Reconciling agriculture, carbon and biodiversity in a savannah transformation frontier.

Rapidly rising populations and likely increases in incomes in sub-Saharan Africa make tens of millions of hectares of cropland expansion nearly inevitable, even with large increases in crop yields. Much of that expansion is likely to occur in higher rainfall savannas, with substantial costs to biodiversity and carbon storage. Zambia presents an acute example of this challenge, with an expected tripling of population by 2050, good potential to expand maize and soya bean production, and large areas of relatively undisturbed miombo woodland and associated habitat types of high biodiversity value. Here, we present a new model designed to explore the potential for targeting agricultural expansion in ways that achieve quantitatively optimal trade-offs between competing economic and environmental objectives: total converted land area (the reciprocal of potential yield); carbon loss, biodiversity loss and transportation costs. To allow different interests to find potential compromises, users can apply varying weights to examine the effects of their subjective preferences on the spatial allocation of new cropland and its costs. We find that small compromises from the objective to convert the highest yielding areas permit large savings in transportation costs, and the carbon and biodiversity impacts resulting from savannah conversion. For example, transferring just 30% of weight from a yield-maximizing objective equally between carbon and biodiversity protection objectives would increase total cropland area by just 2.7%, but result in avoided costs of 27-47% for carbon, biodiversity and transportation. Compromise solutions tend to focus agricultural expansion along existing transportation corridors and in already disturbed areas. Used appropriately, this type of model could help countries find agricultural expansion alternatives and related infrastructure and land use policies that help achieve production targets while helping to conserve Africa's rapidly transforming savannahs.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'.

Structure-activity studies of antitumor agent irofulven (hydroxymethylacylfulvene) and analogues.

Many analogues of the antitumor agent irofulven have been readily prepared by replacing the allylic hydroxyl with a variety of nucleophiles. Analogues of acylfulvene (the precursor to irofulven) were also prepared by Michael reaction with acrolein. The toxicity of the analogues was determined, as well as preclinical antitumor activity. Several analogues exhibited good activity in mouse xenografts. Structural requirements for activity are discussed.

Reduction of vancomycin use in orthopedic patients with a history of antibiotic allergy.

OBJECTIVE: To reduce prophylactic vancomycin use in patients with a history of penicillin or cephalosporin allergy undergoing elective orthopedic surgery by using a targeted allergy consultation and penicillin allergy skin testing. PATIENTS AND METHODS: The participants in this practice improvement study were patients with a history of penicillin or cephalosporin allergy who were scheduled for elective orthopedic surgery and referred by orthopedic surgeons for allergy consultation and penicillin allergy skin testing between September 22, 1998, and April 15, 1999. The primary outcome measure was the percentage of participants who received prophylactic cefazolin during the study period compared with historical controls. RESULTS: Of the 60 study patients, 59 received a penicillin allergy skin test, 58 underwent orthopedic surgery, and 55 received antibiotic prophylaxis. Fifty-five patients had a history of allergy to penicillin, a cephalosporin, or both, and 5 had a history of nonspecific antibiotic allergy. Of the 59 patients, 55 (93%) had negative penicillin allergy skin test results. Fifty-four (90%) of the 60 patients were given clearance by the allergist to receive cefazolin. Of the 55 study patients who received antibiotic prophylaxis, 6 (11%) received vancomycin compared with 38 (30%) of 127 historical controls (P < or = .05). None of the study patients had an immediate reaction to cefazolin or to vancomycin. CONCLUSION: Prophylactic vancomycin use in patients with a history of penicillin or cephalosporin allergy undergoing elective orthopedic surgery can be reduced by a targeted allergy consultation and penicillin allergy skin testing.

Efficacy of MGI 114 (HMAF) against the MRP+ metastatic MV522 lung carcinoma xenograft.

