GM2 gangliosidosis associated with a HEXA missense mutation in Japanese Chin dogs: A potential model for Tay Sachs disease

GM2 gangliosidosis is a fatal lysosomal storage disease caused by a deficiency of β-hexosaminidase (EC 3.2.1.52). There are two major isoforms of the enzyme: hexosaminidase A composed of an α and a β subunit (encoded by HEXA and HEXB genes, respectively); and, hexosaminidase B composed of two β subunits. Hexosaminidase A requires an activator protein encoded by GM2A to catabolize GM2 ganglioside, but even in the absence of the activator protein, it can hydrolyze the synthetic substrates commonly used to assess enzyme activity. GM2 gangliosidosis has been reported in Japanese Chin dogs, and we identified the disease in two related Japanese Chin dogs based on clinical signs, histopathology and elevated brain GM2 gangliosides. As in previous reports, we found normal or elevated hexosaminidase activity when measured with the synthetic substrates. This suggested that the canine disease is analogous to human AB variant of G_M2 gangliosidosis, which results from mutations in GM2A. However, only common neutral single nucleotide polymorphisms were found upon sequence analysis of the canine ortholog of GM2A from the affected Japanese Chins. When the same DNA samples were used to sequence HEXA, we identified a homozygous HEXA:c967G>A transition which predicts a p.E323K substitution. The glutamyl moiety at 323 is known to make an essential contribution to the active site of hexosaminidase A, and none of the 128 normal Japanese Chins and 92 normal dogs of other breeds that we tested was homozygous for HEXA:c967A. Thus it appears that the HEXA:c967G>A transition is responsible for the GM2 gangliosidosis in Japanese Chins.     

50th anniversary of the discovery of ibuprofen: an interview with Dr Stewart Adams

2011 marks the 50th anniversary of the discovery of ibuprofen. This article is a focus on the personal reflections and career of Dr Stewart Adams OBE, the scientist whose research lead to the discovery of the cyclooxygenase inhibitor. When Dr Adams discovered ibuprofen, he was working as a pharmacologist in the Research Department for the Boots Pure Drug Company Ltd. Dr Adams was assigned to work on rheumatoid arthritis (RA) and chose in 1953 to search for a drug that would be effective in RA but would not be a corticosteroid. He was one of the first workers in this field that later became known as NSAIDs (Non-Steroidal Anti Inflammatory Drugs). In 1961, Dr Adams with John Nicholson, the organic chemist, filed a patent for the compound 2-(4-isobutylphenyl) propionic acid, later to become one of the most successful NSAIDs in the modern world, ibuprofen. In this article, Dr Adams gives his modest insight into the early stages and initial observations which led to this world-wide success.     

Every-other-week methotrexate in patients with rheumatoid arthritis

Objective. To determine if patients with rheumatoid arthritis (RA) that is stable with weekly methotrexate (MTX) therapy could be switched to an every-other-week regimen of MTX. Methods. Forty-seven patients with classic or definite RA who had received MTX for at least 8 months were studied. Clinical measurements consisted of the number of tender and swollen joints, physician and patient global evaluation of disease activity on a 5-point scale, grip strength, patient evaluation of pain, morning stiffness, and the interval to onset of fatigue from time of awakening. Laboratory measures included the erythrocyte sedimentation rate (ESR), rheumatoid factor, C-reactive protein (CRP), and baseline serum folate levels. Uptake of MTX was measured with tritiated thymidine from peripheral blood mononuclear cells (PBMC) from patients ex vivo. Serum measures of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNFα) were performed in sera, and TNFα was also measured on PBMC supernatants. Results. Twelve of the 23 patients receiving every-other-week MTX (52%) were able to complete 6 months of this treatment without experiencing a disease flare. Eleven of the 23 patients receiving every-other-week MTX (48%) withdrew from the study before completing 6 months of treatment, because of a flare. No significant differences in clinical or laboratory parameters were seen when the 24 patients receiving weekly MTX were compared with the 12 patients in the every-other-week MTX group who successfully completed 6 months of the study. None of the changes in serum cytokine levels were significantly different between the patients receiving MTX weekly versus those receiving it every other week, and changes in ESR and CRP did not differ between groups. Age, sex, RA disease duration, MTX weekly dose or duration, baseline joint counts, or serum folate status did not predict a flare. Tritiated MTX uptake did not differ between groups. Conclusion. Some patients with RA that is stable on weekly dosing are able to change to every-other-week dosing without experiencing a flare in their disease activity.     

A descriptive study of foot problems in children with juvenile rheumatoid arthritis (JRA)

In this study, we evaluated the feet of 144 consecutive children with juvenile rheumatoid arthritis (JRA) during a routine outpatient visit to discover patterns of foot problems. We found that all but nine subjects had at least 1 of 21 foot problems, categorized as inflammation, limitation of motion, and abnormal alignment. Overall, pronated rearfoot and midfoot were observed in 73% and 72% of JRA patients, respectively. Additionally, 36% had splayfoot, whereas 35% of subjects had ankle limitation of motion. Other common foot problems included pronated forefoot, rearfoot and forefoot synovitis, forefoot limitation of motion, and toe valgus. Significant differences in the occurrence of various foot problems were observed among JRA onset/course subgroups and were influenced by both age and disease duration. Specifically, subjects with polyarticular JRA had more forefoot limitation and toe valgus, whereas subjects with pauciarticular JRA had pronated forefoot more often. Ankle limitation of motion, although unrelated to the JRA subgroup, was related to the duration of JRA. Subjects with longer disease histories also had toe valgus more often. Conversely, forefoot limitation of motion seemed to be more a function of age than of disease duration. These results indicate that foot problems are common in the JRA population, and they underscore the need for thorough evaluation and physical therapy management.     

Congenital erosive and vesicular dermatosis with reticulated supple scarring

Congenital erosive and vesicular dermatosis with reticulated supple scarring is a rare cutaneous disorder of unknown aetiology first described by Cohen and colleagues in 1985. It classically presents in the neonate as erosions and vesicles that heal within the first months of life, with supple scarring of a reticulated pattern. Along with a review of the literature, this article presents two atypical cases of congenital erosive and vesicular dermatosis with reticulated supple scarring. Patient one presented with neither erosions nor vesicles at birth, yet continued to experience sporadic blistering at the age of 15 months and patient two is the second documented case to develop congenital erosive and vesicular dermatosis after birth.