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Gamma-ray bursts (GRBs) are brief flashes of γ-rays and are considered to be the most energetic explosive phenomena in the Universe1. The emission from GRBs comprises a short (typically tens of seconds) and bright prompt emission, followed by a much longer afterglow phase. During the afterglow phase, the shocked outflow—produced by the interaction between the ejected matter and the circumburst medium—slows down, and a gradual decrease in brightness is observed2. GRBs typically emit most of their energy via γ-rays with energies in the kiloelectronvolt-to-megaelectronvolt range, but a few photons with energies of tens of gigaelectronvolts have been detected by space-based instruments3. However, the origins of such high-energy (above one gigaelectronvolt) photons and the presence of very-high-energy (more than 100 gigaelectronvolts) emission have remained elusive4. Here we report observations of very-high-energy emission in the bright GRB 180720B deep in the GRB afterglow—ten hours after the end of the prompt emission phase, when the X-ray flux had already decayed by four orders of magnitude. Two possible explanations exist for the observed radiation: inverse Compton emission and synchrotron emission of ultrarelativistic electrons. Our observations show that the energy fluxes in the X-ray and γ-ray range and their photon indices remain comparable to each other throughout the afterglow. This discovery places distinct constraints on the GRB environment for both emission mechanisms, with the inverse Compton explanation alleviating the particle energy requirements for the emission observed at late times. The late timing of this detection has consequences for the future observations of GRBs at the highest energies.

This study attempts to allocate the fund management expenses of actively managed South African general equity unit trusts between active and passive management portions, thereby calculating the implicit cost of active management. The active expense ratio of a unit trust can be calculated by using the published total expense ratio (TER) of the unit trust, its correlation relative to its benchmark and the expense ratio of a comparable exchange traded fund (ETF) tracking the benchmark of the unit trust.This study focuses on actively managed South African equity unit trusts available to the retail investor for the period March 2007 to February 2015. The active expense ratios of these unit trusts were calculated on the basis of a three-, five- and eight-year analysis period.It was found that the mean active expense ratios of the South African unit trust sample amounted to 4,14%, 4,29% and 4,25% respectively in the case of the three-, five- and eight-year periods. The comparable mean reported TERs amounted to 1,60%, 1,61% and 1,61% respectively. Thus the mean active expense ratio is more than 150% higher than the comparable mean reported TER in each period.A similar study was conducted by Miller (2010), investigating the active expense ratios of actively managed large cap American unit trusts. He found that the mean active expense ratio was 6.44%, compared with a mean TER of 1.20%. However, due to a higher degree of active management being employed by South African managers, the active expense ratios are lower than those of the American counterparts.

We have investigated the effects of cisplatin and 2 novel, water‐soluble platinum (Pt) polymer conjugates, Pt‐6 and Pt‐7, on the production of reactive oxygen species (ROS) by unstimulated human neutrophils, as well as by cells activated with phorbol myristate acetate (PMA). Production of ROS was measured using a lucigenin‐enhanced chemiluminescence (LECL) procedure. Addition of cisplatin to neutrophils resulted in an abrupt, dose‐related, but small increase in the spontaneous generation of ROS by the cells, whereas the PMA‐activated responses were substantially increased by pretreatment of neutrophils with the antineoplastic agent. Importantly, neither the spontaneous nor the PMA‐activated LECL responses of neutrophils were altered after treatment with either Pt‐6 or Pt‐7. Taken together with their impressive and selective anti‐proliferative effects on tumor cells, the absence of pro‐oxidative interactions of Pt‐6 and Pt‐7 with human neutrophils further underscores the clinical potential of these novel anticancer agents. Drug Dev. Res. 66:204–209, 2006. © 2006 Wiley‐Liss, Inc.

The objective of this study was to evaluate the effect of embryonic thermal manipulation and dietary fat source during the finisher period on carcass characteristics and breast muscle myopathies following acute heat stress. Thermal manipulation (TM) of incubation temperatures has been shown to improve bird resistance to heat stress and enhance breast muscle growth. Fat supplementation is frequently used during heat stress and fat source may alter carcass composition, as fat sources rich in unsaturated fatty acids have been shown to reduce fat pad weight. Ross 708 eggs were incubated at 37.5°C except during TM when temperature was increased to 39.5°C for 12 h daily from embryo day 7 to 16. A total of 1,080 chicks were reared under standard conditions until acute heat stress at 43 d. Dietary treatments were applied during the finisher period beginning at 28 d, with diets including 4.5% of soya oil, poultry fat, or olive oil. At 49 d, 240 male birds were processed to assess carcass and portion weights, as well as breast quality. Carcass and portion weights were decreased by TM, however percent yield was similar to the controls. A decrease in breast muscle myopathies was noted but may have been due to the lower BW of the TM birds. Interactions between the treatments suggest that TM may alter lipid metabolism. Differences in dietary fat source did not affect carcass characteristics. The reduction in breast muscle myopathies may be negated by the negative impact of TM on carcass weights.

