The Blood Type Diet Under the Spotlight

That gives me a good idea, but can you be more specific about what you can and can’t eat?
Each of the four blood types has a detailed list of foods that should be avoided and those that can be included. Here’s the lowdown…

Blood Group O
This is the most common blood group in the UK. Dr D’Adamo says that our digestive tract retains the memory of ancient times, and so type Os need to eat a typical hunter-gatherer type diet. In other words, type Os should follow a high-protein, low-carb diet with lots of meat and fish but no dairy products, wheat or grains.

If that sounds familiar, it’s because it is – the diet recommended for people with blood type O is simply a variation on many of the typical high-protein, low-carb diets that are currently popular, such as the Atkins diet. Foods you can eat freely include meat, fish and olive oil; foods you can eat in moderation include eggs, nuts, seeds, certain vegetables and fruits; and foods to avoid include dairy products, beans, cereals, bread, pasta and rice. To complement your food intake, Dr D’Adamo recommends lots of vigorous aerobic exercise such as aerobics and running – just like our hunter-gatherer ancestors did!

Blood Group A
This is the second most common blood type in the UK. Again according to Dr D'Adamo, digestive system is apparently very good at remembering that our ancestors had settled, farming lifestyles, which included eating lots of grains and vegetables but little meat. Consequently, blood type A’s should follow a vegetarian diet but still avoid dairy products. This means nuts, seeds, beans, cereals, pasta, rice, fruit and veg are all on the ‘to eat’ list. Meanwhile, calming exercises are thought to be best for blood type A’s such as yoga or golf.

Blood Group B
Only one person in 10 has blood type B – a real shame when you consider this blood group has the least dietary restrictions! As our type B ancestors were able to thrive on all sorts of foods, thanks to all that travelling, very few foods need to be avoided and this is the closest you’ll get to a healthy, balanced diet from Dr D'Adamo. The only foods that need to be avoided are processed foods, although nuts and seeds aren’t recommended and only small amounts of carb-rich foods should be eaten. When it comes to exercise, Dr D’Adamo recommends activities that have mental component, such as hiking, tennis and swimming – clearly our ancestors did a lot of thinking while they were walking!

Blood Group AB
People with this rare blood type should eat a combination of the foods recommended for blood groups A and B. Somewhat confusing when type B allows you to eat most foods, while type A suggests a vegetarian diet! Dr D’Adamo gets around this by suggesting that type ABs follow a veggie diet most of the time with some meat, fish and dairy products occasionally. It’s the same when it comes to exercise too – blood type ABs should combine calming exercises with moderately intense activities.

What do the experts say?
Medical experts universally agree that the theory is nonsense, and say there is absolutely no link between our blood group and the diet we eat. Consequently you won’t find qualified nutritionists or dietitians recommending this diet.

There are also several concerns, namely that the diets recommended for blood groups O and A are considerably limited and cut out major groups of foods.

In the long term, this can result in a poor intake of nutrients needed for good health. Cutting out dairy products, for example, will lead to poor intakes of calcium, which can put you at risk of osteoporosis (brittle bone disease), while avoiding meat can result in low intakes of iron, which can lead to anaemia. This is even more worrying in view of the fact that most people in the UK are blood group O or A.

Blood Transfusion in the 21st Century

Projected changes in blood transfusion in the 21st century

1-Universal leukoreduction

2-increasing ise of Apheresis technology to collect blood

3-Microbial attenuation of

acellular blood products

cellular blood products

4-Reconinant plasma proteins

5-Enzymatic conversion of group A,B and AB red celld to group O

6-Oxygen carrying substitues

7-Non liquid ( synthetic) platlets

Cellular 'alchemy' transforms skin into blood

Direct conversion of cell types could offer safer, simpler treatments than stem cells.
Ewen Callaway
The right cocktail of chemicals converts human skin cells directly into blood.www.ingrampublishing.comHuman skin cells can be transformed into blood without first being sent through a primordial, stem-cell-like state, according to a ground-breaking study.
The breakthrough, published online today in Nature1, follows work earlier this year showing that fibroblast cells from mouse skin, treated with the right cocktail of chemicals, can be transformed into neurons2 and heart muscle3. However, it is the first study to accomplish this feat with human cells, and the first to create progenitor cells — in this case for blood.
"It takes us a step along the line to believing that you can produce anything from almost anything," says Ian Wilmut, an embryologist and director of the MRC Centre for Regenerative Medicine in Edinburgh, UK. Such 'direct conversions' also offer a potentially safer, simpler tool for creating patient-specific cell therapies than is promised by adult cells reprogrammed to become stem cells (known as induced pluripotent stem cells, or iPS cells).
Mickie Bhatia, a stem-cell researcher at McMaster University in Hamilton, Canada, and his colleagues chose to make blood progenitors from skin cells because red blood cells created from stem cells do not make the adult form of haemoglobin. "Those cells, because they think they're embryonic, make embryonic and fetal blood," he says.
Creating a bloodline To make blood progenitor cells, Bhatia and his team collected skin fibroblasts from several volunteers. They infected the cells with a virus that inserted the gene OCT4, and then grew them in a soup of immune-stimulating proteins called cytokines.
OCT4 is one of a handful of Yamanaka factors used to transform fibroblasts into iPS cells, but Bhatia's team found no evidence that the blood progenitor cells that they had made went through an embryonic state. The cells' gene-expression patterns never resembled those of embryonic stem cells, and the blood progenitor cells didn't cause mice to develop teratomas — tumours that are characteristic of pluripotent cells.
“Everybody has their favourite cell type. There is a lot of this kind of alchemy going on.”

The progenitors did, however, produce all three classes of blood cells — white blood cells, red blood cells and platelets — all of which seemed to function as they should, according to a battery of experiments. The red blood cells made adult haemoglobin, not the fetal form.
The ultimate test would be transplanting the cells into humans, says Bhatia, but that isn't on the cards — at least not yet. "The clinical side is going to be a lot of work," he says. "At least from our estimation, this is the most encouraging result we've seen for using blood cells for cell-replacement therapy."
Sanguine about the possibilities The potential for therapy is very much on the minds of Bhatia and other scientists who are converting cells directly. Because the progenitor cells bypass pluripotency, there is little risk of them forming tumours when implanted into patients, says Wilmut, who is working on creating other progenitor cells in his own lab.
Deepak Srivastava, a developmental biologist and director of the Gladstone Institute of Cardiovascular Disease in San Francisco, California, led the team responsible for making heart muscle from mouse fibroblasts3. He says that directly converted cells could also offer simpler treatments than iPS cells: the fibroblasts that surround the heart could be transformed into new heart muscle using a stent that delivers drugs to reprogram the cells.
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Converted cells aren't without their drawbacks, though. Unlike iPS and embryonic stem cells, they cannot easily multiply in the lab, so producing the large quantities needed for applications such as screening drugs could prove tough, says Wilmut.
Despite lab experiments establishing that the converted blood cells are indistinguishable from adult blood cells, it is still too early to tell whether they will be as good as the real thing once they are inside patients, says George Daley, a stem-cell biologist at Children's Hospital Boston in Massachusetts.
In particular, epigenetic modifications — changes that modify gene expression without altering the DNA sequence — could differ between blood cells produced naturally and those created by direct conversion. "The journey from a zygote to a specialized blood cell is very long. The journey from a fibroblast to a blood cell in a petri dish may take a very different route," says Daley.
Even with these caveats, direct conversion is gaining in popularity. "Everybody has their favourite cell type," says Daley. "There is a lot of this kind of alchemy going on."
References1.Szabo, E. et al. Nature doi:10.1038/nature09591 (2010).
2.Vierbuchen, T. et al. Nature 463, 1035-1041 (2010). | Article | OpenURL | | ChemPort |
3.Ieda, M. et al. Cell 142, 375-386 (2010). | Article | OpenURL

WHO selects UAE among best five countries in blood transfusion

Dr. Amin Al Amiri, Executive Director for Medical Practices and Licenses at the Ministry of Health and Chair of the Blood Transfusion National Committee, emphasized that the organization lauded the efforts of the UAE in blood transfusion, pointing out that it selected the UAE as one of the best five models in the field of blood transfusion and its role in enhancing the World Blood Donor Day.

The five listed countries are: South Africa, United Kingdom, Thailand, Canada and United Arab Emirates which is the first Arab country and seventh country worldwide that has been selected to host the world blood donators day in 2008. The ceremony was organized under the patronage of His Highness Sheikh Khelifa Bin Zayed Al Nahyan, UAE President.

