Beyond endogenous retroviridae, the bugs that made you "you".

This paper has "misunderstandings" in an alliterative title, making it a sure-fire winner, despite verbosity.

Virus geeks will be familiar with the concept of endogenous viruses, and the advantages of heterogeneity in MHC selection are probably also familiar to most medical students. This paper, however, discusses the drive given to MHC diversity caused by the variety of pathogens a population is exposed to. This is really the teeth on the gears of epidemiology with regard to immunogenomics, and something worth thinking about. Population diversity increases in reaction to new pathogens, as novel selection forces influence the advantageousness of minority (or de novo!) alleles. It also gives some basic information about how genomics are assessed to establish the age of an allele, and also how the mechanisms of pathogen-mediated selection cannot easily be differentiated by researchers. Though the thrust of this paper might be a technically minded one about the state of the art, in passing it is a good primer for the uninitated.

Good learning, and, post champagne, Happy New Year (see last post)

Rohan

How to do an antidepressant trial properly

This study:

A Systematic Review of Comparative Efficacy of Treatments and Controls for Depression

Is fantastically considered. A Metastudy incorporating 13000 patients, the authors have gone to considerable length to seek out the truth. DSM classification of depression may have obfuscated the answer given that the trials used spread over DSM II, III and IV, but the authors considered this and retrospectively classified the patients acoording to various narrow classification systems to remove error, I only mention this to point out that these guys know what they're doing.

It begins sleazily enough, unblinded trials show more treatment effect than blinded ones. Published trials likewise perform better than unpublished ones.  Also, placebos had greater effects in unpublished trials than in the published ones, likewise blinded and unblinded trials respectively.

The study establishes the importance of rigorous methodology. Doubting unblinded trials is therefore very much justified. Furthermore, tests of publication bias are worth our attention. Also, the enhanced placebo effect of active engagement with patients is shown to be the most effective part of treatment, so we must always, therefore, include the counselling of the patient by the doctor in the consultation as a confounding factor. As they write, the data shows that the "type of treatment offered is less important than getting depressed patients involved in an active therapeutic program". Finally, very clinically, antidepressants alone do not perform better than various non medical interventions, like sham acupuncture.

Good Learning, and Happy New Year,

Rohan

Epigenetic influence on Neuroplasticity

It appears that neuroplasticity is governed by epigenetic mechanisms, which can be modulated to allow learning of absolute pitch (a.k.a. perfect pitch) beyond the normal age window (4-6 years in humans).
Absolute pitch is thought to require specific training, with association of conceptual labels to specific pitches. In this experiment, the authors report treating young adult men with valproate improved their learning of absolute pitch outside the normal window of opportunity.

Valproate is a drug used primarily for anticonvulsant effects in generalised epilepsy, and it is a known inhibitor of HDAC. Histone deacetylase (HDAC) is an enzyme responsible for removing acetyl groups from histones. Acetylation of histones makes them bind their DNA less tightly, increasing the DNA's accessibility and promoting transcription.
It should be noted that this effect is generalised across all histones.

The study design was randomised, double blind, placebo controlled crossover. The subjects were, interestingly, asked whether they knew which treatment arm was the active substance. 17/18 knew. This is a perfect example of how psychoactive drugs cannot be blinded in the typical way. Essentially the study was un-blinded, making it liable to more confounds.

If we look at the results, after crossover the effect of valproate disappears. This is important, as it puts the validity of the conclusion into question. The authors do not seem concerned, (having got the result they want?), and suggest that the subjects experienced memory interference having already mis-learned that task once while on placebo. They rightly suggest a larger, single stage trial to reveal the truth.

The results are interesting and deserve further attention but are not conclusive, especially given the lack of effect after crossover, with no falsifiable explanation for it.


Valproate reopens critical-period learning of absolute pitch
Gervain Judit, Vines Bradley W., Chen Lawrence M., Seo Rubo J, Hensch Takao K., Werker Janet F, Young Allan H   
Frontiers in Systems Neuroscience
2013

The Supplementary Motor Area and You

It is commonly understood that the primary motor strip, or M1, is where cell bodies of neurons are found in a organised manner, forming the first part of the path innervating striated muscle. But how are impulses through this area orchestrated to create the possible motor actions of our bodies?

