What does glucose look like?

 While I was meant to be revising I found out an interesting bit of biochemistry. One strange property of glucose is that it can reduce Tollen’s solution, a test for an aldehyde group, which is a carbon atom double bonded to an oxygen atom and single bonded to a hydrogen atom carbon at the end of a carbon chain. If you look at a ring structure of alpha and beta glucose you will notice that no such aldehyde group exists:

Where an aldehyde group does exist however is in the straight chain version:

the straight chain version- aldehyde at the top

In a solution the two ring isomers are in equilibrium via the straight chain isomer in what is know as ring closure: an internal or intramolecular reaction. Unlike most chemical reactions when one or more reactants make one or more products this is one molecule essentially reacting with itself.

The straight chain isomer isn’t actually that straight at all we just draw it that way to look good on a page. In reality as the molecule flexes the aldehyde group on carbon-1 comes close to the hydroxyl group (OH^-) on carbon-5. The hydroxyl group can then attack the electron dense aldehyde double bond. The pi-bond of the aldehyde group breaks. The bond is the hydroxyl group then breaks and the hydrogen ends up on the oxygen of carbon-1. Carbon-1 then bonds to the oxygen on carbon-5 to make a ring.

 However there are two ways the hydroxyl group can attack the aldehyde group. If it comes over the carbon atom, alpha-glucose will be formed the OH^- below the molecule. If it comes under beta-glucose with the OH^- above the molecule will form.

Once again things are a bit more interesting and complicated than exam syllabi make things out to be.

Primum Non Nocere

Nonmaleficence exemplified in the Latin maxim ‘primum non nocere” is held up by some to be the most important principle in medical ethics.  Abstaining from harming the patient is usually a good thing to consider given the potential of all medical treatments to damage as well as help but why is the principle considered to be the doctor’s primary concern?

The phrase “primum non nocere” has an uncertain origin. The exact phrase was not used by Hippocrates although he does say things similar such as “the physician must... have two special objects in view with regard to disease, namely, to do good or do no harm”. The “primum” however is nowhere to be seen. The phrase has been attributed to Thomas Sydenham, an English physician born in 1624 and fought for parliament in the English civil war (and incidentally the first to proscribe quinine in the form of cinchona bark for malaria).  However the justification for the nonmaleficence as the sole basis for ethical medicine is probably not for historical reasons.

 In choosing treatments the potential for harm is certainly a factor the must be weighed up against the treatments chance of success. Fixing even simple bone fractures through surgery would be a quick and appealing option if not for the major risks inherent in any surgical operation (and the cost). Even antibiotics have enormous potential to harm especially if used inappropriately when they have a very real risk of leading to the development of antibiotic-resistant strains of bacteria such as MRSA. Whilst the side-effects of any treatment are a serious concern weighing them up does not appear to be more challenging than most of the tasks and issues a doctor has to deal with on a regular basis. Is nonmaleficence unfairly emphasised? Why also are doctors in particular targeted with the responsibility of doing no harm when the roles of, for instance, a soldier or airline pilot have perhaps an even greater potential to cause death and destruction?  

 To some what separates nonmaleficence form other principles of medical ethics for instance beneficence (the duty of doing good) is a matter of scope. Whilst doctors have a duty to everyone to do no harm the doctor’s duty to good is strictly limited to the patients whose treatment he or she is currently involved in.

However just because we have a duty to do no harm to all does not necessarily mean that nonmaleficence has priority when it conflicts with other principles for instance when Nonmaleficence conflicts with respect for autonomy if a patient does not consent to a life saving treatment. Like people’s perception of good and what they seek to gain from a treatment, each patient will have their own perception of risk and harm. Palliative care may be acceptable for some whilst others may want curative treatment options despite major risks involved.  

Whilst nonmaleficence cannot, in my opinion, be the most important principle of ethical medicine I would not goes as far to say that “primum non nocere” deserves to be confined to the history books. The principle of nonmaleficence itself is vital when combined with other ideas such as justice and autonomy in deciding the best course of action. 

How the UK exports death- Tobacco in the developing world

 I was shocked recently by a BMJ article by Tony Dalamothe entitled: “Deaths from smoking: the avoidable holocaust’.  (http://www.bmj.com/content/344/bmj.e2029). He will no doubt cover the topic better than me so I am in debt to him for explaining the subject. In the article he presents a bleak view of the attitude to smoking. “About 100 million people died from smoking in the 20^th century- twice as many as Stalin, Hitler, and Pol Pot were together responsible for.”  He attribute the lack of response to the smoking related diseases pandemic to libertarian views that people have the right to spoil the own health and to the profit-motivated dealings of tobacco companies. He quotes the word of a World Health organisation committee in 2001: “Infectious diseases do not employ multinational public relations firms. There are no front groups to promote the spread of cholera. Mosquitoes have no lobbyists.”

