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ABSTRACTAplaviroc (APL) was a new CCR5 antagonist that was investigated in two dose-ranging studies with antiretroviral therapy-naïve, human immunodeficiency virus-infected adults: ASCENT, in which 147 subjects were randomized 2:2:1 to receive zidovudine-lamivudine (ZDV-3TC) plus APL 600 mg twice a day (BID), APL 800 mg BID, or efavirenz (EFV), respectively, and EPIC, in which 195 subjects were randomized 2:2:2:1 to receive lopinavir-ritonavir (LPV-RTV) plus APL 200 mg BID, APL 400 mg BID, APL 800 mg once a day, or ZDV-3TC BID, respectively. Both studies (and, ultimately, the clinical development of APL) were discontinued after a mean of 14 weeks of therapy because of higher than anticipated severe liver toxicity; grade 2 or higher treatment-emergent elevations in alanine aminotransferase (ALT) levels were observed in 17/281 (6.0%) APL recipients but only 2/55 (3.6%) control recipients, while grade 2 or higher elevations in total bilirubin levels occurred in 29/281 (10.3%) APL recipients but only 4/55 (7.3%) controls. Two APL recipients developed grade 3 or higher treatment-emergent elevations in both ALT and total bilirubin levels, and one of these individuals had a severe case of hepatic cytolysis that was attributed to APL. Despite the high intersubject variability in APL plasma exposures, a Pearson correlation analysis of the combined study data did not reveal any significant associations between plasma concentrations and the liver enzyme elevations observed during the study. The mechanism for the idiosyncratic hepatotoxicity observed in the clinical trials of APL is unknown but is likely intrinsic to the molecule rather than its novel mechanism of action.

Objectives: This study was designed to investigate the effects of the membrane-active, anti-mycobacterial agent, clofazimine, on potassium (K+)-uptake by a mutant of Mycobacterium tuberculosis (MTB), in which the Trk system, the major K+ transporter of this microbial pathogen, had been selectively inactivated.Methods: The ceoB and ceoC genes of MTB, which encode the TrkA proteins, CeoB and CeoC, were deleted by homologous recombination, and the double-knockout mutant and wild-type strains compared with respect to K+ uptake and growth in the presence and absence of clofazimine (0.015–2.5 mg/L) using radioassay procedures.Results: Surprisingly, the magnitudes of K+ uptake and rate of growth of the ceoBC-knockout mutant were significantly (P < 0.05) greater than those of the wild-type strain, due, presumably, to induction of a back-up transporter. Exposure of both the wild-type strain and ceoBC-knockout mutant of MTB to clofazimine was accompanied by dose-related decreases in K+ uptake, as well as growth, which were of comparable magnitude for both strains.Conclusions: These observations demonstrate that the major K+ transporter of MTB, Trk, as well as an uncharacterized inducible back-up system, is equally sensitive to the inhibitory actions of clofazimine.

The effects of platelet-activating factor (PAF) and lyso-platelet-activating factor (L-PAF) at concentrations of 0.25-20 μg/ml on potassium transport and growth of gram-positive and gram-negative bacteria have been investigated in vitro and compared with those of lysophosphatidylcholine (LPC). Potassium transport was determined using ⁸⁶Rb⁺ as tracer, while growth was measured according to the extent of uptake of radiolabeled amino acids. All of the test phospholipids caused dose-related inhibition of ⁸⁶Rb⁺-uptake and growth of gram-positive bacteria, the order of potency being PAF>LPC>L-PAF. Gram-negative bacteria, on the other hand, were less sensitive to the inhibitory effects of the phospholipids on K⁺ transport and growth. Some, but not all, of the gram-positive and gram-negative bacteria were able to degrade LPC, but not PAF or L-PAF, demonstrating that enzymatic degradation of phospholipids does not explain the differential sensitivity to these agents. The bioactive phospholipids LPC, PAF and L-PAF may represent an oxygen-independent antimicrobial host defense system operative primarily against gram-positive bacteria.

