Autosomal recessive spastic ataxia of Charlevoix-Saguenay: compound heterozygotes for nonsense mutations of the SACS gene

Mutations of the SACS gene have been reported in patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay from Canada (Quebec), Tunisia, Japan, Turkey, Belgium, Italy, Spain, the Netherlands, and Germany. Features that distinguish autosomal recessive spastic ataxia of Charlevoix-Saguenay from other recessive ataxias include sensory motor polyneuropathy and hypermyelinated retinal nerve fibers. We describe the clinical, electrophysiological, and radiological features in 2 white American siblings diagnosed with autosomal recessive spastic ataxia of Charlevoix-Saguenay. The 2 affected children are compound heterozygotes for nonsense mutations of the SACS gene (c. 3484 G>T, p. E 1162 X; and c. 11,707 C>T, p. R 3903 X). We have measured allele-specific SACS mRNA abundance in peripheral blood and show that these specific mutant mRNAs are not degraded. We suggest that in children with early onset cerebellar ataxia and spasticity, ophthalmological examination and nerve conduction testing may guide genetic testing.     

Bilateral symmetrical periprosthetic (mirror) fractures of knee fixed with dual plating technique

Introduction

Periprosthetic fracture following total knee arthroplasty is a potentially serious condition. Here we report a case of bilaterally symmetrical (mirror) fracture of supracondylar area following trivial trauma.

Presentation of case

Both fractures were OTA 33A2 and according to Rorabeck classification they were type II. Both fractures were fixed by dual plating technique using non locking plates. Intra operative fracture site biopsy revealed marked osteopenia and hence the patient was treated for osteoporosis.

Discussion

Both fractures united well at 14 weeks. At final follow up of 6 years there were no radiological signs of implant loosening and the patient was able to walk without any aids and had a range of 80° and 60° flexion in the right and left knees respectively.

Conclusion

We conclude that in the pre locking plate''s era such difficult case has been successfully managed by dual plating technique.     

Isoform-specific toxicity of Mecp2 in postmitotic neurons: suppression of neurotoxicity by FoxG1

The methyl-CpG binding protein 2 (MeCP2) is a widely expressed protein, the mutations of which cause Rett syndrome. The level of MeCP2 is highest in the brain where it is expressed selectively in mature neurons. Its functions in postmitotic neurons are not known. The MeCP2 gene is alternatively spliced to generate two proteins with different N termini, designated as MeCP2-e1 and MeCP2-e2. The physiological significance of these two isoforms has not been elucidated, and it is generally assumed they are functionally equivalent. We report that in cultured cerebellar granule neurons induced to die by low potassium treatment and in Aβ-treated cortical neurons, Mecp2-e2 expression is upregulated whereas expression of the Mecp2-e1 isoform is downregulated. Knockdown of Mecp2-e2 protects neurons from death, whereas knockdown of the e1 isoform has no effect. Forced expression of MeCP2-e2, but not MeCP2-e1, promotes apoptosis in otherwise healthy neurons. We find that MeCP2-e2 interacts with the forkhead protein FoxG1, mutations of which also cause Rett syndrome. FoxG1 has been shown to promote neuronal survival and its downregulation leads to neuronal death. We find that elevated FoxG1 expression inhibits MeCP2-e2 neurotoxicity. MeCP2-e2 neurotoxicity is also inhibited by IGF-1, which prevents the neuronal death-associated downregulation of FoxG1 expression, and by Akt, the activation of which is necessary for FoxG1-mediated neuroprotection. Finally, MeCP2-e2 neurotoxicity is enhanced if FoxG1 expression is suppressed or in neurons cultured from FoxG1-haplodeficient mice. Our results indicate that Mecp2-e2 promotes neuronal death and that this activity is normally inhibited by FoxG1. Reduced FoxG1 expression frees MecP2-e2 to promote neuronal death.     

Misplaced peripherally inserted central catheter: an unusual cause of stroke

Stroke in pediatric patients occurs with a frequency of 3 to 8 per 100,000. The postevent evaluation attempts to identify the etiology of ischemia whether anatomic, hematologic, or embolic, with the intention of preventing future events. We present the case of a previously healthy male who developed unilateral facial and extremity weakness 2 weeks after receiving an appendectomy. Once the usual etiologies of stroke in pediatric patients were excluded, an evaluation of the peripheral venous catheter (placed for postoperative antibiotic delivery) demonstrated arterial misplacement. This article presents the first reported case of such an occurrence in the literature and exhibits the need to pursue all avenues of evaluation if the etiology of a pediatric stroke is not initially identified.     

Adult presentation of congenital ectopic vas deferens insertion into ureter with unilateral renal agenesis

Congenital vas deferens–ureteral connection is known to cause epididymitis and scrotal infections in infancy and childhood. Embryologically, the anomaly results from an abnormal high origin of the ureteric bud on the mesonephric duct with a resultant long common excretory duct being incompletely absorbed into the bladder. This report describes a rare adult presentation in a 20-year-old man where evaluation with ultrasonograms, isotope renogram, magnetic resonance imaging scans and cystoscopy with retrograde instillation of contrast into the right ureter confirmed aberrant insertion of vas deferens into the ureter associated with ureterocele and ipsilateral renal agenesis.     

Inter-rater reliability of manual muscle strength testing in ICU survivors and simulated patients

Objective  

The goal of the paper is to determine inter-rater reliability of trained examiners performing standardized strength assessments using manual muscle testing (MMT).     

Genetic aspects of neurocutaneous disorders

Among the conditions that are included under the heading of "neurocutaneous disorders" are neurofibromatosis 1, tuberous sclerosis complex, von Hippel-Lindau, incontinentia pigmenti, Sturge-Weber syndrome, hypomelanosis of Ito, and linear nevus sebaceous syndromes. The clinical features, pathogenesis, and neurobiological basis of some of these disorders are discussed in other articles in this issue. We will focus on genetic aspects of a selected subgroup of these conditions, concentrating on the genetic defect, mutation spectrum, clinical genetic testing, and issues pertinent to counseling.     

Inhibition of matrix metalloproteinase‐2 enhances radiosensitivity by abrogating radiation‐induced FoxM1‐mediated G2/M arrest in A549 lung cancer cells

Matrix metalloproteinase‐2 (MMP‐2), is known to degrade the collagen IV, plays a role in radiation‐induced lung injury. We therefore investigated the antitumor effects of combining MMP‐2 inhibition using an adenovirus expressing siRNA against MMP‐2 (Ad‐MMP‐2‐Si) with radiation therapy (IR) on A549 lung cancer cells in vitro and in vivo. IR increased MMP‐2 mRNA, protein and activity in lung cancer cells. MMP‐2 inhibition along with IR enhanced radiosensitivity as determined by clonogenic assay, flow cytometry and TUNEL assay. We show that MMP‐2 inhibition prior to irradiation reduced p53 phosphorylation, with a corresponding reduction in the expression of the p53 downstream target gene p21^Cip1/Waf1. Irradiated tumor cells induced the FoxM1‐mediated DNA repair gene, XRCC1 and Checkpoint kinases 2/1, which were abrogated with combined treatment of Ad‐MMP‐2‐Si and IR. Further, the combination of Ad‐MMP‐2‐Si with radiotherapy significantly increased antitumor efficacy in vivo compared to either agent alone. Indeed, histological analysis of tumor sections collected from the combination group revealed more apoptotic cells. These studies suggest that MMP‐2 inhibition in combination with radiotherapy abrogates G2 cell cycle arrest leading to apoptosis and provide evidence of the antitumor efficacy of combining MMP‐2 inhibition with irradiation as a new therapeutic strategy for the effective treatment of NSCLC patients. © 2008 Wiley‐Liss, Inc.     

Pharmacokinetics of paclitaxel administered in combination with cisplatin, etoposide and bleomycin in patients with advanced solid tumours

 Purpose: To evaluate the pharmacokinetics of paclitaxel and cisplatin administered in combination with bleomycin and etoposide and Granulocyte Colony-Stimulating Factor (G-CSF) in patients with advanced solid tumours. Methods: Patients were recruited to a phase I trial where escalating doses of paclitaxel (125 to 200 mg/m²) were administered in combination with etoposide 100 or 120 mg/m², and fixed dose of cisplatin 20 mg/m² and bleomycin 30 mg, with the concomitant use of G-CSF. Paclitaxel (3-h infusion) was followed by 1-h etoposide, 4-h cisplatin and 30-min bleomycin infusions, respectively. Pharmacokinetics sampling for paclitaxel analysis was performed in ten patients from dose levels II–V. Results: The mean paclitaxel area under the plasma concentration-versus-time curves (AUC) for the 125-mg/m² dose level (II) was 7.0 ± 3.6 h μmol⁻¹ l⁻¹, for the 175-mg/m² dose level (III) 10.6 ± 2.8 h μmol⁻¹ l⁻¹, for the 200-mg/m² dose level (IV) it was 16.0 ± 5.0 h μmol⁻¹ l⁻¹, and for the 175-mg/m² dose level (V) it was 12.5 ± 6.1 h μmol⁻¹ l⁻¹. The mean peak plasma concentration (C_max) values for dose levels II–V were 1.9 ± 1.1 μmol/l, 3.4 ± 1.2 μmol/l, 4.3 ± 1.0 μmol/l and 3.8 ± 1.2 h μmol/l, respectively. Conclusion: In this study, relevant pharmacokinetic parameters of paclitaxel like AUC, C_max and the paclitaxel plasma concentration above the pharmacologically relevant 0.1-μmol/l threshold concentration (t > 0.1 μM) when administered in combination with cisplatin, etoposide and bleomycin (PEB) were not statistically different from paclitaxel data of historical controls. However, given the trial design, pharmacokinetic interactions between the agents cannot be excluded. Received: 29 June 1998 / Accepted: 29 January 1999