Numerical investigation of motion and deformation of a single red blood cell in a stenosed capillary

It is generally assumed that influence of the red blood cells (RBCs) is predominant in blood rheology. The healthy RBCs are highly deformable and can thus easily squeeze through the smallest capillaries having internal diameter less than their characteristic size. On the other hand, RBCs infected by malaria or other diseases are stiffer and so less deformable. Thus it is harder for them to flow through the smallest capillaries. Therefore, it is very important to critically and realistically investigate the mechanical behavior of both healthy and infected RBCs which is a current gap in knowledge. The motion and the steady state deformed shape of the RBCs depend on many factors, such as the geometrical parameters of the capillary through which blood flows, the membrane bending stiffness and the mean velocity of the blood flow. In this study, motion and deformation of a single two-dimensional RBC in a stenosed capillary is explored by using smoothed particle hydrodynamics (SPH) method. An elastic spring network is used to model the RBC membrane, while the RBC's inside fluid and outside fluid are treated as SPH particles. The effect of RBC's membrane stiffness (kb), inlet pressure (P) and geometrical parameters of the capillary on the motion and deformation of the RBC is studied. The deformation index, RBC's mean velocity and the cell membrane energy are analyzed when the cell passes through the stenosed capillary. The simulation results demonstrate that the kb, P and the geometrical parameters of the capillary have a significant impact on the RBCs' motion and deformation in the stenosed section.

Modified MLVA for genotyping Queensland invasive Streptococcus pneumoniae

Background Globally, over 800 000 children under five die each year from infectious diseases caused by Streptococcus pneumoniae. To understand genetic relatedness between isolates, study transmission routes, assess the impact of human interventions e.g. vaccines, and determine infection sources, genotyping methods are required. The ‘gold standard’ genotyping method, Multi-Locus Sequence Typing (MLST), is useful for long-term and global studies. Another genotyping method, Multi-Locus Variable Number of Tandem Repeat Analysis (MLVA), has emerged as a more discriminatory, inexpensive and faster technique; however there is no universally accepted method and it is currently suitable for short-term and localised epidemiology studies. Currently Australia has no national MLST database, nor has it adopted any MLVA method for short-term or localised studies. This study aims to improve S. pneumoniae genotyping methods by modifying the existing MLVA techniques to be more discriminatory, faster, cheaper and technically less demanding than previously published MLVA methods and MLST. Methods Four different MLVA protocols, including a modified method, were applied to 317 isolates of serotyped invasive S. pneumoniae isolated from sterile body sites of Queensland children under 15 years from 2007–2012. MLST was applied to 202 isolates for comparison. Results The modified MLVA4 is significantly more discriminatory than the ‘gold standard’ MLST method. MLVA4 has similar discrimination compared to other MLVA techniques in this study). The failure to amplify particular loci in previous MLVA methods were minimised in MLVA4. Failure to amplify BOX-13 and Spneu19 were found to be serotype specific. Conclusion We have modified a highly discriminatory MLVA technique for genotyping Queensland invasive S. pneumoniae. MLVA4 has the ability to enhance our understanding of the pneumococcal epidemiology and the changing genetics of the pneumococcus in localised and short-term studies.

Estimating the burden of disease attributable to childhood and maternal undernutrition in South Africa in 2000

OBJECTIVES To estimate the disease burden attributable to being underweight as an indicator of undernutrition in children under 5 years of age and in pregnant women for the year 2000. DESIGN World Health Organization comparative risk assessment (CRA) methodology was followed. The 1999 National Food Consumption Survey prevalence of underweight classified in three low weight-for-age categories was compared with standard growth charts to estimate population-attributable fractions for mortality and morbidity outcomes, based on increased risk for each category and applied to revised burden of disease estimates for South Africa in 2000. Maternal underweight, leading to an increased risk of intra-uterine growth retardation and further risk of low birth weight (LBW), was also assessed using the approach adopted by the global assessment. Monte Carlo simulation-modeling techniques were used for the uncertainty analysis. SETTING South Africa. SUBJECTS Children under 5 years of age and pregnant women. OUTCOME MEASURES Mortality and disability-adjusted life years (DALYs) from protein- energy malnutrition and a fraction of those from diarrhoeal disease, pneumonia, malaria, other non- HIV/AIDS infectious and parasitic conditions in children aged 0 - 4 years, and LBW. RESULTS Among children under 5 years, 11.8% were underweight. In the same age group, 11,808 deaths (95% uncertainty interval 11,100 - 12,642) or 12.3% (95% uncertainty interval 11.5 - 13.1%) were attributable to being underweight. Protein-energy malnutrition contributed 44.7% and diarrhoeal disease 29.6% of the total attributable burden. Childhood and maternal underweight accounted for 2.7% (95% uncertainty interval 2.6 - 2.9%) of all DALYs in South Africa in 2000 and 10.8% (95% uncertainty interval 10.2 - 11.5%) of DALYs in children under 5. CONCLUSIONS The study shows that reduction of the occurrence of underweight would have a substantial impact on child mortality, and also highlights the need to monitor this important indicator of child health.

