Could chronic inflammation predispose the brain to developing Alzheimer’s?

New research has looked at the impact of an immune system challenge in the development of Alzheimer’s disease. Results in mice show that a single late gestation infection is likely to induce significant memory problems at a older age.

These mice, after infection, showed a persistent increase in: inflammatory cytokines, amyloid precursor protein and altered cellular localisation of Tau. Further if the immune system was challenged again, these effects were strongly aggravated. Amyloid β is strongly associated with Alzheimer’s disease in humans. When mice were genetically modified to produce this protein. Post infection levels, of Amyloid β, were dramatically increased in the precise areas where inflammation-induced amyloid precursor protein was deposited.

From this research it appears that chronic inflammation caused by infection could be an early development in the onset of Alzheimer’s disease. This has important repercussions in our treatment and prevention of Alzheimer’s disease. By having a better understanding of what maybe is causing Alzheimer’s disease the pharmaceutical market can develop more targeted therapies to prevent say the build up of amyloid precursor protein and diagnostic tests to detect its localisation.

Thanks for reading

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Infection real time in 3D

Bacterial Invasion – the film, now in real time and 3-D!

We all hopefully know that bacterial infections are bad news. However do we know how an infection spreads in real time and exactly how/when our immune system deals with it?

So far scientist have been quite ignorant in terms of how a disease spreads. We know ‘technically’ what happens, but we don’t really know how infection truly progresses. This poses some potentially serious limitations to our understanding of infection. It’s probably part of the reason why we have not produced a completely new antibiotic in around 40 years.

It appears that for so long science and medicine has been operating by the flicker of candlelight rather than the spotlight required to stay ahead of the game. Now a recent discovery from Imperial College London could change this.

Imperial college have developed a 3-D in vivo imaging system that allows the user to follow an infection in real time. This means we can now see where an infection starts, what area it will localise to, where it will progress to and how the bodies immune system will deal with it.

Watch the video here:

http://helix.imperial.ac.uk/flashcomms/live/mp4/high_res/4F0l9NwBd45fac97_real_time_bacterial_infection.mp4

The video shows the course of infection of an E.coli like mouse pathogen Citrobacter rodentium over a period of 11 days.

Here is how it works.

1. First researchers genetically modified C. rodentium to produce light.
2. These bacterium were then used to infect a mouse
3. This infected mouse was then put into a scanner and the light emitted from the mouse was detected and measured by a scanner
4. These measurements were used to build a map of the exact location of the bacteria in different parts of the body
5. The lighter the area is, the more bacteria there are. Less light means that the bacteria are being killed off.
6. These scans are repeated day after day to build up a full picture of infection

The great thing about this imaging technique is that we can really get a handle on the bigger picture of infection. What infection looks like, how it behaves and how are immune system deals with it. These are the big questions that we have so far been missing answers to.

Another big question, and issue, is how are we going to deal with ever increasing problem of antibiotic resistance? Well this new technology goes some way to answering this question. Now we can visualise infection, we can also monitor it and see how different vaccines and antibiotics work in living animals. That is something that we have never been able to do before. By seeing where vaccines and antibiotics act and how different treatments have different affects, we can now screen for the most promising options.

Game changer?! You tell me!

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Is Gene Xpert in India necessary?

The Xpert® MTB/RIF test (Gene Xpert, Cepheid, Sunnyvale, CA, USA) is a recently developed diagnostic test for identifying mycobacterium tuberculosis (MTB) and potential rifampicin resistance. After being touted as the potential game changer for TB control, it has understandable generated a great deal of interest.

From the manufactures website it looks ideal. It is: highly specific (97-100%), quick (takes a few hours) and easy to use. The WHO technical advisory group (STAG-TB) has recommended Gene Xpert for swift and large-scale implementation at the peripheral level. The hope is to use Xpert to tackle the ever-growing worldwide MDR-TB problem. Gene Xpert can ensure quality diagnosis and at the same time detect a common form of MTB drug resistance.

The planned large-scale implementation of gene Xpert in India is due to commence within the next couple of years. It is proposed that an Xpert machine be installed in each Tuberculosis unit (a TU covers 500,00 population or 250,000 in tribal/difficult areas).  It has been said that the existing microscopy network is going to be maintained. However gene Xpert is going to be used for patients who are: re-treatment cases, HIV positive or any group at risk of developing MDR-TB. Now the calculation of what proportion of samples this represents is beyond me. If anyone can calculate it I would be very interested. Although I would predict that it is reasonable high, the number of TB patients with HIV is around 5% (RNTCP – 3^rd quarter 2011) and treatment failure is close to 13% (RNTCP– 3^rd quarter 2011).

