TMI Friday:...And the mystery of the lost piercing

So let's start this month of "TMI Fridays" focussing on women by talking about penis piercings !
Let us consider the Prince Albert. The legend goes that Queen Victoria's husband, Prince Albert, was rather generously endowed, and as a result required a ring piercing on the end of his member in order to prevent it slipping down his trouser leg. This was meant to explain why Queen Victoria forced him to make so many children with her despite the fact that she despised them. As a result of this urban legend, many young men have also adopted this piercing.

 It is because of this kind of penis piercing that a 20-year old psychology student decided to admit herself into A&E in 2004, in spite of not having any visible symptoms.
Earlier that day she had been intimate with her boyfriend, who possessed a Prince Albert piercing on his manhood. However, during the course of their intimacy, they found that the genital piercing had been lost. Here we come to the central mystery. Where did it go ?

They assumed that it had been unfastened in the student's vagina, and this is why she went to A&E immediately. The Doctors examined her vagina, but it was perfectly healthy and there was absolutley no sign of the piercing. The couple insisted that it was somewhere in the vagina, and the physician performed an X-ray to appease them..
To his surprise, the piercing was found to be high up in the pelvis. So the attendant physician decided that it would be necessary to perform major surgery to remove the Prince Albert ring from her.
But then the couple were seen by another physician, who asked them an important questions about whether the couple had utilised any other orifices for intercourse. It turned out that they had performed oral sex in the course of their intimacy. This was the key to the mystery.

You see, whilst the pelvis of a lady contains their vagina, it also contains their digestive tract. The physicians realised that their initial examination of the patient's vagina was correct. The ring wasn't there. The ring had been accidentally swallowed during oral sex, and had ended up in the intestine. The reason it appeared on the X-ray was that it was working its way though the gut. The piercing would pass naturally through the gut without causing any problems. To the relief of the couple, no invasive surgery would be needed.
Another X-ray performed a week later confirmed that it had passed without incident, and was discharged.
This is another example about how being open and truthful with your doctors can prevent you needing invasive surgery, and other stories have shown what happens when people are too embarrassed to do this.

Das G., Rawal N. & Bolton L.M. (2005). The Case of the Missing “Prince Albert”, Obstetrics & Gynecology, 105 (Supplement) 1273-1275. DOI: 10.1097/01.AOG.0000160487.59892.d8

TMI Friday, Girls Month

Regular readers of the TMI fridays on this blog may have noticed a worrying trend. I didn't notice it until I came across a post on twitter:

@funky49 LMAO - I love that stuff! All the posts were of men's antics...I've no doubt that women have a few Darwin Awards up their...sleeve.
— Mary(@SRQ2U) May 17, 2013

I didn't notice this at first, and I looked through my back catalogue to disabuse this notion, and realised how spot on this tweet was. At first, I thought that maybe there weren't any stories about women's antics out there. But I immediately knew this was wrong, because I had a couple of stories about women on my reject pile. That was when I realised. I've been sexist about the stories I've been telling.
I'll give an example.

I read a story about a man cheating on his wife, and how in retaliation, she slipped a wedding ring over his penis, causing a condition known as "penile" strangulation, and I found this story hilarious. When hearing a story of genital mutilation with the genders reversed, I suddenly felt very ill. 

I realised that I had a mental block that could be summarised like this :

"Violence against women = Not funny"
So when I read a story that could be genuinely be funny about some poor girl injuring themselves whilst masturbating, I don't generally feel like discussing it. But this has to change. I've been missing out on a rich vein of weird and embarrassing stories because of my prejudices.
To redress the balance, for the next month, I will be posting "TMI Friday" stories focussing on stories women, because men don't have the monopoly on stupidity, even if it sometimes feels that way.

Can a bacterium help you lose weight ?

Yes, it's called Cholera. There, story over. Nothing to see here.

All right, I'll try to leave the snark aside for this story.  It's just that every time I look at a story extolling the virtues of a new weight loss treatment based only on data from mice, I get slightly sceptical. But let's take a look at this new piece of research published in PNAS this week and give the research a fair hearing.

The bacterium that is the focus of this research is Akkermansia mucinophila. This bacterium was discovered in 2004 in the guts of humans, where it was suspected to degrade gut mucus. It is one of the "friendly" commensal bacteria which live in the diverse ecosystem of your gut.
A question that has interested a number of researchers worldwide is whether the type of bacteria that inhabit your gut ecosystem affect your weight.
I have mentioned in one of my earlier posts about how researchers can study obesity, through the use of genetically modified mice which don't produce a hormone (called Leptin) which acts to signal to them when they have too much fat and tells them to stop eating. With this gene turned off, mice eat uncontrollably and become fat. Early studies showed that these "Super" fat mice had a different gut ecosystem to the normal mice. Interestingly, if you were to take the "gut ecosystem" of a fat mouse, and gave it to a thin mouse, the thin mouse would start to gain weight. Unfortunately, the researchers didn't show the reverse effect occurring. But it was a promising start.
In other work using humans, the gut ecosystem of a fat person has been shown to be different to the ecosystem of a thin person. In these studies, one bacterium tended to stand out. Akkermansia mucinophila, whilst a key component in the healthy digestive system, is rarely found in obese people.
What is it about this bacterium ?

