Nerve Versus Tendon Transfers in the Management of Isolated Upper Extremity Peripheral Nerve Injuries.

Upper extremity peripheral nerve injuries present functional deficits that are amenable to management by tendon or nerve transfers. The principles of tendon and nerve transfers are discussed, with technical descriptions of preferred tendon and nerve transfers for radial, median, and ulnar nerve injuries.

STING promotes homeostatic maintenance of tissues and confers longevity with aging.

Local immune processes within aging tissues are a significant driver of aging associated dysfunction, but tissue-autonomous pathways and cell types that modulate these responses remain poorly characterized. The cytosolic DNA sensing pathway, acting through cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING), is broadly expressed in tissues, and is poised to regulate local type I interferon (IFN-I)-dependent and independent inflammatory processes within tissues. Recent studies suggest that the cGAS/STING pathway may drive pathology in various in vitro and in vivo models of accelerated aging. To date, however, the role of the cGAS/STING pathway in physiological aging processes, in the absence of genetic drivers, has remained unexplored. This remains a relevant gap, as STING is ubiquitously expressed, implicated in multitudinous disorders, and loss of function polymorphisms of STING are highly prevalent in the human population (>50%). Here we reveal that, during physiological aging, STING-deficiency leads to a significant shortening of murine lifespan, increased pro-inflammatory serum cytokines and tissue infiltrates, as well as salient changes in histological composition and organization. We note that aging hearts, livers, and kidneys express distinct subsets of inflammatory, interferon-stimulated gene (ISG), and senescence genes, collectively comprising an immune fingerprint for each tissue. These distinctive patterns are largely imprinted by tissue-specific stromal and myeloid cells. Using cellular interaction network analyses, immunofluorescence, and histopathology data, we show that these immune fingerprints shape the tissue architecture and the landscape of cell-cell interactions in aging tissues. These age-associated immune fingerprints are grossly dysregulated with STING-deficiency, with key genes that define aging STING-sufficient tissues greatly diminished in the absence of STING. Changes in immune signatures are concomitant with a restructuring of the stromal and myeloid fractions, whereby cell:cell interactions are grossly altered and resulting in disorganization of tissue architecture in STING-deficient organs. This altered homeostasis in aging STING-deficient tissues is associated with a cross-tissue loss of homeostatic tissue-resident macrophage (TRM) populations in these tissues. Ex vivo analyses reveal that basal STING-signaling limits the susceptibility of TRMs to death-inducing stimuli and determines their in situ localization in tissue niches, thereby promoting tissue homeostasis. Collectively, these data upend the paradigm that cGAS/STING signaling is primarily pathological in aging and instead indicate that basal STING signaling sustains tissue function and supports organismal longevity. Critically, our study urges caution in the indiscriminate targeting of these pathways, which may result in unpredictable and pathological consequences for health during aging.

Approach to Tendinopathies of the Upper Limb: What Works.

Tendinopathies are some of the most common diagnoses treated by hand surgeons. Diagnoses such as trigger digit, de Quervain tenosynovitis, extensor carpi ulnaris tendinitis, and epicondylitis often resolve with nonoperative treatment and/or a single ambulatory procedure. When symptoms persist or worsen after surgery, patients are disappointed and treatment can be challenging. This article reviews practical points in evaluation of such cases, and surgical options that work in revision scenarios.

Chronic endotoxin exposure produces airflow obstruction and lung dendritic cell expansion.

Little is known about the mechanisms of persistent airflow obstruction that result from chronic occupational endotoxin exposure. We sought to analyze the inflammatory response underlying persistent airflow obstruction as a result of chronic occupational endotoxin exposure. We developed a murine model of daily inhaled endotoxin for periods of 5 days to 8 weeks. We analyzed physiologic lung dysfunction, lung histology, bronchoalveolar lavage fluid and total lung homogenate inflammatory cell and cytokine profiles, and pulmonary gene expression profiles. We observed an increase in airway hyperresponsiveness as a result of chronic endotoxin exposure. After 8 weeks, the mice exhibited an increase in bronchoalveolar lavage and lung neutrophils that correlated with an increase in proinflammatory cytokines. Detailed analyses of inflammatory cell subsets revealed an expansion of dendritic cells (DCs), and in particular, proinflammatory DCs, with a reduced percentage of macrophages. Gene expression profiling revealed the up-regulation of a panel of genes that was consistent with DC recruitment, and lung histology revealed an accumulation of DCs in inflammatory aggregates around the airways in 8-week-exposed animals. Repeated, low-dose LPS inhalation, which mirrors occupational exposure, resulted in airway hyperresponsiveness, associated with a failure to resolve the proinflammatory response, an inverted macrophage to DC ratio, and a significant rise in the inflammatory DC population. These findings point to a novel underlying mechanism of airflow obstruction as a result of occupational LPS exposure, and suggest molecular and cellular targets for therapeutic development.

