Episodic ataxia type 1: A neuronal potassium channelopathy

Episodic ataxia type 1 is a paroxysmal neurological disorder characterized by short-lived attacks of recurrent midline cerebellar dysfunction and continuous motor activity. Mutations in KCN1A, the gene encoding Kv1.1, a voltage-gated neuronal potassium channel, are associated with the disorder. Although rare, the syndrome highlights the fundamental features of genetic ion-channel diseases and serves as a useful model for understanding more common paroxysmal disorders, such as epilepsy and migraine. This review examines our current understanding of episodic ataxia type 1, focusing on its clinical and genetic features, pathophysiology, and treatment.     

Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference.

Endocannabinoid signaling has recently been implicated in ethanol-seeking behavior. We analyzed the expression of endocannabinoid-related genes in key brain regions of reward and dependence, and compared them between the alcohol-preferring AA (Alko Alcohol) and nonpreferring ANA (Alko Non-Alcohol) rat lines. A decreased expression of fatty acid amidohydrolase (FAAH), the main endocannabinoid-degrading enzyme, was found in prefrontal cortex (PFC) of AA rats, and was accompanied by decreased enzyme activity in this region. Binding of the endocannabinoid-cannabinoid 1 (CB1) receptor ligand (3)[H]SR141716A, and [35S]GTPgammaS incorporation stimulated by the CB1 agonist WIN 55,212-2 were downregulated in the same area. Together, this suggests an overactive endocannabinoid transmission in the PFC of AA animals, and a compensatory downregulation of CB1 signaling. The functional role of impaired FAAH function for alcohol self-administration was validated in two independent ways. The CB1 antagonist SR141716A potently and dose-dependently suppressed self-administration in AA rats when given systemically, or locally into the PFC, but not in the striatum. Conversely, intra-PFC injections of the competitive FAAH inhibitor URB597 increased ethanol self-administration in nonselected Wistar rats. These results show for the first time that impaired FAAH function may confer a phenotype of high voluntary alcohol intake, and point to a FAAH both as a potential susceptibility factor and a therapeutic target.     

In situ detection of human papillomavirus Types 13 and 32 in focal epithelial hyperplasia of the oral mucosa

17 cases of focal epithelial hyperplasia of the oral mucosa (FEH, Heck's disease) were investigated for the presence of human papillomavirus (HPV) nucleic acid sequences by means of in situ DNA hybridization using biotinylated DNA probes of HPV types 1, 6, 11, 13, 16, 18, and 32. Ten of 17 cases were positive for HPV 13 DNA in contrast to 6 of 17 positive cases obtained after application of the HPV 32 probe, with a double infection in one case. The results of our study suggest, that HPV 13 and HPV 32 are very specifically found in lesions of FEH and can be detected in a high percentage of cases using in situ hybridization.     

CT of hepatic schistosomiasis mansoni

Schistosomal periportal fibrosis produced a typical pattern on computed tomography in five patients. Low-density periportal tissue, present throughout the liver, enhanced strongly after the administration of contrast medium. While rounded in cross section, the thickened periportal tissue produced linear and branching patterns when imaged in longitudinal section. In all cases, the sonographic features were typical of schistosomal periportal fibrosis. A lack of awareness of the distinctive features of periportal fibrosis may result in a mistaken diagnosis of hepatic metastases.     

Proton magnetic spectroscopic (PMR) determination of diphenhydramine hydrochloride in dosage forms

Direct dissolution of the bulk material, capsule, or freeze-dried solution for injection and an internal standard in chloroform-d and recording of the PMR spectra provides a simple, specific, and accurate assay method form diphenhydramine hydrochloride [2-(diphenyl-methoxy)-N,N-dimethylethanamine hydrochloride] in pharmaceutical samples. The drug content can be calculated from the integral values for the N-methyl protons of diphenhydramine at ca. 2.85 ppm and for the methyl protons of tert-butyl alcohol at ca. 1.27 ppm. The mean +/- SD% recoveries from synthetic mixtures simulating capsules and injectables were 100.0 +/- 0.2 (n = 11) and 100.1 +/- 0.4 (n = 4), respectively. The method also permits the detection of degradation of diphenhydramine such as benzhydrol, diphenylchloromethane, and 2-(dimethylamino)ethanol to a minimum of about 2% of the parent compound.     

