I have just found our most recent PLOS paper about asthma in Africa being published online
As of the 1980s, there was an overall conviction that asthma had an anthropogenic origin with indoor and outdoor air pollution as the main culprits. Following some overinterpreted epidemiological findings of the â€œhygienicâ€ phase, there is now evidence accumulating that the asthma epidemic might have an iatrogenic origin. There might not only be indirect effects of improved living standards and better medical care, there are even direct effects under discussion, for example by oestrogens, vitamin D, antibiotics, and paracetamol. Infant formula (which contains vitamin D) has already entered the food chain in Africa; paracetamol is the most common drug bought over the counter in Ghana. Do African countries offer any unique observations where singular effects of these drugs can be delineated?
An independent review (that I did not know at time of writing) arrived at similar conclusions. We all, however, forgot to mention sensational news as Gambian president Yahya Jammeh can heal asthma click – click – a more serious appraisal click.
My childhood favorites
Early vitamin D supplementation may have dual effects, protecting against type 1 diabetes and inducing allergy. Is that possible? Yes, individual genes variants may determine the outcome.
In addition to HLA the most prominent type 1 diabetes genes are INS – CTLA4 – PTPN22 – CD25 – IF1H1, the most prominent asthma/allergy genes ADAM33 – DPP10 – IL12 – IL4 – GPR154 – FLG. I canÂ´t see any joint master regulator, however, we know that
Could that be a model to explain the dual involvement of vitamin D in both diseases?
Salamander Candy has an interesting essay about Sir Karl Popper’s demarcation of science
The most informative and useful delineation between those pursuits understood as scientific, such as astronomy, and those of the pseudo-sciences, such as astrology, is that science integrates positive and negative feedback loops. These feedback loops are based on critical analysis, empirical testing, and reformulation of falsifiable statements. This process serves to maximize the accumulation of accurate statements and minimize the accumulation of erroneous statements within an integrated system of statements which describe the physical universe. In other words, the primary function of science, and the thing that makes it different from pseudo-science, is constructive self-criticism. Karl Popper, in his essay â€œScience: Conjectures and Refutationsâ€ (1963), claims that, â€œâ€¦the criterion of the scientific status of a theory is its falsifiability, or refutability, or testability.â€
This is a really nice account on the scientific theory that get nowadays more and more corrupted in daily practice (at least in biomedical research). For example there are currently 30-50 allergy research papers every day; many of these miss recent and important papers. Correct me if I am wrong but most biomedical research is accumulating only facts but not knowledge. The discussion section of many papers follow the boring outline — we found- — others found — some strengths and weaknesses of our research — some strengths and weaknesses of other research — further research required what I consider broken feedback loops. In my experience only half of the authors will respond to email enquiries regarding their articles.
It was therefore a real pleasure to see a new study on antibiotics and allergy with a true discussion wieghting pro and con arguments that was more worth than a meta-analysis on the same topic.
New studies further question the hygiene hypothesis of allergy induction. One study shows that a household bacterial elimination strategy does not lead to more — it even leads to less asthma.
Children living in a house regularly cleaned with bleach were less likely to have asthma (OR, 0.10; CI, 0.02-0.51), eczema (OR, 0.22; CI, 0.06-0.79) and of being sensitized to indoor aeroallergens (OR, 0.53; CI, 0.27-1.02)
Another study, by designing a 16S rRNA chip, examined a snapshot of urban air in San Antonio — the aerosol harbored at least 1,800 diverse bacterial types
a richness approaching that of some soil bacterial communities
You probably know the joke that before taking a deep breath think where the air has been before…
The ecology of human skin has now been also reported – highly diverse, well conserved but low-level interpersonal consensus: scienceblog:doi:10.1073/pnas.0607077104
German Ärzteblatt has some important suggestions “Mehr Mut zum Nein-sagen” how the German healthcare system may be improved. In brief,
(1) patients need to be empowered to make their own health decision – Norwegians have on average only 3 but Germans 16 physician contacs per year
(2) during professional contact patients need more trust in doctor, nurse, pharmacist and physical therapist
(3) more money for the ill, less for the health people
When starting in the asthma field in 1989, the textbooks told me that asthma is a disease of the lung. Some years later, asthma turned out to be a disease of the bone marrow cells. More recently, I raised the question if asthma could be even a disease of the gut – our largest immunological organ being frequently exposed to allergen & plenty of immunological active substances. Although on the different track (vitamin A) also other authors now think of an early impaired immune gut response.
Rather unexpected for me was a study in J Steroid Biochem Mol Biol that 1,25(OH)2D3 inhibits in vitro and in vivo intracellular growth of the parasite Toxoplasma gondii. yea, yea.
The NIH and Jackson ask for nominations of their gene targeting approach (see also A mouse for All Reasons and my previous comment on the 3 R)
KOMP is a trans-NIH initiative to generate a public resource of mouse embryonic stem (ES) cells containing a null mutation in every gene in the mouse genome. Both conditional and null knockouts are being generated. The purpose of this form is to gather input from the scientific community on which genes should have the highest priority for being knocked out.
The Cell paper also explains the hard to understand differences in knockouts
- targeted deletion
- targeted conditional
- trapped conditional
although I still have semantic problems to understand the nomenclature. Anyway my whishlist – you can do me a favor by voting for CYP27B1, VDR, CYP24A1, OPN, IL4, IL5, IL10, IL12, IL13, FLG, CCR5 and CCR9.