The researchers found that Akkermansia had a lower population within the gut of  Leptin deficient mice compared to healthy mice. I mentioned in the previous research that people looked at leptin deficient mice. Whilst these mice are fat, they aren't like most fat humans. Only ten people have ever been shown to have a genetic leptin deficiency. So these leptin deficient mice (called ob/ob) aren't like normal overweight humans.
 A more relevant model would be to feed mice fattier food. The equivalent of moving a human from salads to hamburgers. So they moved mice from the normal standard diet to a high fat diet, which tends to make them gain weight. As a result, the numbers of Akkermansia in these mice was lower than mice fed on a healthy diet.
But what would happen if you tried to increase Akkermansia numbers within the gut of a mouse when you start to feed it high fat food ?

They mixed in a prebiotic compound with the high fat diet to nswer this question. The compound they used was Oligofructose. This compound is known to increase the amount of mucus producing cells in the gut. Thus, it increases the amount of mucus. Since Akkermansia eats mucus, increasing the amount of food available for it causes its population to increase in the gut.

The mice fed on the high fat diet with the prebiotic added did not gain as much weight as the mice on a diet without the prebiotic.
Further more, the researchers noted that there were less inflammatory signals from the intestines from mice fed on the prebiotic than mice which were not. Why were the researchers interested in this ?

They were interested, because of something called Metabolic Endotoxemia.
The story goes like this :

• Fat cells play an important role in regulating the energy balance of the body, telling you when you have had too much to eat, or when you have had too little. 
• In a number of studies, Obese people have been shown to  have muscle and fat cells that send out unhealthy levels of inflammatory signals.
• The increased levels of fat in the blood can be helpful to the immune system during infection, but if the fat levels in the blood remain high for too long, they keep the immune system activated, which leads to chronic inflammation.
• This inflammation leads to the cells of the immune system to send out signals to eachother. The signalling between cells that regulate the immune system and those that regulate your metabolism often interact with eachother in normal situations. But in this case, the signals interfere with eachtoher, leading to some cells to stop producing insulin, which leads to diabetes.

Metabolic Endotoxemia can lead to the cells responsible for regulating the energy balance of you body to become less effective. It not only ruins a persons ability to control their own blood sugar, it also affects their ability to regulate their body fat and energy expenditure.

So with that, we have to look a the next experiment the researchers did. They took groups of mice, and fed them concentrated cultures of Akkermansia every day for four weeks. Mice were either fed on a healthy diet, or the High fat diet. 

They found that once again, mice fed with a high fat diet and Akkermansia gained less weight,and reduced the signs of inflammation caused by a rapid increase in weight. But how do we know whether this is the right kind of weight loss ? What if the mice are losing weight just because these treatments are making them ill ?

To work this out, they had to look at where exactly the mice are losing weight from. Were the fat stores being depleted, or were the mice losing muscle mass instead? So they used a neat piece of technology known as a body composition analyser. The body composition analyser is a tool to analyse the different chemical forms of fat and muscle within the body. They can put a live mouse in the machine and get a reading for the levels of fat in proportion to "lean tissue", and then take it out unharmed. So you can watch exactly what type of fat is accumulating within the mouse throughout the experiment. On all of these scales, the mice who were fed Akkermansia not only put on less fat, but had a body composition similar to healthy mice.

Unfortunately, I don't exactly know what a sick or starving mouse's body composition would look like to compare with these graphs. In fact, despite the fact that they allegedly took measurements every day, they only display the final time points, and seem to show the kind of data that could only be obtained from dissection rather than the use of a body composition analyser.

But fat in itself isn't the most damaging part of obesity. As I've indicated before, Metabolic Endotoxemia can lead to diabetes. They showed that inflammation can occur after this high fat diet. But did the mice show any signs of developing diabetes.

This is why they tested fasting hyperglycaemia. What is fasting hyperglycaemia, and why do we care about it ?
 In normal people you see hyperglycaemia occurring immediately after they have eaten. If a person has not consumed any food for a significant amount of time and is still hyperglycaemic, then it indicates that they cannot control the levels of sugar in their blood. In essence, it is a key sign of diabetes.

So they starved mice on these diets, and then tested to see whether they were still hyperglycaemic after a set amount of time. Mice provided with a high fat diet tended to show fasting hyperglycaemia, but the introduction of Akkermansia changed this. It appeared to lower the amount of sugar in the blood of mice fed on the high fat diet, although not the the levels of healthy mice.

