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Biomedical subjects

M Craig

Publications and source records attributed to M Craig.

At least 19 recordsLinked to original sources
PubMed2000

Distribution of African malaria mosquitoes belonging to the Anopheles gambiae complex.

The distribution of malaria vector mosquitoes, especially those belonging to species complexes that contain non-vector species, is important for strategic planning of malaria control programmes. Geographical information systems have allowed researchers to visualize distribution data on maps together with environmental parameters, such as rainfall and temperature. Here, Maureen Coetzee, Marlies Craig and David le Sueur review our current knowledge on the distribution of the members of the Anopheles gambiae complex.

Africa South of the Sahara↗
PubMed2000

Extended daily dialysis: A new approach to renal replacement for acute renal failure in the intensive care unit.

Continuous venovenous hemofiltration (CVVH) is an effective form of renal replacement therapy for acute renal failure (ARF) that offers greater hemodynamic stability and better volume control than conventional hemodialysis in the critically ill, hypotensive patient. However, the application of CVVH in the intensive care unit (ICU) has several disadvantages, including intensive nursing requirements, continuous anticoagulation, patient immobility, and expense. We describe a new approach to the treatment of ARF in the ICU, which we have termed extended daily dialysis (EDD). In this study, EDD was compared with CVVH in 42 patients: 25 patients were treated with EDD for a total of 367 treatment days, and 17 patients were treated with CVVH for a total of 113 days. Median treatment time per day was 7.5 hours for EDD (range, 6 to 8 hours, 25th to 75th percentile) versus 19.5 hours for CVVH (range, 13.4 to 24 hours; P < 0.001). Mean arterial blood pressures (MAPs) did not differ significantly for patients treated with EDD when measured predialysis (median MAP, 70 versus 67 mm Hg for CVVH; P = 0.078), midway through daily treatment (70 versus 68 mm Hg for CVVH; P = 0.083), or at the end of treatment (71 versus 69 mm Hg for CVVH; P = 0.07). Net daily ultrafiltration was similar for the two treatment modalities (EDD, median, 3,000 mL/d; range, 1,763 to 4,445 mL/d; CVVH, 3,028 mL/d; range, 1,785 to 4,707 mL/d; P = 0.514). Anticoagulation requirements were significantly less for patients treated with EDD (median dose of heparin, 4,000 U/d; range, 0 to 5,800 U/d versus 21,100 U/d; range, 8,825 to 31,275 U/d for patients treated with CVVH; P < 0.001). We found that EDD eliminated the need for constant supervision of the dialysis machine by a subspecialty dialysis nurse, allowing one nurse to manage more than one treatment. Overall, EDD was well tolerated by the majority of patients, offered many of the same benefits provided by CVVH, and was technically easier to perform.

Acute Kidney Injury↗
PubMed2000

A spatial statistical approach to malaria mapping.

BACKGROUND: Good maps of malaria risk have long been recognized as an important tool for malaria control. The production of such maps relies on modelling to predict the risk for most of the map, with actual observations of malaria prevalence usually only known at a limited number of specific locations. Estimation is complicated by the fact that there is often local variation of risk that cannot be accounted for by the known covariates and because data points of measured malaria prevalence are not evenly or randomly spread across the area to be mapped. METHOD: We describe, by way of an example, a simple two-stage procedure for producing maps of predicted risk: we use logistic regression modelling to determine approximate risk on a larger scale and we employ geo-statistical ('kriging') approaches to improve prediction at a local level. Malaria prevalence in children under 10 was modelled using climatic, population and topographic variables as potential predictors. After the regression analysis, spatial dependence of the model residuals was investigated. Kriging on the residuals was used to model local variation in malaria risk over and above that which is predicted by the regression model. RESULTS: The method is illustrated by a map showing the improvement of risk prediction brought about by the second stage. The advantages and shortcomings of this approach are discussed in the context of the need for further development of methodology and software.

Child↗
PubMed1999

Estimating mortality, morbidity and disability due to malaria among Africa's non-pregnant population.

The contribution of malaria to morbidity and mortality among people in Africa has been a subject of academic interest, political advocacy, and speculation. National statistics for much of sub-Saharan Africa have proved to be an unreliable source of disease-specific morbidity and mortality data. Credible estimates of disease-specific burdens are required for setting global and national priorities for health in order to rationalize the use of limited resources and lobby for financial support. We have taken an empirical approach to defining the limits of Plasmodium falciparum transmission across the continent and interpolated the distributions of projected populations in 1995. By combining a review of the literature on malaria in Africa and models of acquired functional immunity, we have estimated the age-structured rates of the fatal, morbid and disabling sequelae following exposure to malaria infection under different epidemiological conditions.