A computer-controlled hyperthermia system

Hyperthermia, raised temperature, has been used as a means of treating cancer for centuries. Hippocrates (400 BC) and Galen (200 BC) used red-hot irons to treat small tumours. Much later, after the Renaissance, there are many reports of spontaneous tumour regression in patients with fevers produced by erysipelas, malaria, smallpox, tuberculosis and influenza. These illnesses produce fevers of about 40 °C which last for several days. Temperatures of at least 40 °C were found to be necessary for tumour regression. Towards the end of the nineteenth century pyrogenic bacteria were injected into patients with cancer. In 1896, Coly used a mixture of erysipelas and B. prodigeosus, with some success...

The Jean Chretien Pledge to Africa act: Patent law and humanitarian aid

This article evaluates the implementation of the WTO General Council Decision in 2003, which resolved that developed nations could export patented pharmaceutical drugs to member states in order to address public health issues - such as HIV/AIDS, tuberculosis, malaria and other epidemics. The Jean Chretien Pledge to Africa Act 2004 (Canada) provides authorisation for the export of pharmaceutical drugs from Canada to developing countries to address public health epidemics. The European Union has issued draft regulations governing the export of pharmaceutical drugs. A number of European countries - including Norway, the Netherlands, France, and Switzerland - are seeking to pass domestic legislation to give force to the WTO General Council Decision. Australia has shown little initiative in seeking to implement such international agreements dealing with access to essential medicines. It is argued that Australia should implement humanitarian legislation to embody the WTO General Council Decision, emulating models in Canada, Norway, and the European Union. Ideally, there should be no right of first refusal; the list of pharmaceutical drugs should be open-ended; and the eligible importing countries should not be limited to members of the WTO.

Incentives for global public health: Patent law and access to essential medicines

This portrait of the global debate over patent law and access to essential medicines focuses on public health concerns about HIV/AIDS, malaria, tuberculosis, the SARS virus, influenza, and diseases of poverty. The essays explore the diplomatic negotiations and disputes in key international fora, such as the World Trade Organization, the World Health Organization and the World Intellectual Property Organization. Drawing upon international trade law, innovation policy, intellectual property law, health law, human rights and philosophy, the authors seek to canvass policy solutions which encourage and reward worthwhile pharmaceutical innovation while ensuring affordable access to advanced medicines. A number of creative policy options are critically assessed, including the development of a Health Impact Fund, prizes for medical innovation, the use of patent pools, open-source drug development and forms of 'creative capitalism'.

Mauve: How one man invented the colour that changed the world

In an essay, "The Books of Last Things", Delia Falconer discusses the emergence of a new genre in publishing - microhistories. She cites a number of recent titles in non-fiction and fiction - Longitude, Cod, Tulips, Pushkin's Button, Nathaniel's Nutmeg, Zarafa, The Surgeon of Crowthorne, The Potato, The Perfect Storm. Delia Falconer observes of this tradition: "One has the sense, reading these books, of a surprising weight, of pleasant shock. In part, it is because we are looking at things which are generally present around us, but modestly out of sight and mind - historical nitty gritty like cod, potatoes, longitudinal clocks - which the authors have thrust suddenly, like a Biblical visitation of frogs or locusts, in our face. Things like spice and buttons and clocks are generally seen to enable history on the large scale, but are not often viewed as its worthy subjects. And by the same grand logic of history, more unusual phenomena like cabinets of curiosities or glass-making or farm lore or sailors' knots are simply odd blips on its radar screen, interesting footnotes. These new books, microhistories, reverse the usual order of history, which argues from the general to the particular, in order to prove its inevitable progress. They start from the footnotes. But by reversing the process, and walking through the back door of history, you don't necessarily end up at the front of the same house." Delia Falconer speculates about the reasons for the popularity of microhistories. She concludes: "I would like to think that reading them is not simply an exercise in nostalgia, but a challenge to the present". In Mauve, Simon Garfield provides a new way of thinking and writing about the history of intellectual property. Instead of providing a grand historical narrative of intellectual property, he tells the story of a particular invention, and its exploitation. Simon Garfield relates how English chemist William Perkin accidentally discovered a way to mass-produce colour mauve in a factory. Working on a treatment for malaria in his London home laboratory, Perkin failed to produce artificial quinine. Instead he created a dark oily sludge that turned silk a beautiful light purple. The colour was unique and became the most desirable shade in the fashion houses of Paris and London. ... The book Mauve will have a number of contemporary resonances for intellectual property lawyers and academics. Simon Garfield emphasizes the difficulties inherent in commercialising an invention and managing intellectual property. He investigates the uneasy collaboration between industry and science. Simon Garfield suggests that complaints about the efficacy of patent offices are perennial. He also highlights the problems faced by courts and law-makers in accommodating new technologies within the logic of patent law. In his elegant microhistory of the colour mauve, Simon Garfield confirms the conclusion of Brad Sherman and Lionel Bently that many aspects of modern intellectual property law can only be understood through an understanding of the past: "The image of intellectual property law that developed during the 19th century and the narrative of identity which this engendered played and continue to play an important role in the way we think about and understand intellectual property law".

