Fatty acid binding protein 5 inhibition attenuates pronociceptive cytokine/chemokine expression and suppresses osteoarthritis pain: A comparative human and rat study.

OBJECTIVE: Osteoarthritis (OA) is often accompanied by debilitating pain that is refractory to available analgesics due in part to the complexity of signaling molecules that drive OA pain and our inability to target these in parallel. Fatty acid binding protein 5 (FABP5) is a lipid chaperone that regulates inflammatory pain; however, its contribution to OA pain has not been characterized. DESIGN: This combined clinical and pre-clinical study utilized synovial tissues obtained from subjects with end-stage OA and rats with monoiodoacetate-induced OA. Cytokine and chemokine release from human synovia incubated with a selective FABP5 inhibitor was profiled with cytokine arrays and ELISA. Immunohistochemical analyses were conducted for FABP5 in human and rat synovium. The efficacy of FABP5 inhibitors on pain was assessed in OA rats using incapacitance as an outcome. RNA-seq was then performed to characterize the transcriptomic landscape of synovial gene expression in OA rats treated with FABP5 inhibitor or vehicle. RESULTS: FABP5 was expressed in human synovium and FABP5 inhibition reduced the secretion of pronociceptive cytokines (interleukin-6 [IL6], IL8) and chemokines (CCL2, CXCL1). In rats, FABP5 was upregulated in the OA synovium and its inhibition alleviated incapacitance. The transcriptome of the rat OA synovium exhibited >6000 differentially expressed genes, including the upregulation of numerous pronociceptive cytokines and chemokines. FABP5 inhibition blunted the upregulation of the majority of these pronociceptive mediators. CONCLUSIONS: FABP5 is expressed in the OA synovium and its inhibition suppresses pronociceptive signaling and pain, indicating that FABP5 inhibitors may constitute a novel class of analgesics to treat OA.

Preoperative chronic steroid use as a risk factor for complications following open reduction internal fixation for proximal humerus fracture.

PURPOSE: The primary objective of this study was to investigate the association between preoperative chronic steroid use and postoperative complications following open reduction internal fixation (ORIF) for proximal humerus fractures (PHF). METHODS: The American College of Surgeons National Surgical Quality Improvement (ACS-NSQIP) database was queried for all patients who underwent PHF ORIF between 2015 and 2021. A total of 6,273 patients were included in this study, of which 3.4% (n = 212) were in the chronic steroid use cohort. Patient characteristics including demographics, comorbidities, and 30-day postoperative complications after PHF ORIF were collected. Bivariate logistic regression and multivariate logistic regression analysis, adjusted for all significantly associated variables, was conducted to investigate the relationship between preoperative chronic steroid use and postoperative complications. RESULTS: Chronic steroid use was significantly associated with age ≥ 75 (p < 0.001), male gender (p =0.006), dependent functional status (p = 0.008), American Society of Anesthesiologist (ASA) ≥ 3 (p < 0.001), CHF (p = 0.007), hypertension (p < 0.001), COPD (p < 0.001), bleeding disorder (p = 0.007), ascites (p = 0.040), disseminated cancer (p< 0.001), and systemic sepsis (p < 0.001). After adjusting for all significantly associated variables, chronic steroid use was independently associated with major complication (OR 1.60, 95% CI 1.06-2.43; p = 0.026), and non-home discharge (OR 1.05, 95% CI 1.01-1.08; p = 0.014). CONCLUSION: Preoperative chronic steroid use is associated with increasing rate of postoperative complications following PHF ORIF. Better understanding and characterizing chronic steroid use as a preoperative risk factor can aid physicians in risk stratification to reduce rates of postoperative complications following PHF ORIF. LEVEL OF EVIDENCE: III. Retrospective Cohort Comparison; Prognosis Study.

Hypoalbuminemia predicts early postoperative complications following noninfectious revision total shoulder arthroplasty.

