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Friday, 30 December 2011

A good time to get weight in trim

New Year is a familiar time for people to make resolutions and aims to improve lifestyle.

Why bother about overweight?
Excess weight increases the burden of cardiovascular risk (high blood pressure, raised cholesterol and diabetes mellitus); causes premature ageing of arteries, leading to heart attacks, strokes and other serious disorders of the heart, brain and circulation; contributes to risk of sleep dusturbance and sleep apnoea syndrome; causes premature joint ageing with arthritis; non-alcholic fatty liver disease is the commonest cause worldwide of liver damage; and increased risk of cancers - weight gain and overweight estimated to be linked to 1 in 5 cancers.
People who have no difficulty in maintaining normal weight may find it difficult to understand the challenges. For those who are currently overweight, the challenges in regaining a more healthy weight include beating the psychological, physical and social addiction to causes of overweight, and resisting peer pressure.

Getting started
Importants steps on the path to reducing excess weight include being ready to think about action, to think about taking action and to prepare to take action. That might mean telling friends and family you are serious about losing weight, and to seek whatever help may work - e.g.  family doctor or nurse or other health professional, and support groups for the overweight.

What works? 
Smaller portion size, cutting down on processed foods and increasing exercise are the big 3 factors that help. Keep a weight chart and if possible find a friend with whom to lose overweight. Wear a belt. Pace your eating and drink water with your food. Eat regular small meals. Avoid snacking, Research evidence suggests that successful measures include recording weight regularly, knowing the approximate energy intake of what you eat, and regular activity.
It is also clear that insight into the personal health risks of overweight provide extra incentive to lose weight. Better of course to reduce excess weight before serious clinical effects of overweight occur.
There are many support groups and diet plans available to order, often at high cost.

Research evidence suggests that success in maintaining weight loss is associated with clear strategies for coping with life stresses and with 'continued adherence to diet and exercise strategies, low levels of depression and disinhibition, and medical triggers for weight loss'. In contrast, unsuccessful weight maintainers are erratic or inconsistent in recording their weight and being vigilant in keeping to healthy types and amounts of food and in continuing regular activity.
Once overweight people have maintained a weight loss for 2-5 years, the chances of longer-term success in maintaining a healthy weight are much greater.
 There an increasing variety of 'apps' for smartphones and PCs, that reinforce the combined impact of healthier dietary intake and maximising exercise. Many are free, with myfitnesspal an excellent example. These and other free lifestyle apps are like your personal health bank. The more active you are, the more energy balance you have towards losing weight, the more you eat, the less reserves in your health bank.

© DRJ Singer

Thursday, 29 December 2011

Favourite poems on a medical theme from entries in the 2012 Hippocrates initiative poll

@HealthMed To mark the launch of the 2012 International Hippocrates Prize for Poetry and Medicine, the organisers invited nominations of favourite poems with a medical theme. The top 5 favourites were:

Dylan Thomas – Do not go gentle into that good night
William Butler Yeats - When you are old
Dannie Abse - The Pathology of Colours
Jo Shapcott - Of mutability
Stevie Smith - Not waving but drowning

You can see examples of comments received and find links to many of the submitted favourite poems on the earlier blog on favourite poems on a medical theme.

'Medical' was to be interpreted in the broadest sense, with only one nomination to be made by any one person. Nominations were to be for poems written by a poet from anywhere in the world and in any language. The poem were to be contemporary or from any historical period.

The Hippocrates Prize of £5000 for the winning poem is one of the highest value awards in the world for an unpublished poem in English on a medical theme.

Entries for the 2012 Awards are now closed. 2012 Hippocrates Prize judges include New York poet and critic Marilyn Hacker and medical researcher Professor Rod Flower, Fellow of the Royal Society. Awards will be presented on Saturday 12th May 2012 at the 3rd International Symposium on Poetry and Medicine, to be held at the Wellcome Collection in London.

Wednesday, 28 December 2011

Stopping smoking - why and how?

@HealthMed UK No Smoking day is 14th March 2012: some helpful Q & As.

But no need to wait until then to stop ...

Why bother?
Apart from the obvious: cost, smell on clothes and breathe, and taste impairment and eventual loss of taste? Smoking is the single most preventable cause of disease and death.
For primary prevention, smokers and their advisers need to be well informed of the personally relevant risks of smoking and benefits of stopping. For younger smokers, risks include premature ageing of the skin, increased risk of impotence, risk to the developing baby in the womb, and increased risk in offspring of serious chest disorders. For older smokers, the more pressing risks are increased risk of cancer of the lung, mouth, throat, bladder and many other types of cancer; premature ageing of arteries, leading to heart attacks, strokes and other serious disorders of the heart, brain and circulation; and serious lung disorders including chronic obstructive lung disease and emphysema. And in the long-term, it is estimated that around half the smokers who do not give up smoking will die from one or more of these and other smoking-related diseases.
For non-smokers and confirmed ex-smokers the question has to be - why bother? Give up now to improve your medical and financial health.
For current smokers, the challenges are to beat the psychological, physical (nicotine), and social addiction, including resisting peer pressure. Useful ammunition to help smokers to stop smoking includes being aware that giving up tobacco can help you live longer, and that the risk of getting cancer is less with each year you stay smoke-free.

