Thursday, 30 January 2014

Can Fungi Be Used to Replace Plastics?

See what you think - this research group says maybe it can! (copied from Youtube)

Fungi, with the exception of shitake and certain other mushrooms, tend to be something we associate with moldy bread or dank-smelling mildew. But they really deserve more respect, say Union College researchers, Steve Horton and Ron Bucinell. Fungi have fantastic capabilities and can be grown, under certain circumstances, in almost any shape and be totally biodegradable. And, if this weren't enough, they might have the potential to replace plastics one day. The secret is in the mycelia.

Wednesday, 29 January 2014

Will we be able to Regenerate Ourselves in the Future?

There has been a lot of focus in the media and in the scientific world over the last 10 - 20 years on the exciting potential of stem cells. Stem cells are literally those cells from which we all began as an embryo - a few cells grew in our mothers' womb over 9 months to eventually form and entire human body - us!

We also know that there are stem cells that persist in our bodies as we grow and which are able to build new tissue, though for the most part these are only able to form one type of tissue and not a whole body. The 'Holy Grail' is a stem cell that can be stimulated into growing into any tissue type and thus potentially be able to grow into any organ - we could replace whole organs as they become defective for example - so if someone is in need of a new pair of lungs or a new heart we could use their cells to grow them a replacement with no risk of tissue rejection!!

Stem cells have proven very difficult to find. The Nobel Prize was awarded in 2012 to two scientists who were able to generate stem cells from mature cells (i.e. the cells that make up our bodies) by introducing four genes into the cells - a major breakthrough in its day. But there were doubts that that technique could be used to treat people for fear of causing cancer.

However the astonishing possibility that replacement organs could be a reality has just come a step closer. Published tomorrow in the journal Nature is a paper by Charles Vacanti (Harvard University, USA) and Haruko Obokata at the Riken Center for Developmental Biology in Kobe, Japan, and colleagues. In it they describe the conversion of ordinary mature spleen cells into stem cells by the disarmingly simple method of incubating them in slightly acid growth conditions for 30 mins. No genes, no chemicals, no manipulation therefore no risk of causing cancer. These cells can form every type of tissue in a body.

There is work to do yet but such a simple method will cause a huge increase in the availability of stem cells to the entire research community. Much more research will be possible in a short time. It is highly likely that progress will quicken markedly. Perhaps in the future it will not be just Dr Who that can regenerate!

Article in Nature
Article in New Scientist

Friday, 24 January 2014

Guidelines to Protect the Severely Immunocompromised Patient from Moulds

Patients undergoing treatment for some forms of cancer may become profoundly vulnerable to infection for a short time during the treatment (at which time they are protected from infection), but may also remain quite weak between treatments.

It isn't thought to be good for the quality of life of a patient to have enforced stays in a hospital for long periods of time, for example the chances of acquiring multiply resistant infections are increased while in hospital and of course the quality of life of the patient can be poor. Commonly therefore between treatments patients are allowed to go home to recover, Unfortunately it is also common for those people to inadvertently come across a source of infection resulting in unwanted treatment and even quite severe infection, particularly if the infecting organism is a fungus as they can be very difficult to treat.

The sources of fungal infection can be obvious to some, but can also be quite obscure, even to doctors trying to advise on avoiding infection. This review attempts to address this problem by going into detail on how to prevent being exposed to infection. Advice includes the following subject areas - some of which many of us would not think about:

  • Personal hygiene
    • Hand washing, avoid swimming pools, cuts, removing sticky tape from skin
  • Water and food
    • Boil water, foods to avoid
  • Family and other close contacts 
    • Pets, stock animals, people with infections
  • The home and its vicinity
    • Avoid dust, house plants, some parts of the world
  • Outdoor activities
    • waterways, walking barefoot, gardening
  • Hobbies and travel
    •  body piercing, smoking, naturopathic remedies
These are just a few of the guidelines mentioned in the review, it is well worth reading the paper and even taking it to your doctor the next time you go to discuss it.

It should be reiterated that these guidelines are intended for chronically and severely immunosuppressed cancer patients. Some of the guidelines may also be of use to those suffering from allergy to moulds but if you are worried about infection and you have a normal immune system the risks are extremely low that any of these activities or other circumstances will result in an infection.

Monday, 20 January 2014

Virulence of Aspergillus fumigatus

Aspergillus fumigatus is a ubiquitous fungus that all humans are exposed to on a daily basis, but it rarely causes disease in healthy people. Ordinarily, when people breathe in Aspergillus spores (or conidia), the immune system kicks in and clears the fungus rapidly. In immunocompromised hosts, however—such as those with AIDS or undergoing transplantation—it can take hold and cause a variety of diseases, not least of which is an invasive form that is fatal in up to 40% of cases in the Western World.

This particular fungus naturally occupies a niche, making it a prime candidate to cause infection in a variety of hosts. It can survive a wide number of environmental conditions, for example, A. fumigatus grows optimally at 37°C and at pH between 3.7-7.6. However, it has been seen to survive between temperatures of 12-65°C, and pH levels between 2.1-8.8, making it a versatile organism. This, combined with it's ability to disperse throughout the air with ease, makes it a prime candidate to spread and rapidly adapt to it's host environment.