Before the 21st century the supplementary motor area (SMA) was recognised as involved in motor activity because of increased blood flow. It lies just anterior to M1.
Another area, called the pre-SMA, is found more anterior and medially; on the superior frontal gyrus.
Compared to the primary motor cortex, the SMA's blood flow was greater during complex motor tasks, and even during visualisation of actions.
Pacing tasks on external stimuli (metronome, visual cues) or internal stimuli correlates with whether the SMA or pre-SMA are active.
Pre-SMA is correlated with novel tasks, or early during skill acquisition, whereas the SMA proper is with established, complex tasks (like playing scales).

It appears that the SMA may, crudely speaking, be necessary for coordinating simple or learned movements. In contrast the pre-SMA is probably necessary to train new movements.
This has clinical relevance for focal brain injury to the motor areas when considering how much function may be recovered with rehabilitation.


Motor areas of the medial wall: a review of their location and functional activation.
Picard N, Strick PL.
Cereb Cortex. 1996

Mental, Neurological, or Nervous system illness?

Psychiatry has been separated from mainstream medicine in part by diagnostic manuals, like the DSM or ICD, which advocate conceptual distinctions between 'mental' and 'neurological' diseases. The fact is that such distinctions are not apparent, being an allusion to the false mind-body dualism that pervades people's thoughts, and indeed our common language.

Evidence of changes to the brain organ in established psychiatric disease abounds; whilst primary changes to the brain from trauma or stroke exact repercussions on the mind and behavior of people. Clearly the mind is borne of the brain and change can occur from both direction.

A realistic view of humans or other animals must consider 'mental' and 'organic' as distinct realms but as methods of enquiry and interaction with a single, cohesive organism.

Some disorders, such as psychogenic non-epileptic seizures, get caught in the middle of each disciple to the detriment of those patients, and society as a whole.

Time to end the distinction between mental and neurological illnesses
P D White, H Rickards, A Z J Zeman 
BMJ 2012

Mechanisms of the Symptoms of Colds and Flu

Cold and flu are common and crappy. This paper is worth reading especially when suffering from one.

Summary:
Most symptoms are due to the inflammatory response, rather than the pathogen itself. Cytokines released from damaged tissue and activated white cells diffuse locally, and circulate systemically, causing the myriad of symptoms we all know.

Symptoms can be split by timing;
early - come on and dissipate over 2-3 days: sore throat, sneeze, chills, malaise, headache
late - develop over days and last over a week; nasal congestion + discharge, malaise, cough

persisting long after infection: cough

Each symptom has its own mechanism;

Sore throat / Pharyngitis

Cytokines - especially bradykinin and prostaglandins - released locally, acting on trigeminal nerves.

Sneezing

A reflex, probably initiated by histamine acting on trigeminal nerves to trigger afferent signal to sneezing centre in brainstem. The efferent reflex is to motor and parasympathic (PS) parts of the facial nerve, and respiratory muscles.

Simultaneous lacrimation and nasal secretions occur via PS facial nerve activity, while eye closing is by somato-motor facial nerve activity. Note relation of eyes to nose, which is reversed in photic sneezing.

Runny nose / rhinorrhoea

Components: neuro-reflex glandular secretion (blocked by antimuscarinics) and capillary proteinaceous ooze due to inflammation induced endothelial junction loosening.

The colour of discharge and sputum does not relate directly to cause (bacterial vs viral) but more the intensity of inflammation, representing recruitment of white cells into the airway.

Neutrophils and monocytes contain azureophilic granules containing myeloperoxidase, giving green-yellow tinge at low concentration or murky green at higher ones.

nasal congestion

Due to venous plexus dilation at the narrow nasal valve region, caused by inflammatory mediators. Usually cycles between each nostril, under the influence of sympathetic vasconstrictor nerves.

Sinus pain

Pain is not dependent on patent ostia, but can be due to increased pressure in sinus, and distension of draining blood vessels.

Watery eyes / epiphora

Obstruction of naso-lacrimal duct as it opens in the nose, due to venous plexus engorgement.

Cough

Stimulated by vagal nerve activity, always at level of larynx or below. Hyper-reactivity of the reflex, which is normally to protect the airway, occurs due to inflammation.

Influenza damages airway epithelium > most cold viri, leading to more cough, rather than a simple head cold.

The progression from sneezing to cough can be explained by progressive inflammation spreading down the respiratory tract, stimulating trigeminal nerves, then vagus nerves.

Headache

Probably from effects of circulating cytokines on central (i.e. hypothalamic or brainstem) nervous system.

