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Biomedical subjects

Robert Davidson

Publications and source records attributed to Robert Davidson.

13 recordsLinked to original sources
PubMed2006

A comparison of liposomal amphotericin B with sodium stibogluconate for the treatment of visceral leishmaniasis in pregnancy in Sudan.

OBJECTIVES: Little is known about the treatment of visceral leishmaniasis (VL) in pregnancy, especially in resource-poor settings. We present a series of pregnant women with VL treated with either sodium stibogluconate or liposomal amphotericin B (AmBisome), or both, in eastern Sudan over 16 months. METHODS: We did a retrospective analysis of all pregnant VL patients treated in the Médecins sans Frontières (MSF) Um el Kher centre between January 2004 and April 2005. We diagnosed VL with laboratory confirmation of clinical suspects, and recorded the outcomes of treatment for pregnant women and their foetuses. We carried out a manual search of relevant publications and a systematic search of the literature in the MEDLINE database. RESULTS: We treated 23 women with sodium stibogluconate, 4 with AmBisome and sodium stibogluconate and 12 with AmBisome alone. There were 13 (57%) spontaneous abortions in the sodium stibogluconate monotherapy group, and none in either of the other two groups. All spontaneous abortions occurred in the first two trimesters. All patients, except one in the sodium stibogluconate group who defaulted, were discharged as cured in good clinical condition. CONCLUSIONS: AmBisome treatment for VL appears to be safe and effective for pregnant women and their foetuses. We recommend the use of AmBisome as first-line treatment for these patients.

Abortion, Spontaneous↗
PubMed2006

Unresponsiveness to AmBisome in some Sudanese patients with kala-azar.

In Sudan, two treatments are currently registered for visceral leishmaniasis: sodium stibogluconate (SSG) as first line and liposomal amphotericin B (AmBisome) as second line. We present 64 patients (52 relapse cases to SSG, 12 new but complicated cases) treated with AmBisome in eastern Sudan. AmBisome was administered at 2.5-8.2mg/kg (15-49mg/kg in total) per dose six times (days 1, 2, 3, 5, 10, 15) as an intravenous infusion. We measured outcome according to clinical response and parasitological clearance (lymph node aspiration). Patient outcomes fell into three groups: group 1, clinical responders (cured) with a negative test of cure (n=35); group 2, clinical responders with a positive test of cure (n=19); group 3, clinical non-responders (failures) with a positive test of cure (n=10). Of the 10 failures, six were already relapse cases. All of group 3, and 15 from group 2, were also treated with additional SSG (20mg/kg intramuscularly daily for 30-50 d) with resulting clinical and parasitological improvement. Parasite persistence and clinical failure were associated with a higher parasite density on admission (P<0.002) and underlying immunosuppressive disease: tuberculosis (three cases) or HIV (two cases). Because AmBisome monotherapy may fail in Sudan, a combination of AmBisome and SSG is recommended for relapse cases.

Adolescent↗
PubMed2006

Optimization of humanized IgGs in glycoengineered Pichia pastoris.

As the fastest growing class of therapeutic proteins, monoclonal antibodies (mAbs) represent a major potential drug class. Human antibodies are glycosylated in their native state and all clinically approved mAbs are produced by mammalian cell lines, which secrete mAbs with glycosylation structures that are similar, but not identical, to their human counterparts. Glycosylation of mAbs influences their interaction with immune effector cells that kill antibody-targeted cells. Here we demonstrate that human antibodies with specific human N-glycan structures can be produced in glycoengineered lines of the yeast Pichia pastoris and that antibody-mediated effector functions can be optimized by generating specific glycoforms. Glycoengineered P. pastoris provides a general platform for producing recombinant antibodies with human N-glycosylation.

Antibodies, Monoclonal↗
PubMed2005

Elevated blood selenium levels in the Brazilian Amazon.