This study is part of an effort to evaluate efficacy of the novel agent MGI 114 (HMAF) against tumors resistant to conventional chemotherapeutic agents. MGI 114 is a novel semisynthetic anticancer agent currently in chemotherapeutic phase II trials to evaluate activity against various solid tumors. Previous studies indicate MGI 114 was active against human MDR1/gp170+ solid tumor xenografts. Recent evidence suggests overexpression of the MRP protein may also be clinically relevant to development of drug resistance in solid tumors. We evaluated the efficacy of MGI 114 against a human MRP+ lung carcinoma xenograft. Parent MV522 lung carcinoma cells were transfected with a MRP cDNA expression vector and resistant cells selected by exposure to vinblastine (30-fold resistance). Analysis of resistant clones indicated 20- to 40-fold increases in expression of both MRP mRNA and MRP protein. Administration of MGI 114 at the maximum tolerated dose (7 mg/kg, 5 x/week for 3 weeks) to MRP tumor-bearing mice demonstrated this novel agent was active against MRP+ tumors and significantly extended their lifespan (p<0.001). In contrast, other cytotoxic agents had minimal activity against this MRP+ xenograft. These results indicate MGI 114 should retain activity in vivo against MRP+ tumor types. The development of this MRP+ xenograft model, in conjunction with the parent MV522 and MDR1/gp170+ xenograft models, will be useful for screening new classes of agents for activity against multidrug-resistant tumors.

Structural organization of the microsomal glutathione S-transferase gene (MGST1) on chromosome 12p13.1-13.2. Identification of the correct promoter region and demonstration of transcriptional regulation in response to oxidative stress.

The structure and regulation of the microsomal glutathione S-transferase gene (MGST1) are considerably more complex than originally perceived to be. The MGST1 gene has two alternative first exons and is located in the 12p13.1-13.2 region. Two other potential first exons were determined to be nonfunctional. The region between the functional first exons cannot direct transcription. Thus, one common promoter element directing transcription exists, and RNA splicing occurs such that only one of the first exons (containing only untranslated mRNA) is incorporated into each mRNA species with common downstream exons. MGST1 expression and regulation are therefore similar to those of other hepatic xenobiotic handling enzymes, which also produce mRNA species differing only in the 5'-untranslated regions to yield identical proteins. MGST1 was previously considered a "housekeeping" gene, as non-oxidant inducers had little effect on activity. However, the promoter region immediately upstream of the dominant first exon transcriptionally responds to oxidative stress. In this respect, MGST1 is similar to glutathione peroxidases that also transcriptionally respond to oxidative stress. The discovery that MGST1 utilizes alternative first exon splicing eliminates a problem with the first description of MGST1 cDNA in that it appeared that MGST1 expression was in violation of the ribosomal scanning model. The identification that the first exon originally noted is in fact a minor alternative first exon far downstream of the primary first exon eliminates this conundrum.

Anti-leukemic action of the novel agent MGI 114 (HMAF) and synergistic action with topotecan.

The illudin derivative MGI 114 (6-hydroxymethylacylfulvene or HMAF) is currently in phase II chemotherapeutic clinical trials for a variety of solid tumors. The illudins were originally thought to be potentially useful agents for myeloid leukemias, because hematopoietic tumor cells were markedly sensitive whereas normal bone marrow progenitors were relatively resistant to the cytotoxic effects of illudins. Due to the marked preclinical efficacy of MGI 114 against a variety of solid tumor xenografts, the current phase II human trials are restricted to solid tumor (breast, lung, colon, ovarian, pancreas, prostate, etc) malignancies. The present studies were undertaken to evaluate the efficacy of MGI 114 in the HL60/MRI myeloid leukemia xenograft. In addition, because of the reported synergistic cytotoxic activity between MGI 114 and the topoisomerase I inhibitor topotecan towards pediatric human tumor cell lines, we tested the activity of MGI 114 and topotecan combinations against HL60 cells in vitro and the HL60/MRI myelocytic xenograft. Our results indicate that MGI 114 at maximum tolerated doses (MTD) of 7 mg/kg, five times per week for 3 weeks does display anti-myeloid leukemic properties in the HL60/MRI xenograft model which exceeds activity noted with other conventional agents (TGI > 70%). A marked therapeutic synergistic action was observed with MGI 114 and topotecan combinations of (1/2) MTD of each agent producing complete tumor remission in 50% of animals, without development of excessive or additive toxicity in animals. These results support further in vitro and clinical investigation into both the anti-myeloid leukemic activity of MGI-114, and the cooperative pharmacologic interaction noted between MGI-114 and topoisomerase I inhibitors. Leukemia (2000) 14, 136-141.

