Computer models show malaria-infected RBCs stiffen, restrict capillary flow

A team of researchers at Brown University and the Massachusetts Institute of Technology has completed the first modeling, followed by experiments, of how red blood cells are infected by a malarial parasite that attacks the brain. The researchers report that infected cells stiffen by as much as 50 times more than healthy cells. Infected cells also tend to stick along blood vessel walls, impeding the flow of blood to critical organs. Results appear in the early online edition of the Proceedings of the National Academy of Sciences.

Although the incidence of malaria has declined in all but a few countries worldwide, according to a World Health Organization report earlier this month, malaria remains a global threat. Nearly 800,000 people succumbed to the mosquito-borne disease in 2009, nearly all of them in the developing world.

Physicians do not have reliable treatment for the virus at various stages, largely because no one has been able to document the malaria parasite’s journeys in the body.

Now researchers at Brown University and the Massachusetts Institute of Technology have used advanced computer modeling and laboratory experiments to show how malaria parasites change red blood cells and how the infected cells impede blood flow to the brain and other critical organs.

Recent review of African health research reveals gaps, opportunities

The McLaughlin-Rotman Center for Global Health has published a series of open-access papers that paints a detailed picture of the state of health innovation research in Africa (link to BiomedCentral International Health and Human Rights, December 2010). Dr. Peter Singer and Dr. Ken Simiyu share their research findings in this engaging studio discussion.

African Innovation: New Hope for Local Health Issues

Key findings of the group include issues in the stagnation of viable technologies, such as diagnostic tests, medical devices, and plant medicine due to lack of commercialization.

Other barriers in bringing these important innovation to the people include lack of infrastructure and scientific equipment, lack of capital financing and enterpreneurship, and inappropriate regulation and policies.

Suggestions to improve these issues comprise the need for a viable innovation network between scientists and entrepreneurs, addition of some modest funds to continue and validate the research, and addressing the gap in research infrastructure and scientific equipment.

These models parallel the situation of health research in Southeast Asia, where similar opportunities and challenges exist for health innovation. These investable ideas, if properly channeled, stand to make a huge difference in the people of Africa and Southeast Asia in the future. It is envisioned for these countries to develop health research so that they can create local products, grow local industries for health products, and provide solutions to local health needs of today.

Reference: McLaughlin-Rotman Center for Global Health. (2010, December). African Innovation: New Hope for Local Health Issues. Accessed December 2010. Retrieved from http://www.mrcglobal.org/projects/african_innovation.

Higher Actual Dengue Incidence Numbers in Cambodia than in National Reports, 2006–2008

Dengue vaccines are now in late-stage development, and evaluation and robust estimates of dengue disease burden are needed to facilitate further development and introduction. In Cambodia, the national dengue case-definition only allows reporting of children less than 16 years of age, and little is known about dengue burden in rural areas and among older persons. To estimate the true burden of dengue in the largest province of Cambodia, Kampong Cham, we conducted community-based active dengue fever surveillance among the 0-to-19–year age group in rural villages and urban areas during 2006–2008.


General Findings

The large-scale active surveillance study for dengue fever in Cambodia found a higher disease incidence than reported to the national surveillance system, particularly in preschool children and that disease incidence was high in both rural and urban areas. It also confirmed the previously observed focal nature of dengue virus transmission.

Small tech with big promise for healthcare

Nanotechnology should not suffer the same fate as GM — potential health and environmental hazards should be monitored and regulated early on. David Dickson, director of SciDev.Net, discusses the promise of nanomaterials. 

If a new and potentially hazardous field of technological innovation is to flourish in a social environment,  two factors are essential, even if the hazards are still relatively speculative.

The first is a clear demonstration of its value to individual welfare, creating a demand for what it promises.

The second is evidence that the potential dangers can be adequately monitored, and regulations put in place to minimise the chance that harmful effects will occur.

Nanotechnology for health: Facts and figures

Can developing countries use nanotechnology to improve health? Priya Shetty looks at nanomedicine's promise at a SciDev report.

Nanotechnology — the science of the extremely small — holds enormous potential for healthcare, from delivering drugs more effectively, diagnosing diseases more rapidly and sensitively, and delivering vaccines via aerosols and patches.