So how were the mice suddenly able to control the levels of glucose in their blood ?
It comes down to insulin. When the liver senses this hormone, it soaks up the excess glucose from the blood, and converts it to glycogen. When there is a drop in the blood glucose levels, the liver converts glycogen back into glucose. In unhealthy animals, the conversion of glycogen into glucose is less well regulated, and leads to more glucose being released into the blood.
They tested the mice to see how well they reacted to insulin. Mice that don't react at all tend to become diabetic. So it is a good sign that the inclusion of Akkermansia  into a high fat diet tended to give the mice a better reaction to insulin than if mice were fed with a high fat diet only.
All of these bits of evidence seem to show that Akkermansia  can somehow prevent weight gain and hamper the progression of diabetes in mice fed with fatty foods.

So the next part of this research is where is gets complicated. You see, the storage of fat in your body is a dynamic process. You have special fat storing cells known as adipocytes, which can differentiate and change and adapt to changes to the way you eat. The amounts of lipids they manufacture, just for the day to day uses in the body, change depending on diet. If you have a high fat diet, they don't manufacture as much fat.  They also can oxidise the fats they store, and break them down. So the researchers took cells from the fat layers of the mice, and tested them to examine what they were doing.
The adipocytes of mice fed a high fat diet tend to differ from those fed a healthy diet. But when you add Akkermansia into the mix, in nearly all cases, it make the adipocytes behave as if they were in a healthy mouse, even if the mouse they are residing within is eating a high fat diet. So somehow, Akkermansia can controlling the way fat is stored within the body.

The researchers suspected it may have something to do with the way the intestine defends itself from infection. Some cells within the intestine can produce chemicals to kill off bacteria, known as Antimicrobial peptides. But they found no statistical differences between any of the treatment groups in terms of antimicrobial compounds.
They looked at the cells that produce these compounds, and found that they were more highly activated in mice fed on a healthy diet when exposed to Akkermansia.  But Akkermansia  produced no such effect in mice fed on a high fat diet.

There is a theory that the gut microbiota can regulate fat levels by communicating with the intestine via compounds known as endocannabinoids.

They examined the levels of three different endocannabinoids, 2-palmitoylglycerol (2-PG) 2-oleoylglycerol (2-OG) and 2-Arachidonoylglycerol (2-AG). These endocannabinoids are signalling compounds which can change the way the intestine absorbs certain compounds.
  The levels of these compounds were much higher in the mice which were fed Akkermansia in groups fed on the healthy and the fat diet. This suggests that the Akkermansia is in communication with these cells in the intestine, and somehow changes the way they absorb molecules.

They then looked inside the gut itself. They wanted to see whether the Akkermansia affected the thickness of the mucus layer within the gut. This acts as a barrier to pathogens, and protects the living cells on the guts surface, whilst still allowing nutrients through. The increase in mucus thickness could impair the guts ability to absorb nutrients. This layer is thinner in mice fed on a high fat diet, but when those mice are instead given Akkermansia, the  mucus layer becomes thicker.

So this draws us to the final set of experiments. They know that Akkermansia is needed to for all of these things to occur, but does it need to be alive ? This a chance for them to test how active Akkermansia is in regulating fat deposits. They repeated all of their previous tests, but this time with an additional control group. One group were fed a high fat diet, with dead Akkermansia  as the supplement. The dead bacteria did nothing.

Paper Readability
I would heartily recommend you read this paper, because why should I be the only one the suffer ? The main problem with this paper is that has been horribly compressed to fit the space allocated to it by the journal, and that a lot of the juiciest results are in the supplementary section. It is because of this that it is really difficult to understand what the researchers did. The methods section has been chopped up between the supplementary section and the actual paper. They only mention the whole body fat analyser in passing, and its unclear whether any of the data they show comes from using that piece of equipment.
It is a complex paper, and it really needs more space than it was given.

Conclusions
There is a great story at the centre of this article.

Once upon a time there was a bacterium in your gut called Akkermansia mucinophila. It lives in the protective mucus lining of your gut, and feeds on it. It always made sure there was enough delicious mucs by telling the cells of your gut to keep making it. This made the mucus layer nice and thick, which was not just good for Akkermansia, it was good for you. That thick mucus layer stopped harmful bacterial components entering your body, and reduced the amount of fat entering your blood stream.
But then you decided to eat your own weight in milkshakes every day for nine years, and everything went downhill from there. The poor Akkermansia couldn't survive in these conditions, and eventually became extinct in your gut. The protective mucus layer in your gut that it had so diligently maintained, became thinner. Harmful bacterial components entered your blood stream, alongside big globs of fat, giving you metabolic endotoxemia. Your fat cells and you immune system couldn't cope, and went to war. The cells that produce insulin were killed in the crossfire. That is when you became diabetic, and it is why you died after one particularly grotesque Oreo milkshake binge. Witnesses say that your last words were "Totally worth it"

The researchers have shown that Akkermansia  could reduce some of the negative outcomes. They have shown that in mice at least, it can reduce insulin sensitivity, and possibly slow down the progression to diabetes. It does this through maintaining the mucus layer in your gut wall for completely selfish reasons.
Hypothetically, this causes the gut to be less absorbent to fats to bacterial compounds.
But whilst this paper produces an interesting case that there is some communication occurring between the bacteria and the gut, it doesn't tell us anything about how this happens. We still don't know what the signals are between the bacteria and the gut wall, and even the immune system.

