Friday, 23 December 2011

Layman's Description of Gene Therapy to Treat Genetic Disorders

People, often children, that live with some genetic disorders are vulnerable to infection by Aspergillus. Chronic Granulomatous Disorder and Cystic Fibrosis are two such disorders but there are more.

This video is aimed at patients & carers of people who live with genetic disorders and decribes how new Gene Therapy techniques aim to provide new treatments for these illnesses.

Wednesday, 21 December 2011

Air-borne Fungi are More Diverse Than We Thought

Sir Alexander Fleming receiving the Nobel Prize in 1945
 The fungus Sir Alexander Fleming isolated (his famous 'lucky' observation) in 1928 which was the first step in the process that brought us antibiotics, and for which Fleming won the Nobel Prize is in the news once again. That fungus was intensively studied 80 years ago and identified as Penicillium chrysogenum and then put into storage.

The Imperial College team
Modern techniques for the identification of fungi are far superior to those available in the 1930's & 40's and a research group at his original place of work St Mary's College - now part of Imperial College, London have shown that those that identified Fleming's fungus got it slightly wrong but in the process have revealed to us a far more complex picture of this fungal species that we realised existed.

It turns out that Flemings isolate is not P. chrysogenum but is a very closely related species which has yet to be named. The species P. chrysogenum is in fact a group of four closely related species.

This discovery highlights that fungi are extremely diverse micro-organisms - as soon as you think you have one categorised several more subgroups are found. It also highlights the importance of understanding this diversity as after Fleming's initial observation many thousands of isolated of P.chrysogenum were analysed for their ability to produce penicillin and only after a lot of work was a suitable isolate found to work on an industrial scale. If they had known then what we know now perhaps that would have been more easily achieved.

For the future our new understanding of fungal biodiversity (including that of Aspergillus) may well lead to new drugs and products.

Friday, 16 December 2011

Patients Die as Aspergillosis is Misdiagnosed as Tuberculosis

Progressive appearance of lung cavities caused by Tb
Tuberculosis (Tb) has a long and terrible history as mankind has fought it for hundreds if not thousands of years. Before the advent of antibiotics it killed millions of people and animals when it was commonly referred to as 'consumption'. 200 years ago it accounted for one in four of all deaths in England, but by the 1980's that had fallen to 5000  deaths per year. More recently that number has started to slowly  rise as the infectious bacteria (Mycobacterium tuberculosis) started to acquire resistance to the antibiotics used against it.

Despite all these advances Tuberculosis today infects or has infected one third of the population of the world (though not all go on to develop Tb) and new infections occur roughly one every second!

Precisely because Tb is such a common infection doctors have to cope with huge numbers of patients, particularly in the developing world. There is a well established routine once doctors see a typical chest X-ray - give antibiotics and continue to monitor and little more is done about it - but unfortunately there is a hidden killer lurking that effects over 1 million people throughout the world.

Macrophage eating Tuberculosis bacteria
Chronic Pulmonary Aspergillosis (CPA) is a fungal disease that can grow in damaged parts of our lungs, evading our immune systems using scar tissue as a 'shield' to avoid detection. It looks very like, or is identical to Tb when doctors look at it on a chest X-ray and has very similar symptoms initially. Doctors mistake it for Tb and prescribe antibiotics as is standard practice.
Unfortunately fungi (e.g. Aspergillus fumigatus) that are as at home in the warm recesses of our lungs as they are in their more natural habitat of compost heaps are not effected by antibiotics and overmore are helped if the patient has poor body weight, diabetes, smokes or has AIDS. If not given correct treatment (antifungal medication) the prognosis is that 50% of those infected will die inside 5 years.

This recent article attempts to highlight this deadly problem and to ask for doctors to look a little more closely at their cases of Tb and how they progress and to consider Chronic Pulmonary Aspergillosis as a real alternative diagnosis. more...

Wednesday, 14 December 2011

Newsbite: Aspergillus hazardous problem in ceramic workers

Ceramic workers are at a high risk of developing respiratory problems as they are exposed to high levels of respirable dust containing silica and high microbial counts, including high Aspergillus counts.
The aim of the study was to study the percentage of ceramic workers with positive Aspergillus (A.) through polymerase chain reaction (PCR) and specific IgE (sIgE) for the different Aspergillus species. PCR and specific IgE (sIgE) for the different Aspergillus species (A. flavus, A. fumigatus and A. niger) were estimated in 40 ceramic workers and 56 control subjects.
 Results revealed that 32.5% of the workers’ sputum was PCR positive for Aspergillus. About 69.2% of them were A. flavus positive, 15.4% A. niger positive, 7.7% A. fumigatus positive and 7.7% A. flavus and A. fumigatus positive. more...

Friday, 9 December 2011

Beep! Beep! Defining the Fungal Barcode for Aspergillus

Many species of fungi including Aspergillus are very difficult to distinguish from one another. They can lack distinct structures, many having very simple forms and many lack sexual forms thus removing one long standing method used to distinguish species from each other i.e. their ability to interbreed.

A more modern way to distinguish species is to look at their DNA sequence. We have started to sequence entire genomes (the complete DNA sequence of an organism) but as yet this is still quite slow and requires a lot of effort and money to carry out - there has to be a quicker, cheaper, more flexible way to tell one species from another.

The ability to distinguish Aspergillus species is very important for several reasons including:

  • to distinguish between medically important (i.e. potentially dangerous) and unimportant (safer) Aspergillus species in the air, in a clinic, in homes, in our lungs
  • to distinguish between species likely to produce mycotoxin when growing on food or growing in damp buildings
  • to improve taxonomy for scientific identification, speed up research, we will get a better idea of the numbers of different species in our environment e.g. in our drinking water
DNA barcoding is a quick, cheap method than can be used on large numbers of samples in a short time. It is a powerful 'quick screen' once you have identified a series of short DNA sequences that are unique to each  species. Short DNA sequences are easy to work with and require minimal equipment to look at, all of which would be portable or available in a small laboratory at little cost - this makes this technique attractive to people working away from large laboratories, and in poorer countries - in other words the vast majority of the world.

Fungal barcoding is an ongoing research effort but a recent news report suggests that breakthroughs have been made in the search for unique short sequences in fungi including Aspergillus species. Reports at the recent International Barcode of Life conference in Australia suggest that an area of the genome of most fungi contains DNA sequences that are unique in most species. More work is yet to be done to make this discovery useful to us all but this is a big step forward.

