Mycobacterium leprae in untreated lepromatous leprosy: more than skin deep.
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Adolescent↗
Biomedical subjects
D S Walsh
Publications and source records attributed to D S Walsh.
Bisphosphonate-ciprofloxacin bound to Skelite is a prototype for enhancing experimental local antibiotic delivery to injured bone.
BACKGROUND: The risk of osteomyelitis after open bone fracture may be reduced by locally applied antibiotics. ENC-41-HP (E41), which comprises ciprofloxacin linked to a 'bone seeking' bisphosphonate, loaded on to carrier Skelite calcium phosphate granules (E41-Skelite) has favourable in vitro characteristics for application to wounded bone. This study assessed E41-Skelite in a rat model of acute tibial osteomyelitis. METHODS: Mechanically induced tibial troughs were contaminated with approximately log10 4 colony forming units (c.f.u.) of Staphylococcus aureus (Cowan 1 strain) 'resistant' to E41 (minimum inhibitory concentration 8-16 microg/ml), lavaged and packed with Skelite alone, or with E41-Skelite slurry. Animals were killed at 24 h (n = 62), 72 h (n = 46) or 14 days (n = 12), and each tibia was assessed for S. aureus load (c.f.u./g tibia) and histological appearance (14 days only). RESULTS: At 24 and 72 h, the tibias of rats treated with E41-Skelite (n = 54) had a significantly lower mean (s.e.m.) load of S. aureus than animals that received Skelite alone (n = 54): log10 3.6(0.2) versus 6.4(0.1) c.f.u./g respectively at 24 h (P < 0.001, Mann-Whitney rank sum test) and log10 4.4(0.2) versus 6.6(0.1) c.f.u./g at 72 h (P < 0.001). At 14 days, E41-Skelite-treated tibias had fewer bacteria, no signs of osteomyelitis and histological signs of healing. CONCLUSION: E41-Skelite, a prototype granulated topical antibiotic delivery system, reduced the development of infection in experimental bone wounds.
Animals↗
A framework for short-term humanitarian health care projects.
BACKGROUND: This opinion piece, based on the experiences of the author, outlines the planning involved for a short-term assignment. With growing demand for humanitarian health care assistance to underserved countries, a framework for organizing short-term trips to such areas would be beneficial to the trip organizers. CONTENT: The key to a successful project lies in focusing on specific populations and interventions while still in the planning stages. The hurdles that need to be cleared before actually embarking on the project are also discussed. OUTCOMES: The lasting result of such ventures lies in the learning experiences of the participants, the care that the population receives, and a deeper appreciation for global health and disparity.
Altruism↗
CpG oligodeoxynucleotide enhances immunity against blood-stage malaria infection in mice parenterally immunized with a yeast-expressed 19 kDa carboxyl-terminal fragment of Plasmodium yoelii merozoite surface protein-1 (MSP1(19)) formulated in oil-based Montanides.
The 19kDa carboxyl-terminal fragment of Plasmodium yoelii merozoite surface protein-1 (MSP1(19)), an analog of the leading falciparum malaria vaccine candidate, induces protective immunity to challenge infection when formulated with complete/incomplete Freund's adjuvant (CFA/IFA), an adjuvant unsuitable for use in humans. In this study, we investigate Montanide ISA51 and Montanide ISA720 as well as CpG oligodeoxynucleotide (ODN) as adjuvants for induction of immunity to MSP1(19). Mice immunized with MSP1(19) adjuvanted with Montanide ISA51 were protected even though some mice experienced low-grade parasitemia before resolving the infection. Mice immunized with MSP1(19) adjuvanted with Montanide ISA720 showed delayed patent parasitemia with all mice ultimately succumbing to infection. Interestingly, when the synthetic CpG ODN 1826 was included in either Montanide formulation, mice were completely protected with no parasites detected in the blood. MSP1(19)-specific antibodies in MSP1(19)-immunized mice adjuvanted with Montanide ISA51 or Montanide ISA720 showed predominantly IgG1 antibody and low levels of IgG2a. CpG ODN 1826 significantly enhanced both IgG1 and IgG2a antibody responses in Montanide ISA51-adjuvanted mice but significantly enhanced only the IgG2a antibody response in Montanide ISA720-adjuvanted mice. To investigate the relative roles of antibody and CD4(+) T cells in protection, MSP1(19)-immunized mice adjuvanted with Montanide ISA720 and CpG ODN 1826 were depleted of CD4(+) T cells just prior to challenge. Results showed that three of nine immunized/T cell depleted mice died following infection. These results suggest that antibody and CD4(+) T cells are critical for protection following immunization with MSP1(19) adjuvanted with Montanide and CpG ODN and that the formulation of a human malaria vaccine candidate in Montanide ISA720 or ISA51 together with human compatible CpG ODN would be useful for improving efficacy.
