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Tamiflu Conundrum

tamifluBy: Christopher Labos MD CM FRCPC

After nearly a year of waiting, the Cochrane Collaboration has issued its much-anticipated report on the flu medications oseltamivir (Tamiflu) and zanamivir (Relenza). The result is unambiguous. The medications have little benefit when it comes to preventing one person from passing the flu onto another person or in preventing complications from the flu, such as pneumonia or hospitalization. But arriving at this result was not easy or straightforward.

Tamiflu is an anti-viral medication designed to block infected cells from releasing more virus particles into your body. The initial reports were promising. In a 2003 meta-analysis, Tamiflu was found to improve influenza symptoms, decrease hospitalizations and complications from influenza. When bird flu and swine flu appeared in 2005 and 2009 respectively, the fear that a global flu pandemic was coming prompted the World Health Organization to recommend stockpiling anti-viral drugs. As a result, countries around the world spent an approximate 7 billion dollars to create stockpiles of Tamiflu.

The money appeared to be well spent. However, in 2009 the UK National Health Service commissioned the Cochrane Collaboration (an international network of researchers) to review and update the evidence on the use of this class of medications. Initially, no one involved believed that the 2009 systematic review would yield any new insights. They were wrong.

The Cochrane researchers found that the 2003 study relied mostly on unpublished data supplied by Roche, the pharmaceutical company that makes Tamiflu. After multiple attempts to get access to the data, researchers ran their analysis with the data they had available. They found no evidence to support claims that Tamiflu prevented the spread of or complications from influenza.

The publication of their report in the British Medical Journal at the end of 2009 was coupled with a call for Roche to make all their data public. What followed was a back and forth media campaign of Byzantine claims, counter-claims and accusations. Those interested can follow it at www.bmj.com/tamiflu. By the end of 2012, the BMJ editor in chief went on record calling for the release of the data. A letter to the editor called for European governments to sue Roche to recoup the money they had spent on their stockpiles of Tamiflu. MPs in the UK were contemplating legislative action. In the end, it seemed that too much pressure was coming from too many sources. On April 2, 2013 Roche announced that it would hand over the data. And today, nearly a year later, we have the result of the newly released data. The benefit simply isn’t there. If you take Tamiflu, your flu symptoms will last 6.3 days rather than 7 days. That means on average you will get back on your feet a day earlier. But in terms of reducing hospitalizations, complications, or transmission during a pandemic (which is what we should care about) it has no benefit.

There are in fact two issues here. First is the issue of how and why governments spent billions of dollars of public money on a medication that apparently is not effective. Second, and in my opinion more importantly, is the issue of access to clinical data. I don’t want to minimize the importance of the mismanagement of public money, but the lack of access to clinical trial data has a more pernicious consequence than misspent funds. Suppressing information on the effectiveness of a medical therapy can lead to bad medical decisions and faulty public policy.

There are many who believe that a global flu pandemic is coming. Whether it will or not is impossible to say and most of my attempts to predict the future have proven to be woefully inadequate up to now. What I will say though is that the current strategy to deal with a potential pandemic has been based largely on stockpiling Tamiflu. If a global pandemic does come, we may find that all our built-up emergency preparedness measures will come down like a house of cards. If that happens we will be in serious trouble.

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FOLLOW DR. KO: Medical Mission to Haiti – Flying Bullets

armed guard“Get down! Get down! It’s gunshots!” The local paramedic yelled out.

I was sitting at my desk in triage in the midst of writing a prescription for albuterol and ipratropium bromide for my COPD (chronic obstructive pulmonary disease) patient when I heard the shooting.  It was my first shift on a medical mission in Port-au-Prince, Haiti, and I was the only doctor covering the hospital that night.

