Tuesday, August 31, 2010

Now the Indian probiotic trial: would it help prevent diarrhea in the poor?

Are probiotics a feasible intervention for prevention of diarrhoea in the developing world?
N Hajela, GB Nair and NK Ganguly
Gut Pathogens 2010, 2:10doi:10.1186/1757-4749-2-10
With about 1.4 million of the just under 9 million child deaths attributed to diarrhoea in 2008 and 49% of them occurring in five countries namely, India, Nigeria, Democratic Republic of the Congo, Pakistan and China, there is an urgent need for interventions to prevent and control diarrhoeal diseases. Of the various interventions to prevent diarrhoea, probiotics offer potential. The past decade has witnessed the validation of their utility for the prevention, treatment and management of a variety of infective and non infective disorders. The most investigated field continues to remain infectious diarrhoea and compelling evidence comes from randomized placebo controlled trails. While results from these studies are encouraging, most of them reflect the outcomes of the developed world. Developing countries like India continue to struggle with nutritional and health challenges and bear the greatest burden of diarrhoea. A paucity of data from the developing countries limits the definite recommendation of probiotics. In these countries curd, often confused for a probiotic, is practiced as an integral part of the culture. While the nutritional benefits of these products cannot be understated, it is still uncertain whether these products can be classified as a probiotic. The emergence of probiotic foods which are scientifically validated for their efficacy and impart defined health benefits offer an excellent opportunity to improve public health. A recent randomized controlled trial conducted by the National Institute of Cholera and Enteric Diseases in Kolkata, India demonstrated a protective efficacy of 14% in preventing diarrhoea among children who received a probiotic. For the developing world, however, the vision for probiotics would mean a fundamental change in perception and developing a well-planned strategy to allow interventions like probiotics to permeate to impoverished settings, where the assault of micro organisms is on a daily basis. This would mean that probiotics be ingrained into the public health system without being seen as a medicine.

Thursday, August 19, 2010

Faculty of 1000’s most viewed top 10 evaluations: Evaluation of Aziz and Nizet, Sci Transl Med 2010 Jan 27 2(16):16ps4

Pathogen Micro-evolution in High Resolution (see the evaluation at F1000)

This perspective by Aziz and Nizet stresses that key hypotheses regarding microbial strain evolution or virulence cannot be addressed through conventional genotyping methods that often do not offer enough resolution of minor changes between closely related strains, such as insertion, deletion and substitution polymorphisms. Just like siblings and identical twins having their own personalities and phenotypes due to genetic, epigenetic or environmental confounders, paired/clonal isolates of bacteria, even if genetically identical, have their own colonization traits and pathogenic potentials due to their 'variome'.

Previously, people used to 'characterize' and individualize strains and isolates of bacterial pathogens by means of genetic fingerprinting or DNA profiling. However, recent revelations based on whole genome sequencing have showed that any two strains, even if (seemingly clonal) could be dramatically different in their functional capabilities, owing mainly to the single nucleotide polymorphisms (SNPs). This article, thus, potentially brings about the importance of a 'variome' in understanding evolution of pathogens, rather than putting emphasis on the core genome. In our own experience, Helicobacter pylori serially isolated from a single patient over a decade were different in containing or losing as much as ~51 open reading frames (ORFs) when whole genomes were sequenced (N Ahmed, T Taylor, F Megraud, unpublished data). These isolates were previously shown to belong to only one parental strain and were clonal according to the randomly amplified polymorphic DNA (RAPD), and MLST based genotyping {1}. As suggested in this paper, genome-wide analyses of SNPs between paired strains isolated from the same patient, or between input vs. output strains generated in a suitable animal model, could reveal important genetic 'switch' mechanisms critical for survival, adaptation and invasion potentials of the bacterial pathogens.

References: {1} Prouzet-Mauléon et al. J Clin Microbiol 2005, 43:4237-41 [PMID:16081988].

Evaluated 10 Aug 2010

New at PLoS ONE: From Grazing Resistance to Pathogenesis: The Coincidental Evolution of Virulence Factors

Sandrine Adiba et al., 2010. PLoS ONE 5(8): e11882. doi:10.1371/journal.pone.0011882


"If you happen to be stranded in a building, it's probably not the occasion to start setting fire to things. But this is perhaps what some bacteria do when they find themselves challenged inside a human; they cause then the diseases that are potentially fatal but not contagious. Loosing thus an opportunity to escape (transmission), they risk getting perished with their host. This seems like a ludicrous strategy but we're looking at it from the wrong perspective – our own. By analogy, we just suffer a collateral damage in an invisible war (caution: this is an oversimplification of the process!). Like all living things, bacteria have to protect themselves against predators such as protists (amoebae). Some microorganisms do so by turning their repertoire of certain genes on, and, by that, they transform them from passive victims into aggressive fighters. And by coincidence, these same adaptations make them more virulent (better survival advantage and colonization traits) in human bodies. We're just caught in the crossfire! " (in syndication with talkrational.org)

Read the abstract of Adiba et al., below:

To many pathogenic bacteria, human hosts are an evolutionary dead end. This begs the question what evolutionary forces have shaped their virulence traits. Why are these bacteria so virulent? The coincidental evolution hypothesis suggests that such virulence factors result from adaptation to other ecological niches. In particular, virulence traits in bacteria might result from selective pressure exerted by protozoan predator. Thus, grazing resistance may be an evolutionarily exaptation for bacterial pathogenicity.