So, can Akkermansia help you lose weight ?

No. There is no evidence in this paper to suggest this. All of the tests looked at the reduction in weight gain. Changing the amount of weight you gain is quite different from weight loss. But Akkermansia is still an interesting example of how the bacteria that coexist within us act for both their own selfish reasons, and for our benefit.


Everard A., Belzer C., Geurts L., Ouwerkerk J.P., Druart C., Bindels L.B., Guiot Y., Derrien M., Muccioli G.G. & Delzenne N.M. & Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.1219451110

TMI Friday: Batteries should NOT be included

There are some days when you have to ask yourself, just what is the deal with men. I don't mean our general demeanour, or the pretensions of superiority over other genders. No, I'm talking about the strange things that men decide to do when left alone for too long.The  men who happily dangle their members inside bottles, or in reach of the spinning blades of a vacuum cleaner not thinking of the consequences.
With this in mind, we arrive at a case study by Bedi et al, where they describe the case of an elderly gentleman who was referred to them from a nursing home. He had been experiencing extreme pain during urination. A year previously, he had a similar problem. On that occasion, it was found that he had stuffed a pen lid inside his penis.
Now, one shouldn't make assumptions about people. Just because he had abused the elasticity of his urethra before was no reason to suspect that it had happened again. He could be experiencing difficulty urinating for a whole number of important medical reasons.
Then he pissed out a rusty Triple A battery.
And he still had trouble urinating ! This is when the nurses at the home realised that they needed to get help from doctors.
An X-ray revealed the source of the problem. Two batteries were still lodged in the man's urethra. Meanwhile one of the residents of the home for the elderly is wondering why the remote stopped working.
So how do you pull these batteries out ? The surgeons decided to use special endoscopic forceps to pull out the batteries. Endoscopic forceps are essentially long tubes with jaws on the end (for grasping things).
They had to insert these forceps up the urethra to grasp at these batteries.
Upon being presented with these batteries, the man admitted to jamming these batteries up his urethra four weeks earlier whilst masturbating. The train of thought which led him to put lead in his pencil may in fact be similar to all of the other male "thrill seekers" who decide to risk their genitalia for the sake of sexual gratification. But even after reading all of these articles, that trainwreck of thought is completely unknown to me.

Bedi N., El-Husseiny T., Buchholz N. & Masood J. (2010). 'Putting lead in your pencil': self-insertion of an unusual urethral foreign body for sexual gratification, JRSM Short Reports, 1 (2) 18-18. DOI: 10.1258/shorts.2010.010014

The Even Earlier Discovery of Antibiotic Resistance

So about a month ago, I wrote about how amazing it was that penicillin resistance was discovered as early as 1940, two years before it went on general sale. But whilst researching that article, I realised that Sulphonamide drugs entered the market long before penicillin, with their discoverer, Gerhard Domagk, being nominated for a Nobel prize in 1939. He had been tasked by Bayer pharmaceuticals to test out a gargantuan number of dye molecules to see whether they could kill off bacteria, and in the process , stumbled across the first antibiotic.
You may recall from the previous instalment that Heinrich Hoerlein was the man to recruit Gerhard Domagk into Bayer. Heinrich Hoerlein was a talented chemist, who had specialised in developing dyes for wool. How did this dye maker end up working to create one of the most important pharmaceuticals that the world had seen up until that point ? Why was it that when Bayer decided to devise new treatments against bacterial disease, they focussed on the compounds used to colour clothes ?

