Saturday, December 31, 2016

Panama & Tribology: New Rx & Old Principles!

  
Panama Canal © 2008 Am Ang Zhang

Most people probably know about the French failure to build the Panama Canal. Many thought that this was due to yellow fever and malaria which were diseases thought to be due to some toxic fume from exposed soil.

In 1879, Ferdinand Marie de Lesseps, with the success he had with the construction of the Suez Canal in Egypt just ten years earlier, proposed a sea level canal through Panama. He was no engineer but a career politician and he rejected outright what the chief engineer for the French Department of Bridges and Highways, Baron Godin de Lépinay proposed, a lock canal.

The engineer was no match for a career politician:

“There was no question that a sea level canal was the correct type of canal to build and no question at all that Panama was the best and only place to build it. Any problems – and, of course, there would be some - would resolve themselves, as they had at Suez.”

“The resolution passed with 74 in favor and 8 opposed. The ‘no’ votes included de Lépinay and Alexandre Gustave Eiffel. Thirty-eight Committee members were absent and 16, including Ammen and Menocal, abstained. The predominantly French ‘yea’ votes did not include any of the five delegates from the French Society of Engineers. Of the 74 voting in favor, only 19 were engineers and of those, only one, Pedro Sosa of Panama, had ever been in Central America.”

The French failed in a spectacular fashion.

Diseases like yellow fever and malaria played their part as a sea level canal involves a good deal more digging.

The discovery of yellow fever being carried by mosquito must be credited to one Cuban physician:Carlos J. Finlay.

For twenty years of his professional life, he stood at the center of a vigorously debated medical controversy: the etiology of yellow fever. Finlay believed that it was waterborne and carried by common mosquitoes: Stegomyia fasciata.

Finlay's advice and experiences proved invaluable to the United States Army Yellow Fever Commission. When the Commission decided to test the mosquito theory, Finlay provided the mosquitoes andWalter Reed of the Commission wrote triumphantly after the success of the experiments of inducing yellow fever by mosquito bites, ‘The case is a beautiful one, and will be seen by the Board of Havana Experts, to-day, all of whom, except Finlay, consider the theory a wild one!’ The US experiments vindicated Finlay's two-decade-long struggle.

Reed acknowledged that ‘it was Finlay's theory, & he deserves much for having suggested it.’

William Crawford Gorgas wrote of Finlay:

"His reasoning for selecting the Stegomyia as the bearer of yellow fever is the best piece of logical reasoning that can be found in medicine anywhere."

The discovery by Major Ronald Ross that malaria was transmitted by mosquitoes (Anopheles)had tremendous impact on the Panama Canal. 

Crude oil was used on stagnant water to prevent the mosquito proliferation and nets were used to protect workers. Quinine was extensively used to treat malaria. A lock canal was eventually built by the Americans. 

Some say that a large part of the eventual success on the part of the United States in building a canal at Panama came from avoiding the mistakes of the French. Knowing the causes of diseases must have helped.

David McCullough in his book "The Path Between the Seas" wrote: "The fifty miles between the oceans were among the hardest ever won by human effort and ingenuity, and no statistics on tonnage or tolls can begin to convey the grandeur of what was accomplished………It is a work of civilization."

Links
  
  

There are things in medicine that we knew nothing about and often we are surprised at how some very basic scientific principle is behind some apparently strange conditions.



Panama reminds me of my friends visit. I have not seen him for years as we went our separate ways as he children were growing up. He was a sporty person and played rugby to a professional level. Here is the blog:


Tribolgy: One Patient, One Disease.

Wednesday, July 27, 2011


© Am Ang Zhang 2011
Did you enjoy your Cruise?

Sure!

So you can get away from blogging and from Medicine.

I got away from blogging but then it was only the slowness of the Internet that was prohibitive.

Then I realised that perhaps we doctors never could get away from medicine and in a sense I did not want to either.

Medicine has become a hobby.

Cruising is an interesting way to have a holiday, you do not have to pack everyday and you get to meet some really interesting people.

On our Cruise we had dinner with an eminent professor and his wife.

Tribology!!!

Yes, a world class Medical Engineer and all I might want to know about hip and knee replacements.

Wow!

A friend came to our tropical resort to play golf with me. 

He was walking a bit funny on the golf course.

“I used to hit 280 yds.”

“What happened”. He now hits 160 yds if he is lucky.

“Bilateral hip replacements.”

Good old rugby.

But that was not all. A year before he had bladder cancer that was diagnosed and luckily it was caught early.