Drug monitoring of antiretroviral therapy for HIV-1 infection: method validation and results of a pilot study.

BACKGROUND: Antiretroviral therapy for HIV-1 infection has become increasingly complex. The availability of new and potent drugs and progress in understanding the pathogenesis of HIV-1 infection have led to the establishment of new treatment paradigms. The varying dosing regimens, associated toxicities, and the potential for drug-drug and food-drug interactions further complicate treatment. This complexity contributes to patient nonadherence. Because clinicians have no tools to monitor adherence or drug-drug interactions and because response requires that therapy exceed the known inhibiting concentration, serum monitoring of antiretroviral therapy may play a role in improving treatment of HIV-1 infection. We report methods to quantify serum concentrations of antiretroviral drugs used to treat HIV-1 infection, precision and interference studies of these methods, and results observed in a pilot evaluation of blood serum concentrations from 12 human subjects. METHODS: HPLC offers adequate sensitivity to measure peak or trough serum concentrations of delavirdine, lamivudine, nevirapine, indinavir, nelfinavir, ritonavir, and saquinavir and peak serum concentrations of stavudine, zidovudine, and didanosine with reasonable precision. RESULTS: Peak indinavir serum concentrations in most patients were in the range of 1-10 mg/L, and trough concentrations were in the range of 0.1-0.5 mg/L. Peak stavudine concentrations were in the range of 0.3-1.3 mg/L, and trough concentrations were in the range of 0.1-0.5 mg/L. Peak zidovudine concentrations were in the range of 0.1-1.1 mg/L. CONCLUSIONS: Because this was a blood serum concentration-seeking pilot study to evaluate analytic performance, we do not report on the correlation of drug response to blood concentration. However, the concentrations observed in patients are generally consistent with blood concentrations reported from studies of monotherapy.

Characterization of MGI 114 (HMAF) histiospecific toxicity in human tumor cell lines.

PURPOSE: The acylfulvenes are a class of antitumor agents derived from the fungal toxin illudin S. One acylfulvene derivative, MGI 114 (HMAF), demonstrates marked efficacy in xenograft carcinoma models when compared to the parent acylfulvene or related illudin compounds. The maximum tolerated dose (MTD) of the two analogs in animals, however, is similar. To help elucidate the basis of the increased therapeutic efficacy of MGI 114, we determined the in vitro cytotoxicity, cellular accumulation and DNA incorporation of this drug and compared the results with those from the parent acylfulvene analog. METHODS: The cytotoxicity of acylfulvene analogs was tested in vitro against a variety of tumor cell lines. Radiolabeled MGI 114 was used for cellular accumulation and DNA incorporation studies. RESULTS: MGI 114 retained relative histiospecific toxicity towards myeloid leukemia and various carcinoma cell lines previously noted with the parent acylfulvene compound. Markedly fewer intracellular molecules of MGI 114 were required to kill human tumor cells in vitro as compared to the parent acylfulvene, indicating that MGI 114 was markedly more toxic on a cellular level. At equitoxic concentrations, however, the incorporation of MGI 114 into genomic tumor cell DNA was equivalent to that of acylfulvene. Analysis of cellular accumulation of MGI 114 into tumor cells revealed a lower Vmax for tumor cells, and a markedly lower Vd for diffusion accumulation as compared to acylfulvene. CONCLUSIONS: The addition of a single methylhydroxyl group to acylfulvene to produce MGI 114 results in a marked increase in cytotoxicity in vitro towards tumor cells as demonstrated by the reduction in IC50 values. There was a corresponding decrease in the number of intracellular molecules of MGI 114 required to kill tumor cells, but no quantitative alteration in covalent binding of the drugs to DNA at equitoxic concentrations. This indicates that cellular metabolism plays a role in the in vitro cytotoxicity of MGI 114. The equivalent incorporation into genomic DNA at equitoxic doses suggests that DNA damage produced by acylfulvene and MGI 114 is equivalent in regard to cellular toxicity and ability to repair DNA. This increased cellular toxicity, together with the decrease in diffusion rate, may explain the increased therapeutic efficacy of MGI 114 as compared to the parent acylfulvene analog.

