The 2.0-Å resolution crystal structure of a trimeric antibody fragment with noncognate VH–VL domain pairs shows a rearrangement of VH CDR3

The 2.0-Å resolution x-ray crystal structure of a novel trimeric antibody fragment, a “triabody,” has been determined. The trimer is made up of polypeptides constructed in a manner identical to that previously described for some “diabodies”: a V_L domain directly fused to the C terminus of a V_H domain—i.e., without any linker sequence. The trimer has three Fv heads with the polypeptides arranged in a cyclic, head-to-tail fashion. For the particular structure reported here, the polypeptide was constructed with a V_H domain from one antibody fused to the V_L domain from an unrelated antibody giving rise to “combinatorial” Fvs upon formation of the trimer. The structure shows that the exchange of the V_L domain from antibody B1-8, a V_λ domain, with the V_L domain from antibody NQ11, a V_κ domain, leads to a dramatic conformational change in the V_H CDR3 loop of antibody B1-8. The magnitude of this change is similar to the largest of the conformational changes observed in antibody fragments in response to antigen binding. Combinatorial pairing of V_H and V_L domains constitutes a major component of antibody diversity. Conformationally flexible antigen-binding sites capable of adapting to the specific CDR3 loop context created upon V_H–V_L pairing may be employed by the immune system to maximize the structural diversity of the immune response.     

Anorectal function in the solitary rectal ulcer syndrome

The anorectal function of nine patients with solitary rectal ulcer syndrome (SRUS) (5 F: 4 M, median age, 27 (range, 19–41 years) and nine control subjects (5 F: 4 M, median age, 47 (35–66)P<0.01) has been investigated by a new technique that radiologically visualizes the anorectum during voiding of a semisolid contrast medium, while simultaneously measuring intrarectal pressure and anal sphincter EMG activity. A degree of rectal prolapse was demonstrated in eight of the SRUS patients; six of these lesions were clinically occult. Abnormal failure of the anal sphincter to relax on voiding was present in seven of the SRUS patients. These abnormalities resulted in the SRUS patients requiring a greater increase in intrarectal pressure (median, 100 cm water) to void than the control subjects (median, 65 cm water,P<0.01). This combination of high intrarectal pressure and rectal prolapse during straining seems to be the cause of SRUS This work was supported by a grant from the Medical Research Council.     

Endoscopic balloon dilatation as a therapeutic option in the management of intestinal strictures resulting from Crohn's disease

Endoscopic balloon dilatation was undertaken in seven patients who presented with obstructive symptoms resulting from Crohn's disease. Five patients had strictures from recurrent disease at the site of an ileotransverse anastomosis, one had duodenal stenosis and one a colonic stricture. The procedures were performed under intravenous sedation on one to four occasions (median 2) and were uncomplicated. Sustained improvement over an 18-24-month follow-up period was achieved in five patients, but dilatation was unsuccessful in two cases. Endoscopic balloon dilatation is a safe and effective option in selected patients with intestinal strictures resulting from Crohn's disease and may overcome the need for surgery.     

A qualitative investigation of seniors' and caregivers' views on pain assessment and management.

The literature suggests that pain in the elderly, especially among seniors with dementia, is under-assessed and under-treated.This qualitative study solicited the perspectives of seniors, front-line nursing staff, nursing-home administrators, and informal caregivers of seniors with dementia on the current status of pain assessment and management. The views of these participants complement the research findings reported in the literature. While some of their explanations and potential solutions concerning under-treatment of pain in seniors echo views that have been presented in the literature, the participants also pointed to factors and avenues that have been given less formal consideration (e.g., systemic barriers to effective assessment and treatment of pain).They also highlighted the need for pain-control strategies beyond medication. The implications of these findings are discussed.