GDNF overexpression fails to provoke muscle recovery from botulinum toxin poisoning: a preliminary study.

Glial cell line-derived neurotrophic factor (GDNF) has potent axonal growth and survival effects on motoneurons. This study used transgenic Myo-GDNF mice to assess the effects of targeted GDNF overexpression on functional recovery after botulinum toxin type A (BTxA) chemodenervation. BTxA (0.1 U) was injected into the tibialis anterior (TA) muscle of wild-type CF1 and transgenic Myo-GDNF mice. On days 1, 7, 14, and 21 after injection, evoked muscle force production and muscle mass were measured (n = 6, for each group at each time point). Greater maximal tetanic force and calculated specific force were evoked in Myo-GDNF animals when compared with control CF1 animals at days 1, 7, and 21. However, the differences were not statistically significant. Similarly, modest reductions in muscle atrophy in the Myo-GDNF group at all time points were not statistically significant. Targeted overexpression of GDNF in the muscles of Myo-GDNF mice did not improve motor recovery in the first 21 days after BTxA chemodenervation.

Efficacy of short-term FK506 administration on accelerating nerve regeneration.

BACKGROUND: The slow rate of nerve regeneration following injury can cause extended muscle denervation, leading to irreversible muscle atrophy, fibrosis, and destruction of motor endplates. The immunosuppressant FK506 (tacrolimus) has been shown to accelerate the rate of nerve regeneration and functional recovery. However, the toxic and immunosuppressive properties of FK506 make it undesirable for long-term use. OBJECTIVE: To take advantage of the regeneration-enhancing effects of FK506 but avoid the potential adverse effects of long-term administration, the current study evaluates and quantifies the efficacy of short-term FK506 treatment in rat models. METHODS: Clinically relevant transection and graft models were evaluated, and walking track analysis (WTA) was used to evaluate functional recovery. FK506 was administered for 5 and 10 days post transection injury and 10 and 20 days post graft injury. Both groups involving a short course were compared with the continuous administration group. RESULTS: In the transection model, FK506 was administered for 5 and 10 days postoperatively. WTA demonstrated that 10 days of FK506 administration was sufficient to reduce functional recovery time by 29% compared with negative controls. In the graft model, FK506 was administered for 10 and 20 days postoperatively. Short treatment courses of 10 and 20 days reduced recovery time by 15% and 21%, respectively, compared with negative controls. Analysis of blood-nerve barrier (BNB) integrity demonstrated that FK506 facilitated early reconstitution of the BNB. CONCLUSIONS: The results of this study indicate that short-term FK506 delivery following nerve injury imparts a significant therapeutic effect.

Evaluation of peripheral nerve regeneration via in vivo serial transcutaneous imaging using transgenic Thy1-YFP mice.

This study uses the saphenous nerve crush model in Thy1-YFP mice and serial transcutaneous imaging to evaluate the rate of nerve regeneration under various FK-506 (tacrolimus) dosing regimens and in the presence of transgenic overexpression of glial cell line-derived neurotrophic factor (GDNF). Thy1-YFP transgenic mice received saphenous nerve crush and were monitored for axonal regeneration via transcutaneous imaging for 7 days. Group A received no FK-506. Groups B and C received FK-506 at 2 or 0.5 mg/kg/day, starting three days before injury (preload). Groups D and E received FK-506 at 2 or 0.5 mg/kg/day, starting on the day of injury. Group F consisted of double transgenic mice with central overexpression of GDNF by CNS astrocytes (GFAP-GDNF/Thy1-YFP). Length and rate of axonal regeneration were measured and calculated over time. Regardless of concentration, FK-506 preload (Groups B and C) improved length and rate of axonal outgrowth compared with controls (Group A) and no preload (Groups D and E). Surprisingly, central overexpression of GDNF (GFAP-GDNF) delayed and stunted axonal outgrowth. Saphenous nerve crush in Thy1-YFP mice represents a viable model for timely evaluation of therapeutic strategies affecting the rate of nerve regeneration. FK-506 administered three days prior to injury accelerates axonal regeneration beyond injury conditioned regeneration alone and may serve as a reliable positive control for the model. GDNF overexpression in the CNS impedes early axonal outgrowth.

The 'Ten Test': application and limitations in assessing sensory function in the paediatric hand.

BACKGROUND: The Ten Test, first described in 1997 by Strauch et al., is a simple, rapid, reliable and sensitive method to evaluate hand sensibility in adults. In this study, we validated its use in children. METHODS: We asked patients to rate sensibility elicited by a light moving touch on the palmar surface of digits in reference to sensibility elicited by the same touch in a digit confirmed as normal. RESULTS: A total of 73 subjects (age range: 1-12 years) were tested. Patients under age 5 years were significantly less likely to complete the test. The kappa statistic for the Ten Test in nine subjects, each tested separately by two examiners, demonstrated very strong inter-observer reliability (kappa=1.0, p<0.003). CONCLUSIONS: The Ten Test is a simple, validated, non-threatening method to evaluate hand sensibility in children and adolescents. We recommend its clinical use in patients age 5 years and older.