Treatment of essential tremor with the barbiturate T2000 (1,3-dimethoxymethyl-5,5-diphenyl-barbituric acid).

The effect of the barbiturate T2000 (1,3-dimethoxymethyl-5,5-diphenyl-barbituric acid; DMMDPB) on essential tremor, given in twice daily doses of 400 and 300 mg, was assessed in two brief, randomized, placebo-controlled, parallel-group, double-blinded, single-center trials in 12 and 22 patients, respectively. These trials represent the first clinical use of T2000 for a specific indication. The primary endpoint was the change in the mean scores of the treated and control groups based on the Fahn-Tolosa-Marin tremor scale. In the first study of 12 patients treated with 400 mg or placebo twice daily for 14 days, the mean change from baseline at day 14 was 19.3 (P < 0.0001) in the treated group and 9.0 (P = 0.0121) in the control group. Using a two-factor mixed ANOVA model to evaluate within group and between group changes, the effect of T2000 was significantly different from that of the placebo group (P = 0.03). In the second study of 22 patients treated with 300 mg of T2000 or placebo twice daily for 20 days, statistically significant changes were seen in treated patients compared to baseline, but the ANOVA model did not demonstrate a significant treatment effect of T2000 compared to placebo. When the treated groups from each study are compared, the 800-mg daily group is significantly different from the 600-mg daily group (P = 0.02). Some treated patients in each study, but no placebo patients, experienced marked improvement. These results support further evaluation of T2000 in the treatment of essential tremor.     

A cluster analysis for threshold perimetry

Cluster analysis in perimetry is a technique used in the evaluation of localised visual field loss. It has previously been applied to suprathreshold data and, unlike the indices currently available to indicate localised loss, it is influenced by the relative positions of individual defects. This paper describes a cluster analysis for use with data from Program 31 of the Octopus perimeter. To demonstrate the technique, sensitivity values of normal 60-year-old subject were altered to simulate localised loss. Illustrative examples of clinical cases are given, showing differing degrees of localised loss that do not influence the corrected loss variance (CLV) but influence the computed cluster parameters. It is hoped that the value of this form of analysis will be demonstrated in clinical follow-up of glaucoma patients.     

Longitudinal predictors of continued tobacco use among patients diagnosed with cancer

Even though continued smoking by cancer patients adversely affects survival and quality of life, about one third of patients who smoked prior to their diagnosis continue to smoke after their diagnosis. The implementation of smoking cessation treatments for cancer patients has been slowed by the lack of data on correlates of tobacco use in this population. Thus, this longitudinal study assessed demographic, medical, addiction, and psychological predictors of tobacco use among 74 head, neck, and lung cancer patients. Multivariable binary logistic regression analyses, with outcome categorized as smoker or nonsmoker, indicated that the likelihoodthat patients would be a smoker was associated with lower levels of perceived risk and a higher level of quitting cons. Multivariable nominal logistic regression, with outcome classified as continuous smoker, continuous quitter, relapser, or follow-up quitter, indicated that: (a) patients categorized as continuous smokers reported significantly lower quitting self-efficacy than follow-up quitters and continuous quitters, (b) relapsers reported a significantly lower level of quitting self-efficacy than either follow-up quitters or continuous quitters, and (c) continuous smokers exhibited a significantly lower level of risk perceptions than continuous abstainers. These findings can be useful for the development and evaluation of treatments to promote smoking cessation among cancer patients. Support for this study was provided by National Institutes of Health Grants CA57708, CA06927, CA88610, CA95678, and CA76644.     

Chlamydial etiology of acute lower respiratory tract infections in children in the Sudan

The role of Chlamydia pneumoniae in 110 Sudanese children with signs of acute lower respiratory tract infections (ALRI) was investigated. Four (3.6%) had evidence of C. pneumoniae infection, of whom 3 were culture-positive, while 1 had an antibody response suggesting a recent infection. IgG antibodies at a titer of ≥1:32 to C. pneumoniae, Chlamydia psittaci and Chlamydia trachomatis were detected in 27 (24.5%), 27 (24.5%) and 7 (6.4%) of the 110 ALRI cases, respectively. C. pneumoniae, C. trachomatis or C. psittaci were not detected in nasopharyngeal secretions from any of 110 patients when fluorescence-labeled specific monoclonal antibodies were used. In a seroepidemiological survey, 318 healthy Sudanese persons aged between 1 month and 67 years were studied for C. pneumoniae antibodies.     

