Synthesis and anti-tubercular activity of N(2)-arylbenzo[g]isoquinoline-5,10-dione-3-iminium bromides.

Tuberculosis has remained a challenge for medicinal chemists worldwide. In the framework of a collaborative program to identify and evaluate novel antitubercular candidate compounds, the biological properties of benzo[g]isoquinoline-5,10-diones have been found to be very promising. In this paper we have further expanded the library by incorporation of an amidinium moiety into the benzo[g]isoquinoline-5,10-dione scaffold. The presence of this functional group also increased the solubility of the quinones in polar solvents. To this purpose N(2)-arylbenzo[g]isoquinoline-5,10-dione-3-iminium bromides were synthesized in a straightforward way by means of a reaction of anilines with 2-(bromomethyl)-3-(cyanomethyl)-1,4-dimethoxynaphthalene. Following the biological evaluation, N(2)-(4-chlorophenyl)-5,10-dioxobenzo[g]isoquinoline-3(2H)-iminium bromide (MIC = 1.16 µM, CC50 = 28.51 µM, SI = 24.58) was selected as the most promising representative. Apart from the nano-molar anti-mycobacterial activity, the compound was able to target intracellular residing Mycobacterium tuberculosis and the susceptibility of a multi-drug-resistant strain towards the compound was confirmed.

[Retroviral restriction factors : from Fv1 to TRIM5α]. / Les facteurs de restriction rétrovirale : de Fv1 à TRIM5α.

During their evolution, mammals have developed cellular factors interfering with retroviral replication, known as « restriction factors ¼. The prototype of these factors, Fv1, was characterized in the late 60's and blocks MLV infection. Some Fv1-like factors interfering with complex retroviruses, including HIV, have recently been discovered in primate cells. These restriction factors are referred to as Ref1, which blocksMLVreplication in human cells, and Lv1, which blocks the infection of non-human primate cells by various retroviruses, including MLV and HIV. These factors are all saturable by an excess of virus, target the viral capsid and interfere with an early step of viral replication. Lv1 and Ref1 have recently been found to be species-specific variants of a single protein called TRIM5α, a member of the TRIM protein family. The mechanism of action of these factors is still unknown. The existence of natural inhibitors of retroviral infection raises new hopes for the development of therapeutic tools against HIV infection.

Mechanistic approach for the toxic effects of perfluorooctanoic acid on isolated rat liver and brain mitochondria.

BACKGROUND: Perfluorooctanoic acid (PFOA) is one of the most widely used perfluoroalkanes as surfactants, lubricants and processing aids in the production of polymers, which has also been detected in the environment, wildlife and human body. Animal studies indicated that PFOA caused a wide array of toxic effects including liver and brain dysfunction, carcinogenicity and reproductive and developmental toxicity. Based on the established role of mitochondria-mediated pathways in the observed toxic effects of many drugs and chemicals, in this study, the potential toxic effects of PFOA on mitochondria isolated from rat liver and brain have been investigated. METHOD: Mitochondria were isolated by differential centrifugation method and incubated with different concentrations of PFOA (0.5-1.5 mM). The effects of PFOA were assessed on a series of mitochondrial parameters including reactive oxygen species (ROS) formation, activities of mitochondrial complexes I/II/III, reduced glutathione (GSH) content, adenosine triphosphate (ATP) level, membrane potential, lipid peroxidation (LPO), mitochondrial swelling and cytochrome c release. RESULTS: The data on liver mitochondria indicated that PFOA-induced ROS elevation in both mitochondrial complexes I and III, mitochondrial membrane potential collapse, swelling, cytochrome c release and decreased ATP level which induces apoptosis or necrosis. On brain mitochondria, PFOA showed fairly similar effects on the above-mentioned parameters. However, different results were obtained when the effect of PFOA was assessed on LPO and complex II activity. CONCLUSIONS: Due to the fact that PFOA had toxic effects on the mitochondria isolated, it could be suggested that mitochondrial toxicity could be a plausible mechanism for the toxic effects of this fluorochemical on liver and brain function.

Peptide alpha-keto ester, alpha-keto amide, and alpha-keto acid inhibitors of calpains and other cysteine proteases.

