Last week’s Scienceonline (December 6 2007) had a most instructive report by American scientists, Timothy Townes, Rudolph Jaenisch, Jacob Hanna, and others from the University of Alabama and Massachusetts Institute of Technology’s Molecular Biology Department. They proved that mice that had been genetically modified in the laboratory to develop sickle cell anaemia can be made to produce embryonic stem cells from cells collected in the skin of their tails. Embryonic stem cells are known to be capable in later life of developing into any of different tissues. These so-called induced pluripotent stem cells (IPS cells) were then made to produce healthy haemoglobin by replacing the defective beta-globin sickle cell gene (S) with normal adult gene producing haemoglobin-A (nothing to with Blood Group A!). These were then injected into similar mice with sickle cell anaemia and, lo and behold, normal adult haemoglobin was produced and the mice improved clinically.

            So far so good news, but the cautionary tale is this: it needs the help of retroviruses to shift the genes around to give the required result, and where did you last hear of retroviral activity? AIDS, of course and as one of the scientists put it: “We need a delivery system that does not integrate itself inside the genome. Retroviruses can disrupt genes that should not be disrupted or activate genes that should not be activated”.

            If skin cells of mice can be made to behave like embryonic cells which obey orders given them to produce this or that, the next question is this: “Can human skin cells from sickle cell anaemia patients be similarly programmed to this end?” We can’t wait, though we know that transplanting induced pluripotent cells carry a high cancer risk, not to mention the effect of the high dose of X-rays required to destroy the faulty blood cells in the body before the new ones are planted.

Two more comments:

(i) How much would a New Yorker pay for the procedure, if it proved successful in humans? Cost itself should not disqualify a process that would abolish pain, but one needs ask the question. Until persons producing inherited ‘ACHEACHE’ haemoglobin begin to be able to produce acquired ‘NORMNORM’ or ‘NORMACHE’ haemoglobin through IPS cell manipulation, we need to pursue the public health measures that I have been stressing for preventing crises, and we must continue urging on our kith and kin genetic counselling with voluntary family size limitation [Konotey-Ahulu FID, The Lancet, 1 December 2007, volume 370, pages 1826-27: “Need for ethnic experts to tackle genetic public health”]       

(ii) A report by one Eric Bender in Cambridge Massachusetts (December 6 2007) began like this: “Mice with a human sickle cell anemia disease trait have been treated successfully…..” Now those familiar with this website know that there is no such thing as “sickle cell anemia disease trait”. There just isn’t! While sickle cell anaemia is also sickle cell disease, sickle cell trait is NEITHER of these. Indeed, as the blog above shows, I was given four bodyguards in Philadelphia for stressing this very point, namely that SICKLE CELL TRAIT IS NOT SICKLE CELL ANAEMIA (SICKLE CELL DISEASE). Please read that blog above again, and turn to my FAQ [Frequently Asked Questions]. Even well educated professionals use the terms interchangeably. Remember this: Only sickle cell anaemia can be referred to as sickle cell disease because both have TWO ‘Ache’ genes. The Sickle Cell Trait has only one ‘Ache’ haemoglobin gene. Insurance companies have been known to blur the distinction and have over charged sickle cell traits (many of whom have won gold medals at Olympic Games, even at a height of 8,000 ft above sea level). How can persons who ran and beat the whole world be charged a greater premium for health insurance, than the people they beat at the games?   

Opiates for pain in dying patients and in those with sickle cell disease

Dorothy Logie and Mhoira Leng’s report of 6 October describes a conference in Nairobi which highlighted opiophobia – the fear of using morphine therapeutically – “as a big obstacle facing palliative care services in the (African) continent” [1]. The conference was concerned with dying patients. In his rapid response, however, Jecko Thachil concentrated on the use of opiates in sickle cell disease patients. He states that while “very high amounts of opiates (often in hundreds of milligrams) are often required for the patients who suffer from recurrent sickle crises” [2], the expected analgesic effect leaves much to be desired, not to mention side-effects. Dealing with terminally ill patients is one thing; opiate administration to sickle cell disease patients is something else entirely.

