Efficacy of albendazole against gastrointestinal nematodes of cattle

Forty-five calves with artificial and pasture-acquired nematode infections were medicated with albendazole at dose levels of 0, 2.5, 5.0, or 10 mg/kg of body weight. A dose level of 2.5 mg/kg removed at least 99% of adult Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia oncophora, and Bunostomum phlebotomum. Burdens of Haemonchus contortus, Strongyloides papillosus, and Ostertagia ostertagi were reduced 79, 88, and 97%, respectively. At a dose level of 5.0 mg/kg, at least 95% of all adult nematodes were removed; at 10 mg/kg, at least 97% were removed. At least 99% of 4th-stage larvae of O ostertagi, T axei, C oncophora and T colubriformis and 96% of H contortus were expelled at a dose level of 2.5 mg/kg. At 5.0 and 10 mg/kg, 99 to 100% of all species of larvae were removed. Trichuris spp adults were slightly susceptible at all dose levels; larvae were susceptible (83%) only at 10 mg/kg.     

Interleukin-12 inhibits hepatitis B virus replication in transgenic mice

Interleukin-12 (IL-12) is a heterodimeric cytokine produced by antigen-presenting cells that has the ability to induce gamma interferon (IFN-gamma) secretion by T and natural killer cells and to generate normal Th1 responses. These properties suggest that IL-12 may play an important role in the immune response to many viruses, including hepatitis B virus (HBV). Recently, we have shown that HBV-specific cytotoxic T lymphocytes inhibit HBV replication in the livers of transgenic mice by a noncytolytic process that is mediated in part by IFN-gamma. In the current study, we demonstrated that the same antiviral response can be initiated by recombinant murine IL-12 and we showed that the antiviral effect of IL-12 extends to extrahepatic sites such as the kidney. Southern blot analyses revealed the complete disappearance of HBV replicative intermediates from liver and kidney tissues at IL-12 doses that induce little or no inflammation in these tissues. In addition, immunohistochemical analysis demonstrated the disappearance of cytoplasmic hepatitis B core antigen from both tissues after IL-12 treatment, suggesting that IL-12 either prevents the assembly or triggers the degradation of the nucleocapsid particles within which HBV replication occurs. Importantly, we demonstrated that although IFN-gamma, tumor necrosis factor alpha, and IFN-alpha/beta mRNA are induced in the liver and kidney after IL-12 administration, the antiviral effect of IL-12 is mediated principally by its ability to induce IFN-gamma production in this model. These results suggest that IL-12, through its ability to induce IFN-gamma, probably plays an important role in the antiviral immune response to HBV during natural infection. Further, since relatively nontoxic doses of recombinant IL-12 profoundly inhibit HBV replication in the liver and extrahepatic sites in this model, IL-12 may have therapeutic value as an antiviral agent for the treatment of chronic HBV infection.     

Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective mu or delta opioid agonists in mice

N-Methyl-D-aspartate (NMDA) receptor antagonists have been shown to block the development of antinociceptive tolerance to morphine. Assessment of the effects of NMDA antagonists on development of antinociceptive tolerance to selective opioid mu (mu) and delta (delta) agonists, however, has not been reported. In these experiments, selective mu and delta receptor agonists, and morphine, were repeatedly administered to mice either supraspinally (i.c.v.) or systemically (s.c.), alone or after pretreatment with systemic NMDA antagonists. Antinociception was evaluated using a warm-water tail-flick test. Repeated i.c.v. injections of mu agonists including morphine, fentanyl, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) or [D-Ala2, Glu4]deltorphin, a delta agonist, or s.c. injections of morphine or fentanyl, produced antinociceptive tolerance as shown by a significant rightward displacement of the agonist dose-response curves compared to controls. Single injections or repeated administration of MK801 (a non-competitive NMDA antagonist) or LY235959 (a competitive NMDA antagonist) at the doses employed in this study did not produce behavioral toxicity, antinociception or alter the acute antinociceptive effects of the tested opioid agonists. Consistent with previous reports, pretreatment with MK801 or LY235959 (30 min prior to agonist administration throughout the tolerance regimen) prevented the development of antinociceptive tolerance to i.c.v. or s.c. morphine. Neither NMDA antagonist, however, affected the development of antinociceptive tolerance to i.c.v. fentanyl, DAMGO, or [D-Ala2, Glu4]deltorphin. Additionally, MK801 pretreatment did not affect the development of antinociceptive tolerance to i.c.v. PL017 or to s.c. fentanyl. Further, MK801 pretreatment also did not affect the development of tolerance to the antinociception resulting from a cold-water swim-stress episode, previously shown to be a delta-opioid mediated effect. These data lead to the suggestion that the mechanisms of tolerance to receptor selective mu and delta opioids may be regulated differently from those associated with morphine. Additionally, these findings emphasize that conclusions reached with studies employing morphine cannot always be extended to 'opiates' in general.     

