Investigation into the mode of action of R-91650, an arylpiperazinyl fluoroquinolone, on feline immunodeficiency virus replication inhibitory activity.

The mode of action of R-91650, an arylpiperazinyl fluoroquinolone, on feline immunodeficiency virus (FIV) replication inhibitory activity was investigated. R-91650 inhibited replication of FIV at non-cytotoxic concentration levels in both acutely infected peripheral blood mononuclear cells and chronically infected P-CrFK cells. The compound reduced the intracellular p24 concentration levels in P-CrFK cells in a dose-dependent manner. Northern blot analysis revealed that R-91650 selectively prevented the accumulation of FIV mRNA in P-CrFK cells. However, the compound did not inhibit FIV-long terminal repeat (LTR) promoter activity in the reporter gene expression analysis. These data suggest that R-91650 is a novel inhibitor of FIV replication that inhibits a certain step or steps following transcription initiation of the FIV-LTR promoter.

8-Difluoromethoxy-4-quinolone derivatives as anti-feline immunodeficiency virus (FIV) agents: important structural features for inhibitory activity of FIV replication.

The inhibitory activities of various 8-difluoromethoxy-4-quinolone derivatives against feline immunodeficiency virus (FIV) replication in the chronically infected cell line P-CrFK were investigated. Certain derivatives were found to inhibit FIV production from P-CrFK cells in a dose-dependent manner without exhibiting cytotoxic effects at inhibitory concentrations. Based on this study, the structures important for anti-FIV activity are suggested to be (i) a carboxyl group at position C-3, and (ii) an aromatic modification at position 4 of the C-7 piperazinyl moiety.

Synthesis and anti-HIV activity of arylpiperazinyl fluoroquinolones: a new class of anti-HIV agents.

Synthesis and anti-HIV activity of a series of novel arylpiperazinyl fluoroquinolones are reported. In the SAR study, the aryl substituents on the piperazine nitrogen were found to play an important role for the anti-HIV-1 activity. A few of the compounds exhibited potent anti-HIV activity: IC50=0.06 microM in chronically infected cells.

A new fluoroquinolone derivative exhibits inhibitory activity against human immunodeficiency virus type 1 replication.

The inhibitory activity of several fluoroquinolone antibiotics against human immunodeficiency virus type 1 (HIV-1) replication was investigated. R-71762, (+/-) 9-fluoro-3-fluoromethyl-2, 3-dihydro-10-[4-(2-pyridyl)-1-piperazinyl]-7-oxo-7H-pyrido[1,2, 3-de][1,4]benzoxazine-6-carboxylic acid, protected MT-4 cells from HIV-1-induced cytopathic effects. Furthermore, the compound inhibited virus replication both in acutely and in chronically HIV-1-infected cells. On the other hand, ofloxacin, levofloxacin, ciprofloxacin, norfloxacin and enoxacin, that were previously reported to be protective against HIV-1-induced cytopathic effects, did not show any protective activity in our assay system. These results indicate that R-71762 is a novel inhibitor of HIV-1 replication and is effective even in HIV-1 chronically infected cells.

Identification and transcriptional analysis of the homologues of the herpes simplex virus type 1 UL41 to UL51 genes in the genome of nononcogenic Marek's disease virus serotype 2.

Studies on Marek's disease virus serotype 2 (MDV2) are important for understanding the natural nonpathogenic phenotypes of MDV. We determined the 16770 bp nucleotide sequence of the MDV2 genome located in the right part the of unique long region. The analysis revealed 12 complete open reading frames (ORFs) with high amino acid sequence identities to the gene products of other alphaherpesviruses. The MDV2 ORFs were arranged collinearly with the prototype sequence of herpes simplex virus type 1 ranging from the UL41 to UL51 genes. Except for the MDV2 UL41 gene, all of the identified genes were confirmed to be transcribed with 3'-coterminal mRNAs and/or a unique transcript in the virus-infected cells. Transcriptional patterns for the regions of the MDV2 UL48 to UL49.5 genes were notably different from the similar area of MDV serotype 1.

Characterization of an integrase mutant of feline immunodeficiency virus.

The role of the integrase region of feline immunodeficiency virus (FIV) in viral replication was examined using an integrase mutant clone of FIV which carries a frameshift mutation in the region. Upon transfection, although the integrase mutant was able to release virus-like particles into the supernatant from the transfected cells, the virions produced by the mutant contained unprocessed gag precursor protein and undetectable levels of reverse transcriptase activity. Furthermore, the mutant virions were unable to direct the synthesis of viral DNA after infection in target cells. To understand this phenotype of the integrase mutant in more detail, we constructed a gag-pol expression plasmid from an FIV molecular clone and assayed roles of the integrase region on virus particle formation following transfection. When an inframe deletion was introduced into the protease region of the expression plasmid, the mutant was able to efficiently release gag- and gag-pol precursor proteins into the supernatant from the transfected cells. An expression plasmid with mutations in both the protease and integrase regions, however, failed to release the gag-pol precursor protein from the cells. These results suggested an essential role for the integrase region for efficient incorporation of the gag-pol precursor into the virions.