He also mentioned that the four international organizations "World Health Organization, International Federation for Red Cross and Red Crescent, International Federation for Blood Transfusion and International Blood Donors Association" lauded the efforts of the UAE which led to its nomination as the headquarters for the WHO's Middle Eastern region. This selection was due to the UAE efforts in supporting blood donators and organizing blood donation ceremonies generally.

Dr. Al Amiri lauded the efforts of the other sectors especially the mosques in encouraging the residents to blood donation and the cooperation of the government sector in disseminating awareness campaigns about blood donation and the usage of modern techniques as well as text messages especially the Ministry of Education, Ministry of Social Affairs to encourage students to participate in the activities of the blood donation center and research in Sharjah.

"We would like to thank the social organizations and institutions for their support to the Ministry of Health referring that the ministry's success could not have been accomplished in the field of blood transfusion campaigns and blood donators without their cooperation", he concluded.

WAM/TF

Prevention is cheaper than therapy

Prevention is cheaper than therapy

Blood Group Diet

The blood group diet is said to have originated from two American Naturopaths, Dr James D'Adamo, and his son Dr Peter D'Adamo, who believe that your blood group type is the key to how you burn your calories, which foods you should eat and how you would benefit from certain types of exercise.

They recommend that eating to suit your blood group may, help you to lose weight, help you fight disease, boost your immune system and slow down the ageing process.

It is believed that a chemical reaction occurs between your blood and foods as they are digested. Lectins, a diverse and abundant protein found in food, may be incompatible with your blood group and adverse side effects may occur. The avoidance of these Lectins which can agglutinate (adhere or stick to one another) can be important if your particular cells-determined by your blood type,may react with them.

There are 4 blood types: A, AB, B, and O

Blood Type O

The O blood type was the first blood type to evolve from the hunter-gatherer era around 50,000 BC. Here the diet was high in red meat and virtually void of grains and dairy. The type-O thrives on a meat-eating diet. As the diet is high in animal protein, the type-O requires intense physical exercise to help burn off the meat.

Type-Os are prone to digestive disorders resulting from over-secretion of stomach acid. They can also be more susceptible to arthritis and thyroid disease due to overactive or hyper -immune system.

Wheat and dairy also promote inflammation in this blood type which can trigger an imbalance in the immune system.

Blood type O individuals can gain a significant amount of weight following a high carbohydrate diet, as their bodies cannot properly metabolize these foods.

Blood Type A

Type-A blood group formed when man began to develop an agricultural lifestyle between 25,000 and 15,000 B.C. People with blood type-A do best on a vegetarian diet for weight loss especially the macrobiotic diet.

The type-A individual hardly produces much hydrochloric acid and therefore does poorly on meat and dairy diets such as the Atkins Diet.

Type-As are generally more prone to cancer, diabetes and heart disease, if they do not take charge of their health. The gene for alcoholism is also found in type-As.

Blood Type B

Type B also evolved from the intermingling of blood type O with the blood type A. This occurred between 15,000 and 10,000 B.C due to man traveling further.

As a result, the type-B individual does best on a dairy diet with some meat (no chicken) and few grains.

The type-Bs suffer from the highest incidence of bladder and urinary tract infections. They are also prone to viral diseases when their immune system is compromised.

Since B blood types can metabolize dairy products and most foods, they will usually lose weight effortlessly as long as peanuts, corn, wheat, and lentils are eliminated from the diet.

Blood Type AB

The rarest and newest blood type to evolve (1500 years old) was the AB blood type. This blood type is the most well adapted to a moderate diet. The type-AB individual benefits from both the A and B type diets.

Meat is not as well digested as seafood, dairy, wheat-free grains and soy foods.

The type-ABs are prone to either diseases encountered by the Type-As or the type-Bs. By undergoing further metabolic typing, it can be determined which diseases they are most likely to be vulnerable.

For weight loss and maintaining a healthy weight, AB's do best on seafood, dairy, nuts and grains.

Not s ingle prescrption

There is not a single prescription drug that offers a "cure" to any ailment.

52 Facts About Blood Donation

1. More than 4.5 million people need blood transfusions each year in the U.S. and Canada.
2. 43,000 pints: amount of donated blood used each day in the U.S. and Canada.
3. Someone needs blood every two seconds.
4. 37% of the U.S. population is eligible to donate blood – less than 10% do annually**.
5. About 1 in 7 people entering a hospital need blood.
6. One pint of blood can save up to three lives.
7. Healthy people who are at least 17 years old (16 with parental consent), and at least 110 pounds may donate whole blood every 56 days. Females receive 53% of blood transfusions; males receive 47%.
8. 94% of blood donors are registered voters.
9. In 1901, Dr. Karl Landsteiner first identified the major human blood groups: A, B, AB and O.
10. People with O- blood are universal donors of red blood cells.
11. People with AB+ blood are universal recipients of red blood cells, and universal donors of plasma.
12. One unit of whole blood can be separated into several components, including red blood cells, plasma, and platelets.
13. Red blood cells carry oxygen to the body's organs and tissues, and live for about 120 days in the circulatory system.
14. Platelets promote blood clotting and give those with leukemia and other cancers a chance to live.
15. Plasma is a pale yellow mixture of water, proteins and salts.
16. Plasma, which is 90% water, makes up 55% of blood volume.
17. Healthy bone marrow makes a constant supply of red cells, plasma and platelets.
18. Blood or plasma that comes from people who have been paid for it cannot be used for human transfusion.
19. Granulocytes, a type of white blood cell, roll along blood vessel walls in search of bacteria to engulf and destroy.
20. White cells are the body's primary defense against infection.
21. Apheresis is a special kind of blood donation that allows a donor to give specific blood components, such as platelets or red blood cells.
22. 42 days: how long most donated red blood cells can be stored.
23. Five days: how long most donated platelets can be stored.
24. One year: how long frozen plasma can be stored.
25. Much of today's medical care depends on a steady supply of blood from healthy donors.
26. 2.7 pints: the average whole blood and red blood cell transfusion.*
27. Children being treated for cancer, premature infants and children having heart surgery may receive blood and platelets during their treatments.
28. Anemic patients may need blood transfusions to increase their red blood cell levels.
29. Cancer, transplant and trauma patients, and patients undergoing open-heart surgery may require platelet transfusions to survive.
30. Sickle cell disease is an inherited disease that affects more than 80,000 people in the U.S., 98% of whom are of African descent.
31. Many patients with severe sickle cell disease receive blood transfusions every month.
32. Over 10 tests are performed on each unit of donated blood.
33. 17% of non-donors cite "never thought about it" as the main reason for not giving blood, while 15% say they're too busy.
34. The #1 reason blood donors say they give is because they "want to help others."
35. Blood centers often run short of types O and B red blood cells.
36. There is no substitute for human blood.
37. If all blood donors gave three times a year, blood shortages would be a rare event (The current average is about two).
38. 46.5 gallons: amount of blood you could donate if you begin at age 17 and donate every 56 days until you are 79 years old.
39. There are four easy steps to donate blood: medical history, a quick physical, donation and snacks.
40. The actual blood donation takes less than 15 minutes. The entire process – from the time you sign in until the time you leave – usually takes under an hour.
41. After donating blood, you replace the fluid in hours and the red blood cells within four weeks. It takes eight weeks to restore the iron lost after donating.
42. You cannot get AIDS or any other infectious disease by donating blood.
43. 10 pints: the amount of blood in the body of an average adult.
44. One unit of whole blood is roughly the equivalent of one pint.
45. Blood makes up about 7% of your body's weight.
46. Newborn babies have about one cup of blood in their bodies.
47. Giving blood will not decrease your strength.
48. Any company, community organization, place of worship or individual may contact their local community blood center to host a blood drive.
49. Roughly half of all blood donations across the U.S. are collected at blood drives.
50. People who donate blood are volunteers and are not paid for their donation.
51. 500,000 Americans donated blood in the days following the events of September 11
52. Blood donation. It's about an hour of your time. It's About Life!