Thursday, 8 December 2011

Special notice: Take Care with your Christmas Tree to Avoid Aspergillus

It is worth reminding everyone at this time of year of a study published in 2007 on the amount of mould spores brought into the home by people who purchase freshly cut Christmas trees to decorate for the holiday period. There is no problem for a few days but as the tree starts to die and deteriorate it was shown to be responsible for the production of many thousands of spores - it is after all slowly dying plant tissue which forms the main course of any Aspergillus meal.

If you must have a cut tree and you are sensitive to Aspergillus or other moulds, or perhaps you are immunocompromised and vulnerable to infection then ensure your tree is freshly cut, install it a few days before Christmas and remove it after Boxing Day! more...

Wednesday, 7 December 2011

Newsbite: Keep Your Wild Birds free from Aspergillosis

At this time of year in the Northern Hemisphere it is common for millions of people to feed wild birds in their gardens in order to enjoy seeing their antics. It is important to keep all feeders clean and dry and food fresh in order to avoid moulds including Aspergillus growing on the foods as the birds can be poisoned by toxins produced by mouldy food. There is also a possibility, especially when they are stressed in poor weather or after long flights of birds contracting aspergillosis after inhaling spores. more...

Friday, 2 December 2011

Over a Million Cases of Chronic Pulmonary Aspergillosis Misdiagnosed and Untreated

Press release from the National Aspergillosis Centre: 

Researchers have discovered that over a million people worldwide diagnosed with TB go on to develop an incurable but manageable fungal infection which is usually left untreated because it is mistaken for a recurrence of the disease.

In a new report published today*, the researchers from University of Manchester (UK) and University of Toronto (CA), say because the X-ray features and symptoms are so similar doctors often misdiagnose and prescribe the wrong treatment which can lead to tens of thousands of unnecessary deaths. The fungal infection responsible, chronic pulmonary aspergillosis (CPA), evades the immune system in the lungs progressing slowly and may lie undetected for years until symptoms (weight loss, tiredness, coughing and bleeding) start to develop. By then it is often too late to treat successfully. 50 per cent of all patients who develop it are unlikely to survive for more than five years, a similar outlook to many cancers.

Now, the report’s authors are calling on the World Health Organisation and others to provide awareness training, particularly for medics in Africa, India and China where under diagnosis of CPA is even more common than in Western countries because of the burden of TB.

The team was led by Professor David Denning, Director of the National Aspergillosis Centre at the University Hospital of South Manchester. He says the report highlights huge global variations in frequency and survival (see the table below). “For example, only 17 per cent of referred CPA patients in Manchester had underlying TB compared with 93 per cent in Korea. This variation reflects differences in diagnosis and inappropriate therapy – or none at all. Identifying CPA early in patients is only possible by means of
microbiological testing for Aspergillus antibodies.”

Professor Donald Cole, Associate Professor & Division Head of Global Health at the University of Toronto’s Dalla Lana School of Public Health is an expert in environmental and public health. He believes doctors have probably underestimated the worldwide burden of CPA. “We based our estimates on WHO data but the information is robust in some countries but not others. Under reporting is common, especially in countries such as China.”

Professor Ian Jacobs is Director of MAHSC – a partnership between the NHS in Manchester and the University of Manchester - and has recently included global health as a focus for its work. He is backing the call for WHO and the leaders of countries in Asia and Africa to take action. “TB is a major scourge worldwide, and to find that over a third of a million people each year then develop an incurable and ultimately fatal fungal complication – which could be diagnosed and treated – demands action. It must also follow that misdiagnosis of TB must be common with patients dying of chronic fungal infection of the lung.”

Notes to Editors

About Aspergillosis

Aspergillus is an airborne fungus that everyone breathes in daily. In those who are immunosuppressed, for example, those undergoing organ transplantation or treatment for haematological malignancies it causes a disease called invasive aspergillosis (IA)). In those with damage in their lungs such as tuberculosis or COPD, it can cause chronic pulmonary aspergillosis a slowly progressive and destructive disease of the lungs. In those with asthma or cystic fibrosis it can cause an allergic condition of the lungs with wheeze, mucous plugging of the airways and loss of lung function called allergic pulmonary aspergillosis.
There are estimated to be over 200,000 IA cases annually worldwide and over 10M patients at risk. Mortality rates vary by patient group ranging from 30% to 85%. For CPA there are estimated to be over 3M cases (as demonstrated in part by this report). For ABPA in asthma there are estimated to be over 4M patients worldwide.

NewsBite: Anti-Malarial Drug Works Well as an Antifungal

Artemesinin, an antimalarial drug, have previously been reported as having some antifungal activity. Gautam et. al. have attempted to identify its molecular targets and have found it has an synergistic relationship with itraconazole, such that together they work better than either apart. This could well be a hint that the target for this antifungal activity is novel and functionally different from currently available antifungal drugs, thus making it a   potential startpoint for a new class of antifungal drugs. more...

Tuesday, 29 November 2011

Aspergillus and Bacteria Team Up

Bacteria and fungi have often been traditionally suspected as being foes competing for the same food resources in their natural environment. Many antibiotics (e.g. Penicillin) for example are antibacterial substances synthesised by fungi, thought by many to be one way that fungi can beat their bacterial competitors to a meal.

It has now been suggested that that impression is too simplistic. Ingham et .al. has shown that Aspergillus fumigatus, a fungus important for the degradation of dead plant material (e.g. compost heaps) and which has an important impact on human health (e.g. aspergillosis), seems to work closely with a highly motile bacterium Paenibacillus vortex.

Paenibacillus is very able at moving over solid surfaces and forms characteristic swarms

Paenibacillus is very adept at moving but cannot travel across gaps, whereas Aspergillus is more than capable of bridging gaps. Aspergillus tends to use up all available nutrients in one place and then stop and sporulate. It then requires 'help' to transport its spores to another substrate and the best known of these is via air currents but that may not be available and is a wasteful process with many spores landing in areas where growth is not possible.