Multiple different authors have raised concerns over applying gene Xpert in developing countries. Here are the major issues:

• It requires a constant electricity supply. This is major problem in India because the power regularly fails. Back up generators are available however these are costly to run and are not always reliable.
• The operating temperature needs to be constantly below 30 °C . India’s climate regularly tops 30 °C, so constant air conditioning would be required. This alongside temperamental electricity supply could cause some major technical and economic problems.
• The cartridges required are bulky therefore pose storage issues. These also need to be stored >28 °C . Consequently a separate storage room with air-conditioning could be required. These cartridges can also only be stored for 18 months.

These issues although weighty can be solved. The biggest issue, which I can see, is financial and wherever it is actually required in the first place. So the company Cepheid who make Xpert, alongside FIND, have agreed a highly discounted unit price of around $17,000. This is very reasonable compared to the prices advertised in the USA and Europe. However this could be a clever business tactic from Cepheid. Sell lots of units at a cheap price and by doing so create a huge captured market for selling Cepheid’s test cartridges. Sort of like what the Amazon Kindle are doing with eBooks, Cepheid is instead replacing books for the TB symptomatic.

If the Indian government buys one Xpert unit per TU it will cost a little under $40,000,000 or 2,000,000,000 INR. So this is maybe a ‘bargain’ but it is still a lot of money. Could this money be used better elsewhere? This is not all; the apparatus requires Cepheid supplied cartridges to carry out each test. For a single test (this includes recalibration of machine etc.) it costs $20 per sample. This is quite a bit more expensive than an Amazon Kindle book, about $8 (sorry bad example). A better comparison is in India this could probably feed a family for perhaps a month. So it’s not cheap. Now I don’t have the numbers for how many tests they expect to do. So I am going to show how much it would cost to do all TB tests using gene Xpert. I know this isn’t totally representative, however it gives you a good idea of the costs involved. So in 3^rd quarter 2011 the RNTCP performed 2,017,536 sputum examinations. If Gene Xpert did these it would cost $40,350,720 per quarter. That’s around $438,595 per day. When you compare this to the price of sputum smear microscopy its quite staggering. Sputum smear microscopy costs $~0.5 per test. That equals $1,008,768 per quarter and around 11,000 per day. A quick bit of maths shows that Gene Xpert is 40 times more expensive than sputum smear microscopy.

So to me and many others it seems strange for the WHO to be pushing this. It seems costly and largely impractical. I understand that MDR-TB is a major issue. Its presence is an indicator of a global crisis waiting to happen, a crisis that needs to be dealt with fast and effectively. However it has been cited that currently there are big issues with the procurement of second line drugs to treat MDR-TB. So why bother diagnosing MDR-TB if you can’t treat it? This poses not just a logistical issue but also a major ethical one.

As I have said it doesn’t really make much sense. So I had a little look into Cepheid.  Upon searching Cepheid I found that in 2009 there was a spike in their lobbying expenditure from $100 thousand to well over $300 thousand for that year. The money was spent lobbying misc. manufacturing and distribution programmes. Is there the potential here for a tied aid agreement? Governments often tie aid to certain conditions such as purchase agreements and market restrictions. Has Cepheid lobbied the USA government in-order to push gene Xpert to developing nations? This would mean commercial interests are at the heart of this decision, rather than positive health outcomes. I do feel slightly uncomfortable writing that, because I understand I could be out of my depth, putting 2+2 together and getting 10. However I believe it is a possibility and one that needs to be thought about. Maybe we are being told “we must implement gene Xpert now, to stop MDR-TB’ however it’s really a financial coup for Cepheid and not a cost effective way to tackle MDR-TB.

So in conclusion it does not seem appropriate to start the large-scale implementation. Pilot studies need to be carried out to determine feasibility. Also other options need to be evaluated to see if this is really the most cost effective way to tackle the ever-growing MDR-TB problem. I believe there are other companies developing similar tests. We require solutions, but these solutions need to be appropriate. Especially when they are concerning such large amounts of money. The major questions I raise are: is the supply of second line drugs sufficient? Are these drugs going to make it to the patients? Are current cure rates good enough in the country to justify the need for increased diagnosis? Is this really the best intervention for tackling TB? Is India ready for Gene Xpert?