A good formula

Sensitivity (positivity in disease)= TP / TP + FN
Specificity (negativity in health) = TN / TN + FP
Positive predictive value PV+ = TP / TP + FP
Negative predictive value PV- = TN / TN + FN

T True
F False
P Pos
N Neg

CBR

The relationship between blood groups and disease

Abstract
Top
Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References


The relative contribution of founder effects and natural selection to the observed distribution of human blood groups has been debated since blood group frequencies were shown to differ between populations almost a century ago. Advances in our understanding of the migration patterns of early humans from Africa to populate the rest of the world obtained through the use of Y chromosome and mtDNA markers do much to inform this debate. There are clear examples of protection against infectious diseases from inheritance of polymorphisms in genes encoding and regulating the expression of ABH and Lewis antigens in bodily secretions particularly in respect of Helicobacter pylori, norovirus, and cholera infections. However, available evidence suggests surviving malaria is the most significant selective force affecting the expression of blood groups. Red cells lacking or having altered forms of blood group-active molecules are commonly found in regions of the world in which malaria is endemic, notably the Fy(a–b–) phenotype and the S-s– phenotype in Africa and the Ge– and SAO phenotypes in South East Asia. Founder effects provide a more convincing explanation for the distribution of the D– phenotype and the occurrence of hemolytic disease of the fetus and newborn in Europe and Central Asia.

Introduction
Top
Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References


Hirszfeld and Hirszfeld1 showed the frequencies of blood groups A and B differ between populations. Their observations raised fundamental questions regarding the causes of these differences, which were eloquently summarized by Mourant et al2(p1):
Were the differences the result of random genetic drift and founder effects, in small populations which later multiplied and stabilized the original, fortuitous, frequencies, or were they the result of natural selection, arising from differences in fitness between the various blood groups, fitnesses which themselves depended upon locally determined features of the external environment?
Mourant et al concluded that "most workers now agree that both processes are operative, but their relative importance remains in question."2
We now have detailed information concerning almost all the genes giving rise to blood group polymorphisms, the structure of the gene products and the antigens themselves, and in many cases functional information sufficient to delineate mechanisms of interaction with external agents.3–5 In addition, studies on the tracking of Y chromosome and mtDNA haplotypes in human populations provide us with unprecedented information concerning the significance of genetic drift and founder effects in determining the genetic background of different world populations.6 Given this new information, it seems an appropriate time to revisit these questions and ask whether we are any nearer understanding the relative importance of natural selection and founder effects in determining the distribution of human blood groups.

Infectious diseases and selection for ABO blood group antigens
Top
Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References


The molecular basis of the ABO blood group system was elucidated in 1990.7 The gene encodes a glycosyltransferase, which transfers N-acetyl D-galactosamine (group A) or D-galactose (group B) to the nonreducing ends of glycans on glycoproteins and glycolipids. The group O phenotype results from inactivation of the A1 glycosyltransferase gene, and the nonreducing ends of the corresponding glycans in group O subjects express the blood group H antigen (Figure 1A). The ABH antigens are not confined to red cells but are widely expressed in body fluids and tissues. The biologic significance of the A/B transferase has not been clearly demonstrated, but it would be expected that loss of this functional protein in group O patients would have some deleterious consequences for patients of this blood type.



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Figure 1. Structure of ABO, H, and Lewis antigens. (A) Structure of ABO and H antigens on human red cells. H antigen formed by the action of FUT1 on oligosaccharide precursor chains in which the terminal D-galactose residue is linked to carbon 4 of the penultimate N-acetyl D-glucosamine residue (type II chain). (B) Structure of Le blood group antigens in bodily secretions. Secretor gene (FUT2) regulates the production of H antigen, which can be converted to A or B antigen if the corresponding active ABO glycosyltransferase is present. The ABH, Leb-active structures are formed on oligosaccharide precursor chains in which the terminal D-galactose residue is linked to carbon 3 of the penultimate N-acetyl D-glucosamine residue (type I chain) If FUT 2 is deficient the Lea active structure predominates.



One of the most significant disease associations described for non-O (subjects of group A, B, or AB) versus O subjects is susceptibility to arterial and venous thromboembolism (VTE).8,9 Non–group O patients have a greater risk of VTE than patients of group O and have greater levels of von Willebrand factor (vWF) and factor VIII.8,10 The risk of VTE is probably related to the level of vWF and factor VIII because patients of group A2 have lower levels of these proteins than A1, B, and AB and have a lower risk of VTE.9 A, B, and H blood group antigens are expressed on N-glycans of vWF and influence the half-life of the protein (10 hours for group O and 25 hours for non-O subjects), providing an explanation for the greater levels in non-O patients.11 These observations raise the possibility that a greater propensity for blood clot formation in non-O patients conferred a survival advantage to early humans. Such an argument has been made for the occurrence of the prothrombotic mutations factor V Leiden and prothrombin 20210G>A, which are commonly found in white humans dated as occurring 20 000 to 24 000 years ago toward the end of the last ice age.12 It is proposed that mutations like factor V Leiden lower the risk of hemorrhage and/or severe infections and thereby the risk of death during pregnancy.13 A similar hypothesis could explain the function of A and B antigens on vWF.
What then was the stimulus that caused the inactivation of this gene and the creation of the group O phenotype, which is so prevalent throughout the world? Evidence supporting the view that blood group O provides a selective advantage against severe malaria has been recently reviewed.14–16 The argument is persuasive. Group O is presumed to have arisen in Africa before the migration of early humans. Severe malaria results in the death of millions each year before they reach child-bearing age, and therefore selects survival genes.17 Experimental support for the hypothesis is provided by Fry et al18 and by Rowe et al.19 Rowe et al19 report reduced rosetting of Plasmodium falciparum isolates from group O Malian children compared with non-O blood groups. Parasitized red cells form rosettes with uninfected red cells and adhere to vascular endothelium, causing vasocclusion and severe disease.
There are other examples of infectious diseases in which the severity of infection can be directly linked to ABO phenotype. The authors of numerous studies have shown that once a person is infected with cholera (Vibrio cholerae strains O1 El Tor and O139) the phenotype group O confers a greater likelihood of severe infections than non-O blood group phenotypes.20 Glass et al21 suggest that the low prevalence of group O and high prevalence of group B in the Ganges Delta in Bangladesh is directly related to selective pressure from cholera. Almost all recent cholera pandemics have emanated from this region of the world.22 Patients of group O were more susceptible in an outbreak of gastrointestinal infections caused by Escherichia coli O157 in Scotland in 1996. A total of 87.5% of patients who died were group O.23
However, suggestions that smallpox selects against A, thereby explaining the high frequency of group A in Europe, and that the low frequency of O in ancient plague centers in Mongolia and the Middle East is also a reflection of selection are not supported by adequate data (Vogel et al [1960], cited in Mourant et al2(p18); Kreiger and Morton24). More recent studies have linked the high frequency of the HIV-1 resistance mutation CCR532 in Europe with protection against smallpox and the Black Death.25 This proposal has also been questioned.26 The mutations AO and CCR32 occurred much earlier in human evolution than the plague and smallpox epidemics of medieval times. As discussed previously, the AO mutation was likely driven by malaria in Africa before the migration of early humans to Europe, and CCR 32 has been described in skeletons from the Bronze Age.25 A combination of selection against infectious diseases, such as plague and smallpox, and genetic drift and founder effects in small populations (resulting from migration patterns of early humans) may ultimately explain the allele frequencies observed today.
The expression of ABH antigens in tissues and body fluids other than blood cells is regulated by the secretor gene (FUT2), which encodes an alpha 1,2-fucosyltransferase capable of transferring L-fucose to carbon 2 of galactose (beta, 1-3) N-acetyl D-glucosamine–containing glycans. In the absence of an active FUT2 gene (nonsecretor), the structure created is the Lea antigen.27 The product of the Le gene is an alpha 1,3/4 fucosyltransferase (FUT3), which transfers L-fucose to carbon 4 of the penultimate N-acetyl-D-glucosamine residue of the same glycans.28 The structure created in tissues by the combined action of FUT2 and FUT3 is the Leb antigen. A and B antigens can only be formed in the tissues of patients with an active FUT2 by the action of alpha-glycosyltransferases capable of transferring N-acetyl D-galactosamine or D-galactose to carbon 3 of the same glycans (Figure 1B). The secretions and tissues of a person with an active FUT2 (a secretor) can express A, B, H, and Leb antigens in those secretions according to the glycosyltransferase genes inherited. In European and African nonsecretors, the homozygous inheritance of a nonsense mutation (G428A) inactivating FUT2 denoted se428 is frequently found (20% of Europeans).29 In the Far East and Pacific regions, the commonest mutation in FUT2 (A385T, se385) causes a single amino acid change (Ile129Phe) in the stem region of the fucosyltransferase, resulting in a 5-fold reduction in active enzyme and a weak Le(a+b+) phenotype.30 Sequencing FUT2 in 732 patients from 39 populations confirmed the widespread occurrence of the se428 allele in Europe, Central Asia, and Africa and the se385 allele in the Far East and Pacific and mapped 2 further se alleles with a more restricted distribution (se302 and se571) to Central and South Asia and Cambodia, respectively.31 Possession of homozygosity for a nonsecretor phenotype has a demonstrable survival advantage for some infectious diseases.
One of the first proven associations of a blood group polymorphism with disease was that between group O and peptic ulceration.32,33 The gastric pathogen H pylori is now known to be a causative agent leading to peptic ulceration and gastric cancer. According to Björkholm et al,34 H pylori has established colonies in the stomachs of approximately one-half the world's population.34 Early studies demonstrated that a South American strain of H pylori P466 bound to blood group O Leb but not ALeb structures on the gastric epithelium, thereby providing a clear explanation for the greater susceptibility of group O secretors.35 More recent studies on strains of H pylori from different parts of the world have shown that not all strains are so specific for O Leb, with many strains from outside South America having binding capabilities for ALeb in addition to OLeb. Nevertheless, these strains have a greater binding affinity for OLeb compared with ALeb (approximately 5-fold [median] greater).36 Sequence analysis of the bacterial surface molecule responsible for binding to gastric epithelium BabA (blood group antigen binding adhesin) from different strains of H pylori showed that Peruvian strains were closely related to Spanish but not to Asian strains, raising the intriguing possibility that the OLeb-specific strains found in South American may have arisen after European colonization of South America in the 16th century and represent adaptation to a population that is almost entirely of the blood group O phenotype.36
Susceptibility to norovirus infection is also closely linked to the expression of ABH and Le antigens in the gastrointestinal tract. Noroviruses are the commonest cause of acute gastroenteritis in humans and are estimated to account for 60% to 85% of all gastroenteritis outbreaks in developing countries.37 They are transmitted by consumption of contaminated food, particularly oysters, which appear able to concentrate the virus, or exposure to contaminated water.37 The pivotal role of secretor status in determining susceptibility to norovirus has been clearly demonstrated by Thorven et al,38 who compared susceptibility to gastroenteritis in patients and medical staff involved in hospital outbreaks in Sweden. The results demonstrated that only those patients homozygous for nonsecretor were protected from infection. Larsson et al39 further demonstrated significantly lower antibody titers to norovirus GGII in nonsecretors compared with secretors. There are many different strains of norovirus, however, and some strains bind to nonsecretor Lea structures and cause symptomatic infection.40,41The variable specificity of different strains for ABH and Leb structures reported reflects a similar diversity to that of the aforementioned H pylori. Evidence for greater susceptibility of secretors to influenza viruses, rhinoviruses, respiratory syncytial virus, and echoviruses has also been presented.42 Reduced risk of HIV type 1 infection was found in Senegalese commercial sex workers with the nonsecretor type.43 Slow disease progression of HIV-1 in nonsecretors was also reported by Kindberg et al.44
Nonsecretors appear more susceptible to infections by Haemophilus influenzae,45 Neisseria meningitidis, and Streptococcus pneumoniae46 and urinary tract infection caused by E coli.47
A mutation (F508) in the cystic fibrosis transmembrane regulator gene (CFTR) is common in European patients and was present in Europe during the Paleolithic period more than 10 000 years ago.48The possibility that differences in A, B, and H antigen expression in the airway mucus might lead to differences in microbial binding and predispose to more severe lung disease was investigated in 808 patients homozygous for F508. No association with ABO, Se, or Le genotype was observed.49

