A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma.

Background: Gliomas are the most common primary brain tumor in adults. Current treatments involve surgery, radiation, and temozolomide (TMZ) chemotherapy; however, prognosis remains poor and new approaches are required. Circadian medicine aims to maximize treatment efficacy and/or minimize toxicity by timed delivery of medications in accordance with the daily rhythms of the patient. We published a retrospective study showing greater anti-tumor efficacy for the morning, relative to the evening, administration of TMZ in patients with glioblastoma. We conducted this prospective randomized trial to determine the feasibility, and potential clinical impact, of TMZ chronotherapy in patients with gliomas (NCT02781792). Methods: Adult patients with gliomas (WHO grade II-IV) were enrolled prior to initiation of monthly TMZ therapy and were randomized to receive TMZ either in the morning (AM) before 10 am or in the evening (PM) after 8 pm. Pill diaries were recorded to measure compliance and FACT-Br quality of life (QoL) surveys were completed throughout treatment. Study compliance, adverse events (AE), and overall survival were compared between the two arms. Results: A total of 35 evaluable patients, including 21 with GBM, were analyzed (18 AM patients and 17 PM patients). Compliance data demonstrated the feasibility of timed TMZ dosing. There were no significant differences in AEs, QoL, or survival between the arms. Conclusions: Chronotherapy with TMZ is feasible. A larger study is needed to validate the effect of chronotherapy on clinical efficacy.

Occurrence and behavior of uranium and thorium series radionuclides in the Permian shale hydraulic fracturing wastes.

Over the last decade, there has been a rapid growth in the use of hydraulic fracturing (fracking) to recover unconventional oil and gas in the Permian Basin of southeastern New Mexico (NM) and western Texas. Fracking generates enormous quantities of wastes that contain technologically enhanced naturally occurring radioactive materials (TENORM), which poses risks to human health and the environment because of the relatively high doses of radioactivity. However, very little is known about the chemical composition and radioactivity levels of Permian Basin fracking wastes. Here, we report chemical as well as radiochemical compositions of hydraulic fracking wastes from the Permian Basin. Radium, the major TENORM of interest in unconventional drilling wastes, varied from 19.1 ± 1.2 to 35.9 ± 3.2 Bq/L for 226Ra, 10.3 ± 0.5 to 21.5 ± 1.2 Bq/L for 228Ra, and 2.0 ± 0.05 to 3.7 ± 0.07 Bq/L for 224Ra. In addition to elevated concentrations of radium, these wastewaters also contain elevated concentrations of dissolved salts and divalent cations such as Na+ (31,856-43,000 mg/L), Ca2+ (668-4123 mg/L), Mg2+ (202-2430 mg/L), K+ (148-780 mg/L), Sr2+ (101-260 mg/L), Cl- (5160-66,700 mg/L), SO42- (291-1980 mg/L), Br- (315-596 mg/L), SiO2 (20-32 mg/L), and high total dissolved solid (TDS) of 5000-173,000 mg/L compared to background waters. These elevated levels are of radiological significance and represent a major source of Ra in the environment. The recent discovery of large deposits of recoverable oil and gas in the Permian Basin will lead to more fracking, TENORM generation, and radium releases to the environment. This paper evaluates the potential radiation risks associated with TENORM wastes generated by the oil and gas recovery industry in the Permian Basin.

Combination ceftaroline and daptomycin salvage therapy for complicated methicillin-resistant Staphylococcus aureus bacteraemia compared with standard of care.