Contaminated fish poses a difficult challenge throughout the world, on the one hand, fish is a very nutritious food source, while on the other hand it accumulates many toxic substances, including mercury (Hg). As part of our efforts in the Brazilian Amazon to maximize nutritional input from fish consumption, a dietary mainstay, and minimize toxic risk, we have been studying the role of selenium (Se), an essential element, that may influence the distribution of Hg in the body and influence Hg neurotoxicity. Se, which is naturally present in the soil, is ingested through consumption of various foods, notably fish, mammals and certain plants. The objectives of the present study were: (i) evaluate whole blood Se (B-Se) and Hg (B-Hg); (ii) characterize B-Se variations with respect to socio-demographic and dietary variables; and (iii) examine the relation between B-Se and B-Hg. A total of 236 persons from six riparian communities of the Tapajós River Basin, a tributary of the Amazon, participated in this study. Whole blood Se and Hg were measured and interview administered questionnaires were used to obtain data on socio-demographic variable, smoking and drinking habits, and fish and fruit consumption. The results show that B-Se are in the upper normal range (median=284.3 microg/L, range=142.1-2029.3 microg/L). No individuals presented B-Se deficiency, but 9 participants from the same extended family had relatively high B-Se levels, potentially a threat to their health. B-Se varied between communities, was significantly higher among alcohol drinkers and farmers, but not associated with age, sex or tobacco consumption. A significant positive relation between B-Se and B-Hg was noted, independently of the overall fish consumption. B-Se increased with consumption of Peacock bass (Cichla sp.), a piscivorous fish species, and coconut pulp (Cocos nucifera L.). The B-Se intercommunity variations may reflect geographic differences in local soil Se levels as well as traditional land use practices in the different ecosystems of the Tapajós River Basin. In this population with relatively high exposure to Hg, Se may play an important role. Further studies should examine, in this region, the sources of Se, its transmission through the terrestrial and aquatic ecosystem and its role with respect to human health.

Animals↗
PubMed2005

Examples of tropical disease control in the humanitarian medical programmes of MSF and Merlin.

Humanitarian medical programmes in the tropics have the opportunity to provide beacons of good practice. The use of modern drugs and diagnostics, a lack of bureaucracy, adequate budgets, motivated staff and well-functioning supply lines all contribute to the success of this approach. At a joint meeting of the Royal Society of Tropical Medicine, the London School of Hygiene and Tropical Medicine, Médecins Sans Frontières and Merlin, new data were presented on the outcomes of recent humanitarian programmes to control malaria (Ethiopia), human African trypanosomiasis (south Sudan), Lassa fever (Sierra Leone) and tuberculosis (Tomsk, former USSR).

Antimalarials↗
PubMed2005

Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-gamma.

Genetic defects in the IFN-gamma response pathway cause unique susceptibility to intracellular pathogens, particularly mycobacteria, but are rare and do not explain mycobacterial disease in the majority of affected patients. We postulated that acquired defects in macrophage activation by IFN-gamma may cause a similar immunological phenotype and thus explain the occurrence of disseminated intracellular infections in some patients without identifiable immune deficiency. Macrophage activation in response to IFN-gamma and IFN-gamma production were studied in whole blood and PBMCs of 3 patients with severe, unexplained nontuberculous mycobacterial infection. In all 3 patients, IFN-gamma was undetectable following mitogen stimulation of whole blood, but significant quantities were detectable in the supernatants of PBMCs when stimulated in the absence of the patients' own plasma. The patients' plasma inhibited the ability of IFN-gamma to increase production of TNF-alpha by both autologous and normal donor PBMCs, and recovery of exogenous IFN-gamma from the patients' plasma was greatly reduced. Using affinity chromatography, surface-enhanced laser desorption/ionization mass spectrometry, and sequencing, we isolated an IFN-gamma-neutralizing factor from the patients' plasma and showed it to be an autoantibody against IFN-gamma. The purified anti-IFN-gamma antibody was shown to be functional first in blocking the upregulation of TNF-alpha production in response to endotoxin; second in blocking induction of IFN-gamma-inducible genes (according to results of high-density cDNA microarrays); and third in inhibiting upregulation of HLA class II expression on PBMCs. Acquired defects in the IFN-gamma pathway may explain unusual susceptibility to intracellular pathogens in other patients without underlying, genetically determined immunological defects.

Adult↗
PubMed2004

Conflict and kala-azar: determinants of adverse outcomes of kala-azar among patients in southern Sudan.

