How Changes in Neurons May Lead to Altered Cortisol in CFS/ME & Sickness Syndrome.

Background: Many research experts believe that endotoxin is a causal factor in the development of chronic fatigue syndrome. (Maes) In addition and as we have discussed on this blog, many of the symptoms may be attributed to sickness behavior or sickness syndrome. Generally, this is regarded as a reflection of immune responses that alter normal functions of hormones, neurotransmitters, etc. resulting in changes in behavior in humans and other animals.

We recently discussed how dysregulation of the hormone, ghrelin, may effect sickness behavior. A study just published provides more details about how another hormone may contribute to sickness syndrome and related alterations in behavior. According to the study, LPS endotoxin suppresses the neuronal circuitry in orexin and histamine neurons. As the abstract describes, the orexin neurons in the brain are important for behaviors including waking, feeding and reward-related behaviors and can be regulated by dopamine (Bubser), provide antinociceptive protection (Mobarakeh) and may reduce gastrointestinal injury through several mechanisms including injury from TLR signaling. In other blogs, we describe in detail how LPS from gram-negative bacteria and other environmental contaminants such as ozone can initiate inflammatory effects through TLR signaling and that genetic or environmental dysruption of the Nrf2 system will enhance the inflammatory effects.

Outside the brain, orexin neurons stimulate the production of cortisol in the adrenal glands and another studies shows orexin can time-dependantly raise cortisol levels as well as, influence steroidogenesis. Orexin studies have also revealed it regulates histamine release in the brain. Interestingly, narcolepsy which is suspected to be an autoimmune-related condition is associated with orexin deficiency. Aran proposes that streptococcus is an environmental trigger of narcolepsy. For this reason, the results of these studies in combination suggest that both gram-negative and gram-positive bacteria may contribute to sickness syndrome by altering orexin levels. In addition, orexin is a sexually-dimorphically expressed hormone which may help to explain the gender differences in the rates of environmental illness. (Johren)

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Alterations of BDNF, Behavior Hormones in PTSD, Fibromyalgia and Other Environmental Illnesses

Many experts believe that the functions of the hypothalamus are dysrupted in environmental illness. We recently blogged about how hypothalamus-stimulated signaling of  BDNF levels are altered in a number of environmental illnesses. In fibromyalgia they are increased while in other are they are lower. A more recent report has indeed supported the fact that BDNF levels are increased in fibromyalgia. Also, they have demonstrated that this hormone is elevated shortly after trauma in PTSD and evens out over time. Interestingly, these findings were independant of severity, psychiatric history and treatments with medication. Because BDNF has been implicated in learning and memory the higher levels of this protein may contribute to the pathology of PTSD and considering they are elevated in fibromyalgia, one may suspect they also contribute to the pathology of fibromyalgia also. Of course, further evidence is warranted but these findings are interesting none-the-less.

Note:

• Orexin is another signaling peptide of the hypothalamus and it has been demonstrated that altered levels are consistent with fibromyalgia, chronic fatigue syndrome, PTSD and panic attacks. We have discussed this hormone in other blogs and explained, it dictates a number of different animal behaviors and is sexually dimorphic and plays a role in sickness behavior.  In addition, there is an important connection between orexins and BDNF. Dopamine are regulators of orexins and low levels are also associated with Parkinson's disease.
• BDNF is mediated by GSk-3b which is implicated in a number of psychological disorders and can be activated by environmental exposures. (Mai)

For further Reading:

• Sleepiness in CFS and Fibromyalgia May Be a Form of Narcolepsy!

Reference Library Tags: orexin, narcolepsy, chronic fatigue syndrome, PTSD, BDNF
                HEIRS Blogs: orexins, BDNF, chronic fatigue syndrome, sickness syndrome, fibromyalgia,  PTSD,