It is estimated that humans breathe over 100 A. fumigatus spores per day, and it uses sialic acid to bind to the respiratory systems of humans. When immune mechanisms are lacking to sufficiently clear these conidia, they rapidly germinate at body temperature and allow for extensive growth. By utilising a number of gene expression techniques, A. fumigatus reduces its need for iron, nitrogen and glucose, and learns to evade pH and oxidative stresses imposed upon it. Furthermore, it produces certain metabolites—such as gliotoxin—which are known to suppress immune mechanisms and even hurt immune cells.

These defensive and offensive mechanisms allow for rapid growth, and subsequent deterioration of human hosts, in immunocompromised individuals. In healthier hosts, such as those with allergic bronchopulmonary aspergillosis (ABPA), it is less an out-right infection but more allergic in nature. Here the fungus rarely evades the immune system effectively enough to outright spread throughout the lungs and body, though it is able to penetrate the immediate alveolar environment in the lungs. Over time, metabolic production can damage the linings of the lungs, but the disease is far less severe than in immunocompromised equivalent cases.

Monday, 13 January 2014

Insufficient investment to UK fungal research

Global prevalence of fungal infections is increasing, with serious infections now thought to affect around 1.7% of the Brazilian populations, 1.9% of the Irish and a huge number in China. Cryptococcal meningitis alone accounts for well over half a million deaths every year worldwide, with aspergillosis and candidiasis, amongst others, topping the total to around 1.35 million deaths globally each year. It is likely that this is a significant underestimate of fungal mortality, with many cases misdiagnosed or missed entirely in developing nations.

Michael Head, from University College London, and colleagues investigated the total research funding allocated in the UK to fungal disease research between 1997-2010. Whilst around £2.5 billion has been spent on infectious disease drug research as a whole, merely £48.4 million (or 1.9% of all funding) of that was allocated to fungal diseases.

The vast majority of this went to preclinical drug development studies, but barely any of the money resulted in progression to clinical trials. Of the £48.4 million spent, only £2 million was spend on clinical trials and half that on developing products after successful trials. Candida and Aspergillus made up the bulk of the funding awarded, with £21.5 million allocated to the former and £4 million awarded to preclinical studies for Aspergillus spp. 

The paper concludes that there are strengths to UK fungal drug research, but growth in the industry is stifled by a lack of investment. Cryptococcosis, despite being the leading fungal cause of death worldwide, is chronically underfunded compared to other diseases. All this is made worse by increasing resistance to fungal infections which is not being countered by an increase in drug development.

Friday, 10 January 2014

Bone Marrow Stem Cells Improve Outcomes in MDR Tuberculosis

This recent paper in The Lancet reports the striking result of giving Tb patients their own stem cells (autologous transplant of  mesenchymal stromal cells) in an attempt to improve the outcome where the infection was resistant to multiple antibiotics.

Striking improvements were observed as reported by the European Lung Foundation:

People with multi drug-resistant (MDR) or extensively drug-resistant (XDR) TB could in future be treated using stem cells taken from their own bone marrow, according to the results of an early-stage trial of the technique. 
The study, published in the Lancet medical journal, found that more than half of 30 drug-resistant TB patients treated with a transfusion of their own bone marrow stem cells were cured of the disease after six months. 
Bone-marrow stem cells are known to move to areas of lung injury and inflammation and repair damaged tissue. Since they also modify the body's immune response and could boost the clearance of TB bacteria, researchers wanted to test them in patients with the disease.
In an initial study, 30 patients with either MDR or XDR TB aged between 21 and 65 who were receiving standard TB antibiotic treatment were also given an infusion of around 10 million of their own stem cells. 
During six months of follow-up, the researchers found that the infusion treatment was generally safe and well tolerated, with no serious side effects recorded. 
Although the study was a phase 1 trial primarily designed only to test a treatment's safety. Further analyses of the results also showed that 16 patients treated with stem cells were cured at 18 months compared with only five of the 30 TB patients not treated with stem cells. 
The researchers stressed that further trials with more patients and longer follow-up were needed to better establish how safe and effective the stem cell treatment was. 
Read the original news articleRead the original research paper

Thursday, 9 January 2014

New Type of Antifungal Drug: Low Toxicity/High Potential?

In common with many antimicrobial drugs, microbes resistant to antibiotic/antifungal drugs are being found with increasing regularity. This indicates that we must look for new drugs that are effective against microbial strains resistant to existing antimicrobials, and preferably we need drugs that microbes find very difficult to become resistant to.

New antifungal drugs have been produced regularly over the last 20 years and clinicians now have a lengthy list to choose from including; amphotericin, itraconazole, voriconazole, posaconazole, micafungin, anidulafungin and several more.