Nanotechnology is the science of materials at the molecular or subatomic level. It involves manipulation of particles smaller than 100 nanometres (one nanometre is one-billionth of a metre) and the technology involves developing materials or devices within that size — invisible to the human eye and often many hundred times thinner than the width of human hair. The physics and chemistry of materials are radically different when reduced to the nanoscale; they have different strengths, conductivity and reactivity, and exploiting this could revolutionise medicine.

For example, a major challenge of modern medicine is that the body doesn't absorb the entire drug dose given to a patient. Using nanotechnology, scientists can ensure drugs are delivered to specific areas in the body with greater precision, and the drugs can be formulated so that the active ingredient better permeates cell membranes, reducing the required dose.

AIDS Vaccine for Asia Network (AVAN): Expanding the Regional Role in Developing HIV Vaccines

Kent SJ, Cooper DA, Chhi Vun M, Shao Y, Zhang L, et al. (2010) AIDS Vaccine for Asia Network (AVAN): Expanding the Regional Role in Developing HIV Vaccines. PLoS Med 7(9): e1000331. doi:10.1371/journal.pmed.1000331


The HIV/AIDS pandemic continues to spread and an AIDS vaccine is urgently needed. While facing unprecedented challenges, AIDS vaccine development activities are continuing around the globe. Recent results of the Thai Phase III vaccine trial are renewing such efforts. In accordance with the goals of the Global HIV Vaccine Enterprise, there is now clear recognition of the role that regional alliances can play in fostering and facilitating AIDS vaccine development, and there is broad agreement that international collaborations are the most effective way forward to develop and evaluate the next generation of AIDS vaccine candidates.

In response to these challenges, the Asian region has recently formed the AIDS Vaccine for Asia Network (AVAN).

AVAN has been initiated to meet these needs and actively facilitate the development of a regional AIDS vaccine strategy that accelerates research and development of an AIDS vaccine through government advocacy, improved coordination and harmonization of research; develops clinical trial and manufacturing capacity; supports ethical and regulatory frameworks; and ensures community participation.

Scripps researchers develop new detection test for river blindness parasite

Innovation will help eliminate tropical malady

In a press release by the Scripps Research Institute in La Jolla, california, the institute announced that its scientists have developed the first screening method that rapidly identifies individuals with active river blindness, a parasitic disease that afflicts an estimated 37 million people. The test could change the current strategy of mass treatment in areas where river blindness, also known as onchocerciasis, is suspected.

The study was published online on October 5, 2010, by the journal PLOS Neglected Tropical Diseases.

"A sensitive and reproducible diagnostic test for this disease is crucial for the success of worldwide control and elimination programs," said Kim Janda, Ph.D., a professor in the Departments of Chemistry and Immunology and Microbial Science, member of The Skaggs Institute for Chemical Biology, and director of The Worm Institute for Research and Medicine (WIRM) at Scripps Research. "This diagnostic tool could be a game-changer for how the disease will be treated in the future."

Judith Denery, Ph.D., a senior research associate in the Janda laboratory and the paper's first author, adds, "Because current tests often give false negatives, they are unreliable indicators of infection. For organizations such as the World Health Organization and others working to eliminate the disease, this lack of accuracy is frustrating, time-consuming, and costly."

Enhanced Detection, Diagnosis of Leishmaniasis in Bangladesh

Mondal D, Nasrin KN, Huda MM, Kabir M, Hossain MS, et al. (2010) Enhanced Case Detection and Improved Diagnosis of PKDL in a Kala-azar-Endemic Area of Bangladesh. PLoS Negl Trop Dis 4(10): e832. doi:10.1371/journal.pntd.0000832

To support the Bangladesh National Kala-azar Elimination Programme (NKEP), the group investigated the feasibility of using trained village volunteers for detecting post-kala-azar dermal leishmaniasis (PKDL) cases, using polymerase chain reaction (PCR) for confirmation of diagnosis and treatment compliance by PKDL patients in Kanthal union of Trishal sub-district, Mymensingh, Bangladesh.