The race to patent the SARS virus: The TRIPS agreement and access to essential medicines

This article considers the race to sequence the Severe Acute Respiratory Syndrome virus ('the SARS virus') in light of the debate over patent law and access to essential medicines. Part II evaluates the claims of public research institutions in Canada, the United States, and Hong Kong, and commercial companies, to patent rights in respect of the SARS virus. It highlights the dilemma of ’defensive patenting' - the tension between securing private patent rights and facilitating public disclosure of information and research. Part III considers the race to patent the SARS virus in light of wider policy debates over gene patents. It examines the application of such patent criteria as novelty, inventive step, utility, and secret use. It contends that there is a need to reform the patent system to accommodate the global nature of scientific inquiry, the unique nature of genetics, and the pace of technological change. Part IV examines the role played by the World Trade Organization and the World Health Organization in dealing with patent law and access to essential medicines. The article contends that there is a need to ensure that the patent system is sufficiently flexible and adaptable to accommodate international research efforts on infectious diseases.

The Doha deadlock: Intellectual property and climate change

In November 2001, Doha hosted trade talks over intellectual property and public health. The discussions resulted in the landmark Doha Declaration on the TRIPS Agreement and Public Health. The Doha Declaration recognised “that the TRIPS Agreement does not and should not prevent members from taking measures to protect public health” - particularly in relation to HIV/AIDS, tuberculosis, malaria and other epidemics.

Investigating the population structure of Queensland invasive Streptococcus pneumoniae isolates in children: Using a modified multi-locus variable number of tandem repeat analysis and a novel minimum SNPs capsular typing method

This research investigated the use of DNA fingerprinting to characterise the bacteria Streptococcus pneumoniae or pneumococcus, and hence gain insight into the development of new vaccines or antibiotics. Different bacterial DNA fingerprinting methods were studied, and a novel method was developed and validated, which characterises different cell coatings that pneumococci produce. This method was used to study the epidemiology of pneumococci in Queensland before and after the introduction of the current pneumococcal vaccine. This study demonstrated that pneumococcal disease is highly prevalent in children under four years, that the bacteria can `switch' its cell coating to evade the vaccine, and that some DNA fingerprinting methods are more discriminatory than others. This has an impact on understanding which strains are more prone to cause invasive disease. Evidence of the excellent research findings have been published in high impact internationally refereed journals.

Clinical factors associated with the humoral immune response to influenza vaccination in chronic obstructive pulmonary disease

Background and objective Individuals with chronic obstructive pulmonary disease (COPD) are at a high risk of developing significant complications from infection with the influenza virus. It is therefore vital to ensure that prophylaxis with the influenza vaccine is effective in COPD. The aim of this study was to assess the immunogenicity of the 2010 trivalent influenza vaccine in persons with COPD compared to healthy subjects without lung disease, and to examine clinical factors associated with the serological response to the vaccine. Methods In this observational study, 34 subjects (20 COPD, 14 healthy) received the 2010 influenza vaccine. Antibody titers at baseline and 28 days post-vaccination were measured using the hemagglutination inhibition assay (HAI) assay. Primary endpoints included seroconversion (≥4-fold increase in antibody titers from baseline) and the fold increase in antibody titer after vaccination. Results Persons with COPD mounted a significantly lower humoral immune response to the influenza vaccine compared to healthy participants. Seroconversion occurred in 90% of healthy participants, but only in 43% of COPD patients (P=0.036). Increasing age and previous influenza vaccination were associated with lower antibody responses. Antibody titers did not vary significantly with cigarette smoking, presence of other comorbid diseases, or COPD severity. Conclusion The humoral immune response to the 2010 influenza vaccine was lower in persons with COPD compared to non-COPD controls. The antibody response also declined with increasing age and in those with a history of prior vaccination.

