Absence of the glucagon-like peptide-1 receptor does not affect the metabolic phenotype of mice with liver-specific G(s)α deficiency.

The stimulatory G protein α-subunit (G(s)α) couples hormone and other receptors to the generation of intracellular cAMP. We previously showed that mice with liver-specific G(s)α deficiency [liver-specific G(s)α knockout (LGsKO) mice] had reduced adiposity and improved glucose tolerance associated with increased glucose-stimulated insulin secretion, pancreatic islet hyperplasia, and very high serum glucagon and glucagon-like peptide 1 (GLP-1) levels. Because GLP-1 is known to stimulate insulin secretion and to have effects on energy balance, we mated LGsKO mice with germline GLP-1 receptor (GLP-1R) knockout mice (Glp1r(-/-)) and compared LGsKO to double-knockout (LGs/Glp1r(-/-)) mice to determine the contribution of excess GLP-1R signaling to the LGsKO phenotype. Loss of the GLP-1R failed to reverse most of the metabolic features of LGsKO mice, including reduced fat mass, increased glucose tolerance, and second-phase glucose-stimulated insulin secretion, islet cell hyperplasia, and very high glucagon and GLP-1 levels. However, loss of GLP-1R impaired first-phase insulin secretion in mice with or without liver-specific G(s)α deficiency. Thus, excess GLP-1 action (or at least through GLP-1R) does not contribute to the LGsKO metabolic phenotype, and other unknown factors involved in the cross talk between the liver G(s)α/cAMP pathway and pancreatic islet function need to be further elucidated.

Effects of deficiency of the G protein Gsα on energy and glucose homeostasis.

G(s)α is a ubiquitously expressed G protein α-subunit that couples receptors to the generation of intracellular cyclic AMP. The G(s)α gene GNAS is a complex gene that undergoes genomic imprinting, an epigenetic phenomenon that leads to differential expression from the two parental alleles. G(s)α is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in a small number of tissues. Albright hereditary osteodystrophy is a monogenic obesity disorder caused by heterozygous G(s)α mutations but only when the mutations are maternally inherited. Studies in mice indicate a similar parent-of-origin effect on energy and glucose metabolism, with maternal but not paternal mutations leading to obesity, reduced sympathetic nerve activity and energy expenditure, glucose intolerance and insulin resistance, with no primary effect on food intake. These effects result from G(s)α imprinting leading to severe G(s)α deficiency in one or more regions of the central nervous system, and are associated with a specific defect in melanocortins to stimulate sympathetic nerve activity and energy expenditure.

Glatiramer acetate immune system augmentation for peripheral nerve regeneration in rat crushed sciatic nerve model.

BACKGROUND: Protective antiself response to nervous system injury has been reported to be mediated by a T-cell subpopulation that can recognize self-antigens. Immune cells have been shown to play a role in the regulation of motor neuron survival after a peripheral nerve injury. The objective of the present study was to evaluate the effects of immune system augmentation with use of the antigen glatiramer acetate, which is known to affect T-cell immunity, on peripheral nerve regeneration. METHODS: Wild-type and nude-type (T-cell-deficient) rats underwent crush injury of the sciatic nerve. Three and six weeks after the injury, the sciatic nerve was examined, both functionally (on the basis of footprint analysis and the tibialis anterior muscle response and weight) and histologically (on the basis of axon count). RESULTS: Significantly greater muscle responses were measured after three weeks in the group of wild-type rats that were treated with glatiramer acetate (control limb:injured limb ratio, 0.05 for the glatiramer acetate group [n = 9], compared with 0.51 for the saline solution group [n = 8]; p < 0.05). Higher axon counts were also found in this group (control limb:injured limb ratio, -0.07 for the glatiramer acetate group [n = 10], compared with 0.29 for the saline solution group [n = 8]; p < 0.05). The nude-type rats showed no response to the intervention after three weeks but showed a delayed response after six weeks. A second dose of glatiramer acetate, delivered forty-eight hours after the injury, did not result in an improved response as compared with the control groups. CONCLUSIONS: We found that a single treatment with glatiramer acetate resulted in accelerated functional and histological recovery after sciatic nerve crush injury. The role of T-cell immunity in the mechanism of glatiramer acetate was suggested by the partial and late response found in the T-cell-deficient rats.