Aspergillus growing across gaps
Paenibacillus is demonstrated in this paper to be able to transport Aspergillus fumigatus spores from locations where there are few nutrients available to new areas where nutrients are plentiful, and where there are antibiotics present which will inhibit the growth of competing bacteria. The speed of movement is around 8cm per hour. 
  • Paenibacillus will not do this for other particles similar in size to Aspergillus spores.
  • Other swarming bacteria where tested and were found not to transport A. fumigatus spores.
  • Paenibacillus will not transport the spores of other fungi similar to A. fumigatus as efficiently as they do for A. fumigatus.
P. vortex flagella 'gripping' A. fumigatus spores during transport
It seems that we are left with a conclusion that P. vortex and A. fumigatus have developed a cooperative symbiotic relationship whereby the efficient spread of each is reliant on the other and each expends energy on behalf of the other when there is no apparent direct advantage for itself.

Friday, 25 November 2011

Newsbite: A Rare Aspergillosis Mimic

Myceliophthora thermophila is a thermophilic mould widely found in the environment
but rarely responsible for human infections. We describe a case of invasive Myceliophthora
thermophila infection mimicking invasive aspergillosis in a neutropenic patient
with haematological malignancy. Cross-reactivity with Aspergillus galactomannan assay
(GM) was demonstrated by repeated positive results and confirmed by cross-reaction
between the fungal isolate and the GM assay. The patient was successfully treated with
voriconazole. Potential GM cross-reactivity must be considered in future studies including
patients categorized as having probable invasive aspergillosis using the GM as the
only mycological criterion. more...

Thursday, 24 November 2011

New Machine gives Asthmatics Relief as they Sleep

National and international media are reporting a new alternative for relief from symptoms of asthma has been granted scientific approval by a recent paper in the journal Thorax.

Asthmatics often suffer from coughs and wheezes at night and current medication involves 2 expensive drugs that must be used frequently.  It has been previously noted that night-time exposure to allergens is particularly important when trying to prevent asthma symptoms at all times of the day and night and there have been several attempts to provide relief by filtering out allergens from the air that a sleeping person is breathing.
Prof Warner pointed to other research suggesting night time allergen exposure has the greatest impact on symptom severity, possibly because of changes in circulating hormone levels and immune responsiveness prompted by the body's internal clock, or circadian rhythm.
None of those attempts were conclusively found to provide relief from symptoms.

The new treatment is a machine made by the Swedish company Airsonnett that simply provides a flow of cooled, filtered air around the sleeping person - the Protexo. This airflow seems to prevent allergens being breathed in by the sleeping person and thus prevents asthma triggers.  Symptom reports by the patients are lower and clinical tests show key clinical markers for asthma have reduced.

Comparing this machine with identical dummy machines has conclusively shown that they work, and they work as well as the two drugs that are currently used to provide relief. This is the first time a treatment strategy that does not involve drugs has been shown to work as well as this.

This non-invasive technique could be useful for a wide range of patients including those who suffer from allergy to molds such as Aspergillus (often the most severe cases of asthma). The machines are not currently available for use in the home but their cost is already far less than the average spend on keeping asthmatic patients stable so they should be cost effective in the home once available.

Thursday, 17 November 2011

Expert Assessments for Off-Label Medicine use

Medications are subject to tight regulation in most parts of the world whereby a particular drug, the group of patients it is used on and they way it is administered must be approved by a governing body prior to its marketing for use. Once authorised the specifics of its use (age group, dose, route of administration etc.) are written into the pack notes for reference by doctors and these form a useful check for the doctor that he/she is using the drug correctly.

In a field of rare diseases such as aspergillosis there is often a serious lack of fully tested and authorised medications for use by doctors. This leads directly to the use of medications which are not authorised to treat the disease, or are not authorised for use in a particular patient group or for use in a particular way - this is referred to as off-label use. This is completely legal in many countries as long as it is carried out by doctor as phsicians have the legal power to do so - they are however doing so without the authorised guidelines and must use their own experience and judgement.

For example the current approval in the US for the use of the antifungal voriconazole is as follows:

Vfend [voriconazole] has been approved by the FDA for the treatment of deadly fungal infections. The medication is indicated for the primary treatment of acute invasive aspergillosis.
The approval in the EU by the European Medicines Agency is very similar. Note that no mention is made of treating chronic aspergillosis, a purpose for which it is used every day by many patients. Likewise itraconazole is not approved for use in allergic broncho-pulmonary aspergillosis (ABPA), or severe asthma with fungal sensitivity (SAFS) for which it has proven benefit.

The central problem seems to be that formal approval is so complicated it takes a very long time to be granted, even when there are excellent cases for approval.

This situation is less than ideal and the UK NHS have decided to begin providing expert assessments for off-lable drug use via the National Institute for Clinical Excellence (NICE). The principle will be to provide a summary based on current available evidence which doesn't replace formal guidence but will support local decision making. Read more here.

Wednesday, 16 November 2011

Aspergillosis and Congenital Immune Deficiencies - What we learn

Some of the many genetic deficiencies of our immune systems
Children with congenital immune deficiencies have been born having lost specific parts of their immune system and are thus vulnerable to infection by a number of infecting microrganisms.
At first thought we might think that such children are infected by any passing germ, and as such they become infected by the first microrganism that comes their way but this is not the case. Some immune deficiencies predispose children to one type of infection by a particular micro-organism and while others do not seem to be vulnerable to that 'bug' and instead are predisposed to other infections.

Why is this? Each genetic deficiency effects different parts of the immune system leaving some parts still active, so by looking at the species that can most commonly infect we can gain information on which parts of the immune system are most important for resisting each infecting organism and the types of infection. This principle is summarised in some detail in a recent paper by Bustmante where they review the patterns of fungal infections in children with congenital immune deficiencies.

Those parts of the immune system that are revealed to be particularly important for resisting infection by Aspergillus are phagocytes (mutated in Chronic Granulomatous Disorder, CGD) and more specifically their ability to produce superoxide ions. This presumably is one part of our immune systems that Aspergillus is partucularly sensitive to. This discovery of an Aspergillus infection of the lung of a young child and a clinical presentation of a granuloma seems to be a strong enough to point to a diagnosis of CGD if it is not already susected, so close is the association between this pathogen, infection of young children and CGD.