We analyzed data obtained from 3365 patients with kala-azar (KA) or post-KA dermal leishmaniasis (PKDL) treated by Medecins Sans Frontieres-Holland in south Sudan from October 1998-May 2002. Patients were malnourished (median body mass index [BMI], 15.5; median weight for height [WFH], 75.5%) and anemic (median hemoglobin (Hb) level, 8.5 g/dL). The proportion of patients with primary KA who were children <5 years old increased from 2.5%, in 1998, to 19.8%, in 2002 (P<.0001). Therapy with sodium stibogluconate cured 91.9% of patients with primary KA, and dosages of >850 mg per day did not decrease the chances of survival. Risk factors for death among adults were age > or =45 years (odds ratio [OR], 4.6), malnutrition (BMI, <13; OR, 11.0), anemia (Hb level, <8 g/dL; OR, 4.0), and duration of illness (duration, > or =5 months; OR, 2.3). Risk factors for death among children and adolescents were age <2 years (OR, 5.4,), malnutrition (WFH, <60%; OR, 5.0), anemia (Hb level, <6 g/dL; OR, 3.7), and splenomegaly (OR, 2.9). A higher risk of death was associated with episodes of diarrhea (OR, 1.4), vomiting (OR, 2.7), and bleeding (OR, 2.9). Relapse and PKDL occurred in 3.9% and 10.0% of cases, respectively.

Adolescent↗
PubMed2004

Rosuvastatin reduces MMP-7 secretion by human monocyte-derived macrophages: potential relevance to atherosclerotic plaque stability.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to reduce cardiovascular morbidity and mortality by their actions on atherogenic lipid profiles and by pleiotropic effects. In this study, we have investigated the effect of a new statin, rosuvastatin (Crestor), on sterol synthesis and the expression of metalloproteinases (MMPs) in human monocyte-derived macrophages (HMDM). Rosuvastatin dose-dependently inhibited sterol synthesis from acetate with an IC(50) of 70 nM. In addition, MMP-7 levels were reduced in a dose-dependent manner with maximal inhibition of 50% (P < 0.01) at 1 microM. Also, addition of isoprenoids such as farnesyl pyrophosphate (Fpp) or geranylgeranyl pyrophosphate (GGpp) fully overcame the inhibitory effect of rosuvastatin on MMP-7. Neither quantitative PCR nor transient transfection of HMDM with a luciferase reporter construct under the control of human MMP-7 promoter (2300 bp of the 5' region on MMP-7 gene) showed a decrease in MMP-7 mRNA following treatment with rosuvastatin (10(-6)M). However, the inhibitory effect of the statin occurred at the post-transcriptional level as determined by actinomycin D experiment. In conclusion, several studies have reported a high expression of active MMP-7 in human atherosclerotic plaques indicating a potential role in the weakening of the fibrous cap, predisposing it to rupture. The effect of rosuvastatin in reducing MMP-7 might protect fibrous caps from degradation and in turn stabilize atheromatous plaques.

Arteriosclerosis↗
PubMed2003

Eating tropical fruit reduces mercury exposure from fish consumption in the Brazilian Amazon.

This study aimed to examine the influence of the consumption of traditional foods on the relationship between fish consumption and mercury (Hg) exposure. A 12-month prospective dietary survey was carried out with 26 adult women from a fish-eating community in the Brazilian Amazon. Food ingestion was determined using a daily food diary, and total hair Hg levels were assessed for each month through sequential analyses using cold vapor atomic absorption spectrometry. Simple and multiple regression analyses showed that the strong relationship between fish consumption and Hg exposure was significantly modified by fruit consumption: for the same number of fish meals, those who ate more tropical fruits had lower hair mercury levels. The findings of this study indicate different ways of maintaining fish consumption while reducing Hg exposure in the Amazon. A number of phytochemicals and nutritional fibers present in fruits might be interacting with Hg in several ways: absorption and excretion, transport, binding to target proteins, metabolism, and sequestration. More studies are required on larger populations to further elucidate the extent and public health implications of the use of fruits to counteract the toxic action of methylmercury.

Absorption↗
PubMed2003

Comparison of an rK39 dipstick rapid test with direct agglutination test and splenic aspiration for the diagnosis of kala-azar in Sudan.