Rh blood groups and the origin of hemolytic disease of the fetus and newborn
Top
Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References


The major clinical disease associated with the Rh blood group system is hemolytic disease of the fetus and newborn (HDFN). HDFN usually arises when a mother who is blood group D– carries a fetus who is blood group D+, and fetal red cells released into the maternal circulation immunize the mother to make antibody to D, which traverses the placenta and damages the fetus. Before the introduction of a successful prophylactic treatment in 1968, the frequency of the disease in England and North America was approximately 1 per 170 births.3 Recognition of the disease as a single entity was slow to emerge. In severe cases anti-D crosses the placenta and causes death of the fetus in utero, a condition known as hydrops fetalis. More commonly, disease occurs in the neonatal period, where severe and acute anemia and severe jaundice is fatal, a condition known as icterus gravis neonatorum. Roberts50 cites an account of Louyse Bourgeois, a midwife of Marie de Medici, who published in 1609 what is probably the earliest account of hydrops fetalis in one twin and neonatal jaundice in the other and credits Auden (1905) with several key observations relating to neonatal jaundice, in particular its appearance in successive children of the same parents. The recognition that hydrops fetalis and neonatal jaundice were manifestations of the same disease gradually emerged during the 1920s, and anti-D was shown to be the causative agent in 1939.51
There is now a formidable body of evidence to support the hypothesis that humans originated in Africa and to inform the timescale of various migrations from Africa, which have led to the world populations we have today.6 Simply by overlaying the known distribution of blood group frequencies on the world map of human migrations, the potential significance of genetic drift and founder effects is apparent. Wells6 argues, for example, that it is possible to account for all of the mtDNA and Y-chromosome types in Native Americans with a founding population of 10 to 20 people. Little wonder then that Native Americans are almost exclusively blood group O52 or that the Dia blood group polymorphism tracks the migration of humans from East Asia to the Americas.52 The occurrence of the Dia antigen in South East Poland also provides a measure of the extent to which the Mongol invasions penetrated Europe in more recent times.53,54
In Europe a similar founder effect can be invoked to explain the high frequency of the D– phenotype. The emergence of Paleolithic ancestors surviving the last ice age from refuges in the Basque region of Northern Spain and Southern France and the Ukraine 10 000 to 15 000 years ago and subsequent interbreeding of these survivors with Neolithic migrants from the Middle East provides an explanation for the occurrence of HDFN. To explain the high frequency of the D– allele in Europe, Mourant55 proposed a mixing of 2 populations, one essentially D– and the other D+. He noted that D– frequency was very high in the Basques and postulated the mixing of Paleolithic peoples from the Basque region with Neolithic migrants as the cause. This hypothesis has been largely ignored in the succeeding years, but recent observations made with the use of mtDNA and Y-chromosome markers have led to wide acceptance of the population-mixing hypothesis (Figure 2).52,56–58



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Figure 2. Paleolithic settlers from the last glacial maximum may be the source of the high frequency of D– allele in Europeans. (Top) European location of Paleolithic refuges at the time of the last glacial maximum. Note migration of population containing marker M173 (from Gibbons58; reprinted with permission from American Association for the Advancement of Science). (Bottom) Distribution of the D– allele in Europe (from Mourant et al52; reprinted by permission of Oxford University Press).



Tracking of haplotypes emerging from the Basque and Ukrainian refuges has shown that these populations migrated throughout Europe and Central Asia and into India and Pakistan.59 HDFN is found in all these regions. Mourant55 also suggested a link between the Basques and the Berbers of North Africa because of the high frequency of D– phenotypes among Berbers. This hypothesis is now supported by evidence from maternal DNA markers showing that ancestral Berbers occupied the Basque refuge area and migrated back into North Africa.60 In Western Europe, the D– phenotype results from a complete deletion of RHD.61 The molecular basis of D– phenotype has not been formally determined for Ukrainian D– people. Loss of RhD protein does not appear to be of significant detriment to red cell function. The best available structural models for RhD protein and its homologue RhCE protein indicate they do not function as transport proteins but rather serve to facilitate the assembly of the band 3 protein gas transport complex in the red cell membrane. These observations suggest there is considerable functional redundancy, with D and CE proteins effectively substituting for each other (Figure 3).62



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Figure 3. Structure of the human red cell membrane showing the major surface proteins and minor proteins Fy and CR1. Two major membrane complexes linked to the underlying red cell skeleton are depicted. The Band 3 complex containing glycophorins A (GPA) and B (GPB) and Rh proteins, Rh-associated protein (RhAG), CD47, LW glycoprotein (intercellular adhesion molecule–4), and the junctional complex comprising glycophorins C and D (GPC, GPD), Kell glycoprotein, XK glycoprotein, and Duffy (Fy) glycoprotein. Aquaporin 1 (AQP1), the glucose transporter (GLUT1), decay accelerating factor (DAF, CD55), and complement receptor 1 (CR1) are also shown. ABH active oligosaccharides known to be present on all major surface proteins except Rh proteins are not depicted.