Still naïve and incredulous, I thought the loud noises could’ve been, oh I don’t know, fireworks? Something that broke? The truth was, I had no idea.  Despite working in the South Bronx, I wasn’t quite familiar with the sound of gunshots so close to me. I nonchalantly peeled my eyes away from my paper script – something I wasn’t quite used to writing – since at home everything is computerized, and looked at the paramedic who had already ducked to the ground and was knocking on the wall to see if it was made of concrete or wood.

“Is this for real?” was all I could muster to say. This had got to be a joke, I thought. Where are we? In the movies?

“Get down! Get down!” He shouted again.

I then realized that this was no joke and quickly dove under my desk. The Haitian paramedic, although alarmed, had an amused expression on his face. I guess they go through this all the time. I saw him scurry gingerly along the concrete wall to get to the light switch and turn all the lights off. So there I was, in complete darkness, squatting under a desk in a local hospital in Haiti, hiding from flying bullets. We hid there for a while in silence. The only sound was the labored breathing of my COPD patient who was sitting across the room. He did not try to hide or even move from his seat; he was too out of breath.

After we were fairly certain that the shooting was over, we slowly emerged from our hiding spots. A few ventured out to see what was going on. No one was sure where the shooting had come from. Some speculated that perhaps one of the hospital guards, stationed outside the metal gate of the hospital, was the one who fired the shots after seeing something suspicious. Or perhaps he was the one who got shot. When I suggested that someone go check on our guard to see if he was ok, no one budged. It was self-preservation.

Although Haiti is now in a “rebuilding” phase after the catastrophic earthquake that took away hundreds of thousands of lives and changed the lives of millions on January 12, 2010, many areas of the country still remain dilapidated and crime-infested.

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Bacterial heroes and viral villains – snipping the way to the future

spider man By: Emily Brown, PhD

The most recent Spider-Man film grossed nearly $800 million worldwide, and cinemas are set to unleash a new and improved Spider-Man 2 this May. Whilst the great charm and beauty of actors Tobey Maguire and Kirsten Dunst most likely helped fuel the initial success of the film series, our fascination with the part-man-part-beast concept has spanned far beyond the glitter of Hollywood. Peter Parker’s DNA may have flashed before our eyes as his body assimilated superhuman powers, but the idea of genetic modification existed in both the fantasy and real worlds long before the advent of such impressive computer generated images. Wikipedia, arguably the source of all valuable knowledge, lists 85 characters, comics or films that involve some form of genetic engineering. Ranging from the less suspecting (Tracy Strauss, Madelyn Pryor, Julian Bashir) to the more ridiculous (Shaggy Man, Venus Bluegenes, The DNAgents), these characters share in common a possession of extraordinary powers, and sometimes the adoption of highly colourful and figure-hugging body suits.

But how exactly is the acquisition of such power explained by the respective literary proponents? Peter Parker’s body-wide changes are initiated by radioactive mutagenic enzymes present in the venom of the lethally irradiated spider un(fortunate) enough to bite him. Not long after this bite does Parker start to display spider-like characteristics -superhuman strength (the jumping spider can for example hold 170 times its own body weight), reflexes, balance, a subconscious sense of danger (the so-called ‘spider-sense’) and the ability to cling to any surface. No doubt all highly desirable traits. But as unlikely as this might sound, the suggestion that enzymes can alter DNA is not such a wild idea. Genetic modification, the direct manipulation of an organism’s DNA, requires the DNA to first be cut so that it can then be joined or spliced together with DNA from another source. A restriction enzyme is an enzyme that cuts DNA at or near specific recognition nucleotide sequences, known as restriction sites. These ‘molecular scissors’ are routinely used for DNA modification in laboratories and are a vital tool in molecular cloning.

