Evaluation of the reliability of the Cutaneous Dermatomyositis Disease Area and Severity Index and the Cutaneous Assessment Tool-Binary Method in juvenile dermatomyositis among paediatric dermatologists, rheumatologists and neurologists.

BACKGROUND: The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and Cutaneous Assessment Tool-Binary Method (CAT-BM) have been shown to be reliable and valid outcome measures to assess cutaneous disease in adult dermatomyositis (DM) and juvenile DM (JDM), respectively. OBJECTIVES: This study compared the CDASI and CAT-BM for use by paediatric dermatologists, paediatric rheumatologists and paediatric neurologists in patients with JDM. METHODS: Five paediatric dermatologists, five paediatric rheumatologists and five paediatric neurologists each evaluated 14 patients with JDM using the CDASI, CAT-BM, and skin Physician Global Assessment (PGA) scales. Inter-rater reliability, intra-rater reliability, construct validity and completion time were compared. RESULTS: Inter-rater reliability for CDASI activity and damage scores was good to moderate for paediatric dermatologists and rheumatologists, but poor for paediatric neurologists. The inter-rater reliability for CAT-BM activity scores was moderate for paediatric dermatologists and rheumatologists, but poor for paediatric neurologists and poor across all specialties for damage scores. Intra-rater reliability for the CDASI and CAT-BM activity and damage scores was moderate to excellent for paediatric dermatologists, rheumatologists and neurologists. Strong associations were found between skin PGA activity and damage scores and CDASI or CAT-BM activity and damage scores, respectively (P < 0·002). The CDASI had a mean completion time of 5·4 min compared with that for the CAT-BM of 3·1 min. CONCLUSIONS: Our data confirm the reliability of the CDASI activity and damage scores and the CAT-BM activity scores when used by paediatric dermatologists and rheumatologists in assessing JDM. Significant variation existed in the paediatric neurologists' scores.

CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis.

BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. CONCLUSIONS: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. CLINICAL TRIAL REGISTRATION: ID number NCT01193075.

Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy.

BACKGROUND: Genomic copy number variants have been shown to be responsible for multiple genetic diseases. Recently, a duplication in septin 9 (SEPT9) was shown to be causal for hereditary neuralgic amyotrophy (HNA), an episodic peripheral neuropathy with autosomal dominant inheritance. This duplication was identified in 12 pedigrees that all shared a common founder haplotype. METHODS AND RESULTS: Based on array comparative genomic hybridisation, we identified six additional heterogeneous tandem SEPT9 duplications in patients with HNA that did not possess the founder haplotype. Five of these novel duplications are intragenic and result in larger transcript and protein products, as demonstrated through reverse transcription-PCR and western blotting. One duplication spans the entire SEPT9 gene and does not generate aberrant transcripts and proteins. The breakpoints of all the duplications are unique and contain regions of microhomology ranging from 2 to 9 bp in size. The duplicated regions contain a conserved 645 bp exon within SEPT9 in which HNA-linked missense mutations have been previously identified, suggesting that the region encoded by this exon is important to the pathogenesis of HNA. CONCLUSIONS: Together with the previously identified founder duplication, a total of seven heterogeneous SEPT9 duplications have been identified in this study as a causative factor of HNA. These duplications account for one third of the patients in our cohort, suggesting that duplications of various sizes within the SEPT9 gene are a common cause of HNA.

Usage of a fixed dose of radioactive iodine for the treatment of hyperthyroidism: one-year outcome in a regional hospital in Hong Kong.

OBJECTIVES: To evaluate the efficacy of a fixed dose of radioactive iodine (131-I) in the treatment of thyrotoxicosis, and to identify risk factors associated with treatment failure. DESIGN: Retrospective study. SETTING: Thyroid Clinic of a regional hospital in Hong Kong. PATIENTS: Patients receiving their first dose of radioactive iodine for the treatment of thyrotoxicosis during the inclusive period September 1999 to August 2004. MAIN OUTCOME MEASURES: Relapse rate and time to relapse. RESULTS: A total of 113 patients received a fixed dose of 5 mCi (185 MBq), 6 mCi (222 MBq), 8 mCi (296 MBq), and 10 mCi (370 MBq) 131-I in a proportion of 1:6:71:35. At 1 year, 42 (37%) of the patients had relapsed, of which 69% received a second 131-I dose. The median time to relapse after first receiving 131-I was 4 months. At 1 year, the remaining 71 (63%) of the patients were successfully treated; 46 (41%) were euthyroid, and 25 (22%) had became permanently hypothyroid. Basal free thyroxine level and goitre size were significantly associated with a relapse rate after a single dose of 131-I; larger goitres showed a trend towards high rates of relapse. Patients pretreated with propylthiouracil had a higher rate of relapse during the first year after radioactive iodine than those pretreated with carbimazole, but the difference was not significant when combined with other pretreatment variables. CONCLUSIONS: A single fixed dose of radioactive iodine is a simple, safe, and effective treatment for hyperthyroidism. High basal free thyroxine concentration and large goitre size are associated with higher chance of relapse. Higher radioiodine doses may be considered to improve the cure rate.

Autosomal dominant transmission of Dejerine-Sottas disease (HMSN III).

Hereditary motor-sensory neuropathy type III (HMSN III) (Dejerine-Sottas disease) is a severe demyelinating neuropathy that is traditionally considered autosomal recessive. We report a father and daughter diagnosed with HMSN III by clinical, electrophysiologic, and pathologic criteria, thus showing that it may be transmitted in an autosomal dominant fashion in selected families.