Inhibition of high affinity uptake of GABA by branched fatty acids

Several branched fatty acids including an antiepileptic agent nDPA were tested as potential inhibitors of high affinity uptake of GABA by brain slices and synaptosomes. Only three compounds (2-butyl-3-propylhexanoic acid, 5-propyloctanoic acid, 2-propylpenten-2-oic acid) were found to be relatively weak inhibitors of the uptake system. There was no correlation between anticonvulsant properties of the branched fatty acids and their potencies as inhibitors of high affinity uptake of GABA.     

HIV and other sexually transmitted diseases at a rural hospital in Zimbabwe

OBJECTIVE: To define the epidemiological characteristics of STD patients attending an outpatient clinic in rural Zimbabwe, to examine the aetiologic agents causing infection and to determine their relationship with HIV infection. SUBJECTS: 319 men and 146 women, making a sample of about 7% all patients attending an STD clinic during the 3 month study period. Microbiological data were collected from 104 men and 72 women selected randomly from these. Pregnant women were excluded and patients who had received antibiotics within the previous 14 days were excluded from the microbiology sub-sample. SETTING: An outpatient STD clinic at a District Hospital on a major truck route about 300 km north of the capital, Harare. METHODS: All new patients attending the clinic during a 3 month period were enrolled for clinical and epidemiological investigations using a standard procedure. Specimens for microbiological investigation were taken from every second patient seen on the first three days of each week. RESULTS: The typical patient was male (m:f ratio 2.2) aged 20-29 years (68% patients), not married (56% men) and in paid employment (66% men vs. 27% for the district). In men the most common presenting feature was genital ulceration, while in women, discharges were more common. Genital warts were noted frequently in both sexes. In the sub-sample examined microbiologically, H ducreyi was isolated from 46% ulcers clinically diagnosed as chancroid, and motile spirochaetes were detected in 25% painless ulcers. Neither of these were detected in ulcers in women, but HSV antigen was found as frequently in ulcers from men (19%) as from women (17%). In patients with genital discharges, gonococcal infection occurred in 64% men and 17% women, while T vaginalis was isolated from 39% women and only 8% men. Over 60% gonococcal isolates were PPNG, and 18% showed in vitro resistance to tetracycline. Yeasts, mainly C albicans were isolated from 42% women with a discharge and 25% women with ulcers. In men the presence of yeasts was associated with superficial ulceration and itchiness of the glans. Positive HIV-1 serology was found in 64% patients. There was no statistical association with current genital ulcers, though there was an association with previous STD episodes and particularly with serological evidence of syphilis. Apart from yeasts, there was no association between positive HIV-1 serology and the presence of pathogens in the genital tract. CONCLUSIONS: The high prevalence of HIV-1 antibodies in STD patients in Karoi suggests integration of STD and AIDS control programmes to be a necessity. Since paid employment was a common feature of both STD clinic attendance and HIV-1 seropositivity, these programmes may be effectively directed through the work place.     

Inhibition of tolbutamide 4-methylhydroxylation by a series of non-steroidal anti-inflammatory drugs in V79-NH cells expressing human cytochrome P4502C10

1. To study the role of cytochrome P4502C10 in the metabolism of the non-steroidal antiinflammatory drugs (NSAIDs) diclofenac, phenylbutazone, fenoprofen, ibuprofen, flurbiprofen, ketoprofen and naproxen, a cell line was developed stably expressing CYP2C10 cDNA. A retroviral vector construct, containing a human CYP2C10 cDNA, was transfected in V79-NH Chinese hamster lung cells by calcium phosphate co-precipitation. Sublines stably expressing human cytochrome P450 cDNA were established by selection with the neomycin analogue G418. 2. Enzymatic activity of CYP2C10 was detected by 4-methylhydroxylation of tolbutamide. This activity was inhibited to background levels by preincubation with the CYP2C9/10 inhibitor sulphaphenazole. 3. Preincubations with the NSAIDs ketoprofen, phenylbutazone, flurbiprofen and diclofenac (all 250 microM) caused a decrease in 4-methylhydroxylation of tolbutamide (500 microM), significantly different from control values (p < 0.05). Inhibition of this activity was not seen in preincubations with the NSAIDs fenoprofen, ibuprofen and naproxen (250 microM). 4. The V79-NH CYP2C10 cell line we have developed has been shown to be a useful tool to predict drug-drug interactions.     

The growth of Malawian preschool children from different socioeconomic groups

Productive infection with HIV-1, the virus responsible for AIDS, requires the involvement of host cell factors for completion of the replicative cycle, but the identification of these factors and elucidation of their specific functions has been difficult. A human cDNA, TRBP, was recently cloned and characterized as a positive regulator of gene expression that binds to the TAR region of the HIV-1 genome. Here we demonstrate that this factor is encoded by a gene, TARBP2, that maps to human chromosome 12 and mouse chromosome 15, and we also identify and map one human pseudogene (TARBP2P) and two mouse TRBP-related sequences (Tarbp2-rs1, Tarbp2-rs2). The map location of the expressed gene identifies it as a candidate for the previously identified factor encoded on human chromosome 12 that has been shown to be important for expression of HIV-1 genes. Western blotting indicates that despite high sequence conservation in human and mouse, the TARBP2 protein differs in apparent size in primate and rodent cells.