PURPOSE: This study investigates the association between preoperative hypoalbuminemia and 30-day postoperative complications following noninfectious revision total shoulder arthroplasty (TSA). METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for all patients who underwent noninfectious revision TSA from 2015 to 2021. The study population was divided into two groups based on preoperative serum albumin: normal albumin (≥ 3.5 g/dL) and hypoalbuminemia (< 3.5 g/dL). Logistic regression analysis was conducted to investigate the relationship between preoperative hypoalbuminemia and postoperative complications. RESULTS: Compared to normal albumin, hypoalbuminemia was independently associated with a significantly greater likelihood of experiencing any complication (odds ratio [OR] 3.26, 95% confidence interval [CI] 2.04-5.19; P < .001), sepsis (OR 9.92, 95% CI 1.29-76.35; P = .028), blood transfusions (OR 2.89, 95% CI 1.20-6.93; P = .017), non-home discharge (OR 2.88, 95% CI 1.55-5.35; P < .001), readmission (OR 3.46, 95% CI 1.57-7.58; P = .002), and length of stay > 2 days (OR 3.00, 95% CI 1.85-4.86; P < .001). CONCLUSIONS: Preoperative hypoalbuminemia was associated with early postoperative complications following revision TSA. LEVEL OF EVIDENCE: Level III; Retrospective Cohort Comparison; Prognosis Study.

Role of insulin-dependent and non-insulin-dependent diabetes in aseptic revision total shoulder arthroplasty.

PURPOSE: This study investigates the association between insulin-dependent and non-insulin-dependent diabetes and 30-day postoperative complications following aseptic revision total shoulder arthroplasty (TSA). METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for all patients who underwent aseptic revision TSA from 2015 to 2021. The study population was divided into three groups based on diabetic status: nondiabetes, insulin-dependent diabetes, and non-insulin-dependent diabetes. Logistic regression analysis was conducted to investigate the relationship between diabetic status and postoperative complications. RESULTS: Compared to nondiabetes, insulin-dependent diabetes was independently associated with a significantly greater likelihood of experiencing any complication (OR 1.59, 95% CI 1.08-2.35; P = 0.020) and LOS > 2 days (OR 1.73, 95% CI 1.13-2.65; P = 0.012). Compared to nondiabetes, non-insulin-dependent diabetes was not independently associated with a significantly greater likelihood of experiencing complications. Preoperative insulin-dependent diabetic status was significantly associated with a greater rate of early postoperative complications following aseptic revision TSA, while preoperative non-insulin-dependent diabetic status was not. CONCLUSION: Preoperative insulin-dependent diabetic status was significantly associated with a greater rate of early postoperative complications following aseptic revision TSA. A better understanding of the role diabetes, both insulin-dependent and non-insulin-dependent, as a risk factor may help physicians better risk stratify and select surgical candidates for revision TSA.

Is delayed time to surgery associated with increased postoperative complications in patients with pathologic humerus fractures?

INTRODUCTION: Delayed time to surgery, in the case of orthopedic trauma, is well known to be associated with higher morbidity and mortality, an extended duration of hospitalization, and an associated rise in overall cost. Delayed time to surgery of at least 3 days following hospital admission is associated with elevated risk of complications following surgery for a standard, non-pathologic, humeral shaft fracture. To our knowledge, it is unknown whether the same association is present for pathologic humerus fractures. The primary objective of this study was to identify risk factors, including patient characteristics, comorbidities, and postoperative complications, that are associated with delayed time to surgery following pathologic humeral fracture. METHODS: All patients undergoing surgical management of pathologic humerus fractures across a 6-year period from 2015 to 2021 were queried using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Postoperative complications were reported within 30 days of procedure. Delayed time to surgery was defined by ≥ 2 days from hospital admission to surgery. We identified a total of 248 patients, and 39.9% (n = 99) of patients had delayed time to surgery. Multivariate logistic regression adjusted for all significantly associated variables was employed to identify predictors of delayed time to surgery for pathologic humerus fractures. RESULTS: The characteristics of patients significantly associated with delayed time to surgery were ASA classification ≥ 3 (p = 0.016), dependent functional status (p = 0.041), and congestive heart failure (p = 0.008). After adjusting for all significantly associated patient variables, the characteristics of patients independently associated with delayed time to surgery were non-home discharge (OR: 2.93, 95% CI 1.53-5.63; p = 0.001) and extended length of stay (OR: 2.00, 95% CI 1.06-3.77; p = 0.033). CONCLUSION: Delayed time to surgery of at least 2 days was independently associated with non-home discharge and extended postoperative length of stay. After controlling for baseline patient characteristics and comorbidities, delayed time to surgery was not independently associated with increased 30-day complications after surgical treatment of pathologic humeral fractures. This is in contrast to standard, non-pathologic humerus fractures in which delayed time to surgery is associated with an increased risk of postoperative complications. LEVEL OF EVIDENCE III: Retrospective Cohort Comparison; Prognosis Study.