“It was painful but the BCG treatment was good!”

So perhaps my professor was wrong: one patient one disease.

He obviously had hip problems from rugby and then bladder cancer.

So I asked my new found friend.

“There is a theoretical risk as the cobalt in the alloy in particular could be a problem. Check out the Swedish research.”

I told him about my friend and my professor.

“Interesting approach!”

“I know. But it concentrates the mind.”

Lisa B. Signorello et al

In summary, overall cancer risk among hip implant patients was close to expectation. However, we observed these patients to have a statistically significant excess of melanoma and prostate cancer and, after a latency of 15 years or more, of multiple myeloma and bladder cancer.

In contrast, we noted a statistically significant deficit of stomach cancer and suggestive evidence for decreased colorectal cancer risk. The incidence of bone and connective tissue cancers was not statistically significantly higher than expected for either sex in any follow-up period.

Further evidence suggesting an antibiotic effect  comes from a study in Denmark (14),   where a lowered risk of stomach cancer was found among patients with osteoarthritis who underwent hip implant surgery (presumably exposed to both NSAIDs and antibiotics) but not among those who did not have surgery (presumably exposed only to NSAIDs).

However, because this investigation provided the first opportunity to adequately evaluate the long term cancer-related effects of hip implants, the associations that we observed with bladder cancer and multiple myeloma, while also potentially attributable to chance or bias, should be considered carefully and require further in-depth study.

 J Natl Cancer Inst 2001;93:1405–10


A year later my friend called me:

"But Cockroach Catcher, you wrote about it in July of last year! Some even had bladder cancer!"

I suppose Medicine is still of great interest to me and one should never accept what is known now as the whole truth. Medicine cannot stagnate nor should we forget basic principles. 

The Telegraph:

One of the participants in the trial, David Jose, 51, from Clifton, near Bristol, had a hip "resurfacing" operation in 2007, a year before retiring as a police officer.

The father of two had been suffering hip pain from playing football and rugby.
In May last year he was told that the tests had found atypical cells which were not at this stage cancerous.

He saw Angus Maclean, an orthopaedic surgeon at Southmead Hospital involved in the study, who said that the trial had established three cases in which patients had developed bladder cancer, and 14 more including Mr Jose who had changes to their chromosomes.

The doctor told him researchers "could not believe" what had been found, describing the findings as "shocking".

Not as shocked as my friend.




To remember our eminent yet formidable Professor of Medicine, Professor MacFadzean: One Patient One Disease.
I would like to pay tribute to our eminent yet formidable Professor of Medicine, Professor MacFadzean, 'Old Mac' as he was 'affectionately' known by us. He taught us two important things right from the start:

First - One patient, one disease. It is useful to assume that a patient is suffering from a single disease, and that the different manifestations all spring from the same basic disease.

Second - Never say never. One must never be too definitive in matters of prognosis. What if one is wrong?

Mysterious Psychosis: One Patient One Disease


Teratoma: An Extract,

Saturday, December 17, 2016

Gold Standard: Clozapine & Finland


Autumn Gold and Gold Standard in Finland:


© 2012 Am Ang Zhang

There have been many challenges to Clozapine but to the Cockroach Catcher it will remain the Gold Standard for the treatment of Schizophrenia for a long long time.

An extract from The Cockroach Catcher:

……...Martina was already at the adolescent inpatient unit when I arrived. She was supposed to be schizophrenic. The family were refugees from Sudan. They were a small Sect of Catholics that were said to be persecuted.
Martina was not very communicative but her records and observations by her outpatient psychiatrist indicated that the diagnosis was robust enough. However, after over a year in hospital she was not improving and we had tried the newer antipsychotic without making much headway.
There was one thing left to do – to put her on Clozapine.
I was once at one of these big drug firm meetings when all the big boys on the newer antipsychotics were there.
Having filled my plate from the delicious buffet, I sat next to two nicely clad representatives.
“So you ladies are from Novartis?” I did my usual stunt.
“How did you work that one out?”
“Well, you two have the best designer outfits and I guessed you must be from the makers of Clozapine.”
They were there to see what the opposition might come up with but as far as I was concerned no other pharmaceutical would touch them for decades.

After today’s Lancet publication they might not need to worry at all!

The Lancet, Early Online Publication, 13 July 2009
11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study) Jari Tiihonen et al. 

According to Reuters:
…………An analysis of 10 years' records for 67,000 patients in Finland found that, compared to treatment with the first-generation drug perphenazine, the risk of early death for patients on clozapine was reduced by 26 percent.

