Characterization of hepatitis B virus mutations in untreated patients co‐infected with HIV and HBV based on complete genome sequencing

Co‐infection of HBV with HIV results in an accelerated course of HBV‐associated chronic liver disease. Several studies have shown that viral mutations are related to disease progression in mono‐infection with HBV. However, it is unclear whether HBV mutation patterns might differ between co‐infected and mono‐infected patients. To compare the frequencies and mutation patterns in the HBV genome between co‐infection and mono‐infection. Twenty‐four treatment‐naïve co‐infected and 31 treatment‐naïve mono‐infected Thai patients were included. HBV mutations were characterized by whole genome sequencing of virus serum samples. The clinical features and frequency of known clinically significant mutations were compared between the two groups. No significant difference between the groups was found with respect to sex, age and HBeAg. However, HBV DNA levels were significantly higher in co‐infected patients. The distribution of HBV genotypes was comparable between the two groups and restricted mostly to sub‐genotypes C1 and B2. An isolate with recombinants of genotypes G/C1 was also identified in a patient with co‐infection. There was no difference in the prevalence of mutations in the enhancer II/basal core promoter/precore region, pre‐S/S and polymerase genes between the two groups. In conclusion, dual infections tend to engender increased HBV DNA levels. There was no major difference in the frequencies of common HBV mutations between co‐infected and mono‐infected patients. Thus, HBV mutations may not contribute to disease pathogenesis in Thai patients with co‐infection. J. Med. Virol. 85:16–25, 2012. © 2012 Wiley Periodicals, Inc.     

Acute and Subchronic Toxicity Study of Tud-Rak-Ka-Sai-Puu Recipe in Rats

Acute and subchronic toxicities of Tud-Rak-Ka-Sai-Puu (TR) recipe were studied in male and female rats. After 14 days of a single oral administration of test substance (5,000 mg/kg body weight), measurement of the body and organs weights, necropsy and health monitoring were performed. No signs and differences in the weights and behavior were observed relative to the control rats, suggesting that TR recipe in the dose of 5,000 mg/kg body weight does not produce acute toxicity. The subchronic toxicity was determined by oral feeding in male and female rats daily with the test substance at 2, 20, 200 and 2,000 mg/kg body weight for 90 days. No defects of animal behavior were observed in the test groups. Both test and control groups (on the 90^th day) as well as the satellite group (on the 118^th day) were analyzed by measuring their final body and organ weights, taking necropsy, and examining hematology, blood clinical chemistry, and microanatomy. These results together with the information of signs, behavior and health monitoring can lead to a conclusion that an oral administration of TR recipe at 2, 20, 200 and 2,000 mg/kg body weight for 90 days did not cause subchronic toxicity.     

Modulation of natural killer activity by 12-O-tetradecanoylphorbol-13-acetate and benzoyl peroxide in phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice

Following two weeks of topical application of 12-O-tetra-decanoylphorbol-13-acetate(TPA)at 2, 4 and 8 µg/mouse on alternate days (7 x total) orbenzoyl peroxide (BZP) at 10, 20 and 40 mg/mouse, natural killer(NK) activity was determined in local (lymph nodes drainingthe lower dorsal region)n and systemic (spleen) lymphoid tissuein phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice.SENCAR mice, sensitive to tumor induction by TPA in two-stagechemical-induced carcinogenesis protocols, demonstrated suppressionof NK activity in the spleen (no significant change in lymphnodes) and substantial dose-dependent increases in cell numbersin these organs after topical exposure to TPA. B6C3F1 (C57BL/6x C3H Fl) mice, reported to be resistant to TPA-induced promotion,demonstrated significant increases in NK activity in lymph nodes/spleenwith an increase in cell numbers in the draining nodes only.Unlike the C57BL/6 parental Strain, B6C3F1 mice are also reportedto be resistant to promotion with BZP. Significantly, studiesin this laboratory indicated that B6C3F1 mice dosed with BZPdemonstrated increased NK activity in the spleen as was observedafter dosing with TPA. These data suggest that alterations inNK activity as a result of exposure to tumor promoters may,in part, account for the resistance of particular strains ofmice to tumor development. In both SENCAR and B6C3F1 mice, theblastogenic response of spleen cell suspensions isolated fromTPA-dosed animals to phytohemagglutinin (PHA), a T cell lectin,was suppressed in a dose-dependent manner; BZP had no effecton spleen cell responses in either strain. Blastogenic responsesof lymph node cells to PHA were enhanced in both strains ofmice after topical application of TPA and BZP. Therefore, alterationsin lymphoid cell responsiveness to PHA appeared unrelated tothe reported sensitivities of SENCAR and B6C3F1 mice to tumorpromotion.     

Structure-activity relationships of 4-position diamine quinoline methanols as intermittent preventative treatment (IPT) against Plasmodium falciparum

A library of diamine quinoline methanols were designed based on the mefloquine scaffold. The systematic variation of the 4-position amino alcohol side chain led to analogues that maintained potency while reducing accumulation in the central nervous system (CNS). Although the mechanism of action remains elusive, these data indicate that the 4-position side chain is critical for activity and that potency (as measured by IC(90)) does not correlate with accumulation in the CNS. A new lead compound, (S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(2-(cyclopropylamino)ethylamino)ethanol (WR621308), was identified with single dose efficacy and substantially lower permeability across MDCK cell monolayers than mefloquine. This compound could be appropriate for intermittent preventative treatment (IPTx) indications or other malaria treatments currently approved for mefloquine.     

Association of IL-18 gene polymorphism (?137C) with arthritis manifestations in SLE: combined effect with IFN gamma gene polymorphism (+874A)

We analyzed the association between single nucleotide polymorphisms in IL-12 and IL-18 genes in disease susceptibility and severity of SLE in Thais. A weak association was observed between A allele of the IL-12 gene at the 3′ untranslated region in SLE patients with proteinuria (OR = 1.89, 95% CI = 1.05–3.40, P = 0.02, Pc = 0.06). In addition, we found a significant association between C allele of IL-18 (−137) with arthritis (OR = 6.88, 95% CI = 1.54–42.93, P = 0.003, Pc = 0.009). The presence of one C allele (C/C+C/G) was associated with significant OR of 8.72 (95% CI = 1.83–56.71, P = 0.001, Pc = 0.003). Interestingly, we found the combined effect between the G/C genotype of IL-18 (−137) and the A/A genotype of IFNG (+874) gene causing susceptibility of arthritis in SLE patients (OR = 13.22, 95% CI = 1.56–291.66, P = 0.004).