Another genetic defect strongly associated with serious Aspergillus infection is Hyper IgE syndrome. Here we see mutations in STAT3, a gene responsible for turning other genes off and on. This is a particularly complicated disorder as STAT3 respnonds to stumili from many different genes - it is a kind of central signalling post for a whole variety of systems, one of which is the immune system. Its involvement in our immune system is illustrated by one of the first noted featured of this syndrome - sufferers overexpress at least one part of their immune system - the IgE part. Normally a fast response system for infection IgE is designed to be produced quickly and then just as quickly fade away as more procise parts of the immune system take over the job of fighting the infection - it could be partly described as a broadly effective attack on infection that buys our bodies enough time for the slower but more effective parts of our immune systems to become fully activated.

The fact that Aspergillus can infect children that cannot control production of IgE might be another clue that IgE control is important for our resistance to Aspergillus, but as several (many) other genes are also involved we cannot yet come to such a clear conclusion.

These defects are giving us clues as to how Aspergillus and many other fungal infections (e.g.  Candida) can get past our normally efficient immune systems. The study of the defects will give us more clues in the future, and hopefully also give us ways to better treat children with these disorders.

Friday, 11 November 2011

Newsbite: MycAssay Shows Promise for the Rapid Detection of Invasive Aspergillosis

MycAssay (Lab21) was utilised among a mixed population of 158 patients with underlying haematological or critical illness, in order to assess its reliability and performance compared with clinical diagnosis and conventional diagnostic tests.

Analysis of bronchoalveolar lavage samples showed that MycAssay Aspergillus offers sensitive and specific detection capabilities, performing better than other assays and showing marked superiority to culture-based methods. more...

Tuesday, 8 November 2011

Aspergillus Catches a Cold

Can Aspergillus catch the equivalent of 'flu? Apparently it can as reported in a new paper published recently.  Several Aspergillus fumigatus isolates have been shown to be infected with mycovirus. They were 'cured' of infection and then re-infected to prove that there was a virus passing between the different isolates. Once 'cured' the fungus had a different growth rate and appearance. When re-infected they took on the same appearance that they had had prior to 'curing'.

On left - 'cured'           On right virally infected

Interestingly those isolates that were infected showed a number of physical changes including poorer growth - they grew less well in several different types of growth media, so this suggests that the virus disables the fungus to some extent.

We know that mycovirus' cannot infect humans so perhaps here is a potential route for treatment of people with chronic infections by Aspergillus fumigatus? One thought is that if we could use these viruses to infect the fungus growing in the lungs or sinus' of people living with aspergillosis then we might be able to reduce the pathogenicity or virulence of the resident fungus with little damage to the host? This may help us resist the infection.

Another possibility is to genetically engineer a mycovirus so as to make it a deadly agent we could use against the fungus. The virus can only infect the fungus so the toxin would only be present in the fungus and not in the surrounding tissues of the human host - this is particularly attractive in the case of fungi that have become resistant to antifungal drugs as there is no known resistance in fungi to mycovirus infection and it would represent the opening of a whole new route of attack against the fungus.

Does this sounds a bit unlikely? Not really. In fact there are already extensive research efforts underway to do precisely this and to try to selectively transport antifungal toxins into fungi using mycovirus - see van de Sande et. al. 2011. Who knows? perhaps using a natural pathogen of fungi will help us overcome many of their defences, reduce our exposure to toxic drugs and act as the 'magic bullet' of the future to help us fight off these insidious invaders.

Monday, 7 November 2011

Obituary: The contribution of John Pateman to Fungal Genetics

1965 Photo of Pateman's colleagues taken by himself
Professor John Arthur Pateman FRS died on 18th May 2011. He was a PhD student of John Fincham at Cambridge University.
Professor Pateman played a large part in our understanding of fungal genetics, in particular the process by which gene products from two separate fungal nuclei can complement each other within the cell to partially restore wild-type function - known as complementation. His work in the 1950's and 60's helped define what we know as a gene.
For information on more figureheads of Aspergillus research, refer to our Hall of Fame.

Thursday, 3 November 2011

Newsbite: The First Case of Onychomycosis due to Aspergillus nomius

Onychomycosis (infection of the nails) accounts for more than 50% of nail disorders and is commonly caused by the fungi Aspergillus flavus, A. terreus, A. niger, A. fumigatus and A. nidulans. Also commonly caused by the fungi Fusarium, Acremonium and Scopulariopsis, but never before recorded as an infection of the Aspergillus species nomius.
There were 48 species of Aspergillus recorded as being pathogenic out of over 700 recorded species names, this latest find increases that number to 49. more...

Wednesday, 2 November 2011

The Steph Smith Appeal: Pre-race relaxation

The Steph Smith Appeal: Pre-race relaxation: Saturday 15 th Oct On arrival at the rather unconventional Bagdogra airport we were hurried into an awaiting jeep by the race organisers. ...

Tuesday, 1 November 2011

Newsbite: Farmers Should Take Care Handling Contaminated Grain

At this time of year in some parts of the world there are large harvests of grain, including the US. In some areas the grain can become contaminated with aflatoxin after growth of Aspergillus in some parts of a field - it is difficult to predict where  as Aspergillus tends to infect crops that have become stressed, often by drought and/or insect damage.

Contamination is detected in most parts of the developed world by tests run by government agencies  responsible for ensuring food is of good quality and of course grain buyers can also run their own tests. If a farmer finds out he has a contaminated batch of grain he has a few options, depending on the extent of the contamination, but often the grain must be disposed of.

This report suggests that in the past the grain has been simply dumped outside - perhaps on a spare bit of land or in a landfill site. The report warns that this makes the contaminated grain highly available to wildlife for whom the toxic grain is fatal. Adding to the problem is the large number of hungry migrant birds passing through many areas at the time of year. Farmers are being asked to ensure that any contaminated grain is not available to passing wildlife. more...

Monday, 31 October 2011

Newsbite: Lewis Successfully Completes his Himalayan Challenge for the Fungal Research Trust

Aaron McKevitt and Lewis Fraser successfully completed their 100mile, 12 000 feet of climbing challenge on behalf of the Steph Smith Appeal for the Fungal Research Trust well within the 5 days required. That is the equovalent of running 4 marathons one after the other while at the same time climbing Ben Nevis ( the highest peak in Britain) nearly 3 times - and all of this starting at 6000ft of altitude.

At 6000 feet of altitude people standing still are at risk from altitude sickness if they are not acclimatised as the amount of oxygen present in the air is down to 18% (it is 21% at sea level). Aaron & Lewis touched 12000 feet at some parts of the challenge where there is only 15% oxygen in the air.