A counterargument to the population mixing hypothesis would be provided by a clear demonstration of selection for D– phenotype by environmental factors. In a thorough review of early studies seeking to identify associations between the D polymorphism and diseases, Mourant et al2 revealed no convincing associations. More recently, 2 studies have reported an association of the D polymorphism with disease. Busquets et al,63 in a study from Barcelona, reported an increased incidence of biliary complications in transplant recipients of livers mismatched for D. The presence of biliary complications in D-nonidentical graft-host cases (23 [30%] of 76) was greater than in D-identical grafts (47 [17%] of 269). Rh polypeptides are not expressed in liver,64 and therefore the mechanism of such an association is not clear. The fact that the study took place in the Basque region of Spain, where the D– phenotype is very common and may result from ancestral Paleolithic settlements, may be very relevant to the interpretation of these findings because it raises the possibility that other genes more relevant to transplantation and also occurring more commonly in Basques than in other populations may be influencing the results. In this context it is interesting to note evidence that donor human leukocyte antigen C (HLA-C) genotype has a profound impact on the outcome of liver transplants.65 HLA-C is the major inhibitory ligand for killer cell immunoglobulin-like receptors (KIRs). KIR genes are highly polymorphic and are expressed on natural killer cells and a subset of T lymphocytes.66,67 Several KIR genes (KIR2DS5, KIR3DS1, KIR2DL2) are significantly different in frequency in Basques, and 3 novel haplotypes were identified by Santin et al.68
Flegr et al69 in a study from the Czech Republic report an association of the polymorphism with Toxoplasma gondii infection whereby subjects (military conscripts) with the D– phenotype who were infected with T gondii (11 [6.08%] of 181) had slower reaction times and consequently were involved in more road traffic accidents than D+ patients infected with T gondii (17 [2.4%] of 709). Rh D protein is not reported to be expressed in brain; therefore, the likely mechanism of such an association is obscure, and given the small numbers of T gondii-infected patients involved in the study, a much larger cohort study will be required to prove the validity of this association.
Considering the evidence thus far, it appears most likely that the frequency of D+ and D– negative phenotypes in Europe and Central Asia is a reflection of genetic drift and migration rather than natural selection, with the early colonists of Europe emerging from Africa with a deletion of RHD (Figure 2). There remains the possibility the original stimulus driving this deletion occurred in Africa as a result of selection. The concomitant occurrence of the D– phenotype in African populations resulting from a different molecular mechanism70,71 may be suggestive of some ancient selective pressure.

Malaria: evidence for selection of blood group phenotypes that are rare outside areas in which malaria is endemic
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Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References


It appears likely that the most devastating effects of malaria on human populations coincided with a change of lifestyle from hunter gatherer to more sedentary agricultural practices circa 10 000 years ago.15 The clearance of trees from forest areas created the potential for pools of stagnant water and breeding grounds for the mosquitoes carrying parasites.
The clearest examples of selection in the face of malaria are reflected in the widespread distribution of inherited anemias, particularly sickle cell anemia and alpha thalassemia and the occurrence of hemoglobin C in regions of the world where malaria is endemic.72,73 The mutation giving rise to sickle cell disease (SCD; HbS) may have arisen at 3 different sites in Africa (Atlantic West Africa, Central West Africa, and Bantu-speaking Central and Southern Africa) with expansion of the mutation occurring 2000 to 2500 years ago.74 In this case, patients who inherit an HbS gene from both parents have SCD, whereas those who are heterozygous inheriting the HbS gene from 1 parent and the normal HbA gene from the other parent have substantial protection against malaria. A similar protective effect for the heterozygote seems likely in South East Asia, where HbE is very common and red cells from patients of genotype HbAE are markedly less susceptible to malaria parasite invasion in vitro.75
Further illustrations of the diversity of mutations that have arisen in response to malaria are deficiency of glucose-6 phosphate dehydrogenase, which is widespread in Mediterranean and India,72 and a polymorphism in the promoter of inducible nitric oxide synthase.76
Plasmodium vivax and the blood group Fy(a–b–) phenotype
Complete absence from red cells of the molecule carrying the Duffy blood group antigens (aka DARC) is found in almost 100% of West Africans, and this absence is clearly and unambiguously demonstrated to provide protection from P vivax.77 The molecular basis of this Duffy deficiency is a point mutation in the binding site for the transcription factor GATA-1.78 GATA-1 is a DNA-binding protein essential for erythropoiesis, and its failure to bind to the Duffy gene promoter means that the Duffy protein is absent from the red cells of affected subjects. In Africans the mutation occurs on a Duffy allele that would otherwise generate a Fy(b+) phenotype. The same GATA-1 mutation appears to have occurred on a second occasion in South East Asia, where it occurs on a Duffy allele that would otherwise generate a Fy(a+) phenotype.79 Another mutation creating weak expression of Duffy (Fyx) may also be relevant to malaria, but relevant population studies have not been reported.80 Recently, evidence for the emergence of P vivax strains capable of invading Fy(a–b–) red cells has emerged in South America and East Africa.81,82
The protective effect of the Fy(a–b–) phenotype against P vivax is clear and unambiguously established. Not so clear are any deleterious consequences of this mutation for the subjects expressing the phenotype. Duffy protein is expressed on endothelial cells in these subjects but not on red cells,83 so any attempt to understand the consequences of red cell Duffy deficiency must take account of the functional role of endothelial Duffy. The Duffy protein is a member of the 7 membrane-spanning chemokine receptor family (Figure 3) but unlike most chemokine receptors does not effect intracellular signaling through G proteins. It binds several proinflammatory chemokines of both the CXC and CC subfamilies but does not bind homeostatic chemokines.84 Recent evidence suggests Duffy protein on endothelial cells binds chemokines and facilitates leukocyte extravasation contributing to disease pathogenesis through inflammation.85 Evidence for up-regulation of Duffy expression in the vascular endothelium during infection and transplant rejection supports this view.86,87
The lack of Duffy on red cells in Fy(a–b–) patients alters the balance of proinflammatory chemokines in the body because the very large capacity of red cell binding is absent but the consequences of this change are presently unclear. Lee et al88 provide evidence that red cell and endothelial Duffy regulate the kinetics of chemokine bioavailability between the circulation and extravascular sites during inflammation. Clearly this regulation would be altered in Fy(a–b–) subjects. In a mouse model, inflammation induced by polycytidylic acid significantly enhanced alloimmunization to red cells.89 In this context it is interesting to note that patients with SCD are predominantly of the Fy(a–b–) phenotype and that the production of multiple red cell alloantibodies upon transfusion (usually with blood from white donors) is a frequent and significant problem encountered by employees of blood banks seeking to provide compatible blood for the patients (reviewed in Anstee90). SCD patients in sickle cell crisis and mouse models of human SCD have many indicators of an inflammatory response.91 These data suggest that the enhanced propensity for alloimmunization in SCD patients is related to inflammation and also pose the question as to the significance of Fy(a–b–) in this process. Are Fy(a–b–) SCD patients more likely to make alloantibodies in response to transfusion than SCD patients of normal Fy phenotype? Is there a link between regulation of proinflammatory chemokine availability by red cell Fy and the adaptive immune response?
The data of Afenyi-Annan et al92 provide evidence that SCD patients with the Fy(a–b–) phenotype are more susceptible to chronic organ damage and proteinuria than SCD patients of normal Fy phenotype and are consistent with such an hypothesis. Interpretation is likely also influenced by genetic differences of immune response and cytokine genes in African populations compared with other world populations,93,94 but the genetic backgrounds of SCD patients with normal and Fy(a–b–) phenotype may be sufficiently comparable to allow conclusions regarding alloimmunization and the role of Fy to be drawn. Should Fy(a–b–) subjects be more susceptible to alloimmunization, then the potential use anti-inflammatory therapies in the treatment of vaso-occlusion95,96 may have the added bonus of reducing rates of red cell alloimmunization and provide a much needed alternative approach to a major transfusion problem.
A further consequence of selection for the Fy(a–b–) phenotype in Africa may be to alter the kinetics of HIV-1 infection in those with this phenotype. Several HIV-1 strains bind to Duffy on normal red cells, facilitating the transfer of HIV-1 to its target cells (CD4+/CCR5+ T lymphocytes) with 5- to 12-fold greater efficiency than Fy(a–b–) red cells.97 He et al97 calculate that patients with the Fy(a–b–) phenotype have a 40% greater likelihood of acquiring HIV than those lacking the phenotype; however, the disease, once acquired, has a slower progression than in infected patients of normal Fy type. They conclude that these differences are related to loss of competition for binding HIV-1 between plasma chemokine CCR5 and Duffy on red cells in Fy(a–b–) subjects and consequent changes in the inflammatory state those infected. The findings of this study have been contested by Walley et al,98 who used different methodology to analyze a different cohort of HIV+ and HIV– African American subjects and found no association between Fy genotype and progression to AIDS or risk for HIV acquisition. They also point out that the number of HIV– patents used by Walley et al98 was much smaller (227 vs 814) and suggest this difference may be a major factor affecting the analysis.99
Different strains of P falciparum use different blood group proteins as receptors
The dual availability of in vitro culture systems to study the invasion of human red cells by P falciparum and well-characterized rare blood group phenotypes made it possible to identify red cell receptors used by different parasite strains. Early studies on cells lacking Glycophorin A (Ena– cells100) and glycophorin B (S-s– cells101) provided evidence that these sialic acid–rich red cell-surface glycoproteins were parasite receptors and these observations have been confirmed.102–105 Glycophorins C (GPC) and D (Ge– red cells) are also receptors for some strains of P falciparum.106–108 Glycophorins are major proteins at the red cell surface (Figure 3). Glycophorin A (GPA) and the major anion transport protein (AE1, Band 3) with approximately 106 copies/red cell are the most abundant red cell surface proteins with glycophorins B, C, and D together accounting for a further 450 000 copies per red cell.109,110
Perhaps surprisingly, there is little experimental evidence to suggest selection against the expression of GPA has occurred in response to P falciparum infection. Red cells from patients having the hybrid GPA-GPB protein Dantu, which is common in certain parts of Africa, are reported to resist invasion,111 and it has been suggested that elevated expression of Band 3 occurring in patients with the GPB-GPA-GPB MiIII protein common in South East Asia may be relevant to malaria survival.112 The importance of sialic acid on GPA in forming a receptor for P falciparum102 suggests that red cells expressing glycosylation variants of GPA found commonly in Africans in which N-acetyl D-glucosamine is present in some of the sialic acid–rich O-glycans at the N-terminus (patients with the M1 antigen113) may be relevant to one's susceptibility to malaria.
In contrast to the situation with GPA, subjects lacking glycophorin B are found in high frequency in central Africa.105 Patients with red cells lacking GPC and glycophorin D (Ge–, Leach phenotype) are very rare, but those with Ge– red cells having an altered GPC resulting from deletion of exon 3 of GYPC114,115 are common in Melanesians, most notably in Papua New Guinea, and the resulting phenotype provides protection against P falciparum (Figure 4).72,108 Clearly, different strains of P falciparum target glycophorins associated with one or other of the membrane complexes, providing key cytoskeletal linkages maintaining the stability of the red cell membrane (Figure 3) and selection, resulting in loss or alteration of glycophorins in either of these sites confers a survival advantage.