Chills

Chills occur regardless of skin temperature, due to central nervous activity, connected to shivering, changing appraisal of somatic sensation. Chills are not from peripheral vasoconstriction causes skin temperature decrease, perceived as coldness. 

Fever

Occurs more in novel exposures, i.e. pandemic viri, or in infants. Interleukins 1 and 6 are most important, circulating to the hypothalamus or to vagus nerve neurons, effecting a change in temperature set point.

Malaise and psychological effects

As well as the cumulative effects of all the above, there are separate effects on neurological activity from circulating cytokines.

Features include: psychomotor slowing, ahedonia, sleep disturbance, hyperalgesia.

Interleukins 1, 2, 6 and tumour necrosis factor are thought responsible.

Anorexia

seems to be a protective response, saving energy, starving pathogens of zinc and iron, and stimulating monocytes sand macrophages. It occurs via effects on the hypothalamic feeding centre.

Muscle aches and pains / myalgia

Probably mediated through prostaglandin E2, causing myocyte catabolism and nerve stimulation. This releases amino acids for the liver to create immune molecules like complement. the pain and breakdown can be blocked with cyclooxygenase inhibitors.

Lancet Infect Dis. 2005 Nov;5(11):718-25.
Understanding the symptoms of the common cold and influenza. 
Eccles R.

Chronotype (night owl or early bird) on MRI scans

This paper is interesting for two reasons:

1. It confirms the obvious fact that people with different sleep rhythms have different white matter properties. 
2. It fails to do much more.

Before looking critically at the paper, I will say that I agree with many of the conclusions it comes to. for instance that society's clock driven culture leaving people in chronic jet-lag states which drain them, and that flexible working hours would help those people (and the transport network).

I'm writing about it because it demonstrates an example of how many MRI neuroimaging studies are flawed.
The authors relate chronotype (early bird or night owl) to brain changes, and also to use of recreational drugs (alcohol and nicotine).
Now anybody can see that people who might stay up late may be using stimulants or hedonistic substances. However in this paper they use a crude test to 'control' for this effect, by looking for a Pearson correlation coefficient between each MRI variable and each social measure (alcohol, nicotine etc). Why is this flawed?
1. Self reported consumption levels are inaccurate
2. consumption does not linearly relate to the effect on that person
3. many other substances were not included, such as chocolate, refined sugar, cannabis
4. there was no reference values for the correlation coefficient. this would probably need to be defined in a separate study, properly powered for the purpose.

This paper is the tip of the iceberg of similar studies which have the basic formula;
Take small sample of healthy males. Do MRI scans. Relate scans to some ill-defined phenomena in lay-psychology, such as 'niceness' or 'funny'. Had this study clearly defined chronotype, and dissected it out from the numerous confounding factors, it might have been of more value.
Ideally the study would have had matched pairs, or have used genuinely jet lagged people, to add relevant comparison.

“Early to bed, early to rise”: Diffusion tensor imaging identifies chronotype-specificity
Jessica Rosenberga  et al
NeuroImage 2013

Neuroscience and Genetics of PTSD

Welcome Back.

At no point was I taught about the state of the art in the pathoaetiology of stress-related disorders. I was however taught about the now defunct monoamine hypothesis. Let's assume you suffered the same fate and  talk about the neuroscience of PTSD.

The fear conditioning model of PTSD suggests that:

• Fear conditioning plasticity would have an evolutionary advantage in facilitating the rapid recognition of danger
• Malfunction in this could lead to overconditioning wherein a patient might experience too great a response to the stimulus OR develop too vague a pattern recognition system for that event
• This may be caused by elevated cortisol at the time OR elevated catecholamines

Amstadter et al discuss the three main neurobiological systems that are implicated in this model:

• The Locus Coeruleus (and noradrenargic system)
• The HPA Axis
• The Limbofrontal neurocircuitry of fear

They then discuss the genetics of PTSD - making this a really fun and varied read (as long as you just accept that there will be a lot of acronyms, because hey, this is genetics). Unsurprisingly there is a lot of difficulty in separating genetic risk factors from environmental ones but there is some solid evidence relating to serotonin receptor- and transport-related alleles, alleles relating to BDNF, Dopamine receptor modulation of traumatic memories, Corticotrophin-releasing hormone related alleles and much more.

Also they flag up lots of research that should be done. No mention of epigenetics which I positively GUARANTEE will be involved somehow, but ho hum.