Complicated methicillin-resistant Staphylococcus aureus bloodstream infections (MRSA-BSIs), particularly those with delayed culture clearance, are associated with high mortality. Combination therapy with daptomycin and ceftaroline (DAP+CPT) represents a novel therapeutic approach to MRSA-BSI owing to synergistic bactericidal activity. This study aimed to compare DAP+CPT with historical standard of care (SoC) for treatment of complicated MRSA-BSI. This single-centre retrospective cohort study included patients with complicated MRSA-BSI at University of Colorado Hospital. Patients receiving DAP+CPT for ≥48 h between November 2013 and March 2020 or SoC with vancomycin or DAP ± gentamicin and/or rifampicin from November 2011 to December 2013 were compared. The primary outcome was clinical failure defined as a composite of MRSA-related mortality and recurrent infection at 60 days. A total of 60 patients received DAP+CPT (n = 30) or SoC (n = 30). Median age was 56 years and median Pitt bacteremia score was 3. Common infectious sites were endovascular (63%) and musculoskeletal (40%). DAP+CPT was associated with a numerically lower incidence of clinical failure compared with SoC (20% vs. 43%; P = 0.052). Multivariable analysis controlling for immunocompromised status (OR, 6.90, 95% CI 1.08-44.15), Charlson comorbidity index (OR, 1.12, 95% CI 0.90-1.39) and source control (OR, 0.35, 95% CI 0.08-1.46) associated DAP+CPT with 77% lower odds of clinical failure (OR, 0.23, 95% CI 0.06-0.89). In patients with complicated MRSA-BSI with delayed clearance, DAP+CPT trended towards lower rates of clinical failure than SoC and was significantly associated with decreased clinical failure after adjustment for baseline differences.

Bio-crude oil from hydrothermal liquefaction of wastewater microalgae in a pilot-scale continuous flow reactor.

To explore the feasibility of scaling up hydrothermal liquefaction (HTL) of algal biomass, a pilot-scale continuous flow reactor (CFR) was operated to produce bio-crude oil from algal biomass cultivated in urban wastewater. The CFR system ran algal slurry (5 wt.% solids loading) at 350 °C and 17 MPa for 4 h without any clogging issues. Bio-crude oil chemistry was characterized by high-resolution Fourier transform mass spectroscopy (FT-MS), proton nuclear magnetic resonance spectroscopy (1H NMR), bomb calorimetry, and elemental analysis. Bio-crude oil yield of 28.1 wt% was obtained with higher heating values of 38-39 MJ/kg. The quality of light bio-crude oil produced from the CFR system was comparable in terms of molecular structures to bio-crude oil produced in a batch reactor.

Endogenous Neoantigen-Specific CD8 T Cells Identified in Two Glioblastoma Models Using a Cancer Immunogenomics Approach.

The "cancer immunogenomics" paradigm has facilitated the search for tumor-specific antigens over the last 4 years by applying comprehensive cancer genomics to tumor antigen discovery. We applied this methodology to identify tumor-specific "neoantigens" in the C57BL/6-derived GL261 and VM/Dk-derived SMA-560 tumor models. Following DNA whole-exome and RNA sequencing, high-affinity candidate neoepitopes were predicted and screened for immunogenicity by ELISPOT and tetramer analyses. GL261 and SMA-560 harbored 4,932 and 2,171 nonsynonymous exome mutations, respectively, of which less than half were expressed. To establish the immunogenicities of H-2Kb and H-2Db candidate neoantigens, we assessed the ability of the epitopes predicted in silico to be the highest affinity binders to activate tumor-infiltrating T cells harvested from GL261 and SMA-560 tumors. Using IFNγ ELISPOT, we confirmed H-2Db-restricted Imp3D81N (GL261) and Odc1Q129L (SMA-560) along with H-2Kb-restricted E2f8K272R (SMA-560) as endogenous tumor-specific neoantigens that are functionally immunogenic. Furthermore, neoantigen-specific T cells to Imp3D81N and Odc1Q129L were detected within intracranial tumors as well as cervical draining lymph nodes by tetramer analysis. By establishing the immunogenicities of predicted high-affinity neoepitopes in these models, we extend the immunogenomics-based neoantigen discovery pipeline to glioblastoma models and provide a tractable system to further study the mechanism of action of T cell-activating immunotherapeutic approaches in preclinical models of glioblastoma. Cancer Immunol Res; 4(12); 1007-15. ©2016 AACR.

Early eradication of persistent Salmonella infection primes antibody-mediated protective immunity to recurrent infection.