Methods
In this cross-sectional study, Field Research Assistants (FRAs) conducted census in the study area, and the research team trained village volunteers on how to look for PKDL suspects. The trained village volunteers (TVVs) visited each household in the study area for PKDL suspects and referred the suspected PKDL cases to the study clinic. The suspected cases underwent physical examinations by a qualified doctor and rK39 strip testing by the FRAs and, if positive, slit skin examination (SSE), culture, and PCR of skin specimens and peripheral buffy coat were done. Those with evidence of Leishmania donovani (LD) were referred for treatment. All the cases were followed for one year.

Results
The total population of the study area was 29,226 from 6,566 households. The TVVs referred 52 PKDL suspects. Probable PKDL was diagnosed in 18 of the 52 PKDL suspect cases, and PKDL was confirmed in 9 of the 18 probable PKDL cases. The prevalence of probable PKDL was 6.2 per 10,000 people in the study area. Thirteen PKDL suspects self-reported from outside the study area, and probable and confirmed PKDL was diagnosed in 10 of the 13 suspects and in 5 of 10 probable PKDL cases respectively. All probable PKDL cases had hypopigmented macules. The median time for PKDL development was 36 months (IQR, 24–48). Evidence of the LD parasite was documented by SSE and PCR in 3.6% and 64.3% of the cases, respectively. PCR positivity was associated with gender and severity of disease. Those who were untreated had an increased risk (odds ratio = 3.33, 95%CI 1.29–8.59) of having persistent skin lesions compared to those who were treated. Patients' treatment-seeking behavior and treatment compliance were poor.

Conclusion
Improved detection of PKDL cases by TVVs is feasible and useful. The NKEP should promote PCR for the diagnosis of PKDL and should find ways for improving treatment compliance by patients.

External Quality Control Assessment for the Molecular Diagnosis of Dengue Infections

Domingo C, Niedrig M, Teichmann A, Kaiser M, Rumer L, et al. (2010) 2nd International External Quality Control Assessment for the Molecular Diagnosis of Dengue Infections. PLoS Negl Trop Dis 4(10): e833. doi:10.1371/journal.pntd.0000833

Currently dengue viruses (DENV) pose an increasing threat to over 2.5 billion people in over 100 tropical and sub-tropical countries worldwide. International air travel is facilitating rapid global movement of DENV, increasing the risk of severe dengue epidemics by introducing different serotypes. Accurate diagnosis is critical for early initiation of preventive measures. Different reverse transcriptase PCR (RT-PCR) methods are available, which should be evaluated and standardized. Epidemiological and laboratory-based surveillance is required to monitor and guide dengue prevention and control programmes, i.e., by mosquito control or possible vaccination (as soon as an effective and safe vaccine becomes available).

Objective

The purpose of the external quality assurance (EQA) study described is to assess the efficiency and accuracy of dengue molecular diagnosis methods applied by expert laboratories.

Study Design

A panel of 12 human plasma samples was distributed and tested for DENV-specific RNA. The panel comprised 9 samples spiked with different DENV serotypes (DENV-1 to DENV-4), including 10-fold dilution series of DENV-1 and DENV-3. Two specificity controls consisted of a sample with a pool of 4 other flaviviruses and a sample with chikungunya virus. A negative control sample was also included.

Results

Thirty-seven laboratories (from Europe, Middle East Asia, Asia, the Americas/Caribbean, and Africa) participated in this EQA study, and reports including 46 sets of results were returned. Performance among laboratories varied according to methodologies used. Only 5 (10.9%) data sets met all criteria with optimal performance, and 4 (8.7%) with acceptable performance, while 37 (80.4%) reported results showed the need for improvement regarding accomplishment of dengue molecular diagnosis. Failures were mainly due to lack of sensitivity and the presence of false positives.

Conclusions

The EQA provides information on each laboratory's efficacy of RT-PCR techniques for dengue diagnosis and indicates for most laboratories an urgent need to improve sensitivity and specificity.

New dermal patch delivers influenza vaccine for needle phobics

PVP microneedles confer better immunity compared to intramuscular injections in mice.