Development and evaluation of the McKnight Risk Factor Survey for assessing potential risk and protective factors for disordered eating in preadolescent and adolescent girls.

OBJECTIVE: To describe the development, test-retest reliability, internal consistency, and convergent validity of the McKnight Risk Factor Survey-III (MRFS-III). The MRFS-III was designed to assess a number of potential risk and protective factors for the development of disordered eating in preadolescent and adolescent girls. METHOD: Several versions of the MRFS were pilot tested before the MRFS-III was administered to a sample of 651 4th through 12th- grade girls to establish its psychometric properties. RESULTS: Most of the test-retest reliability coefficients of individual items on the MRFS-III were r > .40. Alpha coefficients for each risk and protective factor domain on the MRFS-III were also computed. The majority of these coefficients were r > .60. High convergent validity coefficients were obtained for specific items on the MRFS-III and measures of self-esteem (Rosenberg Self-Esteem Scale) and weight concerns (Weight Concerns Scale). CONCLUSIONS: The test-retest reliability, internal consistency, and convergent validity of the MRFS-III suggest that it is a useful new instrument to assess potential risk and protective factors for the development of disordered eating in preadolescent and adolescent girls.

Efficacy of MGI 114 (6-hydroxymethylacylfulvene, HMAF) against the mdr1/gp170 metastatic MV522 lung carcinoma xenograft.

Illudins are a novel class of agents with a chemical structure entirely different from current chemotherapeutic agents. A new semisynthetic derivative, MGI 114 (NSC 683,863, 6-hydroxymethyl-acylfulvene, HMAF), is markedly effective in a variety of lung, breast and colon carcinoma xenograft models. This analogue, MGI 114, is currently in phase I human clinical trials, and is scheduled for two different phase II trials. To determine if MGI 114 could be effective in vivo against mdr tumour cells, we generated an mdr1/gp170-positive clone of the metastatic MV522 human lung carcinoma line by transfecting a eukaryotic expression vector containing the cDNA encoding for the human gp170 protein. This MV522/mdr1 daughter line retained the metastatic ability of parental cells. The parental MV522 xenograft is mildly responsive in vivo to mitomycin C and paclitaxel, as evidenced by partial tumour growth inhibition and a small increase in life span, whereas MV522/mdr1 xenografts were resistant to these agents. In contrast to mitomycin C and paclitaxel, MGI 114 produced xenograft tumour regressions in 32 of 32 animals and completely eliminated tumours in more than 30% of MV522/mdr1 tumour-bearing mice. Thus, MGI 114 should be effective in vivo against mdr1/gp170-positive tumours.

Review of pharmacokinetics and pharmacodynamics of antimicrobial agents.

Pharmacokinetics is a science that has long been used in ascertaining the appropriate antimicrobial dose. It refers to the disposition of drugs in the body and includes absorption, bioavailability, distribution, protein binding, metabolism, and elimination. Pharmacodynamics is a newer science that relates to the interaction between the drug concentration at the site of action over time and the desired antimicrobial effect. This article reviews the principles of pharmacokinetics and pharmacodynamics as well as the clinical application of these two sciences to design antimicrobial dosing regimens for optimal results in individual patients.

Factors associated with weight concerns in adolescent girls.