Adjuvants, Immunologic↗
Isolation and characterization of rhesus blood dendritic cells using flow cytometry.
Recognition of dendritic cells (DCs) as initiators and modulators of immune responses and growing use of rhesus monkeys for the preclinical optimization of vaccine formulations prompted characterization of the phenotype and function of isolated rhesus peripheral blood DCs. We developed a flow cytometric method to directly identify and isolate DCs from rhesus peripheral blood whereby a T cell depleted population negative for CD3, CD14, CD16 and CD20 but positive for CD83 yielded a cell population with surface markers, morphology, and a cytokine profile similar to human myeloid DCs. Rhesus blood DCs were more effective than monocytes and B cells in mixed lymphocyte reactions and in the presentation of recombinant malaria blood stage antigen MSP-1((42)) to autologous T cells. The ability to isolate rhesus blood DC from peripheral blood should be a useful tool for immunological investigations.
Animals↗
Whole blood cultures to assess the immunostimulatory activities of CpG oligodeoxynucleotides.
Specially designed oligodeoxynucleotide (ODN) sequences known as 'CpG' ODNs elicit innate and acquired immune responses. In general, screening of new CpG ODNs has been conducted by conventional lymphoproliferative assays or expression of activation markers in peripheral blood mononuclear cell (PBMC) cultures. Here, we compared conventional in vitro human PBMC assays with whole blood assays for screening the immunostimulatory properties of CpG ODNs. Commercially available DNA preparations and mycobacterial-based adjuvants were used as comparators. Activation was assessed by flow cytometry and cytokine production. CpG ODNs, identified by four-letter codes, consisted of 2006 (strong human cell stimulant), 1826 (strong murine cell stimulant), 1840 (weak immunostimulant), and 2041, a non-CpG ODN. In both test systems, and in accordance with previous reports, 2006 was an effective up-regulator of CD40 on human dendritic cells (DC1, DC2), monocytes, and B cells, and of CD69 on NK cells. In contrast to murine cells exposed to CpG ODNs, IL-12 (p40) and IFN-gamma production in human immune cells was negligible, but greatly enhanced by adding GM-CSF. Like 2006, two comparator mycobacterial adjuvant formulations activated DC1, DC2, monocytes and natural killer (NK) cells, but only 2006 had a strong effect on B cells. The usefulness of the whole blood assay was further demonstrated by studies in small volumes of umbilical cord mononuclear cells, that like adult blood cells, showed up-regulation of CD40 expression on B cells, DC, and monocytes, and CD69 on NK cells. The whole blood assay, in conjunction with flow cytometry, is useful for assessing the immunological properties of CpG ODN sequences.
Adult↗
Population pharmacokinetics of the new antimalarial agent tafenoquine in Thai soldiers.