Researchers from Emory University in Atlanta, Georgia have developed a new method for influenza prophylaxis, published in Nature Medicine [1].

Sullivan et al. has fabricated plastic microneedles made of polyvinylpyrrolidone (PVP) to encapsulate a dried form of inactivated influenza virus. The microneedles penetrate the skin up to the portion of the dermis where antigen-presenting cells are present, and where PVP encapsulation dissolves and releases the influenza vaccine.

Influence of Age, Sex, Ethnicity and IgE on Human Exposure and Immunity to Schistosomiasis Infections

Pinot de Moira A, Fulford AJC, Kabatereine NB, Ouma JH, Booth M, et al. (2010) Analysis of Complex Patterns of Human Exposure and Immunity to Schistosomiasis mansoni: The Influence of Age, Sex, Ethnicity and IgE. PLoS Negl Trop Dis 4(9): e820. doi:10.1371/journal.pntd.0000820

Numerous factors may influence Schistosoma infection intensity and prevalence within endemic communities, including exposure-related factors such as local environment and behaviour, and factors relating to susceptibility to infection such as immunology and genetics. While animal studies performed in the laboratory can be tightly controlled, human populations are highly heterogeneous, varying according to demographic characteristics, genetic background and exposure to infection. The heterogeneous nature of human water contact behaviour in particular makes it difficult to distinguish between a lack of cercarial exposure and reduced susceptibility to infection as the cause for low levels of infection in the field.

Methods and Principal Findings

In this study we investigate risk factors for Schistosoma mansoni infection in a rural Ugandan fishing community receiving treatment as part of a multi-disciplinary longitudinal reinfection study. More specifically, we examine the influence that age, sex and ethnic background have on susceptibility to reinfection after anti-helminth drug treatment, but use individual estimates of cercarial exposure and multivariable methods in an attempt to remove noise created by environmental and behavioural heterogeneities. We then investigate whether schistosome-specific IgE immune responses could account for any remaining variations in susceptibility to reinfection. Our findings suggest that observed ethnic- and sex-related variations in S. mansoni reinfection were due to variations in cercarial exposure, as opposed to biological differences in susceptibility to infection. Age-related differences in reinfection were not explained by exposure, however, and appeared linked to the balance of IgE and IgG4 to the tegumental antigen SmTAL1 (formerly Sm22.6), which itself was significantly related to resistance to reinfection.

Conclusions

This study highlights the benefit of taking a multidisciplinary approach in complex field settings; it allows the ecology of a population to be understood and thus more robust conclusions to be made.

Material reposted under the Creative Commons License.

Multi-Country Evaluation of Two Commercial Dengue Diagnostic Kits

Guzman MG, Jaenisch T, Gaczkowski R, Ty Hang VT, Sekaran SD, et al. (2010) Multi-Country Evaluation of the Sensitivity and Specificity of Two Commercially-Available NS1 ELISA Assays for Dengue Diagnosis. PLoS Negl Trop Dis 4(8): e811. doi:10.1371/journal.pntd.0000811

Early diagnosis of dengue can assist patient triage and management and prevent unnecessary treatments and interventions. Commercially available assays that detect the dengue virus protein NS1 in the plasma/serum of patients offers the possibility of early and rapid diagnosis.

Methodology/Principal Findings

The sensitivity and specificity of the Pan-E Dengue Early ELISA and the Platelia™ Dengue NS1 Ag assays were compared against a reference diagnosis in 1385 patients in 6 countries in Asia and the Americas. Platelia was more sensitive (66%) than Pan-E (52%) in confirmed dengue cases. Sensitivity varied by geographic region, with both assays generally being more sensitive in patients from SE Asia than the Americas. Both kits were more sensitive for specimens collected within the first few days of illness onset relative to later time points. Pan-E and Platelia were both 100% specific in febrile patients without evidence of acute dengue. In patients with other confirmed diagnoses and healthy blood donors, Platelia was more specific (100%) than Pan-E (90%). For Platelia, when either the NS1 test or the IgM test on the acute sample was positive, the sensitivity versus the reference result was 82% in samples collected in the first four days of fever. NS1 sensitivity was not associated to disease severity (DF or DHF) in the Platelia test, whereas a trend for higher sensitivity in DHF cases was seen in the Pan-E test (however combined with lower overall sensitivity).