This hypothesis was tested by subjecting a well characterized collection of 31 Escherichia coli strains (human commensal or extra-intestinal pathogenic) to grazing by the social haploid amoeba Dictyostelium discoideum. We then assessed how resistance to grazing correlates with some bacterial traits, such as the presence of virulence genes. Whatever the relative population size (bacteria/amoeba) for a non-pathogenic bacteria strain, D. discoideum was able to phagocytise, digest and grow. In contrast, a pathogenic bacterium strain killed D. discoideum above a certain bacteria/amoeba population size. A plating assay was then carried out using the E. coli collection faced to the grazing of D. discoideum. E. coli strains carrying virulence genes such as iroN, irp2, fyuA involved in iron uptake, belonging to the B2 phylogenetic group and being virulent in a mouse model of septicaemia were resistant to the grazing from D. discoideum. Experimental proof of the key role of the irp gene in the grazing resistance was evidenced with a mutant strain lacking this gene. Such determinant of virulence may well be originally selected and (or) further maintained for their role in natural habitat: resistance to digestion by free-living protozoa, rather than for virulence per se.

This is an Open Access article and available therefore free of cost from PLoS ONE journal website.

Sunday, August 15, 2010

India-centric Lancet ‘superbug’ story: a murky ‘courier express’ collaboration?

Amid huge media frenzy over the LANCET Infectious Diseases article that appeared on August 11, 2010, there are reasons why India should try retracting the story 'Emergence of a new antibiotic resistance mechanism in India…' (sorry, it's a closed access article despite that it was funded by EU and Wellcome Trust, and you will have to shed ample money to read it in full!). On a quick, editorial read out, it appears that the authors have possibly flouted several pre-publishing requirements:

  1. None of the Indian and other South Asian authors is very well known researcher or clinician (by their publication record); why were they invited for this study and their trips paid out by Pharma players; just for hunting isolates?
  2. Why convenient sampling at tertiary hospitals?
  3. Who cleared transfer of isolates from India to UK? Do Indian hospitals mentioned in the study hold export licenses for classified biological agents? Do they have HMSC [an Indian Council of Medical Research (ICMR) watch-dog] clearances?
  4. Were the culture and antibiotic sensitivity screening protocols approved by biosafety committees at respective Indian centers and hospitals?
  5. Why Hinduja Hospital Team dropped for authorships when there were analyses of isolates presented from Mumbai? How many isolates did Hinduja ship to UK and how?
  6. How the isolates got shipped to UK? Did the first author Kumarasamy carried them over to UK and his trip funded by Wyeth as mentioned?
  7. If my doubts above are genuine, then, should they be overlooked, especially, when the study falls within the ambit of prestigious funding agencies such as EU and Wellcome Trust?

There are additional problems:

(a) No mention of how many isolates supplied by whom? (b) much of the discussion directed towards denting medical tourism in India and the premise based on popular media reports and articles from 'God-forsaken' journals (J Assoc Physician India and J Infect Dev Ctries ) (c) it seems that the involvement of Indian centers was merely for collecting the isolates and such a research collaboration can not be justified. Authorships should not be given just for the isolation of cultures and provision of demographic and patient data.

The above points must be investigated and taken up (by the ICMR and the Indian Health Ministry) with the journal and the Indian institutions/hospitals that cleared implementation of the study. Unless documents supporting ethical and biosafety clearances produced, the journal should be asked to retract the report with apology. Moreover, the ICMR and the Indian agencies should formulate concrete policies on such ad-hoc collaborations which are meant only for hunting and exporting the genetic material and patient isolates.

Sunday, August 8, 2010

GRK1674: German Research Foundation's New International Research Training Group at Freie Universität Berlin/University of Hyderabad

(Press Release)
Research in Collaboration with Indian University of Hyderabad Studies Expression of Infectious Diseases as a Function of Genetic Factors.

The German Research Foundation (DFG) has set up a new international research training group (GRK) at Freie Universität Berlin. The projects of GRK 1673 "Functional Molecular Epidemiology Infection" at the Department of Veterinary Medicine (Speaker, Lothar H Wieler) deal with the factors that determine the severity and the geographic spread of infectious diseases. Among other things, the research deals with the immediate causes of tuberculosis, filariasis, or malaria. The University of Hyderabad in India is the cooperation partner (Speaker, Niyaz Ahmed).
Research at the joint facilities of Freie Universität Berlin, which acts as the host university, and the University of Hyderabad focuses on the areas of host-pathogen genomics and economic analysis of genetic variations. The comparative analysis of infectious diseases in Germany and India will provide information on the pathogen and host factors that influence the disease. "The outstanding expertise of the Indian partner(s) in the areas of bioinformatics and disease cohorts managed in Greater Hyderabad coupled with the extensive expertise of the Berlin partner in infection biology and epidemiology are a wonderful basis for an exciting and successful intercultural collaboration for the benefit of patients," said Professor Lothar H. Wieler, director of the research training group.
The new DFG research training groups offer graduate students an opportunity to complete their doctorates in a structured research and training program at a highly specialized level. "Students of medicine, veterinary medicine, or biology will find excellent conditions at Freie Universität," said Professor Wieler. "Our new international research training center offers outstanding conditions for completing a doctorate in one of these areas." This also means the opportunity to gain international experience: the program at Freie Universität includes a stay in India.
Overall, the DFG has set up 12 new research training groups to further improve conditions for young researchers in Germany. During the first funding period of four and a half years, they are being supported by the DFG with a sum of around 45 million euros. Three of the new facilities are international research training groups, which cooperate closely with foreign universities. The DFG currently funds 219 research training groups, including 55 international ones.