Strawn, J. R., Pyne-Geithman, G. J., Ekhator, N. N., Horn, P. S., Uhde, T. W., Shutter, L. A., Baker, D. G., and Geracioti, T. D. (2010). Low cerebrospinal fluid and plasma orexin-a (hypocretin-1) concentrations in combat-related posttraumatic stress disorder. Psychoneuroendocrinology. http://www.citeulike.org/user/HEIRS/article/6644003
Thannickal, T. C., Lai, Y.-Y., and Siegel, J. M. (2007). Hypocretin (orexin) loss in parkinson's disease. Medscape Today.  http://www.citeulike.org/user/HEIRS/article/6640584
Bubser, M., Fadel, J. R., Jackson, L. L., Meador-Woodruff, J. H., Jing, D., and Deutch, A. Y. (2005). Dopaminergic regulation of orexin neurons. The European journal of neuroscience, 21(11):2993-3001. http://www.citeulike.org/user/HEIRS/article/6463668
Gaykema, R. P. and Goehler, L. E. (2009). Lipopolysaccharide challenge-induced suppression of fos in hypothalamic orexin neurons: their potential role in sickness behavior. Brain, behavior, and immunity, 23(7):926-930. http://www.citeulike.org/user/HEIRS/article/4967509
Stanley, S., Wynne, K., McGowan, B., and Bloom, S. (2005). Hormonal regulation of food intake. Physiol. Rev., 85(4):1131-1158. http://physrev.physiology.org/cgi/content/full/85/4/1131/F2
Mai, L., Jope, R. S., and Li, X. (2002). Bdnf-mediated signal transduction is modulated by gsk3β and mood stabilizing agents. Journal of Neurochemistry, 82(1):75-83. http://www.citeulike.org/user/HEIRS/article/6621876

Sleepiness in CFS and Fibromyalgia May Be a Form of Narcolepsy!

In our recent blog discussed how orexin(hypocretin) effects sleep patterns and may have an important role in CFS and sickness syndrome. A new study using a pharmaceutical called sodium oxybate showed significant improvement in patients in fatigue with both chronic fatigue syndrome and fibromyalgia and point to the "real possibility" that sleep problems in these conditions are similar to narcolepsy. In addition, the study suggests, even though further study is warranted that both CFS and FM are similar or not the same condition because of the improvements seen in patients with them.  We have noted similarities to sickness syndrome in these conditions and have emphasized that sickness syndrome also occurs in animals and importantly, narcolepsy also is not exclusive to humans and in often seen in dogs. Some breeds more commonly than others.

Other recent discoveries indicate that the major pathophysiology of human narcolepsy "is the loss of lateral hypothalamic neurons that produce the neuropeptide hypocretin (orexin). Approximately 90% of people diagnosed as having narcolepsy with cataplexy are hypocretin ligand deficient." Narcolepsy is thought to be an autoimmune related disorder and can alter regulation of cortisol and influence steroid production which also may initiate panic.  In our recent blog, we wrote how streptococcus pneumoniae may be an important trigger of orexin-influenced narcoleptic sleep behavior. This is important because this pathogen effects the severity of H1N1 and may mean that patients with EI may be more susceptible to both. Parkinsonism is also associated with alterations in hypocretin and future therapies in PD may involve treatments involving orexin. Some suggest that narcolepsy and Parkinson's disease have a common and therefore, one must begin to hypothesize that CFS and fibromyalgia may have the same or similar causal factors as PD and and narcolepsy.

For Further Reading About Orexins in CFS, Sickness Syndrome and Fibromyalgia, see

• How Changes in Neurons May Lead to Altered Cortisol in CFS/ME & Sickness Syndrome. HEIRS, January 1, 2010.
• Hormone Linked to Panic Attacks Also Linked to Endotoxin and Sickness Behavior

Spitzer, A. R. and Broadman, M. (2010). Treatment of the narcoleptiform sleep disorder in chronic fatigue syndrome and fibromyalgia with sodium oxybate. Pain Practice, 10(1):54-59. http://www.citeulike.org/user/HEIRS/article/6512085
Zeitzera, J. M., Nishinob, S., and Mignotc, E. (2006). The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends in Pharmacological Sciences, (27):368-374. http://www.citeulike.org/user/HEIRS/article/6512089
Thannickal, T. C., Lai, Y.-Y., and Siegel, J. M. (2007). Hypocretin (orexin) loss in parkinson's disease. Medscape Today. http://www.citeulike.org/user/HEIRS/article/6512132

Ammonia, Methamphetamine, Cigarette Smoke and Parkinson's Disease

A number of noxious fumes and toxins are produced in the manufacturing process of the illegal drug methamphetamine and in recent months there have been a number of broadcasts on dangers associated with "meth lab homes". If you have missed these broadcasts it may interest you to know that 1 pound of meth produces 6 pounds of toxic chemicals. If you're not in the market for renting or buying a home, you might not be concerned by this now but these chemicals end up in the soil, air and water that surround the manufacturing site or are dumped along the roadside from mobile labs. Chemicals produced indoors from meth labs absorb into any porous material including carpets, clothing, blankets, food products, paint, flooring etc and get distributed onto all surfaces through air flow, ventilation and duct work and tracked into "clean" environments by contaminated shoes. Cars that house mobile labs are also a lifetime hazard because upholstery is porous and absorbs toxins.  

