Extracellular-Vesicle Catch-and-Release Isolation System Using a Net-Charge Invertible Curvature-Sensing Peptide.

Extracellular vesicles (EVs) carry various informative components, including signaling proteins, transcriptional regulators, lipids, and nucleic acids. These components are utilized for cell-cell communication between donor and recipient cells. EVs have shown great promise as pharmaceutical-targeting vesicles and have attracted the attention of researchers in the fields of biological and medical science because of their importance as diagnostic and prognostic markers. However, the isolation and purification of EVs from cell-cultured media remain challenging. Ultracentrifugation is the most widely used method, but it requires specialized and expensive equipment. In the present study, we proposed a novel methodology to isolate EVs using a simple and convenient method, i.e., an EV catch-and-release isolation system (EV-CaRiS) using a net-charge invertible curvature-sensing peptide (NIC). Curvature-sensing peptides recognize vesicles by binding to lipid-packing defects on highly curved membranes regardless of the expression levels of biomarkers. NIC was newly designed to reversibly capture and release EVs in a pH-dependent manner. NIC allowed us to achieve reproducible EV isolation from three human cell lines on resin using a batch method and single-particle imaging of EVs containing the ubiquitous exosome markers CD63 and CD81 by total internal reflection fluorescence microscopy (TIRFM). EV-CaRiS was demonstrated as a simple and convenient methodology for EV isolation, and NIC is promising for applications in the single-particle analysis of EVs.

Thoracic Outlet Syndrome Caused by a Primary Tumour in the Brachial Plexus.

Thoracic outlet syndrome (TOS) caused by a primary brachial plexus tumour is very rare. A male politician in his 40s presented with numbness, left limb pain and positive Wright and Roos test results. Magnetic resonance imaging (MRI) revealed a tumour located just below the clavicle, compressing the subclavian artery during left arm elevation. Despite concerns regarding postoperative nerve deficits, surgery was performed because of worsening symptoms during the election campaigns. The pathology report revealed a schwannoma. Few reports have described TOS caused by primary tumours of the brachial plexus. While the decision to perform surgery for primary tumours of the brachial plexus requires careful consideration, surgery may be indicated in cases where the tumour location causes such symptoms. Level of Evidence: Level V (Therapeutic).

Association Between Torque Teno Virus and Systemic Immunodeficiency in Patients With Uveitis With a Suspected Infectious Etiology.

PURPOSE: To determine the correlation between the presence of torque teno virus (TTV) in the aqueous humor of patients with uveitis and clinical information, including immunodeficiency history. DESIGN: Multicenter, retrospective, cross-sectional study. METHODS: Fifty-eight patients with uveitis with a suspected infectious etiology and 24 controls with cataract or age-related macular degeneration were included. We used quantitative polymerase chain reaction to test all subjects for TTV and multiplex polymerase chain reaction to test uveitis subjects for common ocular pathogens. When possible, both serum and aqueous humor samples were tested. Ocular TTV positivity was compared with age, sex, and a history of systemic immunodeficiency with logistic analysis. RESULTS: Ocular TTV positivity was found in 23%, 11%, and 0% of patients with herpetic uveitis, nonherpetic uveitis, and controls, respectively. Among patients with herpes infection, positivity for ocular TTV was found in 43%, 8%, 14%, and 50% of patients with cytomegalovirus retinitis, iridocyclitis, acute retinal necrosis, and Epstein-Barr virus-positive uveitis, respectively. Patients with cytomegalovirus retinitis showed a significantly higher rate of ocular TTV infection than controls (P = .008). Serum analysis revealed TTV positivity in 90% of patients with uveitis and in 100% of controls. Age- and gender-adjusted logistic analysis revealed a correlation between ocular TTV positivity and systemic immunodeficiency (P = .01), but no correlations between ocular TTV and age, gender, or viral pathogenic type. CONCLUSIONS: These findings suggest that positivity for ocular TTV was correlated with a clinical history of systemic immunodeficiency.

Structural factors governing binding of curvature-sensing peptides to bacterial extracellular vesicles covered with hydrophilic polysaccharide chains.