By contrast, mortality risk was 41 percent higher for those on Seroquel, known chemically as quetiapine; 34 percent higher with Johnson & Johnson's Risperdal, or resperidone; and 13 percent higher with Eli Lilly's Zyprexa, or olanzapine.
"We know that clozapine has the highest efficacy of all the antipsychotics and it is now clear, after all, that it is not that risky or dangerous a treatment," study leader Jari Tiihonen of the University of Kuopio said in a telephone interview.
"We should consider whether clozapine should be used as a first-line treatment option."Tiihonen estimates clozapine is given to around one fifth of Finnish schizophrenia patients, but less than 5 percent in the United States.Clozapine's side effects include agranulocytosis, a potentially fatal decline in white blood cells, and current rules stipulate the drug can only be used after two unsuccessful trials with other antipsychotics.Tiihonen and colleagues wrote in the Lancet medical journal that these restrictions should be reassessed in the light of their findings, since not using the drug may have caused thousands of premature deaths worldwide.
According to AP:

James MacCabe, a consultant psychiatrist at the National Psychosis Unit at South London and Maudsley Hospital, called the research "striking and shocking." He was not linked to the study.
"There is now a case to be made for revising the guidelines to make clozapine available to a much larger proportion of patients," he said.
Tiihonen and colleagues found that even though the use of anti-psychotic medications has jumped in the last decade, people with schizophrenia in Finland still die about two decades earlier than other people.

Tiihonen said the pharmaceutical industry is partly to blame for why clozapine has often been overlooked. "Clozapine's patent expired long ago, so there's no big money to be made from marketing it," he said.


Clozapine Data: FinlandRCPU.K.NEJM
Abstract:The Lancet.

Related Posts
Abilify/aripiprazole: Akathisia-gate
Alaska Zyprexa: DOJ at last.
Alaska, Good Friday Earthquake and Zyprexa 
Alaska Zyprexa: Follow Up
Bipolar and ADHD: Boys and Breasts
Antipsychotics: Really?
Humber Mental Health Teaching NHS Trust: Learning From The Past.

Monday, December 12, 2016

Puerto Rico & Ponce: Pre-Raphaelites!

So we spent a week in Puerto Rico before our Caribbean Cruise thinking it will be food and beach adventure and some Spanish historical sights. Imagine our surprise when we were told that the Ponce Museum of Art is a must see.



This Caribbean Island Museum has one of the best collections of Pre-Raphaelites. Yes, Pre-Raphaelites.

 Dante Gabriel Rossetti: Roman Widow
 Gustav PopeDaughters of King Lear



Edward Burne-Jones's The Sleep of Arthur in Avalon



The Guardian.

We did not get to see The Flaming June as it was back home in London. 


Frederic Leighton, Flaming June, 1895.
Courtesy of Museo de Arte de Ponce, The Luis A. Ferré Foundation, Inc.

Also: Vanity Fair.



Jul 21, 2015 ... The Art Institute of Chicago has quite an interesting collection. What caught my eye the other afternoon was a Pre-Raphaelite, well one of three ...

Nov 28, 2015 ... Earlier in June we spent some time with our friends in Dorchester . Somehow the after dinner conversation turned to the Pre-Raphaelites and ...

Sunday, December 11, 2016

The Power of Prayers & Teratoma: Brain & NMDA!

As the BBC reported on the work on NMDA, this blog post was from Sep 1, 2013 and it was an answer to my case of Teratoma induced coma/psychosis.


In medicine, truly new discoveries are uncommon and with the emergence of guidelines and protocols it has become even more difficult to make new discoveries. It has taken over 30 years before I could understand what happened to my Teratoma patient. Luckily for her, the treatment she received would have been in line with what we know now of the condition.


Hospital Medicine indeed has its important place and most important of all in the discovery of new conditions and establishing diagnostic and treatment programmes.

It is perhaps timely to remind the next generation of Bright Young Things that become doctors to remember that psychiatric symptoms presented by a patient may indeed be the presentation of a neurological condition.

This is more so for bizarre combinations of psychiatric and other symptoms. It was in the last five years or so that much progress has been made on what is now called Anti-NMDA Receptor Encephalitis.

Who knows, one day medical scientists might be able to decipher the most difficult of psychiatric conditions: Schizophrenia. Bright Young Psychiatrist might have noticed that Clozapine, one of the most effective drugs for schizophrenia has a marked effect on the immune system. 