Typhoid fever is a systemic, persistent infection caused by host-specific strains of Salmonella. Although the use of antibiotics has reduced the complications associated with primary infection, recurrent infection remains an important cause of ongoing human morbidity and mortality. Herein, we investigated the impacts of antibiotic eradication of primary infection on protection against secondary recurrent infection. Using a murine model of persistent Salmonella infection, we demonstrate protection against recurrent infection is sustained despite early eradication of primary infection. In this model, protection is not mediated by CD4(+) or CD8(+) T cells because depletion of these cells either alone or in combination prior to rechallenge does not abrogate protection. Instead, infection followed by antibiotic-mediated clearance primes robust levels of Salmonella-specific antibody that can adoptively transfer protection to naïve mice. Thus, eradication of persistent Salmonella infection primes antibody-mediated protective immunity to recurrent infection.

Schistosomiasis and neglected tropical diseases: towards integrated and sustainable control and a word of caution.

In May 2001, the World Health Assembly (WHA) passed a resolution which urged member states to attain, by 2010, a minimum target of regularly administering anthelminthic drugs to at least 75% and up to 100% of all school-aged children at risk of morbidity. The refined global strategy for the prevention and control of schistosomiasis and soil-transmitted helminthiasis was issued in the following year and large-scale administration of anthelminthic drugs endorsed as the central feature. This strategy has subsequently been termed 'preventive chemotherapy'. Clearly, the 2001 WHA resolution led the way for concurrently controlling multiple neglected tropical diseases. In this paper, we recall the schistosomiasis situation in Africa in mid-2003. Adhering to strategic guidelines issued by the World Health Organization, we estimate the projected annual treatment needs with praziquantel among the school-aged population and critically discuss these estimates. The important role of geospatial tools for disease risk mapping, surveillance and predictions for resource allocation is emphasised. We clarify that schistosomiasis is only one of many neglected tropical diseases and that considerable uncertainties remain regarding global burden estimates. We examine new control initiatives targeting schistosomiasis and other tropical diseases that are often neglected. The prospect and challenges of integrated control are discussed and the need for combining biomedical, educational and engineering strategies and geospatial tools for sustainable disease control are highlighted. We conclude that, for achieving integrated and sustainable control of neglected tropical diseases, a set of interventions must be tailored to a given endemic setting and fine-tuned over time in response to the changing nature and impact of control. Consequently, besides the environment, the prevailing demographic, health and social systems contexts need to be considered.

A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance.

BACKGROUND: Cardiac complications secondary to iron overload are the leading cause of death in beta-thalassemia major. Approximately two thirds of patients maintained on the parenteral iron chelator deferoxamine have myocardial iron loading. The oral iron chelator deferiprone has been demonstrated to remove myocardial iron, and it has been proposed that in combination with deferoxamine it may have additional effect. METHODS AND RESULTS: Myocardial iron loading was assessed with the use of myocardial T2* cardiovascular magnetic resonance in 167 patients with thalassemia major receiving standard maintenance chelation monotherapy with subcutaneous deferoxamine. Of these patients, 65 with mild to moderate myocardial iron loading (T2* 8 to 20 ms) entered the trial with continuation of subcutaneous deferoxamine and were randomized to receive additional oral placebo (deferoxamine group) or oral deferiprone 75 mg/kg per day (combined group). The primary end point was the change in myocardial T2* over 12 months. Secondary end points of endothelial function (flow-mediated dilatation of the brachial artery) and cardiac function were also measured with cardiovascular magnetic resonance. There were significant improvements in the combined treatment group compared with the deferoxamine group in myocardial T2* (ratio of change in geometric means 1.50 versus 1.24; P=0.02), absolute left ventricular ejection fraction (2.6% versus 0.6%; P=0.05), and absolute endothelial function (8.8% versus 3.3%; P=0.02). There was also a significantly greater improvement in serum ferritin in the combined group (-976 versus -233 microg/L; P<0.001). CONCLUSIONS: In comparison to the standard chelation monotherapy of deferoxamine, combination treatment with additional deferiprone reduced myocardial iron and improved the ejection fraction and endothelial function in thalassemia major patients with mild to moderate cardiac iron loading.

Morbidity and nutrition patterns of three nomadic pastoralist communities of Chad.