Extracellular vesicles (EVs) have attracted an attention as important targets in the fields of biology and medical science because they contain physiologically active molecules. Curvature-sensing peptides are currently used as novel tools for marker-independent EV detection techniques. A structure-activity correlation study demonstrated that the α-helicity of the peptides is prominently involved in peptide binding to vesicles. However, whether a flexible structure changing from a random coil to an α-helix upon binding to vesicles or a restricted α-helical structure is an important factor in the detection of biogenic vesicles is still unclear. To address this issue, we compared the binding affinities of stapled and unstapled peptides for bacterial EVs with different surface polysaccharide chains. We found that unstapled peptides showed similar binding affinities for bacterial EVs regardless of surface polysaccharide chains, whereas stapled peptides showed substantially decreased binding affinities for bacterial EVs covered with capsular polysaccharides. This is probably because curvature-sensing peptides must pass through the layer of hydrophilic polysaccharide chains prior to binding to the hydrophobic membrane surface. While stapled peptides with restricted structures cannot easily pass through the layer of polysaccharide chains, unstapled peptides with flexible structures can easily approach the membrane surface. Therefore, we concluded that the structural flexibility of curvature-sensing peptides is a key factor for governing the highly sensitive detection of bacterial EVs.

Structural Dissection of Epsin-1 N-Terminal Helical Peptide: The Role of Hydrophobic Residues in Modulating Membrane Curvature.

Spatiotemporal structural alterations in cellular membranes are the hallmark of many vital processes. In these cellular events, the induction of local changes in membrane curvature often plays a pivotal role. Many amphiphilic peptides are able to modulate membrane curvature, but there is little information on specific structural factors that direct the curvature change. Epsin-1 is a representative protein thought to initiate invagination of the plasma membrane upon clathrin-coated vesicles formation. Its N-terminal helical segment (EpN18) plays a key role in inducing positive membrane curvature. This study aimed to elucidate the essential structural features of EpN18 in order to better understand general curvature-inducing mechanisms, and to design effective tools for rationally controlling membrane curvature. Structural dissection of peptides derived from EpN18 revealed the decisive contribution of hydrophobic residues to (i) enhancing membrane interactions, (ii) helix structuring, (iii) inducing positive membrane curvature, and (iv) loosening lipid packing. The strongest effect was obtained by substitution with leucine residues, as this EpN18 analog showed a marked ability to promote the influx of octa-arginine cell-penetrating peptides into living cells.

Development of Antimicrobial Peptide-Antibiotic Conjugates to Improve the Outer Membrane Permeability of Antibiotics Against Gram-Negative Bacteria.

Antibiotics have been widely used in the medical field as a treatment for infectious diseases, but they are not effective against all Gram-negative bacteria because of their low permeability to the outer membrane. One of the strategies to improve the antibacterial activity of antibiotics is the coadministration of antibiotics and membrane-perturbing antimicrobial peptides for their synergistic effects. However, because of their different pharmacokinetics, their coadministration may not exert expected effects in the clinical stage. Here, we designed various antimicrobial peptide-antibiotic conjugates as a novel approach to improve the antimicrobial activity of antibiotics. Ampicillin was chosen as a model antibiotic with poor outer membrane permeability, and the effects of the chemistry and position of conjugation and the choice of antimicrobial peptides were examined. One of the ampicillin conjugates exhibited significantly improved antimicrobial activity against ampicillin-resistant Gram-negative bacteria without exerting cytotoxicity against human cultured cells, demonstrating that our novel approach is an effective strategy to improve the antimicrobial activity of antibiotics with low outer membrane permeability.

Hemopexin as a Potential Binding Partner of Arginine-Rich Cell-Penetrating Peptides in Serum.

Serum proteins affect the in vivo fate and cellular uptake of arginine-rich cell-penetrating peptides (CPPs) and drugs delivered by CPPs. Although the binding of CPPs to serum proteins may possibly reduce their cellular uptake to some extent, it may also prolong their circulation half-life in vivo. We aimed to identify novel binding proteins of arginine-rich CPPs in serum to better understand their in vivo fate and develop more sophisticated drug delivery systems using CPPs. Isothermal titration calorimetry analysis suggests that albumin, the most abundant protein in serum, binds to d-forms of oligoarginine; however, the dissociation constants are several tens of a micromolar. Candidate proteins with the potential of binding to arginine-rich CPPs in serum were then explored using nondenaturing polyacrylamide gel electrophoresis followed by mass spectrometry analysis. Studies using fluorescence correlation spectroscopy determined hemopexin as a potential binding partner of d-forms of arginine-rich CPPs, including d-octaarginine (r 8) and the d-form of the peptide, corresponding to HIV-1 Rev (34-50), with dissociation constants of submicromolar to micromolar range. Using flow cytometry and a split-luciferase-based system, the promotion effect of hemopexin on the total cellular uptake and cytosolic localization of cargos conjugated with these CPPs was confirmed. Therefore, this study elucidated hemopexin as a potential binding partner of d-arginine-rich CPPs that may affect their in vivo fate and cellular uptake.