Good Learning and happy new academic year.

Marblecake

Fluid resuscitation: what works best

The NEJM produced a review recently covering fluids for resuscitation. There are pretty pictures in the original paper.

The theory:
The compartment model is useful in predicting where different types of fluid go. Interstitial oedema is the primary concern with fluid loading. Cardiac overload and neuro-humoural effects can also be problematic.
The glycocalyx is an endothelial structure on the luminal side which affects oncotic pressure. Glycocalyx disruption occurs in inflammatory states (i.e. sepsis, surgery) and leads to protein leak into the interstitium.
Interstitial protein increase oncotic pressure, shifting fluid from other spaces, causing interstitial oedema. organ specific consequences of interstitial oedema include respiratory failure and intra-cranial hypertension.

One study of febrile, dehydrated children showed increased mortality with either normal saline or albumin, bringing doubt on whether fluids are beneficial in other conditions.

What to use:

There is some evidence for what fluids are best to use, but nobody knows what volumes are ideal.
Resuscitation to endpoints, like arterial or venous blood pressure, has limitations.
Albumin and normal saline are largely equivalent, except that albumin achieves similar physiological endpoints with lower volumes (ratio ~ 1 : 1.5).
Albumin can increase mortality in neuro-trauma, probably from intra-cranial hypertension.
Normal saline promotes hyper-chloraemic metabolic acidosis;
'Balanced' solutions like Haartmanns have specific side effects depending on what is used to replaced sodium chloride (lactate, acetate and calcium).  Lactate - hypotonicity; acetate - cardiotoxicity; calcium - microthrombi with citrate stabilised blood products.
Compared to balanced solutions, Normal saline was associated with more renal impairment and infections in the operative setting.
Hydroxyethyl starch (HES) is of little benefit over any other, but with greater risks.

Summary:
Fluids can be bad for patients. balanced solutions are usually > saline.


Resuscitation Fluids
John A. Myburgh, M.B., B.Ch., Ph.D., and Michael G. Mythen, M.D., M.B., B.S.
N Engl J Med 2013; 369:1243-1251September 26, 2013DOI: 10.1056/NEJMra1208627

Psychogenic disorders - somatisation, conversion, malingering and facticious disorders

Psychogenic disorders are very common, but attract a proportionally tiny spot in medical education and in research budgets. Much clinical time and resources are used mistreating people with these conditions. Stigma is common, and doctors talk of 'real' and 'not real' symptoms; such judgements are more a reflection of medical ignorance than ability to see into the patient's mind.

Stigma probably arises from the patients being difficult, and the doctors being impotent to manage them.

A key distinction used in diagnostic manuals is between voluntary disorders (factitious and malingering) versus involuntary ones (conversion and sanitisation). However these distinctions are largely inadequate  outside of conceptual distinctions, because they rely on mind reading.

Mind body dualism abounds in all these discussions, with references to "psychological or neurological", or "in the mind or a real disease". Perpetuating those dualist throwbacks are an obstacle to the patient's recovery: giving patients clear and accurate information on their condition improves their outcome substantially. Saying "your condition doesn't have a known cause other than stress and emotion" validates the condition whilst being honest. To often clinicians will feign from discussion, perhaps not knowing what to say. But patients are reliant on clear advice from doctors in order to engage in their treatment and improve.

The plot thickens when we consider that existing neurological disease can be fuel for an psychogenic predisposition, resulting in one disease's symptoms being exaggerated or morphed from recognition.

A shift is required in how we perceive the psychological dimensions of illness, and to be compassionate toward them.

Psychogenic DisordersThe Need to Speak Plainly

Joseph H. Friedman, MD; W. Curt LaFrance Jr, MD, MPH

Arch Neurol. 2010;67(6):753-755. doi:10.1001/archneurol.2010.91.

Sugar, will and cognitive performance

It is a common folk psychology belief that eating or drinking something carbohydrate rich will benefit performance in concentration, study or work. This phenomena was recently examined in a small but well designed study, with similarities to the placebo-balanced design as popularised by researchers like Fabrizio Benedetti.
The explicit hypothesis is that a view that willpower is limited and can be replenished with sugar will be a self fulfilling prophecy, whilst an unlimited model of willpower will lead to neutral responses to sugar.
This study is essentially about placebo effects of sugar, and suggests that our beliefs about energy, willpower and carbohydrates shape our cognitive responses.
The authors make the commendable point that we can be liberated from dependency on health ruining foods and drinks in the hope of performing better.