Help from friends and family
Now is a good time for smokers to be ready to think about stopping, to think about stopping and to prepare to stop. That might mean telling friends and family you are serious about stopping, and to seek whatever help may work - e.g. from pharmacist, family doctor or nurse, or other health professional, and smoking cessation support groups. The US National Institutes of Health recommend:
- 'Try not to view past attempts to quit as failures. See them as learning experiences'.
- 'Make a plan about what you will do instead of smoking at those times when you are most likely to smoke'.
- 'Satisfy your oral habits in other ways'. 
Their website provides excellent advice on other ways to help to smoking including how to plan stopping, setting a stop date, and having alternative strategies for times you associate with smoking. 

Stop smoking apps
There are now several free or low cost 'apps' which may be helpful. For example, the UK NHS mobile 'Quit smoking' app provides links for UK smokers to the NHS Stop Smoking helpline and other UK NHS Stop Smoking Servces. 'My Last Cigarette' - MLC provides a dashboard with daily changing reminders of dangers of smoking, and updating estimates of effects of stopping smoking on risk of heart disease, lung disease and other serious medical problems, money saved since stopping, life expectancy gained, and number of smoking-related deaths since the time a smoker has stopped.

Benefits of training health professionals and funding nicotine replacement treament
A controlled study in Germany reported benefits from extra training for family doctors, and further benefit when costs of anti-smoking treatment are subsidized. However, for these over 10/day cigarette smokers, although very helpful for those who succeed in stopping, outcomes were very modest: by
12 months after intervention, 1 in 30 had stopped with usual support, 1 in 10 when their family doctor had received training and been paid a €130 incentive for each patient who stopped, and 1 in 7 where patients also had costs of treatments subsidized.

Unexpectedly rapid benefits from banning smoking in public places
More recent encouragement for anti-smoking campaigns has come from evidence of the rapid time to benefit from stopping: around 1 in 5 fewer heart attacks within 1 year of stopping in countries which have moved to ban smoking in public places. That provides clear evidence to smokers that their cardiovascular risk reduces very rapidly after stopping smoking.

Avoiding temptation to smoke
A recent review of a large number of trials of ways to help people to stop smoking concluded that the evidence for success was 'strongest for interventions focusing on identifying and resolving tempting situations'.

If you are a smoker you quit, what worked for you? Please add a comment ...

© DRJ Singer

Monday, 19 December 2011

Notes on Leonardo da Vinci at the National Gallery, London

Despite reports of a sell-out, good news for the visitor to London that morning queuing (and not too early) has at least up to mid-December been rewarded by entry to the Leonardo da Vinci: Painter at the Court of Milan exhibition' at the National Gallery in London, described by the organizers as ''the most complete display of Leonardo's rare surviving paintings ever held.' 
What’s to see? Sketches in red crayon, chalk and ink, work by his pupils, paintings in evolution and finished, and a tantalising copy of La Cenacolo [‘The Last Supper’], supported by preparatory drawings of key figures at the supper.  During my visit, the paintings were the main attraction, not many visitors showing interest in the sketches. Therefore although the rooms seemed very busy, by avoiding the crowds close to the walls, it was easy to have unhurried close views of all exhibits.

The drawings
There was a surprising contrast between drawings detailing accurate anatomy of human bone and  muscle vs. cross-sections of human skull and brain, which, apart from the frontal sinus, are imagined from perceived wisdom of the time. Most striking were ventricles as a mid-line set of 3 chambers, reported in the gallery notes as attributed by Leonardo to locations for imagination, intellect, memory and the seat of the soul.

Close inspection of the sketches revealed how hatching brings out soft contours and boundaries, part of Leonardo’s sfumato style;- the hatching upper left to lower right, typical of the work of a left-handed artist. And little waste, several sheet showing not only many different figures or views from multiple angles but unrelated engineering drawings.
Thanks to colleague DS for alerting me to the 1977 exhibition at the Royal Academy of Arts of Leonardo's Drawing from the Royal Collection.  Copies of the exhibition catalogue are still available with some detective work.