The effects of dapsone on polymorphonuclear leukocyte functions and lymphocyte mitogen-induced transformation were assessed in vitro and in vivo in normal individuals and in newly diagnosed untreated patients with lepromatous leprosy. The effects of dapsone on the cell-free generation of superoxide by the xanthine: xanthine oxidase system and iodination of bovine serum albumin by horseradish peroxidase were also investigated. In normal individuals dapsone mediated stimulation of polymorphonuclear leukocyte migration in vitro and vivo. Dapsone had no effect on postphagocytic hexose monophosphate shunt activity in vivo. Similar effects were found in patients with lepromatous leprosy. Dapsone also decreased the inhibitory activity of serum from patients with lepromatous leprosy on normal polymorphonuclear leukocyte migration in vitro. Progressive loss of serum-mediated inhibition of migration was observed after ingestion of dapsone by the patients. Further experiments showed that stimulation of polymorphonuclear leukocyte motility was related to inhibition of lymphocyte transformation at high concentrations in vitro, but had slight stimulatory activity on phytohemagglutinin-induced transformation in controls and patients in vivo.

The effects of the oral gold compound auranofin (AF), at concentrations well within the therapeutic range (0.04-1.5 microM), on human neutrophil functions and energy metabolism were investigated in vitro. At the concentrations tested, this agent had minimal effects on neutrophil degranulation and phagocytosis. However, AF caused dose-related inhibition of neutrophil chemotaxis and stimulus-activated generation of superoxide, which was evident at concentrations as low as 0.04 microM. Inhibition of superoxide generation by activated neutrophils increased with the time of preincubation of the cells with AF at 37 degrees. At low concentrations of AF (less than 0.75 microM), early events (within 5 min) involved in the transduction, assembly, and activity of the neutrophil superoxide-generating enzyme NADPH oxidase appeared to be normal, but the cells were unable to sustain the level of oxygen consumption, superoxide production, and NADPH oxidase activity of the corresponding drug-free control cells. On a mechanistic level, coincubation of neutrophils with AF was associated with decreased glycolytic activity and depletion of intracellular ATP, apparently due to drug-mediated, dose-related inactivation of the glycolytic enzyme phosphofructokinase (PFK). Using purified PFK, the triethylphosphine gold (TEPG) moiety of AF, but not AF per se, caused dose-related inactivation of enzyme activity. These data indicate that the potent inhibition of neutrophil migration and reactive oxidant generation observed during treatment of neutrophils with low, therapeutically attainable concentrations of AF is related to TEPG-mediated inactivation of PFK and consequent interference with cellular energy metabolism and functions.

Benoxaprofen was previously found to inhibit the random and leucoattractant-induced migration of human polymorphonuclear leucocytesin vitro by a pro-oxidative mechanism [1]. In this study the effects of benoxaprofen on the binding to PMNL of the synthetic chemotactic tripeptide FMLP, on the oxidative inactivation of this leucoattractant by PMNL and on PMNL chemotaxis, chemokinesis and orientation in an FMLP gradient have been investigated. At concentrations of 10−5M (3 μg/ml) benoxaprofen inhibited PMNL random and leucoattractant-induced migration and increased PMNL membraneassociated oxidative metabolism and cellular auto-oxidation. These effects of benoxaprofen on PMNL migration and auto-oxidation were prevented by the anti-oxidant cysteine (10−3M). Benoxaprofen inhibited both FMLP-induced chemotaxis and chemokinesis but did not affect the binding of radiolabelled FMLP to PMNL or orientation of the cells in a positive gradient of the leucoattractant. Benoxaprofen at concentrations of 5×10−5M significantly increased the oxidative inactivation of FMLP by PMNL. Inhibition of PMNL migration by benoxaprofen is mediated by the two different pro-oxidative mechanisms, viz. a cell-directed auto-oxidative mechanism and potentiation of the oxidative inactivation of leucoattractants by PMNL.