Split luciferase-based estimation of cytosolic cargo concentration delivered intracellularly via attenuated cationic amphiphilic lytic peptides.

Intracellular delivery of biomacromolecules is challenging as these molecules are taken up by cells and encapsulated into vesicular compartments called endosomes, and the fraction of molecules that are translocated to the cytosol are particularly important to obtain desired biological responses. This study aimed to estimate the cytosolic concentrations of intracellularly delivered peptides and proteins to aid the design of novel and effective biopharmaceutical delivery systems. To this end, we employed the split NanoLuc luciferase system, using the 11-residue HiBiT peptide segment as a probe for the delivered molecules in cells expressing the complementary LgBiT protein segment. The efficacy in cytosolic HiBiT delivery was determined by measuring the resultant luciferase activity when the HiBiT segment delivered into the cytosol forms a complex with LgBiT. Mean cytosolic HiBiT concentration was calculated using cell number and cell volume analysis. L17E and HAad peptides, developed in our laboratory for intracellular protein delivery, yielded approximately 6-fold cellular HiBiT concentrations than that obtained in their absence.

Effect of Antimicrobial Prophylaxis Duration on Health Care-Associated Infections After Clean Orthopedic Surgery: A Cluster Randomized Trial.

Importance: Postoperative health care-associated infections are associated with a greater deterioration in patients' general health status and social and economic burden, with at least 1 occurring in approximately 4% of acute care hospital patients. Antimicrobial prophylaxis prevents surgical site infections in various orthopedic procedures; however, its relationship with health care-associated infections remains unknown. Objective: To examine whether a shorter antimicrobial prophylaxis duration of less than 24 hours after surgery is not inferior to a longer duration in preventing health care-associated infections after clean orthopedic surgery. Design, Setting, and Participants: This open-label, multicenter, cluster randomized, noninferiority clinical trial was conducted in 5 tertiary referral hospitals in greater Tokyo metropolitan area, Japan, from May to December 2018. Adult patients undergoing clean orthopedic surgery were recruited until the planned number of participants was achieved (500 participants per group). Statistical analysis was conducted from July to December 2019. Interventions: Antimicrobial prophylaxis was discontinued within 24 hours after surgery in group 24 and 24 to 48 hours after surgery in group 48. Group allocation was switched every 2 or 4 months according to the facility-based cluster rule. Study-group assignments were masked from participants. Main Outcomes and Measures: The primary outcome was the incidence of health care-associated infections requiring antibiotic therapies within 30 days after surgery. The noninferiority margin was 4%. Results: Of the 1211 participants who underwent cluster allocation, 633 participants were in group 24 (median [IQR] age, 73 [61-80] years; 250 men [39.5%] and 383 women [60.5%]), 578 participants were in group 48 (median [IQR] age, 74 [62-81] years; 204 men [35.3%] and 374 women [64.7%]), and all were eligible for the intention-to-treat analyses. Health care-associated infections occurred in 29 patients (4.6%) in group 24 and 38 patients (6.6%) in group 48. Intention-to-treat analyses showed a risk difference of -1.99 percentage points (95% CI, -5.05 to 1.06 percentage points; P < .001 for noninferiority) between groups, indicating noninferiority. Results of adjusted intention-to-treat, per-protocol, and per designated procedure population analyses supported this result, without a risk of antibiotic resistance and prolonged hospitalization. Conclusions and Relevance: This cluster randomized trial found noninferiority of a shorter antimicrobial prophylaxis duration in preventing health care-associated infections without an increase in antibiotic resistance risk. These findings lend support to the global movement against antimicrobial resistance and provide additional information on adequate antimicrobial prophylaxis for clean orthopedic surgery. Trial Registration: Identifier: UMIN000030929.