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Figure 4. Distribution of rare blood group phenotypes selected by malaria in Africa and South East Asia. The location of rare blood group phenotypes lacking glycophorin B (S-s–), having altered glycophorin C (Ge–; Gerbich-negative), Fy (Duffy) blood group–null allele (Fy), Sl(a–) allele of complement receptor 1 (CR1), and the Band 3 mutation causing South East Asian ovalocytosis (SAO) in comparison with the distribution of HbS and HbE alleles.72



Melanesians also exhibit another example of selection, affording protection against cerebral malaria, a phenotype known as South East Asian ovalocytosis. South East Asian ovalocytosis cells, as the name implies, have an abnormal shape. They are also characterized by weakened expression of a large number of blood group antigens, including antigens found on Band 3, GPA, and the Rh blood group proteins.116 In this case selection favors the heterozygote. Heterozygotes inherit a normal Band 3 gene together with a mutant inactive Band 3 gene resulting from a deletion, causing a loss of 9 amino acids at the point at which the cytoplasmic N-terminal domain enters the cytosolic face of the lipid bilayer (reviewed in Bruce117). Homozygous inheritance of this mutation would result in total Band 3 deficiency. Because Band 3 is essential for respiration (Cl/HCO3 exchange) and for maintaining the integrity of the red cell membrane, it must be assumed in evolutionary terms that such an inheritance is incompatible with survival. Rare subjects with total Band 3 deficiency states have been described, but survival depends on extensive medical support, particularly in the neonatal period.118
Complement receptor 1 (CR1; Figure 3) carries antigens of the Knops blood group system. CR1 expression is very variable between patients and red cells expressing fewer than 100 copies CR1 per cell show reduced rosetting with P falciparum strain R29R, as do red cells expressing the Sla– blood group phenotype. The Sla– phenotype, which results from a single nucleotide polymorphism (R1601G) in long homologous repeat D, occurs in only 1% of the white population but reaches 70% in Malians.119–121

Conclusions
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Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References


The significance of human blood groups can now be seen more clearly in the context of population movement, and the constant battle between humans and infectious disease. Evidence for selection by infectious diseases at the level of the ABO and secretor genes is persuasive but for other blood group antigens, founder effects appear more likely to account for the distribution of blood group polymorphisms except that is, in parts of the world in which malaria is endemic. Available data suggest survival from malaria has been the most significant selective force acting on the blood groups.
Rare blood group phenotypes revealed through compatibility testing in transfusion centers and blood banks throughout the world have provided powerful tools with which to investigate the mechanisms whereby malarial parasites invade human red cells. However, a comprehensive study of the distribution of known blood group polymorphisms in areas in which malaria is endemic has not been undertaken. Now that almost all the blood group genes have been cloned and the molecular bases of most antigens determined, it is feasible to conduct such a study with the use of high-throughput DNA-based methods.122–125 Furthermore, the availability of rapid DNA sequencing methodologies presages an era in which mass screening of genes encoding red cell membrane proteins could be used to identify new polymorphisms of relevance to malarial invasion. Studies of this type, focused in tropical Africa, South East Asia, and Latin America, would provide a valuable database of new information about blood group diversity in populations inhabiting these regions not only for malarial epidemiologists but also for those investigating human susceptibility to new emerging infectious diseases given that zoonoses from wildlife in these regions have been identified as the most significant growing threat to global health of all emerging infectious diseases.126

Authorship
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Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References


Contribution: D.J.A. wrote the manuscript.
Conflict-of-interest disclosure: The author declares no competing financial interests.
Correspondence: David Anstee, Bristol Institute for Transfusion Sciences, NHS Blood and Transplant, Bristol, BS34 7QG United Kingdom; e-mail: david.anstee@nhsbt.nhs.uk .

Acknowledgments

The author thanks Lesley Bruce of the Bristol Institute for Transfusion Science for preparing Figure 3, David Briggs of NHS Blood and Transplant for helpful discussions regarding HLA-C and KIR receptors, and Geoff Daniels of the Bristol Institute for Transfusion Science for critical reading of the manuscript.
The author's work is supported by Department of Health (England).

Footnotes

Submitted January 21, 2010; accepted February 18, 2010.
Prepublished online as Blood First Edition Paper, March 22, 2010 DOI: 10.1182/blood-2010-01-261859


References
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Rh blood groups and...
Malaria: evidence for selection...
Conclusions
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References



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Artificial type 0 blood thanks to embryonic stem cells

After making news on several occasions, scientists may have made a definitive breakthrough, with the first possible transfusion using blood obtained from embryonic stem cells possibly coming within the next three years. The transfusion would be done with type O blood, which can be donated to any patient, and would be obtained by researchers using excess embryos from assisted fertilization. The project, which will be led by Marc Turner of Edinburgh University, will also receive contributions from the Transfusion and Transplant Service of the British National Health Service, as well as the same department and Scotland, and the Welcome Trust, a large charitable group for medical research. The story was reported by the Independent and immediately created controversy and distorted information.

“This isn’t just talk, this time it is a serious breakthrough, and the group behind the project is very serious,” said Professor Carlo Alberto Redi, the scientific director of the IRCCS (Hospital and Medical Treatment) Foundation of the San Matteo General Hospital in Pavia, commenting on the story. Redi emphasized that the capability for the regeneration of the hematopoietic progenitor cells in vitro is well-known and the time is right for real blood to be created, with the term artificial blood no longer appropriate. “When the term synthetic blood is used, people imagine silicone blood, when in reality, in all effects, this is real blood,” said Redi.