Adolescent↗
PubMed1997

Bispecific monoclonal antibody complexes facilitate erythrocyte binding and liver clearance of a prototype particulate pathogen in a monkey model.

We used Anger camera imaging in a monkey model to investigate the organ localization of a prototype particulate pathogen, 131I-labeled bacteriophage phi X174, after it was bound to the primate erythrocyte complement receptor and then cleared from the circulation. This 131I-labeled phi X174 was infused into the circulation of an immunized monkey, and the nascently formed immune complexes showed rapid and quantitative binding to erythrocytes via the immune adherence reaction (complement-mediated binding). Alternatively, phi X174 was infused into the circulation of a naive animal, and then cross-linked bispecific mAb complexes (heteropolymers, anti-CR1 x anti-phi X174) were infused into the circulation. The infused heteropolymers also facilitated rapid and quantitative binding of phi X174 to erythrocytes. In both cases, after a short lag period, the erythrocyte-bound phi X174 was rapidly cleared from the circulation, and the vast majority of the radiolabel was cleared to the liver, with a small amount clearing to the spleen. Further liver imaging confirmed that within 24 h most of the bacteriophage previously cleared to the liver via the heteropolymer system was phagocytosed and destroyed. The findings in this model system provide additional evidence for the potential utility of heteropolymers to facilitate the safe and rapid clearance of blood-borne pathogens as a potential treatment for infectious diseases.

Animals↗
PubMed1997

14C-labeled microcystin-LR administered to Atlantic salmon via intraperitoneal injection provides in vivo evidence for covalent binding of microcystin-LR in salmon livers.

The tissue distribution and clearance of radiolabeled microcystin-LR administered to Atlantic salmon via i.p. injection has been re-examined using uniformly 14C-labeled toxin. Significant differences were found to exist between these results and those obtained when fish received an i.p. injection of tritium-labeled dihydromicrocystin-LR. In addition, MeOH liver extracts were assayed by both phosphatase assay and 14C counts and the results compared with the total levels of incorporation determined by digestion and subsequent 14C counting of the same live tissues. An attempt to investigate the metabolism and to document the putative products was also undertaken. It was found that microcystin-LR was extensively metabolized to compounds that are more polar than the parent compound.

Animals↗
PubMed1997

Bioaccumulation and clearance of microcystins from salt water mussels, Mytilus edulis, and in vivo evidence for covalently bound microcystins in mussel tissues.

Over a period of 3 days saltwater mussels, Mytilus edulis, were fed a cyanobacteria, Microcystis aeruginosa, that contained a high concentration of microcystins. The mussels were killed on a periodic basis over the course of 2 months. Mussels were also collected at two sites were high levels of microcystins in tissues had been noted. A strategy based on the chemically unique nature of the C20 beta-amino acid, (2S,3S,8S,9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6- dienoic acid (Adda), portion of the microcystins was used in conjunction with a protein phosphatase (PPase) assay to analyse for both covalently bound microcystins and free microcystins in the mussel tissues. The mussel PPase assay results were compared with the Lemieux oxidation gas chromatography-mass spectrometry (GCMS) analysis. Less than 0.1% of the total microcystin burden in the mussel tissue was found to be extractable with MeOH. Thus, direct evidence was provided for the existence of covalently bound microcystins in mussel tissues in vivo. The mussels rapidly cleared the covalently bound microcystins when transferred to untreated seawater. Within 4 days the total microcystin burden dropped from a high of 336.9 (+/- 45.8) micrograms/g wet tissue to 11.3 (+/- 2.6) micrograms/g. After 4 days postexposure until completion of the experiment the total levels remained below the detection limits of the GCMS method. The levels of free microcystins, extracted with MeOH and detected by the PPase assay, fell from 204 ng/g wet tissue to a residual 14 ng/g over a 53 day postexposure period. Presumably the bound microcystin present in the mussel tissue exists as a covalent complex with the PP-1 and PP-2A enzymes. We conclude that in any shellfish monitoring program it is the total tissue microcystin burden that needs to be considered.

Animals↗
PubMed1997

Evidence for a covalently bound form of microcystin-LR in salmon liver and Dungeness crab larvae.