A series of dipeptidyl and tripeptidyl alpha-keto esters, alpha-keto amides, and alpha-keto acids having leucine in the P2 position were synthesized and evaluated as inhibitors for the cysteine proteases calpain I, calpain II, cathepsin B, and papain. In general, peptidyl alpha-keto acids were more inhibitory toward calpain I and II than alpha-keto amides, which in turn were more effective than alpha-keto esters. In the series Z-Leu-AA-COOEt, the inhibitory potency decreased in the order: Met (lowest KI) > Nva > Phe > 4-Cl-Phe > Abu > Nle (highest KI) with calpain I, while almost the reverse order was observed for calpain II. Extending the dipeptide alpha-keto ester to a tripeptide alpha-keto ester yielded significant enhancement in the inhibitory potency toward cathepsin B, but smaller changes toward the calpains. Changing the ester group in the alpha-keto esters did not substantially decrease KI values for calpain I and calpain II. N-Monosubstituted alpha-keto amides were better inhibitors than the corresponding alpha-keto esters. alpha-Keto amides with hydrophobic alkyl groups or alkyl groups with an attached phenyl group had the lower KI values. N,N-Disubstituted alpha-keto amides were much less potent inhibitors than the corresponding N-monosubstituted peptide alpha-keto amides. The peptide alpha-keto acid Z-Leu-Phe-COOH was the best inhibitor for calpain I (KI = 0.0085 microM) and calpain II (KI = 0.0057 microM) discovered in this study. It is likely that the inhibitors are transition-state analogs and form tetrahedral adducts with the active site cysteine of cysteine proteases and form hydrogen bonds with the active site histidine and possibly another hydrogen bond donor in the case of monosubstituted amides. Several inhibitors prevented spectrin degradation in a platelet membrane permeability assay and may be useful for the treatment of diseases which involve neurodegeneration.

Laparoscopically assisted enterolithotomy for a gallstone ileus in an atypical location.

Mechanical intestinal obstructions caused by gallstones occur in approximately 1% to 2% of cases. In most of the patients, the obstruction occurs at the ileocecal valve. However, gallstones may cause obstruction anywhere along the gastrointestinal tract from the stomach to the sigmoid colon. Laparoscopically assisted enterolithotomy can be used as a treatment method. This report describes a case in which a gallstone blockage caused a mechanical obstruction in an atypical location, which was successfully treated with a laparoscopically assisted approach.

Aural symptoms and hearing loss in patients with lupus.

OBJECTIVE: Systemic lupus erythematosus causes widespread tissue injury from deposition of immune complexes. The prevalence of aural symptoms in this disease was evaluated. METHODS: The presence of tinnitus, hearing loss, and fluctuating hearing was evaluated by a self-directed questionnaire in patients aged 65 or less from a lupus clinic. Patients reporting aural symptoms were compared with those reporting none, by use of demographics and disease duration. Comparison was also made with historic serologic data. Audiometry was offered to all patients with lupus reporting aural symptoms and was completed in 10. RESULTS: Twenty-six (31%) of 84 patients with lupus reported aural symptoms. Patients reported a combination of symptoms: unilateral hearing loss with or without tinnitus in 13 (15%) of 84 and bilateral hearing loss with or without tinnitus in 14 (17%) of 84. No statistical difference was measured between symptomatic and asymptomatic patients when compared by average age, duration of disease, history of noise exposure, head trauma, and infectious ear diseases. Statistically significant differences were detected only when comparing average creatinine and C3 levels. Of those patients tested by audiometry, 7 of 10 had abnormal pure-tone thresholds. Asymmetric findings were present in 6 of these 7 patients tested. CONCLUSION: Aural symptoms are prevalent among patients with lupus. Asymmetric symptoms and hearing loss are most common. The cause may relate to immune-complex disease and/or vasculitis.

Midline spikes.

Midline spikes are characterized by spike foci recorded at Cz, Fz, or Pz with amplitude ranging from 20 to 350 microvolts. Out of 7,929 EEGs performed at the Neurodiagnostics Laboratory, Kaiser Permanente Medical Center, Anaheim, California, between 1996 and 2006, 17 EEGs (0.21%) were identified as having interictal midline spikes with or without other epileptiform discharges. Eight EEGs showed midline spikes at Cz, 2 at Fz, 2 at Cz and Fz, 1 at Cz and C3, 1 at Cz, C3, and P3, 1 at Cz and F8, 1 at Cz and T4, and 1 at Cz with 2 Hz generalized spike and slow wave complex. Midline spikes were recorded in 10 males and 7 females. The age ranged from 4 days to 38-years-old with a mean age of 10.8 years. Twelve patients (70.6%) were children. Twelve patients (70.6%) had generalized tonic-clonic seizures and 5 had partial motor seizures. Of the 17 patients, 14 had no known causes, 1 had an agenesis of corpus callosum, 1 had a left frontal arteriovenous malformation, and 1 had a left frontal area stroke. We postulate that the mechanism for the genesis of midline spikes may be heterogeneous. Midline spikes may be triggered by thalamocortical network in a generalized tonic-clonic seizure, or may originate in the parasagittal cortex in a partial motor seizure.

[Development of seminiferous tubules in guinea pigs during puberty]. / Evolution du tube séminifère chez le cobaye au cours de la puberté.

The study of development of the seminiferous tubules of the guinea-pig along the puberty is based on diameter, length and volume relate to testicular weight and age. During this period the development is linear. A correlation exist between testicular testosterone concentration and growth of seminiferous tubules in diameter and in length from day 16 to 60, stage of puberty in which the first spermatozoa appear.