A novel agonist with homobivalent single-domain antibodies that bind the FGF receptor 1 domain III functions as an FGF2 ligand.

Fibroblast growth factor (FGF) is a multifunctional protein that exhibits a wide range of biological effects. Most commonly, it acts as a mitogen, but it also has regulatory, morphological, and endocrine effects. The four receptor subtypes of FGF are activated by more than 20 different FGF ligands. FGF2, one of the FGF ligands, is an essential factor for cell culture in stem cells for regenerative medicine; however, recombinant FGF2 is extremely unstable. Here, we successfully generated homobivalent agonistic single-domain antibodies (variable domain of heavy chain of heavy chain antibodies referred to as VHHs) that bind to domain III and induce activation of the FGF receptor 1 and thus transduce intracellular signaling. This agonistic VHH has similar biological activity (EC50) as the natural FGF2 ligand. Furthermore, we determined that the agonistic VHH could support the proliferation of human-induced pluripotent stem cells (PSCs) and human mesenchymal stem cells, which are PSCs for regenerative medicine. In addition, the agonistic VHH could maintain the ability of mesenchymal stem cells to differentiate into adipocytes or osteocytes, indicating that it could maintain the properties of PSCs. These results suggest that the VHH agonist may function as an FGF2 mimetic in cell preparation of stem cells for regenerative medicine with better cost effectiveness.

Variable-angle locking plate with or without double-tiered subchondral support procedure in the treatment of intra-articular distal radius fracture.

BACKGROUND: Double-tiered subchondral support (DSS) procedure is two-row fixation in which proximal screws support the dorsal subchondral bone, whereas distal screws support the volar central subchondral bone, using the volar variable-angle locking plate to achieve better anatomical reduction. We examined whether DSS improves clinical outcome, complication rate, and loss of correction for dorsally displaced Arbeitsgemeinschaft für Osteosynthesefragen (AO) type C3 distal radius fractures. MATERIALS AND METHODS: We reviewed dorsally displaced intra-articular AO C3-type distal radius fractures treated at our institutions with a variable-angle volar locking plate. We assessed 49 patients (27 DSS; 22 non-DSS) treated with volar locking plates, with a mean age of 59.9 years and average follow-up of 20.2 months (range 12-56 months). We evaluated differences in functional outcome, complication rates, and loss of correction between groups using radiographic parameters. RESULT: There were no differences in clinical outcome and complications. Final volar tilt and ulnar variance were better maintained in the DSS group (P = 0.01 and 0.03). Change in volar tilt of the non-DSS group was more than that of the DSS group (P = 0.00). CONCLUSION: Though there were no significant differences in clinical outcomes, we identified a significant reduction in final volar tilt, ulnar variance, and change in volar tilt. DSS procedure is useful to avoid correction loss when treating unstable C3 distal radius fractures and thus would reduce posttraumatic arthrosis. LEVEL OF EVIDENCE: Level IV.

Transdermal delivery of CaCO3-nanoparticles containing insulin.

BACKGROUND: This study evaluates the pharmacokinetic and pharmacodynamic effects of a transdermally delivered insulin using novel CaCO(3)-nanoparticles in normal mice and those with diabetes. METHODS: CaCO3-nanoparticles encapsulating insulin (nanoinsulin) were transdermally applied to the back skin of normal ddY mice and dB/dB and kkAy mice with diabetes after fasting for 1 h. Serum insulin levels of ddY mice were analyzed by enzyme immunoassay, and blood glucose of normal mice and those with diabetes was monitored. RESULTS: Maximum serum insulin was 67.1 +/- 25.9 microIU/mL at 4 h with 200 microg of transdermal nanoinsulin in ddY mice, whereas that after subcutaneous injection of 3 microg of monomer insulin was 462 +/- 20.9 microIU/mL at 20 min. Transdermal nanoinsulin decreased glucose levels in a dose-dependent manner. A maximum decrease in blood glucose of 48.3 +/- 3.9% (ddY), 32.5 +/- 9.8% (dB/dB), and 26.2 +/- 7.6% (kkAy) after 6 h was observed with 200 microg of transdermal nanoinsulin, compared with 64.1+/-1.0% (ddY), 57.9 +/-3.4% (dB/dB), and 24.1 +/- 6.7% (kkAy) after 1 h with 3 microg of subcutaneous monomer insulin. Insulin bioavailability until 6 h with transdermal nanoinsulin in ddY mice was 0.9% based on serum insulin level and 2.0% on pharmacodynamic blood glucose-lowering effects. CONCLUSIONS: This CaCO(3)-nanoparticle system successfully delivered insulin transdermally, as evidenced by a significant sustained decrease in blood glucose in normal mice and those with diabetes. These results support the feasibility of developing transdermal nanoinsulin for human applications.

[A case of Poncet's disease (tuberculous rheumatism) in a patient with chronic renal failure undergoing hemodialysis therapy].

A 78-year-old man who was undergoing hemodialysis therapy was admitted to our hospital because of sore throat, remittent cervical lymphadenopathy, and polyarthritis over the preceding 4 weeks. On admission, he had bilateral cervical lymphadenopathy. He complained of arthralgia associated with tenderness, warmth and swelling of both elbows, left side wrist and left shoulder joint. The C-reactive protein level on admission was 15.3 mg/dl. Rheumatoid factor, antinuclear antibodies, tuberculin skin test and blood culture were negative. Joint fluid was not aspirated. Radiographs of the joints did not reveal any abnormalities. Acid-fast bacilli were demonstrated in the smear of the cervical lymph node with a fluorochrome rhodamine-auramine stain. Mycobacterium tuberculosis DNA was identified by polymerase chain reaction. We found the presence of caseating granuloma on the biopsy specimens and M.tuberculosis was detected from culture. At that point, we diagnosed this patient as having tuberculous lymphadenitis. His general symptoms resolved rapidly after starting with a three-drug regimen consisting of isoniazid, rifampin and pyrazinamide. His polyarthritis also improved dramatically. Finally we considered that his polyarthritis was tuberculous rheumatism, also called Poncet's disease. Poncet's disease is characterized by sterile polyarthritis during active tuberculosis infection. It is considered a reactive arthritis, which is a different entity from tuberculous arthritis. Although this is a rare disease, we should be aware of it in hemodialysis patient clinics, because the incidence of tuberculosis infection has been reported to be increasing in patients with end-stage renal failure.