Key points:

• Existing beliefs that willpower is unlimited correlate with no response to sugar on cognitive tasks
• Actual consumption of sugar has different effects to the taste of sweetness, or the belief it is sugar.
• Beliefs can be modified quickly and exert effects on response to sugar.
• The performance enhancement form glucose is in part due to socially perpetuated beliefs that willpower is limited, deplete-able and replenished with sugar.

Beliefs about willpower determine the impact of glucose on self-control
Veronika Joba,1, Gregory M. Waltonb, Katharina Berneckera, and Carol S. Dweckb,1

fMRI and BOLD - what do the pretty lights actually mean?

Functional magnetic resonance imaging (fMRI) relies on the blood oxygen level dependent signal (BOLD). fMRI is best known for pretty pictures of brains with lights on certain bits, which incidentally are often of little utility for medicine or science due to poor study design (see Uttal).
This paper goes from basics to advanced and is well worth a read if interested in the edge of current controversy.
Key points:

• BOLD signal arises from the relative overshoot in blood supply to increasing metabolic activity, leading to higher Oxy-haemoglobin, which is detected in venules.
• The most metabolically demanding activity in neurons is maintenance of resting potentials
• Glia are also metabolically active
• Local field potentials (LFPs) are probably the greatest cause of metabolic activity, and correlate strongly with BOLD in monkey experiments
• Neuronal action potentials (APs) have varying correlation with BOLD in monkey experiments, which may depend on when LFPs correlate with AP rates
• Different brain regions have different relationships between LFPs and AP rates; i.e hippocampus shows dissociation
• Dissociation can, theoretically, occur because of circuitry and vascular phenomena

Paper:

How and when the fMRI BOLD signal relates to underlying neural activity: The danger in dissociation

Arne Ekstrom, 2010

Epigenetics by way of Sexual Dimorphism

A tutor once taught me what epigenetics was. He confused it with the extended phenotype. In case you also have a bad tutor, read The demoiselle of X-inactivation: 50 years old and as trendy and mesmerising as ever.

Summary:
Why don't women produce twice as many X-chromosome-coded proteins as men? Something to do with Calico cats, right? These clever-sounding questions serve as a great starting point to review the recent and promising field of epigenetics, and the process of X-inactivation!

How does the cell know how many chromosomes it has? How does it turn one and only one off? The eponymous Trendy Demoiselle reveals the secret of chromosomal random inactivation herein.

Elsewhere in the field of epigenetics, we may remember the process of DNA imprinting from discussions of Prada-Willi and Angelman's syndrome. This is a very important process, giving varying phenotyes for a given genotype. The process is discussed in great detail in Genomic imprinting: recognition and marking of imprinted loci.

The processes of DNA methylation, acetylation and ubiquitination are very important in epigenetics, as well as the rearrangement and packaging of DNA within the nucleus. They were mentioned in a previous post but that was before I had realised how important the field is.

Finally, for a lighthearted bit of (ahem) learning, this genetics website lets you lick virtual rats in order to affect the epigenetics of their hippocampus!

Have fun.

Marblecake

Statement of Purpose

The Pertinent List will:

1. Publicise scientific review papers relevant to the medical profession. These papers will:
2. Err on the side of in depth, comprehensive papers.
3. Be up to date, whilst well received in peer review.
4. Overall be well written and fascinating to read!

If you know of a good paper, and want to share it, please get in touch and we'll be happy to see it.

This blog is moderated by a pair of geeks.

Fetal origins hypothesis

Embryology is normally a killer word for a lecture at medical school, dropping attendance down from the usual 8% to something embarrassingly low. This said, if done right, it can provide fascinating insight into the underlying themes of physiology and pathophysiology in almost every speciality.

One of the most obvious areas is cardiology, where the subject is a contorted, asymmetrical knot of the few remaining vessels from what was an organised, symmetrical network in early pregnancy. The paper "Fetal origins of coronary heart disease" takes the focus away from the obvious structural and pressure-related discussions we learn about the heart at birth, and looks at metabolic disease in a much more exciting way to usual. The paper is an oldie (1995) but is still a goldie.

