differences between the 2 groups. CONCLUSIONS: The nerve transfer group demonstrated greater grip strength, but both groups had improved pain, function, and satisfaction postoperatively. Patients who present early and can tolerate longer time to functional recovery would be optimal candidates for nerve transfers. Both tendon transfers and nerve transfers are good options for patients with radial nerve palsy.

Management of Highly Comminuted Intra-articular Fracture Subluxations at the Proximal Interphalangeal Joint by Subchondral Buttress Fixation and Early Mobilization.

This article describes our technique of managing highly comminuted intra-articular fracture subluxations at the proximal interphalangeal joint by subchondral buttress fixation followed by early mobilization. This technique has proven to be reliable and all patients have been able to return to their preinjury level of activity.

Median Nerve Compression in the Forearm: A Clinical Diagnosis.

Background: Median nerve entrapment in the forearm (MNEF) without motor paralysis is a challenging diagnosis. This retrospective study evaluated the clinical presentation, diagnostic studies, and outcomes following surgical decompression of MNEF. Methods: The study reviewed 147 patient medical charts following MNEF surgical decompression. With exclusion of patients with combined nerve entrapments (radial and ulnar), polyneuropathy, neurotmetic nerve injury, or median nerve motor palsy, the study sample included 27 patients. Data collected include: clinical presentation and pain, strength, provocative testing, functional outcomes, and Disabilities of the Arm, Shoulder and Hand (DASH) scores. Results: The study included 27 patients (mean follow-up = 7 months), and 13 patients had previous carpal tunnel release (CTR). Clinical presentation included pain (n = 27) (forearm, n = 22; median nerve innervated digits, n = 21; and palm, n = 21) and positive clinical tests (forearm scratch collapse test, n = 27; pain with compression over the flexor digitorum superficialis arch/pronator, n = 24; Tinel sign, n = 11). Positive electrodiagnostic studies were found for MNEF (n = 2) and carpal tunnel syndrome (n = 11). Primary CTR was performed in 10 patients and revision CTR in 7 patients. Postoperatively, there were significant (P < .05) improvements in strength, pain, quality of life, and DASH scores. Conclusions: The MNEF without motor paralysis is a clinical diagnosis supported by pain drawings, pain quality, and provocative tests. Patients with persistent forearm pain and median nerve symptoms (especially after CTR) should be evaluated for MNEF. Surgical decompression provides satisfactory outcomes.

Blinking Dermatitis: A Case Report.

CASE REPORT: Quincke sign manifested on the wrist of a young healthy man. The patient had self-treated with topical antibiotics and steroids for a second-degree burn, but then developed contact dermatitis followed by cellulitis. He presented to the emergency department with a "blinking" effect of the skin lesion. CONCLUSION: The "blinking" effect is the result of focal subcutaneous arterial dilatation in the zone of subcutaneous inflammation.

Oral administration of OKT3 monoclonal antibody to human subjects induces a dose-dependent immunologic effect in T cells and dendritic cells.

INTRODUCTION: Parenteral OKT3 is used to treat transplant rejection and a humanized anti-CD3 Mab has shown positive clinical effects in new onset diabetes. Oral administration of anti-CD3 has not been tested in humans, but suppresses autoimmunity in animal models. Beta-glucosylceramide enhances NKT cell and regulatory T cell activity and enhances the effects of oral anti-CD3 in animals. MATERIALS AND METHODS: Fifteen healthy volunteers (three per group) received orally administered OKT3 over a dose range of 0.2 to 5.0 mg daily with or without beta-glucosylceramide 7.5 mg for 5 days. Safety and immune parameters were measured on days 5, 10, and 30. RESULTS AND DISCUSSION: Oral OKT3 enhanced T cell proliferation, suppressed Th1 and Th17 responses by 43% and 41%, respectively, increased TGF-beta/IL-10 expression and decreased IL-23/IL-6 expression by dendritic cells, and affected the IgG repertoire as measured by antigen arrays. Co-administration of oral beta-glucosylceramide induced similar effects. No side effects were observed and no subjects developed human anti-mouse antibodies. CONCLUSION: These findings demonstrate that oral anti-CD3 monoclonal antibody is safe and biologically active in humans and presents a new avenue for the treatment of autoimmune diseases.

Beta-glycoglycosphingolipid-induced alterations of the STAT signaling pathways are dependent on CD1d and the lipid raft protein flotillin-2.