Read their Tweets here:

Lewis Fraser

Up at 0430 tomorrow to start the first leg- 24miles up hill to 11500ft.
17 Oct

Lewis Fraser

0430 is early. Here goes everything
Lewis Fraser

Day 3 complete. First marathon complete after a 44mile run the previous 2 days. Only 30 miles to go.
20 Oct
Lewis Fraser

Day 1 was a killer!! 24 miles and a 10000ft ascent. Suffered from altitude sickness. Had to stop every 30m or so to catch my breath.
20 Oct
Lewis Fraser

Half marathon starts in an hour and it's raining. I thought the monsoon season was over. :0(
21 Oct
Lewis Fraser

Day 4 complete. Got very wet and I have a dodgy knee. Had to use my walking poles as crutches. Only 17 miles to do tomorrow. :0)
21 Oct
Lewis Fraser

Finally the last day is here. Only 7 more hours an it will all be over.
22 Oct
Lewis Fraser

It's all over. 100 mile Himalayan stage race complete. It's been emotional, thanks everyone for all your support.
22 Oct
Please support this outstanding effort and help us provide researchers for the diagnosis of aspergillosis






Thursday, 27 October 2011

Concentration of antifungal agents within host cell membranes

  1. Posaconazole has been used successfully for preventing invasive fungal infections in at risk patients, despite it giving relatively low serum concentrations. However, high tissue levels of this agent have been reported in treated patients.

  2. A recent study has tested the theory that it is the intracellular levels of posaconazole which are important for determining the success of this antifungal for prophylaxis. see Campoli et al

  3. By exposing endothelial cells to posaconazole or itraconazole, then removing any extracellular drug, prior to allowing infection with various fungal species - they were able to inhibit growth of A. fumigatus for at least 48 hours and the cells were protected from damage caused by infection. Cell-associated posaconazole levels were 40 to 50-fold higher than extracellular levels and the drug was predominantly detected in cellular membranes. Fungistatic levels of posaconazole persisted within epithelial cells for up to 48 hours.

    The protective effect was not possible for antifungals other than posaconazole and itraconazole. The study suggests that the concentration of posaconazole in the cellular membranes is responsible for its effectiveness when used as a prophylactic drug, and explains the discrepancy between serum levels of these drugs and their effectiveness.
  4. Measurement of the pharmacokinetics of the cellular and membrane fractions respectively- may enable the refinement of dosing strategies to enhance action of the drugs whilst minimising exposure to the antifungal agent.

Friday, 21 October 2011

Marine Aspergillus species produce substances which can protect liver cells from alcohol damage

A number of Aspergillus species produce substances of great commercial use to mankind. For example A. niger is used to produce citric acid and A. oryzae and A. sojae are used to make miso and soya sauce.

It now seems that some aspergillus species also may produce substances which can protect the liver from alcohol related damage as reported by Xian et al .
Alcohol is metabolised in the liver but excess alcohol can lead to acute and chronic liver diseases such as hepatitis, cirrhosis, fatty liver and liver cancer. The problem is even more concerning, as alcohol abuse can lead to other organ failures and damage including the heart, pancreas, immune system and reproductive system. There is much evidence indicating that oxidative stress by reactive nitrogen and oxygen molecules is harmful to the liver, whilst ethanol stress causes a decrease in the antioxidative function of liver cells rendering them susceptible to damage in this way.

All aspergillus species produce metabolites of a diverse nature. A particular Aspergillus species derived from a marine brown algae - produces two such metabolites - emodin and chrysophanol, which have now been shown to protect liver cells from ethanol toxicity, when studied in a lab culture system. By measuring a number of different markers of oxidative stress in a well studied liver cell line - it was shown that emodin and crysanophol were able to inhibit an enzyme - gamma glutamyl transferase - produced in reponse to alcohol damage of liver cells.

Potentially these aspergillus derived substances may be of therapeutic benefit in protecting the liver from alcohol damage and may be of use commercially.

Tuesday, 18 October 2011

Newsbite: Lewis & Aaron begin their Himalayan Challenge

Tue 18th Oct (Race Day 1) 24 miles
We depart Mikik at 0530!! A 1.5 hour drive will take us to the start of the race at 6600ft.  The race starts at 0730, after a Tibetan ceremony blessing all participants.  We will run 24 miles to Sandakphu (11815ft).  Sleeping arrangements for the run are sleeping bags and we will be staying in bungalows with no hot water for two nights.  The temperatures are expected to be between 10C and -3C overnight.

Friday, 14 October 2011

The Mysteries of Sake Brewing with Aspergillus

What makes the Japanese alcoholic drink different to alcoholic drinks traditionally brewed in the west? What  makes the taste of Sake distinctive? Why do different makes of Sake taste different? The answer to all of these questions is Aspergillus oryzae.

Malted barley
Brewing in the west is usually begun by the breakdown of the complex carbohydrates (starch) in grain using the natural process of germination. Prior to growing a seedling needs to use simple sugars for energy so part of the process of germination involves the release of enzymes within the seed that turn the starch stored in the seed (starch is great for energy storage because it is difficult to use and thus won't get 'accidentally' eaten!) into simple sugars which are easy for the germinating plant to use. This is of course a completely natural process (referred to as 'malting') and has been used for many centuries.

Different drinks tend to use difference sources for their starch - whisky uses barley, wheat or rye and these can impart a characteristic taste to the drink. Other sources of starch can be used e.g. potato, sweet potato and other vegetables though not often commercially - the brewer tends to use starch sources readily available in the part of the world they are working.

Moromi, the main mash
In the East the principle starchy food is rice so that forms to basis for its brewing industries e.g. Sake. The grain that is used for Sake brewing is that which is unsuitable for eating and is often weak. Germination is not carried out as perhaps this weaker grain would not germinate well, but all the parts of the seed are also thought to be contaminants that impair the flavour of the drink. Only the pure, polished starch grains are used. This leaves the brewer with a problem - how to convert the starch into simpler sugars for consumption and conversion into alcohol?

Grain of rice on which
koji is propagating
Aspergillus oryzae is a 'domesticated' species of Aspergillus that has been used by the Sake industry for centuries (named koji). Over this time each company has jealously guarded its own strain of koji, resulting in multiple slightly different strains gradually evolving all over Japan. Koji is seeded onto the rice starch and proceeds to release enzymes to break down the starch into simple sugars. Starting two days later yeast is added which now finds a plentiful supply of sugar to turn to alcohol and proceeds to grow along with the koji over the next few days.