Thanks for reading, please comment.

Simon Packer

Refs:

Scott, L. E., McCarthy, K., Gous, N., Nduna, M., Van Rie, A., Sanne, I., Venter, W. F., et al. (2011). Comparison of Xpert MTB/RIF with Other Nucleic Acid Technologies for Diagnosing Pulmonary Tuberculosis in a High HIV Prevalence Setting: A Prospective Study. (M. Pai, Ed.)PLoS Medicine, 8(7), e1001061. doi:10.1371/journal.pmed.1001061

Trébucq, a, Enarson, D. a, Chiang, C. Y., Van Deun, a, Harries, a D., Boillot, F., Detjen, a, et al. (2011). Xpert® MTB/RIF for national tuberculosis programmes in low-income countries: when, where and how? The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 15(12), 1567-72. doi:10.5588/ijtld.11.0392

 

WHO. (2011). Rapid Implementation of the Xpert MTB / RIF diagnostic test. World Health.

Global Fund Crisis

India is still in the midst of a rampant tuberculosis (TB) epidemic.  Every day in India 20,000 people become newly infected with Mycobacterium tuberculosis and more than 5000 people will develop the active disease.   This dramatic spread has caused India to become the highest TB burdened country in the world. 1.8 million new cases are diagnosed here annually. This leads to a depressingly high death rate – 1,000 people die from TB each day. That’s nearly one person dying from TB every minute.

India, although being touted as an emerging superpower, is still a developing country. India posses 17% of the world’s population but accounts for 35% of the worlds poor and 40% of the illiterates. 50% of Indian women suffer from anemia due to acute nutritional deficiencies.  This is compounded by gross cultural and gender discrimination; 8% of India’s population comes from scheduled tribes (ST) but the ST’s share of poverty and illiteracy is double its population share. India is still far from a developed country.

The government is working hard to combat the disease. In 1993 India launched the largest National TB control program in the world: The Revised National TB control Program (RNTCP). The RNTCP has worked well to put 1.5 million people onto DOTS treatment. However the RNTCP can only partially stem the tide of TB. The Indian government has yet to raise its health spending from 2.5% of its GDP to the WHO recommended 5%. This under financing of the health system causes it remains weak. Multiple NGOs support the RNTCP program, through a collaboration called The Partnership for TB Control India.  This partnership’s contribution to strengthening TB services is essential, as it ensures good control of the TB epidemic within India.

The partnership NGO’s have become understandable dependent upon money from the Global Fund. So far the Global Fund has contributed $873,797,225 to fight HIV, TB and Malaria in India. The total amount given to NGO TB programs comes to around $110,00000. This money has been well used: with 790,00 new smear positive TB cases being detected between 2003 and 2010. NGO’s have now become reliant upon the Global Funds money. Without it they will no longer be able to provide support to the RNTCP program.

In November 2011 it was announced that there would be no funding for Global Fund round 11. This was because the major economic superpowers of the world, namely the G8 (USA, UK, Japan, Italy, France, Germany, Canada and Russia) as well many more donor countries, have not contributed their full and fair amount to this life saving Fund. How can you replace $110,00000? You cant.

We cannot let this funding cut happen. This money is urgently required to maintain and develop TB services in India. We now live in such a globalised world; it is no longer just India’s problem. By not solving this problem we are in danger of loosing the control we have upon the TB pandemic. It has been calculated that these countries contribution equals the same as one day of their military budget. Instead of endangering lives this money can be used to save them. So I am writing this to inform and motivate you all. Don’t let the G8 countries cut their global fund contributions. The civil societies of India need this money to continue their progress in tackling the Indian TB crisis head on.

http://tbassnindia.org/FactSheetonTB.html

http://www.wpro.who.int/media_centre/fact_sheets/fs_20050324.htm

http://www.stoptb.org/

Kurian, N. J. (2007). Widening economic & social disparities: implications for India. The Indian journal of medical research, 126(4), 374-80. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/18032812

http://www.searo.who.int/en/Section10/Section2097/Section2106.htm

http://www.theglobalfund.org/en/regionalmeetings/meetings/India_October_2011_PR/

Antibiotics

This blog is a load of shit. So last week in India, I dined out on some suspicious looking chicken. At the time i was hungry for my lunch so didn’t think about the consequences of eating it. As a result i developed a nice dose of food poisoning. This food poisoning laid me down for the whole of saturday, with a slight fever and some explosive events within my digestive system. On Sunday I felt better but I was still very much afraid of being further than 10 metres from the nearest toilet. I can handle this fear and although it was uncomfortable and not very nice you can live with it for a few days. 5 days later, I was still feeling bad, not exactly off my food but my stomach was defiantly still quite upset, and on the whole being quite unreasonable.