The effects of clofazimine on neutrophil activities such as random motility, migration to the leukoattractants endotoxin-activated serum and N-formyl-L-methionyl-L-leucyl-L-phenylalanine phagocytosis of Candida albicans, postphagocytic hexose-monophosphate shunt activity, and myeloperoxidase-mediated iodination and the effects of clofazimine on lymphocyte transformation to mitogens were assessed in vitro and after ingestion of the drug by normal individuals and patients with lepromatous leprosy. For in vitro studies, the concentration range of the drug investigated was 10(-6) M to 10(-2) M. for in vivo studies, subjects ingested 200 mg of clofazimine daily for a period of 5 days. At concentrations of 5 X 10(-6) M to 5 X 10(-3) M clofazimine caused a progressive dose-dependent inhibition of neutrophil motility without detectable effects on phagocytosis, postphagocytic hexose-monophosphate shunt activity, or myeloperoxidase-mediated iodination. Over the same concentration range, clofazimine inhibited lymphocyte transformation. The inhibitory effect on neutrophil motility was associated with a spontaneous stimulation of oxidative metabolism and could be prevented by coincubation of dapsone with clofazimine. after ingestion of clofazimine responsiveness of lymphocytes to mitogens was decreased in normal volunteers and leprosy patients: neutrophil motility in normal individuals was likewise inhibited.

The relationship between the phospholipase-stimulating and immunosuppressive properties of cyclosporin A (CsA) has been investigated in vitro. At concentrations of 0.025 microM and upwards, CsA caused dose-related inhibition of both mitogen- and alloantigen-stimulated uptake of tritiated thymidine by human mononuclear leukocytes (MNL), which was associated with a time- and dose-related enhancement of the generation of lysophosphatidylcholine (LPC), arachidonic acid, and prostaglandin E2 from mitogen-stimulated cells. Arachidonate alone, at concentrations of up to 20 microM, did not affect lymphocyte activation, whereas cyclooxygenase and 5'-lipoxygenase inhibitors failed to protect the cells against the antiproliferative effects of CsA. However, LPC caused dose-related inhibition of MNL proliferation. Moreover, coincubation of MNL with alpha-tocopherol, a lysophospholipid-complexing agent, or with lysophospholipase protected the cells against CsA, as well as against LPC. The Na+,K(+)-ATPase activity of mitogen-activated lymphocytes was also inhibited by CsA, whereas inclusion of alpha-tocopherol or lysophospholipase protected this enzyme. Excessive production of lysophospholipids and consequent inhibition of Na+,K(+)-ATPase during CsA treatment of mitogen- or antigen-activated lymphocytes is a possible biochemical mechanism of the immunosuppressive activity of this agent.

We have investigated the effects of cyclosporin A (CsA, 3–50 ng/ml) in combination with the riminophenazine agents clofazimine and B669 (60–500 ng/ml) on the mitogen- and alloantigen-activated proliferative responses of human mononuclear leukocytes (MNL), as well as on the phospholipase A2 and Na+, K+-adenosine triphosphatase activities of these cells. When used in combination these agents caused inhibition of the proliferative responses of both mitogen- and alloantigen-activated MNL which was at least additive. Combinations of CsA with the riminophenazines also caused augmentative activation of PLA2 and inhibition of Na+, K+-ATPase. The inhibitory effects of these agents, both individually and in combination, on the Na+, K+-ATPase and proliferative responses of MNL were neutralized by the membrane-stabilizing, lysophospholipid complex-forming agent alpha-tocopherol (vitamin E, 20 µg/ml). These observations suggest that combinations of CsA with riminophenazines cause interactive enhancement of the activity of PLA2 in MNL leading to lysophospholipid-mediated inactivation of Na+, K+-ATPase and consequent inhibition of the proliferative responses of these cells. In the therapeutic setting combinations of these agents may enable reduction in the dose of CsA required to achieve meaningful immunosuppression with a consequent decrease in the risk of chemotherapy-related organ toxicity.

The susceptibilities of a range of gram-positive and gram-negative microbial pathogens to clofazimine and its analog B669 (0.1 to 32 micrograms/ml), as well as the effects of these agents on membrane phospholipid metabolism in Staphylococcus aureus and Escherichia coli, have been investigated in vitro. Gram-positive bacteria were found to be generally susceptible to these agents, whereas gram-negative organisms were uniformly resistant. Exposure of S. aureus to both agents (1 to 5 micrograms/ml), especially B669, caused dose-related enhancement of the activity of phospholipase A2, according to an increase in the release of 3H-radiolabeled arachidonate and lysophosphatidylethanolamine ([3H]LPE) from bacterial-membrane phospholipids. Treatment of E. coli with the riminophenazines also increased the release of [3H]arachidonate and [3H]LPE. Growth of gram-positive but not gram-negative bacteria was inhibited by LPE and lysophosphatidylcholine. Moreover, coincubation with alpha-tocopherol (vitamin E), a lysophospholipid complex-forming agent, or with lysophospholipase protected gram-positive bacteria against the riminophenazines as well as against lysophospholipids. The results from this study are consistent with a mechanism whereby lysophospholipids mediate the activities of the two drugs.