One effect of this 'co-culture' technique is that the yeast continues to work for longer, producing more alcohol and a stronger drunk compared with western brews (beers 5-7%, wines 11-14%, sake 14 - 20% alcohol). Another is that the use of a 'pure' source of starch gives a distinctive flavour, and that flavour is contributed to by the particular strain of koji in use in each factory.

The use of Aspergillus to brew the beverage is more efficient, allows more starch to be turned into alcohol and gives the drink a distinctive taste!

 An introduction to Sake (Esquire)

Wednesday, 12 October 2011

Newsbite: Aspergillus Infections of the Immunocompetant Host

165 Aspergillus spp. isolates were detected in the respiratory cultures of 139 patients. Of these patients, 62 (45%) were colonized with Aspergillus spp. and displayed no clinical symptoms of aspergillosis, while 77 (55%) had a form of pulmonary aspergillosis, characterized as either chronic necrotizing pulmonary aspergillosis (CNPA) (48%), aspergilloma (29%), IPA (13%), or allergic bronchopulmonary aspergillosis (ABPA) (10%).
The dominant species were Aspergillus fumigatus (41%), A. niger (32%), and A. versicolor (12%). A. fumigatus was most commonly isolated in patients with IPA, aspergilloma, and CNPA, whereas A. niger was the dominant species in colonized patients and those with ABPA.

Friday, 7 October 2011

Running to the Top of the World for Aspergillosis Research

On the 18th October 2011 Lewis Fraser and his friend Aaron McKevitt are taking on one of the most difficult challenges possible in order to raise money for the Fungal Research Trust, a major contributor to UK research into aspergillosis.

They are going to attempt to run 100 miles over 5 days which in itself is an extremely tough challenge, however Lewis & Aaron are doing this in the Himalayan Challenge where the air is thinner making breathing more difficult, altitude sickness a prime possibility and they have tens of thousands of feet to be climbed - they run equivalent of running up Ben Nevis three times on the first day alone!

Lewis is quoted in this article in a newspaper close to his home in Scotland

"It is going to be a gruelling event that will push us to our limits, dealing not only with the distance, but terrain and - most difficult of all - the altitude. I'm not worried about the competition - I just want to get to the finish line and raise as much money as we can for the charity. Originally we hoped to raise about £5,000, but already the figure is over £7,000, which is absolutely fantastic."

The Fungal Research Trust is a non-profit charity established in 1991 which aims to raise awareness of Aspergillus fumigatus.
You can read about the several severely debilitating forms of aspergillosis caused by Aspergillus in the Aspergillus Website. If the person infected has a compromised immune system the fungus can invade their body quickly and thus needs to be detected and treated quickly. We have an array of effective drugs with which to treat aspergillosis, many of which have been developed over the last 10 years but in some cases we still cannot detect the infection quickly enough to use the drugs early enough to make a difference. A major focus of the research funded by the Fungal Research Trust is to develop new tests to detect Aspergillus infections much more quickly.

Research like this costs a lot of money. We estimate £150 000 to fund a research project for 3 years which sounds a lot but if everyone in the UK alone who has been diagnosed with aspergillosis gave £1 a week we would be able to start straight away. The project funding can be applied for from anywhere in the world so we are asking for donations from anywhere in the world - no matter where you live we can help you with our research - the research could actually take place in the US or Europe.
Stunning views, extreme effort in 2010

If you have any form of aspergillosis you will be able to find extensive support on the Aspergillosis for Patients website  and on the website of the National Aspergillosis Centre, the only centre of its type anywhere in the world which is located in the University Hospital of South Manchester, Manchester, UK We specialise in treating several specific types of aspergillosis and severe asthma and advise doctors all over the world on how to treat aspergillosis of all types.

Read of other runners' experiences in this challenge in 2010 here and here. Lewis & Aaron, it is probably best you don't read these experiences until after the challenge is over!

To support this extreme effort and an extremely worthy cause, donate here

Tuesday, 4 October 2011

Newsbite: National Aspergillosis Centre Patients Support Meeting Shortlisted for National Award

Patient nursing & support staff at the National Aspergillosis Centre, Manchester, UK have been shortlisted for a Nursing Times award for their 'Actual and virtual' patients support meetings that happen once per month. Extensive efforts to put patients first means that monthly meetings are held to provide advice, information and mutual support as well as encourage patients involvement in their own health management, research at the NAC and more. Patients and their carers can attend the meeting both actually (physically attending the meeting) or virtually (tuning in to watch via the internet, asking questions of the speaker using the internet) and the novelty of this approach is proving very successful.
The winner is decided on November the 2nd 2011 - Well done team and Good Luck!

Friday, 30 September 2011

NewsBite: Combination Antifungal Drug Trial Disappoints

Reuters article: Pharmaceutical company Pfizer's trial featured two of their antifungal drugs given together to treat invasive aspergillosis. Vfend (voriconazole) and Eraxis (anidulafungin) given together appeared to show some improvement over using Vfend alone but the data was not statistically significant in the final analysis.

Monday, 26 September 2011

Breath testing for 2-pentylfuran as a diagnostic test for pulmonary aspergillosis- an update

Breath testing methods to diagnose pulmonary aspergillosis is attractive because of the proximity of the infection (lung) and simplicity of obtaining samples for treatment. The detection of volatile organic compounds in the breath has been reported previously and 2-pentylfuran was isolated as a potential marker for aspergillus infections (link), also this compound is not produced by normal mammalian metabolism.
In May 2011, we ran a blog reporting initial data by Chambers et al that 2 pentylfuran could be detected in two immunocompromised patients with Aspergillus fumigatus infections. Initial studies also suggested that some foods which give rise to 2-pentylfuran may give false positive readings which would interfere with the tests.
A further report from the same group of researchers has determined new limits and possibilities for the potential breath test.
Of 45 foodstuffs tested 10 gave detectable 2-pentylfuran. Levels were highest from soymilk, lower from pumpkin, rolled oats, tinned asparagus, tinned beans and marmite. No 2-pentylfuran was detected from antifungal medicines. No difference in the time of day of testing or in relation to fasting or not, was observed. However the breath test could be accurately conducted on people who had ingested 2-pentylfuran positive foods - without an overnight fast -by simply rinsing the mouth with water - and waiting 30 mins or more before carrying out the breath test. The lower limits of detection were around 1 attogram of 2-pentylfuran.
This latest data decreases the problem of false positive results for this potentially diagnostic test.