Management of scaphoid nonunions.

Scaphoid nonunions can exist with or without avascular necrosis of the proximal pole, and waist fractures may have an associated humpback deformity. CT best shows the deformity and bone loss, whereas MRI will show avascular necrosis. Operative treatment should be directed at correcting the deformity with open reduction and internal fixation and bone grafting. Vascularized bone grafts should be used in cases of avascular necrosis.

Diagnosis and anatomic reconstruction of extensor carpi ulnaris subluxation.

PURPOSE: To evaluate the efficacy of dynamic ultrasound to diagnose extensor carpi ulnaris (ECU) subluxation and assess the results of a new technique for anatomic ECU tendon sheath reconstruction. METHODS: Dynamic ultrasound was used to confirm the diagnosis of ECU tendon subluxation in patients presenting with painful snapping of the ulnar wrist during supination and pronation. Twenty-one patients with persistent subluxation had reconstruction of the ECU tendon sheath using a new technique. In this procedure, the ECU tendon is elevated within its sheath dorsally and radially. The distal ulnar groove is deepened with a power burr, and 2 or 3 suture anchors are placed along the ulnar margin of the reconstructed groove. The sutures are passed through the ulnar border of the ECU sheath and tied, securing tendon sheath to bone. Preoperative wrist flexion-extension, radial-ulnar deviation, pronation-supination, grip strength, and ratings of pain, satisfaction, and Disabilities of the Arm, Shoulder, and Hand (DASH) scores were recorded and compared with postoperative values in a prospective study. Fourteen male patients and seven female patients were followed from 24 to 45 months postoperatively (mean, 31 mo). RESULTS: Twenty-one patients presented with symptomatic ECU tendon subluxation confirmed by dynamic ultrasound of the wrist. We noted a statistically significant increase in arc of wrist flexion-extension, radial-ulnar deviation, pronation-supination, and grip strength after reconstruction. There was a statistically significant improvement in pain, satisfaction, and DASH scores after ECU stabilization. CONCLUSIONS: Dynamic ultrasound is an effective and noninvasive method of diagnosing ECU tendon subluxation. Our technique of anatomic ECU tendon sheath reconstruction improved postoperative wrist range of motion, grip strength, pain, satisfaction, and DASH scores. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Management of scaphoid nonunions.

Scaphoid nonunions can exist with or without avascular necrosis of the proximal pole, and waist fractures may have an associated humpback deformity. CT best shows the deformity and bone loss, whereas MRI will show avascular necrosis. Operative treatment should be directed at correcting the deformity with open reduction and internal fixation and bone grafting. Vascularized bone grafts should be used in cases of avascular necrosis.

Biomechanic analysis of trapeziectomy, ligament reconstruction with tendon interposition, and tie-in trapezium implant arthroplasty for thumb carpometacarpal arthritis: a cadaver study.

PURPOSE: Thumb carpometacarpal joint arthritis has been commonly treated with some combination of resection of the trapezium and interposition of a spacer using either a biologic or artificial material plus tenodesis to reconstruct the volar oblique ligament. The purpose of this study was to evaluate the biomechanic stability of the classic ligament reconstruction with tendon interposition (LRTI) or without tendon interposition compared with a newly developed 1-piece silicone trapezium implant. METHODS: Twelve cadaver arm specimens had the following procedures: resection of the trapezium, tendon interposition, ligament reconstruction, LRTI, and the silicone implant. Biomechanic testing of joint stability was performed with a physiologic loading protocol before and after each procedure. RESULTS: The implant significantly corrected the axial displacement after trapeziectomy and resulted in less radial displacement than LRTI. It significantly reduced angulation of the thumb metacarpal base but resulted in more rotation of the thumb during simulated pinch. There was no significant difference in stability measures between trapeziectomy and LRTI or ligament reconstruction without tendon interposition. CONCLUSIONS: We found several biomechanic advantages to the implant compared with LRTI. Advantages include reduction in axial and radial displacement and maintenance of the trapezial space. We attribute these advantages to the effect of the implant as a spacer. The significant rotation with the implant, however, raises questions concerning implant design and fixation. We found no biomechanic advantage to LRTI or ligament reconstruction without tendon interposition over trapeziectomy alone.