OBJECTIVE: This study examined the association of weight concerns with potential risk factors for the development of eating disorders. METHOD: A self-report survey was given to 103 elementary (Grades 4 and 5) and 420 middle (Grades 6-8) school students in Arizona and California. Of these, 78 elementary and 333 middle school students provided complete data and were used in the analyses. RESULTS: In a multivariate stepwise regression analysis, the importance that peers put on weight and eating was most strongly related to weight concerns in the elementary school girls, accounting for 34% of the variance after adjusting for site differences. Trying to look like girls/women on TV and in magazines as well as body mass index (BMI) entered the final model that accounted for 57% of the variance in weight concerns. In middle school, the importance that peers place on weight and eating was also the strongest predictor accounting for 33% of the variance followed by confidence, BMI, trying to look like girls/women on TV and in magazines, and being teased about weight. Together these variables accounted for 55% of the variance. DISCUSSION: Prevention programs aimed at reducing weight concerns need to address these factors.

Potential risk factors associated with weight control behaviors in elementary and middle school girls.

The purpose of this study was to examine the relationship between weight control behaviors and potential risk factors for disordered eating in a sample of young girls. The McKnight Risk Factor Survey was administered to 523 elementary and middle school girls. In the sample of elementary school girls, results from the multiple regression analyses indicated that frequency/severity of weight control behaviors was associated with body mass index (BMI), self-confidence, peers' weight-related pressures, ethnicity, and the interaction between having divorced/separated parents and BMI. Sensitivity to peers' weight-related pressures and BMI were also associated with weight control behaviors in the middle school girls, along with poor body image, substance use, having divorced/separated parents, and the interaction between having divorced/separated parents and father's pressure for thinness. Longitudinal research is needed to determine how risk factors change over time, beginning in elementary school and continuing through high school.

Attachment style and weight concerns in preadolescent and adolescent girls.

OBJECTIVE: The purpose of this study was to assess the association between attachment style and weight concerns, a major risk factor for eating disorders, in preadolescent and adolescent girls. METHOD: Three hundred and five female elementary and middle school students completed measures of attachment style and weight concerns. RESULTS: Insecurely attached subjects reported higher weight concerns than did securely attached subjects. A greater proportion of insecurely attached subjects obtained "at risk" weight concerns scores than securely attached subjects. DISCUSSION: The findings suggest that attachment style may play an important role in the development of weight concerns, which, in turn, have been shown to be associated with the onset of eating disorders.

Characterization of acylfulvene histiospecific toxicity in human tumor cell lines.

PURPOSE: Acylfulvene derivatives demonstrate marked efficacy in xenograft carcinoma models as compared with the parent illudin compounds. To elucidate the increased therapeutic efficacy of acylfulvene analogs, we compared them with the illudin compounds in terms of their in vitro cytotoxicity, cellular accumulation and DNA incorporation. METHODS: The cytotoxicity of various acylfulvene analogs was tested in vitro against a variety of tumor cell lines. Radiolabelled acylfulvene analog was prepared and used for cellular accumulation and DNA incorporation studies. RESULTS: The prototype acylfulvene analog retained selective histiospecific toxicity towards myeloid leukemia and various carcinoma cell lines. In vitro killing of tumor cells by acylfulvene required up to a 30-fold increase in molecules per cell, as compared with illudin S, indicating that acylfulvene was less toxic on a cellular level. At equitoxic concentrations, acylfulvene incorporation into genomic tumor cell DNA was equivalent to illudin S suggesting that cellular metabolism has a role in acylfulvene cytotoxicity. Analysis of cellular accumulation of acylfulvene into tumor cells revealed a markedly higher Vmax for tumor cells, and a lower Vd for diffusion accumulation into other cells. CONCLUSIONS: The combination of higher Vmax and lower Vd may explain the increased in vivo efficacy of acylfulvene.

Heterologous expression of carbonyl reductase: demonstration of prostaglandin 9-ketoreductase activity and paraquat resistance.