IT CANNOT REPLACE BLOOD DONATIONS

The blood that the British researchers plan to use in human treatments in the next three years will only “support and complement” blood donation. Giuseppe Novelli, a geneticist of the University of Rome Tor Vergata, commenting to Adnkronos Salute, was less optimistic. “This is only an announcement, and it seems premature to talk about a victory. This research is starting off well because it has millions in financing and is based on evidence that is very hopeful. But we are only talking about one piece of a very complex puzzle.”

The puzzle, in this case, is represented by the blood that runs through our veins and arteries, “made up of red and white blood cells, platelets, and plasma,” said Novelli. “It is a very complex liquid, which carries out an essential function in our body.” The British study which is currently being launched “is limited to red blood cells, which are certainly not able to resolve all of the problems with transfusions”. The British studies are also developing type O negative blood, a group that is able to donate to any patient without any risk of rejection. “This is blood that can be used, and is used, only in case of emergency.” Novelli continued to say that “the new blood will not be able to replace real blood donation, and I don’t want these announcements to inhibit people from donating blood, or make them underestimate the value or the importance blood donation”.

As for an estimate on how much time it will take to create a synthetic blood that will resolve all problems linked to a lack of donations, Novelli said: “I’m not a magician! Science needs realism, and predictions cannot be made for this type of study. Certainly,” he concluded optimistically, “the progress made with stem cells in the past 12 years since their discovery is a great cause for hope”.

The adhesion molecule esam1 is a novel hematopoietic stem cell marker

Abstract
Hematopoietic stem cells (HSCs) have been highly enriched using combinations of 12-14 surface markers. Genes specifically expressed by HSCs as compared with other multipotent progenitors may yield new stem cell enrichment markers, as well as elucidate self-renewal and differentiation mechanisms. We previously reported that multiple cell surface molecules are enriched on mouse HSCs compared with more differentiated progeny. Here, we present a definitive expression profile of the cell adhesion molecule endothelial cell-selective adhesion molecule (Esam1) in hematopoietic cells using reverse transcription-quantitative polymerase chain reaction and flow cytometry studies. We found Esam1 to be highly and selectively expressed by HSCs from mouse bone marrow (BM). Esam1 was also a viable positive HSC marker in fetal, young, and aged mice, as well as in mice of several different strains. In addition, we found robust levels of Esam1 transcripts in purified human HSCs. Esam1(-/-) mice do not exhibit severe hematopoietic defects; however, Esam1(-/-) BM has a greater frequency of HSCs and fewer T cells. HSCs from Esam1(-/-) mice give rise to more granulocyte/monocytes in culture and a higher T cell:B cell ratio upon transplantation into congenic mice. These studies identify Esam1 as a novel, widely applicable HSC-selective marker and suggest that Esam1 may play roles in both HSC proliferation and lineage decisions.


Ooi AG, Karsunky H, Majeti R, Butz S, Vestweber D, Ishida T, Quertermous T, Weissman IL, Forsberg EC.

Institute of Stem Cell Biology and Regenerative Medicine, Department of Pathology, Stanford University School of Medicine, California, USA.

Stem cell niche

Stem cell niche is a phrase loosely used in the scientific community to describe the microenvironment in which stem cells are found, which interacts with stem cells to regulate stem cell fate. The word 'niche' can be in reference to the in vivo or in vitro stem cell microenvironment. During embryonic development, various niche factors act on embryonic stem cells to alter gene expression, and induce their proliferation or differentiation for the development of the fetus. Within the human body, stem cell niches maintain adult stem cells in a quiescent state, but after tissue injury, the surrounding micro-environment actively signals to stem cells to either promote self renewal or differentiation to form new tissues. Several factors are important to regulate stem cell characteristics within the niche: cell-cell interactions between stem cells, as well as interactions between stem cells and neighbouring differentiated cells, interactions between stem cells and adhesion molecules, extracellular matrix components, the oxygen tension, growth factors, cytokines, and physiochemical nature of the environment including the pH, ionic strength (e.g. Ca2+ concentration) and metabolites, like ATP, are also important. The stem cells and niche may induce each other during development and reciprocally signal to maintain each other during adulthood.
Scientists are studying the various components of the niche and trying to replicate the in vivo niche conditions in vitro. This is because for regenerative therapies, cell proliferation and differentiation must be controlled in flasks or plates, so that sufficient quantity of the proper cell type are produced prior to being introduced back into the patient for therapy.
Human embryonic stem cells are often grown in fibroblastic growth factor-2 containing, fetal bovine serum supplemented media. They are grown on a feeder layer of cells, which is believed to be supportive in maintaining the pluripotent characteristics of embryonic stem cells. However, even these conditions may not truly mimic in vivo niche conditions.
Adult stem cells remain in an undifferentiated state throughout adult life. However, when they are cultured in vitro, they often undergo an 'aging' process in which their morphology is changed and their proliferative capacity is decreased. It is believed that correct culturing conditions of adult stem cells needs to be improved so that adult stem cells can maintain their stemness over time.
A Nature Insight review defines niche as follows:
"Stem-cell populations are established in 'niches' — specific anatomic locations that regulate how they participate in tissue generation, maintenance and repair. The niche saves stem cells from depletion, while protecting the host from over-exuberant stem-cell proliferation. It constitutes a basic unit of tissue physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms. Yet the niche may also induce pathologies by imposing aberrant function on stem cells or other targets. The interplay between stem cells and their niche creates the dynamic system necessary for sustaining tissues, and for the ultimate design of stem-cell therapeutics...The simple location of stem cells is not sufficient to define a niche. The niche must have both anatomic and functional dimensions"
—David T. Scadden, The stem-cell niche as an entity of action, Nature, 441 (7097), 1075-1079 (29 June 2006

Essential Stem Cell Methods

ESSENTIAL STEM CELL METHODS




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Edited By
Robert Lanza, Chief Scientific Officer, Advanced Cell Technology, MA, USA; Adjunct Professor, Institute of Regenerative Medicine, Wake Forest University School of Medicine, NC, USA Robert Lanza Advanced Cell Technology 381 Plantation Street Worcester, MA 01605
Irina Klimanskaya, Advance Cell Technology, Worcester, MA, USA

Included in series
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Contents




Section 1: Organ-Derived Stem Cells

1. Neural Stem Cell Isolation and Characterization ; Rodney L. Rietze and Brent A. Reynolds
2. Neural Stem Cells and Their Manipulation; Evan Snyder
3. Retinal Stem Cells; Thomas A. Reh and Andy J. Fischer
4. Dental Pulp Stem Cells; He Liu, Stan Gronthos and Songtao Shi
5. Spermatogonial Stem Cells; Jon M. Oatley and Ralph L. Brinster
6. Stem Cells in the Lung; Xiaoming Liu, Ryan R. Driskell and John F. Engelhardt
7. Pancreatic Cells and Their Progenitors; Seth J. Salpeter and Yuval Dor
8. Pluripotent Stem Cells from Germ Cells; Candace L. Kerr, Michael J. Shamblott and John D. Gearhart
9. Amniotic Fluid and Placental Stem Cells; Dawn M. Delo, Paolo De Coppi, Georg Bartsch, Jr. and Anthony Atala
10. Cord Blood Stem and Progenitor Cells; Mervin C. Yoder
11. Purification of Hematopoietic Stem Cells Using the Side Population; K.K. Lin and Margaret A. Goodell
12. Microarray Analysis of Stem Cells and Differentiation; Howard Y. Chang
13. Tissue Engineering Using Adult Stem; Cells Daniel Eberli
14. Mesenchymal Stem Cells and Tissue Engineering; Nicholas W. Marion and Jeremy J. Mao


Section II: Embryonic Stem Cells

15. Murine Embryonic Stem Cells; Andras Nagy and Kristina Vintersten
16. Human Embryo Culture; Amparo Mercader, Diana Valbuena and Carlos Sim n
17. Human Embryonic Stem Cells; Douglas Melton
18. Characterization and Evaluation of Human Embryonic Stem Cells; Chunhui Xu
19. Feeder-Free Culture of Human Embryonic Stem Cells; Michal Amit and Joseph Itskovitz-Eldor
20. Neural Stem Cells, Neurons, and Glia; Steven M. Pollard, Alex Benchoua and Sally Lowell
21. Hematopoietic Cells; Malcolm A.S. Moore, Jae-Hung Shieh and Gabsang Lee
22. Cardiomyocytes; Xiangzhong Yang, Xi-Min Guo, Chang-Yong Wang and X. Cindy Tian
23. Insulin-Producing Cells; Insa S. Schroeder, Gabriela Kania, Przemyslaw Blyszczuk
24. Transgene Expression and RNA Interference in Embryonic Stem Cells; Holm Zaehres and George Q. Daley
25. Lentiviral Vector-Mediated Gene Delivery into Human Embryonic Stem Cells; Michal Gropp and Benjamin Reubinoff
26. Engineering Embryonic Stem Cells with Recombinase Systems; Frank Schn tgen, A. Francis Stewart, Harald von Melchner and Konstantinos Anastassiadis
27. Tissue Engineering Using Embryonic Stem Cells; Shahar Cohen, Lucy Leshanski and Joseph Itskovitz-Eldor

Blood Substitutes

“If this really works all the way, then mankind will have taken a big step forward. This is like landing on the moon."