earlier in the week  i had thought why not try probiotics? In theory probiotics make good sense eat ‘good’ bacteria to out compete the ‘bad’ bacteria which is making you sick. However the evidence for the effectiveness of probiotics is reasonable sparse and on the whole quite inconclusive. One study however did say that probiotic treatment reduced diarrhoea by one day. The unfortunate thing about probiotics is that an immediate effect wasn’t present, it didn’t exactly make me feel better and it didn’t reduce my symptoms. So even if it has the potential to reduce the infection by a day, I wanted it sorted now! I don’t want to wait.

So after the 5th day I had had enough, So i went to the pharmacy and bought some antibiotics…. Now this is what is crazy about india, I went into a pharmacy and said “can i have some ciprofloxacin 500 mg” he replies “yes, here you go” and hands over a strip of tablets, no box, no information leaflet and above all no prescription required. I think most of us have heard that we have to be careful with antibiotics but how much danger are we really in? should antibiotics only be provided with a prescription? and how can we solve the current antibiotic crisis?

Now I would say I’m a reasonable responsible person and I have also previously read extensively on the topic of antibiotic resistance. I even had a course module titled ‘antibiotic crisis’ (Coincidently I got my worse grade in this course, but in my defence it was a really hard exam, and my notes resembled a abstract piece of art, so weren’t that useful). So i think i can say I know a bit about antibiotics. How important they are to society is often taken for granted; as well as the risks we are facing with the ever developing resistance in multiple clinically significant bacteria. Despite knowing the dangers I went against everything I have learnt and purchased antibiotics without a prescription.

In my defence I had read about what antibiotic to take and the dose that was required (CDC). I wanted them because I was traveling back to the UK in a couple of days. So I really wanted to feel better before then. So I took these antibiotics and I did start to feel better, maybe it was placebo, maybe it was me naturally getting better, but i defiantly did get a whole lot better!

Adherence however now became an issue. I was travelling and my symptoms had gone and surprise surprise I forgot my final dose of the regime. This is a major error because it provides conditions which are sub-optimal for killing bacteria. These conditions positively select for resistance genes and allows resistant bacteria to propagate. My actions therefore were careless and dangerous in terms of providing conditions which can develop and foster resistant bacteria.

This experience for me has raised so many questions surrounding antibiotics and it really worries me about their future: will we have a future when we no longer posses this ‘magic’ bullet in our armoury? The very real answer is yes. In a way if I can be irresponsible enough to go out and look for a short term fix for my problem (which would of cleared up on its own) and miss the final dose. This happened when I knew the risks to medicine and the precarious position we are in. I still went out there and looked for a short term solution to my problem. How many other people are going to look for this short fix? When they dont know the risks or maybe wouldn’t care if they did?

I have heard that in India there is a practise of pharmacists providing one antibiotic tablet (the person can’t afford a full course) and couple this with a steroid (to reduce the symptoms). This is a extremely dangerous practise because just as you provide a sub-optimal dose you also reduce the bodies defences against the bacteria, therefore you basically spoon feed these bacteria conditions conducive to the development of resistance. This makes me think how often is this happening? and what needs to be done to stop it?

Bacteria are clever and highly adaptable. In this case we need to behave in the same manner. Antibiotics are the life blood of medical microbiology. Without them we face some major challenges, we basically turn back the clocks 50 years. People will again start to die from simple bacterial infections because we no longer have anything to treat them with. Therefore it is the upmost importance to protect antibiotics and introduce worldwide regulations for their production, distribution and administration. If this means implementing hard and un-flexable regulations, so be it. We need regulations to guide us because when we get sick, we get desperate and when we get desperate we don’t listen to logical arguments. We need to act now rather than later to stem the tide of antibiotic resistant bacteria.

Lots of questions from this I may try to answer them in my next blog.

Peace

Simon