Distal Interphalangeal Joint Arthroplasty: A Narrative Review.

Background: Symptomatic distal interphalangeal (DIP) joint arthritis is frequently treated by arthrodesis, though DIP arthroplasty has been reported as a treatment option since 1977. This study reviews the current evidence on DIP joint arthroplasty for the treatment of arthritis refractory to non-operative management. Methods: A systematic search of PubMed, MEDLINE and Embase databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Risk of bias was assessed using the ROBINS-I tool. Results: The search yielded 55 records, of which six studies were included in the narrative review. All the included studies were of level IV evidence (case series or cohort studies). DIP arthroplasty was effective in relieving pain and reducing subsequent dysfunction. The average total arc of motion was 30°-40° but with an extension lag of 10°-15°. The overall complication rate was 15% with a re-operation rate of 8%. Joint instability (incidence of 2.5%) and infection (incidence of 2.1%) were the most common complications, while implant fracture was seen in 1% of cases. Joints that failed after DIP arthroplasty were salvaged by DIP arthrodesis. Conclusions: DIP arthroplasty is an effective treatment for painful arthritis but with a complication rate of 15%. Its main advantage over arthrodesis is the preservation of DIP motion. However, due to the limited high-quality evidence available, its use should be limited to circumstances where there is a desire or vocational need to maintain motion at the DIP joint. Level of Evidence: Level V (Therapeutic).

Mechanical Memory Impairs Adipose-Derived Stem Cell (ASC) Adipogenic Capacity After Long-Term In Vitro Expansion.

INTRODUCTION: Adipose derived stem cells (ASCs) hold great promise for clinical applications such as soft tissue regeneration and for in vitro tissue models and are notably easy to derive in large numbers. Specifically, ASCs provide an advantage for in vitro models of adipose tissue, where they can be employed as tissue specific cells and for patient specific models. However, ASC in vitro expansion may unintentionally reduce adipogenic capacity due to the stiffness of tissue culture plastic (TCPS). METHODS: Here, we expanded freshly isolated ASCs on soft and stiff substrates for 4 passages before adipogenic differentiation. At the last passage we swapped the substrate from stiff to soft, or soft to stiff to determine if short term exposure to a different substrate altered adipogenic capacity. RESULTS: Expansion on stiff substrates reduced adipogenic capacity by 50% which was not rescued by swapping to a soft substrate for the last passage. Stiff substrates had greater nuclear area and gene expression of nesprin-2, a protein that mediates the tension of the nuclear envelope by tethering it to the actin cytoskeleton. Upon swapping to a soft substrate, the nuclear area was reduced but nesprin-2 levels did not fully recover, which differentially regulated cell commitment transcriptional factors. CONCLUSION: Therefore, in vitro expansion on stiff substrates must be carefully considered when the end-goal of the expansion is for adipose tissue or soft tissue applications.

Ulnar-sided wrist pain: a prospective analysis of diagnostic clinical tests.

BACKGROUND: Identifying the cause of pain on the ulnar side of the wrist can be challenging. The outcome and recovery following surgery can be unpredictable. The aim of this study was to document and analyse the clinical tests used to evaluate the cause of ulnar-sided wrist pain and determine their diagnostic relevance. METHODS: This is a prospective evaluation of 110 patients who presented with pain on the ulnar side of the wrist. The clinical evaluation and results from radiological investigations were documented and analysed. RESULTS: There were 17 different diagnoses. Eighty-five percent of the diagnoses were triangular fibrocartilage complex (TFCC) injuries, ulnocarpal abutment syndrome (UCAS), pisotriquetral arthritis (PTA), triquetral fracture or non-union, distal radioulnar joint arthritis (DRUJ OA) and extensor carpi ulnaris (ECU) pathology. The ulnocarpal stress test and ulnar foveal sign were positive in several diagnoses. The ulnar foveal sign had a sensitivity and specificity of 89% and 48% for TFCC injuries, and 85% and 37% for UCAS, respectively. The sensitivity and specificity of pisotriquetral shear test for PTA was 100% and 92%, respectively. Patients with PTA or ECU pathology localised their pain better on the patient's pain localisation chart. CONCLUSION: Diagnosis of TFCC injuries, UCAS, DRUJ OA and ECU injuries are challenging as the clinical symptoms and signs for the four diagnoses were similar and required either magnetic resonance imaging or computed tomography for diagnostic confirmation after clinical examination. The ulnocarpal stress test and the ulnar foveal sign were not sufficiently specific.