Thursday, 22 September 2011

Newsbite: New species in Aspergillus section Terrei

Three new species have been described in the section Aspergillus terrei. These have been identified by sequence analysis of parts of the beta-tubulin and calmodulin genes and the ITS region. The identification of hepatotoxic and neurotoxic metabolites are identified amongst many other metabolites produced by this species. more

Friday, 16 September 2011

NewsBite: Ochratoxin detected in 20% of Chronic Rhinosinusitis patients

Researchers in the New York University School of Medicine checked 18 patients for a range of mycotoxins. All specimens were negative for aflatoxin, deoxynivalenol, zearalenone, and fumonisin. Four (22%) of 18 specimens were positive for ochratoxin. The clinical significance of this finding remains to be determined.

Thursday, 15 September 2011

Advance in Prevention of Medical Implant Infections

Medical implants such as heart valves and catheters commonly fail because of fungal infections of the implant which form a biofilm - a thin viscous layer that forms on the surfaces of the device which resists the absorption of antifungal drugs and therefore effectively protects fungi growing within the film.
This is a major cause of failure of these devices and often require the surgical removal of the device in order to clean up the infection. Mortality following some types of infection is as high as 30% so this is a highly important issue for both doctor and patient.

Robbins et. al. have discovered an effective treatment target that may effectively prevent the ability of biofilms to protect the fungus in the future. Heat shock protein (Hsp90) has already been directly implemented in drug resistance and here it is shown that if the amount of Hsp90 expression in the fungus is reduced then biofilm formation is greatly reduced and resistance to antifungals also prevented.

Yeasts are the most common infecting fungus in this situation. Once the expression of Hsp90 was prevented by genetic deletion it became vulnerable to antifungal treatment by the azole group of antifungals.

Aspergillus is the most lethal infecting organism in this situation, but once Hsp90 expression had been prevented it became more vulnerable to treatment with the new echinocandin group of antifungal drugs.

This study used isolates of fungi that had had Hsp90 expression genetically altered and also tested the effect of treating infections in mice with drugs that inhibit Hsp90. This research suggests that if we could develop new drugs to downregulate Hsp90 expression (or possibly even use existing drugs if appropriate e.g. if toxicity is low) then we could treat infections using a combination of Hsp90 inhibitor and antifungal to bring about a much more effective elimination of the fungal infection, hopefully without the need for surgery.

Hsp90 inhibitors already exist that may be directly testable in human experiments so perhaps we will see a  introduction of this technique in the not to distant future.

Friday, 9 September 2011

Hurricane Irene causes Explosion in Mould Counts

Hurricanes are of course associated with high winds and a lot of rain and flooding. Measurements of airborne mould levels in the outside air before and after Irene struck show mold at 100-fold normal levels, peaking at up to 10 000 spores per cubic metre.
The air indoors is also vulnerable to increases in mould as the hurricane pushes humidity levels up and of course causes physical damage allowing rain to enter many properties along with large scale flooding. Some water ingress is obvious and can be dealt with but other leaks could be hidden e.g. in wall spaces and under the floor and these can cause just as much damage. It is important to dry, clean and remediate as soon as possible.

Symptoms of problems caused by increases in airborne moulds are those of respiratory discomfort especially for those with pre-existing breathing problems such as asthma and bronchitis and of course allergies to moulds. After Hurricane Katrina had blown itself out and destroyed many thousands of homes in New Orleans in 2005 some people seemed to develop 'Katrina Cough' which was almost certainly caused by irritation caused by the large amount of airborne dust including moulds.
NB It follows that any people with a compromised immune system should take more care than most, avoiding the worse effected areas and using HEPA grade facemasks to avoid breathing in microrganisms.

There is also some evidence that exposed people's sensitivity to moulds was not hugely effected by Hurricane Katrina. Rabito tested the sensitivity of hundreds of residents of New Orleans for sensitivity to moulds in the months and years after Katrina. One third reported mould damage to their homes and continued to live there during remediation work so we would expect them to have been quite heavily exposed to airborne moulds - figures reported in this paper mention levels up to 500 000 spores per cubic metre of indoor air. However only 10% showed any sensitivity to moulds and this did not differ greatly from the sensitivity levels found in residents of undamaged homes. Mold sensitivity did not correlate with damage to homes or the level of mould in those homes.

Consequently: Are we imagining Katrina Cough?

The authors go on to admit that their study does not capture several groups of ill people e.g. those who are not responsive to mould will also probably have symptoms of respiratory irritation - these symptoms are might still be caused by moulds using a mechanism other than allergy.
They also admit that they could not check if the patients they tested were resident in New Orleans at the time the hurricane struck - so this study lacks precision. Likewise the study depended on people being able to afford to be tested and thus missed the least well off part of the population.
This was a rather 'rough & ready' study that did not show gross effects caused by high mould counts in indoor air, but its limitations do not allow it to rule out all health problems caused by moulds and other airborne irritants in contaminated homes, especially those of the poorest people in New Orleans.

We can probably expect similarities in the health problems experienced by people living in New Orleans  and those effected by Hurricane Irene and moulds may well play their part in causing them.

CDC recommendations for cleaning up in the aftermath of a Hurricane

Thursday, 1 September 2011

Pandemic influenza A and development of aspergillosis in immunocompromised patients

A report has highlighted the need for awareness of the possibility of developing invasive aspergillosis in severely immunocompromised patients, following hospitalisation due to infection with pandemic influenza A strain.
In 2010 the new strain of influenza - H1N1 resulted in a pandemic, with acute respiratory infection and a high mortality.
This report identifies 5 out of 57 patients who were immunosuppressed because of leukaemia treatment or transplantation, who required hospitalization due to influenza A (H1N1), then went on to develop invasive aspergillosis. The case reports indicate a higher level of frequency of invasive aspergillosis in these two high risk groups (8.8%), compared to other reported levels - raising the question of whether infection with H1N1 predisposes this patient at risk group, to developing invasive aspergillosis. This may be supported by the fact that no aspergillosis cases were seen amongst any haemotology - stem cell transplant patients.
Implementing preventative measures against infection with influenza A, H1N1 and prompt action by clinicians to consider a diagnosis of aspergillosis, is essential for these patients.