Localization of 125I-labelled antigen in germinal centres of mouse spleen: effects of competitive injection of specific or non-cross-reacting antigen

Studies were performed on localization of ¹²⁵I-human γ-globulin in spleen lymphatic tissue germinal centres during the primary and secondary immune response as influenced by competitive injections of specific or non-cross-reacting antigens. Isologous mouse 7S serum protein labelled with ¹²⁵I was used as the control. The results of these studies support the following conclusions:

(1) Antigen retention in germinal centres during the primary immune reaction is a dynamic process. For some antigens there may be opsonins available at the the time of injection which promote initial localization in germinal centres. However, the continued localization of antigen over weeks and months is a function of specific antibody production.

(2) For some period of time, germinal centres are specific to the antigen that stimulated their development, and eventually these centres will respond to a different antigen.

(3) Antigen persisting in germinal centres is functional in the development of the secondary immune potential.

     

Synthesis and evaluation of 5-amino-1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine and certain related nucleosides as inhibitors of purine nucleoside phosphorylase

The 5-amino and certain related derivatives of the powerful purine nucleoside phosphorylase (PNPase) inhibitor 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine (TCNR,3) have been prepared and evaluated for their PNPase activity. Acetylation followed by dehydration of 5-chloro-1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (4a) gave 5-chloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-1,2,4-triazole-3- carbonitrile (5). Ammonolysis of 5 furnished 5-amino-1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine (5-amino-TCNR, 6), the structure of which was assigned by single-crystal X-ray analysis. Acid-catalyzed fusion of methyl 5-chloro-1,2,4-triazole-3-carboxylate (7a) with 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose (8) gave methyl 5-chloro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)- 1,2,4-triazole-3-carboxylate (9a) and the corresponding positional isomer 9b. Transformation of the functional groups in 9a afforded a route to 5'-deoxyribavirin (9i). Compound 9a was converted in four steps to 5-amino-1-(5-deoxy-beta-D-ribofuranosyl)-1,2,4-triazole-3- carboxamidine (5'-deoxy-5-amino-TCNR, 9g). Similar acid-catalyzed fusion of 1,2,4-triazole-3-carbonitrile (7b) with 8 and ammonolysis of the reaction product 9h gave yet another route to 9i. Treatment of 9h with NH3/NH4Cl furnished 1-(5-deoxy-beta-D-ribofuranosyl)- 1,2,4-triazole-3-carboxamidine (5'-deoxy-TCNR, 9k). The C-nucleoside congener of TCNR (3-beta-D-ribofuranosyl- 1,2,4-triazole-5-carboxamidine, 12) was prepared in two steps from 3-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)- 1,2,4-triazole-5-carbonitrile (10) by conventional procedure. 5-Amino-TCNR (6) displayed a more potent, high-affinity inhibition than TCNR, with a Ki of 10 microM. In contrast, 5'-deoxy-5-amino-TCNR (9g) was a significantly less potent inhibitor of PNPase, compared to 5'-deoxy-TCNR (Ki = 80 and 20 microM, respectively). Neither the C-nucleoside congener of TCNR (12) nor that of ribavirin were found to inhibit inosine phosphorolysis.     

Conformationally restricted analogs of histamine H1 receptor antagonists: trans and cis-1-benzyl-3-dimethylamino-6-phenylpiperidine.

The syntheses of trans- and cis-1-benzyl-3-dimethylamino-6-phenylpiperidine (1 and 2) are described. Compounds 1 and 2 were found to be inhibitors to histamine, acetylcholine, and barium chloride induced contractions of the isolated guinea pig ileum. Compounds 1 and 2 do not exhibit appreciable stereoselectivity in their ability to inhibit smooth muscle contractions. The cis compound 2 is a more effective inhibitor of histamine N-methyltransferase than the trans isomer 1.     

A method for measuring neuroretinal rim area

A practical method for measuring the neuroretinal rim area (NRA) of the optic nervehead is described. Sequential stereo photographs are taken on 35 mm colour transparencies using a Zeiss fundus camera with Allen stereoseparator. While examining a stereo pair with a pocket viewer the disc and cup margins are traced against the stereo image with a Rotring pen (0.1 mm tip) on a clear transparency overlying one of the photographs. This tracing is digitised and analysed by an 'edge detection' algorithm which measures the area between the traced lines, i.e. NRA. The intraobserver intraphotograph coefficient of variation (standard deviation/mean) was calculated for measurements of disc area, cup area and NRA made on 10 stereo photographs of discs with various topographies. Coefficients for NRA ranged from 3.2% to 3.9% for discs with easily discernible cup margins and from 1.6% to 7.2% for discs with less obvious cups.