Characterization of one monoclonal antibody against feline immunodeficiency virus p24 and its application to antigen capture ELISA.

Several monoclonal antibodies (mAbs) were produced against feline immunodeficiency virus (FIV) p24 capsid antigen. One of these, F2710, reacted strongly, not only with viral p24 and recombinant p24, but also with p50 Gag precursor protein in Western blot. Epitope mapping analysis revealed that mAb F2710 recognizes a heptapeptide, SFIDRLF, in the FIV p24 amino acid sequence. As this portion of FIV p24 is highly conserved among various FIV strains, the mAb seems to be a useful tool for detecting FIV p24 antigen in various samples. By means of this mAb and rabbit anti-p24 polyclonal antibody, an antigen capture ELISA was developed. The ELISA detected viral p24 antigen with good linearity. The lower detection limit of this assay is 40 pg/ml of recombinant p24 antigen, which is at least as sensitive as the reverse transcriptase assay in detecting FIV virion. Thus, this system is valuable for monitoring FIV replication in vitro.

Folie à deux in Japan -- analysis of 97 cases in the Japanese literature.

In order to clarify the characteristics of folie à deux in Japan, we examined a total of 97 cases of folie à deux in the Japanese literature covering a period of 90 years, and compared them with the cases reported in Western countries. About 75% of the Japanese cases occur in two individuals, and of these are family cases. The most common combinations are mother-child and married couple. Mother-child combinations are much more common than father-child combinations. Female subjects are more often involved than males. The most common diagnosis for the dominant partner is schizophrenia, and the most common diagnosis for the submissive partner is paranoid reaction. Delusion is the most common symptom shared by both partners in Japan. Comparing these Japanese cases to Western ones, sister-sister combinations are less frequent, younger subjects influence the older ones more, and acute religious delusion is more common in Japan than in Western countries.

The classification of idiopathic spasmodic torticollis: three types based on social adaptation and frustration tolerance.

In this study, idiopathic spasmodic torticollis (ST) has been classfied into three types from the opinion of social adaptation and the differences of frustration tolerance. The three types were as follows: type I (overadaptive type), type II (maladaptive type), and type III (compatible type). Type I is a typical psychosomatic with high frustration tolerance. Type II is personality disorder with low frustration tolerance. In type III, frustration tolerance varies depending on social circumstances (i.e., different at home and at the office). In type I, the prognosis of ST is generally unfavorable, since it is associated with recurrence and prolongation of the symptoms. In type II, the prognosis of ST is generally favorable. However, type II patients experience relationship or social difficulties. One characteristic of type III is that the onset of symptoms is usually found in an older person because of proper use of frustration tolerance at home and at the office.

A neutral sugar is responsible for serovar specificity of the antigenic determinant of Leptospira interrogans serovar canicola.

To provide information on the chemical structures of antigenic determinants of leptospira, glycolipids of Leptospira interrogans serovar canicola strain Hond Utrecht IV (Ut-IV) and its antigenic variant selected in the presence of a serovar-specific monoclonal antibody were compared physicochemically. Gas-liquid chromatography-mass spectrometry analysis revealed that the glycolipid of Ut-IV contained 6 neutral sugar species; rhamnose, mannose, galactose, glucose, and unknown sugars III and IV, in addition to unknown sugars I and II that had been previously reported. On the other hand, the glycolipid of the variant lacked unknown sugar III, suggesting that this sugar is responsible for the serovar-specific antigenic determinant.

[Problems of psychotropic drugs in psychopharmacotherapy].

This is the summary of the lecture that the author, as a clinical psychiatrist, gave to the Japanese researchers of basic psychopharmacology who are not involved in clinical medicine. I. The author considers the problems of psychotropic drugs in Japan in 2 categories: those unique to Japan (1-5) and those related to psychotropic drugs in general (6-9). 1. "Arbitrary" administration (i. e., the prescription is different with each psychiatrist, therefore standardization is necessary). 2. Polypharmacy (i. e., unreasonable combination is made). 3. Many different drugs with similar effect (therefore, new drugs should be controlled). 4. "Stereotype" of doctor's prescription for long-term use. 5. Limited prescription due to health insurances. 6. Doubtful effect on long-term prognosis of chronic schizophrenics. 7. Psycho-social burden of patients taking drugs continuously. 8. Undesirable effects like prolongation of depressive episode, lowered mental activity, or blunting of affect. 9. Side effects such as dependence, tardive dyskinesia, malignant syndrome, or teratogenecity. II. Tardive dyskinesea, malignant syndrome and teratogenecity are explained in detail. III. The author expresses the wishes for future development of psychotropic drugs as follows: 1. Good balance of "effect", "side effect", and "price" of clinical drugs. 2. Introduction of safe long-acting drugs which promote social rehabilitation of mental patients. 3. Development of more specifically effective drugs. 4. Convenient way of measurement of drug serum level. 5. Contribution to understanding of pathogenesis of mental disorders through researches on effects and side effects of drugs. Finally, the author stresses the necessity of more cooperation between clinical and basic medicine.