Over 3000 restriction enzymes have been studied in detail, and more than 600 are available commercially. Whilst the idea of an irradiated spider might seem far-fetched, restriction enzymes are naturally found in bacteria and archaea (a group of single-celled microorganisms). Here they provide a defence mechanism against invading viruses; the foreign viral DNA is cut up by the restriction enzymes, while the host DNA is protected by an enzyme that modifies the DNA and blocks cleavage. The term restriction enzyme originates in fact from the studies of phage l (a virus that infects the bacteria Escherichia coli, better known as E. coli). In the early 1950s, in the laboratories of Italian scientists Salvador Luria and Giuseppe Bertani, it was discovered that a phage could grow well in one strain of bacteria, yet fare significantly worse in another. In the latter case, the bacterial host cell was evidently capable of reducing the biological activity of the virus (in a process known as restriction), although the exact mechanism remained unclear. This mystery was solved in the 1960s, this time in the laboratories of Werner Arber and Matthew Meselson, where it was shown that the restriction is caused by enzymatic cleavage of the phage DNA. Unsurprisingly, the enzyme involved was termed a restriction enzyme.

The restriction enzymes studied by Arber and Meselson were type I restriction enzymes that recognise a restriction site, but cleave the DNA at a non-specific point located some distance away. Another decade later, in 1970, Hamilton O. Smith, Thomas Kelly and Kent Welcox isolated and characterised the first type II restriction enzyme, HindII, found in the bacteria Haemophilus influenzae. This type of restriction enzyme differs in that it cleaves DNA at the restriction site, and in doing so serves to be much more useful in the laboratory. Cohesive end cutter type II restriction enzymes cut the two DNA strands (most DNA molecules are double-stranded helices) at different points within the restriction site. The result is a staggered cut that generates a short single-stranded sequence or overhang, known as the sticky or cohesive end. These overhangs become very useful in genetic engineering, since the unpaired nucleotides that make up the sticky end can pair with other overhangs made using the same restriction enzyme. If DNA from two different sources are cut with the same enzyme, it is highly probable that the two DNA fragments will splice together because of the complementary overhang. The product is a recombinant DNA molecule, composed of DNA from two different origins, created by DNA technology.

Since the first discovery of restriction in the 1950s, the use of recombinant DNA technology has become commonplace, as new products from genetically altered plants, animals and microbes have become available. In 1997, Dolly the sheep dominated the headlines as the world’s first animal to be cloned from an adult cell. Whilst her early death may have left some scientist ‘wooly’ on the cloning issue (thanks to Jim Giles and Jonathan Knight for this clever pun), the technology has since gone on to bring advances to various areas of life, from treatments for cancer to transgenic insect-resistant crops. As far as is known however, we are yet to see the technology confer super-human strength and power. Thankfully we are not currently at risk of encountering deadly villains and their counterpart heroes on a daily basis, sporting their ridiculous costumes and egos. Instead, we are surrounded by the unseen heroes, the special enzyme molecules that battle to fight invading viral villains, and the scientific geniuses that brought them to light. Mr Muscle may argue that bacteria are best destroyed, but we should also thank these microorganisms for opening a whole new realm of our world, whatever that world may hold.

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Naked mole rats are living long cancer-free lives, and now we know why