Postoperative complications associated with congestive heart failure in aseptic revision total shoulder arthroplasty.

PURPOSE: The aim of this study is to explore potential complications and risk factors associated with revision TSA in patients with congestive heart failure (CHF). METHODS: This study examined all individuals who underwent revision total shoulder arthroplasty (TSA) from 2015 to 2022, sourced from the American College of Surgeons National Surgical Quality Improvement database. The analysis encompassed patient demographics, comorbidities, and 30-day postoperative complications. Logistic regression was employed to analyze the postoperative complications linked to patients with preoperative CHF. RESULTS: Compared to patients without CHF, patients with CHF were significantly associated with dependent functional status (P < .001), chronic obstructive pulmonary disease (P < .001), and hypertension (P = .002). Compared to patients without CHF, patients with CHF were independently associated with a significantly greater likelihood of experiencing any complication (OR 2.19, 95% CI 1.12-4.29; P = .022) and non-home discharge (OR 3.02, 95% CI 1.37-6.65; P = .006). CONCLUSION: Congestive heart failure was identified as an independent risk factor for experiencing any complication and non-home discharge in patients undergoing revision TSA. Awareness of the cardiovascular health status of a patient and its severity can influence the decision-making process when considering revision TSA. LEVEL OF EVIDENCE III: Retrospective Cohort Comparison Using Large Database; Prognosis Study.

Novel Positioning Feedback System as a Guidance in Bone Tumor Resection.

Need: Bone resection using customized 3D-printed guides can improve accuracy, but the technique is still associated with clinically significant errors.Technical solution: We developed an inexpensive optical feedback system (OFS) that compares intraoperative 2D camera images to the pre-operative plan, and accurately depicts the surgeon's guide placement prior to cutting, reducing the errors in resection.Proof of concept: We simulated wide resections of a bone sarcoma on 24 cadaver femurs using 3 cutting guide types. Guide placement was measured using the OFS and compared to CT-scans showing the actual guide position. We carried out a second, controlled study on 20 sawbones, comparing the accuracy of the final bone cuts with and without the surgeon actively using the OFS to adjust the guide position before cutting.Results: For cadavers, in 2 of 3 planes, the position of the jig recorded by the OFS closely matched its actual position, with an accuracy of .87° ± .65°(r = .94) and 1.2° ± 1.3°(r = .81) in the transverse and sagittal planes, respectively. In the second study, OFS increased accuracy of the final cut about the transverse and sagittal planes, respectively by 53.1% (P = .011)/54.7% (P = .04) and 33% (P = .051)/38% (P = .042) in terms of rotation and translation.Next steps: Developing the OFS as a mobile application to reduce the processing time and improve accessibility in the operating room.Conclusion: The OFS could accurately depict the guide placement on the bone and significantly improve the surgical accuracy of 3D printed jigs.

Abstinence following intermittent methylphenidate exposure dose-dependently modifies brain glucose metabolism in the rat brain.