The Index Finger Metacarpal Tubercle.

Purpose: The region of the index finger metacarpophalangeal joint is a common source of hand pain with variable, well-known etiologies. We have identified the tubercle at the dorsoradial neck of the index finger metacarpal as a distinct and specific site of pain in a subset of patients who presented with a chief report of index finger pain. Although experienced hand surgeons may recognize this clinical entity, we found no previous description within the literature. Methods: After institutional review board approval, we performed a retrospective review of all patients presenting to a single surgeon practice with severe pain at the dorsoradial tubercle of the index finger metacarpal unattributable to known etiologies. Patients underwent initial management of steroid injection followed by surgical excision if conservative measures failed. Results: Steroid injection was administered as initial management in 9 of 10 afflicted hands. Five of these hands experienced complete resolution of pain at 4 weeks after injection whereas 4 developed recurrence at an average of 3 months after injection. Among patients with recurrence, one patient opted for a second injection that led to pain resolution 4 weeks later, whereas the remaining 3 hands had surgical excision. All patients who underwent surgical excision reported minimal discomfort and marked improvement in pain after surgery. Conclusions: We identified the tubercle at the dorsoradial neck of the index finger metacarpal as a distinct and specific site of pain in a subset of patients. We postulate that the pathophysiology of pain at the prominent index finger metacarpal tubercle may be related to a subacute radial collateral ligament injury. Steroid injection to the tubercle is a reasonable initial treatment option and satisfactory results may also be obtained with surgical excision. Type of study/level of evidence: Therapeutic IV.

Safety in Hand Surgery: Eliminating Wrong-Site Surgery.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand the definition of wrong-site surgery and what it may encompass. 2. State the causes of wrong-site hand surgery. 3. Give examples of initiatives used to prevent wrong-site surgery. 4. Describe a process to minimize the risk of performing wrong-site surgery. SUMMARY: Wrong-site surgery remains a problem in our ever-evolving culture of surgical safety, and hand surgeons are at particularly high risk. Broadly speaking, wrong-site surgery is a procedure performed at an incorrect anatomical site. In hand surgery, this includes errors in laterality, wrong digit(s), wrong procedure(s), or even a failure to complete all indicated procedures. This article examines the scope of this safety issue, the current challenges to preventing wrong-site surgery, and the authors' proposed solutions to eliminating wrong-site surgery and establishing a culture of safety in hand surgery.

Myeloid neoplasm demonstrating a STAT5B-RARA rearrangement and genetic alterations associated with all-trans retinoic acid resistance identified by a custom next-generation sequencing assay.

We describe the case of a patient presenting with several weeks of symptoms related to pancytopenia associated with a maturation arrest at the late promyelocyte/early myelocyte stage of granulocyte differentiation. A diagnosis of acute promyelocytic leukemia was considered, but the morphologic features were atypical for this entity and conventional tests for the presence of a PML-RARA fusion gene were negative. Additional analysis using a custom next-generation sequencing assay revealed a rearrangement producing a STAT5B-RARA fusion gene, which was confirmed by reverse transcription polymerase chain reaction (RT-PCR) and supplementary cytogenetic studies, allowing the diagnosis of a morphologically atypical form of acute promyelocytic leukemia to be made. Analysis of the sequencing data permitted characterization of both chromosomal breakpoints and revealed two additional alterations, a small deletion in RARA exon 9 and a RARA R276W substitution, that have been linked to resistance to all-trans retinoic acid. This case highlights how next-generation sequencing can augment currently standard testing to establish diagnoses in difficult cases, and in doing so help guide selection of therapy.

CEBPG Exhibits Allele-Specific Expression in Human Bronchial Epithelial Cells.

Inter-individual variation in CCAAT/enhancer binding protein gamma (CEBPG) transcript expression in normal human bronchial epithelial cells (NBEC) is associated with predisposition to lung cancer. We hypothesize that this inter-individual variation is in part explained by cis-acting genetic variation in CEBPG. To test this hypothesis we measured transcript expression derived from each parental copy of CEBPG (ie, allele-specific expression; ASE). There was a significant 2.9-fold higher cell cycle-specific variation in ASE of CEBPG rs2772 A compared to C allele (P < 0.001). In 20% of NBEC samples, CEBPG rs2772 A allele was expressed on average 2.10 fold greater than rs2772 C allele. These data support the hypothesis that genetic variation in linkage disequilibrium with rs2772 influences regulation of CEBPG transcript expression through a trans-effect downstream of RNA polymerase II transcription and confirm that cis-acting genetic variation contributes to inter-individual variation in CEBPG transcript expression in NBEC, which is associated with variation in lung cancer risk.