The paper: "Diet, Nutrition and Modulation of Genomic Expression in Fetal Origins of Adult Disease" approaches the fetal origins hypothesis as an epigenetic problem. PPAR-gamma genes' role in diabetes is discussed in the context of their activation in utero, and animal models show different gene expressions under metabolic fetal stress. Hypomethylation, a process implicated in the smoking related damage to the fetus, here explains how Folic acid reverses the effects of maternal diets and also changes the behaviour of several genes to a separate epigenotype. Outcomes of fetal gene switching as diverse as Cancer, Liver function, Renal function, Stunted growth and even Psychological disorders.

As per that questionable adage of the embryology lecturer: "Embryology will help you understand other areas".

The Old Paper:
Fetal Origins of Coronary Heart Disease
The New Paper:
Diet, Nutrition and Modulation of Genomic Expression in Fetal Origins of Adult Disease

Good Learning!

Cardiorenal Syndrome

Summary:
Why on earth are renal physicians so keen on cardiovascular examination? Well, the anatomically distinct heart and kidneys are entwined in a dance of homoeostatic elegance... a dance to the death, where if one goes, it takes the other with it. Hence chronic kidney disease leading to heart failure, or arrhythmias causing kidney injury.
This paper has gorgeous diagrams of the pathophysiology.

Link:
Cardiorenal Syndrome - J Am Coll Cardiol. 2008;52(19):1527-1539

Key Points explored:
What are the factors which cause renal disease to injure the heart?
Similarly what heart factors injure the kidney?
How do the physiological homoeostatic mechanisms go awry?
What can you do to keep these people on track?

Restless legs syndrome: pathophysiology, clinical presentation and management.

Summary:
Restless leg syndrome (RLS) is common; estimated prevalence is 1/10. The symptoms can be debilitating, but are usually mild. "URGE" is an acronym for the 4 key symptoms: urge to move, rest aggravates, getting active relieves, evening and night is worse. Only some people are troubled enough to require treatment, but at that point complexity starts. Both iron supplements and dopamine agonists benefit the majority of patients. Yet numerous underlying conditions may explain RLS. What follows is an exploration of a problem with metabolic, genetic and neurological causes.

Link:
Restless legs syndrome: pathophysiology, clinical presentation and management.
or PDF

Key points explored:
What are the essential diagnostic features of RLS?
What roles do Iron, Dopamine and genetics have in RLS pathogenesis?
What underlying diagnoses should be considered, and how should patients be managed?
How does RLS relate to other movement disorders, like parkinsonism?

Resolving inflammation, better than suppressing it?

Summary:
Inflammation is a crucial process in health and disease. Medical training has inflammation as a centrepiece, extolling the importance of molecules and processes which trigger and amplify the inflammatory response. Increasingly the interdependence of the nervous system and immune system have been accepted as scientific fact, allowing more coherent understanding of chronic pain and chronic inflammatory states. Medications have been targeted on increasingly subtle components of the inflammatory cascade, from prostaglandins, to cytokines.
However, why all this talk about starting inflammation? Nobody seems too verbal about what exactly resolves the normal inflammatory process?
Medicines to calm inflammation are typically crude and ineffective, dulling the entire body's response. It is becoming clear that nature has a sophisticated system for terminating inflammatory reactions. A set of key chemical mediators has been termed resolvins: fatty acid molecules derived from Omega 3 polyunsaturated fats. Fascinating research is uncovering how the solution to chronic pain and inflammation may not in fact be suppressing the inflammatory response, but making it resolve earlier.

Link:

Emerging roles of resolvins in the resolution of inflammation and pain

Key Points explored:
What are the properties of Resolvins in animal models of pain?
How do Resolvins mediate analgesia?
What are the links between pain and inflammation?

Enjoy

When doctors and patients talk: making sense of the consultation

Summary:
In this splendidly evidence based report on how doctors and patients interact in the NHS, there is a wealth of insight for both care givers and seekers. Unlike many resources on the Doctor-patient relationship, which explore exceptional cases, or focus on theory, this report is based on common issues, and grounded in research. A valuable read for anyone who wants to better perceive the consultation, and to become more skilful at navigating it; creating a successful outcome for both parties.

Link:
When doctors and patients talk: making sense of the consultation

Key Points Explored:
What are the commonest experiences that doctors and patients have in the NHS?
What are the driving forces which shape typical consultations?
What is the scope for change from doctors?
How much responsibility do patients have?
Is the professional and cultural normality a necessary focus of change?