Methylphenidate (MP) is a psychostimulant chronically prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). Additionally, MP users may take breaks from using the medication during "drug holidays," which may include short-term or long-term breaks from medication. The present study utilized fluorodeoxyglucose (FDG) positron emission tomography (PET) to analyze the effects of chronic oral MP use and abstinence on brain glucose metabolism (BGluM) in rats at two different doses: high dose (HD) and low dose (LD). The schedule of treatment was 3 weeks on-treatment and 1 week off-treatment for a period of 13 weeks, followed by an abstinence period of 4 total weeks. Results showed that chronic MP treatment using this schedule did not lead to significant changes in BGluM when comparing the control to HD MP groups. However, significant activation in BGluM was observed after periods of abstinence between control and HD MP rats in the following brain regions: the trigeminal nucleus, reticular nucleus, inferior olive, lemniscus, mesencephalic reticular formation, inferior colliculus, and several areas of the cerebellum. These brain regions and functional brain circuit play a role in facial sensory function, the auditory pathway, organizing connections between the thalamus and cortex, motor learning, auditory function, control over eye movement, auditory information integration, and both motor and cognitive functions. These results, when considered with previous studies, indicate that MP schedule of use may have differing effects on BGluM. BGluM following long-term MP use was dependent on MP dose and schedule of use in rats. This study was conducted in non-ADHD model rats with the aim to establish an understanding of the effects of MP itself, especially given the growing chronic off-label and prescribed use of MP. Further studies are needed for analysis of the drug's effects on an ADHD model.

ADAMTS9 and ADAMTS20 are differentially affected by loss of B3GLCT in mouse model of Peters plus syndrome.

Peters plus syndrome (MIM #261540 PTRPLS), characterized by defects in eye development, prominent forehead, hypertelorism, short stature and brachydactyly, is caused by mutations in the ß3-glucosyltransferase (B3GLCT) gene. Protein O-fucosyltransferase 2 (POFUT2) and B3GLCT work sequentially to add an O-linked glucose ß1-3fucose disaccharide to properly folded thrombospondin type 1 repeats (TSRs). Forty-nine proteins are predicted to be modified by POFUT2, and nearly half are members of the ADAMTS superfamily. Previous studies suggested that O-linked fucose is essential for folding and secretion of POFUT2-modified proteins and that B3GLCT-mediated extension to the disaccharide is essential for only a subset of targets. To test this hypothesis and gain insight into the origin of PTRPLS developmental defects, we developed and characterized two mouse B3glct knockout alleles. Using these models, we tested the role of B3GLCT in enabling function of ADAMTS9 and ADAMTS20, two highly conserved targets whose functions are well characterized in mouse development. The mouse B3glct mutants developed craniofacial and skeletal abnormalities comparable to PTRPLS. In addition, we observed highly penetrant hydrocephalus, white spotting and soft tissue syndactyly. We provide strong genetic and biochemical evidence that hydrocephalus and white spotting in B3glct mutants resulted from loss of ADAMTS20, eye abnormalities from partial reduction of ADAMTS9 and cleft palate from loss of ADAMTS20 and partially reduced ADAMTS9 function. Combined, these results provide compelling evidence that ADAMTS9 and ADAMTS20 were differentially sensitive to B3GLCT inactivation and suggest that the developmental defects in PTRPLS result from disruption of a subset of highly sensitive POFUT2/B3GLCT targets such as ADAMTS20.

Level of obesity is directly associated with complications following arthroscopic rotator cuff repair.

