Neurological effects of traffic pollution
The link between air pollution and respiratory disorders is quite well known [1]. The association between air pollution and cardiovascular diseases has been reviewed in a previous post.
The latest research on air pollution looks into the neurological effects with following results:
Air pollution and brain function [2]
Exposure to diesel fumes triggers a stress response in the human brain. Researchers were able to demonstrate this using dilute diesel exhaust fumes (300 µg/m3) as model for ambient particulate matter exposure and monitoring brain activities by quantitative encephalogram (QEEG). In this double-blind randomized crossover study, those exposed to diesel exhaust showed a significant increase in the median power frequency of the QEEG after 30 minutes of exposure. This functional response in the brain continued to rise with longer exposure.
Air pollution and children`s IQ [3]
Children exposed to traffic-related pollution perform poorly in intelligence and memory tests compared those who breathe cleaner air. This prospective birth cohort study looked into children`s exposure to black carbon, a particulate matter component generated by traffic vehicles. Heavy exposure to black carbon translated to drops in averages scores in intelligence, vocabulary, memory and learning scales and indices. “Higher levels of black carbon predicted decreased cognitive function across assessments of verbal and nonverbal intelligence and memory constructs.”
It is speculated that “ultrafine” or “nanoparticles” found in the environment translocate to the brain and cause increased oxidative stress and brain inflammation.
Sources:
1 Andersen et al. Ambient Air Pollution Triggers Wheezing Symptoms in Infants. Thorax.Published Online First: 11 February 2008
2. Cruts et al. Exposure to diesel exhaust induces changes in EEG in human volunteers. Particle and Fibre Toxicology. Particle and Fibre Toxicology 2008, 5:4.
3. Franco Suglia et al. Association of black carbon with cognition among children in a prospective birth cohort study. American Journal of Epidemiology 2008 167(3):280-286.
A season of retractions, a question of accountability
So early in the year and already so many high-profile retractions in the biomedical field.
Retraction 1 [1]: A review paper [2] published in Best Practice & Research Clinical Rheumatology was retracted by the Harvard researcher Lee Simon after the software eTBlast and the database Déjà vu [3] marked the paper as a possible plagiarism. The paper supposedly had 55% text similarity with another paper published in 2003.
Retraction 2 [4]: Nobel prize winner Linda Buck retracted a 2001 Nature paper on the olfactory system [5] which she co-authored due to inconsistencies and inability of other researchers to reproduce the published results. Although Buck was named co-author, the primary author Zhihua Zou was cited “as solely responsible for providing data and figures for the paper” [4]. Buck won together with Richard Axel, the Nobel Prize in physiological medicine in 2004.
Retractions 3 and 4 [6]: One paper in Science [7] and another in Nature Chemical Biology [8] are being retracted by Korean researchers after doubts over the “scientific truth” of these molecular biology papers arose. The team of researchers in question works at the prestigious Korea Advanced Institute of Science and Technology (KAIST), led by the senior scientist Tae Kook Kim.
Issues to be linked to these stories are scientific integrity and author(s) [and co-author(s)!] accountability. Especially the accountability part. Who is accountable in cases of doubts and disputes? The supervisor or the PhD student? The team leader or the junior researcher?
References:
- Review article retracted amid plagiarism claims. Nature 451, 619 (2008).
- Simon LS. The treatment of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2004 Aug;18(4):507-38.
- Errami M. Déjà vu–a study of duplicate citations in Medline. Bioinformatics. 2008 Jan 15;24(2):243-9.
- Nobel prizewinner’s paper retracted. Nature 452, 13 (2008).
- Zhihua Z et al. Genetic tracing reveals a stereotyped sensory map in the olfactory cortex. Nature 414, 173-179 (8 November 2001).
- Korean institute inquiry prompts two retractions. Nature 452, 267 (2008).
- Won J. et al. A magnetic nanoprobe technology for detecting molecular interactions in live cells. Science 309 (5731):121 – 125; July 2005.
- Won J. et al. Small molecule-based reversible reprogramming of cellular lifespan. Nature Chem. Biol. 2, 369–374; 2006.