The paintings?
-  their excellence even more evident by pairings with works by members of his workshop;
-  the ‘Musician’ illustrating Leonardo’s interest in physiology, with eyes painted at different times reflected in asymmetric pupil size - the nearer right eye much larger, indicating that light was much lower than when the left eye was painted; and not explained by contrasts in room lighting – the darker background for  the left side of the face would have caused left pupil enlargement;
- examples of later owners aiming to improve or sanctify Leonardo’s originals – for example, in the later National Gallery version of Virgin on the Rocks, addition of halos and a crucifix.
- numerous symbols explained, from the ermine for purity, to violets for humility, and the red-faced goldcrest, clutched by a breast-feeding Christ child, for torture, in ‘The Madonna Litta’.
-  mood – wonderful examples of melancholy, adoration, serenity; and the sullen, in Beatrice d’Este, wife of the Duke of Milan, Ludovico Sforza.

And within the exhibition there is a mystery. Beatrice is described as ‘La Belle Feronnière’. However ‘The ‘Lady with an Ermine’, Cecilia Galerani, the ~16 year old mistress of the Duke of Milan has the phrase ‘La Bele Feroniere' in golden capitals at the top of the dark background. The curators leave this for observant visitors to decode: obvious explanations – a misattribution, or a view that the sitter was in common for both portraits. Upstairs part of the exhibition provides engaging insight into the Last Supper, all the better for passing a series of Titian portraits – including a 'Young man with quilted jacket', a more self-confident subject, painted around 20 years later than (c. 1510) and perhaps in homage to the more tense features of the sitter for Leonardo's ‘Portrait of a Musician’ (from c. 1490).
Access to the heavily restored ‘original’ Last Supper in Milan is now very restricted. Identified hazards include further pollution from the Milan air, volatile lipids from the skin of visitors and acid damage from carbonic acid generated by exhaled carbon dioxide. In the 1970s, when I first saw the fresco in the Refectory of Santa Maria della Grazie in Milan, with a pre-med student friend, other than by ticket, viewing was unrestricted. My recollections are of a large faded painting in poor state of preservation – and photographs from the Second World War recording the remarkable survival of a sandbag-protected Cenacolo, the other walls severely damaged by wartime bombing.

What next? The Prado has announced discovery after restoration a painting contemporary to the Mona Lisa, considered to be from his studio - either a copy or a simultaneous portrait of the same sitter, a similar Tuscan landscape revealed by removal of later black background. This to be displayed soon alongside the Mona Lisa at the Louvre, to be seen toogether for the first time in over 500 years.

Further sources:
Leonardo exhibition catalogue

The Louvre: all the paintings
Leonardo's Notebooks
Paper engineered Leonardo inventions

© DRJ Singer

Sunday, 18 December 2011

US - European perspectives on potential impact of promoting cycling

As a response to my summer notes on 'city cycling', I was sent a link by @jenicarhee to a graphic (see below) on potential impact of regional schemes to promote cycling. Projected advantages include for health, environment and financial benefit. This approach lends itself to regular update on actual outcomes and imaginative ways to assess impact. See for yourself via: 'How bikes can save us [infographic]'.

Thursday, 24 November 2011

Hippocrates initiative wins national award for Excellence and Innovation in the Arts

The Hippocrates initiative was named winner of the Award for Excellence and Innovation in the Arts in the 2011 Times Higher Education awards, announced on 24th November 2011 in London. This award aims to recognise the collaborative and interdisciplinary work that is taking place in universities to promote the arts. 

Entries are now closed for the 2012 Hippocrates Prize for poetry and medicine, which is for unpublished poems in English.  

The awards will be announced on 12th May 2012 at a symposium in London at the Wellcome Collection rooms on the Euston Road.

The Hippocrates poetry and medicine initiative was co-founded by clinical professor Donald Singer and poet and translator Michael Hulse, and has been supported by many organizations interested in medicine and the arts, including the Fellowship of Postgraduate Medicine, the Wellcome Trust, the University of Warwick's Institute for Advanced Study, the Cardiovascular Research Trust, and Heads, Teachers and Industry. 

In its first 3 years, the Hippocrates Awards have attracted over 4000 entries from 44 countries, from the Americas to Fiji and Finland to Australasia.

With a 1st prize for the winning poem in each category of £5,000, the Hippocrates prize is one of the highest value poetry awards in the world for a single poem. In each category there is also a 2nd prize of £1,000, 3rd  prize of £500, and 20 commendations each of £50.  

