In a recent post I talked about a metabolic poison that can decouple electron transport and oxidative phosphorylation.  You may be interested to know that this process is a known mechanism in infants.  This is not mediated by the same metabolic poison as I mentioned before, but rather by a naturally produced protein called thermogenin.  This protein causes the uncoupling of electron transport and oxidative phosphorylation in a cell’s mitochondria.  Check back a few posts for the mechanism if you’re interested.

So where does this take place?  If it took place in all cells (like if someone were to take that metabolic poison) the infant would be unable to survive.  Infants have specialized cells called brown adipose tissue or “brown fat” where this takes place.  These cells have many small fat vacuoles and mitochondria.  The normal fat found in adults is referred to as white fat.  Adults don’t have much (if any) brown fat.  By decoupling electron transport and oxidative phosphorylation the cell redirects the metabolic energy.  This results in the generation of heat and infants don’t need to shiver.  Neat, huh?

Dengue is a medically relevant virus that is common in tropical climates. The virus itself is a single stranded RNA virus. It is spread by the mosquito Aedes aegypti. It causes two diseases, dengue fever and dengue hemorrhagic fever. One cannot contract the second without having had the first. This is a very interesting component of dengue infection that relies on the host’s immune response. It is also why vaccination for dengue is seen as a risky proposition.

There are four different strains of dengue virus. These strains are very similar; so similar in fact that the immune system recognizes all of them after seeing only one. But recognition is not protection. Human T-cells each are programmed to recognize a specific pattern (or antigen). In the first infection virus particles will be captured and processed by so-called antigen presenting cells. These viruses will be presented to T-cells causing them to become activated. And likewise B-cells will encounter their antigen free floating and become activated. B-cells produce antibodies. Antibodies are used (among other things) to tag the viruses to encourage their uptake by macrophages (called opsonization) and inactivate them.

This first infection is known as dengue fever and will last 6 or 7 days. Its symptoms are much like a severe flu. Most people get over it without incident. If one becomes infected again things could go wrong. There are four strains of Dengue, all of which are all very similar. If you are infected with a different strain than you encountered the first time, you will contract dengue hemorrhagic fever.

But why does this happen? As it turns out, the antibodies from the first infection will attach to the virus particles but will not inactivate them. The strains are just different enough to remain active in the presence of another strain’s antibodies. These are referred to as “non-neutralizing antibodies”. These antibodies will still cause opsonization. So Macrophages willingly take up infectious viruses. This accelerates the course on infection to such a degree that hemorrhagic symptoms are seen. It’s one of those interesting times when our immune systems fail us. Imagine if people were vaccinated for dengue. What if someone missed one of the four vaccines or one was innactivated by improper storage? They would be quite prone to dengue hemorrhagic fever.

In case you’re confused I have changed the title of this article. The old title was attracting search engine hits from the wrong crowd. Not only were these searches disconcerting, these people were spamming my blog.

There is a fad out there right now. Some very body conscious people are using a substance, that for all intents and purposes, is a poison. You may wonder why they would do this. Because they can loose weight with it. We’ll call this DN (as I don’t want to give any impressionable people any ideas) and it is categorized as a highly toxic metabolic poison. Users of it know what I’m referring to. The mechanism by which it operates is downright interesting, and the consequences of it’s use are just as frightening.

Here’s a little background… DN was originally used in the 1930’s as a diet aid. It was one of those instances where people thought they had stumbled upon a miracle drug. People lost weight and everything was all well and good. Until they began to realize even a small overdose could cause a fever so high that it resulted in death. Not to mention the longterm effects include such favorites as cataracts. It fell out of use in the late 30’s and it stayed that way until the 90’s. Having apparently forgotten the lessons learned the first time around people began using it again. It is still popular with bodybuilders, models, athletes, and even some people with eating disorders. But how does it work, and what makes it so dangerous?