I’ll expand on what Tony Dalamothe says slightly. Whilst the smoking rate in the UK (shown here as a percentage) has been steadily falling since 1960, step by step due to one piece of legislation then another, the future of smoking is unclear. If the observed trend continues (line A on the graph) the UK will be smoker free by 2040. Line B is the scenario where the smoking rates reduces to just a small number of die-hard smokers who refuse to quit despite all legislation. Line C shows the ideal situation; smoking rates decline until smoking itself becomes considered socially unacceptable and smoking rates plummet because it become easier to legislate against without political opposition. Whatever happens smoking in the UK looks to be going down.

 The situation in the developing world is shockingly different however where smoking rates are increasing by about 3.4% per year. For every three cigerettes smoked world wide at least one is in China.(http://news.bbc.co.uk/1/hi/3758707.stm#china0). Tobacco companies have looked to the developing world for a market with enough wealth to afford a luxury (albeit a deadly on) like smoking under government which lack the tough control needed to enforce smoking legislation and cannot afford to ignore the tax benefits smoking provides. In this environment tobacco companies can make millions at the expense of the health of the people. As two of the biggest tobacco companies, British American Tobacco and Imperial Tobacco, are British this effectively means the UK is a net exporter of smoking-related diseases.

 How we respond to the spread of tobacco in the developing world is a difficult issue. It would be hard to instruct and help developing countries to legislate on tobacco without fitting the much-hated stereotype of the prosperous westerners reliving the glorious days of the British Empire when a white man was needed to solve the big problems for the blacks. Given that our own companies are doing the damage any move of this sort would be obviously hypocritical. Tony Dalamothe takes the view that the only thing we can do is chuck these companies out of the country because they shame us all the time they are here. Is the only ethical way to deal with the problem would be to try to ignore the death and suffering from tobacco until developing countries have the confidence to legislate against the problem themselves?

 (I recommend visiting the website of British American Tobacco and Imperial Tobacco for an entertaining PR masterpiece in excuses and apologies: http://www.bat.com/group/sites/uk__3mnfen.nsf/vwPagesWebLive/DO52AMD7?opendocument&SKN=1

http://www.imperial-tobacco.com/index.asp

 The company’s overall message about delivering a high quality product, value for shareholders and responsibly farmed goods tries to hide the spread of smoking-related death and irresponsible selling that goes on. Worse still the companies are trying to jump on the anti-smoking bandwagon by campaigning against black-market tobacco that is more easily accessed by children (and no doubt harming their profit margins).)

Prions

The standard model of pathogens (agents that cause disease) that you will have been taught is that there are three main types of pathogen: viruses, bacteria and fungi. Even when we include Protoctista like plasmodium (the organism that causes malaria) and the delightful parasitic worms there is still one remaining. It is the prion, a misfolded protein. Whilst they are barely relevant to medicine they have the potential to shatter long held scientific beliefs about disease.

 Prion diseases are exceedingly rare. The three prion diseases affecting humans I could find are Kuru, a disease confined to the Fore people of New Guinea who eat the brain of their dead relatives out of respect and Creutzfeldt-Jakob disease, a human form of mad cow disease, and the amazingly titled Gerstmann–Sträussler–Scheinker syndrome, an extremely rare hereditary condition. Animal prion diseases are a little more common, mad cow disease and Scrapie are the most relevant.

Members of the Fore tribe that have not suffered from kuru apparently due to a
genetic mutation offering increased resistance

 All prion diseases are incurable and inevitably fatal and all work in roughly the same way. Infection begins with a prion, a misfolded protein entering or being accidentally made in the body. Somehow the prion propagates by transferring its misfolded state to a similar but normally folded proteins. This causes an exponential growth in the number of prions. Death usually occurs not by the lack of the normal protein but by the prions accumulating in the brain and spinal cord. There they damage neurones and form cavities. For this reason prion diseases are also called Transmissible Spongiform Encephalopathies (transmissible because it can be passed on through contaminated blood or tissue, spongiform because of the sponge-like result on the brain and encephalopathies refers to diseases of the brain). The first symptoms of this condition are usually personality changes, depression and loss of movement control and an unsteady gait. Insomnia has also been reported. These develop into extreme dementia and death.

the result of  spongiform encephlopathies

 The existence of prions has had an impact on the treatment of surgical apparatus. All surgical tools are decontaminated before re-use but ones used on the brain now especially so. Prions appear to be able to survive normal protease, heat and radiation treatments. Only extremely high temperature or an extreme pH guarantee that something is prion free.

 The discovery of prion diseases caused such controversy because it appears to go against the “central dogma of molecular biology” which puts nucleic acids as the basic unit of information. Prions appear to replicate without any sort of nucleic acid to code for the protein. This seems to defy normal biology. Where does the information of the order of amino acids come from if not from DNA or RNA? We still aren’t quite sure how prions are able to replicate. Several hypotheses have been made but all are a bit vague.

 The protein only hypothesis is the idea that no nucleic acids are involved and that prions replicate from proteins by some form of self-catalysis (it catalyses a reaction which forms it as a product). Supporting this hypothesis is the observation that animals lacking a protein that can become protease resistant aren’t affected by prion diseases. Presumably this type of protein is reactant in the prion replication.

How is it done?