Resistance to these drugs is relatively widespread and one reason is that there are relatively few drug classes so drugs tend to be quite similar in structure and mode of action, so resistance mechanisms that defeat one drug in a class sometimes also defeat another in the same class. We need new types of antifungal drugs that form new classes!

The recent paper in Nature Communications suggests that progress has been made towards the development of a new type of drug, one that is efficient and pathogen specific (thus hopefully less toxic to the patient). Earlier work with Macromolecular antimicrobial agents such as cationic polymers and peptides has demonstrated that they can have antifungal properties and a markedly targetable against microbial cell membranes, thus leaving human cell membranes undamaged.

Self assembly of polymers
These tiny particles self assemble into highly active structures once they become dissolved in water and are biodegradable - making them highly attractive as medication as they will be eliminated from the patients body once their job is done.

Their mode of action is similar to that of amphotericin as they incorporate themselves into microbial cell membranes and form large pore-like structures, allowing the cell contents to escape - an assault that microbes find extremely difficult to resist or to develop resistance to - there is currently very little resistance to drugs based on amphotericin in clinics for example even after many years of use. Unlike amphotericin there seems to be much less tendency to attack human cell membranes, and we can easily dissolve these polymers in water (unlike amphotericin) so effectively we get all the advantages offered by amphotericin without the drawbacks of toxicity & irritant solvent. An added bonus is that these polymers are nanoparticles and capable of penetration into biological tissue & through inhibiting biofilms.

Successful testing of these new synthetic polymers (cheap to manufacture to large scale) is reported in the latest paper and has shown positive results both in vitro (in laboratory test dishes) and in vivo (in living animals) - with successful treatment of fungal keratitis (fungal eye infection) in a mouse model.

At the moment this type of drug depends on getting sufficient particles to the site of infection. This is far more difficult when giving as an injection or as oral medication so its use is restricted to sites we can directly reach (e.g. the eye) but now that the principle is established we can hope that this will change and we may see 'whole body' versions of these drugs in the future.

Monday, 6 January 2014

Fungi in space

Fungal cultures, obtained over several decades, have been studied in terms of their appearance and characteristics. Space-flight, under zero and low-gravity conditions, is known to influence the colonies of fungi that can grow in various mediums such as water.

Previous research on a fungus called Ulocladium chartarum -- a species harmless to healthy humans -- underwent a variety of changes when grown in space compared to on Earth. The appearance of hyphae (the protrusive part of fungal cells involved in absorption of nutrients) was less dense, and hyphae were significantly shorter. The colour of the colony also changed, with a yellowish appearance instead of a colourless colony.

A recent study published in the PLoS ONE journal describes the effect of space-flight on Candida albicans. Similarly to Aspergillus, Candida species can cause a variety of infections, from mucosal infection (thrush) to systemic and often fatal infections called candidiasis. Since astronauts are considered at risk in terms of immune function, and because systemic C. albicans infections occur more commonly in those with a reduced immune function, the aim of this study was to determine any genetic and physical changes to the fungus which could lead to an impact on human health in space.

Overall, 452 genes were found to be expressed differently by C. albicans in space compared to when the same strain is grown in normal gravity conditions. The genes involved had a variety of functions, from helping the yeast cells stick together to influencing resistance to antifungal drugs. Whether this translates to a more resistant organism, though, has yet to be determined by laboratory testing.

Nevertheless, the study presents interesting variations on the C. albicans strain testing and it is the first example of a common human fungal pathogen (and commensal organism) being studied under a microgravity scenario. Crucially, the study also opens the way for further testing of fungal species including the common mould Aspergillus fumigatus.

Thursday, 2 January 2014

Therapeutic drug monitoring guidelines

Treatment of aspergillosis is a complex entity. In order to successfully treat many fungal infections, treatment regimens must be strictly adhered to in order to improve clinical outcome and decrease risks from resistant strains. The number of available antifungal compounds is low relative to other antimicrobials, despite systemic fungal infections often holding worse prognoses than other infections. Furthermore a number of antifungals can, if improperly given, cause serious side effects.

It is therefore that clinicians can monitor drug levels to ensure that effective concentrations are available in the blood to treatment the infections. This process is called therapeutic drug monitoring (TDM).

Until recently there had been no exhaustive evaluation of the literature regarding TDM for each antifungal drug. The British Society for Medical Mycology recently published a review in the Journal of Antimicrobial Chemotherapy, reviewing the the available literature and providing recommendations for antifungal TDM. The review was conducted according to the GRADE system, which ranks their recommendations alongside the quality of evidence available, and therefore the relative strength of each recommendation.

Amongst the 16 recommendations made within the paper, the authors recommended that the majority of patients taking itraconazole should undergo TDM. The main basis for this was that the absorption of itraconazole into the blood in different people varies significantly, and clinical impact is decreased when levels are too low. This occurs for many reasons, including non-compliance, diet and stomach pH levels at the time of taking the tablet.

The paper benefits laboratory scientists involved in TDM as well as clinicians as it measures the strength of evidence for target concentrations of each antifungal drug.

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