Synthesis and Properties of V-Shaped Xanthene Dyes with Tunable and Predictable Absorption and Emission Wavelengths.

V-shaped xanthene dyes capable of predicting absorption and emission wavelengths are described. These dyes were synthesized by bridging a xanthene ring and an aryl moiety of fluorescein through ether covalent bonds. These dyes showed longer absorption and emission wavelengths than those of the parent fluorescein. Furthermore, substituents introduced on the aryl moiety mainly affected the lowest unoccupied molecular orbital energy level of the molecule. Therefore, the Hammett substituent constants could be used to predict the absorption and emission wavelengths of the compound.

Design of the N-Terminus Substituted Curvature-Sensing Peptides That Exhibit Highly Sensitive Detection Ability of Bacterial Extracellular Vesicles.

Extracellular vesicles (EVs) have emerged as important targets in biological and medical studies because they are involved in diverse human diseases and bacterial pathogenesis. Although antibodies targeting the surface biomarkers are widely used to detect EVs, peptide-based curvature sensors are currently attracting an attention as a novel tool for marker-free EV detection techniques. We have previously created a curvature-sensing peptide, FAAV and applied it to develop a simple and rapid method for detection of bacterial EVs in cultured media. The method utilized the fluorescence/Förster resonance energy transfer (FRET) phenomenon to achieve the high sensitivity to changes in the EV amount. In the present study, to develop a practical and easy-to-use approach that can detect bacterial EVs by peptides alone, we designed novel curvature-sensing peptides, N-terminus-substituted FAAV (nFAAV) peptides. The nFAAV peptides exerted higher α-helix-stabilizing effects than FAAV upon binding to vesicles while maintaining a random coil structure in aqueous solution. One of the nFAAV peptides showed a superior binding affinity for bacterial EVs and detected changes in the EV amount with 5-fold higher sensitivity than FAAV even in the presence of the EV-secretory bacterial cells. We named nFAAV5, which exhibited the high ability to detect bacterial EVs, as an EV-sensing peptide. Our finding is that the coil-α-helix structural transition of the nFAAV peptides serve as a key structural factor for highly sensitive detection of bacterial EVs.

Evaluation of Restricted Motion Area of the Median Nerve in Patients with Carpal Tunnel Syndrome: A New Measurement Method Using an Ultrasonographic Video Image.

Background: The precise etiology of carpal tunnel syndrome (CTS) remains unclear. One of the accepted factors for CTS is the restriction of the median nerve. Previous reports using ultrasound had only observed and measured the movement of parts of the median nerve. In this study, we aimed to elucidate the difference in the movement of the entire median nerve in patients with CTS (before and after surgery) and healthy volunteers using a new measurement method. Methods: We expressed the amount of movement of the entire nerve by a new method creating the motion area of the median nerve (MAMn) from an ultrasonographic video image on the computer. We compared the MAMn, the real MAMn (RMMn) (the value obtained by subtracting the nerve cross-sectional area from the MAMn), and mobile ratio (MR) (the value obtained from dividing the MAMn by the nerve cross-sectional area) between six wrists of six cases of CTS (before and at an average of 3.5 months after surgery) and six wrists of six healthy volunteers. Results: During passive wrist flexion, the average MAMn, RMMn, and MR of healthy cases were 23.1 mm2, 16.4 mm2, and 3.52, respectively. The average MAMn, RMMn, and MR of cases of CTS were respectively 11.8 mm2, 5.4 mm2, and 1.86 preoperatively; and 16.2 mm2, 7.3 mm2, and 1.87, postoperatively. The MAMn, RMMn, and MR decreased more significantly in patients with CTS than in healthy volunteers (p < 0.01). The MAMn and RMMn increased postoperatively (p < 0.05), but the MR remained low. Conclusions: The new measurement method revealed that the mobility of the entire median nerve was significantly restricted in cases of CTS compared to healthy participants. However, after surgery, nerve restriction was not restored despite improvements in symptoms, suggesting that decreases in nerve mobility contribute to CTS but are not a direct cause of symptoms.

Membrane anchoring of a curvature-inducing peptide, EpN18, promotes membrane translocation of octaarginine.