You can also leave some input at the Environmental Genome Project.
said the Denver Post giving a nice overview of vitamin D research. This was just 1 day too early for a fascinating nature immunology paper (scienceblog:doi:10.1038/ni1433:) that links for the first time natural sunlight induced vitamin D action on dendritic cells. Seems that D3 will influence homing of T cells – we are again at “Licht und Leben“, yea, yea.
Last week Science has an update on differential antigen processing by DCs including a key sentence on immature DCs:
Cultured immature DCs capture antigen but only process and present it on MHC II after exposure to inflammatory stimuli or TLR ligation.
Although the authors were not aware of current allergy research, they perfectly summarize how vitamin D renders DC immature, while hygiene (infections or LPS farm exposure ) may antagonize it.
Most people in the field search Pubmed but there is another site that I frequently visit – the European patent database that often have more concise information. Look at current allergy patents – the last one will definitely work you may also use a big plastic bag ;-)
Be aware that being cynical is probably bad for your heart.
This is the title of an editorial in The Am J Respir Crit Care Med commenting on current asthma research.
Another editorial in the ERJ asks “The human lung: did evolution get it wrong?”
So I am confused: Did pulmonary science or lung evolution (or both) get it wrong?
The Korea Herald writes – as noticed by Hsien Hsien Lei
The government yesterday released a set of new regulations to ban or restrict genetic tests in 20 categories amid ethical concerns over DNA tests … According to the new guidelines, DNA labs will be banned from conducting tests in 14 categories including body mass, intelligence, strength, propensity for violence, longevity, mental health, diabetes, blood pressure and asthma.
Although I do not believe that genetic testing for “asthma genes” will make any sense without the context of scientific studies, I think that such regulations are overdue – at least when genetic testing does not provide any benefit but may pose harm. If you have asthma or not, is a clinical question – and the answer will be an appropriate treatment or not. If you ever will get asthma is a question that nobody can answer. Even if genetic prediction will be ever possible, there is still no preventive measurement (at least by Jan 18, 2006, 16:14:23) . Yea, yea.
My previous work on vitamin D focused mainly on allergy but according to new research of Bosse et al vitamin D also stimulates bronchial smooth muscle and airway remodeling
Genetic variants in the vitamin D receptor (VDR) gene were recently associated with asthma. The biological mechanisms explaining this association is unknown, but are likely to involve many cell types given the pleiotropic effect of its ligand … The most significant network of up-regulated genes included genes involved in morphogenesis, cell growth and survival as well as genes encoding structural proteins, which are potentially involved in airway remodelling.
Another study published more or less at the same time by Wittke shows
Conversely, WT splenocytes, Th2 cells and hematopoetic cells induced some symptoms of experimental asthma when transferred to VDR KO mice, but the severity was less than that seen in the WT controls … Lipopolysaccharide (LPS) induced inflammation in the lungs of VDR KO mice was also less than in WT mice. Together the data suggest that vitamin D and the VDR are important regulators of inflammation in the lung…
In a previous paper I have questioned if LPS
nanogram exposure on the pulmonary epithelium will supersede the gram-wise exposure on the gut mucosa.
This may indeed work as now shown by Eyal Raz in a commentary in Nature Immunology where previous TLR studies
typically reproduce the splenic version of innate immunity (the spleen is used here as a metaphor for the sterile internal environment).
In the lung only the alveolar space is thought to be sterile while macrophages should not be in a constant state of activation (as inflammation would compromise gas exchange).
There are now several indicators for a lung-specific regulation of innate immunity: TLR9 is expressed in human plasmacytoid dendritic cells while TLR4 is only on myeloid DCs; TGFB-ß mediated crosstalk between alveolar macrophages and epithelial cells seems to be unique in the lung; in addition indeolamine induction or surfactant production is not found elsewhere. Yea, yea.
A new series of pro- and con editorials in the Am J Res Crit Care Med discusses the question why in some instances mouse models have “misdirected resources and thinking”. You may have noticed that I have only rarely used animals for research; the authors of this editorial have collected empirical data on the exploding use of murine models. Despite their attractiveness from a technological point, they are useless because
- mice do not have asthma as even the most hyperresponsive strain does not show spontaneous symptoms
- mice do not have allergy – although sensitization can be manipulated by high intraperitoneal allergen/adjuvant injection, this does not involve immediate and late airway obstruction.
- immune reaction in mice is quite different – the interfering of some substances like vitamin D cannot be reliable tested, there is no pure Th1 and Th2 reaction in human and less stronger IL-13 response
- mice typically can not be challenged with the complex (and interacting) human exposure – oxidant stress, viral infection, obesity, diet, smoke, pollutants, ….
- time course is difficult to mimicking in the mouse, there is no longterm model
- structure of mouse airways is different – there are fewer airway generations, much less hypertrophy of smooth muscle
- inflammation in mouse is parenchymal rather than restricted
- humans are outbred, mice are inbred
- many promising interventions of mice pathways failed in humans (VLA-4, IL4, IL5, bradykinine, PAF,…)
I am sure there are even more arguments – I suggest that the authors have deserved the Felix-Wankel price.
15 Dec 06: The BMJ has 6 more examples about the discordance between animal and human studies: steroids in acute head injury, antifibrinolytics in haemorrhage, thrombolysis or tirilazad treatment in acure ischaemic stroke, antenatal steroids to prevent RDS and biphosphonate to treat osteoporosis.
19 Dec 06: Another pitfall paper
31 Dec 06: A blog on animal welfare
25 Apr 07: Call for better mouse models