The chemically unique nature of the C20 beta-amino acid (2S,3S,8S,9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6- dienoic acid (Adda) portion of the microcystins has been exploited to develop a strategy to analyze for the total microcystin-LR (1; see Figure 1) burden in salmon liver and crab larvae tissues. Lemieux oxidation of microcystin-LR (1) gives 2-methyl-3-methoxy-4-phenylbutanoic acid (2), a unique marker for the presence of microcystins. The butanoic acid 2 can be isolated and detected by GC/MS from the livers of Atlantic salmon that received an ip injection of microcystin-LR (1) and from tissues of wild-caught crab larvae. The Lemieux oxidation-GC/MS results are compared with those from MeOH extraction-PPase analysis. Only approximately 24% of the total microcystin-LR (1) burden in salmon liver tissue is found to be extractable with MeOH. Similarly, the Lemieux oxidation-GC/MS method detected 10,000-fold greater microcystin concentrations in Cypress Island Dungeness crab larvae than did the MeOH extraction-PPase method. The disparity in microcystin concentrations measured by the two methods is taken as direct evidence for the existence of covalently bound microcystins in vivo.

Animals↗
PubMed1996

Molecular mechanisms underlying he interaction of motuporin and microcystins with type-1 and type-2A protein phosphatases.

Heptapeptide microcystin and pentapeptide motuporin (nodularin-V) are equipotent inhibitors of type-1 and type-2A protein phosphatase catalytic subunits (PP-1c and PP-2Ac). Herein we describe elucidation of the molecular mechanisms involved in the interaction of these structurally similar hepatotoxins with PP-1c/PP-2Ac and identification of an important functional difference between their mode of interaction with these enzymes. Microcystin-LR, microcystin-LA, and microcystin-LL were found to interact with PP-2Ac and PP-1c by a two-step mechanism involving rapid binding and inactivation of the protein phosphatase (PPase) catalytic subunit, followed by a slower covalent interaction (within hours). Covalent adducts comprising PPase-toxin complexes were separated from free PPase by C-18 reverse-phase liquid chromatography, thus allowing the time course of covalent adduct formation to be quantitated. In contrast to microcystins, motuporin (nodularin-V) and nodularin-R were unable to form covalent complexes with either PP-1c or PP-2Ac even after 96 h incubation. Specific reduction of microcystin-LA to dihydromicrocystin-LA abolished the ability of the toxin to form a covalent adduct with PP-2Ac. Specific methyl esterification of the single Glu residue in microcystin-LR rendered this toxin inactive as a PPase inhibitor and abolished subsequent formation of a covalent adduct. Our data indicate that inactivation of PP-2Ac/PP-1c by microcystins precedes covalent modification of the PPases via a Michael addition reaction between a nucleophilic phosphatase residue and Mdha in the heptapeptide toxin. In contrast, following rapid inactivation of PP-2Ac/PP-1c by motuporin, the equivalent N-methyldehydrobutyrine residue in this toxin is unreactive and does not form a covalent bond with the PPases. These results are consistent with structural data for (i) the NMR solution structures of microcystin-LR and motuporin, which indicate a striking difference in the relative positions of their corresponding dehydroamino acids in the toxin peptide backbone, and (ii) X-ray crystallographic data on an inactive complex between PP-1c and microcystin-LR, which show a covalent bond between Cys-273 and the bound toxin.

Enzyme Inhibitors↗
PubMed1993

Identification and characterization of hydrophobic microcystins in Canadian freshwater cyanobacteria.

Hepatotoxic microcystins produced by cyanobacteria in freshwater lakes represent a significant health hazard to humans and agricultural livestock. Liquid chromatography (LC)-linked protein phosphatase (PPase) bioassay analysis of blooms of Microcystis aeruginosa produced in a Canadian drinking water lake identified several PPase inhibitors with significantly greater hydrophobicity than microcystin-LR, based on their retention time on C18 reverse phase LC columns. Seven PPase inhibitors were purified to homogeneity by bioassay-guided fractionation involving Sephadex LH-20 chromatography and two-step reverse phase at pH 6.5 and 2.0. One of the PPase inhibitors, isolated in a final yield of 1.5 micrograms/g lyophilized cyanobacteria, was identified as microcystin-LL by amino acid analysis and mass spectrometry. A further PPase inhibitor (20 ng/g cyanobacteria) was identified as microcystin-LL but with D-Ala replaced by an unknown amino acid. Four PPase inhibitors (< 20 ng/g cyanobacteria) were characterized by amino acid analysis and identified as microcystin-LV, -LM, -LF and -LZ (where Z represents an unknown hydrophobic amino acid). A further microcystin was also identified (< 10 ng/g cyanobacteria) in which arginine was apparently absent. The biological activity of the seven microcystins as inhibitors of the catalytic subunit of protein phosphatase-1 (PP-1c) was compared with microcystin-LR and motuporin (a hydrophobic analogue of nodularin). All of the compounds inhibited PP-1c with IC50 values of 0.06-0.4 nM, consistent with their identification as microcystins. These findings further demonstrate the applicability of a sensitive PPase bioassay for the identification of variant microcystins in the natural environment.

Amino Acids↗