As a part of an interdisciplinary research and action programme, morbidity and nutritional patterns were assessed in three nomadic communities: Fulani and Arab cattle breeders and Arab camel breeders, of two prefectures in Chad. The predominant morbidity pattern of Chadian nomadic pastoralists (representing approximately 10% of the total population of the country) had not been documented so far. A total of 1092 women, men and children was examined by a physician and interviewed during two surveys in the dry season and one in the wet season (1999--2000). Participants with no complaint were rare. Pulmonary disorders (e.g. bronchitis) were most often diagnosed for children under 5 years of age. Of the adult participants, 4.6% were suspected of tuberculosis. Febrile diarrhoea occurred more often during the wet season when access to clean drinking water was precarious. Malaria was only rarely clinically diagnosed among Arabs during the dry season, whereas Fulani, who stayed in the vicinity of Lake Chad, were also affected during this period. A 24-h dietary recall showed that less Arab women than men consumed milk during the dry season (66% versus 92%). Malnutrition was only documented for 3 out of 328 children (0--14 years). Arab women in childbearing age had a higher proportion of children not surviving when compared to Fulani women (0.2 versus 0.07). This study identified several implications for reseach and interventions in nomadic settings. Innovative and integrated health services for nomads can possibly be extended to many settings as nomadic pastoralists have in common a similar way of life driven by the needs of their animals.

Instrumentation and method for ultrahigh resolution field desorption ionization fourier transform ion cyclotron resonance mass spectrometry of nonpolar species.

We describe the construction and application of a 9.4-T FT-ICR mass spectrometer interfaced to a commercial field desorption ion source for high-resolution, high-mass accuracy measurements of nonpolar species. The FT-ICR MS instrument includes a liquid injection field desorption ionization source, octopole ion guides, external octopole ion trap capable of an axial potential gradient for ion ejection, capacitively coupled open cylindrical ion trap, and pulsed gas valve for ion cooling. Model compound responses with regard to various source and instrument conditions provide a basis for interpretation of broadband mass spectra of complex mixtures. As an example, we demonstrate broadband speciation of a Gulf Coast crude oil, with respect to numerous heteroatomic classes, compound types (rings plus double bonds), and carbon number distributions.

Copper-induced hepatotoxicosis with hepatic stellate cell activation and severe fibrosis in North Ronaldsay lambs: a model for non-Wilsonian hepatic copper toxicosis of infants.

Copper-sensitive North Ronaldsay sheep represent a possible model for certain hepatic-overload syndromes of infancy and childhood that are clinically, pathologically and genetically distinct from Wilson's disease. The purpose of this study was to simulate in artificially reared lambs the syndrome produced by copper exposure in susceptible human infants. Twenty four North Ronaldsay lambs were assigned to three groups of eight animals, namely, an unsupplemented control group and two trial groups given milk replacer to which copper (CuSO4) had been added at the rate of 5 mg/litre and 10 mg/litre. Four lambs from each group were killed at 40 or 69 days. Livers were fixed in 10% formalin and analysed for copper by mass spectrometry. Paraffin wax-embedded sections were stained with rhodanine for copper and labelled immunohistochemically for alpha smooth muscle actin (ASMA). At 40 days the maximum amounts of copper in the livers of both copper-supplemented groups was 1466-1605 microg/g dry weight (control group 172-201 microg/g Cu dry weight). Histochemically, copper was demonstrated within hepatocytes, together with marked apoptosis. At 69 days there was a florid pericellular fibrosis complemented by strong ASMA immunolabelling, confirming phenotypic modulation of hepatic stellate cells. Such primary copper-induced fibrogenesis confirms the unique status of this animal model in respect of childhood copper toxicosis.

Taux sérique de rétinol chez les femmes nomades pastoralistes tchadiennes en relation avec la teneur en rétinol et en carotène dans le lait de leur bétail