In the mean time Pennsylvania might have something they could be proud of: the discovery of this new neurological condition.


WoodlochPennsylvania ©2012 Am Ang Zhang

For now, my patient’s parents’ prayer has been answered. 

Chapter 29  The Power of Prayers


Anti-NMDA Receptor Encephalitis

NEW ORLEANS — A mysterious, difficult-to-diagnose, and potentially deadly disease that was only recently discovered can be controlled most effectively if treatment is started within the first month that symptoms occur, according to a new report by researchers from the Perelman School of Medicine at the University of Pennsylvania. The researchers analyzed 565 cases of this recently discovered paraneoplastic condition, called Anti-NMDA Receptor Encephalitis, and determined that if initial treatments fail, second-line therapy significantly improves outcomes compared with repeating treatments or no additional treatments (76 percent versus 55 percent). The research is being presented at the American Academy of Neurology's 64th Annual Meeting in New Orleans.

565 cases! Not so rare!

The condition occurs most frequently in women (81 percent of cases), and predominately in younger people (36 percent of cases occurring in people under 18 years of age, the average age is 19). Symptoms range from psychiatric symptoms, memory issues, speech disorders, seizures, involuntary movements, to decreased levels of consciousness and breathing. Within the first month, movement disorders were more frequent in children, while memory problems and decreased breathing predominated in adults.

My patient was under 18 and presented with catatonia symptoms. She later lose consciousness and was ventilated.

"Our study establishes the first treatment guidelines for NMDA-receptor encephalitis, based on data from a large group of patients, experience using different types of treatment, and extensive long-term follow-up," said lead author Maarten TitulaerMD, PhD, clinical research fellow in Neuro-oncology and Immunology in the Perelman School of Medicine at the University of Pennsylvania. "In addition, the study provides an important update on the spectrum of symptoms, frequency of tumor association, and the need of prolonged rehabilitation in which multidisciplinary teams including neurologists, pediatricians, psychiatrists, behavioral rehabilitation, and others, should be involved."

The disease was first characterized by Penn's Josep Dalmau, MD, PhD, adjunct professor of Neurology, and David R. Lynch, MD, PhD, associate professor of Neurology and Pediatrics, in Annals of Neurology in 2007. One year later, the same investigators in collaboration with Rita Balice-Gordon, PhD, professor of Neuroscience, characterized the main syndrome and provided preliminary evidence that the antibodies have a pathogenic effect on the NR1 subunit of the NMDA receptor in the Lancet Neurology in December 2008. The disease can be diagnosed using a test developed at the University of Pennsylvania and currently available worldwide. With appropriate treatment, almost 80 percent of patients improve well and, with a recovery process that may take many months and years, can fully recover.

Teratoma: finally!

In earlier reports, 59 percent of patients had tumors, most commonly ovarian teratoma, but in the latest update, 54 percent of women over 12 years had tumors, and only six percent of girls under 12 years old had ovarian teratomas. In addition, relapses were noted in 13 percent of patients, 78 percent of the relapses occurred in patients without teratomas.
As Anti-NMDA Receptor Encephalitis, the most common and best characterized antibody-mediated encephalitis, becomes better understood, quicker diagnosis and early treatment can improve outcomes for this severe disease.
The study was presented in a plenary session on Wednesday, April 25, 2012 ET at 9:35 AM at the American Academy of Neurology's annual meeting.
[PL01.001] Clinical Features, Treatment, and Outcome of 500 Patients with Anti-NMDA Receptor Encephalitis

Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies

Of 100 patients with anti-NMDA-receptor encephalitis, a disorder that associates with antibodies against the NR1 subunit of the receptor, many were initially seen by psychiatrists or admitted to psychiatric centres but subsequently developed seizures, decline of consciousness, and complex symptoms requiring multidisciplinary care. While poorly responsive or in a catatonic-like state, 93 patients developed hypoventilation, autonomic imbalance, or abnormal movements, all overlapping in 52 patients. 59% of patients had a tumour, most commonly ovarian teratoma. Despite the severity of the disorder, 75 patients recovered and 25 had severe deficits or died.

Related paper:

Chapter 29  The Power of Prayers             

Saturday, December 10, 2016

Specialism & Neurology: Generalism & Integration!

After my recent visit to Vietnam a book I have been looking forward to became available, and what a read.


