Therapy-resistant Complex Regional Pain Syndrome Type I: to amputate or not?

Background: Amputation for the treatment of long-standing, therapy-resistant complex regional pain syndrome type I (CRPS-I) is controversial. An evidence-based decision regarding whether or not to amputate is not possible on the basis of current guidelines. The aim of the current study was to systematically review the literature and summarize the beneficial and adverse effects of an amputation for the treatment of long-standing, therapy-resistant CRPS-I. Methods: A literature search, using MeSH terms and free text words, was performed with use of PubMed and EMBASE. Original studies published prior to January 2010 describing CRPS-I as a reason for amputation were included. The reference lists of the identified studies were also searched for additional relevant studies. Studies were assessed with regard to the criteria used to diagnose CRPS-I, level of amputation, amputation technique, rationale for the level of amputation, reason for amputation, recurrence of CRPS-I after the amputation, phantom pain, prosthesis fitting and use, and patient functional ability, satisfaction, and quality of life. Results: One hundred and sixty articles were identified, and twenty-six studies with Level-IV evidence (involving 111 amputations in 107 patients) were included. Four studies applied CRPS-I diagnostic criteria proposed by the International Association for the Study of Pain, Bruehl et al., or Veldman et al. Thirteen studies described symptoms without noting whether the patient met diagnostic criteria for CRPS-I, and nine studies stated the diagnosis only. The primary reasons cited for amputation were pain (80%) and a dysfunctional limb (72%). Recurrence of CRPS-I in the stump occurred in thirty-one of sixty-five patients, and phantom pain occurred in fifteen patients. Thirty-six of forty-nine patients were fitted with a prosthesis, and fourteen of these patients used the prosthesis. Thirteen of forty-three patients had paid employment after the amputation. Patient satisfaction was reported in eight studies, but the nature of the satisfaction was often not clearly indicated. Changes in patient quality of life were reported in three studies (fifteen patients); quality of life improved in five patients and the joy of life improved in another six patients. Conclusions: The previously published studies regarding CRPS-I. as a reason for amputation all represent Level-IV evidence, and they do not clearly delineate the beneficial and adverse affects of an amputation performed for this diagnosis. Whether to amputate or not in order to treat long-standing, therapy-resistant CRPS-I remains an unanswered question

In vivo and in vitro degradation of poly (50/50 (85/15 L/D)LA/e-cl) and the implications for the use in nerve reconstruction

Nerve guides can be used for the reconstruction of peripheral nerve defects. After serving their function, nerve guides should degrade. p[50/50 (85/15L/D)LA/ε-CL] degrades completely within 1 year without the formation of a slow degrading crystalline fraction. Although the tensile strength (TS) of a p[50/50 (85/15L/D)LA/ε-CL] nerve guide is negligible after 2 months, nerve regeneration across a 1-cm gap in the sciatic nerve of the rat is faster and qualitatively better than after reconstruction using autologous nerve grafts. During degradation p[50/50 (85/15L/D)LA/ε-CL] swells, especially during the first 3 months. This can have a negative influence on the regenerating nerve. p[50/50 (85/15L/D)LA/ε-CL] nerve guides could only be used in the clinical situation in case of short nerve gaps (several mm) in small nerves (for instance digital nerves). Refinements will be needed to successfully reconstruct longer nerve gaps (several cm)

In vivo and in vitro degradation of poly[50/50 (85/15L/D)LA/ε-CL], and the implications for the use in nerve reconstruction

Nerve guides can be used for the reconstruction of peripheral nerve defects. After serving their function, nerve guides should degrade. p[50/50 (85/15L/D)LA/ε-CL] degrades completely within 1 year without the formation of a slow degrading crystalline fraction. Although the tensile strength (TS) of a p[50/50 (85/15L/D)LA/ε-CL] nerve guide is negligible after 2 months, nerve regeneration across a 1-cm gap in the sciatic nerve of the rat is faster and qualitatively better than after reconstruction using autologous nerve grafts. During degradation p[50/50 (85/15L/D)LA/ε-CL] swells, especially during the first 3 months. This can have a negative influence on the regenerating nerve. p[50/50 (85/15L/D)LA/ε-CL] nerve guides could only be used in the clinical situation in case of short nerve gaps (several mm) in small nerves (for instance digital nerves). Refinements will be needed to successfully reconstruct longer nerve gaps (several cm)

Mutations in potassium channel KCND3 cause spinocerebellar ataxia Type 19

Objective: To identify the causative gene for the neurodegenerative disorder spinocerebellar ataxia type 19 (SCA19) located on chromosomal region 1p21-q21. Methods: Exome sequencing was used to identify the causal mutation in a large SCA19 family. We then screened 230 ataxia families for mutations located in the same gene (KCND3, also known as Kv4.3) using high-resolution melting. SCA19 brain autopsy material was evaluated, and in vitro experiments using ectopic expression of wild-type and mutant Kv4.3 were used to study protein localization, stability, and channel activity by patch-clamping. Results: We detected a T352P mutation in the third extracellular loop of the voltage-gated potassium channel KCND3 that cosegregated with the disease phenotype in our original family. We identified 2 more novel missense mutations in the channel pore (M373I) and the S6 transmembrane domain (S390N) in 2 other ataxia families. T352P cerebellar autopsy material showed severe Purkinje cell degeneration, with abnormal intracellular accumulation and reduced protein levels of Kv4.3 in their soma. Ectopic expression of all mutant proteins in HeLa cells revealed retention in the endoplasmic reticulum and enhanced protein instability, in contrast to wild-type Kv4.3 that was localized on the plasma membrane. The regulatory beta subunit Kv channel interacting protein 2 was able to rescue the membrane localization and the stability of 2 of the 3 mutant Kv4.3 complexes. However, this either did not restore the channel function of the membrane-located mutant Kv4.3 complexes or restored it only partially. Interpretation: KCND3 mutations cause SCA19 by impaired protein maturation and/or reduced channel function. ANN NEUROL 2012;72:870-880

Dysregulation of the MMP/TIMP Proteolytic System in Subependymal Giant Cell Astrocytomas in Patients With Tuberous Sclerosis Complex: Modulation of MMP by MicroRNA-320d In Vitro

Tuberous sclerosis complex (TSC), a rare genetic disorder caused by a mutation in the TSC1 or TSC2 gene, is characterized by the growth of hamartomas in several organs. This includes the growth of low-grade brain tumors, known as subependymal giant cell astrocytomas (SEGA). Previous studies have shown differential expression of genes related to the extracellular matrix in SEGA. Matrix metalloproteinases (MMPs), and their tissue inhibitors (TIMPs) are responsible for remodeling the extracellular matrix and are associated with tumorigenesis. This study aimed to investigate the MMP/TIMP proteolytic system in SEGA and the regulation of MMPs by microRNAs, which are important post-transcriptional regulators of gene expression. We investigated the expression of MMPs and TIMPs using previously produced RNA-Sequencing data, real-time quantitative PCR and immunohistochemistry in TSC-SEGA samples and controls. We found altered expression of several MMPs and TIMPs in SEGA compared to controls. We identified the lowly expressed miR-320d in SEGA as a potential regulator of MMPs, which can decrease MMP2 expression in human fetal astrocyte cultures. This study provides evidence of a dysregulated MMP/TIMP proteolytic system in SEGA of which MMP2 could be rescued by microRNA-320d. Therefore, further elucidating microRNA-mediated MMP regulation may provide insights into SEGA pathogenesis and identify novel therapeutic targets