Rheumatic disorders as paraneoplastic syndromes

Summary:
So your patient has a new rash and muscle ache, and is diagnosed by a rheumatologist as having dermatomyositis. Or, your patient has symmetrical polyarthritis, and is diagnosed with rheumatoid arthritis. They have a poor response to first line therapy. Two years later they are found to have cancer. Then when the cancer is removed surgically and the patient treated with cytotoxic chemotherapy, their rheumatic disease disappears. This is the mysterious realm of paraneoplastic rheumatic syndromes, which can offer early warnings about growing neoplasms, and can also be a source of diagnostic deliberation.

Link:
Rheumatic disorders as paraneoplastic syndromes

Key points explored:
Why do some tumours produce rheumatic diseases?
What kind of neoplasms can provoke rheumatic paraneoplastic disease?
How can paraneoplastic rheumatic diseases be differentiated from typical cases?

The placebo response: How words and rituals change the patient’s brain

Benedetti et al's "The Placebo effect" is a step into the Ben Goldacre-y side of things that even the most reluctantly academically keen medical student reads in their spare time. As the paper notes:
"The placebo effect, or response, has evolved from being thought of as a nuisance in clinical and
pharmacological research to a biological phenomenon worthy of scientific investigation in its own right."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055515/pdf/npp201081a.pdf

Juicy things that the paper looks into are:

1. The effect of wording on the placebo effect (and other aspects of the pomp and circumstance surrounding administration)
2. The fascinatingly paradoxical world of administering a drug without any effect in the area suggested it would, but instead having an effect which interferes with the suspected messengers in the placebo effect itself.
3. The suspected anatomical regions involved.
4. The dark art of analgesia.
5. The relationship between placebos and the neurology of emotion.
6. An ending which gives hints as how better to use the placebo effect in clinical medicine or in trials and to avoid the nocebo effect (the evil twin).

Some of the things discussed in this review are a bit bewildering, because they seem very counter-intuitive, but never-the-less it makes a great read for anyone who wants to know the TRUTH about  something as simple as opioid administration.

Good learning,

Marblecake

The Pathophysiology of Eczema and Psoriasis

This paper has been suggested by one of my esteemed colleagues:

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2230.2005.01980.x/pdf

Allam and Novak's "the Pathophysiology of Eczema" discusses the processes behing eczematic inflammation. It is particularly good for a review of acute chemotaxis and the underlying chemical messengers and cell activity.

Specifically for eczema, the section on genetics places the disease in the context of malfunctioning immune response. The paper is also pleasingly succinct, with a very nice image AND there is a very medical student-friendly summary at the end as learning points.

And as a nice counterpart, while you are in the mood for dermatology and immunology.

http://ard.bmj.com/content/64/suppl_2/ii30.full.pdf+html

Krueger and Bowcock's "Psoriasis Pathophysiology: Current concepts of pathogenesis" is more dense than Allam and Novak, and a bit turgid to begin with, but assumes very little knowledge of immune cells. It contains a lot of transferable knowledge. There is more genetics than anyone could possibly need, but as with Allam and Novak, the immunology is well described and as all good papers do, it has a great big diagram with arrows in it.

Sit down with a coffee and try to work through these papers when studying atopy or dermatology - it will be very rewarding.
Good learning,

Marblecake

The Beginning - The Hallmarks of Cancer

Welcome to the Medical Student's Pertinent Reading List, wherein one can find accessible links to papers that fit following criteria:

• They provide a review of an area of study, rather than specifically investigating one theorem
• If they err on the side of having too much information, then it is all information that helps provide a basis for complete understanding of the subject at hand
• They are established papers that are up to date, but well recieved in peer review
• They are mostly on the subject of the scientific basis of medicine, albeit with a clinical leaning
• They are well written, and fascinating

Here is the paper that inspired the creation of the blog, "The Hallmarks of Cancer: The Next Generation" by Hanrahan et al. I hope you read it and find it as enjoyable as I did.

http://www.medicina1.uniroma1.it/UPLOADS/docs/690/the-hallmarks-of-cancer-the-next-generation.pdf

In summary, the paper establishes a few "hallmarks" that define the cellular behaviour of a malignancy. It does this with very neat diagrams, with a particularly good one showing the relationship between cellular behaviour and the macropatholoical processes that lead to metastasis.

I am open to suggestions of papers to post on here, just make sure they fit the criteria above. I think this endeavour works best as a blog rather than a wiki, because I want the papers to be very carefully regulated, unlike on wikis.

Enough from me, read the paper, and good learning!

Marblecake