Most people are familiar with the fact that one of the most common chemicals associated with meth lab exposure is ammonia that can be toxic at certain amounts. Of course, the level of what determines the effects of toxicity is going to depend on the concentration, the route of exposure, the duration and metabolic characteristics of those exposed. Different people have different levels of detoxification that ultimately determines how serious the exposure to ammonia or to any chemical will be and there are a number of factors that influence this including genetics. One author explains ammonia toxicity can occur as a result of "alterations of ammonia metabolism including enzyme issues within the urea cycle, Reyes Syndrome and liver failure and the effects of these conditions may lead to brain edema and severe neurological impairment. Generally, it is now known that ammonia crosses the blood-brain barrier and interacts with a number of cellular processes including neurotransmission and brain metabolism." (Butterworth)

 For several years now, health experts have been aware that the illegal use of  methamphetamine may lead to long-lasting health consequences including dental disease and mental health problems in addition to those associated with addiction. Another consequence is an increased risk for Parkinson's disease for those who abuse methamphetamine, later in life. While there are a number of reasons for this, there are two that stand out in importance in addition to ammonia-inducing mitochondria dysfunction. The first is because of the vulnerability of certain neurons including those that regulate dopamine to the toxic effects of ammonia. There are also "lasting decrements in something called the dopamine transporter" and the elevation of oxidative stress by dopamine which damages tissues and causes neural injury. Luckily, under normal circumstances and at normal concentrations and when all things are working properly these kinds of toxic processes can be neutralized through the activities of antioxidants but meth labs are not considered normal circumstances and produce ammonia levels at much higher levels than normal.  

Unfortunately and as noted above, a number of physiological conditions influence how toxins are detoxified and levels of antioxidants may be reduced as a consequence of genetic polymorphisms, injury or the natural processes associated with aging. As far as antioxidant production in PD, the antioxidant system Nrf2 has been found to modulate the severity of toxicity associated with drugs and other toxic exposures. In experimental models, the loss of the expression of Nrf2  results in a greater loss of the dopamine transporter and much greater oxidative stress and greater neural damage.  While this process is more complex than what is explained here, the main point is expression of the Nrf2 is necessary to reduce the kinds of toxicity implicated in PD. (McCann) Nrf2 also regulates the production of certain cofactors necessary that are used in mitochondrial biogenesis which further influences neurological health. Oxidative stress at optimal levels is important for activation of different protective mechanisms including Nrf2 but too much is just too much to continue homeostasis (Widmer) and these conditions significantly complicate methods for treatment. Alterations in functions of antioxidant systems influence a number of diseases and specifically, dysfunction of the Nrf2 system has been implicated in several including cancer, respiratory diseases like COPD and autoimmune diseases.

  

Notes:

• Interestingly, it has been suggested that cigarette manufacturers add ammonia to cigarettes to make it more addictive because it enhances the effects of nicotine. This is achieved by "the addition of ammonia in the manufacturing process which helps convert bound nicotine molecules in tobacco smoke into free nicotine molecules and commonly known as "freebasing." This process is similar to that of freebasing cocaine, the end result is an enhanced effect of the drug on the user. This becomes a real problem upon cigaratte exposure for those who may have inborn errors for ammonia detoxificaton or genetic alteractions in other protective pathways such as Nrf2. (Martin)
• It takes a number of months before a baby's detoxification system is developed and so exposures to toxins in the womb and after birth can take a tremendous toll on the "little ones".
• Alterations in metabolic pathways that influence the excretion of ammonia are negatively influenced by heavy metals. One can be exposed to them from exposure to methamphatamine or meth precursors.
• Elevated levels of ammonia have been implicated in health conditions such as autism and may contribute to different types of brain injury.
• Because physical activity improves neural function and toxic exposure may negatively influence olfaction which also dictates behavior --- there is potential for increase atrophy and damage. Olfactory deficits present themselves often years before PD motor deficits appear.  
• Sleep deprivation from drug abuse has potential to speed mitochodrial dysfunction and shut off the antioxidant system. (Kresiun) Hyperammonemia alters expression of orexins which have a responsibility in control of sleep wake cycles and as a result may alter circadian rhythm and hormone function. (Ahabach) Specific dopamine signals regulate orexins and studies show the loss of orexin neurons is correlated to disease severity of PD. (Bubser, Thannickal)