Beta-glucosylceramide has been shown to affect natural killer T cell function in models of inflammation. We, therefore, investigated the effects of different beta-glycosphingolipids, including beta-glucosylceramide, on STAT (signal transducers and activators of transcription) signaling pathways and determined whether these effects were mediated by lipid raft microdomains and/or CD1d molecules. The effects of alpha- and beta-structured ligands on the lipid raft protein flotillin-2 were studied in both natural killer T hybridoma cells and leptin-deficient mice. To determine whether CD1d was involved in the effects of the beta-glycosphingolipids, an anti-CD1d blocking antibody was used in a cell proliferation assay system. The downstream effects on the protein phosphorylation levels of STAT1, STAT3, and STAT6 were examined in both immune-mediated hepatitis and hepatoma models. The effects of beta-glycosphingolipids on the STAT signaling pathways were found to be dependent on CD1d. Lipid rafts were affected by both the dose and ratio of the beta-glycosphingolipids and the acyl chain length, and these effects were followed by downstream effects on STAT proteins. Our results show that beta-glycosphingolipids have beneficial effects in natural killer T cell-dependent immune-mediated metabolic and malignant animal models in vivo.

Using electrodiagnostics to define injury patterns amenable to nerve transfer surgery in tetraplegia: an illustrative case report.

INTRODUCTION: Spinal cord injury is a devastating condition affecting a person's independence and quality of life. Nerve transfers are increasingly used to restore critical upper extremity function. Electrodiagnostic studies guide operative planning but the implications for clinical outcomes is not well defined. This case study delineates how clinical examination and electrodiagnostics can define the varying patterns of neuronal injury to guide timing and strategy for optimal outcomes in nerve transfers. CASE PRESENTATION: We discuss a 20-year-old man with a C6-7 spinal cord injury (SCI). We illustrate how history, physical examination, and electrodiagnostic studies predicted patterns of upper and lower motor neuron injury, confirmed intraoperatively via direct nerve stimulation. We undertook brachialis nerve transfer to the median fascicles supplying flexor digitorum superficialis and anterior interosseous nerve (to restore digit flexion), and supinator nerve transfer to posterior interosseous nerve (to restore digit extension). Preoperative electrodiagnostics of the right upper extremity demonstrated a pure upper motor neuron injury to median innervated muscles, and mixed upper and lower motor neuron injury to radial innervated muscles. These findings were confirmed via intraoperative direct neuromuscular stimulation. The preoperative studies provided important information regarding the anatomic basis and time sensitivity of the proposed nerve transfers. At 2 years post operatively the reconstructed digit flexion and extension resulted in improved hand function and independence. DISCUSSION: Upper and lower motor neuron injuries can coexist in individuals with SCI. This example provides proof-of-concept that preoperative electrodiagnostic studies predict LMN injury, and surgery can achieve positive outcomes if completed soon after SCI.

Personalized inherent randomness of the immune system is manifested by an individualized response to immune triggers and immunomodulatory therapies: a novel platform for designing personalized immunotherapies.

The considerable variability of responses amongst subjects to disease triggers and immunotherapies is a major obstacle to designing better immune-based therapies. Therefore, development of patient-tailored precision medicine that improves the efficacy of immunomodulatory drugs is necessary. The individualized response to disease triggers and immunomodulatory therapies was studied using the concanavalin A (ConA) immune-mediated hepatitis model and the oral administration of anti CD3 or ß-glucosylceramide (GC). Mice were treated with anti-CD3 antibodies or GC followed by an injection of ConA. The effects of these treatments on liver damage and the immune profile were then analyzed. An individualized response to ConA and orally administered immunomodulatory agents was observed in eight consecutive experiments. While alleviation of the immune-mediated liver injury, as measured by serum levels of liver enzymes, was seen, and high intra-group and inter-experimental variabilities were detected. A similar individualized response was observed for the effect on serum levels of IFN-γ, TNF-α, and IL-10 and on CD4+CD25+, CD8+CD25+, and CD3+NK1.1+ lymphocytes. A personalized form of inherent randomness in an isolated system was documented, which may underlie the variability in responses to immune triggers and immunomodulatory therapies. The data support the use of personalized randomness-based platforms for improving the response to chronic therapies.

Compound Muscle Action Potential Amplitude Predicts the Severity of Cubital Tunnel Syndrome.