Dans le cadre d'une étude sur le statut sanitaire des pasteurs nomades et de leur bétail exécutée en étroite colla-boration entre les services de santé publique et vétérinaire tchadiens,le taux de rétinol sérique humain a été analysé en cor-rélation avec celui contenu dans le lait du bétail. Parmi les femmes examinées (n = 99),43% (IC95% 33 - 54 %) étaient défi-c i t a i resen rétinol (tauxde0,35µmol/Là0,7µmol/L) et 17% (IC95% 10 -26%) sévèrement défi c i t a i resen rétinol (tauxinféri e u rà0,35µmol/L). Aucunedesfemmesinterrogées(n=87)n'indiquaituneconsommation defruitset seulesdeux avaientconsommédeslégumesfraisau coursdesdern i è res 24 heures. Lelait était donc pratiquement la seule source devitamineA pour ces popu-lations. Parmi le bétail,les chèvres (n=6) avaient les taux moyens de rétinol les plus élevés dans leur lait (329 ± 84 µg/kg),sui-vies des bovins (n=25; 247 ± 32 µg/kg) et des dromadaires (n=12; 120 ± 18 µg/kg). Les concentrations de rétinol dans le sérumhumain dépendaient de manière significative de la concentration de rétinol dans le lait du bétail (pente partielle 0,23; inter-valle de confiance de 95% 0,008 - 0,47). Notre étude confirme que le lait de chèvre et de vache est une source importante devitamine A chez les pasteurs nomades. Par ailleurs,la promotion de la consommation de légumes verts,de fruits et de sup-pléments vitaminés reste nécessaire pour lutter contre les carences en vitamine A

The potential of artemether for the control of schistosomiasis.

Schistosomiasis continues to rank--following malaria--at the second position of the world's parasitic diseases in terms of the extent of endemic areas and the number of infected people. There is yet no vaccine available and the current mainstay of control is chemotherapy with praziquantel used as the drug of choice. In view of concern about the development of tolerance and/or resistance to praziquantel, there is a need for research and development of novel drugs for the prevention and cure of schistosomiasis. Interestingly, derivatives of artemisinin, which are already effectively used in the treatment of malaria, also exhibit antischistosomal properties. Significant advances have been made with artemether, the methyl ether derivative of artemisinin. We review the discovery of the antischistosomal activity of artemether by Chinese scientists two decades ago; the detailed laboratory studies of the susceptibility of, and effect on, the different developmental stages of Schistosoma japonicum, Schistosoma mansoni and Schistosoma haematobium to artemether; the possible mechanism of action and the potential long-term toxicity. Finally, we look at the effect of combined treatment with artemether and praziquantel; and clinical findings thus far obtained from randomised controlled trials with oral artemether for the prevention of patent infections and morbidity. The review intends to create a forum for strategic discussion of how these laboratory and clinical findings could be translated into public health actions. We conclude that artemether--as part of integrated current control measures and adapted to specific socio-ecological and epidemiological settings--has considerable potential to significantly reduce the current burden of schistosomiasis in many parts of the world.

Tegumental alterations in juvenile Schistosoma haematobium harboured in hamsters following artemether treatment.

We report the findings of a detailed temporal study on tegumental alterations in juvenile Schistosoma haematobium, induced by artemether, using scanning electron microscopy. Hamsters infected with S. haematobium cercariae for 28 days were treated intragastrically with a single dose of 300 mg/kg artemether. Groups of two hamsters were killed 24 h, 72 h and 7 days after treatment, and schistosomula were recovered from livers by perfusion and subsequent systematic examination of the tissue, before routinely processing for scanning electron microscopic examination. Most schistosomula collected 24 h after artemether administration showed severe tegumental damage, usually including swelling, fusion, vesiculation, peeling and collapse of enlarged sensory structures. After 72 h, tegumental damage had increased and schistosomula generally showed contraction with extensive swelling, erosion and peeling of the tegument. Seven days post-treatment, severe tegumental damage was only seen in a single male specimen with swelling of the worm body and destruction of the oral sucker. The other schistosomula showed only light to moderate damage, suggesting that schistosomula surviving the treatment began to recover. Our findings of tegumental damage following artemether treatment correlate with the efficacy of this novel antischistosomal drug in killing the juvenile stages of S. haematobium and complement recent findings with S. japonicum and S. mansoni.

Effect of combined treatment with praziquantel and artemether on Schistosoma japonicum and Schistosoma mansoni in experimentally infected animals.