To answer that we’ll need a quick review of biochemistry. In our cells we have many proteins called enzymes. Enzymes are used to catalyze reactions that would not proceed on their own. Almost every reaction on the molecular level involves an enzyme in some way. Many of these enzymes are powered by that all important molecule, ATP. When an enzyme binds and hydrolyzes (breaks apart) ATP it allows the enzyme to undergo a conformational change (change shape). So we can think of ATP as imparting energy to the enzyme. This allows the enzyme to preform it’s specific reaction.

You need lots of ATP and most of it is produced in the mitochondria of your cells. These are small membrane bound structures that are probably the descendants of engulfed bacteria (but that’s another story). I won’t get into the intricacies here but this process relies on a series on enzymes that transport protons into a space between the mitochondria’s two membranes (known as the electron transport chain). This “proton gradient” leaks back out through another enzyme called ATP synthase. As the protons pass through the channel of the enzyme they initiate a conformational change that allows ATP synthase to make ATP. This is called oxidative phosphorylation.

Now, when you eat food the sugars eventually result in the production of ATP which allows your cells to synthesize complex molecules like fatty acids (among other things). If all you care about is loosing weight you can turn the production of ATP off and you body will begin breaking down fat for energy. This is called decoupling oxidative phosphorylation and it’s what DN does. It is capable of passing back and forth between the mitochondria’s membranes. It picks up protons from the gradient and releases them when it passes back to the other side, effectively undoing the work of the electron transport chain.

The problem with this is that that energy has to go somewhere instead of to ATP. It gets released as heat. Lots of heat. So much in fact, that even a small overdose causes core body temperature to rise above 104F. This is absolutely deadly. Proteins denature from the heat.

But still people use this stuff for quick results. It’s just not worth the risk here people. If you have body image problems seek professional help and don’t resort to these quick fix gimicks. You never know how dangerous it could be. Before trying ANY weight loss plan, consult a doctor. But just lay off the pills… they can be dangerous, as I’ve outlined above. And to those that use it professionally for that little extra edge (in athletics or bodybuilding), you are idiots. If anyone is interested in the identity of this substance, drop me a line. I’ll let it slip so long as you have a legitimate reason for asking.

Prion diseases operate differently than any other class of disease we are currently aware of. It is reliant on mutated forms of a common mammalian protein known as prion protein (PrPc). PrPc is highly homologous among mammals. In humans this protein is expressed in the central nervous system as well as in leukocytes and the gut. Common diseases known to be prion in nature include kuru, scrapie, Creutzfeldt–Jacob disease (CJD), Bovine Spongiform Encephalopathy (BSE/”mad cow”), and Gerstmann Straussler Scheinker (GSS) disease. Prion diseases are unique also in that there are three known ways for one to contract them: infectious, inherited, and sporadic.

A modified prion protein (PrPsc) has properties very different from those of the unmodified PrPc. PrPsc is highly resistant to the enzymatic degradation of the ubiquitin-proteasome system causing them to build up. This is a result of the changes in the secondary structure of PrPc, that is PrPsc has many areas of alpha helixes converted to beta sheets. These proteins build up in the brain causing cell death.

When a PrPsc molecule in introduced into a healthy animal it causes conformational changes in the healthy PrPc forms of the protein. This process is known as “Pruisner’s Theory”. This theory is evidenced by the tendency of aggregates to resemble the primary structure of the PrPc of a particular organism.

Recent studies have hinted that PrPsc aggregates are not necessary for prion-related neurotoxicity. If proteins are non-functional they are tagged by ubiquitin and degraded in a proteasome. This goes for PrPc as well. It has been discovered that if the ubiquitin-proteasome is inhibited, misfolded PrPc will build up in the cytosol and cause classic prion-related neurotoxicity. These PrPc proteins will aggregate in the cytosol and cannot be cleared by reinitializing the ubiquitin-proteasome system.

There are several findings in mouse studies that must be taken into consideration when thinking about the role of PrPsc in disease. It cannot cause disease when no PrPc is present. In a study mice with out the PrP gene (prpn) the PrPsc was unable to cause disease. Mice with truncated prpn producing non-functional PrP have high levels of cytosolic PrP and have massive neuronal loss. Older mice can spontaneously develop these symptoms, presumably sporadically. If PrPc production is inhibited in early PrPsc infection symptoms will not develop. The concentration of PrPsc does not seem to have an effect on the severity of the disease.

