Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease.

Factors that influence response to drug treatment are of increasing importance. We report an analysis of genetic factors affecting response to cholinesterase inhibitor therapy in 165 subjects with Alzheimer's disease (AD). The presence of apolipoprotein E ε4 (APOE ε4) allele was associated with early and late cognitive response to cholinesterase inhibitor treatment in mild AD (Mini-Mental State Examination (MMSE) ≥21) (P<0.01). In moderate-to-severe AD (MMSE ≤15), presence of the BCHE-K variant was associated with late response to cholinesterase inhibitor treatment (P=0.02). Testing for APOE and BCHE genotypes may be useful in therapeutic decision making.

Myelodysplasia terminating in acute myeloid leukemia in a hairy cell leukemia patient treated with 2-deoxycoformycin.

Purine analogs are effective in the treatment of several chronic lymphoproliferative disorders (CLPD) including hairy cell leukemia (HCL). To date, little evidence exists that these drugs are oncogenic. We report a case of HCL in a 66-year-old male treated with 2-deoxycoformycin. Just over 1 year following completion of his treatment, falling platelet and white cell counts were associated with the development of dysplastic features in his bone marrow and a rising blast cell count, culminating in the development of acute myeloid leukemia (AML). To the best of our knowledge only two previous cases of AML have been linked to treatment of HCL with purine analogs, both with 2-chlorodeoxyadenosine. We emphasize the need for long term follow up of patients treated with purine analogs and suggest that even those who are apparently cured be monitored periodically.

When the drug trial fails: an approach to clinical drug studies.

Drug development involves the chemical identification and characterization of a compound to determine stability and define the drug's preliminary actions. Preclinical research follows in animals to develop a pharmacokinetic profile to determine dose range, biotransformation, elimination, and toxicology. The 4 phases of clinical research, phase 1 to phase 4, encompass a progressive investigation of healthy subjects, otherwise healthy patients, to patients with a target disease to obtain US Food and Drug Administration (FDA) approval. Clinical studies include open-label noncomparative studies during phases 1 and 2, and double-blind, comparative, and placebo-controlled studies during phases 2 and 3. Approval from the FDA follows the successful evaluation of the drug. After drug marketing, phase 4 clinical trials continue to collect safety and efficacy information. Many drugs that undergo this drug development process succeed in obtaining FDA approval and are marketed for clinical use. There are several circumstances, however, that preclude the successful completion of drug development, FDA approval, and marketing. This study describes a clinical trial of a new benzodiazepine, Ro 48-6791. Ro 48-6791 was being developed as an ultra-short-acting benzodiazepine with clinical effects of shorter duration than midazolam. The purpose of this study was to define a safe dose range for the induction and maintenance of conscious sedation of patients in an outpatient gastroenterology laboratory. Efficacy criteria to be evaluated included time to onset of action, duration of action, and psychomotor fitness upon recovery. Patients were assessed by using the Observer's Assessment of Alertness/Sedation score (OAA/S) and a 5-m heel-toe-line-walk test (HTLW). The patients were divided into 2 groups. Group 1 patients received Ro 48-6791. Group 2 patients were premedicated with meperidine before administration of Ro 48-6791. Ro 48-6791 was titrated over 30 seconds, and patients were observed for 90 seconds before the next dose was given. The OAA/S score, oxygen saturation, and vital signs were charted every minute through induction and every 5 minutes during the procedure. Patients received Ro 48-6791 until they reached on OAA/S score of 3, corresponding to slowed patient response to name calling. Group 1 (Ro 48-6791 alone) required greater induction doses and increased time to induction. Maintenance doses were the same for both groups. The duration of action of Ro 48-6791 as measured by the OAA/S score and HTLW test did not differ between groups. Ro 48-6791 seemed to be a safe and effective agent to achieve conscious sedation in outpatients undergoing short invasive procedures. However, clinical drug development of Ro 48-6791 was stopped because it did not meet the efficacy criteria of an ultra-short-acting benzodiazepine.

Perceptions of facial aesthetics in two and three dimensions.

The aims of this study were to investigate whether the preferred facial relationship chosen by professionals and the general public is Class I and to ascertain whether viewing two-dimensional (2D) or three-dimensional (3D) images had any effect on the ranking of facial attractiveness. Orthodontists (n = 47), maxillofacial surgeons (n = 25) and members of the general public (n = 78) assessed 2D and 3D facial scans of two males and two females that had been morphed to produce five images reflecting different skeletal patterns: Class I, mild and moderate Class II, and mild and moderate Class III. Each assessor placed the images in rank order of preference, after viewing alternate 2D and 3D image formats for each face. The data were analysed using logistic regression. In 2D, professionals (orthodontists and maxillofacial surgeons) chose Class I as the preferred facial image more frequently than the general public for only one of the four faces. However, in 3D format they chose Class I as the preferred facial image for some subject faces more, and others less, frequently when compared with the general public. The gender of the assessor was not significant when assessing the preferred facial relationship for Class I images in either 2D or 3D formats. The oldest assessors (56+ years) were significantly less likely than the younger age groups to select Class I as the preferred facial relationship in both 2D and 3D. In summary, there was too great a degree of variation to say that a difference between 2D and 3D facial images was evident.

Expression and activity of beta-site amyloid precursor protein cleaving enzyme in Alzheimer's disease.

Several lines of evidence indicate that the Abeta peptide is involved at some level in the pathological process that results in the clinical symptoms of AD (Alzheimer's disease). The N-terminus of Abeta is generated by cleavage of the Met-Asp bond at position 671-672 of APP (amyloid precursor protein), catalysed by a proteolytic activity called beta-secretase. Two 'beta-secretase' proteases have been identified: BACE (beta-site APP-cleaving enzyme) and BACE2. The cause of sporadic AD is currently unknown, but some studies have reported elevated BACE/beta-secretase activity in brain regions affected by the disease. We have demonstrated that robust beta-secretase activity is also detectable in platelets that contain APP and release Abeta. This review considers the current evidence for alterations in beta-secretase activity, and/or alterations in BACE expression, in post-mortem brain tissue and platelets from individuals with AD.

High resolution two-dimensional gel electrophoresis of human erythrocyte membrane proteins.

Three different two-dimensional (2-D) gel electrophoretic techniques have been modified to provide high resolution of human erythrocyte membrane proteins. The resulting gels were referenced to the established one-dimensional (1-D) sodium dodecylsulfate (SDS) gel electrophoretic profile, and the effects of endogenous proteolysis and cytosolic contamination were studied. It is concluded that in vitro proteolysis and cytosolic contamination do not contribute significantly to the patterns observed on the 2-D gels, under the conditions used for erythrocyte ghost preparation. The procedures require only small quantities of blood; as many as twenty 2-D gel profiles can be obtained from 5 ml of blood. The combination of nonequilibrium isoelectric focusing (IEF) in the first dimension, SDS electrophoresis in the second dimension, and very sensitive silver staining techniques resolves more than 250 individual protein spots. This appears to be the most useful single procedure for the analysis of red cell membrane proteins. Membrane protein profiles from patients with Duchenne muscular dystrophy, Wernicke-Korsakoff syndrome, and acanthocytosis with degeneration of the basal ganglia were compared with normal controls. The patterns for Duchenne muscular dystrophy and Wernicke-Korsakoff syndrome were not different from normal patterns. The pattern for the patient with acanthocytosis and degeneration of the basal ganglia consistently showed a high level for one protein in the 100,000 mol. wt. range.