Reduced Striatal Dopamine Transporter Density in Abstinent Methamphetamine and Methcathinone Users: Evidence from Positron Emission Tomography Studies with [11C]WIN-35,428: "McCann, U. D., Wong, D. F., Yokoi, F., Villemagne, V., Dannals, R. F., and Ricaurte, G. A. (1998). Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: Evidence from positron emission tomography studies with [11c]win-35,428. J. Neurosci., 18(20):8417-8422." http://www.citeulike.org/user/HEIRS/article/6639032
Butterworth, R. F. (2001). Glutamate transporter and receptor function in disorders of ammonia metabolism. Mental Retardation and Developmental Disabilities Research Reviews, 7(4):276-279. http://www.citeulike.org/user/HEIRS/article/6639166
Martin, Terry. Boosting the Impact of Nicotine with Ammonia. About.com. Retrieved on February 7, 2010. http://quitsmoking.about.com/od/chemicalsinsmoke/p/nicoboost.htm
Emergency Protocal. Urea Cycle Disorders. The Neonate with Hyperammonemia. Retrieved on February 7, 2010. http://www.citeulike.org/user/HEIRS/article/6639971
Widmer, R., Kaiser, B., Engels, M., Jung, T., and Grune, T. (2007). Hyperammonemia causes protein oxidation and enhanced proteasomal activity in response to mitochondria-mediated oxidative stress in rat primary astrocytes. Archives of biochemistry and biophysics, 464(1):1-11. http://www.citeulike.org/user/HEIRS/article/6640113
Ahabrach, H., Piedrafita, B., Ayad, A., El Mlili, N., Errami, M., Felipo, V., and Llansola, M. (2009). Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats. Journal of neuroscience research. http://www.citeulike.org/group/5070/article/6638140
Kresiun, V. I. and Rozhkovskiĭ, I. a. V. (1991). [disruption of the structural organization of brain mitochondrial membranes during deprivation of the paradoxal sleep phase and correction for it using lithonite]. Ukrainskiĭ biokhimicheskiĭ zhurnal, 63(3):59-65. http://www.citeulike.org/user/HEIRS/article/6640249
Cagnon, L. and Braissant, O. (2009). Cntf protects oligodendrocytes from ammonia toxicity: intracellular signaling pathways involved. Neurobiology of disease, 33(1):133-142. http://www.citeulike.org/user/HEIRS/article/6640251?updated=1265582259
Inui, A. (1999). Cancer anorexia-cachexia syndrome: Are neuropeptides the key? Cancer Res, 59(18):4493-4501. http://www.citeulike.org/user/HEIRS/article/6640255
Hermenegildo, C., Montoliu, C., Llansola, M., Muñoz, M. D., Gaztelu, J. M., Miñana, M. D., and Felipo, V. (1998). Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic gmp pathway in cerebellar neurons in culture and in the rat in vivo. The European journal of neuroscience, 10(10):3201-3209. http://www.citeulike.org/user/HEIRS/article/6640260
Bubser, M., Fadel, J. R., Jackson, L. L., Meador-Woodruff, J. H., Jing, D., and Deutch, A. Y. (2005). Dopaminergic regulation of orexin neurons. The European journal of neuroscience, 21(11):2993-3001. http://www.citeulike.org/group/5070/article/6463668
Thannickal, T. C., Lai, Y.-Y., and Siegel, J. M. (2007). Hypocretin (orexin) loss in parkinson's disease. Medscape Today. http://www.citeulike.org/user/HEIRS/article/6640584