Evaluation of immune responses to influenza vaccination in chronic obstructive pulmonary disease

Background: Given that viral infections are common triggers for exacerbations of Chronic Obstructive Pulmonary Disease (COPD), current clinical guidelines recommend that all patients receive annual influenza vaccinations. A detailed examination of the immune response to vaccination in COPD has not previously been undertaken, so this study aimed to compare immune responses to influenza vaccination between COPD patients and healthy subjects. Methods: Twenty one COPD patients and fourteen healthy subjects were recruited and cellular immune function was assessed pre- and post- vaccination with trivalent inactivated influenza vaccine. Results: One month after vaccination, H1N1 specific antibody titres were significantly lower in COPD patients than in healthy controls (p=0.02). Multivariate analysis demonstrated that post vaccination antibody titres were independently associated with COPD, but not with age or smoking status. Innate immune responses to the vaccine preparation did not differ between the two populations. Serum concentrations of IL-21, a cytokine that is important for B cell development and antibody synthesis, were also lower in COPD patients than in healthy subjects (p<0.01). In vitro functional differences were also observed, with fewer proliferating B cells expressing CD27 (p=0.04) and reduced T-cell IFN-γ synthesis (p<0.01) in COPD patients, relative to healthy subjects. Conclusions: In conclusion, COPD was associated with altered immune responses to influenza vaccination compared to healthy controls with reductions in both T-cell and B-cell function. These findings provide a foundation for future research aimed at optimising the effectiveness of influenza vaccination in COPD.

Adaptive immunity to rhinoviruses: Sex and age matter

Background: Rhinoviruses (RV) are key triggers in acute asthma exacerbations. Previous studies suggest that men suffer from infectious diseases more frequently and with greater severity than women. Additionally, the immune response to most infections and vaccinations decreases with age. Most immune function studies do not account for such differences, therefore the aim of this study was to determine if the immune response to rhinovirus varies with sex or age. Methods: Blood mononuclear cells were isolated from 63 healthy individuals and grouped by sex and age (≤50 years old and ≥52 years old). Cells were cultured with rhinovirus 16 at a multiplicity of infection of 1. The chemokine IP-10 was measured at 24 h as an index of innate immunity while IFNγ and IL-13 were measured at 5 days as an index of adaptive immunity. Results: Rhinovirus induced IFNγ and IL-13 was significantly higher in ≤50 year old women than in age matched men (p < 0.02 and p < 0.05) and ≥52 year old women (p < 0.02 and p > 0.005). There was no sex or age based difference in rhinovirus induced IP-10 expression. Both IFNγ and IL-13 were negatively correlated with age in women but not in men. Conclusions: This study suggests that pre-menopausal women have a stronger adaptive immune response to rhinovirus infection than men and older people, though the mechanisms responsible for these differences remain to be determined. Our findings highlight the importance of gender and age balance in clinical studies and in the development of new treatments and vaccines.

Antimicrobial treatment of non-cystic fibrosis bronchiectasis

Bronchiectasis unrelated to cystic fibrosis is characterized by chronic wet or productive cough, recurrent exacerbations and irreversible bronchial dilatation. After antibiotics and vaccines became available and living standards in affluent countries improved, its resulting reduced prevalence meant bronchiectasis was considered an ‘orphan disease’. This perception has changed recently with increasing use of CT scans to diagnose bronchiectasis, including in those with severe chronic obstructive pulmonary disease or ‘difficult to control’ asthma, and adds to its already known importance in non-affluent countries and disadvantaged Indigenous communities. Following years of neglect, there is renewed interest in identifying the pathogenetic mechanisms of bronchiectasis, including the role of infection, and conducting clinical trials. This is providing much needed evidence to guide antimicrobial therapy, which has relied previously upon extrapolating treatments used in cystic fibrosis and chronic obstructive pulmonary disease. While many knowledge gaps and management challenges remain, the future is improving for patients with bronchiectasis.

Acute infectious diarrhea lessons learned from the past?

The Journal of Pediatric Gastroenterology and Nutrition (JPGN) has been at the forefront of many of the seminal advances into research on infectious diarrhea. In 1982, the first article of the JPGN was entitled “Oral Therapy for Dehydration in Diarrheal Diseases as a Global Problem” and has set the scene for several thousand subsequent articles. In his initial editorial, Finberg (1) posed several questions, which still have relevance 30 years later: 1. When is oral rehydration not appropriate, if ever? 2. What should be the composition of the oral solution and should there be more than one? 3. Should recommended practice be different in lesser-developed countries from those in developed countries? 4. Should the salts and glucose be prepackaged or should home supplies be used by instructed mothers? 5. When should standard feedings be resumed?