Ha Long Bay, Vietnam © 2016 Am Ang Zhang
"......It was only in the late 1970s that the power of this integrative idol manifested. It was a period, historian Paul Forman has observed, that began embracing a culture that worshiped technology, multidisciplinarity, and entrepreneurialism. At precisely this moment of cultural conjuncture, at the moment when neuropharmacology, scanning technologies, and biomolecular science also began to give very real shape to neuroscience and neurobiology and began as well to vest neurology with wholly new understandings of the nerves in sickness and in health, neuroculture began to reframe human self-understanding. ‘The fundamental justification’, as authors of a report for the US National Academy of Sciences for Manpower in Basic Neurologic and Communicative Sciences put it, ‘is that basic insights into neuroscience constitute one of the major scientific achievements of contemporary civilization. Neurology’s long legacy of definitional ambiguity, the propensity of its practitioners for generality, their obvious interests in psychiatry and physiology, and their long history of engaging evolutionary theory had thus served up the feast of arguments, tropes, and rhetorical devices that would feed the appetites of the ‘cerebral subject’ and the Huxlian ‘neurochemical self ’.74
In short, after the Second World War, people figuratively became their brains. They dreamed of and then manufactured extended minds. They used neuroscience to question personhood, behavioural economics, animal-hood, gender, diversity, and even to recast ‘man as machine metaphors’ into new forms. Mind became a digital product of matter; the brain became a computer; the nerves – picking up on an old refrain – became cyber-networks. Snails made manifest the mechanisms of memory. Florescent proteins embedded addiction into the reductive substance of the cell membrane. The brain became a cultural refrain. And many educated people believed it, and many uneducated and young people practised reiterating it. The brain was its own justification. It was civilisation.
Any number of figures in the history of science and medicine could be claimed to have constructed this neurologic metanarrative. Given its claims to historical transcendence, it is easy to imagine as well that any number of figures could be reconstructed in hindsight as the heroes who constructed this new cultural understanding. Yet it was the neurologists who made this world. Indeed, it was the Jacksonian ideal that would ultimately underpin the emergent logic of neuroculture. It was the neurologists, among the physicians, who were most ‘fully engaged in the philosophical status of man’.75 And while that story was not solely a British one, it was nevertheless the British neurologists who resisted the inexorable trends of rational modernity, of progressive administration, and who held on to the promise of generality and catholicity, and defended a world of Newtons and Darwins and a tradition of Jacksons and Sherringtons against a world of normal science and its would-be tradition of scriveners.
What then was the ‘neuro’ in neurology as the British neurologists understood it? If it was a tradition of generalism and integration, and hero worship too, then it was also a powerful and transformative cultural discourse. It was one that borrowed heavily from artistic and literary currents even as it transformed those movements. It was a discourse that saw in the action of disease a new understanding of the living subject, being, and knowing. It drew heavily upon evolutionary theory. And it eventually reforged the essence of humanity into a story of gene regulation, neurotransmitters, membrane physiology, nerve impulses and synaptic transmission. Accordingly sleep, pleasure, pain, memory, language, even fighting and fleeing, became the stuff of central nervous system organisation and limbic systems. It was, in other words, a particular strand of British neurology that provided neuroculture with its essential shape, integrative social structure, and, alas, also laid the foundations for the now-emergent hegemony of the brain and nerves......"                  Stephen T. Casper
© 2016 Am Ang Zhang
Museum of Science, Boston.
"....While Leonardo da Vinci is best known as an artist, his work as a scientist and an inventor make him a true Renaissance man. He serves as a role model applying the scientific method to every aspect of life, including art and music. Although he is best known for his dramatic and expressive artwork, Leonardo also conducted dozens of carefully thought out experiments and created futuristic inventions that were groundbreaking for the time.

His keen eye and quick mind led him to make important scientific discoveries, yet he never published his ideas. He was a vegetarian who loved animals and despised war, yet he worked as a military engineer to invent advanced and deadly weapons. He was one of the greatest painters of the Italian Renaissance, yet he left only a handful of completed paintings...."



Nobel Laureate: Eric Kandel’s recent book The Age of Insight.



"....In many respects, The Age of Insight imitates those famous Viennese salons, in which artists, scientists and doctors exchanged ideas and gave birth to a new way of thinking about the mind."  Wired


The current Dean of my Medical School is a Conductor as well:

"....As an educator, his pedagogical philosophy of a renaissance education for all young people, with music as a medium to develop intellectual, social and emotional qualities have won praises from students and parents alike."


I have no doubt in my mind that doctors and scientists should embrace art to become better doctors and scientists.