BACKGROUND: The purpose of this study was to investigate the association between increasing levels of obesity and postoperative complications within 30 days of arthroscopic rotator cuff repair (ARCR). METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program database for all patients who underwent ARCR from 2015 to 2017. Patients were stratified into 3 cohorts according to their body mass index (BMI). Patients with a BMI < 30 kg/m2 were placed in the non-obese cohort, patients with a BMI between 30 and 40 kg/m2 were placed in the obese cohort, and patients with a BMI > 40 kg/m2 were placed in the morbidly obese cohort. Postoperative complications within 30 days of the procedure were collected. Multivariate logistic regression was used to investigate the relationship between increasing levels of obesity and postoperative complications. RESULTS: There were 18,521 patients included in this study. Of these patients, 9548 (51.6%) were non-obese, 7438 (40.2%) were obese, and 1535 (8.3%) were morbidly obese. A comparison among non-obese, obese, and morbidly obese patients showed increasing rates of medical complications (0.5% vs. 1.0% vs. 1.4%), pulmonary complications (0.1% vs. 0.3% vs. 0.5%), renal complications (0.0% vs. 0.1% vs. 0.2%), readmission (0.9% vs. 1.2% vs. 1.6%), nonhome discharge (0.4% vs. 0.5% vs. 1.2%), and overall complications (0.8% vs. 1.3% vs. 1.8%). In comparison to non-obesity, both obesity and morbid obesity were identified by multivariate analysis as significant predictors of medical complications (odds ratio [ORs] of 1.72 and 2.16, respectively), pulmonary complications (ORs of 2.66 and 4.06, respectively), and overall complications (ORs of 1.52 and 1.77, respectively). CONCLUSION: This study used a large national database to identify increasing levels of obesity as a risk factor for medical complications, pulmonary complications, and overall complications within 30 days of ARCR.

In vivo evaluation of human patellar tendon microstructure and microcirculation with diffusion MRI.

BACKGROUND: Patellar tendon (PT) microstructure integrity and microcirculation status play a crucial role in the progression of tendinopathy and tendon repair. PURPOSE: To assess the feasibility and robustness of stimulated-echo based diffusion-weighted MRI with readout-segmented echo-planar imaging (ste-RS-EPI) for noninvasive assessment of microstructure and microcirculation of human PT. STUDY TYPE: Prospective. SUBJECTS: Fifteen healthy volunteers. FIELD STRENGTH/SEQUENCE: PT diffusion tensor imaging (DTI) and intravoxel incoherent motion (IVIM) were acquired with an ste-RS-EPI protocol on a 3T MRI scanner. ASSESSMENT: Subjects were positioned with their PT at the magic angle. DTI-derived parameters including axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), and fractional anisotropy (FA) were estimated with b-values of 0 and 800 s/mm2 and 12 diffusion directions. IVIM-derived parameters, f p , D* × f p , V b , and D* × V b were assessed in the central-third and the outer-two thirds of the PT with b-values of 0, 20, 30, 60, 80, 120, 200, 400, and 600 s/mm2 in three orthogonal directions. STATISTICAL TESTS: Paired t-tests were used to evaluate differences in IVIM parameters between the central-third and outer-two thirds regions of the patellar tendon. Paired t-tests and within-subject coefficient of variation were used to assess the intra- and intersession reproducibility of PT DTI and IVIM parameters. RESULTS: DTI parameters for healthy PT were 1.54 ± 0.09 × 10-3 mm2 /s, 1.01 ± 0.05 × 10-3 mm2 /s, 1.18 ± 0.06 × 10-3 mm2 /s, and 0.30 ± 0.04 for AD, RD, MD, and FA, respectively. Significantly higher (P < 0.05) IVIM parameters f p and D* × f p were observed in the outer-two thirds (6.1% ± 2.4% and 95.2 ± 49.6, respectively) compared with the central-third (3.8% ± 2.3% and 48.6 ± 35.2, respectively) of the PT. DATA CONCLUSION: Diffusion MRI of PT with an ste-RS-EPI protocol is clinically feasible. Both DTI- and IVIM-derived parameters of the PT demonstrated good test-retest reproducibility and interrater reliability. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:780-790.

Brief and extended abstinence from chronic oral methylphenidate treatment produces reversible behavioral and physiological effects.