-Dr. Pierre LaFolie

Types of stem cells

ASC (adipose stem cells)
CSC (cochlear stem cells)
CTP (connective tissue progenitors)
ESC (embryonic stem cells)
HSC (hematopoietic stem cells)
HB1 (AC133+ hemangioblasts from umbilical cord blood)
iPS (induced pluripotent stem cells)
MSC (mesenchymal stem cells)
MAPC (multi-potent adult stem cells)
NSC (neural stem cells/oligodendrocyte progenitors)
SKMB (skeletal myoblasts and muscle stem cells), and
UCB (umbilical cord blood derived stem cells)

Professor Martin L Olsson

The Regional Blood Center, Lund University Hospital, Sweden
Martin Olsson is a Professor of Transfusion Medicine at Lund University, Lund, Sweden and a Visiting Associate Professor/Lecturer at Harvard Medical School, Boston, MA, USA. He received his medical degree and PhD at Lund University. His main clinical and research interests are in the molecular genetics of red cell surface markers with a special emphasis on carbohydrate histo-blood group systems and blood typing. His scientific contributions have focused on clarifying the correlation between red cell phenotypes and the underlying genetic polymorphisms, as well as glycosyltransferase function in different blood groups. He is also interested in pathogen-related aspects of blood group antigens and different mechanisms of protection against hemolysis, including exoglycosidase-treated red cells for ABO-universal transfusion. Dr. Olsson serves as Associate Editor of Transfusion Medicine and is a member of the Editorial Board of Transfusion. His awards include the Jean Julliard Prize from the International Society of Blood Transfusion, the Race and Sanger Award from the British Blood Transfusion Society, the Fernstrِm Prize at Lund University and the Hain Foundation Prize

scapegoating

scapegoat

In the Old Testament, a goat that was symbolically burdened with the sins of the people and then killed on Yom Kippur to rid Jerusalem of its iniquities. Similar rituals were held elsewhere in the ancient world to transfer guilt or blame. In ancient Greece, human scapegoats were beaten and driven out of cities to mitigate calamities. In early Roman law, an innocent person was allowed to assume the penalty of another; Christianity reflects this notion in its belief that Jesus died to atone for the sins of mankind.

Artificial Blood Products And Artificial Oversight?

Artificial blood products increased the risk of death by 30 percent and almost tripled the risk of heart attacks in 16 clinical trials, according to a study in the Journal of the American Medical Association. The researchers write that the FDA should have stopped the studies eight years ago, but meanwhile five trials are still under way and another is about to begin.

Eight years ago, the FDA received data on individual studies showing increased risks that should have triggered suspension of testing until a large-scale analysis could be conducted, according to the researchers, who say the FDA should end the trials and Congress should review rules forcing the agency to keep info on new products confidential for competitive reasons.

“One straightforward solution to these problems would be for Congress to reverse the FDA’s policy of treating as confidential all corporate materials submitted during the product development process, including the investigational drug application,” the researchers wrote. The blood products studied were made by Baxter International, Biopure, Hemosol BioPharma, Northfield Laboratories and Sangart.

“If you have secret science, things like this can happen,” Charles Natanson, a septic shock researcher at the National Institutes of Health, tells Bloomberg News. “Once you’ve randomized patients, your results can’t be a trade secret. It’s a measure of protection to the American public.”


But Jay Epstein, director of the FDA’s office of blood research and review, tells Bloomberg that analyzing several studies together as one has its limitations. And he adds that the agency also has unpublished info not available to the study’s authors that shows potential benefits of artificial blood. It’s not clear whether that info will be discussed at an FDA workshop being held tomorrow to review the products.

Filgrastim

Filgrastim is a granulocyte colony-stimulating factor (G-CSF) analog used to stimulate the proliferation and differentiation of granulocytes. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. The G-CSF then produced by E. coli is only slightly different from G-CSF naturally made in humans. It is marketed by Amgen with the brand name Neupogen, Reliance Biopharmaceuticals with the brand name Religrast,Zenotech Laboratories Limited with the brand name Nugrafand also by Raichem lifesciences with the brand name Shilgrast.Filgrastim is used to treat neutropenia (a low number of neutrophils), stimulating the bone marrow to increase production of neutrophils. Causes of neutropenia include chemotherapy and bone marrow transplantation.Filgrastim is also used to increase the number of hematopoietic stem cells in the blood before collection by leukapheresis for use in hematopoietic stem cell transplantation.It is produced by many companies worldwide.

Lund Stem Cell Center

Established in January 2003, the center focuses on stem cell and developmental biology of the central nervous and blood systems, and development of stem cell and cell replacement therapies in these organ systems as well as research in non-mammalian model systems.

Consisting of many strong research groups and almost 130 people under "one roof", the Center is already one of the largest in the field, with the goal of becoming a major force in translational research and career development in biomedical research.

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Complementary signaling through flt3 and interleukin-7 receptor alpha is indispensable for fetal and adult B cell genesis

Extensive studies of mice deficient in one or several cytokine receptors have failed to support an indispensable role of cytokines in development of multiple blood cell lineages. Whereas B1 B cells and Igs are sustained at normal levels throughout life of mice deficient in IL-7, IL-7Ralpha, common cytokine receptor gamma chain, or flt3 ligand (FL), we report here that adult mice double deficient in IL-7Ralpha and FL completely lack visible LNs, conventional IgM+ B cells, IgA+ plasma cells, and B1 cells, and consequently produce no Igs. All stages of committed B cell progenitors are undetectable in FL-/- x IL-7Ralpha-/- BM that also lacks expression of the B cell commitment factor Pax5 and its direct target genes. Furthermore, in contrast to IL-7Ralpha-/- mice, FL-/- x IL-7Ralpha-/- mice also lack mature B cells and detectable committed B cell progenitors during fetal development. Thus, signaling through the cytokine tyrosine kinase receptor flt3 and IL-7Ralpha are indispensable for fetal and adult B cell development.

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Interleukin-3 supports expansion of long-term multilineage repopulating activity after multiple stem cell divisions in vitro

David Bryder and Sten E. W. Jacobsen


Although long-term repopulating hematopoietic stem cells (HSC) can self-renew and expand extensively in vivo, most efforts at expanding HSC in vitro have proved unsuccessful and have frequently resulted in compromised rather than improved HSC grafts. This has triggered the search for the optimal combination of cytokines for HSC expansion. Through such studies, c-kit ligand (KL), flt3 ligand (FL), thrombopoietin, and IL-11 have emerged as likely positive regulators of HSC self-renewal. In contrast, numerous studies have implicated a unique and potent negative regulatory role of IL-3, suggesting perhaps distinct regulation of HSC fate by different cytokines. However, the interpretations of these findings are complicated by the fact that different cytokines might target distinct subpopulations within the HSC compartment and by the lack of evidence for HSC undergoing self-renewal. Here, in the presence of KL+FL+megakaryocyte growth and development factor (MGDF), which recruits virtually all LinSca-1+kit+ bone marrow cells into proliferation and promotes their self-renewal under serum-free conditions, IL-3 and IL-11 revealed an indistinguishable ability to further enhance proliferation. Surprisingly, and similar to IL-11, IL-3 supported KL+FL+MGDF-induced expansion of multilineage, long-term reconstituting activity in primary and secondary recipients. Furthermore, high-resolution cell division tracking demonstrated that all HSC underwent a minimum of 5 cell divisions, suggesting that long-term repopulating HSC are not compromised by IL-3 stimulation after multiple cell divisions. In striking contrast, the ex vivo expansion of murine HSC in fetal calf serum-containing medium resulted in extensive loss of reconstituting activity, an effect further facilitated by the presence of IL-3. (Blood. 2000;96:1748-1755)

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