To understand how this state of affairs occurred, we need to go back further in time to the 1800s, and look at bacteria. If we were to do this in this era, we would need to get a good microscope. Bacteria tend not to be visible to the naked eye. So let us look down our microscope, what would we see ?
We would probably see tiny transparent blobs. This could mean that we either have lots of bacteria, or are looking at some air bubbles. There are various legends of scientists proclaiming that they have found an entirely new type of bacteria, only to later realise that this bacteria was nothing more than a bubble of air in the wrong place at the wrong time.
This is where dyes become important. The odds are that you are wearing clothes which have undergone the dye process. A dye works by chemically binding to the surface of whatever you want coloured.
A number of scientists of that era began to work on dyes that bind to cells, allowing them to be more easily seen under a microscope. This allowed scientists to see that bacteria came in all sorts of shapes and sizes, and that different species were associated with different diseases.
One of the pioneers of this research was a man named Paul Ehrlich. His PhD had been dedicated to studying how aniline dyes, which had previously only been used for fabrics, could actually be used to colour cells. He also noticed that dyes he used would colour some cells differently to others. Some cells would take up a lot of the dye, whilst others would not and remain transparent. At the age of 24, using the new "staining" techniques, he had managed to discover a new type of cell, known as a Mast cell.
A lot of his scientific achievements  could be tracked down to the one simple question he asked himself when he saw this effect: Why did some cells take up more dye than others?
He theorised that cells took up specific nutrients, and that receptors on the surface of these cells played a crucial role in this process. Different cell types have different receptors on their surface. some of these receptors allow dye molecules to enter the cell, and some do not. The reason that different cells "stained" differently was due to the different receptors on their surfaces.
He suggested that toxins on the surface of the bacteria bound the receptors on the surface of the host during infection. In response, the host cell would secrete these receptors to flood the toxins on the surface of the bacteria, thus neutralising them. He called these secreted receptors antibodies.
 Whilst this is far from our modern understanding of antibodies, it was a crucial step in the right direction, and he would be credited as one of the founders of immunology as a result of it.
He also suspected that bacteria also had receptors which they used to ingest dye molecules. He noted that some dyes were taken up by bacterial cells, but not human cells. He suggested that this was because the dye molecules resembled nutrients that the bacteria eat. If he could manufacture the chemical structures of these dye molecules to include poison, then he could have a chemical that kills of bacterial cells, and leave human cells alone. He termed these chemicals "Magic Bullets".
In 1904 came his first breakthrough, with a compound, known as Trypan Red, due to it's colour, and sucess for treating mice infected with trypanosomes. Whilst this was useful as a proof of concept, Trypan Red only worked against the types of trypanosomes that infect mice, but not those which attack humans
It was while he was working on this problem that researchers at the Liverpool School of Tropical Hygiene, Anton Breinl and Harold Wolferstan Thomas, discovered that a compound known as Atoxyl, though to be non-toxic for humans, could kill off trypanosomes. From 1906, a number of expeditions to Africa took it with them to protect themselves from the Sleeping Sickness caused by these organisms. Robert Koch, one of the founders of microbiology, used it to treat patients on the shore of Lake Victoria. It became incredibly popular at the time.
Intrigued, Paul Ehrlich investigated this wonder drug, in addition to the other dye based drugs he was developing. During the course of his research, he noticed a worrying trend. After prolonged therapy with these drugs, the resistance of the trypanosomes to these chemicals increased, until they were completely resistant to the therapy. He coined the term "fastness" to describe this trait in bacteria. The fact that he had observed this "fastness" occurring in response to such a broad range of chemicals suggested to him that this was an inevitable event.
Ehrlich was unexpectedly energised by this discovery of resistant organisms. This was because of the finding that once an organism became resistant compound, it was also resistant to chemicals with the same shape and structure. This provided evidence for his fledgling theory of surface receptors which bind to specific chemicals based on their shape and structure.
But his discovery of resistance put him on a crash course with Robert Koch, who had not observed this effect, and thus disputed that it had ever occurred outside of the lab. The main differences were that Robert Koch used much higher doses of Atoxyl than Ehrlich. Either way, Atoxyl was fast falling from popularity. Patients treated with it would go blind due to its severe side effects. A study in 1910 would show that it merely halted progression of trypanosome disease, and that patients were no better off using it.
 Ehrlichs lab was still screening drugs to fight off pathogens, and it came across compound 606, a derivative of atoxyl that not only had less severe side effects, but had proven utility against syphilis.
This was marketed as Salversan, and became an important drug in the fight against syphilis, and was used up until the 1940's, when penicillin replaced it.
The discovery of these drugs, and the apt demonstration that dye molecules could make good antibiotics cemented his place in history. One of his assistants, Wilhelm Roehl, would go on to head a research department at Bayer. It was he who would recruit a Dye chemist, Heinrich Hoerlein, to find the next big drug.
So whilst Ehrlichs theory of "magic bullets" would live on, and laid the foundations for the discoveries of Domagk and Fleming, what happened to his theories on antibiotic resistance ?
There were a number of weaknesses in Ehrlichs theories that a number of researchers called into question. Ehrlichs theories of antibiotics and antibiotic resistances were too simplistic. He posited that for each compound, there was a single path to resistance through the mutation of a single receptor. But we know that bacteria and other pathogens can adapt to antibiotics in multiple ways. This made it difficult to replicate his results, and even more difficult for him to explain why they didn't replicate.  The rules he had set out for explaining antibiotic resistance did not always hold true. The disparity observed between his experiments of Atoxyl, and of Kochs experiments did not help his case.
 This apparent wooliness would mask the threat of antibiotic resistance as a merely theoretical phenomenon. It would for the next 30 years be regarded as a curiosity that would never pose a threat to people.
Over a hundred years after Ehrlich's initial observation of antibiotic resistance, we have a slightly different perspective on his discovery than his contemporaries.

References

Gradmann C. (2011). Magic bullets and moving targets: antibiotic resistance and experimental chemotherapy, 1900-1940, Dynamis, 31 (2) 305-321. DOI: 10.4321/S0211-95362011000200003

Titford M. (2010). Paul Ehrlich: Histological Staining, Immunology, Chemotherapy, Laboratory Medicine, 41 (8) 497-498. DOI: 10.1309/LMHJS86N5ICBIBWM

Casanova J.M. (1992). Bacteria and their dyes: Hans Christian Joachim Gram, Historia de La Immunologia, 11 (4) DOI:

Ehrlich P. Address in Pathology, ON CHEMIOTHERAPY: Delivered before the Seventeenth International Congress of Medicine., British medical journal, PMID: 20766753

Kaufmann S.H.E. (2008). Immunology's foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff, Nature Immunology, 9 (7) 705-712. DOI: 10.1038/ni0708-705

The Earlier discovery of Antibiotic Resistance

A couple of weeks ago, I wrote about how quickly penicillin resistance was discovered not long before it was distributed to the public, and how even Alexander Fleming noted his worries over penicillin resistance in the closing of his Nobel prize acceptance speech.