Praziquantel and artemether are safe and efficacious antischistosomal drugs that act against different developmental stages of the parasite: praziquantel against adult worms and artemether against schistosomula. A combined treatment has been suggested as a strategy for transmission control. Recent laboratory experiments with rabbits with a mixed infection of Schistosoma japonicum parasites of different ages confirmed the effectiveness of a combination therapy. In the present work, we assessed the effect of a combined treatment on adult worms of S. japonicum and found significantly higher worm reduction rates than with a single dose of praziquantel. In a next step, we extended the study of the combined treatment to Schistosoma mansoni. A combined treatment with 75 mg/kg praziquantel and 150 mg/kg artemether was administered to hamsters infected with juvenile and adult S. mansoni. The two drugs, administered simultaneously or spaced by 6 h, 1, 3 or 7 days, resulted in significantly higher worm reduction rates than a single treatment with praziquantel. A combination therapy with increased doses of 100 mg/kg praziquantel and 300 mg/kg artemether showed very high worm reduction rates of 90% and above, however, some hamsters died in five different combined treatment experiments, suggesting that these drug concentrations were too high. We conclude that a combined treatment with praziquantel and artemether at the lower doses is safe and more effective than praziquantel alone, which forms a foundation for designing respective clinical trials in humans.

Histopathological changes in juvenile Schistosoma haematobium harboured in hamsters treated with artemether.

Histopathological changes in juvenile Schistosoma haematobium, caused by artemether administered to the infected hamsters, were studied. Hamsters were infected with S. haematobium cercariae, and after 28 days, a single dose of artemether (300 mg/kg) was administered intragastrically. After 24 h, 72 h and 7 days, groups of two hamsters were sacrificed, and livers were removed, fixed and processed routinely, and examined by light microscopy. After 24 h, 93% of the schistosomulae examined showed degeneration, which included swelling of the tegument, adherence of inflammatory cells to the damaged tegument, collapsed and damaged intestine, and infiltration of inflammatory cells, predominantly lymphocytes. After 72 h, the intensity of damage increased, including severe swelling of the tegument, loss of definition in the internal structures, collapse of intestine accompanied by release of pigment particles to the parenchymal tissues, and emergence of dead schistosomulae. Seven days after treatment, the number of dead schistosomulae increased, and most of them developed to an early- or late stage of dead worm granuloma. Meanwhile, 12% of the schistosomulae showed a normal appearance, which suggested that those schistosomulae that had survived the treatment were recovered to normal. The results demonstrated that artemether effectively acts against the juvenile stages of S. haematobium and confirms earlier results with S. japonicum and S. mansoni.

Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo-controlled trial.

BACKGROUND: Clinical malaria and severe anaemia are major causes of paediatric hospital admission and death in many malaria-endemic settings. In the absence of an effective and affordable vaccine, control programmes continue to rely on case management while attempting the large-scale deployment of insecticide-treated nets. We did a randomised, placebo-controlled trial to assess the efficacy and safety of intermittent sulphadoxine-pyrimethamine treatment on the rate of malaria and severe anaemia in infants in a rural area of Tanzania. METHODS: We randomly assigned 701 children living in Ifakara, southern Tanzania, sulphadoxine-pyrimethamine or placebo at 2, 3, and 9 months of age. All children received iron supplementation between 2 and 6 months of age. The intervention was given alongside routine vaccinations delivered through WHO's Expanded Program on Immunisation (EPI). The primary outcome measures were first or only episode of clinical malaria, and severe anaemia in the period from recruitment to 1 year of age. Morbidity monitoring through a hospital-based passive case-detection system was complemented by cross-sectional surveys at 12 and 18 months of age. Results were expressed in terms of protective efficacy (100 [1-hazard ratio]%) and analysis was by intention to treat. FINDINGS: 40 children dropped out (16 died, 11 migrated, 12 parents withdrew consent, and one for other reasons). Intermittent sulphadoxine-pyrimethamine treatment was well tolerated and no drug-attributable adverse events were recorded. During the first year of life, the rate of clinical malaria (events per person-year at risk) was 0.15 in the sulphadoxine-pyrimethamine group versus 0.36 in the placebo group (protective efficacy 59% [95% CI 41-72]), and the rate of severe anaemia was 0.06 in the sulphadoxine-pyrimethamine group versus 0.11 in the placebo group (50% [8-73]). Serological responses to EPI vaccines were not affected by the intervention. INTERPRETATION: This new approach to malaria control reduced the rate of clinical malaria and severe anaemia by delivering an available and affordable drug through the existing EPI system. Data are urgently needed to assess the potential cost-effectiveness of intermittent treatment in areas with different patterns of malaria endemicity.