moleBy: Chloe Nevitt
It’s not surprising to hear the word rat associated with scientific research. Of course, most people immediately imagine the red-eyed furry white lab rat that runs through mazes. However, recent cancer research has focused the microscope on its’ furless cousin, the naked mole rat.
These sausage-like creatures live in huge underground colonies, centered on a queen, similar to ants. Some of the moles are responsible for foraging for food for the colony, while others tend to the queen. While blind mole rats do possess eyes, they are located beneath the skin and fur, and instead they rely on sensitive hairs found on the ends of their snouts to find their way.
The naked mole rat also has an astonishingly long life span, upward of 30 years, and is apparently cancer-resistant. Not a single incidence in cancer in the African rodent has been found, ever. Compared to their lab rat cousins, whose life spans hover around four years and are extraordinarily cancer prone – a 47% cancer rate, these curious observations make the naked mole rat a novel model for new cancer-fighting methods.
Scientists went searching for the answer. A team at the University of Rochester attempted to trigger cancer in naked mole rats by infecting them with viruses known to commonly cause cancers in mice and rats. Dr. Gorbunova and Dr. Seluanov, a husband-and-wife team of biologists at Rochester, then tried growing the cells in culture mediums. Here, they began to uncover the naked mole rats’ secret.
The naked mole rats cells stopped growing at a third of the density that mouse cells do. They also noticed that the nutritional medium they were in, after a few days, turned into syrup. “We need to find out what this goo is,” said Dr. Gorbunova. Their postdoctoral researcher, Christopher Hine, discovered that the goo was composed of a large polymer called Hyaluronan.
The team at the University of Rochester found, simultaneously as scientists at the University of Haifa, was the Hyaluronan in naked mole rats was five times as large as human Hyaluronan. This sugar was called high-molecular-mass Hyaluronan (HMM-HA). HMM-HA is a form of Hyaluronan, a polysaccharide found in the extracellular matrix and soft connective tissue. Commonly found in humans, it is responsible for signaling and elasticity.
HMM-HA secretion by naked mole rat cells has been shown to prevent overcrowding and the formation of tumours. “Experiments showed that when HMM-HA was removed from naked mole rat cells, they became susceptible to tumours and lost their contact inhibition.” Explains Prof. Eviatar Nevo, from the Institute of Evolution at the University of Haifa.
Contact inhibition when observed in normal cells is the arrest of growth when two cells’ plasma membranes touch. Cancer cells, on the other hand, will continue to grow until overtaking the other cells, ultimately creating a tumour.
HMM-HA in naked mole rats also accumulates in abundant amounts, owing to decreased enzymatic degradation and increased synthesis by a protein called HAS2. On a genetic level, theHas2 naked mole rat gene differs in sequence by only two amino acids, this substitution perhaps the reason for its’ high output levels.
When the scientists shut down this gene in naked mole rats and then inserted a cancer-causing virus, the hyaluronan-free cells multiplied uncontrollably. The researchers moved these cells into mice and watched as tumours developed. The new cells were just as cancer susceptible as the mouse, or human cells.
Researchers owe the increased HMM-HA as necessary for subterranean life. “If you grab an animal, it feels like you’re removing their skin,” Dr. Seluanov said. Stretchy skin is necessary for moving around in underground tunnels. And HA provides this elasticity.
While the questions of how exactly HA fights cancer and how increased levels of HA will react in human and mice cells have yet to be answered, we are perhaps on our way for new types of cancer prevention.

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An Analysis of the Milkian Problem of Modern Teaology

Teaology-Fiore-Borosilicate-Blooming-Teapot-and-Glass-Set
By: Daniel W. Galef, TGFOP

What scientific debate today is more discussed than that of how to make tea? As the issue currently stands (a hotly-contested and bitter stalemate), the field is divided into two main camps: the Tea-Firsts and the Milk-Firsts. Not since Swift’s Endian Dilemma over how to crack an egg has such fierce culinary fervor been whipped up without even so much as a whisk. I hope here to present a thorough documentation and comparison of several of the extant expert opinions and published work on the subject, with a critical eye toward empiricism, chemistry, and humor.

 Ignoring those who leave tea un-milked or drink a tea incompatible with milk or unthinkably drink something other than tea, most will either introduce milk, cream, half-and-half, or correction fluid into their cup, mug, thermos, or volute krater before tea, or after (one small subculture subscribes to simultaneously introducing the two but is decried as heretic by both major schools of thought). The British are clearly the experts, and there is no dearth of literature from their corner. George Orwell establishes himself staunchly on the Tea-First side in “A Nice Cup of Tea,” proclaiming, “by putting the tea in first and stirring as one pours, one can exactly regulate the amount of milk whereas one is liable to put in too much milk if one does it the other way around.”