Histamine and Orexin in the Control of Arousal, Locomotion, and Motivation

Histamine and Orexin in the Control of Arousal, Locomotion, and Motivation

ATP-Sensitive Potassium Channel-Mediated Lactate Effect on Orexin Neurons: Implications for Brain Energetics during Arousal

ATP-Sensitive Potassium Channel-Mediated Lactate Effect on Orexin Neurons: Implications for Brain Energetics during Arousal

Hormone Linked to Panic Attacks Also Linked to Endotoxin and Sickness Behavior

CiteULike: Lipopolysaccharide challenge-induced suppression of Fos in hypothalamic orexin neurons: their potential role in sickness behavior.: "Gaykema, R. P. and Goehler, L. E. (2009). Lipopolysaccharide challenge-induced suppression of fos in hypothalamic orexin neurons: their potential role in sickness behavior. Brain, behavior, and immunity, 23(7):926-930."

Runaway vigilance hormone linked to panic attacks. National Institute of Mental Health. http://www.citeulike.org/user/HEIRS/article/6463151

PTSD, Environment and Gene Variants in COMT

A new study reports that variants in the gene for catechol-O-methyltransferase (COMT) Val158Met and the amount of "traumatic load" influences the likelihood of PTSD and other reports show that COMT may be located both in the glia and certain neurons. The toxic destruction  of dopamine neurons in striatum does not result in loss of COMT and therefore, striatal dopaminergic neurons do not contain a high level of this protein. In areas where COMT neurons are present such as the prefrontal cortex, variants may influence the dopamine signaling and increase the length of time for this neural transmitters elimination. These findings provide a foundation for understanding the difference in cognitive performance including executive functioning, of COMT variants as well as, their association with mental health disorders. (Yavich)

Notes:

• We suggested in an earlier blog that because hyperammonemia may influence cellular pathways associated with PTSD -- conditions that influence endogenous levels of ammonia from exogenous environmental factors or alterations in metabolism may have implications on development of this disorder.
• "COMT catalyzes the methylation of various endobiotic and xenobiotic substances preventing quinone formation and redox cycling, and therefore might protect DNA from oxidative damage."  Availability and variants of this protein therefore may influence the biological effect related to toxic exposures. (Hung) 

References:

• Hyperammonemia, Subordination, Hypoxia Influence Stress Hormone CRF Production in Fish.

Kolassa, I.-T. T., Kolassa, S., Ertl, V., Papassotiropoulos, A., and De Quervain, D. J.-F. J. (2010). The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferase val(158)met polymorphism. Biological psychiatry, 67(4):304-308. http://www.citeulike.org/user/HEIRS/article/6250832
Hung, R. J., Boffetta, P., Brennan, P., Malaveille, C., Gelatti, U., Placidi, D., Carta, A., Hautefeuille, A., and Porru, S. (2004). Genetic polymorphisms of mpo, comt, mnsod, nqo1, interactions with environmental exposures and bladder cancer risk. Carcinogenesis, 25(6):973-978. http://www.citeulike.org/user/HEIRS/article/6643978
Strawn, J. R., Pyne-Geithman, G. J., Ekhator, N. N., Horn, P. S., Uhde, T. W., Shutter, L. A., Baker, D. G., and Geracioti, T. D. (2010). Low cerebrospinal fluid and plasma orexin-a (hypocretin-1) concentrations in combat-related posttraumatic stress disorder. Psychoneuroendocrinology. http://www.citeulike.org/user/HEIRS/article/6644003

Abstracts on Pneumococcal Infection (& other bacteria) Added to the Library

Villena, J., Barbieri, N., Salva, S., Herrera, M., and Alvarez, S. (2009). Enhanced immune response to pneumococcal infection in malnourished mice nasally treated with heat-killed lactobacillus casei. Microbiology and immunology, 53(11):636-646.
http://www.citeulike.org/user/HEIRS/article/6467481

Saini, A., Harjai, K., Mohan, H., Punia, R. P. S. P., and Chhibber, S. (2009). Long-term flaxseed oil supplementation diet protects balb/c mice against streptococcus pneumoniae infection. Medical microbiology and immunology.
http://www.citeulike.org/user/HEIRS/article/6226768