But even in the process of researching this article, I realised that I was merely scratching the surface. You see penicillin was not the first antibiotic discovered. If I want to talk about the first discovery of antibiotic resistance, then I will  need to tell this story as well.

In 1932 in Germany, a scientist patented an incredibly important discovery, one that would eventually win him the Nobel prize.

Domagk had been working at Bayer pharmaceuticals at the time of his discovery. In the early 1920's, Bayer had begun to experimenting with different methods for treating bacterial diseases. The experiences of World War 1 had left many researchers with the desire to find ways of preventing deaths from wound infections. Domagk had served in World War 1, and had worked in a cholera hospital near the eastern front. He noted the seeming futility of treating patients with infections. 

He came to the attention of Bayer pharmaceuticals after Professor Heinrich Hoerlein* had come across his thesis and decided to hire him. Hoerlein believed that dye molecules could be the key to solving bacterial infection.

The chemists at Bayer would synthesise new chemicals, and then send them to Domagk, and he would then test them on whether they could kill bacteria in vitro, or whether they could prevent mouse deaths from Streptococcus infection. Domagk managed to speed up this process to the point where he could test 30 new chemicals every week.

The chemist on the other end of this process was a man named Josef Klarer. He was the one rushing to make the chemicals for testing. He had tried a number of quinine derivatives, but had no luck. However, in 1932, things would change when he decided to make products based off of  Azo Dye molecules. His first success came with Kl-695**, which Domagk found to protect mice during an infection, even though it didn't seem to kill the bacteria in the petri dish. But based off of this finding, Klarer modified Kl-695 again and again. Until it came to a red dye compound that was at the time named Kl-730. 

Of course, even though this chemical had been proven in mice, it was as of yet unknown whether it would work in humans. But then Domagks daughter fell ill with a streptococcal disease, and desperate, he gave her a dose of the drug, curing her of the disease.

By 1935, Prontosil Red was being trialled internationally, with Leonard Colebrook, himself a frequent experimenter with antibiotics, demonstrating the effectiveness of Prontosil Red in treating pregnant women, albeit with the side effect of turning his patients bright red.  Prontosil Red was the first Sulphanilamide drugs.

Such was the success of this drug that he was nominated for a Nobel Prize in 1939. However, at this time the Nazi's were running Germany. They held a dim view of the Nobel prizes due to the previous German to win a prize. Carl von Ossietzky was a pacifist, who exposed the Nazi's breaking of the treaty of Versailles by training an air corp, and won the Nobel peace prize for his opposition to the Nazi's. As a result of this, the Nazi's forbade any German from accepting Nobel prizes

So when Domagk won a Nobel prize, he was immediately thrown in jail for a week by the Gestapo. This was enough to convince him not to accept the Nobel prize until 1947, two years after Fleming. 

By this time, Doctors were already discovering the limits of antibiotics. A.J. Cokkinis wrote in 1938 

Inadequate dosage and too short a period not only fail to do any good but seem to lead to the development of acquired resistance on the part of the organism to the drug

.

Amongst the first to analyse these limitations were a group of researchers based at St Mary's, one of whom was Alexander Fleming**. They had discovered that bacteria could adapt to antibiotic concentrations. The same year, Connor Macleod, a researcher based in New York, investigated this in more detail. He discovered that gradually increasing the amount of antibiotics in broth could increase the numbers of resistant bacteria.

Sulfa drugs like Prontosil Red changed the way medicine worked, and laid down the foundations upon which modern medicine would arise. Unlike penicillin, Prontosil and the related sulphonamide and sulphanilamide drugs could be created entirely synthetically from available chemicals. 

Bayer's technique for finding drugs could best be compared to throwing spaghetti against a wall until it sticks, testing random chemicals until they produced the effects they wanted. and people say that Alexander Fleming relied on luck ! Bayer appeared to be basing its company policy on it.

But the question remains as to why they decided to use dye compounds as antibiotics, how did they even know it could work. It's not like there was someone before them who discovered antibiotics even earlier...was there ?

To be continued tomorrow........