Differential correlation of serum BDNF and microRNA content in rats with rapid or late onset of heavy alcohol use.

Heavy alcohol use reduces the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of rodents through the upregulation of microRNAs (miRs) targeting BDNF mRNA. In humans, an inverse correlation exists between circulating blood levels of BDNF and the severity of psychiatric disorders including alcohol abuse. Here, we set out to determine whether a history of heavy alcohol use produces comparable alterations in the blood of rats. We used an intermittent access to 20% alcohol using the two-bottle choice paradigm (IA20%2BC) and measured circulating levels of BDNF protein and miRs targeting BDNF in the serum of Long-Evans rats before and after 8 weeks of excessive alcohol intake. We observed that the drinking profile of heavy alcohol users is not unified, whereas 70% of the rats gradually escalate their alcohol intake (late onset), and 30% of alcohol users exhibit a very rapid onset of drinking (rapid onset). We found that serum BDNF levels are negatively correlated with alcohol intake in both rapid onset and late onset rats. In contrast, increased expression of the miRs targeting BDNF, miR30a-5p, miR-195-5p, miR191-5p and miR206-3p, was detected only in the rapid onset rats. Finally, we report that the alcohol-dependent molecular changes are not due to alterations in platelet number. Together, these data suggest that rats exhibit both late and rapid onset of alcohol intake. We further show that heavy alcohol use produces comparable changes in BDNF protein levels in both groups. However, circulating microRNAs are responsive to alcohol only in the rapid onset rats.

Three-and-a-half to 18 year outcome data for costal osteochondral grafts for salvage of the proximal pole of the scaphoid.

Twelve patients who had undergone costal osteochondral graft reconstruction of the proximal pole of scaphoid were evaluated with clinical examination, patient-reported outcome scores and radiographs with an average follow-up of 10 years (range 3.5-18). The range of wrist motion was not significantly changed compared with the preoperative range of motion and functional outcomes scores were acceptable. The patients reported low pain scores despite the universal presence of radiographic changes of reduced carpal height and arthritis of the midcarpal and radiocarpal joints. Costal osteochondral graft reconstruction of the proximal pole of scaphoid offers good long-term pain relief and function.Level of evidence: IV.

Eosinophilic Fasciitis - Beware of the Rare Form of Hand Contracture.

Eosinophilic fasciitis (EF) is a rare form of fibrosing disorder associated with peripheral eosinophilia with scleroderma-like skin induration and fasciitis in the extremities resulting in painful swelling, erythema and progressive contracture. We present a case report of EF and a literature review to raise awareness of this unusual condition and also highlight key features in its management.

Scaffold stiffness influences breast cancer cell invasion via EGFR-linked Mena upregulation and matrix remodeling.

Clinically, increased breast tumor stiffness is associated with metastasis and poorer outcomes. Yet, in vitro studies of tumor cells in 3D scaffolds have found decreased invasion in stiffer environments. To resolve this apparent contradiction, MDA-MB-231 breast tumor spheroids were embedded in 'low' (2 kPa) and 'high' (12 kPa) stiffness 3D hydrogels comprised of methacrylated gelatin/collagen I, a material that allows for physiologically-relevant changes in stiffness while matrix density is held constant. Cells in high stiffness materials exhibited delayed invasion, but more abundant actin-enriched protrusions, compared to those in low stiffness. We find that cells in high stiffness had increased expression of Mena, an invadopodia protein associated with metastasis in breast cancer, as a result of EGFR and PLCγ1 activation. As invadopodia promote invasion through matrix remodeling, we examined matrix organization and determined that spheroids in high stiffness displayed a large fibronectin halo. Interestingly, this halo did not result from increased fibronectin production, but rather from Mena/α5 integrin dependent organization. In high stiffness environments, FN1 knockout inhibited invasion while addition of exogenous cellular fibronectin lessened the invasion delay. Analysis of fibronectin isoforms demonstrated that EDA-fibronectin promoted invasion and that clinical invasive breast cancer specimens displayed elevated EDA-fibronectin. Combined, our data support a mechanism by which breast cancer cells respond to stiffness and render the environment conducive to invasion. More broadly, these findings provide important insight on the roles of matrix stiffness, composition, and organization in promoting tumor invasion.

mTORC1 in the orbitofrontal cortex promotes habitual alcohol seeking.

The mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in dendritic translation and in learning and memory. We previously showed that heavy alcohol use activates mTORC1 in the orbitofrontal cortex (OFC) of rodents (Laguesse et al., 2017a). Here, we set out to determine the consequences of alcohol-dependent mTORC1 activation in the OFC. We found that inhibition of mTORC1 activity in the OFC attenuates alcohol seeking and restores sensitivity to outcome devaluation in rats that habitually seek alcohol. In contrast, habitual responding for sucrose was unaltered by mTORC1 inhibition, suggesting that mTORC1's role in habitual behavior is specific to alcohol. We further show that inhibition of GluN2B in the OFC attenuates alcohol-dependent mTORC1 activation, alcohol seeking and habitual responding for alcohol. Together, these data suggest that the GluN2B/mTORC1 axis in the OFC drives alcohol seeking and habit.

Preliminary Evidence that Melatonin Is not a Biomarker in Children and Adolescents With Episodic Migraine.

BACKGROUND: To date, there have not been reliable biomarkers to identify impending migraine episodes. A prior study in adults with migraine demonstrated a reduction in the urinary metabolic substrate of melatonin (urinary 6-sulfatoxymelatonin; aMT6s) during a migraine. The aim of this study was to examine whether evening urinary melatonin metabolite levels could predict migraine the next day in children and adolescents with migraine. METHODS: Twenty-one children and adolescents with migraine (aged 5-17 years) were recruited to this observational study conducted at UC San Francisco to provide urine samples for 10 days and maintain a prospective headache diary during the same period. Nightly melatonin metabolite 6-sulfatoxymelatonin in urine was assayed and results from nights preceding migraine were compared to nights preceding a non-headache day. RESULTS: Mean (±SD) aMT6s levels the night prior to a migraine attack were 56.2 ± 39.0 vs 55.4 ± 46.6 ng/mL (P = .915), and mean melatonin metabolite levels the night following migraine were 55.5 ± 46.9 vs 57.0 ± 37.7 ng/mL (P = .841). However, in post hoc exploratory analyses, aMT6s levels were lower the night before a migraine in those who experienced aura or premonitory symptoms. CONCLUSION: While urinary melatonin metabolites do not predict migraine attacks in children and adolescents overall, they may be predictive in those who experience premonitory phase symptoms as part of their migraine attacks.

Angioinvasive fungal infections impacting the skin: Diagnosis, management, and complications.

As discussed in the first article in this continuing medical education series, angioinvasive fungal infections pose a significant risk to immunocompromised and immunocompetent patients alike, with a potential for severe morbidity and high mortality. The first article in this series focused on the epidemiology and clinical presentation of these infections; this article discusses the diagnosis, management, and potential complications of these infections. The mainstay diagnostic tests (positive tissue culture with histologic confirmation) are often supplemented with serum biomarker assays and molecular testing (eg, quantitative polymerase chain reaction analysis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry) to ensure proper speciation. When an angioinvasive fungal infection is suspected or diagnosed, further workup for visceral involvement also is essential and may partially depend on the organism. Different fungal organisms have varied susceptibilities to antifungal agents, and knowledge on optimal treatment regimens is important to avoid the potential complications associated with undertreated or untreated fungal infections.

Angioinvasive fungal infections impacting the skin: Background, epidemiology, and clinical presentation.

Angioinvasive fungal infections cause significant morbidity and mortality because of their propensity to invade blood vessel walls, resulting in catastrophic tissue ischemia, infarct, and necrosis. While occasionally seen in immunocompetent hosts, opportunistic fungi are emerging in immunosuppressed hosts, including patients with hematologic malignancy, AIDS, organ transplant, and poorly controlled diabetes mellitus. The widespread use of antifungal prophylaxis has led to an "arms race" of emerging fungal resistance patterns. As the at-risk population expands and new antifungal resistance patterns develop, it is critical for dermatologists to understand and recognize angioinvasive fungal pathogens, because they are often the first to encounter the cutaneous manifestations of these diseases. Rapid clinical recognition, histopathologic, and culture confirmation can help render a timely, accurate diagnosis to ensure immediate medical and surgical intervention. Superficial dermatophyte infections and deep fungal infections, such as blastomycosis and histoplasmosis, have been well characterized within the dermatologic literature, and therefore this article will focus on the severe infections acquired by angioinvasive fungal species, including an update on new and emerging pathogens. In the first article in this continuing medical education series, we review the epidemiology and cutaneous manifestations. The second article in the series focuses on diagnosis, treatment, and complications of these infections.

Mammalian target of rapamycin complex 1 and its downstream effector collapsin response mediator protein-2 drive reinstatement of alcohol reward seeking.