A recombinant bisphosphoglycerate mutase variant with acid phosphatase homology degrades 2,3-diphosphoglycerate.

To date no definite and undisputed treatment has been found for sickle cell anemia, which is characterized by polymerization of a deoxygenated hemoglobin mutant (HbS) giving rise to deformed erythrocytes and vasoocclusive complications. Since the erythrocyte glycerate 2,3-bisphosphate (2,3-DPG) has been shown to facilitate this polymerization, one therapeutic approach would be to decrease the intraerythrocytic level of 2,3-DPG by increasing the phosphatase activity of the bisphosphoglycerate mutase (BPGM; 3-phospho-D-glycerate 1,2-phosphomutase, EC 5.4.2.4). For this purpose, we have investigated the role of Gly-13, which is located in the active site sequence Arg9-His10-Gly11-Glu12-Gly13 in human BPGM. This sequence is similar to the Arg-His-Gly-Xaa-Arg* sequence of the distantly related acid phosphatases, which catalyze as BPGM similar phosphoryl transfers but to a greater extent. We hypothesized that the conserved Arg* residue in acid phosphatase sequences facilitates the phosphoryl transfer. Consequently, in human BPGM, we replaced by site-directed mutagenesis the corresponding amino acid residue Gly13 with an Arg or a Lys. In another experiment, we replaced Gly13 with Ser, the amino acid present at the corresponding position of the homologous yeast phosphoglycerate mutase (D-phosphoglycerate 2,3-phosphomutase, EC 5.4.2.1). Mutation of Gly13 to Ser did not modify the synthase activity, whereas the mutase and the phosphatase were 2-fold increased or decreased, respectively. However, replacing Gly13 with Arg enhanced phosphatase activity 28.6-fold, whereas synthase and mutase activities were 10-fold decreased. The presence of a Lys in position 13 gave rise to a smaller increase in phosphatase activity (6.5-fold) but an identical decrease in synthase and mutase activities. Taken together these results support the hypothesis that a positively charged amino acid residue in position 13, especially Arg, greatly activates the phosphoryl transfer to water. These results also provide elements for locating the conserved Arg* residue in the active site of acid phosphatases and facilitating the phosphoryl transfer. The implications for genetic therapy of sickle cell disease are discussed.     

Sweet's syndrome—therapy with cyclosporin

We report the case of a 39-year-old female patient suffering from Sweet's syndrome after an upper respiratory tract infection. Cyclosporin A at a dose of 10 mg/kg per day was given as initial treatment. Skin lesions and general malaise resolved within 9 days. The cyclosporin dose was decreased within 21 days, without recurrence of the eruption. Cyclosporin is a potent inhibitor of T lymphocytes, but affects granulocyte and monocyte functions as well. Success of treatment in our case shows that cyclosporin represents an alternative to steroid treatment in patients with Sweet's syndrome.     

Comparative distribution,pharmacokinetics and placental permeabilities of all-trans-retinoic acid, 13-cis-retinoic acid,all-trans-4-oxo-retinoic acid,retinyl acetate and 9-cis-retinal in hamsters

Pregnant hamsters were given a single oral dose (35 mol/kg) of all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, 9-cis-retinal or all-trans-retinyl acetate during the early primitive streak stage of development. The radioactivity associated with the acidic retinoids was distributed to all tissues sampled (including placenta and fetus), with the largest accumulation in the liver and the least accumulation in fat. Radioactivity from 9-cis-retinal or retinyl acetate concentrated in the liver and lung. The all-trans-retinoic acid was oxidized in vivo to all-trans-4-oxo-retinoic acid and isomerized to 13-cis-retinoic acid; 13-cis-retinoic acid was oxidized to 13-cis-4-oxo-retinoic acid and isomerized to all-trans-retinoic acid. No parent 9-cis-retinal or retinyl acetate could be detected in maternal plasma. Plasma concentrations of the parent acidic retinoids reached their maxima within 60 min and then followed exponential decay. Of all the retinoids examined here, 13-cis-retinoic acid showed the largest area under the plasma curve, the slowest clearance and the longest elimination t 1/2. Total plasma radioactivity, consisting of unidentified metabolites, remained elevated at 4 days after dosing. Maternal peak circulating concentrations of the parent retinoids, total radioactivity, plasma pharmacokinetic parameters or the total concentrations of residual radioactivity in fetal tissues could not be correlated with the differential teratogenic potencies of these retinoids.