BBC broadcaster and journalist Martha Kearney has joined New York poet and critic Marilyn Hacker and medical scientist Professor Rod Flower FRS to complete the judging panel for the 2012 Hippocrates Awards for Poetry and Medicine.
For more on the 2012 Hippocrates Awards and the Hippocrates initiative see my recent update

Saturday, 19 November 2011

Drugs don't work if patients don't take them

@HealthMed A surprisingly common problem: WHO estimates published in 2003 and more recent studies suggest that in the developed world around 50% of patients with chronic medical disorders such as diabetes and asthma do not take their medicines regularly. Indeed, for example, for high blood pressure, around half the patients on drug treatment have stopped taking their tablets within the first year of starting treatment. Despite this evidence that many patients are not benefiting from prescribed medicines, these data may even be underestimates of prevalence of low adherence to medicines, as clinical studies are typically conducted in patients willing to participate, who have less co-morbidity and have fewer prescription medicines than is usual in the general population of patients.
There are multiple potential contributory factors, including costs of paying for medicines, lack of insight into medical conditions or awareness of ways in which medicines may help, perceptions that medicines are not working, and concerns about potential or actual adverse effects of medicines.
Personalising medicines using genetic and other companion diagnostics may help to improve adherence by avoiding drugs more likely to cause adverse effects.
Identifying and improving poor adherence is important to maximise disease control, improve quality of life, and to avoid unnecessary investigation, avoidable treatment escalation and avoidable adverse effects if treatments not normally taken are taken variably by a patient or are dispensed e.g. during acute medical admission.
Poor adherence can be recognized in a number of ways, including direct discussion with the patient, tablet counts, checking timeliness of prescription renewal, and both clinical and laboratory clues from expected biological effects of the medicines.
More studies are needed to identify ways to be more effective in helping patients to be more adherent to their medicines. Meantime the UK'S NICE recommends regular informed discussion with patients to improve adherence to their medicines.

© DRJ Singer

Saturday, 12 November 2011

Broadcaster Martha Kearney joins judges for 2012 Hippocrates Awards for Poetry and Medicine

@HealthMed BBC broadcaster and journalist Martha Kearney has joined New York poet and critic Marilyn Hacker and medical scientist Professor Rod Flower FRS to complete the judging panel for the 2012 Hippocrates Awards for Poetry and Medicine.
Martha Kearney, Marilyn Hacker and Rod Flower, FRS.

In its first 2 years, the Hippocrates Prize attracted over 3000 entries from 32 countries, from the Americas to Fiji and Finland to Australasia.

The Hippocrates poetry and medicine initiative was co-founded by a team from the University of Warwick, supported by several external organizations interested in medicine and the arts. 

The Hippocrates initiative was named winner of the Award for Excellence and Innovation in the Arts in the 2011 Times Higher Education awards, announced 24th November 2011 in London. This award aims to recognise the collaborative and interdisciplinary work that is taking place in universities to promote the arts.

Entries are now closed for the 2012 Hippocrates Prize for poetry and medicine, which is for unpublished poems in English.

With a 1st prize for the winning poem in each category of £5,000, the Hippocrates prize is one of the highest value poetry awards in the world for a single poem. In each category there is also a 2nd prize of £1,000, 3rd  prize of £500, and 20 commendations each of £50. 

Medicine may be interpreted in the broadest sense. Themes for prize entries may include the nature of the body and anatomy; the history, evolution, current and future state of medical science; the nature and experience of tests; the experience of doctors, nurses and other staff in hospitals and in the community. 

Other topics might include experience of patients, families, friends and carers; experiences of acute and long-term illness, dying, birth, cure and convalescence; the patient journey; the nature and experience of treatment with herbs, chemicals and devices used in medicine.

Awards are in an Open category, which anyone in the world may enter, and an NHS category, which is open to UK National Health Service employees, health students and those working in professional organisations involved in education and training of NHS students and staff.

Awards will be presented in London on Saturday May 12th 2012, at the 3rd International Symposium on Poetry and Medicine, to be held at the Wellcome Collection rooms in London.

Marilyn Hacker's book of poetry Presentation Piece (1974) won the National Book Award. In 2009, she won the PEN Award for Poetry in Translation for King of a Hundred Horsemen by Marie Étienne. In 2010, she received the PEN/Voelcker Award for Poetry.

Rod Flower is Professor of Biochemical Pharmacology at the WIlliam Harvey Research Institute[21] in London. His main scientific research interests concern inflammation and anti-inflammatory drug mechanisms. He was formerly President of the British Pharmacological Society and is a Fellow of the Academy of Medical Sciences.

Martha Kearney is the main presenter for BBC Radio 4’s lunchtime news programme ‘The World at One’. She previously worked for Channel 4, presented the BBC’s Woman’s Hour, Today and PM and was political editor for Newsnight.  She has been commended for her national and international reporting, including for work on child poverty. She has been a judge for the Webb Essay Prize and the Guardian First Book Award, and has chaired the judging panel for the Orange Prize for Fiction.  

Marilyn Hacker said: ‘The enormous scope and the intense focus provided by this conjunction combine to entice and hold a reader's attention. The poems I read from the 2011 submissions touched basic and utterly complex human issues, with extreme attention and with admirable verbal bravura. I look forward to reading the new ones.’ 