Effects of a 10-minute back rub on cardiovascular responses in healthy subjects.

This study determined the cardiovascular responses to a 10-minute back rub. Twelve healthy, college-age males and females (mean age = 22 years) volunteered to participate as subjects. Using an ABA design, the subjects tested for 10 minutes (Control #1) on a padded plinth lying on one side. During the Treatment period, the back rub was administered, which was followed by Control #2. Oxygen consumption (VO2) was determined via the Medical Graphics CPX/D metabolic analyzer, which also estimated cardiac output (Q) using the CO2 rebreathing (equilibrium) method. A repeated measures ANOVA was performed to statistically compare the cardiovascular responses across the three periods. The back rub, when compared to Control #1, had no significant effect on VO2, but the central and peripheral components of VO2 were changed. Cardiac output was decreased as a result of the decreased stroke volume (SV), as a function of the increased peripheral vascular resistance (PVR). We also found an increase in the extraction of oxygen (a-vO2 diff) in the peripheral tissues. These results indicate that the VO2 response during the back rub was achieved by reciprocal central (SV,Q) and peripheral (a-vO2 diff) adjustments. Following the back rub, (i.e., Control #2 vs. Treatment), the decrease in VO2, VCO2, Ve, and a-vO2 diff appears to indicate that it was effective in inducing relaxation. Since HR, SV, and Q were unchanged, the VO2 response was a result of the decreased a-vO2 diff. Hence, the findings suggest certain positive implications for the health care industry.

Artemether administered together with haemin damages schistosomes in vitro.

We conducted experiments in vitro to assess the effect of artemether in combination with haemin on adult Schistosoma japonicum, S. mansoni and S. haematobium. When schistosomes were maintained in a medium containing artemether at concentrations of 20 micrograms/mL or less for 72 h, no apparent effect on the schistosomes was seen. When the medium contained 50 or 100 micrograms/mL haemin as well as artemether, the schistosomes showed decreased motor activity 2-24 h after exposure, which was followed by the staining of the whole worm body a reddish-yellow colour, dilatation of the intestine, and extensive vesiculation of the tegument. Some of the schistosomes died 24 h after exposure, and almost all died within 48-72 h. When schistosomes were exposed to the same concentrations of haemin alone, they were stained a light yellow colour but there was no apparent effect on their survival. Our findings suggest that artemether interacts with haemin to exert a toxic effect on the worms, which might be of importance in the further elucidation of the mechanism of action of artemether on schistosomes.

Current progress in the development and use of artemether for chemoprophylaxis of major human schistosome parasites.

Human schistosomiasis, a chronic and debilitating parasitic disease of the tropics, is ranked second after malaria in terms of public health importance. At present, there is no vaccine available, and chemotherapy is the cornerstone of schistosomiasis control. Praziquantel is the drug of choice. Oxamniquine has become difficult to obtain and metrifonate has recently been withdrawn from the market. Rapid re-infection following treatment and concern about praziquantel resistance called for the search of novel drugs for prevention and cure of schistosomiasis. Significant progress has been made with artemether, the methyl ether of dihydroartemisinin, already widely used for the treatment of malaria. The present article reviews the literature that led to the development of artemether for chemoprophylaxis in schistosomiasis, and it summarises the experiences so far obtained with its use to control schistosomiasis in different endemic settings. Topics covered include an overview of the global burden of schistosomiasis and approaches for its control; the nature and features of artemisinin and related derivatives, initially discovered as antimalarials, other bioactivities, and their recent discovery of antischistosomal properties; a historic account disclosing the antischistosomal activity of artemether; in vivo assessment of drug susceptibility of different developmental stages of schistosome parasites; artemether-induced pathology evidenced by scanning and transmission electron microscopy; the possible mechanism of action; in vivo studies with combination therapy of artemether and praziquantel; results of randomised controlled clinical trials of oral artemether for the prevention of patent infection and morbidity; and, ultimately the translation of this knowledge into public health action in different endemic settings towards a more integrated approach of schistosomiasis control.