EpN18 is a curvature-inducing peptide, which loosens lipid packing upon interaction with the cell membrane, and facilitates cell-membrane penetration by arginine-rich cell-penetrating peptides, including octaarginine (R8). In the present study, we conjugated the N-terminal of EpN18 with a pyrenebutyryl (pBu) moiety, which acts as an anchoring unit that increases membrane interactions. Enhanced lipid-packing loosening and cytosolic translocation of R8 were observed by the pBu anchoring of EpN18.

Influence of the Dabcyl group on the cellular uptake of cationic peptides: short oligoarginines as efficient cell-penetrating peptides.

Cell-penetrating peptides (CPPs) are promising delivery vehicles. These short peptides can transport wide range of cargos into cells, although their usage has often limitations. One of them is the endosomatic internalisation and thus the vesicular entrapment. Modifications which increases the direct delivery into the cytosol is highly researched area. Among the oligoarginines the longer ones (n > 6) show efficient internalisation and they are well-known members of CPPs. Herein, we describe the modification of tetra- and hexaarginine with (4-((4-(dimethylamino)phenyl)azo)benzoyl) (Dabcyl) group. This chromophore, which is often used in FRET system increased the internalisation of both peptides, and its effect was more outstanding in case of hexaarginine. The modified hexaarginine may enter into cells more effectively than octaarginine, and showed diffuse distribution besides vesicular transport already at low concentration. The attachment of Dabcyl group not only increases the cellular uptake of the cell-penetrating peptides but it may affect the mechanism of their internalisation. Their conjugates with antitumor drugs were studied on different cells and showed antitumor activity.

Metal Complex Lipids for Fluid-Fluid Phase Separation in Coassembled Phospholipid Membranes.

We demonstrate a fluid-fluid phase separation in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) membranes using a metal complex lipid of type [Mn(L1)] (1; HL1=1-(2-hydroxybenzamide)-2-(2-hydroxy-3-formyl-5-hexadecyloxybenzylideneamino)ethane). Small amount of 1 produces two separated domains in DMPC, whose phase transition temperatures of lipids (Tc ) are both lower than that of the pristine DMPC. Variable temperature fluorescent microscopy for giant-unilamellar vesicles of DMPC/1 hybrids demonstrates that visible phase separations remain in fluid phases up to 37 °C, which is clearly over the Tc of DMPC. This provides a new dimension for the application of metal complex lipids toward controlling lipid distributions in fluid membranes.

Three cases of brolucizumab-associated retinal vasculitis treated with systemic and local steroid therapy.

PURPOSE: To describe three Japanese cases of retinal vasculitis that occurred following intravitreal brolucizumab injections and the systemic and local steroid treatment administered. CASES: Three patients developed intraocular inflammation (IOI) and retinal vasculitis following the first injection of brolucizumab for age-related macular degeneration. For two eyes, monthly aflibercept injections did not control exudation, and therapy was changed to brolucizumab; one eye was treatment-naïve. All three patients noticed blurry vision and floaters 11-18 days after brolucizumab injections, and the treated eyes exhibited anterior chamber cells, fine keratic precipitates, vitreous cells, and vitreous haze. Ultra-widefield color images of the fundus showed retinal hemorrhage in the peripheral retina and, in two cases vascular sheathing. Ultra-widefield fluorescein angiography (FA) showed segmental vascular leakage in all eyes and leakage from the optic disc in two eyes. Vascular filling defects were noted in the peripheral retinae of two eyes. Brolucizumab-associated retinal vasculitis was diagnosed, and treated with 30 mg/day of oral prednisolone, subtenon triamcinolone acetonide injection (20 mg/0.5 ml), and 0.1% betamethasone sodium phosphate solution. After 1 week, color fundus images and FA showed improvements in vascular sheathing, leakage from retinal vessels, and optic disc leakage, but the vascular filling defects remained. Visual acuity was restored in all three eyes 6 weeks after the onset. CONCLUSION: Brolucizumab-associated IOI, including retinal vasculitis and retinal occlusion, is a rare but important adverse event that can cause severe vision loss. Prompt diagnosis with FA and treatment with systemic or local steroids should be considered.

Development of a Simple and Rapid Method for In Situ Vesicle Detection in Cultured Media.