Methylphenidate (MP) is a commonly prescribed psychostimulant to individuals with Attention Deficit Hyperactivity Disorder, and is often used illicitly among healthy individuals with intermittent breaks to coincide with breaks from school. This study examined how intermittent abstinence periods impact the physiological and behavioral effects of chronic oral MP self-administration in rats, and whether these effects persist following prolonged abstinence from the drug. Rats were treated orally with water, low-dose (LD), or high-dose (HD) MP, beginning at PND 28. This daily access continued for three consecutive weeks followed by a 1-week abstinence; after three repeats of this cycle, there was a 5-week abstinence period. Throughout the study, we examined body weight, food intake, locomotor activity, and anxiety- and depressive-like behaviors. During the treatment phase, HD MP decreased body weight, food intake, and depressive- and anxiety-like behaviors, while it increased locomotor activity. During intermittent abstinence, the effects of MP on locomotor activity were eliminated. During prolonged abstinence, most of the effects of HD MP were ameliorated to control levels, with the exception of weight loss and anxiolytic effects. These findings suggest that intermittent exposure to chronic MP causes physiological and behavioral effects that are mostly reversible following prolonged abstinence.

Severity of heterotopic ossification in patients following surgery for hip fracture: a retrospective observational study.

BACKGROUND: Heterotopic ossification (HO) is a relatively common complication following hip surgery treated with open reduction and internal fixation, total arthroplasty or hemiarthroplasty. Development of HO after hip surgery is an important clinical issue as it can affect functional status. We aimed to determine whether there was association between severity of heterotopic ossification about the hip and the interval between the time of hip fracture and surgery. MATERIALS AND METHODS: Our retrospective study included 151 patients (age range 33-95 years) treated for hip fractures by hemiarthroplasty. Medical records were reviewed for time interval to surgery, laterality, surgical approach, and patient age. Patients who had any post-operative complications were excluded. Radiographs were semiquantitatively assessed for the degree of heterotopic ossification based on Brooker Classification (5-point scale). Statistical analysis was performed utilizing Chi-square, Kruskal-Wallis, and Score tests, and also a proportional odds model (significance level set at 0.05). RESULTS: Thirty eight patients had no heterotopic ossification, 43 had class 1, 55 had class 2, and 15 had class 3 or greater heterotopic ossification. The majority of patients (59.6%) had surgery within 2 days of acute injury. Severe heterotopic ossification (HO 3+) was associated with the longer interval between the time of acute hip fracture and surgery (median 6 days) vs. median 2 days in all other groups (HO classes 0-2) (p = 0.0015). The odds ratio and 95% CI for one level higher HO class was 1.296 (1.152, 1.459), which meant that the odds of having HO class one level higher increased by about 29.6% for every one-day increase in the days to surgery. No significant association was found for other variables. CONCLUSION: Class 3 or greater HO was associated with longer time interval between time of acute hip fracture and surgery compared to all other groups (HO class 0-2).

Abbreviated quantitative UTE imaging in anterior cruciate ligament reconstruction.

BACKGROUND: Existing ultrashort echo time magnetic resonance imaging (UTE MRI) methods require prohibitively long acquisition times (~ 20-40 min) to quantitatively assess the clinically relevant fast decay T2* component in ligaments and tendons. The purpose of this study was to evaluate the feasibility and clinical translatability of a novel abbreviated quantitative UTE MRI paradigm for monitoring graft remodeling after anterior cruciate ligament (ACL) reconstruction. METHODS: Eight patients who had Graftlink™ hamstring autograft reconstruction were recruited for this prospective study. A 3D double-echo UTE sequence at 3.0 Tesla was performed at 3- and 6-months post-surgery. An abbreviated UTE MRI paradigm was established based on numerical simulations and in vivo validation from healthy knees. This proposed approach was used to assess the T2* for fast decay component ([Formula: see text]) and bound water signal fraction (fbw) of ACL graft in regions of interest drawn by a radiologist. RESULTS: Compared to the conventional bi-exponential model, the abbreviated UTE MRI paradigm achieved low relative estimation bias for [Formula: see text] and fbw over a range of clinically relevant values for ACL grafts. A decrease in [Formula: see text] of the intra-articular graft was observed in 7 of the 8 ACL reconstruction patients from 3- to 6-months (- 0.11 ± 0.16 ms, P = 0.10). Increases in [Formula: see text] and fbw from 3- to 6-months were observed in the tibial intra-bone graft ([Formula: see text]: 0.19 ± 0.18 ms, P < 0.05; Δfbw: 4% ± 4%, P < 0.05). Lower [Formula: see text] (- 0.09 ± 0.11 ms, P < 0.05) was observed at 3-months when comparing the intra-bone graft to the graft/bone interface in the femoral tunnel. The same comparisons at the 6-months also yielded relatively lower [Formula: see text] (- 0.09 ± 0.12 ms, P < 0.05). CONCLUSION: The proposed abbreviated 3D UTE MRI paradigm is capable of assessing the ACL graft remodeling process in a clinically translatable acquisition time. Longitudinal changes in [Formula: see text] and fbw of the ACL graft were observed.