Rod Flower observed that ‘poetry can reconnect us with ourselves, and with the outside world, in a way that promotes a feeling of well-being and acceptance…and in some mysterious way, poetry enables us to gain traction on the conflicting emotions stirred up by the suffering of disease or the triumph of the cure.’

He added that ‘As a professional pharmacologist with a deep interest in the discovery and use of new medicines to mitigate the ravages of disease, I am delighted to be amongst the panel of judges this year and am eagerly anticipating the challenge of enjoying – and assessing – this year’s entries.’  

The 2012 Awards are supported by the Fellowship of Postgraduate Medicine and the Cardiovascular Research Trust.
The Hippocrates initiative for poetry and medicine was co-founded by clinician and medical researcher Professor Donald Singer and poet and translator Michael Hulse. The 2012 awards are co-organized by humanities researcher Sorcha Gunne.
See also 
- Register for the 12th May International Symposium on Poetry and Medicine

Poems entered are to be of no more than 50 lines and submitted online, accompanied by an entry fee (£6 per poem). 
Judging of submissions will be anonymised.
The deadline for submissions is 31st January 2012.
For more details please visit the website

The Fellowship of Postgraduate Medicine is a national medical society founded in 1918 and publisher of the Postgraduate Medical Journal and Health Policy and Technology.

The Cardiovascular Research Trust is a charity founded in 1996, which promotes research and education for the prevention and treatment of disorders of the heart and circulation. The charity founded Healthy Heart Awards for schools and colleges.

Sunday, 30 October 2011

Kew, angel's trumpet and artemisia - from dream plant and poison to herbal remedy.

@HealthMed Guides to plants have a large number of entries labelled as 'medicinal use' and 'poison'.

The ancient Greeks recognized this overlap, in using the same word for drug, poison and magic charm: pharmakon. This remains in current use in the word pharmacology - the study of drugs of all types.
The Temperate House at Kew Gardens, the largest surviving Victorian glasshouse in the world, has a tantalising display of medicinal plants, for most the scientific name the only clue to properties. Nearby there are two  examples of contrasting properties of plants.

Artemisia [in this case A. austriaca - Austrian wormwood] is there as scrawny, pale green, ground cover. This plant is thought to be named after 4th century BC  queen of Persia and botanical expert Artemisia, or after Artemis, sister of Apollo and Greek goddess of the wilderness, the hunt, fertility and both bringer and treater  of disease in women. This bitter herb is said to have been used by the ancient Greeks to treat parastic infestation by intestinal worms. A large number of medicinal properties are claimed for wormwood species. Artemisinin, the extract of Chinese Wormwood, is used as an anti-malarial however resistant strains of malaria are now being reported. Recent experimental evidence suggests that artemisinin may have anti-cancer effects through limiting proliferation and cause programmed cell death (apoptosis) in certain sub-types of cancer cell. Other research indicates that artemisinin may induce cancer cell resistance to other types of cancer treatment. Much more work is needed on effectiveness and safety of artemisia extracts in the clinic.

Angel's Trumpet [Brugmansia aurea] in contrast has more sinister properties. This tree, native to sub-tropical South America from Colombia to Ecuador, has delicate, orange, trumpet-shaped, hanging, lemon-scented flowers. All parts of the plant are considered poisonous through antagonism of muscarinic cholinergic receptors and other effects of tropane alkaloids, including the racemic mixture atropine, its laevo-stereoisomer hyoscyamine [M1-antagonist], and scopolamine. Actions include belladonna-like effects, hallucinations, sedation and pupil enlargement, which may be symmetrical or asymmetrical. Local shamans are reported still to use plant extracts to aid their ceremonies through inducing visual hallucinations. Historically it is believed that in the Americas extracts of this plant, combined with alcohol and tobacco, were used to induce sleep in slaves or wives before their immolation after the death of their king.

© DRJ Singer

The Tempest and Prospero's curse - magic, pleurisy, and other thoughts

@HealthMed In response to Caliban's cursing in 'The Tempest', Prospero rewards him with a threatening prophecy: 
Side-stitches that shall pen thy breath up ...'
This is a plausible symptomatic description of the intermittent, breath-restricting pain caused by pleurisy [earlier known as pleuritis], a suggestion at least as early as 1886. In contrast, as used by Shakespeare, the word pleurisy denoted a plethora, or excess of blood. This use is thought to have arisen from the idea that the word pleurisy was derived from plus pluris. 
e.g  in Hamlet Act IV, Scene 7:  
"For goodness, growing to a plurisy
 Dies in his own too much."

Pleurisy, local pain and difficulty in breathing, usually arises from inflammation of the pleura - the membranes that lines the lungs and inner walls of the thoracic cage. These inflammatory processes lead to adhesion of the visceral to the parietal pleura.  