The new research raises many questions about the role of PrPc in relation to PrPsc exposure. It seems clear that PrPsc converts PrPc to the highly toxic form. However, it also seems clear that PrP itself can contribute to disease if the ubiquitin-proteasome system is not working properly.

It is put forth by researchers that the introduction of PrPsc may not be the determining factor in the development of neurodegenerative symptoms. This could be caused by a defect in the processing or metabolism of PrPc, or in the prpn gene itself. They state that an exogeneous form of PrPsc may initiate the events leading to the build up of PrPc in the cytosol and that this PrPc may fuel the further accumulation of PrPsc aggregates. This process may actually explain infectious, inherited, and sporadic prion disorders.

This article is a summary of recent reports released by the the World Health Organization. I hope to characterize the WHO proposed framework for preventing chronic disease.

With over 58 million deaths each year chronic disease will account for over 35 million of them. These include heart disease, stroke, cancer, and other chronic diseases. 15 million of these deaths occur in people under the age of 70. Contrary to popular belief, these are not “diseases of affluence”. Four out of five deaths from chronic disease are seen in low to middle income nations. These figures are increasing, which is especially alarming considering much of it is avoidable. Over 80% of heart disease, stroke, and diabetes as well as 40% of cancer could be avoided through life style modifications. In many afflicted nations medical treatment is spotty at best and medications are hard to come by. The goal of a WHO initiative is to reduce deaths from chronic disease by 2% each year.

In fact physical exercise, avoidance of tobacco, and a reasonable diet are the most important first steps in reducing the death rate. This may seem a daunting task for many nations, but the WHO has developed a stepwise plan of action. There are three main planning steps and three main implementation steps.

In the planning steps the first part is the acceptance of this framework by the national government. Without this support the effort will inevitably fail. Indonesia’s attempt at implementation is evidence of this. Chronic disease rates doubled there between 1981 and 2001 but only when all government groups collaborated were they able to get a plan in place. The next step is to adopt a plan for combating chronic disease that will take action in the next 5-10 years. The final planning step is to evaluate which steps will provide the most benefit and where. Also, determining what groups will be responsible for what steps.

This implementation steps are often known as core, expanded, and desirable. It is up to each nation to decide what issues they want to focus on (the core). It is important that they not overextend themselves in the expansion phase. It is bet that they do fewer things well than many things poorly. Finally, those in charge must assure that these reforms fit with those already in place.

It is nearly impossible for a single group to institute a national framework in this way. It requires the cooperation of health-based and non-health sectors to function. Indeed, this process requires the involvement of the civil, private and international sectors. Several nations including Tonga, Vietnam, and the Philippines have used this framework to institute programs to combat chronic disease.

All nations could benefit from this process. If we were able to decrease the incidences of death from chronic disease by 2% a year 36 million lives would have been saved by 2015. It is a mater of fact that we must support these programs, especially in low-income nations. Many of these diseases are endemic in these areas and could be corrected with a small amount of political attention. It would not take decades to see a change as some would believe. Many heath benefits can be seen very quickly; for example, tobacco-free policies. People will eventually die of something but no one deserves to go through life with chronic disease.

Firstly, let me thank the agricultural biotech groups and newsletters that picked up my last post about GM crops. It’s nice you enjoyed it enough to distribute it, and for the record I have no qualms about it. This post will probably less divisive (read: popular) though.  I encourage people to comment, even argue with me if they want.  But seriously, I don’t speak German.  Certain individuals (you know who you are) obviously understand English well enough to be pissed off.  If you want to tell me off, do it in English.

Francisella tularensis is an intracellular pathogen that is a potential bioweapon. It causes the disease tularemia; there is no vaccine for Francisella. It infects and replicates in macrophages by a novel mechanism that sets it apart from other intracellular pathogens. It is capable of interfering with the fusion of the Francisella-containing phagosome (FCP) with the lysosome, thereby creating a niche for itself. This organism diverges from the accepted mechanisms of other intracellular organisms. There are four different subspecies of F. tularensis: tularensis, holarctica, mediasiatica and novicida. F. t. tularensis is the most common pathogen associated with humans.