AIMS: To describe the population pharmacokinetics of tafenoquine in healthy volunteers after receiving tafenoquine for malaria prophylaxis. METHODS: The population consisted of 135 male Thai soldiers (mean age 28.9 years; weight 60.3 kg). All soldiers were presumptively treated with artesunate for 3 days plus doxycycline for 7 days to remove any pre-existing malaria infections. After the treatment regime, 104 soldiers (drug group) received a loading dose of 400 mg tafenoquine base daily for 3 days followed by 400 mg tafenoquine monthly for 5 consecutive months. In the placebo group, 31 soldiers were infected with malaria during the study period. They were re-treated with artesunate for 3 days plus doxycycline for 7 days followed by a loading dose of 400 mg tafenoquine daily for 3 days and then 400 mg tafenoquine weekly for prophylaxis. Blood samples were randomly collected from each soldier on monthly and weekly prophylaxis. Plasma tafenoquine concentrations were measured by h.p.l.c. Population pharmacokinetic modelling was performed using NONMEM. RESULTS: A one-compartment model was found best to describe the pharmacokinetics of tafenoquine after oral administration. Age and weight influenced volume of distribution (V/F), and subjects who contracted malaria had higher clearance (CL/F), but none of these factors was considered to have sufficient impact to warrant change in dosing. The population estimates of the first-order absorption rate constant (Ka), CL/F and V/F were 0.694 h(-1), 3.20 l h(-1) and 1820 l, respectively. The intersubject variability in these parameters (coefficient of variation, CV%) was 61.2%, 25.3% and 14.8%, respectively. The absorption and elimination half-lives were 1.0 h and 16.4 days, respectively. The residual (unexplained) variability was 17.9%. CONCLUSIONS: The population pharmacokinetics of orally administered tafenoquine have been determined in Thai soldiers under field conditions. This information, together with its known potent antimalarial activity, portends well for the application of tafenoquine as a useful prophylactic drug or for short-term radical treatment of vivax malaria.
Administration, Oral↗
Malignant T-cell lymphoma mimicking lepromatous leprosy.
We describe a 16-year-old Filipino boy who presented with skin lesions highly suggestive of lepromatous leprosy, but further assessment established a diagnosis of malignant T-cell lymphoma. This case emphasizes the extensive differential diagnosis of leprosy, as well as the importance of obtaining skin biopsies for diagnostic confirmation.
Adolescent↗
Improvement in psoriasis after intradermal administration of delipidated, deglycolipidated Mycobacterium vaccae (PVAC): results of an open-label trial.
The aim of new treatments for psoriasis is to induce extended remissions with fewer side-effects. Previous studies suggest that Mycobacterium vaccae, a harmless organism prepared as a heat-killed suspension, may induce periods of remission in some psoriasis patients after intradermal administration. To assess a more potent derivative of M. vaccae, we conducted an open-label study in which 20 patients with moderate to severe psoriasis (Psoriasis Area and Severity Index of 12-35) received two intradermal inoculations of heat-killed, delipidated, deglycolipidated M. vaccae (DD-MVAC or 'PVAC') in lesion-free deltoid skin, separated by a period of 3 weeks. Twelve weeks after the injections, 13 out of 20 patients (65%) showed marked improvement in the PASI score (> 50% reduction), three were unchanged (< 25% reduction), three had worsened (> 5% increase), and one was withdrawn from the trial because of an exfoliative flare. At 24 weeks, 13 out of 19 patients continued to show > 50% improvement that, in some, lasted for 6 months or longer. Patients classified as good responders at 12 or 24 weeks were then offered additional PVAC injections after 24 weeks if the PASI reached 8 or higher. Intra-dermal administration of PVAC was safe, well tolerated, and induced clinically significant improvement in many psoriasis patients. A randomized, double-blind, controlled study is warranted.
Adolescent↗
Hand rash in trichinosis.
Trichinosis patients may develop peri-orbital oedema, conjunctival haemorrhages, splinter haemorrhages of the fingernails, and nonspecific skin rashes. Here, we describe an unusual hand rash noted in several patients enrolled in a treatment study for trichinosis.
Adult↗
Malaria rapid diagnostic devices: performance characteristics of the ParaSight F device determined in a multisite field study.