Dr Charles Buckmill, writing in 1860, was sceptical of the medical nature of Prospero's curse, seeing it as a blend, half health, half magical in character.
How could Prospero have predicted this would happen to Caliban? Were there poisons at the time [1610-11] that Prospero could have given to Caliban to cause reversible pleurisy? And how did doctors of Shakespeare’s day diagnose pleurisy? The pain of pleurisy is often knife like or cramp-like pain, and worse on inspiration. Pleuritic pain is typically altered by posture, eased in some positions, made worse in others.

These symptoms we now recognize as pleurisy were well-established in Tudor and early Jacobean times; and post-mortem examination was then in European medical centres a route to understanding (or misunderstanding) the nature of disease in retrospect.  The Hippocratic writers were already diagnosing pleuritis from a cluster of symptoms: pain in the side, fever, shivering, rapid breathing, difficulty in breathing when lying flat [orthopnoea] and cough productive of pomegranate-peel coloured or blood-stained sputum. From 300BC, discussion moved to the pathology of pleurisy, with a distinction between disease in the lung (e.g. Herophilus: modern pneumonia) and pleuritis as a disease of the membrane that lines the inner part of the ribs [membrana hypezocota] and resulting in increased pain on lying on the unaffected side [because lung movements than are greater at the site of pleural inflammation], or in some greater when lying on the affected part. 

Pleurisy results in abnormal lung sounds, which, if loud, would have been audible by a physician placing an ear against the chest [auscultation]. This medical diagnostic method is thought to have been used by Ancient Egyptian physicans. However the key early method of diagnosing pleurisy was ‘hardening of the pulse’.

On listening with a stethoscope, a pleural friction rub is heard. Laennec, the inventor in 1816 of the stethoscope, called this friction sound ‘frottement ascendant et descendant’ and ascribed it to emphysematous change in the lungs. Descriptions of the rub include - a scratchy sound similar to that of a door opening on a rusty hinge; or similar to the sound or two pieces of sandpaper rubbed together.  Laennec also used described ‘aegophony’ in pleurisy - a sound like the bleating cry of a goat. Laennec considered that pleurisy was typically associated with modest accumulation of fluid in the pleural cavity (pleural effusion). However with too much pleural fluid, lung sounds disappear, including pleural rubs.

Recognition of pleural effusion goes back to early Babylonian medicine.  Small lead tubes discovered in ancient Babylonian sites are considered to have been trochars – implements inserted through the chest wall to drain pleural fluid. With the benefit of modern imaging, it is now easy to be clear in life that both ‘wet’ and ‘dry’ forms of pleurisy may develop.

Contributors to the germ theory of disease range from Varro in 36BC, to microscope inventor Van Leeuwenhoek’s reports in the 17th Century, and Semmelweiss and Pasteur in the 19th Century. Modern medicine recognizes pleurisy, pleuritic pain and its other symptoms as part of a syndrome. Investigations aim to identify the cause of the pleurisy, which might include viral or bacterial infection, pulmonary embolism, immune-mediated disease, kidney failure and tumours. In addition pneumothorax may present wth pleuritic pain. Of note as early as the early 17th Century, the Paduan Vincent Baronius recognized that patients with pneumonia can also develop pleurisy [pleuripneumony], a concept more widely disseminated by Morgagni a century later.

Back to Prospero’s curse. If not just author’s invention, here are some possible recurrent disorders symptoms of which Prospero could be predicting.
- Pleurisy is typical worse at night, when during attempts at sleep the sufferer may turn to adopt a posture likely to make pleurisy worse and thus awake in pain and breathless.
- Tuberculosis may not be fatal but may leave a patient with pleurisy.
- Malaria was endemic in Shakespeare’s day, including in Mediterranean islands such as Sicily. Attacks of malaria are known sometimes to present with cramping chest pains – and the anaemia of malaria could have made Caliban breathless, especially if were already anaemic. For example his inherited deformed appearance could have had a physical rather than imaginary basis. Thalassaemia – common in the Eastern Mediterranean setting of ‘The Tempest’ - may cause of chronic severe anaemia and is associated with facial deformity.  
- And familial Mediterranean fever (FMF), a genetic disorder common in the Mediterranean,  is a recurrent painful disorder of membranes, including the pleura. And FMF induced joint disease could contribute to a deformed appearance.
Prospero may thus simply have been reminding Caliban of previous or likely medical afflictions. Clearly the scientific details are modern, however these conditions were endemic at the time and present in the right geographical setting for the play.

More on history of pleurisy, stethoscopes and older treatments:

5. The medical knowledge of Shakespeare by Sir John Charles Buckmill MD, Longman, 1860.

© DRJ Singer

Saturday, 15 October 2011

Companion diagnostics - a new concept for safer medicines?