A Biomechanical Comparison of Alternative Graft Preparations for All-Inside Anterior Cruciate Ligament Reconstruction.

PURPOSE: To biomechanically compare alternative graft constructs for all-inside anterior cruciate ligament (ACL) reconstruction in the event that the semitendinosus harvested is too narrow or too short to make a graft larger than 8 mm. METHODS: Bovine extensor tendons were used to make 6 different 9-mm-diameter grafts: traditional 4-strand, anastomosis 4-strand, 6-strand, 3-strand, button-fixation 4-strand, and loop-and-tack 4-strand grafts. The grafts were then subjected to cyclic biomechanical testing followed by failure loading. Force at 3 and 5 mm of displacement and ultimate force were recorded for all grafts. RESULTS: Compared with the traditional 4-strand graft, the only graft that showed significant biomechanical differences during the cyclic phase of testing was the button-fixation 4-strand graft, which was characterized by lower force at 3 mm of displacement (74 ± 34 N vs 122 ± 13 N, P = .004) and 5 mm of displacement (122 ± 35 N vs 172 ± 3 N, P = .006). During failure loading, ultimate force was significantly lower for both the 6-strand graft (491 ± 186 N, P = .041) and button-fixation 4-strand graft (326 ± 27 N, P < .001) than for the traditional 4-strand graft (778 ± 176 N). All other grafts were equivalent for the parameters tested. CONCLUSIONS: The anastomosis 4-strand, 3-strand, and loop-and-tack 4-strand grafts do not biomechanically differ in cyclic loading and ultimate force from traditional 4-strand grafts. This study supports the use of anastomosis 4-strand, 3-strand, or loop-and-tack 4-strand grafts in the event that a traditional all-inside 4-strand graft cannot be prepared from a harvested semitendinosus tendon in ACL reconstruction. CLINICAL RELEVANCE: This study tests and describes alternatives to the traditional 4-strand semitendinosus autograft for all-inside ACL reconstruction in the event that the harvested tendon is not adequate.

Collagenase Clostridium histolyticum for the Treatment of Distal Interphalangeal Joint Contractures in Dupuytren Disease.

PURPOSE: To explore the efficacy of injectable collagenase Clostridium histolyticum (CCH) in distal interphalangeal (DIP) joint contractures in Dupuytren disease. METHODS: A retrospective review was conducted for patients with DIP joint contractures treated with CCH. Baseline contracture and posttreatment residual contracture were recorded. The primary end point was achievement of 0° to 5° of residual contracture 30 days postmanipulation. Recurrence and adverse events are also reported. RESULTS: Twenty-one patients were treated with collagenase for DIP joint contractures and had a mean follow-up of 2.6 months. Seventeen of 21 patients reached the primary end point of less than 5° residual flexion contracture. Eleven of 21 patients experienced an adverse event, most commonly bruising and edema. No serious complications such as neurovascular injuries or tendon ruptures were recorded. Two patients had recurrence of disease. CONCLUSIONS: Injection with CCH is an option for the treatment of DIP joint contractures in Dupuytren disease. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Chronic oral methylphenidate treatment increases microglial activation in rats.