References
Wollheim Memorial- Phillip Heinrich Hoerlein
Bayer- Gerhard Domagk
Nobel Prize- Gerhard Domagk

Bentley R. (2009). Different roads to discovery; Prontosil (hence sulfa drugs) and penicillin (hence β-lactams), Journal of Industrial Microbiology & Biotechnology, 36 (6) 775-786. DOI: 10.1007/s10295-009-0553-8

Macleod C. & Daddi G. (1939). A ''Sulfapyridine-Fast'' Strain of Pneumococcus Type 1, Proceedings of the Society for Experimental Biology and Medicine, 41 69-71. DOI: 10.3181/00379727-41-10575P

Cokkinis A.J. (1938). SULPHONAMIDE CHEMOTHERAPY IN SURGICAL INFECTIONS--I, BMJ, 2 (4059) 845-847. DOI: 10.1136/bmj.2.4059.845


Gerhardt Domagk: The First Man to Triumph Over Infectious Diseases  By Ekkehard Grundmann

* Heinrich Hoerlein would eventually rise up to the managing board of IG farben, which was the conglomerate which ran a number of companies, including Bayer. Originally, it was primarily a dye making company. But it's activities during World War 2 were infamous. It was the company that developed Zyklon B, in the time that Hoerlein served on its board, which is why he found himself at the Nuremberg trials alongside many of the other company directors. It didn't help that at least one of these directors had been conducting experiments at Auschwitz under the direction of the SS. These experiments involved inducing artificial infections deliberately, and then giving the test subject antibiotics to cure the disease. Heinrich Hoerlein was amongst a number of IG Farbens executives who tried to stop the supply of these chemicals once he had found out what the Nazis were doing with them. When this came to light, the charges were dropped, but the reputation of IG Farben never really recovered, and the conglomerate didn't last long after the war, although some of it's constituent companies are still around today.

** Unfortunately the original paper is locked in the vaults of the Lancet, and so I am forced to diminish his role in the discovery of Antibiotic resistance, because there is no way for me to find out exactly what he did.

TMI Friday: Taking it to third base ..literally

The variety of foreign bodies in the rectum tests a surgeon's ingenuity to solve a myriad of geometric puzzles

So begins Major PT Mcdonald's  1976 paper, in which he has to deal with a  patient with a somewhat unique problem.
The patient, a 49 year old baseball fan, who had serious trouble with his bowels ever since the Oakland A's won the world series in 1974. The doctors examined him, and noticed

 " a firm, fixed, round object barely palpable which was lodged high in the rectum"

It was a baseball. To celebrate the Oakland A's victory, he had his sexual partner force the hardball up his rectum, where it got lodged. Unable to get any purchase on the surface of the ball, retrieval seemed impossible.
Thus it was left to the surgeon to figure out how to get the ball out. They drained the man's bladder using a catheter to take some of the pressure off the baseball. They tried to hook the ball, and drag it out as you would a particularly large fish. But this anal fishing expedition was for naught, as they only managed to rip some of the skin from the baseball.
They then decided that perhaps a better way of extracting the ball was through using obstetrics forceps. For those of you who don't know, these are generally used to deliver babies. So they pumped a little bit of air around the baseball, and tried to use the forceps to grab the ball.
It didn't work. They realised what the problem was. The baseball had travelled up through the pelvic arches, and after it had done so, it had become swollen with fluid, and become lodged in the pelvis.
It was a dire situation. The surgeon decided to cut into the man's abdomen to get access to the baseball. It was still stuck fast, and he needed to get some grip on the surface. So he skewered the baseball with a corkscrew, and tried to use it to pull it out. It still wasn't enough.  So he got an assistant to stick their fingers up the patients arse from the other end whilst also pulling on the corkscrew, and with " a force enough to lift the patient off the table", popped the baseball out.

McDonald M.P.T. & Rosenthal C.D. (1977). An unusual foreign body in the rectum—A baseball report of a case, Diseases of the Colon & Rectum, 20 (1) 56-57. DOI: 10.1007/BF02587455

TMI Friday: Using a Bottle for a Throttle

Today we once again must again take a look at men who take incredible risks in order to find new and grotesque methods of masturbation. You have been warned.

This week, the object of their fascination is.. the plastic bottle. 

In the grand scheme of things, at least the plastic bottles don't have spinning blades inside them, so in theory, these individuals are better off than those who turn on the vacuum cleaner for stimulation.

The first case we shall be examining comes from 2004, when a 27 year old man in India was admitted to hospital with a peculiar problem. His penis was stuck in a hard plastic bottle. There apparently were no attempts at an excuse, just the simple explanation that he had attempted to use it for masturbation. They called in the hospital carpenter to cut away the bottle *very* carefully using an Iron cutting saw. After 15 minutes of struggle, the bottle was removed.

In 2009, a 77 year old man in Singapore was admitted into hospital with complaints of blood in his urine, and difficulty urinating. Initially he wasn't forthcoming about his case history, for reasons that will soon become clear. You see, one week previously he had pushed a 1.5 litre bottle over his genitals, and got stuck. Over the next 3 days, he managed to cut away most of the bottle. But he still couldn't remove the neck of the bottle, despite attempts at lubricating it with soap. The surgeons managed to pry off the bottle neck with scissors, and they managed to repair some of the damage, but he died 3 days after admission.