@HealthMed Diagnostics can be used in several ways: to establish the nature, subtype and severity of disease; to monitor wanted response to treatment with lifestyle, drugs and/or devices; to monitor for disease progression and for adverse effects of treatment. The term 'companion diagnostics' describes coupling diagnostic imaging or laboratory investigations with selection and monitoring of treatment. Although a logical idea, its use in the medical setting appears surprisingly recent.

In the late and 1980s and 1990s, reports of the use of combination diagnostics appear largely applying to veterinary and dental practice.

The partner term 'companion therapeutics' was used in a 2003 commentary on the FDA  "Draft Guidance for Industry: Pharmacogenomic Data Submission" issued on November 3, 2003, which noted that the [pharmaceutical and biotech] 'industry is now expected to accelerate its development of diagnostics and companion therapeutics towards the goal of personalized medicine'. Implicit in this evolution of a personalised approached to medicines is the recognition that diagnostics will not necessarily identify that a given patient may have a safe or effective treatment flagged as the result of testing.

An early example of a pharmacogenetic companion diagnostic is the UGT1A1 molecular assay for in vitro diagnostic use. This pharmacogenetic test was approved in 2005 by the FDA for use as a companion diagnostic to a specific drug therapy. The test was to be used to identify mutations in this gene in patients who may as a result be at increased risk of adverse reaction to the anti-cancer drug irinotecan. 

2006 and 2007 discussion of companion diagnostics pointed both to more efficient patient selection for clinical trials and a more profitable approach for drug developers. 

Current descriptions use narrower definitions of companion diagnostics as referring to tests to 'identify and detect genetic, protein, or gene expression markers to predict whether a drug works or causes adverse effect in patients'. However there is a long history of coupling tests with treatment choice and refinement, in every therapeutic area from cardiovascular disorders such as hypertension and raised cholesterol, to anaemia and treatment of lung, gastro-intestinal, renal and neurological disease.

To date there are only 75 publications in the PubMed research database with companion diagnostics as a key term, with a typical recent example from August 2011 in Nature Reviews on Clinical Oncology by La Thangue and Kerr applied to cancer chemotherapy: Predictive biomarkers: a paradigm shift towards personalized cancer medicine.

© DRJ Singer 

Monday, 3 October 2011

Ahead of their time

@HealthMed An example from this weekend's episode of the series 'Downton Abbey' of the challenges of historical accuracy in broadcast media. Set during the Great War, a keen enlister is turned down on medical grounds because of a heart murmur citing 'mitral valve prolapse' as the reason. This condition is often benign however was not recognised until the 1960s. The condition was first reported by John Barlow and colleagues in the American Heart Journal in Feb 1966 (Barlow's syndrome). The phrase 'mitral valve prolapse' was first used by Michael Criley and colleagues later that year in the July issue of the British Heart Journal.

Thursday, 29 September 2011

Toll-like receptor on brain glial cells - a new target to reduce acute toxic effects of alcohol?

@HealthMed Researchers in Adelaide, Australia led by Mark Hutchinson have attracted international media interest with headlines heralding a new treatment to protect from hazards of alcohol. How close is the research to human treatment? And is there a risk this could be a drug of abuse for people over-indulging in alcohol and hoping to avoid harmful effects? My discussion below complements two radio interviews, one with a Californian station, the other with BBC Radio Ulster. To listen to the interviews, use the podcast links at the foot of this blog.

This was an experimental study looking in mice at ways to prevent some of the harmful effects of a single large dose of alcohol. The authors were following up previous research suggesting a link between alcohol and the immune system. The Toll-like Receptor 4 is a member of a family of inflammation-inducing receptors, first described in the fruit fly. TLR-4 is present on immune defence white blood cells in the circulation. TLR-4 is also present on glial cells in the brain. Glial cells make up around 90% of cells in the brain and have an important defence role against brain infection.

The scientists used two approaches to find out whether TLR-4 is involved in unwanted effects of a large single intake of alcohol: animals with genetic absence of TLR-4 and its pro-inflammatory signalling pathway partner MyD88; and the drug (+)-naloxone.  This is the mirror-image version of the (-)-naloxone in clinical use to treat an overdose of an opiate such as diamorphine (heroin) or morphine. (+)-naloxone blocks TLR-4 without blocking the enkephalin receptor through which opiates act.

Hutchinson and colleagues studied two adverse effects of alcohol overdose: sedation and unsteadiness. Their model of sedation was the time taken to regain normal posture (loss of righting reflex). Their model of unsteadiness was the mouse equivalent of keeping balance on a rolling log.
What did they find? The drug (+)-naloxone halved the duration of sedation after acute alcohol and shortened the recovery time for loss of balance.  These effects could have been due to 'off-target' effects of the naloxone, however findings were similar in animals genetically deficient in TLR-4 and MyD88 - reduction in severity and duration of sedation and unsteadiness. The authors also showed that alcohol switched on inflammatory protein production by cells from the hippocampal part of the brain; and they ruled out differences in alcohol metabolism between models.