Methylphenidate (MP) is a widely prescribed psychostimulant used to treat attention deficit hyperactivity disorder. Previously, we established a drinking paradigm to deliver MP to rats at doses that result in pharmacokinetic profiles similar to treated patients. In the present study, adolescent male rats were assigned to one of three groups: control (water), low-dose MP (LD; 4/10 mg/kg), and high dose MP (HD; 30/60 mg/kg). Following 3 months of treatment, half of the rats in each group were euthanized, and the remaining rats received only water throughout a 1-month-long abstinence phase. In vitro autoradiography using [3H] PK 11195 was performed to measure microglial activation. HD MP rats showed increased [3H] PK 11195 binding compared to control rats in several cerebral cortical areas: primary somatosensory cortex including jaw (68.6%), upper lip (80.1%), barrel field (88.9%), and trunk (78%) regions, forelimb sensorimotor area (87.3%), secondary somatosensory cortex (72.5%), motor cortices 1 (73.2%) and 2 (69.3%), insular cortex (59.9%); as well as subcortical regions including the thalamus (62.9%), globus pallidus (79.4%) and substantia nigra (22.7%). Additionally, HD MP rats showed greater binding compared to LD MP rats in the hippocampus (60.6%), thalamus (59.6%), substantia nigra (38.5%), and motor 2 cortex (55.3%). Following abstinence, HD MP rats showed no significant differences compared to water controls; however, LD MP rats showed increased binding in pre-limbic cortex (78.1%) and ventromedial caudate putamen (113.8%). These findings indicate that chronic MP results in widespread microglial activation immediately after treatment and following the cessation of treatment in some brain regions.

Emerging Strategies on Adjuvant Therapies for Nerve Recovery.

Current strategies for promoting faster and more effective peripheral nerve healing have utilized a wide variety of techniques and approaches. Nerve grafts, conduits, and stem cell therapy all have their respective advantages. However, there are still some difficulties in attaining complete functional recovery with a single treatment modality. The utilization of adjuvant treatments, in combination with current standard-of-care methods, offers the potential to improve patient outcomes. This paper highlights the current landscape of adjuvant treatments for enhancing peripheral nerve repair and regeneration.

Chronic oral methylphenidate treatment reversibly increases striatal dopamine transporter and dopamine type 1 receptor binding in rats.

Previously, we created an 8-h limited-access dual bottle drinking paradigm to deliver methylphenidate (MP) to rats at two dosages that result in a pharmacokinetic profile similar to patients treated for attention deficit hyperactivity disorder. Chronic treatment resulted in altered behavior, with some effects persisting beyond treatment. In the current study, adolescent male Sprague-Dawley rats were split into three groups at four weeks of age: control (water), low-dose MP (LD), and high-dose MP (HD). Briefly, 4 mg/kg (low dose; LD) or 30 mg/kg (high dose; HD) MP was consumed during the first hour, and 10 mg/kg (LD) or 60 mg/kg (HD) MP during hours two through eight. Following three months of treatment, half of the rats in each group (n = 8-9/group) were euthanized, and remaining rats went through a 1-month abstinence period, then euthanized. In vitro receptor autoradiography was performed to quantify binding levels of dopamine transporter (DAT), dopamine type 1 (D1R)-like receptors, and dopamine type 2 (D2R)-like receptors using [3H] WIN35,428, [3H] SCH23390, and [3H] Spiperone, respectively. Immediately following treatment, HD MP-treated rats had increased DAT and D1R-like binding in several subregions of the basal ganglia, particularly more caudal portions of the caudate putamen, which correlated with some previously reported behavioral changes. There were no differences between treatment groups in any measure following abstinence. These findings suggest that chronic treatment with a clinically relevant high dose of MP results in reversible changes in dopamine neurochemistry, which may underlie some effects on behavior.