The third case we will look at came from 2010 , and also occurred in India. A 47 year old man came in 14 hours after attempting to masturbate himself with a plastic bottle. That in itself is not the hair raising part of this case. We are told that the bottle neck was placed in such a position that it was impossible to access with a normal cutting device. So what did they use ? A soldering iron. Think about that. They mitigated the heat somewhat through adding cold saline in order to regulate the temperature. Still, it's not exactly a pleasant thought.

The final case I'll be talking about involves a 58 year old man. His flatmate called an ambulance for him after recognising that he was behaving oddly. But he sent them away, claiming that he didn't have anything wrong with him. Two days later his flatmate found him dead. The autopsy revealed that his genitals had been constricted with a plastic bottleneck. This bottleneck had cut off the circulation to this region, and allowing parts of his genitals to begin decaying. This lead to bacteria entering the bloodstream, and eventually caused multiple organ failure.

So how could these people stick their members into such small openings, and then get stuck. In order to answer this, we must examine how the penis works. Essentially it is a balloon filled with blood.  To become erect, arteries dilate in order to increase blood flow. However, if the veins that take the blood out of the penis are constricted, by say, a plastic bottleneck, then blood takes longer to escape, and so it swells up and gets stuck. This can actually be very dangerous. when the circulation is cut off, it can become gangrenous and in severe cases of penile strangulation, the only option is amputation. this is not even the worst case scenario, as we have seen, if this is not dealt with as soon as possible, then there is a risk of death.

 Penile strangulation appears to have a higher body count than men who stick their appendages into the whirling blades of a vacuum cleaner !

References

Jain S., Gupta A., Singh T., Aggarwal N., Sharma S. & Jain S. (2004). Penile strangulation by a hard plastic bottle : A case report, Indian Journal of Surgery, 66 (3) 

Ooi C.K., Goh H.K., Chong K.T. & Lim G.H. Penile strangulation: report of two unusual cases., Singapore medical journal, PMID: 19296009

Shamrao Kumbhar U., Dasharathimurumu & Bhargavpak (2011). Acute penile incarceration injury caused by a plastic bottle neck., International Journal of Biological & Medical Research, 2 (4) 

Morentin B., Biritxinaga B. & Crespo L. (2011). Penile strangulation: report of a fatal case., The American journal of forensic medicine and pathology, PMID: 22101437

TMI Friday: An Unusual Rectal Injury

The year was 1953, it was the fifth of November and a 24 year old man stumbled into Beckett Hospital complaining of abdominal pains. He told the doctors that it was a regular occurrence, that he had been plagued by abdominal pain for the past ten years. He told them that the evening before, he had noticed blood issuing from his bowels, and that he had vomited that morning.

As the doctor noting his horribly swollen and tender belly, he fainted.  This made finding the source of the problem more difficult. The doctor checked for tumours, and ended up trying to perform a proctoscopy. This involved the insertion of an instrument known as a proctoscope up the anus in order to get a look at the inside of the rectum. However, the copious amount of blood and faecal matter belching from the anus made it impossible to see anything.

This called for more drastic measures. The patient was anaesthetised, and the abdomen was opened up to get some idea what was going on. The abdominal cavity was full of blood, that was likely caused by some form of internal bruising. In the absence of an obvious injury, the abdomen was closed up. The doctor took another examination of the rectum, which was easier now that the patient was sedated, and found the source of the bleeding, a three cm rip in the rectum. With this established, surgery was performed to heal the wound, and to reverse the damage. But an important question still remained.

How did this injury occur ? Clearly, the patient had not told the whole story about what had happened to him. The three centimetre rip was clearly caused by a traumatic injury. The patient admitted this, and then gave them another explanation for what happened.

It was the fifth of November, Bonfire night, where the English stage fireworks displays to celebrate the foiling of the gunpowder plot. The man said that he had bent over at the wrong moment, and a carefully aimed firework had shot up his anus.

But this story didn't make sense. There would be damage to the anal sphincter and the butt cheeks had this been the case. When confronted with this evidence, the man told them a third story. I shall now quote directly from the article.

For domestic reasons he had become unhappy and morose, and on the evening of November 4 he decided to explode a firework up his seat. He accordingly fashioned a narrow tube, using cartridge paper, and with the aid of a pencil introduced one end of this tube, approximately 6 inches (15cm.) in length, into his rectum. He then placed a lighted firework into the end of the tube projecting out of his anus...

This story still left the question as to where the firework went, as no fragments were found. and there was a distinct lack of singeing. It is possible that the sheer volume of effluence issuing from the anus could have washed out the bits of firework. The patient maintained their story under psychiatric evaluation, so we must assume that this was the true story.There is no escaping the image of a man not only lighting a firework up his own anus, but then hitching up his pants and waiting until the next day to actually go to hospital.
The frustrating thing about this tale is that the patient went to some length to deceive the doctors with a fake medical history. Had he told the doctors the truth, he would have been put under anaesthesia, and have been treated more rapidly. That is one of the lessons we can draw from this study, aside from the obvious one.


Butters A.G. (1955). Unusual Rectal Injury, The British Medical Journal, 2 (4939) 602-603. DOI: 10.1136/bmj.2.4939.602