Monday, 29 August 2011

NewsBite: Molecular mechanism of Aspergillus fumigatus adherence to host constituents

Inhaled conidia of Aspergillus fumigatus rapidly adhere to pulmonary epithelial cells and other host constituents. Identifying molecular mechanisms underlying A. fumigatus adherence has therefore been the focus of a number of studies aimed at identifying novel therapeutic targets.
Recent advances have suggested an important role for fungal carbohydrate components of the cell wall and extracellular matrix in adherence, including sialic acid and mannose residues, and the
newly described polysaccharide galactosaminogalactan. Read more

Wednesday, 24 August 2011

Assessment of exposure to harmful mycotoxins through breast milk in Egyptian babies

Aspergillus species cause health problems in humans and animals by direct colonisation through the lungs, but can also cause harm through the production of substances called mycotoxins. These can contaminate crops and grain when food is not dried and stored correctly.

If contaminated grain is eaten over longer periods of time -then the aspergillus mycotoxins can cause cancers, they are highly toxic also causing DNA mutations.

A recent study of 150 mothers and infants fed exclusively on breast milk in Egypt has produced some alarming results. Mothers are exposed to many toxins that can reach infants through breast milk. Scientists measured aflatoxin M1 which is excreted in breast milk and derives from several well known types of Aspergillus - such as flavus and parasiticus, found as crop contaminants.

Infant weights were documented at birth and 6 months. At 6 months - prior to weaning - aflatoxin M1 was measured along with liver markers alanine and aspartate aminotransferases, in both mothers and infants.

65% of mothers had aflatoxin M1 (>0.05ug/ml) in their breast milk - the range was 0.2- 19ug/ml. The infants of aflatoxin positive mothers had lower standard deviation scores both at birth and at 6 months. Also the levels of liver enzymes in both mothers and infants whose breast milk contained aflatoxin were significantly higher than those who were aflatoxin negative.

The study concludes that aflatoxins represent a real health threat in Egypt and the raised levels of liver enzymes in this group must be taken seriously as a potential warning for monitoring for liver cancers. Increased public education about correct food storage and aflatoxin hazards must be a priority. Link to paper

Friday, 12 August 2011

Yeast as a Universal Antifungal Vaccine?

We mentioned a few weeks ago that a research group in the US was working on a vaccine to help prevent aspergillosis. This is an alternative to attempts to identify and isolate specific antigens on the Aspergillus fungus which might form a viable basis for a vaccine that specifically prevents infection by Aspergillus. Developing specific vaccines is a long process and although they are very precise and well worth the time and effort it takes to make them there will be a long delay before they are available.

Liu et. al. set out to test which pieces of Aspergillus were most suitable to act as a vaccine by cloning them into yeast, but then realised that the yeast controls without any cloned Aspergillus were acting as a good vaccine!
To use killed yeast as a vaccine could be available relatively quickly as it is far simpler to achieve than a specific vaccine and already has a good safety record with regard to toxicity.

The researchers have shown that using yeast as a protective vaccine works well against aspergillosis in a mouse model system, so we must assume that a component of yeast is so similar to Aspergillus (both are of course fungi) that it stimulates our immune system in the same way as Aspergillus. Work so far indicates that the important components are cell wall components glucan and mannan.

Other fungi share these cell wall components so we seem to have the makings of a pan-fungal vaccine that would be useful for a wide variety of fungal infections.
What would normally happen now is that the component of the heat killed yeast that is active in providing a protective effect would be isolated and subcloned, but in this case the crude preparation is already known to be safe and lacks toxicity so the possibility remains that the crude preparation could be used as a rapidly available vaccine to provide protection against aspergillosis and a variety of other fungal infections - a remarkable discovery if hopes are borne out.

Wednesday, 10 August 2011

NewsBite: Immobilization of Aspergillus oryzae β galactosidase on nanoparticles

A demonstration of the immobilization of Aspergillus oryzae β galactosidase on native zinc oxide (ZnO) and zinc oxide nanoparticles (ZnO-NP) by simple adsorption mechanism. Useful for a wide variety of applications in constructing enzyme-based analytical devices for clinical, environmental and food technology (biosensors).

Friday, 5 August 2011

Collaborative Cross Mice and Mapping Susceptibility to Aspergillus fumigatus

The ability of a pathogen to infect one of its hosts involves complex  interactions between the two parties. The host organism can bear genetic propensities to be resistant or susceptible to the infection and this can take many different forms, some known and some not. Unfortunately in natural populations each individual differs from other individual - this is the primary mechanism that protects every species from attack by pathogens as if an infection rapidly spreads through a population the chances are that it will not be able to infect every individual - some will be resistant.

Why aren't all individuals resistant? One reason is that it would be very costly in terms of energy or other resources for any organism to carry all 'resistance genes', and of course it is not able to predict which organism will attack & how it will attack so effectively it is unable to know which gene is likely to confer resistance. One illustrative example is the genes that confer resistance to malaria in humans. Recessive genetic differences that make the host resistant to malaria also make the host likley to produce double recessive offspring that have a crippling blood disorder - the positive finely balances the negative.

One model of choice for investigating these genes is the mouse. Over many years laboratory mice have been bred that are very close to being genetically identical. These represent the living 'blank canvas' on which to study isolated groups of genes. If all of the genes of the mouse are the same except for a small group it is possible to ignore the unchanging gene effects - this is a way to study the effects of several gene differences at once in the same mouse line. This is thought to be the next step after years of looking at single genes changes in the mouse.

This paper uses this technology to identify genes in the mouse which are important for resistance and susceptibility to aspergillosis. 371 mice from 66 separate lines were tested for resistance to Aspergillus fumigatus using a well established pulmonary infection protocol. Survial times were assessed and found to vary significantly between the lines, indicating that some loci conferred resistance better than others.

The authors were able to further narrow down the indicated loci to suggest several candidate genes conferring resistance to infection. Irf2 (Harada et al. 1989; Masumi et al. 2009) which is involved in host reposnse to infection, Laptm4b (Kawai et al. 2001) which is a transmembrane protein, Hrsb12 (Samuel et al. 1997) which is a heat responsive protein.

This demonstrates the power of this approach and more specifically indicates several novel targets for research into aspergillosis.

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