Foreign particles are taken up by macrophages and degraded in low pH vacuoles called lysosomes. As with most intracellular pathogens Francisella tularensis must prevent the phagosome it is contained in from merging with the lysosomal vacuole. A phagosome is simply the vacuole that a bacterium is contained in after it is internalized. Different intracellular organisms have different methods of disrupting the fusion of the phagosome and lysosome. The more common method used by Legionella and Chlamydia involves exporting bacterial effectors to the cytosolic surface of the phagosome. This prevents it from merging with a lysosome and does not interfere with the biochemical processes of the cell. The second and less common method is for the pathogen to export effector molecules to the cytosol where they interfere with all endocytic vesicles.

F. tularensis has decidedly different properties and thus is unique. It is taken up by what appears to be a microtubule dependent mechanism. The macrophage’s compliment receptor may be involved with internalizing the bacterium. Interestingly, this same novel mechanism is seen even with heat or formalin killed F. tularensis. The phagosome is remodeled quickly after infection. The bacterium has an unknown mechanism for keeping the phagosome from becoming too acidic. By 3-4 hours after infection the membrane of the phagosome will be weakened and breaks down releasing bacteria into the cytosol at about the 8 hour mark. It is here that they will replicate. However, the same killed bacteria from above have been found to be degraded in lysosomes just as any other particle would be.

Despite how quickly F. tularesis replicates it cannot propagate in activated macrophages. Though, no known pathogen can. The mechanism for this varies from one pathogen to another. In this case it seems to be that the phagosome does fuse with a lysosomal vacuole. In addition to this the bacterium seems to be unable to affect the phagosome to break it down.

Recently new details of the pathogenicity have been discovered. A pathogenicity island (FPI) has been identified in several subtypes of Francisella. Many of the genes in the FPI are integral to the intracellular nature of F. tularensis. It seems likely that these gene products are needed for escape from the phagosome. This would explain why killed bacteria are degraded but can still be internalized normally.

This is a very interesting bacterium with many unknowns. With such a pathogenic organism it is important threat we unravel these mysteries as quickly as possible. The effects of infection can be truly horrible so we must not allow ignorance to be our downfall.

Helicobacter pylori has been living with humans for a long time. But it was first characterized in 1875 as strange spiral bacteria in the stomach. However, it could not be grown in culture so it was disregarded. In 1982 two Australian doctors Barry J. Marshall and J. Robin Warren isolated the bacteria. It was eventually discovered that H. pylori plays a major role in the development of peptic ulcers and stomach cancer. Not long after research began to work out the role of H. pylori in humans, evidence indicated that the bacterium was disappearing. It seems that in developed nations antibiotics and better sanitation have decreased the incidence of H. pylori colonization. As it turns out, that’s not as good a development as one might think.

H. pylori is made up of 1.7 million base pairs comprising about 1550 genes. Remarkably, 6% of this bacteria’s genome is not shared by other strains of H. pylori. Humans share over 99% of our genome with chimpanzees, which are a completely different species. This tells us that H. pylori has many distinct yet functional forms that have developed over a very long time in humans.

One notable variant of this organism is the presence or lack of a protein called CagA. CagA is protein whose genes reside near those for a type IV secretion system. This seems to indicate that CagA utilizes this system to enter host cells. Once in the cell it causes the cell to signal to the immune system resulting in an inflammatory response. Those carrying strains of H. pylori expressing the CagA are more likely to develop gastric cancer.

Another variant of interest is the production of VacA. This is a toxin secreted by H. pylori that caused the formation of vacuoles in endothelial cells and (more importantly) turns off leukocytes in the area. Several different versions of this gene have been noted. The first were S1, S2 and M1, M2. The S1 variant had been divided into 3 distinct sub classes: s1a, s1b and s1c. It seems that the S1 and M1 forms produce the most potent version of the VacA toxin. Thus organisms with both CagA and VacA are the most likely to cause disease. The subtypes of the S1 gene have been used to track human movement in the past.