Wenger, J. D., Zulz, T., Bruden, D., Singleton, R., Bruce, M. G., Bulkow, L., Parks, D., Rudolph, K., Hurlburt, D., Ritter, T., Klejka, J., and Hennessy, T. (2009). Invasive pneumococcal disease in alaskan children: Impact of the seven-valent pneumococcal conjugate vaccine and the role of water supply. The Pediatric infectious disease journal.
http://www.citeulike.org/user/HEIRS/article/6467478

Lacapa, R., Bliss, S. J., Larzelere-Hinton, F., Eagle, K. J., McGinty, D. J., Parkinson, A. J., Santosham, M., Craig, M. J., and O'Brien, K. L. (2008). Changing epidemiology of invasive pneumococcal disease among white mountain apache persons in the era of the pneumococcal conjugate vaccine. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 47(4):476-484.
http://www.citeulike.org/user/HEIRS/article/6467475

Phipps, J. C., Aronoff, D. M., Curtis, J. L., Goel, D., O'Brien, E., and Mancuso, P. (2009). Cigarette smoke-exposure impairs pulmonary bacterial clearance and alveolar macrophage complement-mediated phagocytosis of s. pneumoniae. Infection and immunity.
http://www.citeulike.org/user/HEIRS/article/6467469

Maddox, J. F., Amuzie, C. J., Li, M., Newport, S. W., Sparkenbaugh, E., Cuff, C. F., Pestka, J. J., Cantor, G. H., Roth, R. A., and Ganey, P. E. (2010). Bacterial- and viral-induced inflammation increases sensitivity to acetaminophen hepatotoxicity. Journal of toxicology and environmental health. Part A, 73(1):58-73.
http://www.citeulike.org/user/HEIRS/article/6465503

Saw, C. L. L. L., Huang, Y., and Kong, A.-N. N. (2010). Synergistic anti-inflammatory effects of low doses of curcumin in combination with polyunsaturated fatty acids: docosahexaenoic acid or eicosapentaenoic acid. Biochemical pharmacology, 79(3):421-430.http://www.citeulike.org/user/HEIRS/article/5765677

Sebai, H., Ben-Attia, M., Sani, M., Aouani, E., and Ghanem-Boughanmi, N. (2009). Protective effect of resveratrol in endotoxemia-induced acute phase response in rats. Archives of toxicology, 83(4):335-340.
http://www.citeulike.org/user/HEIRS/article/6463192

Aran, A., Lin, L., Nevsimalova, S., Plazzi, G., Hong, S. C. C., Weiner, K., Zeitzer, J., and Mignot, E. (2009). Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep, 32(8):979-983.
http://www.citeulike.org/user/HEIRS/article/6463176

Gaykema, R. P. and Goehler, L. E. (2009). Lipopolysaccharide challenge-induced suppression of fos in hypothalamic orexin neurons: their potential role in sickness behavior. Brain, behavior, and immunity, 23(7):926-930.
http://www.citeulike.org/user/HEIRS/article/4967509

Tokairin, Y., Shibata, Y., Sata, M., Abe, S., Takabatake, N., Igarashi, A., Ishikawa, T., Inoue, S., and Kubota, I. (2008). Enhanced immediate inflammatory response to streptococcus pneumoniae in the lungs of mice with pulmonary emphysema. Respirology (Carlton, Vic.), 13(3):324-332.
http://www.citeulike.org/user/HEIRS/article/2651950

Ozlu, T., Celik, I., Oztuna, F., Bulbul, Y., and Ozsu, S. (2008). Streptococcus pneumoniae adherence in rats under different degrees and durations of cigarette smoke. Respiration; international review of thoracic diseases, 75(3):339-344.
http://www.citeulike.org/user/HEIRS/article/6462971

Garbin, U., Fratta Pasini, A., Stranieri, C., Cominacini, M., Pasini, A., Manfro, S., Lugoboni, F., Mozzini, C., Guidi, G., Faccini, G., and Cominacini, L. (2009). Cigarette smoking blocks the protective expression of nrf2/are pathway in peripheral mononuclear cells of young heavy smokers favouring inflammation. PLoS ONE, 4(12):e8225+. http://www.citeulike.org/user/HEIRS/article/6467492

Columbia University's Mailman School of Public Health (2009, December 31). Severity of H1N1 influenza linked to presence of Streptococcus pneumoniae. ScienceDaily. Retrieved January 1, 2010, from http://www.sciencedaily.com/releases/2009/12/091230201419.htm