How Genetic Variation is Affecting Drug Development
In the March 2 issue of the Swiss newspaper “SonntagsZeitung” is an interesting article entitled “Pillen in Massanzug” which can be translated as “Custom-made Pills” [1]. The article basically explores how increased knowledge of human genetics is creating changes in drug development and speculates on the possibility of personalized medicine.
Here are some examples:
Carbamazepine
In December last year, The US FDA recommended genetic testing in connection with the prescription of the drug carbamazepine. Carbamazepine is commonly used for the treatment of epilepsy, bipolar disorder and neuropathic pain. Recently, certain patients – notably of Asian ancestry - were observed to develop serious skin disorders as adverse reaction to the drug. “Studies have found a strong association between certain serious skin reactions and an inherited variant of a gene, HLA-B* 1502, an immune system gene, found almost exclusively in people with Asian ancestry.” [2] Prior to this recent recommendation, genetic testing was recommended for all patients regardless of ethnicity. However, with the recent results of genetic studies, genetically high-risk patients have been narrowed down to an ethnic group, making life easier for health professionals and their patients, as well as the drug manufacturers themselves.
Statins
The use of the anti-cholesterol drugs statins has been associated with muscle pains and weakness. Researchers have recently identified the gene that may hold the key to statin-induced muscle toxicity. The atrogin-1 gene is associated with different types of muscle atrophy. In vitro and in vivo studies show that statins activate atrogin-1 gene leading to skeletal muscle damage [3]. Atrogin-1 gene expression may differ in different people, explaining the wide range of muscle symptoms (from very mild to debilitating) in statin users.
Trastuzumab
The anti-cancer drug Herceptin (trastuzumab) is a HER2/neu receptor antagonist and is indicated only for patients with HER2-overexpressing breast cancer. The drug specifically targets a gene (HER2) that causes breast cancer so that patients with other types of breast cancer cannot benefit from this drug. Considering the rather serious side effects involved (cardiomyopathy and pulmonary toxicity), HER2 gene testing is highly recommended before chemotherapy can be started. [4]
Ezetimibe
Ezetimibe is one of 2 combination drugs tested by the controversial ENHANCE trial. The study participants have heterozygous familial hypercholesterolemia, a genetic disorder characterized by cholesterol deposition and high plasma concentrations of low-density lipoprotein cholesterol [5]. Unfortunately, the trial results did not show any benefit from ezetimibe. However, drug testing on genetically distinct populations is becoming a common practice in drug development.
So how far are we from personalized medications? I personally think this will soon be technologically possible but whether it`s financially feasible is a different matter.
References:
1. SonntagsZeitung, 2 March 2008, p.73
2. FDA News, 12 December 2007.
3. Hanai et al. J Clin Invest. 2007 December 3; 117(12): 3940–3951.
4. Herceptin prescribing information, Jan 2008.
5. Yuan et al. CMAJ • April 11, 2006; 174 (8).
Latest approvals by the US FDA
• The proton pump inhibitor (PPI) Nexium (esomeprazole magnesium) is indicated for short-term treatment of gastroesophageal reflux disease (GERD) in children ages 1 to 11 years old. Nexium is manufactured by AstraZeneca [1].
• Xyntha Antihemophilic Factor (Recombinant) Plasma/Albumin Free is a new treatment for hemophilia A. Hemophilia A is a hereditary blood-clotting disorder that affects mainly males. It is caused by a mutation of the factor VIII, resulting in clotting factor VIII deficiency. Xanthia is a genetically engineered version of factor VIII. It is manufactured by Wyeth Pharmaceuticals Inc. [2].
• The Interleukin-1 blocker Arcalyst (rilonacept) is an orphan drug indicated for the treatment of two Cryopyrin-Associated Periodic Syndromes (CAPS) disorders. CAPS are very rare conditions of inflammation. Orphan drugs are drugs intended for the treatment of rare diseases. To make it worthwhile for drug companies to develop such drugs in the US, manufacturers of orphan drugs enjoy tax incentives and longer period of exclusivity as provided for by the US Orphan Drug Act. Arcalyst is manufactured by Regeneron Pharmaceuticals Inc. [3].
References: