James Nelson

Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial

To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis.

Identification of Intron and Exon Sequences Involved in Alternative Splicing of Insulin Receptor Pre-mRNA

The insulin receptor exists as two isoforms, A and B, that result from alternative splicing of exon 11 in the primary transcript. We have shown previously that the alternative splicing is developmentally and hormonally regulated. Consequently, these studies were instigated to identify sequences within the primary RNA transcript that regulate the alternative splicing. Minigenes containing exons 10, 11, and 12 and the intervening introns were constructed and transfected into HepG2 cells, which contain both isoforms of the insulin receptor. The cells were able to splice the minigene transcript to give both A (− exon 11) and B-like (+ exon 11) RNAs. A series of internal deletions within intron 10 were tested for their ability to give A and B RNAs. Intron 10 contained two sequences that modulated exon 11 inclusion; a 48-nucleotide purine-rich sequence at the 5′ end of intron 10 that functions as a splicing enhancer and causes an increase in exon 11 inclusion, and a 43-nucleotide sequence at the 3′ end of intron 10 upstream of the branch point sequence that favors skipping of exon 11. Increasing the length of the polypyrimidine tract at the 3′ end of intron 10 caused exon 11 to be spliced constitutively, indicating that a weak splice site is required for alternative splicing. Finally, point mutations, insertions, and deletions within exon 11 itself were able to regulate inclusion of the exon both positively and negatively.

The PROMiSe trial: baseline data review and progress report

The PRO MiSe trial is a multinational, multicentre, double-blind, placebo -controlled trial evaluating the effects of glatiramer acetate treatment over 3 years in patients with primary progressive multiple sclerosis (PPMS). A total of 943 patients were enrolled, and all those remaining on-study had completed at least 24 months as of O ctober 2002. Baseline clinical and MRI character istics and select correlations are reported here. A total of 3.9% of patients exhibited confirmed relapse over 1904 patient-years of exposure, indicating success of efforts to exclude relapsing MS types. O f the 26.3% of patients who have prematurely withdrawn from the study, only 36% discontinued after meeting the study primary endpoint of disease progression. The progression rate in patients in the low Expanded Disability Status Scale (EDSS) stratum (3.0-5.0) observed thus far is markedly lower than the 50% annual progression rate estimate used for determining size and statistical power of the trial; progression was observed in 16.1% of patients with 12 months of study exposure. These early findings raise some concern about the ability of the trial to demonstrate a significant treatment effect, and suggest that the short-term natural history of PPMS may not be as aggressive as previously assumed.

The obesity-hypoventilation syndrome and respiratory failure in the acute trauma patient.

BACKGROUND The Emergency Department experience, for many patients, involves procedures and therapies that can compromise ventilation. In the acute trauma patient, these include spinal immobilization, supine positioning, and the administration of sedative and analgesic medications. Patients with the obesity-hypoventilation syndrome have a syndrome distinct from mere obesity, and are more sensitive to these insults. OBJECTIVE To describe a case of respiratory failure in a patient with the obesity-hypoventilation syndrome resulting from injuries and therapies that in any other patient would not be expected to cause respiratory failure. CASE REPORT A 59-year-old woman suffered a mechanical fall, fractured her T6 vertebral body and right proximal humerus, and, after spinal immobilization and the administration of routine doses of opioid analgesics, suffered significant hypoxemia and respiratory acidosis. Reversal agents were ineffective, but non-invasive mechanical ventilation restored adequate respiration. CONCLUSION Although obesity-hypoventilation syndrome occurs in only a minority of morbidly obese patients, it is important because the consequences of respiratory failure can be severe if not recognized and anticipated. Such patients will not be able to adequately increase ventilation in response to mounting hypercapnia. The condition is easily addressed through non-invasive ventilation.

COMPARTMENT PRESSURE MEASUREMENTS HAVE POOR SPECIFICITY FOR COMPARTMENT SYNDROME IN THE TRAUMATIZED LIMB

BACKGROUND Osseofascial compartment syndrome is defined by ischemic necrosis of muscle caused by elevated pressure within fascial compartments. The diagnosis can be made either clinically or through compartment pressure measurements. Compartment pressure above 30 mm Hg was traditionally used as the threshold for diagnosis of compartment syndrome, but was challenged due to a high number of false-positive results. Perfusion pressure (diastolic blood pressure - compartment pressure) <30 mm Hg came to be promoted as a confirmatory diagnostic test. OBJECTIVE The objective of this article is to review the specificity of perfusion pressure for compartment syndrome in the acutely traumatized limb. DISCUSSION Perfusion pressure has been shown to generate false-positive results in 18-84% of patients with tibial fractures. Two studies showed that not a single patient with measurements qualifying for fasciotomy actually needed the procedure. CONCLUSION Both absolute compartment pressure and tissue perfusion pressure generate a high rate of false-positive results in the acutely traumatized limb. An alternative diagnostic test or process is needed to prevent overtreatment. In the meantime, emergency medicine and orthopedic surgery textbooks and guidelines should promote awareness of the limitations of the test.

Safe emergency department removal of a hardened steel penile constriction ring.

BACKGROUND Penile constriction devices are used for the enhancement of sexual performance. These devices have the potential to become incarcerated, leading to necrosis and amputation if not removed promptly. OBJECTIVE This article presents a step-by-step approach for the safe removal of a hardened steel penile constriction device using somewhat unorthodox tools found in a hospital. CASE REPORT We present a case of an incarcerated hardened steel penile constriction ring that was not able to be removed with conventional techniques. We describe a novel technique using an electric grinder and laryngoscope blade. CONCLUSION The technique described in this article is a valuable and relatively safe technique for the Emergency Physician to facilitate the timely removal of a hardened steel constriction device.

Rapid whole genome sequencing identifies a novel GABRA1 variant associated with West syndrome

A 9-mo-old infant was admitted with infantile spasms that improved on administration of topiramate and steroids. He also had developmental delay, esotropia, and hypsarrhythmia on interictal electroencephalogram (EEG), and normal brain magnetic resonance imaging (MRI). West syndrome is the triad of infantile spasms, interictal hypsarrhythmia, and mental retardation. Rapid trio whole-genome sequencing (WGS) revealed a novel, likely pathogenic, de novo variant in the gene encoding γ-aminobutyric acid (GABA) type A receptor, α1 polypeptide (GABRA1 c.789G>A, p.Met263Ile) in the proband. GABRA1 mutations have been associated with early infantile epileptic encephalopathy type 19 (EIEE19). We suggest that GABRA1 p.Met263Ile is associated with a distinct West syndrome phenotype.

Electrocardiographic manifestations: wide complex tachycardia due to accessory pathway.

Tachycardia with a wide QRS complex is usually due to ventricular tachycardia (VT), supraventricular tachycardia (SVT) with aberrant intraventricular conduction, or an accessory pathway-mediated dysrhythmia. The most common type of accessory pathway causing a wide complex tachycardia is the atrioventricular bypass tract. Distinguishing the accessory pathway-mediated tachycardia from VT or SVT with aberrancy is often difficult, but has important clinical consequences. This article will review the diagnosis of wide complex tachycardia due to an accessory pathway and its related management in the emergent setting.