Different populations have different proportions of these genes. For example, s1b is prevalent in Spain and Portugal as it is in areas of Latin America settled by Spain and Portugal. The s1c variant was found in high numbers in some Amazonian areas as it is in the far east. This seems to show that H. pylori was with humans when they crossed the Bering Straight over 11,000 years ago. Genetic evidence from H. pylori can place it in the human population as far back as 60,000 years.

In developed nations only about 10% of people are colonized with H. pylori; whereas 70-100% of people are in developing nations. Humans have been carrying this organism for thousands of years and now the microenvironment is changing. The drop in H. pylori has corresponded with a drop in the incidences of certain types of stomach cancer as one would expect. However, we are seeing a massive jump in esophageal adenocarcinoma, rising 7-9% each year. This is a cancer of the esophagus just above the stomach with a 5 year survival rate of 10%. The primary risk factor gastroesophageal reflux disease (GERD) has gone up; it was completely unknown before the 1930’s. The correlation is hard to miss, When H. pylori colonization decreased these diseases increased.

The key is a negative feedback loop with the host. Humans and H. pylori have been coexisting for so long that there are certain adaptations involved on both sides. The bacteria use various signals to protect themselves as well as the host. An example is pH; if the stomach is too acidic the bacteria die, if it’s not acidic enough opportunistic pathogens can invade. When the acidity is high H. pylori will secrete large amounts of CagA. The resulting inflammatory response will lower acidity. The opposite is also true, low acidity slows production of CagA allowing the acidity to rise. Carrying H. pylori without the CagA gene results in weaker pH control and in people without H. pylori this regulation does not happen at all. If there is no control it is more likely that the esophagus will be exposed to highly acidic stomach contents as in GERD.

In the not too distant future could H. pylori be used as a probiotic? It is certainly not outside the realm of possibility. It is certainly more likely than using species of lactobacillus that are not so intertwined with humans. As we learn more about H. pylori it may become possible to give an individual the right bacterial load of Helicobacter to result in the lowest likelihood of stomach and esophageal cancers.

Those with bleeding disorders like hemophilia have long felt the brunt of the unknown in medical transfusions. Despite recent advances in this area of care the risk posed by emerging pathogens is great. The emergence of HIV is an example of what can occur if we are not vigilant in the search for new human pathogens. Coagulation-factor Concentrates (CFC) have been beneficial in that they are treated more thoroughly, but the threat remains.

When a virus enters the human population it goes through three main steps. The first is introduction. This means a new virus come into contact with humans or an existing human virus adapts in some way. An example of this is how SARS was originally introduced by zoonotic transmission from birds, or HIV from chimpanzees.

The next phase is adaptation. At this stage a pathogen establishes itself and spreads in the species. This often occurs after an alteration in the environment; it can be related to expansion of industry, new medical technology, or a change in public health practices. For example the construction of Aswan dam caused 200,000 deaths from Rift Valley fever which was originally spread via an arthropod vector.

In the final stage a pathogen becomes actively dangerous in a population. This is called emergence. This can occur one of two ways: abruptly with a shorter outbreak (like Ebola) or more gradually and thus more wide spread (like HIV).

There are many viruses that blood products are screened for but the question remains if an emerging pathogen will be caught in time. Part of the problem is that some diseases present no clinical symptoms for a time even though the plasma may be highly infective. One such pathogen is West Nile Virus, a flavivirus. At the peak of the epidemic in New York West Nile infection through transfusion was thought to be about 1.5 in 1000. CFC is usually treated in such a way that West Nile is inactivated. West Nile and other lipid envelope viruses are relatively easy to inactivate compared to the non-enveloped viruses.