Objective To evaluate HIV-1 reverse transcriptase (RT) drug resistance in patients receiving abacavir, lamivudine and zidovudine therapy.Methods In a randomized, double-blind study, 173 anti-retroviral treatment-naive HIV-1-infected adults received abacavir/lamivudine/zidovudine or lamivudine/zidovudine for up to 48 weeks. After week 16, patients could switch to open-label abacavir/lamivudine/zidovudine, and those with plasma HIV-1 RNA (vRNA) >400 copies/ml could add other antiretrovirals. From weeks 16 to 48, samples with vRNA >400 copies/ml were collected for genotyping and phenotyping.Results At baseline, 90% of isolates were wild-type (WT). At week 16, vRNA was >400 copies/ml in seven of 72 (10%) patients receiving abacavir/lamivudine/zidovudine and in 41 of 66 (62%) receiving lamivudine/ zidovudine. At week 16, the genotypes in isolates from the abacavir/lamivudine/zidovudine group were M184V alone (n=3 cases), WT (n=3) and M184V plus thymidine analogue mutations (TAMs) (n=1). The genotypes in isolates from the lamivudine/zidovudine group were M184V alone (n=37), WT (n=1) and M184V plus TAMs (n=3). In the four cases where M184V plus TAMs were detected some mutations were present at baseline. Despite detectable M184V in 74% of patients on lamivudine/zidovudine, addition of abacavir with or without another antiretroviral therapy resulted in a reduction in vRNA, with 42 of 65 (65%) patients having week 48 vRNA <400 copies/ml (intent-to-treat with missing=failure). At week 48, the most common genotype was M184V alone in the abacavir/ lamivudine/zidovudine group (median vRNA 1–2 log10below baseline), and M184V with or without TAMs in patients originally assigned to lamivudine/zidovudine. At week 48, phenotypic results were obtained for 11 isolates for patients from both arms, and all had reduced susceptibility to lamivudine but all remained sensitive to stavudine, all protease inhibitors and all non-nucleoside reverse transcriptase inhibitors. Three, three and two isolates had reduced susceptibility to abacavir, didanosine and zidovudine, respectively.Conclusions Abacavir retained efficacy against isolates with the M184V genotype alone. TAMs did not develop during 48 weeks of abacavir/lamivudine/zidovudine therapy and were uncommon when abacavir was added after 16 weeks of lamivudine/zidovudine therapy. Limited mutations upon rebound on this triple nucleoside combination allows for several subsequent treatment options.

The effects of the novel tetramethylpiperidyl (TMP)-substituted phenazine, B4128 (0.6-2.5 mg/L), on growth, phospholipase A2(PLA2) activity, cation (K+, Ca2+) fluxes and energy metabolism (ATP) of Mycobacterium aurum A(+) and Mycobacterium tuberculosis (H37Ra) have been investigated in vitro. Growth, PLA2 and cation fluxes were measured radiometrically, while microbial ATP was assayed by means of a luciferin/luciferase chemiluminescence method. Exposure of the mycobacteria to B4128 resulted in immediate, dose-related enhancement of microbial PLA2 activity and inhibition of K+ influx, which preceded effects on microbial ATP, influx of Ca2+ and growth. These results demonstrate that B4128 possesses membrane-directed antimycobacterial properties that are similar to those of clofazimine.