 Other hypotheses place the misshapen prion proteins as a side effect not a cause of Transmissible Spongiform Encephalopathies. One hypothesis denies the lack of nucleic acids and attributes the diseases to a slow-acting virus. Supporting the idea are the subtle changes in pathology in prion diseases (different strains perhaps) and the finding of virus like particle in a small number of scrapie-infected animals. Another hypothesis, a masterpiece of lateral thinking, attributes the disease to a complicated form of manganese poisoning.¹ the idea is supported by evidence that manganese can turn normal proteins into protease resistant polymers and brain diseases do seem to be prevalent around areas of manganese mining. None of the hypotheses explain all of the evidence and prions remain an unexplained mystery in the side of the otherwise stable science of pathogenesis.

1-Prion protein polymerisation triggered by manganese-generated prion protein seeds.

http://www.ncbi.nlm.nih.gov/pubmed/22007749

PolyPill- Treating the Healthy

 PolyPill was an idea conceived by two professors: Nicolas Ward and Malcolm Law in 2001. The idea was simple. On pill, taken once a day by all people over 55, all diabetics over 35 and all people with cardiovascular disease, containing a mixture of drugs and vitamins could be a cheap and easy solution to reduce the risk  (according to their research) of ischaemic heart disease (IHD) by 88% and strokes by 80%¹. They claimed that such a pill, which they called PolyPill, would have “a greater impact on the prevention of disease in the western world than any single intervention.

 Whilst the concept is easy to understand the exact composition and research for the PolyPill is more complicated. The trial Ward and Law used to justify their idea di not take people give them a pill containing a drug-vitamin mix and then record how many suffered from IHD and strokes. Rather the study looked was a meta-analysis. It looked at all previous research into the drugs they were interested in and cleverly linked them together.  IHD and strokes are not like a broken bone or a pathogenic disease in that they have a single obvious cause. Both are related to a number of risk factors. Having high levels of such risk factors would not mean you would get IHD or strokes it would only be more probable. There are similar difficulties in trying to persuade smoker of the link between smoking and lung cancer. All smokers will know one lucky sod that smoked for years without developing cancer and forget the large numbers of people who unfortunately do.

 Previous trial targeted people at risk of developing IDH due to being on the extremely high or low end of one one risk factor distribution and tested to see if they could reduce the number of people developing IHD by using a drug that is designed to return that single risk factor to within normal limits. What Ward and law did was to suggest that if all these drugs were taken together in one pill it could return all known risk factor to normal limits and have a significant effect on the majority of people not just people in the extreme ends of one risk factor distribution.
 The suggested ingredient of a PolyPill would be:

• A number of drugs to reduce blood pressure (a significant risk factor of IHD) such as: 

1.  a diuretic (a chemical that increases the excretion of fluid from the body via the kidney nephrons
2.     a beta-blocker (a drug that reduces the effect of the hormones epinephrine and norepinephrine (see my post on Brunner’s syndrome))
3. an ACE inhibitor ( a chemical that inhibits the enzyme angiotensin-converting enzyme (ACE) which is part of the blood pressure regulating system. The net result is a reduction in blood volume and therefore a reduction in blood pressure)

How ACE Inhibitors work

• A statin which is a drug that reduces blood cholesterol levels by inhibiting the enzyme HMG-CoA reductase thus slowing a chain of metabolic reactions leading to cholesterol production.
• Aspirin, which among other things reduces clot formation by inhibiting the production of thromboxane a chemical that binds platelets together.  
• Folic acid, a vitamin that among other things, reduces the levels of the non-protein amino acid Homocystiene in the blood.

a Folic acid molecule

Homocystiene: Like cysteine but with an extra methyl group 

The advantages of PolyPill are that it could significantly reduce the human and financial cost of IHD and strokes which are together responsible for a third of all deaths in western countries. The pill helpfully contains ingredients that cannot be patented by drug companies so it could be made as cheaply a 10p for one daily pill. (this does however explain why drug companies have been unwilling to fund trial into PolyPill despite its huge potential benefits).

 PolyPill has not gone without criticism however. Ignoring entertaining but pretty irrelevant satire such as proposals for a PolyMeal² (a daily meal containing a small number of healthy ingredients such as almonds, garlic and fruit) the concept has also come under considerable criticism about some of the contents (it appears homocystine which the folic acid is there to reduce has only a correlative role not a causative role in IHD so the folic acid will not reduce IDH just make the blood tests look better) and because it appears Ward and law were too enthusiastic in describing PolyPill as a solution to preventing IHD and strokes (primary prevention) not preventing existing conditions of the early stages of IHD developing to the stage where it causes significant morbidity (secondary prevention). Also bear in mind that the drugs in PolyPill are not without risk. Ward and Law admit that 8-15% of people may experience some side effect.

 But PolyPill has come under most criticism for discouraging people from taking care of dietary and social risk factors associated with IHD. Why have a moderate alcohol intake, healthy diet and lots of exercise if there is a pill to do it for you? It worries me that PolyPill may become a danger to public health by medicalizing your chemical intake and distracting from simple causes of disease however much I like the idea for its simplicity and apparent efficiency. 

1-Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. http://www.bmj.com/content/326/7404/1419.full

2- PolyMeal- http://www.ncbi.nlm.nih.gov/pubmed/15604180