Alcohol use disorder is a chronic relapsing disease. Maintaining abstinence represents a major challenge for alcohol-dependent patients. Yet the molecular underpinnings of alcohol relapse remain poorly understood. In the present study, we investigated the potential role of the mammalian target of rapamycin complex 1 (mTORC1) in relapse to alcohol-seeking behavior by using the reinstatement of a previously extinguished alcohol conditioned place preference (CPP) response as a surrogate relapse paradigm. We found that mTORC1 is activated in the nucleus accumbens shell following alcohol priming-induced reinstatement of alcohol place preference. We further report that the selective mTORC1 inhibitor, rapamycin, abolishes reinstatement of alcohol place preference. Activation of mTORC1 initiates the translation of synaptic proteins, and we observed that reinstatement of alcohol CPP is associated with increased protein levels of one of mTORC1's downstream targets, collapsin response mediator protein-2 (CRMP2), in the nucleus accumbens. Importantly, the level of mTORC1 activation and CRMP2 expression positively correlate with the CPP score during reinstatement. Finally, we found that systemic administration of the CRMP2 inhibitor, lacosamide, attenuates alcohol priming-induced reinstatement of CPP. Together, our results reveal that mTORC1 and its downstream target, CRMP2, contribute to mechanisms underlying reinstatement of alcohol reward seeking. Our results could have important implications for the treatment of relapse to alcohol use and position the Food and Drug Administration approved drugs, rapamycin and lacosamide, for the treatment of alcohol use disorder.

The Fyn kinase inhibitor, AZD0530, suppresses mouse alcohol self-administration and seeking.

Fyn is a member of the Src family of protein tyrosine kinases (PTKs) that plays an important role not only in normal synaptic functions but also in brain pathologies including alcohol use disorder. We previously reported that repeated cycles of binge drinking and withdrawal activate Fyn in the dorsomedial striatum (DMS) of rodents, and that Fyn signaling in the DMS contributes to rat alcohol intake and relapse. Here, we used AZD0530, a CNS penetrable inhibitor of Src PTKs developed for the treatment of Alzheimer disease and cancer and tested its efficacy to suppress alcohol-dependent molecular and behavioral effects. We show that systemic administration of AZD0530 prevents alcohol-induced Fyn activation and GluN2B phosphorylation in the DMS of mice. We further report that a single dose of AZD0530 reduces alcohol operant self-administration and promotes extinction of alcohol self-administration without altering basal and dopamine D1 receptor-dependent locomotion. Together, our findings suggest that AZD0530, through its inhibitory actions on Fyn kinase, dampens alcohol seeking and drinking.

Clinical Examination of the Extensor Pollicis Brevis: Anatomical Study and Description of a Novel Clinical Sign.

BACKGROUND: The Extensor Pollicis Brevis (EPB) is an extrinsic thumb muscle whose main function is extension of the first metacarpophalangeal joint (MCPJ). It is subject to significant anatomical variation and may be absent, vestigial or have an anomalous distal attachment. Clinical examination of EPB is notoriously difficult and no reliable test has yet been described. We propose a novel test for the accurate examination of EPB. We sought to clarify the anatomical variations of EPB and to validate our clinical test using human cadaveric anatomical tests. METHODS: A structured literature review of all human cadaveric anatomical studies describing the attachments of EPB was performed using MEDLINE and Embase with the key words "Extensor Pollicis Brevis". A cadaveric anatomical study was performed using 18 unembalmed upper limbs. Positive and negative tests were simulated by manipulating the tendons of EPB, Extensor Pollicis Longus (EPL) and Flexor Pollicis Longus (FPL). Changes in tendon tension and joint position were measured and recorded. The EPB anatomy was then determined by dissection. RESULTS: Anatomical variations were present in the majority of wrists, with only 35% of EPB tendons having a distal attachment to the proximal phalanx alone. EPB was absent in 5% of specimens. There was a significant difference between the change in MCPJ position between a positive (36 degrees; 95% CI 25 to 47 degrees) and negative (19 degrees; 95% CI 14 to 25 degrees) clinical test (p = 0.002). CONCLUSIONS: The functional importance of EPB depends on its congenital architecture in addition to the functional demands of the patient. We report a novel clinical test which is effective in demonstrating the integrity of the EPB. A positive test result is observed when a change in MCPJ position that occurs while the interphalangeal joint is brought into flexion from full thumb extension is 25 degrees or more.