Conclusions/Significance

Collectively, this multi-country study suggests that the best performing NS1 assay (Platelia) had moderate sensitivity (median 64%, range 34–76%) and high specificity (100%) for the diagnosis of dengue. The poor sensitivity of the evaluated assays in some geographical regions suggests further assessments are needed. The combination of NS1 and IgM detection in samples collected in the first few days of fever increased the overall dengue diagnostic sensitivity.


Material reposted under the Creative Commons License.

Identification of Attractive Drug Targets in Neglected-Disease Pathogens Using an In Silico Approach

Crowther GJ, Shanmugam D, Carmona SJ, Doyle MA, Hertz-Fowler C, et al. (2010) Identification of Attractive Drug Targets in Neglected-Disease Pathogens Using an In Silico Approach. PLoS Negl Trop Dis 4(8): e804. doi:10.1371/journal.pntd.0000804

Increased sequencing of pathogen genomes and the subsequent availability of genome-scale functional datasets are expected to guide the experimental work necessary for target-based drug discovery. However, a major bottleneck in this has been the difficulty of capturing and integrating relevant information in an easily accessible format for identifying and prioritizing potential targets. The open-access resource TDRtargets.org facilitates drug target prioritization for major tropical disease pathogens such as the mycobacteria Mycobacterium leprae and Mycobacterium tuberculosis; the kinetoplastid protozoans Leishmania major, Trypanosoma brucei, and Trypanosoma cruzi; the apicomplexan protozoans Plasmodium falciparum, Plasmodium vivax, and Toxoplasma gondii; and the helminths Brugia malayi and Schistosoma mansoni.

Methodology/Principal Findings

Here we present strategies to prioritize pathogen proteins based on whether their properties meet criteria considered desirable in a drug target. These criteria are based upon both sequence-derived information (e.g., molecular mass) and functional data on expression, essentiality, phenotypes, metabolic pathways, assayability, and druggability. This approach also highlights the fact that data for many relevant criteria are lacking in less-studied pathogens (e.g., helminths), and we demonstrate how this can be partially overcome by mapping data from homologous genes in well-studied organisms. We also show how individual users can easily upload external datasets and integrate them with existing data in TDRtargets.org to generate highly customized ranked lists of potential targets.

Conclusions/Significance

Using the datasets and the tools available in TDRtargets.org, we have generated illustrative lists of potential drug targets in seven tropical disease pathogens. While these lists are broadly consistent with the research community's current interest in certain specific proteins, and suggest novel target candidates that may merit further study, the lists can easily be modified in a user-specific manner, either by adjusting the weights for chosen criteria or by changing the criteria that are included.

Material reposted under the Creative Commons License.

Targeting HIV at its source

Promising cure for HIV induces apoptosis, targets infected cells in vitro

Current HIV treatments do not eradicate HIV from host cells but rather inhibit virus replication and delay the onset of AIDS. However, a new research published in BioMed Central's open access journal, AIDS Research & Therapy describes an innovative approach to eliminate HIV in host by targeted killing of only HIV infected cells. This approach if successful could lead into an anti-HIV therapy that will eradicate the virus.

On infection, HIV spreads through the human body after the viral DNA is incorporated into the genome of host cells. Current Highly Active Anti-Retroviral Therapies (HAART) work by blocking HIV replication at various steps but does not eliminate the infected cells. Now, Professors Abraham Loyter, Assaf Friedler and their colleagues at Hebrew University, Jerusalem, focussed on the elimination of infected cells.

Effects of global health initiatives on national health systems

Recent Global Health Initiatives (GHI) have been created to address single disease issues in low-income countries, such as neonatal tetanus, poliomyelitis, trachoma, etc. Empirical evidence on the effects of such GHIs on local health systems remains scarce.

This study by Dormael and colleagues explored positive and negative effects of the Integrated Neglected Tropical Disease (NTD) Control Initiative, comprising mass preventive chemotherapy for five targeted NTDs, on Mali's health system where it was first implemented in 2007.