Transfection of murine NIH3T3 fibroblasts with a pSV2-derived eukaryotic expression vector for human cytosolic carbonyl reductase (E.C. 1.1.1.141) resulted in clones with increased carbonyl reductase activity as demonstrated by an elevation in cellular NADPH-dependent alcohol (menadione) reductase activity. Prostaglandin 9-ketoreductase (9KR) activity, previously noted only in purified enzyme preparations, was also elevated. Although the cellular molar capacity of 9KR activity was less than menadione reductase activity (picomoles versus nanomoles per mg of protein), when compared to endogenous activity there was a greater relative increase in 9KR activity as compared to menadione activity (10 fold increase versus 3 fold). Thus, the 9KR properties of carbonyl reductase may have a physiologic role in prostaglandin regulation. Most transgenic clones lost their enhanced carbonyl reductase activity despite continuous selection, but two clones retained enhanced enzyme activity. RNA analysis indicated that these two murine clones expressed human carbonyl reductase mRNA. These two clones overexpressing carbonyl reductase did not display resistance to menadione, in agreement with a previous report. There was, however, a demonstrable increase in resistance to paraquat of a magnitude similar to that previously noted with transgenic cell lines overexpressing manganese superoxide dismutase.

Characterization of cellular accumulation and toxicity of illudin S in sensitive and nonsensitive tumor cells.

Illudins are novel low molecular weight natural products cytotoxic to human tumor cells in vitro. Illudin-derived analogs are effective against experimental human cancers nonresponsive to conventional anticancer agents. It is not known why some illudin analogs are more efficacious in vitro and in vivo than other analogs. Therefore, the in vitro cytotoxicity of the parent compound illudin S towards tumor cells was characterized using radiolabeled drug. Two cell lines sensitive at nanomolar concentrations using only a 15-min exposure period displayed a saturable, energy-dependent accumulation of illudins with relatively low K(m) and high Vmax values. A nonsensitive cell line, requiring millimolar concentrations to achieve in vitro toxicity, showed minimal illudin uptake with higher K(m) and lower Vmax values. No release of radioactivity could be demonstrated from tumor cells, indicating that there was no efflux of illudin S (or metabolites) from these cells. The number of intracellular illudin S molecules required to kill 50% of cells of different tumor cell lines varied from 78000 to 1114000 molecules per cell and was correlated with the 2-h IC50 value determined using a colony-forming assay. Illudin S was cytotoxic to a variety of multidrug-resistant tumor cell lines regardless of whether resistance was mediated by gp170/mdrl, gp180/MRP, GSHTR-pi, topoisomerase I, topoisomerase II, increased DNA repair capacity, or alterations in intracellular thiol content. Information obtained in this study could be used to design clinical phase I trials and to develop analogs with improved therapeutic indexes.

(Hydroxymethyl)acylfulvene: an illudin derivative with superior antitumor properties.

Reaction of the fungal sesquiterpene illudin S with excess paraformaldehyde in dilute H2SO4 gives (hydroxymethyl)acylfulvene. The primary allylic hydroxyl thus formed can undergo very facile replacement by a variety of nucleophiles. (Hydroxymethyl)acylfulvene (MGI.114) was more toxic than a precursor, acylfulvene, but less toxic than the parent compound illudin S to HL 60 cells.

Eating disturbances among American minority groups: a review.

OBJECTIVE: The purpose of this paper was to review the research literature related to eating behaviors and disturbances among American minority groups. METHOD: A computer-based literature search was conducted to locate articles pertaining to this topic. RESULTS: This review indicates that, compared to Caucasian females, eating disturbances are equally common among Hispanic females, more frequent among Native Americans, and less frequent among Black and Asian American females. Risk factors for eating disorders (EDs) are greater among minority females who are younger, heavier, better educated, and more identified with White, middle-class values. DISCUSSION: Further studies of EDs among American minority groups are needed, especially studies that are longitudinal and developmental in nature and that focus more specifically on the effects of racism in the development of EDs.