What do these results mean for people?
Firstly, they are important in raising the question whether genetic variation in activity of TLR-4 inflammatory pathways plays a role in explaining major differences in tolerance of alcohol.
These results provide an interesting complementary mechanism for protective effects of naloxone on alcohol-toxicity to those reported by Badawy and Evans 30 years ago using different experimental methods.
Secondly, these findings suggest that targeting TLR-4 in the brain may be a new way to reverse some of the serious adverse effects of major alcohol overdose in patients attending emergency departments.
What about (+)-naloxone as the drug to use? Studies would be needed to confirm that TLR-4 is also important in alcohol-mediated toxicity in humans, and if so to understand more about the wider range of adverse effects of alcohol which may be prevented or reduced.

What about cautions? 
- This is experimental research which would need to be repeated in human subjects with TLR-4 blocking strategies which pose minimal toxic risk.
- Naloxone has to be given by injection - it is not sufficiently absorbed by mouth to be clinically active.
- Use (+)-naloxone is no exception to the rule that all drugs can have harmful effects. There is concern that risks of harmful effects from (+)- naloxone mean that is unlikely to be safe to use in general alcohol users.
-  (+)-naloxone may block some of the wanted mood-altering effects of more moderate alcohol intake. For example, it is known to affect other brain pathways e.g. blocking stimulant effects of cocaine and amphetamines. This may well lead to loss with this drug of the wanted effects of alcohol.
- The published study showed reduction in severity and duration of alcohol's effects not their prevention: if confirmed in people, general hazards of alcohol, for example when driving, would remain.
- (+)- naloxone is unlikely to prevent the 'hangover' from alcohol, which is recognized to be due to many factors, including dehydration (alcohol is a diuretic), low blood sugar, and other chemicals (congeners) present in alcoholic drinks and contributing to colour and taste.

The most interesting aspects of this study are that:
- if confirmed in further research in humans, assessment of TLR-4 variability may be developed as a test for susceptibility to alcohol;
- safe, effective TLR-4 inhibitors for use in humans could be a treatment for some of the physical effects of a severe overdose of alcohol in people presenting to hospital.

See the article
Podcasts of radio interviews with Professor Donald Singer about research on alcohol, the immune system and new potential treatment:
Interview with Jon Bristow on San Francisco KGO Radio     12.17 PDT 29th Sep, 2011.

© DRJ Singer

Sunday, 25 September 2011

Companion diagnostics to personalise medicine

@HealthMed What common link is there between confusion, dementia, dyspepsia, heart failure, hypertension, liver failure and stroke (apart of course from excess alcohol in some)? They are all syndromes - clusters of symptoms and physical signs with many possible causes, risk factors and co-morbidities.
Earlier approaches to treating these health-related conditions were largely based on trial on error until the most effective treatment(s) were identified. While pragmatic, in many that may lead to a delay in achieving effective disease control, while exposing some patients to unnecessary risk of adverse drug reactions.
The relatively new term 'companion diagnostics' describes the concept that coupling careful selection of biomarkers of disease and risk factor phenotype, of therapeutic response and early warning of risk of adverse reactions, will provide a more rapid route to safe and effective drug selection and monitoring.
Major current challenges include the relative immaturity of research evidence on cost and clinical effectiveness of combining companion diagnostics with specific therapeutic strategies. A major potential driver to improve systematic assessment of companion diagnostics will come from the extension of the activities of NICE (the UK's National Institute for Health and Clinical Excellence) from pharmaceutical and other treatments into assessment of diagnostic technologies (Diagnostics Assessment Programme), including companion diagnostics. This will be complemented by the role of NICE in commissioning new research where significant gaps are identified. 
A further important challenge is the fragmentation of diagnostic services within clinical health services. There are practical reasons for having multiple local diagnostic capacity for serious acute illnesses for which very rapid access to sophisticated diagnostics is potentially life-saving or critical to minimise preventable complications, from early selection of effective treatment. Where there is the luxury of more than a few hours delay without significant risk to the patient, e.g. while using 'holding' empirical treatment, there needs to be more research on relative effectiveness of local compared with remote lab diagnostic strategies. There are also practical issues to be resolved among biotechnology companion diagnostic developers where joint licensing agreements are needed when multiple diagnostics are indicated from different source providers. And standardisation of testing is needed across national health service and private laboratories to ensure that results of these new diagnostic tests are validated.
And of course when there is a single test, implementation is more straightforward. However where multiple tests are needed within a companion diagnostics portfolio, there will need to be a regular programme of induction and refresher education for prescribers on how best to use and interpret results of this new testing strategy. This will be particularly important for interpreting the currently less familiar genotype based tests.