TORC1 suppression predicts responsiveness to RAF and MEK inhibition in BRAF-mutant melanoma.

RAF and MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase) inhibitors are effective in treating patients with BRAF-mutant melanoma. However, most responses are partial and short-lived, and many patients fail to respond at all. We found that suppression of TORC1 activity in response to RAF or MEK inhibitors, as measured by decreased phosphorylation of ribosomal protein S6 (P-S6), effectively predicted induction of cell death by the inhibitor in BRAF-mutant melanoma cell lines. In resistant melanomas, TORC1 activity was maintained after treatment with RAF or MEK inhibitors, in some cases despite robust suppression of mitogen-activated protein kinase (MAPK) signaling. In in vivo mouse models, suppression of TORC1 after MAPK inhibition was necessary for induction of apoptosis and tumor response. Finally, in paired biopsies obtained from patients with BRAF-mutant melanoma before treatment and after initiation of RAF inhibitor therapy, P-S6 suppression predicted significantly improved progression-free survival. Such a change in P-S6 could be readily monitored in real time by serial fine-needle aspiration biopsies, making quantitation of P-S6 a valuable biomarker to guide treatment in BRAF-mutant melanoma.

Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models.

KRAS is the most commonly mutated oncogene, yet no effective targeted therapies exist for KRAS mutant cancers. We developed a pooled shRNA-drug screen strategy to identify genes that, when inhibited, cooperate with MEK inhibitors to effectively treat KRAS mutant cancer cells. The anti-apoptotic BH3 family gene BCL-XL emerged as a top hit through this approach. ABT-263 (navitoclax), a chemical inhibitor that blocks the ability of BCL-XL to bind and inhibit pro-apoptotic proteins, in combination with a MEK inhibitor led to dramatic apoptosis in many KRAS mutant cell lines from different tissue types. This combination caused marked in vivo tumor regressions in KRAS mutant xenografts and in a genetically engineered KRAS-driven lung cancer mouse model, supporting combined BCL-XL/MEK inhibition as a potential therapeutic approach for KRAS mutant cancers.

EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib.

UNLABELLED: BRAF mutations occur in 10-15% of colorectal cancers (CRCs) and confer adverse outcome. While RAF inhibitors such as vemurafenib (PLX4032) have proven effective in BRAF mutant melanoma, they are surprisingly ineffective in BRAF mutant CRCs, and the reason for this disparity remains unclear. Compared to BRAF mutant melanoma cells, BRAF mutant CRC cells were less sensitive to vemurafenib, and P-ERK suppression was not sustained in response to treatment. Although transient inhibition of phospho-ERK by vemurafenib was observed in CRC, rapid ERK re-activation occurred through EGFR-mediated activation of RAS and CRAF. BRAF mutant CRCs expressed higher levels of phospho-EGFR than BRAF mutant melanomas, suggesting that CRCs are specifically poised for EGFR-mediated resistance. Combined RAF and EGFR inhibition blocked reactivation of MAPK signaling in BRAF mutant CRC cells and markedly improved efficacy in vitro and in vivo. These findings support evaluation of combined RAF and EGFR inhibition in BRAF mutant CRC patients. SIGNIFICANCE: BRAF valine 600 (V600) mutations occur in 10% to 15% of colorectal cancers, yet these tumors show a surprisingly low clinical response rate (~5%) to selective RAF inhibitors such as vemurafenib, which have produced dramatic response rates (60%­80%) in melanomas harboring the identical BRAF V600 mutation. We found that EGFR-mediated MAPK pathway reactivation leads to resistance to vemurafenib in BRAF-mutant colorectal cancers and that combined RAF and EGFR inhibition can lead to sustained MAPK pathway suppression and improved efficacy in vitro and in tumor xenografts.

Millimetre wave spectroscopy of PANHs: phenanthridine.

The pure rotational spectrum of phenanthridine (C(13)H(9)N), a small polycyclic aromatic nitrogen heterocycle (PANH), has been measured from 48 to 85 GHz employing Stark modulated millimetre wave absorption spectroscopy of a supersonic rotationally cold molecular beam. Initial survey search scans were guided by rotational constants obtained through quantum chemical calculations performed at the B3LYP/cc-pVTZ level of theory. Close agreement--to well within 1%--is found between the calculated equilibrium and experimentally derived ground state rotational constants. From the moments of inertia a substantial negative inertial defect of Delta = -0.4688(44) amu Angstroms(2) is obtained which can be explained by the presence of several energetically low-lying out-of-plane vibrational modes. Corresponding density functional theory calculations of harmonic fundamental frequencies indeed yield four such low frequency modes with values as low as 96 cm(-1). The data presented here will also be useful for deep radio astronomical searches for PANHs employing large radio telescopes.