Altered phospholipase A2 (PLA2) activity and its relationship to cation (K+, Ca2+) uptake and growth were investigated in mycobacteria exposed to the riminophenazine antimicrobial agents, clofazimine and B669 (0.15-2.5 mg/L). Microbial PLA2 activity was measured using a radiometric thin-layer chromatography procedure, whereas K+ and Ca2+ transport were measured using 86Rb+ or 42K+ and 45Ca2+, respectively. Short-term exposure (15-30 min) of Mycobacterium aurum A+ or the virulent and avirulent isolates of Mycobacterium tuberculosis H37R to the riminophenazines resulted in dose-related enhancement of microbial PLA2 activity, which was associated with inhibition of K+ influx and growth. Uptake of Ca2+ by mycobacteria was unaffected, or minimally affected, by the riminophenazines at concentrations of < or = 0.6 mg/L, whereas higher concentrations resulted in increased uptake of the cation in the setting of decreased microbial ATP concentrations. The results of kinetic studies using a fixed concentration (2.5 mg/L) of B669 demonstrated that riminophenazine-mediated enhancement of PLA2 activity and inhibition of K+ uptake in mycobacteria are rapid and probably related events that precede, by several minutes, any detectable effects on microbial ATP concentrations and uptake of Ca2+. Inclusion of the extracellular and intracellular Ca2+-chelating agents EGTA (0.2-7.2 g/L) and BAPTA/FURA-2 (0.2-9.5 mg/L), individually or in combination, did not prevent the effects of B669 on mycobacterial PLA2 activity or K+ transport, whereas alpha-tocopherol, which neutralizes PLA2 primary hydrolysis products, antagonized the inhibitory effects of the riminophenazines on microbial K+ uptake and growth. These results demonstrate that the antimycobacterial activities of clofazimine and B669 are related to a Ca2+-independent increase in mycobacterial PLA2, leading to interference with microbial K+ transport.

In order to determine the indications and usefulness of MRI scanning in evaluating spinal cord trauma, MRIs on 43 subacute and chronic spinal cord injured children were compared with CT myelograms and other diagnostic tests. MRI scans were superior to CT myelograms in evaluating post-traumatic syrinx, disc pathology and the physiological status of the cord. CT myelogram remains an essential study before considering spinal cord decompression. The presence of internal fixation is not a contraindication to MRI scanning.

China's H-beam export market softened this week due to a drop in bookings and lower domestic prices. [ABSTRACT FROM AUTHOR]

China's spot rebar prices stopped falling on Thursday March 7 after declining for two consecutive days, although actual transactions did not change a lot. [ABSTRACT FROM AUTHOR]

China's spot rebar prices slipped further on Wednesday March 6 as end-users held off purchases until the country's political advisory body and legislative house conclude their meetings. [ABSTRACT FROM AUTHOR]

China's plate export prices declined again on Wednesday March 6 on low bookings and a weaker domestic market. [ABSTRACT FROM AUTHOR]

China's spot steel market declined on Tuesday March 5 on lower-than-expected demand, slow trading and ex-works price cuts. [ABSTRACT FROM AUTHOR]

China's cold rolled coil export prices continued to lose ground on Tuesday March 5 amid slow transactions and a weakening domestic market. [ABSTRACT FROM AUTHOR]

China's domestic hot rolled coil market declined again on Monday March 4 after Beijing announced changes to its resale property sector last Friday evening. [ABSTRACT FROM AUTHOR]

The Chinese hot rolled coil export market remained weak on Monday March 4 as bookings were still low. [ABSTRACT FROM AUTHOR]

China's spot steel market pricing stopped sliding on Friday March 1, but prices ended the week lower amid slow trading. [ABSTRACT FROM AUTHOR]

China's hot-dipped galvanised coil producers have maintained their export prices this week, as they await further market cues. [ABSTRACT FROM AUTHOR]

We have used a phospholipase C (PLC)-deletion mutant (&lt;it>plcABC&lt;/it>) of the H37Rv strain of &lt;it>Mycobacterium tuberculosis&lt;/it> (MTB), as well as a &lt;it>plcA&lt;/it>-insertion mutant of &lt;it>Mycobacterium smegmatis&lt;/it>, to investigate the possible involvement of PLCs in clofazimine-mediated inhibition of mycobacterial K&plus; transport and growth. Inactivation of the PLCs of MTB and insertion of the &lt;it>plcA&lt;/it> gene into &lt;it>M. smegmatis&lt;/it> resulted in a substantial reduction and increase in hydrolysis of phosphatidylcholine (PC), respectively. However, both the mutant and wild-type strains of MTB and &lt;it>M. smegmatis&lt;/it> were equally sensitive to the inhibitory effects of clofazimine on K&plus; uptake and growth. These observations demonstrate that the PLCs of MTB are not involved in the antimicrobial activity of clofazimine.