BACKGROUND: Cubital tunnel syndrome has a spectrum of presentations ranging from mild paresthesias to debilitating numbness and intrinsic atrophy. Commonly, the classification of severity relies on clinical symptoms and slowing of conduction velocity across the elbow. However, changes in compound muscle action potential (CMAP) amplitude more accurately reflect axonal loss. We hypothesized that CMAP amplitude would better predict functional impairment than conduction velocity alone. METHODS: A retrospective cohort of patients who underwent a surgical procedure for cubital tunnel syndrome over a 5-year period were included in the study. All patients had electrodiagnostic testing performed at our institution. Clinical and electrodiagnostic variables were recorded. The primary outcome was preoperative functional impairment, defined by grip and key pinch strength ratios. Multivariable regression identified which clinical and electrodiagnostic variables predicted preoperative functional impairment. RESULTS: Eighty-three patients with a mean age of 57 years (75% male) were included in the study. The majority of patients (88%) had abnormal electrodiagnostic studies. Fifty-four percent had reduced CMAP amplitude, and 79% had slowing of conduction velocity across the elbow (recorded from the first dorsal interosseous). On bivariate analysis, older age and longer symptom duration were significantly associated (p < 0.05) with reduced CMAP amplitude and slowing of conduction velocity across the elbow, whereas body mass index (BMI), laterality, a primary surgical procedure compared with revision surgical procedure, Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire scores, and visual analog scale (VAS) scores for pain were not. Multivariable regression analysis demonstrated that reduced first dorsal interosseous CMAP amplitude independently predicted the loss of preoperative grip and key pinch strength and that slowed conduction velocity across the elbow did not. CONCLUSIONS: Reduced first dorsal interosseous amplitude predicted preoperative weakness in grip and key pinch strength, and isolated slowing of conduction velocity across the elbow did not. CMAP amplitude is a sensitive indicator of axonal loss and an important marker of the severity of cubital tunnel syndrome. It should be considered when counseling patients with regard to their prognosis and determining the necessity and timing of operative intervention. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men.

Bone marrow adipose tissue (MAT) is influenced by nutritional cues, and participates in whole body energy metabolism. To investigate the role of Sirtuin1 (Sirt1), a key player in metabolism, in MAT, marrow adiposity was evaluated in inbred 5-month-old 129/Sv Sirt1 haplo-insufficient (Sirt1 Δ/+) and wild type (WT) mice. Decreased expression of the thermogenic genes: Prdm16, Pgc1α, Foxc2, Dio2, and ß3AR was detected in whole tibiae derived from Sirt1 Δ/+ compared to WT female mice. Similarly, decreased expression of Prdm16 and Pgc1α was observed in primary bone marrow mesenchymal stem cell (BM-MSC) cultures obtained from Sirt1 Δ/+ compared to WT female mice, suggesting a cell autonomous effect of Sirt1 in BM-MSCs. In vitro, Sirt1 over-expression in the mesenchymal embryonic fibroblast stem cell line C3HT101/2 increased Pgc1α and Prdm16 protein level. Similarly, pharmacologic activation of Sirt1 by SRT3025 increased Foxc2, Pgc1α, Dio2, Tfam, and Cyc1 expression while inhibition of Sirt1 by EX527 down-regulated UCP1 in C3HT101/2 cells. Importantly, in human femoral BM-MSCs obtained from female patients undergoing hip operations for fracture or osteoarthritis, Sirt1 activation by SRT3025 increased PGC1α mRNA and protein level. Blocking sclerostin, an inhibitor of the WNT pathway and a Sirt1 target, by the monoclonal humanized antibody (Sc-AbII), stimulated ß3AR, PRDM16, and UCP1 gene expression, and increased PGC1α protein level. These results show that Sirt1 stimulates a thermogenic gene program in marrow adipocytes in mice and humans via PGC1α activation and sclerostin inhibition. The implications of these findings to bone health, hematopoiesis and whole body energy metabolism remain to be investigated.

Closed Humeral Fracture Complicated with Acute Hematogenous Osteomyelitis: A Case Report.

INTRODUCTION: Acute hematogenous osteomyelitis (AHO) has been noted mainly in open fractures injuring soft tissue immunological defenses and in immuneincompetent patients. Osteomyelitis complicating closed fractures in immunocompetent adult patients is, therefore, a rare clinical entity with scarce literature. CASE REPORT: We report a case of primary Staphylococcus aureus bacterial infection of a closed, humeral shaft fracture occurring in a previously healthy 28-year-old male patient. The patient was involved in a motorcycle accident and was admitted to the surgical ward with a chest drain. While hospitalized, a peak of fever was noted, but no source was found. Diagnosis of the closed fracture infection was noted on primary open reduction and internal fixation (ORIF), and although the patient was treated with antibiotics, local osteomyelitis developed. Treatment including serial debridements utilizing gentamycin beads and an additional ORIF procedure until the full union was achieved. The patient regained full, painless, motion of the arm and shoulder. CONCLUSION: Although AHO complicating a closed fracture in immunocompetent adults is very rare, it should not be overlooked, and special attention should be sought in such cases. Meticulous debridement and rigid fixation are utmost for the eradication of infection and fracture union. Patients presenting with such infections should, therefore, be followed closely and treated promptly.

Glycosphingolipids Prevent APAP and HMG-CoA Reductase Inhibitors-mediated Liver Damage: A Novel Method for "Safer Drug" Formulation that Prevents Drug-induced Liver Injury.