Extracellular membrane vesicles (EMVs) are biogenic secretory lipidic vesicles that play significant roles in intercellular communication related to human diseases and bacterial pathogenesis. They are being investigated for their possible use in diagnosis, vaccines, and biotechnology. However, the existing methods suffer from a number of issues. High-speed centrifugation, a widely used method to collect EMVs, may cause structural artifacts. Immunostaining methods require several steps and thus the separation and detection of EMVs from the secretory cells is time-consuming. Furthermore, detection of EMVs using these methods requires specific and costly antibodies. To tackle these problems, development of a simple and rapid detection method for the EMVs in the cultured medium without separation from the secretory cells is a pressing task. In this study, we focused on the Gram-negative bacterium Shewanella vesiculosa HM13, which produces a large amount of EMVs including a cargo protein with high purity, as a model. Curvature-sensing peptides were used for EMV-detection tools. FAAV, a peptide derived from sorting nexin protein 1, selectively binds to the EMVs even in the presence of the secretory cells in the complex cultured medium. FAAV can fully detect the EMVs within a few minutes, and the resistance of FAAV to proteases enables it to withstand prolonged use in the cultured medium. Fluorescence/Förster resonance energy transfer was used to develop a method to detect changes in the amount of the EMVs with high sensitivity. Overall, our results indicate the potential applicability of FAAV for in situ EMV detection in cultured media.

Isolated Axillary Nerve Rupture due to Closed Nondislocating Injury of the Shoulder in Contact Sports: A Report of 2 Cases.

CASE: Axillary nerve rupture without shoulder joint fracture or dislocation in contact sports is very rare. To date, there has been no detailed report on such cases. We present 2 rare cases of axillary nerve rupture in contact sports who were successfully treated with free nerve grafting. CONCLUSION: In contact sports, the deltoid muscle is sometimes paralyzed temporarily after a collision. However, similar to our cases, the axillary nerve can be lacerated without fracture or dislocation. It is necessary to watch the course of paralysis carefully and consider nerve reconstruction if it does not recover.

Pseudo-Membrane Jackets: Two-Dimensional Coordination Polymers Achieving Visible Phase Separation in Cell Membrane.

Cell membranes contain lateral systems that consist of various lipid compositions and actin cytoskeleton, providing two-dimensional (2D) platforms for chemical reactions. However, such complex 2D environments have not yet been used as a synthetic platform for artificial 2D nanomaterials. Herein, we demonstrate the direct synthesis of 2D coordination polymers (CPs) at the liquid-cell interface of the plasma membrane of living cells. The coordination-driven self-assembly of networking metal complex lipids produces cyanide-bridged CP layers with metal ions, enabling "pseudo-membrane jackets" that produce long-lived micro-domains with a size of 1-5 µm. The resultant artificial and visible phase separation systems remain stable even in the absence of actin skeletons in cells. Moreover, we show the cell application of the jackets by demonstrating the enhancement of cellular calcium response to ATP.

The Tenosynovitis of Fingers Associated with Transthyretin Amyloidosis.

Background: Amyloidosis treatment has advanced rapidly along with the discovery of drugs to prevent amyloid deposition. Therefore, it is vital to detect amyloidosis at an early stage. Wild-type transthyretin, which can cause carpal tunnel syndrome, may also cause finger tenosynovitis. However, the correlation between wild-type transthyretin amyloid and finger tenosynovitis is unclear. Here, we investigated pathological and clinical findings for 20 patients with finger tenosynovitis who underwent operation at our hospital to determine the frequency of transthyretin amyloid deposition in idiopathic finger tenosynovitis. Methods: To check for the presence of amyloid deposition, all specimens (tendon synovium tissue or flexor tendon sheath) resected during the operation were stained by the direct fast scarlet method. Amyloid-positive specimens were evaluated by immunohistochemical staining using an anti-transthyretin antibody. Patient characteristics were evaluated with respect to amyloid presence. Results: Thirteen (65%) of 20 finger tenosynovitis cases had amyloid deposition. Nine (69.2%) of the 13 amyloid-positive cases exhibited extensive transthyretin staining and were considered to have transthyretin amyloid. Amyloid deposition was more frequent in men. The mean number of fingers with tenosynovitis was significantly higher in amyloid-positive cases (3.8 fingers) than in amyloid-negative cases (2.0 fingers). Conclusions: Men with multiple finger tenosynovitis tended to have transthyretin amyloid deposition. Our results support that multiple finger tenosynovitis may serve as an initial indication of evaluation for transthyretin amyloidosis.