Douglas Adams, however, is an unashamed Milk-First, outlining his position in “Tea” from The Salmon of Doubt: “It’s probably best to put some milk into the bottom of the cup before you pour in the tea. If you pour milk into a cup of hot tea, you will scald the milk.” A footnote says, “This is socially incorrect. The socially correct way of pouring tea is to put the milk in after the tea.” This adds the benefit of etiquette to the Tea-Firsts.

But writers, citizenship notwithstanding, are not necessarily experts; the problem is a scientific one. The International Organization for Standardization (ISO), whose expertise in the field of making things make sense evidently does not extend to acronyms, in 1980 described precisely and finally a standardized method for brewing tea. The standard, winner of the 1999 Ig Nobel Prize for Literature, also advocates Milk-First brewing. While it is important to note that ISO standards are not so much suggested ways to make good tea, but rather detailed descriptions for making consistent tea, ISO 3103:1980 logically represents an ideal modus operandi in the eyes of the largest standards organization in the world.

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FOLLOW DR. KO: Counting Needles

needleThere she was in her bed, face buried in her pillow, her rear end pointing directly at me. I’m not sure what she was doing in that position. Rosa was a woman in her fifties, but with her pigtails appeared much younger. I don’t remember the reason she was admitted to our service… probably for “altered mental status” secondary to drug abuse. What I do remember, is that she came with a whole lot of junk and even more attitude.

By junk, I mean morsels of food, random pieces of paper, countless lancets (small needles used to prick a diabetic’s finger to check their blood sugar level), a myriad of prescriptions, new and old. All that was scattered all over her bed, and Rosa was sitting on the edge of said bed, dosing and almost falling off.

“Mrs. Rosa, I am Dr. Ko. Would you like to lie in your bed? Let me help you clean this up.” I offered kindly.

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Epigenetics – Could the central dogma be in danger?

DNA moleculeIn 1859, Charles Darwin set out his theory of evolution by natural selection, a theory that consists of three vital components – variation, inheritance and differential reproductive success. We are not all as beautiful as Angelina Jolie, for example (number one on the Official Top 30 World’s Most Beautiful Women of 2013), but her biological children likely will be, and no doubt many a man would be willing to father those children. Parents and offspring can share more than looks, however, and we can only hope that Angelina’s biological daughters are not also at risk of developing breast cancer. Without inheritance, adaptations (such as good looks), and maladaptations (for example heritable cancer risk) alike, could not be passed on from one generation to the next.  A century’s worth of work aimed at understanding this process of inheritance, including experiments with peas and bacteria viruses, finally culminated in 1953, when James Watson and Francis Crick revealed the structure and properties of DNA, the molecule that carries genetic information from generation to generation.

Eight years later in 1961, a young biochemist Marshall Nirenberg made a breakthrough discovery that allowed the genetic code – ‘the blueprint for life’ – to be deciphered. According to the code, the great diversity of life on our planet is generated in a remarkably simple manner – a 5-letter alphabet (the bases or nucleotides A, C, G, T and U), written to form 64 three-letter words (codons, such as AGG), codes for twenty amino acids that serve as the building blocks of proteins, and in turn the building blocks of life. Discovering the genetic code allowed us to understand how the variation essential for Darwin’s theory of natural selection could arise. Mutations that cause a change of a base from an A to a C, for example, can cause a different amino acid to be produced and a different protein to be built. This might sound trivial, but such minor changes in the genetic code can have dramatic impacts on an organism – how it appears physically, how it behaves, how likely it is to develop cancer.  Who we are as humans and our uniqueness relative to others appeared to be controlled quite tangibly and inflexibly by what is written in our DNA.

It almost seems foolish to have believed it so simple. The burgeoning field of epigenetics has more recently forced us to see the DNA world in a completely different light. Epigenetics (‘epi’ = ‘on top of’ or ‘above’) is the study of changes in gene activity that are not caused by changes in the DNA sequence. You can see the dilemma here – modification of gene function without change in the nucleotide sequence surely breaks the previously accepted rules.