Background and Aims: Acetaminophen (APAP) and HMG-CoA reductase inhibitors are common causes of drug-induced liver injury (DILI). This study aimed to determine the ability to reduce APAP- and statins-mediated liver injury by using formulations that combine glycosphingolipids and vitamin E. Methods: Mice were injected with APAP or with statins and treated before and after with ß-glucosylceramide (GC), with or without vitamin E. Mice were followed for changes in liver enzymes, liver histology, hepatic expression of JNK, STAT3 and caspase 3, as well as intrahepatic natural killer T cells (NKT) and the serum cytokine levels by flow cytometry. Results: Administration of GC before or after APAP alleviated the liver damage, as noted by a reduction of the liver enzymes, improvement in the liver histology and decreased hepatic caspase 3 expression. Beneficial effect was associated with a reduction of the intrahepatic NKT, JNK expression in the liver, and increased glutathione in the liver, and decreased TNF-α serum levels. Synergistic effect of co-administration of GC with vitamin E was observed. Similar protective effect of GC on statin-mediated liver damage was documented by a reduction in liver enzymes and improved liver histology, which was mediated by reduction of NKT, increased STAT3 expression in the liver, and reduced the TGF-ß and IL17 levels. Conclusions: ß-glycosphingolipids exert a hepatoprotective effect on APAP- and statins-mediated liver damage. Vitamin E exerted a synergistic effect to that of GC. The generation of "safer drug" formulations, which include an active molecule combined with a hepatoprotective adjuvant, may provide an answer to the real unmet need of DILI.

Potential role of NKT regulatory cell ligands for the treatment of immune mediated colitis.

Natural killer T lymphocytes (NKT) have been implicated in the regulation of autoimmune processes in both mice and humans. In response to stimuli, this subset of cells rapidly produces large amounts of cytokines thereby provoking immune responses, including protection against autoimmune diseases. NKT cells are present in all lymphoid compartments, but are most abundant in the liver and bone marrow. They are activated by interaction of their T-cell receptor with glycolipids presented by CD1d, a nonpolymorphic, major histocompatibility complex class I-like molecule expressed by antigen presenting cells. Several possible ligands for NKT cells have recently been suggested. beta-glucosylceramide, a naturally occurring glycolipid, is a metabolic intermediate in the anabolic and catabolic pathways of complex glycosphingolipids. Like other beta-glycolipids, beta-glucosylceramide has an immunomodulatory effect in several immune mediated disorders, including immune mediated colitis. Due to the broad impact that NKT cells have on the immune system, there is intense interest in understanding how NKT cells are stimulated and the extent to which NKT cell responses can be controlled. These novel ligands are currently being evaluated in animal models of colitis. Here, we discuss strategies to alter NKT lymphocyte function in various settings and the potential clinical applications of natural glycolipids.

A Technique for Treating Dorsal Instability of the Distal Radioulnar Joint.

We describe a technique for the treatment of chronic dorsal instability of the distal radioulnar joint by creating a strong dorsal radioulnar restraint using opposing flaps from the extensor retinaculum and dorsal capsule of the radioulnar joint. This technique has been used in 18 patients and has proven to be very easy and reliable with all patients demonstrating good stability of the distal radioulnar joint at final follow-up.

Should Patients With Frozen Shoulder Be Screened for Diabetes Mellitus?

BACKGROUND: Idiopathic frozen shoulder (nontraumatic) is commonly encountered in patients between the ages of 35 and 60 years in general orthopaedic practice. While the prevalence of frozen shoulder among the general population is estimated to be between 2% and 4%, a significantly higher prevalence of 10% to 22% has been reported in patients with diabetes mellitus. Since diabetic patients are more prone to develop frozen shoulder than nondiabetics, the question arises as to whether patients diagnosed as having idiopathic frozen shoulder are at greater risk to develop diabetes mellitus and should be routinely screened for this condition. PURPOSE: To compare the prevalence of diabetes mellitus and prediabetes among patients diagnosed with idiopathic frozen shoulder who are not known to have either diabetes mellitus or prediabetic conditions with that of an age-matched group from the general population. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients at a shoulder clinic with a diagnosis of idiopathic frozen shoulder were asked to participate in the study if they were aged between 35 to 60 years and had no known previous diagnosis of diabetes mellitus or prediabetic conditions. These patients underwent a 2-hour oral glucose tolerance test. According to their fasting and 2-hour plasma glucose levels, patients were diagnosed as normal glucose tolerance, prediabetic, or diabetic. Findings were matched with the prevalence in an age-matched general population. RESULTS: Fifty patients completed the test. Four patients with idiopathic frozen shoulder (8%) were found to be prediabetic. No patient was found to be diabetic. All 4 patients reported a history of diabetes in their parents or siblings. CONCLUSION: Patients diagnosed with idiopathic frozen shoulder who are 60 years or younger and are not known diabetics have a similar probability of having diabetes or prediabetes to an age-matched population. No routine diabetic workup is warranted specifically for these patients.