Modern broilers have been selected for rapid growth but demonstrate reduced heat tolerance toward market age. As the poultry industry expands globally, strategies must be developed to support broiler performance in challenging climates. The objective of this study was to evaluate the effect of embryonic thermal manipulation (TM) and dietary fat source during the finisher period on broiler performance during acute heat stress (AHS) close to market age. The cyclic exposure to high temperatures during mid-incubation used in TM has been demonstrated to improve broiler tolerance to heat stress. However, high incubation temperatures can be detrimental to embryonic development and impair posthatch broiler performance. Embryos were exposed to 39.5°C for 12 h daily from incubation day 7 to 16 to assess the impact of TM on hatching and broiler performance. Dietary fat is commonly added to poultry diets during heat stress and it was theorized that differences in fat source may further impact bird performance. Finisher diets were supplemented with soya oil, poultry fat, or olive oil at 4.5% each. Broilers were exposed to a period of AHS at 43 d. Embryo mortality was increased, and hatchability was reduced by TM. Broiler performance was also decreased for the TM birds, but mortality during AHS was markedly reduced. Dietary fat source did not influence bird performance but was shown to interact with incubation treatment. Overall, the present data suggest optimal performance in modern broiler strains may be at odds with improved heat tolerance.

Trichomonas vaginalis is an important and common cause of urogenital infections in both developed and in developing countries. In view of the high prevalence, increase in resistance to drug therapy and associated risk of acquisition and transmission of HIV, we screened the aqueous extracts of 29 plants. These plants are used to treat venereal diseases and infections in the Venda region. Extracts of four plants showed trichomonicidal activity:Securidaca longepedunculata Fresen. (Polygalaceae; 0.10 mg/ml), Solanum aculeastrum Dun. (Solanaceae; 1.06 mg/ml), Piper capense L.f. (Piperaceae; 11.19 mg/ml) andCassine transvaalensis (Burtt. Davy) Codd (Celastraceae; 9.69 mg/ml). Further investigations are required to determine whether these plants possess the potential to be developed as new drugs for the treatment of trichomoniasis.

Ethionamide (ETH) and isoniazid (INH) are part of the backbone regimen used for the treatment of multidrug-resistant tuberculosis (MDR-TB). Both ETH and INH are structurally similar and are activated by ethAand katGgene products. Resistance to INH among MDR-TB patients may cause ETH to be ineffective, as both target nicotinamide adenine dinucleotide-dependent enoyl-acyl carrier protein reductase inhAprotein and mutations within inhAgene may lead to their cross-resistance. Furthermore, ETH resistance is caused by mutations within ethAand ethRgenes forming part of the ETH drug activation pathway. Nicotinamide adenine dinucleotide is coded by the ndhgene, and its overexpresion may lead cross-resistance between INH and ETH drugs. Phenotypic drug susceptibility testing of ETH is difficult and often unreliable. We used whole genome sequencing to compare inhA, inhApromoter, ethA, ethR ndh, and katGgenetic regions in serial isolates (baseline and follow-up) with treatment outcomes.

The intraphagocytic bioactivities for Staphylococcus aureus of amoxicillin, clindamycin, and erythromycin (0.0075-20 µ/ml) were measured in human polymorphonuclear leukocytes (PMNLs) with the combination of a fluorochrome microassay and a radioassay. PMNLs with normal or depleted membrane-associated oxidative metabolism were used to investigate the interactions that may occur between the intrinsic O2 dependent antimicrobial systems of human phagocytes and antimicrobial agents in the elimination of intracellular microbial pathogens. Neutralization of 02-dependent antimicrobial systems with retention of phagocytic capacity was achieved with use of PMNLs.from four children with chronic granulomatous disease (COD) or NaF-pulsed normalPMNLs. None of the test antibiotics possessed intracellular bactericidal activity. Clindamycin and erythromycin possessed significant intracellular bacteriostatic activity relativ~ to the modest activity of amoxicillin. Optimal intracellular bioactivity of all three antibiotics was obtained with normal PMNLs relative to NaF-pulsed or COD PMNLs, a result indicating the existence of beneficial interactions between the antimicrobial agents and the O2 dependent antimicrobial systems of PMNLs.