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Cellulose has a bark, but no bite!

Pillsbury

Long chemical names on the back of food labels very frequently send people running for the hills. These “food additives” quickly get pegged as dangerous food fillers out to ruin the digestive systems and the very lives of consumers. One of these “scary” chemicals found in our daily diet is carboxymethylcellulose, also known as cellulose gum. It comes from the cell walls of plants, and is used to make paper. That’s right – trees, in your food. Sort of.

Fiber One, Pillsbury, Betty Crocker, and even Duncan Hines, whose Devil’s Food Cake mix pierces both your heart and arteries, contains cellulose gum. And while many resent the “lies” spewed by large food companies, proclaiming that additives are taking away from other “natural” ingredients, remember that every food we eat is made up of chemicals.

Apples are known to contain trace amounts of cyanide, and cassava, more commonly known in North America as tapioca, has enough cyanide to actually kill a man. And yet, there is no hesitation in eating these products. It is important to realize that the synthesis of a compound in a lab can be safer than one found in nature. Nature, more frequently than not, produces the most toxic compounds known to man.

The U.S. Food and Drug Administration, along with international organizations, regulate food additives, such as cellulose gum. After the passage of the Food Additives Amendment in 1958, any ingredient must be reviewed by the FDA to be approved as an additive.

Cellulose is an abundant, natural polysaccharide found in all plants. Cellulose gum is water-soluble gum based on cellulose. Manufactures will use an acetic acid derivative, the same acid found in vinegar, to break down the cells and form the gum. It has been used for over 50 years as a thickening agent, a stabilizer, and an emulsifier.

Gums provide many positive functions in food, without the benefit of not changing the flavor of the food to which they’ve been added.

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FOLLOW DR. KO: The Unfortunate Case of the “Drug Mule”

Screen Shot 2013-12-31 at 6.08.10 PMOn a crisp Saturday morning, Internal Medicine Residents from all over the state of New York trickled into the University of Rochester’s School of Medicine, sporting ties and dresses in lieu of their usual white coats and scrubs. In their hands they clutched a precious cargo, a cylinder that protected a poster to be used for a presentation about their research or about an unusual clinical case.

I was among the ninety-seven young (when does one cease to be called young, I wonder?) residents who had been selected to present their work at the annual New York American College of Physicians’ abstract competition. I had to rush to the airport right after work on a Friday afternoon, and then with barely six hours of sleep, (no, six hours is not enough) drag myself up and out into the cold air of Rochester, firmly gripping my poster, all the while wondering why I was giving myself all this extra work on my only free weekend of the month.

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Scientists Behaving Badly

salt shaker

By Ronald Doering, LLB

The zeal to recommend extreme reductions in sodium…is a case of ideology replacing good science.” Is this the statement of some right-wing newspaper columnist or food industry executive? No. This is Dr. Salim Yusuf, the Heart and Stroke Foundation chair in Cardio- vascular Disease at McMaster Univer- sity, arguing that there has been far too much focus on the policy of sodium reduction as a means to curb cardio- vascular disease. Immediately, another leading Canadian scientist, Dr. Norman Campbell of the University of Calgary, came out swinging, not only disputing Yusuf’s science as having “fatal flaws,” but getting down in the scientific gutter questioning his competence in the field by claiming that Yusuf “is way off his expertise…he doesn’t have a strong understanding of what the evidence is.” Not to be outdone, Yusuf countered that while he considers that Campbell is well-meaning, the poor chap is basing his dramatic public health measures on “scant” evidence. Moreover, “Norman has been one of those — in polite terms — evangelists about sodium — in impolite terms, Talibans about sodium.” Them’s fighting words!

With this level of “scientific” debate, what’s the consumer or policy-maker to do? Only two years ago sodium reduction was widely presented as an area of relatively settled science, and senior managers (and the minister) were criticized for not follow- ing more aggressively their scientists’ advice to get tougher with the food industry.

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