Microscopic detection of parasites has been the reference standard for malaria diagnosis for decades. However, difficulty in maintaining required technical skills and infrastructure has spurred the development of several nonmicroscopic malaria rapid diagnostic devices based on the detection of malaria parasite antigen in whole blood. The ParaSight F test is one such device. It detects the presence of Plasmodium falciparum-specific histidine-rich protein 2 by using an antigen-capture immunochromatographic strip format. The present study was conducted at outpatient malaria clinics in Iquitos, Peru, and Maesod, Thailand. Duplicate, blinded, expert microscopy was employed as the reference standard for evaluating device performance. Of 2,988 eligible patients, microscopy showed that 547 (18%) had P. falciparum, 658 (22%) had P. vivax, 2 (0.07%) had P. malariae, and 1,750 (59%) were negative for Plasmodium. Mixed infections (P. falciparum and P. vivax) were identified in 31 patients (1%). The overall sensitivity of ParaSight F for P. falciparum was 95%. When stratified by magnitude of parasitemia (no. of asexual parasites per microliter of whole blood), sensitivities were 83% (>0 to 500 parasites/microl), 87% (501 to 1,000/microl), 98% (1,001 to 5,000/microl), and 98% (>5,000/microl). Device specificity was 86%.
Animals↗
Orientia tsutsugamushi in peripheral white blood cells of patients with acute scrub typhus.
Scrub typhus, caused by Orientia tsutsugamushi, is an acute illness that occurs in many parts of Asia. Clinical manifestations range from inapparent to organ failure. Organisms disseminate from the skin to target organs, suggesting that they may enter the peripheral circulation. Here, peripheral blood cell smears from patients with acute scrub typhus were obtained before treatment and for 2 days after treatment and reacted with antibodies specific for O. tsutsugamushi. White blood cells from 3 of 7 patients with acute scrub typhus stained positively for O. tsutsugamushi. Cells containing O. tsutsugamushi were mononuclear and were detected on each day of sampling. The presence of O. tsutsugamushi in peripheral white blood cells of patients with acute scrub typhus is a new finding with clinical and pathogenic implications.
Adult↗
Effects of hydroxypyridinone iron chelators in combination with antimalarial drugs on the in vitro growth of Plasmodium falciparum.
Using standard in vitro drug susceptibility methods, we assessed the antimalarial activity of 3 orally administered iron chelators (hydroxypyridinones) alone and in combination with conventional antimalarials drugs (quinine, mefloquine, artesunate, tetracycline, atovaquone) against a chloroquine-resistant Plasmodium falciparum isolate. When tested alone, all iron chelators and antimalarial compounds inhibited the growth of the parasites. IC50 values for iron chelators were 60-70 microM, whereas the IC50 values for antimalarial drugs were in nM ranges, with artesunate being the most potent. The derived isobolograms for the interaction of hydroxypyridinones and antimalarial drugs showed addition or mild antagonism, similar to desferroxamine (Sum of Fractional Inhibitory Concentration, sigma FIC < 0.5 or > 4.0). Despite the absence of synergy with conventional drugs, intrinsic antimalarial activity of hydroxypyridinones supports the continued assessment of these iron chelators as treatment adjuncts.
Animals↗
Malaria prophylaxis/radical cure: recent experiences of the Australian Defence Force.
Since the eighties, the Australian Defence Force has deployed soldiers in malaria-endemic areas: Cambodia, Somalia, Rwanda, Bougainville, and East Timor. Currently, doxycycline is used as first line prophylactic drug and mefloquine is recommended for those who cannot tolerate the antibiotic. In 1998, the Australian Defence Force participated in the evaluation of tafenoquine for prophylaxis of both falciparum and vivax malaria in Thai soldiers. At the completion of this six-month study, 29 of 205 soldiers had come down with malaria including eight with falciparum malaria, 20 with vivax malaria, and one with mixed infection. A total of 28 of the 101 soldiers in the placebo group were infected with malaria as compared with only one of the 104 soldiers in the tafenoquine group. In 1999, another study was started on the island of Bougainville to compare the effectiveness a 3-day course of tafenoquine and a 14-day course of primaquine for radical cure of vivax malaria. At the present time, 411 soldiers have completed the study including 201 in tafenoquine arm and 210 in primaquine arm. Seven soldiers in each arm developed vivax malaria after returning to Australia. These results indicate that tafenoquine is not superior to primaquine in preventing vivax malaria. However study participants preferred the shorter course using tafenoquine and operationally it was found to be more suitable than primaquine.