We compared an rK39 dipstick rapid test (Amrad ICT, Australia) with a direct agglutination test (DAT) and splenic aspirate for the diagnosis of kala-azar in 77 patients. The study was carried out under field conditions in an endemic area of north-east Sudan. The sensitivity of the rK39 test compared with splenic aspiration was 92% (46/50), the specificity 59% (16/27), and the positive predictive value 81% (46/57). Compared with the diagnostic protocol used by Médecins sans Frontières, the sensitivity of the rK39 test was 93% (50/54), the specificity 70% (16/23), and the positive predictive value 88% (50/57). Compared with splenic aspirates, the sensitivity of a DAT with a titre > or =1:400 was 100% (50/50), but its specificity only 55% (15/27) and the positive predictive value was 80% (50/62). Using a DAT titre > or =1:6400, the sensitivity was 84% (42/50), the specificity 85% (23/27) and the positive predictive value 91% (42/46). All four patients with DAT titre > or =1:6400 but negative splenic aspirate were also rK39 positive; we consider these are probably 'true' cases of kala-azar, i.e. false negative aspirates, rather than false DAT and rK39 seropositives. There were no false negative DATs (DAT titre < or =1:400 and aspirate positive), but there were four false negative rK39 tests (rK39 negative and aspirate positive). The rK39 dipstick is a good screening test for kala-azar; but further development is required before it can replace the DAT as a diagnostic test in endemic areas of the Sudan.

Adolescent↗
PubMed2002

Ca(2+) influx through the osteoclastic plasma membrane ryanodine receptor.

We predict that the type 2 ryanodine receptor isoform (RyR-2) located in the osteoclastic membrane functions as a Ca(2+) influx channel and as a divalent cation (Ca(2+)) sensor. Cytosolic Ca(2+) measurements revealed Ca(2+) influx in osteoclasts at depolarized membrane potentials. The cytosolic Ca(2+) change was, as expected, not seen in Ca(2+)-free medium and was blocked by the RyR modulator ryanodine. In contrast, at basal membrane potentials (approximately 25 mV) ryanodine triggered extracellular Ca(2+) influx that was blocked by Ni(2+). In parallel, single-channel recordings obtained from inside-out excised patches revealed a divalent cation-selective approximately 60-pS conductance in symmetric solutions of Ba-aspartate [Ba-Asp; reversal potential (E(rev)) approximately 0 mV]. In the presence of a Ba(2+) gradient, i.e., with Ba-Asp in the pipette and Na-Asp in the bath, channel conductance increased to approximately 120 pS and E(rev) shifted to 21 mV. The conductance was tentatively classified as a RyR-gated Ca(2+) channel as it displayed characteristic metastable states and was sensitive to ruthenium red and a specific anti-RyR antibody, Ab(34). To demonstrate that extracellular Ca(2+) sensing occurred at the osteoclastic surface rather than intracellularly, we performed protease protection assays using pronase. Preincubation with pronase resulted in markedly attenuated cytosolic Ca(2+) signals triggered by either Ni(2+) (5 mM) or Cd(2+) (50 microM). Finally, intracellular application of antiserum Ab(34) potently inhibited divalent cation sensing. Together, these results strongly suggest the existence of 1) a membrane-resident Ca(2+) influx channel sensitive to RyR modulators; 2) an extracellular, as opposed to intracellular, divalent cation activation site; and 3) a cytosolic CaM-binding regulatory site for RyR. It is likely therefore that the surface RyR-2 not only gates Ca(2+) influx but also functions as a sensor for extracellular divalent cations.

Animals↗
PubMedDate not supplied

Public health response actions and the use of emergency operations centers.

In the wake of 11 September 2001, many public health agencies are reassessing their institutional capabilities and procedures to respond to mass-casualty incidents involving weapons of mass destruction. Prior to the fall of 2001, planning by the public health and other sectors addressed more conventional or naturally occurring events such as earthquakes, hurricanes, tornados, and chemical spills, although attacks with weapons of mass destruction were a growing concern. While the nature of natural versus intentional events differs, the management and coordination of response activities to them follows the same incident command system. A major lesson learned during the response operations to the 11 September 2001 attacks in New York City was the value of disaster planning, conducting exercises, and developing relationships among the various response agencies. Although New York City's physical Emergency Operations Center (EOC) at 7 World Trade Center was destroyed in the attack, the medical and health response community was able to react effectively to the possibility of mass casualties as well as to the more usual needs. This was enabled by the pre-existing relationships that had been developed between city, state, federal, and non-governmental agencies while planning and exercising for such events and their aftermaths.

Disaster Planning↗