Fractures of the clivus: classification and clinical features

Fractures of the clival complex were diagnosed in a series of 17 patients admitted to the Maryland Institute for Emergency Medical Services System and the University of Maryland Medical System over a 30-month period. These fractures were divided pathologically into three types based upon their appearance on computed tomography: longitudinal, transverse, and oblique. The mechanisms of injury were similar in all groups, and the Glasgow Coma Scale scores at admission were comparable, regardless of fracture type, in survivors and nonsurvivors. Longitudinal fractures were associated with severe injury to the central nervous system and with brain stem infarction, and 4 of 6 (67%) of these patients died. Transverse fractures of the clival complex were found in 6 patients, 3 of whom (50%) died. All of these patients had fractures of the petrous ridge; 2 of the 3 survivors had multiple cranial nerve deficits, and one patient developed a carotid-cavernous fistula. Of the 5 patients with oblique clival fractures, 2 survived (40%), both of whom had multiple cranial nerve palsies; in addition, one of these patients developed a carotid-cavernous fistula. Using the present generation of computed tomographic scanners, fractures of the clival complex can be reliably diagnosed; they are probably more common than previously believed and can be separated into three groups based on the characteristics on computed tomographic scans and clinical findings.     

Successful Pregnancy in the Didmoad Syndrome (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness)

Summary: A case of successful pregnancy in a patient with the complete DIDMOAD syndrome is described. Attention is drawn to the need to monitor fluid balance carefully during and after pregnancy in this condition. The current literature in the area is reviewed.     

Specificity and mechanism of the histone methyltransferase Pr-Set7

Methylation of lysine residues of histones is an important epigenetic mark that correlates with functionally distinct regions of chromatin. We present here the crystal structure of a ternary complex of the enzyme Pr-Set7 (also known as Set8) that methylates Lys 20 of histone H4 (H4-K20). We show that the enzyme is exclusively a mono-methylase and is therefore responsible for a signaling role quite distinct from that established by other enzymes that target this histone residue. We provide evidence from NMR for the C-flanking domains of SET proteins becoming ordered upon addition of AdoMet cofactor and develop a model for the catalytic cycle of these enzymes. The crystal structure reveals the basis of the specificity of the enzyme for H4-K20 because a histidine residue within the substrate, close to the target lysine, is required for completion of the active site. We also show how a highly variable component of the SET domain is responsible for many of the enzymes' interactions with its target histone peptide and probably also how this part of the structure ensures that Pr-Set7 is nucleosome specific.     

Pharmacokinetics of CAMPATH-1H: assay development and validation

CAMPATH-1H is a humanised monoclonal antibody against the CD52 antigen which is being developed for treatment of chronic lymphocytic leukaemia (CLL), autoimmune disease and prevention of transplant rejection. Measurement of antibody serum levels is important for optimising dose regimens but difficult owing to the low concentration compared with normal human IgG.

After consideration of various methods, a suitable assay was developed based on indirect immunofluorescence. Test samples were incubated with target cells (HUT-78, a human T cell line) and the CAMPATH-1H was detected by binding of a fluorescent-labelled anti-human Ig using a flow cytometer. Robustness of the assay was demonstrated under a range of experimental conditions. Because of the low affinity of CAMPATH-1H, only a weak signal was seen at low concentrations. The limit of detection was 0.15 μg/ml and the limit of quantitation was 0.25 μg/ml. Since serum samples were diluted at least 1:2, the lowest concentration which can be measured in patient serum was 0.5 μg/ml. The overall precision (coefficient of variation) was ±13% and the overall accuracy (bias) was +9%. There was a low incidence of false-positive results (<2%) in normal or pre-treatment patient serum. Quantitative recovery was obtained from serum samples spiked with CAMPATH-1H and stored under a variety of conditions, including being treated at 56 °C for 30 min and frozen and thawed up to four times.

This validated assay is suitable for the measurement of CAMPATH-1H levels in clinical trials and the same principles may be applied to any other cell-binding monoclonal antibody.