Effects of TRH-analog treatment on tissue cations, phospholipids and energy metabolism after spinal cord injury.

Effects of thyrotropin-releasing hormone analog CG3703 on biochemical changes following impact spinal cord trauma were investigated by 31P magnetic resonance spectroscopy, atomic absorption spectrophotometry, high-pressure liquid chromatography and radioimmunoassay using parallel injury models in rabbits and rats. Treatment with CG3703 at 45 min after trauma in rabbits significantly attenuated decreases in intracellular pH and reversed increases in phosphodiester to phosphomonoester ratio, as shown by 31P magnetic resonance spectroscopy. The improved phosphodiester/phosphomonoester ratio was correlated with improved ATP status after treatment, although there was no improvement in aerobic bioenergetic capacity as reflected by phosphocreatine to inorganic phosphate ratios. In rats, treatment with CG3703 significantly reduced changes in tissue cations (Na+, K+, Mg2+) and water content following trauma, but did not significantly alter the accumulation of free fatty acids or thromboxane B2. Thus, the beneficial effects of treatment with thyrotropin-releasing hormone or thyrotropin-releasing hormone analogs on outcome following traumatic spinal cord injury may be due, in part, to actions relating to ion homeostasis.

Lipid alterations correlate with tissue magnesium decrease following impact trauma in rabbit spinal cord.

Secondary neurochemical events contribute to progressive tissue damage and subsequent neurological deficit after traumatic spinal-cord injury (SCI). Among proposed injury factors are alterations of phospholipids and certain cations. To clarify the relationship of membrane lipid changes (phospholipids, cholesterol, and arachidonic acid) to changes in tissue content of water and selected ions (sodium, potassium, and magnesium) after SCI, these variables were examined in spinal-cord segments from anesthetized ventilated rabbits subjected to laminectomy or to moderate (40 g-cm) or severe (150 g-cm) impact trauma at the lumbar (L2) segment. Trauma caused significant increases in tissue sodium, water, and arachidonic acid content, and significant decreases in phospholipids, cholesterol, potassium, and magnesium content. Alterations in magnesium were significantly related to injury severity. In contrast, changes in spinal-cord water content occurred to a similar degree in the two injury groups, as did tissue sodium and potassium content. Decreases in phospholipids were strongly correlated with decreases in tissue magnesium content, whereas changes in sodium and potassium were less well-correlated. Because magnesium ions play a critical role with regard to cellular bioenergetic state, calcium flux, amino acid receptor function, and eicosanoid production, reductions in tissue magnesium after injury may be important in the progression of secondary tissue damage.

Comparison of the neuroprotective effects of the N-methyl-D-aspartate antagonist MK-801 and the opiate-receptor antagonist nalmefene in experimental spinal cord ischemia.

Both N-methyl-D-aspartate (NMDA)-receptor antagonists and opiate-receptor antagonists have been shown to limit tissue damage after ischemic central nervous system injury. We compared the neuroprotective effects of the noncompetitive NMDA-receptor antagonist MK-801 and the opiate-receptor antagonist nalmefene in a model of global spinal cord ischemia and reperfusion in unanesthetized rabbits. MK-801 (1 mg/kg) or nalmefene (0.1 mg/kg) was administered intravenously 5 minutes after reperfusion. MK-801 treatment and nalmefene treatment each significantly improved the neurologic and histologic outcome compared with saline controls. Differences in these outcome measures between MK-801 treatment and nalmefene treatment did not reach statistical significance. Our results are consistent with the hypothesis that multiple factors, including endogenous opioids and excitatory amino acids, contribute to the secondary tissue injury after central nervous system ischemia. These data also provide further evidence that therapeutic interventions with opiate-receptor antagonists or NMDA antagonists may be beneficial in limiting neurologic dysfunction after ischemic brain or spinal cord injury.

Alteration in extracellular amino acids after traumatic spinal cord injury.

It has recently been demonstrated that N-methyl-D-aspartate antagonists limit tissue damage after spinal cord trauma, implicating excitatory amino acids in the secondary injury response. To determine whether spinal cord trauma alters the concentrations of extracellular amino acids, microdialysis was conducted in spinal cord during and after administration of impact trauma. Extracellular concentrations of excitatory, inhibitory, and nontransmitter amino acids were elevated after trauma, with the degree of increase related to severity of injury. Moderate trauma resulted in an immediate but transient increase (200-400%) in the extracellular levels of all amino acids measured. Severe trauma produced a more prolonged and significant increase (400-630%) in the concentrations of extracellular amino acids, including aspartate and glutamate. These results are consistent with the hypothesis that excitatory amino acids may contribute to delayed tissue injury after central nervous system trauma.

Traumatic spinal cord injury in rabbits decreases intracellular free magnesium concentration as measured by 31P MRS.

The mechanisms by which traumatic injury to the central nervous system cause irreversible tissue damage remain speculative. Recent reports suggest that a decrease in tissue total and free Mg2+ concentration may be an important factor in the development of such injury after experimental brain trauma. Although total Mg changes have been reported following spinal cord trauma, no studies have examined spinal cord-free Mg2+. In the present study, we have used phosphorus magnetic resonance spectroscopy to determine intracellular free Mg2+ concentration and atomic absorption spectrophotometry to measure total tissue Mg concentration in rabbit spinal cord prior to and following impact trauma. We report that intracellular free Mg2+ concentration decreases from a pre-injury value of 0.80 +/- 0.12 mM (mean +/- S.E.M.) to 0.31 +/- 0.05 mM at 2 h post-trauma. Following injury there was an associated decrease in total tissue Mg and K concentration, but no alterations in tissue Na or water content.