Aminoquinolines↗
Lymphocyte activation after non-thermal trauma.
BACKGROUND: Severe injury causes immunological changes that may contribute to a poor outcome. Longitudinal characterization of lymphocyte response patterns may provide further insight into the basis of these immunological alterations. METHODS: Venous blood obtained seven times over 2 weeks from 61 patients with injury severity scores above 20 was assessed for lymphocyte phenotypic and activation markers together with serum levels of interleukin (IL) 2, IL-4, soluble IL-2 receptor (sIL-2R), soluble CD4 (sCD4), soluble CD8 (sCD8) and interferon gamma. RESULTS: Severe injury was associated with profound changes in the phenotypic and activation profile of circulating lymphocytes. Activation was indicated by increased numbers of T cells expressing CD25, CD69 and CD71, and raised serum levels of IL-2, sIL-2R, sCD4 and sCD8. Relatively higher levels of sIL-2R and sCD4 were found in patients with sepsis syndrome. CONCLUSION: Polytrauma is associated with dramatic alterations in the phenotypic and activation profile of circulating lymphocytes which are generally independent of clinical course. In contrast, several lymphocyte soluble factors, including sCD4 and sIL-2R, paralleled the clinical course. These data provide new insight into lymphocyte responses after injury and suggest that further assessment of soluble factors as clinical correlates, including those related to lymphocyte activation or generalized inflammation, may be warranted.
Adult↗
Improvement in psoriasis after intradermal administration of heat-killed Mycobacterium vaccae.
BACKGROUND: New treatments for psoriasis are being developed, but many are associated with limited efficacy, side-effects, or rapid recurrence after discontinuation. Thus, the aim of new agents is to induce longer term remissions with fewer side-effects. Preliminary studies have shown that Mycobacterium vaccae, a nonpathogenic organism prepared as a heat-killed suspension, may induce periods of remission in some psoriasis patients when administered intradermally. METHODS: To further assess the efficacy and tolerability of M. vaccae in patients with moderate to severe psoriasis (psoriasis area and severity index (PASI) of 12-35), we conducted an open label study whereby 24 patients received two intradermal inoculations of M. vaccae in lesion-free deltoid skin, separated by a period of 3 weeks. RESULTS: Twelve weeks after starting treatment, 14 of 24 patients (58%) showed marked improvement in the PASI score (greater than 50% reduction), two had moderate improvement (25-50% reduction), six were unchanged (< 25% reduction), and two had worsened (> 5% increase). By 24 weeks, 11 of 22 patients continued to show greater than 50% improvement. Five patients had complete clearance of skin lesions that lasted for at least 6 months. CONCLUSIONS: Intradermal administration of heat-killed M. vaccae suspension was well tolerated and induced clinically significant improvement in a majority of psoriasis patients in this cohort. Placebo-controlled testing to further define the efficacy of this treatment is warranted.
Adolescent↗
Oral penicilliosis in a patient with human immunodeficiency virus in northern Thailand.
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Adult↗
Superior mesenteric venous thrombosis in malrotation with chronic volvulus.
Malrotation can be difficult to diagnose after the newborn period because of intermittent symptoms and vague clinical findings, but malrotation with midgut volvulus is usually quite striking in its presentation. Early diagnosis and surgical treatment are essential to prevent acute ischemic infarction of the bowel, although chronic complications are rare. The authors present an unusual case of mesenteric venous thrombosis secondary to chronic midgut volvulus. A 13-year-old girl presented with an 11-year history of recurrent bouts of abdominal pain evaluated at 3 other institutions without a diagnosis. At the referring hospital, an episode of bilious emesis associated with abdominal pain prompted a computerized tomography scan of the abdomen. This showed a calcified thrombus within the superior mesenteric vein (SMV). At laparotomy, malrotation with chronic 270 degree volvulus was found with evidence of mesenteric venous hypertension. Segmental occlusion was documented on magnetic resonance angiography. SMV thrombosis is an unusual complication of malrotation with chronic midgut volvulus.
Adolescent↗