The non-enveloped, or naked viruses, may cause a greater risk to CFC as some methods will be ineffective at eliminating them. Many different serotypes of enteroviruses have been isolated from human donations. Some of these are potential pathogens. Enterovirus 70 is a known cause of acute hemorrhagic conjunctivitis and Enterovirus 71 seems to cause various encephalitis diseases. Circoviruses are even smaller and resist nanofiltration. There are no known human diseases associated with Circoviruses but it has show the ability to jump species.

Prions are also of particular interest here. The emergence of variant Creutzfeldt – Jakob disease showed that spongiform encephalopathies can be easily transmitted. The normal prion protein (PrPc) is present in the plasma meaning that there is potential for PrPsc to be present as well. The altered prion protein (PrPsc) has been shown to be transmissible 10-20% of the time in sheep. While it is possible to transmit this disease in blood products it is only a theoretical threat at this point.

Those with coagulation disorders like hemophilia have a special risk of contracting these diseases. Receiving transfusions of blood products for their entire life increases the odds dramatically. After the AIDS epidemic got into full swing the life expectancy for a patient with hemophilia went from 57 years to only 35 years by 1995. These patients also tend to be infected with hepatitis B and C, which complicate their care. Recent advancements in clotting factor replacement therapy have shown promise though. While plasma derived clotting factors could carry disease, new recombinant technologies may put an end to this threat.

Clotting factors can be made by immortal cell cultures with less chance of viral contamination. So called first generation cell cultures contain human proteins and thus have the capability to carry prions. In second generation cultures the stabilizing animal proteins are replaced with carbohydrates reducing the risk of prion transmission. Finally, in third generation no human or animal proteins are added. This is believed to be the safest source of human clotting factors.

Hemophilic patients are exposed to the sum of human disease and often pay dearly for it. Recent advances may provide safer sources of the clotting factors they need. But it will never come soon enough for some.

We’ve all heard of the “flesh-eating” bacteria. It sounds scary doesn’t it? It is scary, but not in the way you’d expect. To put it simply, the bacteria don’t actually eat you… YOU eat you. That probably doesn’t make a whole lot of sense as I’ve just explained it… Necrotizing fasciitis (as it’s properly called) is most frequently caused by a bacteria known as Streptococcus pyogenes.

Even a relatively minor abrasion can lead to infection if the bacteria is present. All the action takes place in the Fascia, a layer of connective tissue and blood vessels covering the muscle. The bacteria multiplies like any other, but this is the twist. The strains of S. pyogenes capable of causing necrotizing fasciitis produce a super-antigen.

So what’s a super antigen? It’s a regular antigen but super But really… your immune system recognizes foreign material as “antigens”. Each T-cell and B-cell recognize only one antigen.

This specific antigen can be a part of the bacteria itself or something they secrete. This interaction is usually specific to the T-cell and causes them to become activated. T-cells then direct the immune response through the release of cytokines. Cytokines then activate other immune cells and attract them to the infected area. On average, an antigen activates 1 in 30,000 T-cells.

A super-antigen is not specific to a particualr T-cell. Rather, it simply binds (very strongly) to most T-cell receptors. This activates them just as if they had encountered their specific antigen. This process activates 1 in 5 T-cells… waaaaaaay more than should be activated. With all these cells secreting cytokines things get … confused.

You have immune cells called macrophages. These cells are what actually cause the damage. These are normally activated by T-cells. They phagocytose (take in) pathogens and destroy them. They have the ability to use oxygen radicals to kill these pathogens. With all those T-cells releasing cytokines these macrophages become over stimulated. They begin over producing oxygen radicals and bathe your tissues in them. This causes massive cell death and necrosis.

The treatment for necrotizing fasciitis is straight forward: surgical debridement. ALL the infected tissue must be removed to stop the infection. This often means removal of limbs. If the infection is not on an extremity the options are somewhat limited. Due to the extensive thrombosis caused by the infection antibiotics cannot reach the site of infection very well. The wounds can be irrigated with antibiotic solutions… but this is often ineffective.

This is a truly terrifying disease. Your own defences are turned against you in a matter of hours. The tissues are not really “eaten” but rather destroyed. The very cells meant to protect you can cost you your life.