The paper offered that disease-specific interventions implemented as parallel activities in fragile health services may further weaken their responsiveness to community needs, especially when several GHIs operate simultaneously. Health system strengthening will not result from the sum of selective global interventions but requires a comprehensive approach.

MRSA-lysing paint for hospital walls

Building on an enzyme found in nature, researchers at Rensselaer Polytechnic Institute have created a nanoscale coating for surgical equipment, hospital walls, and other surfaces which safely eradicates methicillin resistant Staphylococcus aureus (MRSA), the bacteria responsible for antibiotic resistant infections.

In tests, 100 percent of MRSA in solution were killed within 20 minutes of contact with a surface painted with latex paint laced with the coating.

The new coating marries carbon nanotubes with lysostaphin, a naturally occurring enzyme used by non-pathogenic strains of Staph bacteria to defend against Staphylococcus aureus, including MRSA. The resulting nanotube-enzyme "conjugate" can be mixed with any number of surface finishes — in tests, it was mixed with ordinary latex house paint.

Creative strategies for obtaining informed consent in rural clinical trials

David Diemert of George Washington Unversity and his collaborators in Brazil used an informational video to explain a hookworn vaccine trial in the rural community of Minas Gerais in Southeastern Brazil. The group measured attitudes, fears, and perceptions through a structured questionnaire before and after the clinical trial.

In the paper, they observed that video materials were a successful tool among patients in resource-limited populations to increase understanding about the purpose of vaccination and possible adverse effects of a novel vaccine under study. Although more than 90% said that they would participate in a hookworm vaccine trial, an increase in the number who expressed fear of being vaccinated with an experimental vaccine was seen after viewing the video (51.4% post-video versus 29.2% pre-video).

The group concluded that educational tools can be specially designed to significantly improve understanding and likelihood of obtaining truly informed consent for participation in clinical research.

read full article: Gazzinelli, et al. 2010. CT educ thru analogies

Material reposted under the Creative Common License.

Nature Asia Pacific releases 2009 index

The Nature Publishing Group (NPG) Nature Asia-Pacific has pioneered an effort to rank the research output of institutions in the Asia Pacific region with the release of the Nature Asia-Pacific Publishing Index.

The index provides data on the number of primary research articles published in Nature journals by institutions from the Asia-Pacific region, India, and Australasia. The Nature Asia-Pacific Publishing Rankings 2009 is the first print issue of this ambitious and pioneering project.

According to a written introduction by David Swinbanks, publishing director and CEO of NPG Nature Asia-Pacific, the index also displays "rankings by country, institution and research journal as well as historical data by country extending back to 1998. This historical data shows the dramatic rise of output of high quality research from some countries in region, in particular China".

The 2009 report is free for download at http://www.natureasia.com/en/publishing-index/2009/. Unregistered users of the site are advised to sign up for free.

disease burden correlates with national IQ

Christopher Eppig and colleagues made an intriguing proposition that infections and parasites affect brain development.

In the Proceedings of the Royal Society B: Biological Sciences, Eppig's paper argues that national intelligence is correlated negatively with the national rate of infectious disease. Support is provided by correlation and linear modelling techniques. The graph shows the position of countries included in the study in terms of disease burden and national IQ level.



Like all other hypotheses for causation, these proposals must be taken with a grain of salt. Further studies must be done to establish causation, such as by longitudinal studies on the rate of infectious disease over time.

It has been previously theorized that national differences on intelligence may explain the differences in economic development of rich and poor countries. Now, policymakers is provided some evidence that lack of development itself, e.g., inadequate social welfare and health provisions, may explain the difference in intelligence.

read full article: Eppig, C. et al. 2010. Parasite prevalence and the worldwide distribution of cognitive ability

At last, malaria-free mosquitoes

by Patrick Reilly, July 16, 2010
http://www.plos.org/cms/node/538

In a study published on July 15 in PLoS Pathogens, researchers demonstrate how to genetically alter mosquitoes so they no longer transmit the Plasmodium falciparum parasite, which causes malaria in humans.

read full PLoS Pathogens article: Riehle, et al. 2010. Akt activation in Anopheles mosquitoes