Dr Thachil feels an “increased need for additional education regarding sickle cell disease…” Has he examined the experiences of two physicians who personally supervised thousands of people with sickle cell disease on both sides of the Atlantic continuously for years? [3, 4] Treating sickle cell disease is not the same as managing the sickle cell disease patient [5]; the difference in the two approaches tending to separate haematologists on the one hand, from physicians and family practitioners on the other. When a white British consultant physician in a London teaching hospital complained that “the haematologists here have created a cohort of addicts” [6] a white consultant haematologist in another London teaching hospital tore strips off him, accusing him of being a racist for depriving suffering black patients of pain relief, an attack which made me respond thus: “White physicians who, at the risk of being misunderstood by (that haematologist), voice their displeasure at what they see happening on their wards deserve commendation, not condemnation” [7].

Not far from where Dr Jacko Thachil works, also on Merseyside, “during a ward round in a provincial teaching hospital with consultant haematologists on March 6, 1997, I was shown a woman who had been on continuous opiate infusion since September, 1996” [7]. I went on to say in my Lancet communication: “Far from the consultants taking umbrage because I pointed out that the patient could not have been in sickle cell crisis for 6 months, they were happy to discuss with me the way forward” [7]. Dr Thachil feels “an increased need for additional education regarding …addiction to pain medication…and treatment of pain” and he concludes “but who and where these should be focussed on is a matter for debate” [2].

Not a matter for debate at all in my opinion: May I suggest to him certain facts he might wish to probe in his quest for education?

(a) “In Jamaican experience ..morphia or its derivatives are rarely used or necessary” [8] How did Graham Serjeant achieve this?

(b) “Most painful crises may be treated in a day-care centre, the patient returning home in the evening” [9] How is this possible if hooked up on morphine or diamorphine pump “as in the recommended UK protocol”? [6]

(c) “We are convinced that the chest syndrome in the UK and the USA is not entirely unrelated to the routine use of opiates in those countries for sickle cell crises”. [10] Some nurses I am in touch with can write an MSc thesis on this.

(d) Goodman from the USA (where diamorphine is banned for patients) found the use of ketorolac in painful sickle cell crises as efficient as morphine but without the latter’s respiratory depression [11]. So why do British haematologists prefer to use morphine and diamorphine? Answer: “Ketorolac has no product licence in the UK for this indication” [12]

(e) Two questions that I have asked British Haematologists several times but which have never been answered, and which Dr Thachil may now ask the National Institute of Clinical Excellence (NICE) for help in answering:

(i) “Why do West African and West Indian patients with sickle cell disease who did without morphine in their countries have to be given morphine pumps during sickle cell crises when they come to the United Kingdom?” [6, 13]

(ii) If pain from whatever cause deserved the most potent analgesic, and dysmenorrhoea has been known to be intolerably painful, would a British haematologist “not consider it unwise for a hospital to administer diamorphine as routine management of young women?” [7]

Four encouraging signs have emerged in the UK since I have been voicing my displeasure at the use of diamorphine and morphine pumps for patients with sickle cell crises: (1) Some haematologists in the UK and the European continent have abandoned the practice in spite of what the ‘approved protocol’ displays in the emergency rooms. (2) Some sickle cell disease patients have become more vocal in their displeasure of the practice. To them ‘opiophobia’ is not to be condemned [1], but commended. (3) Some family practitioners are looking after their patients at home, using intravenous fluids and other than powerfully addictive opiates to help these patients instead of submitting them to hospital care. (4) A clearer grasp of the causes of crisis has put more emphasis on public health measures (fluids, warmth, treatment of infections, dressing properly, anticipating hazards, immunisations, avoiding tobacco and alcohol), enabling patients prevent crises and helping them use the excellent non-sickling genes they have inherited from their parents to achieve as much of their full potential intellectually as possible [10].

It is therefore not surprising to find that the sickle cell disease patients who have become lawyers, teachers, businessmen and women, nurses & midwives, pharmacists, and even doctors are those whose haematologists have abandoned the opiate culture. Occasionally, however, one found even professors of haematology who would defend the prescribing of diamorphine for a sickle cell disease patient with severe difficulty in breathing. “Chest syndrome” was always there to blame, if the patient died [6].

When in my genetic counselling and family size limitation (GCFSL) drive in Ghana and in the Ghanaian community here in the UK I sense that the urgency of my message is being glossed over I tell my fellow countrymen and women in plain language that if they continue to procreate at the rate they are doing, and more sickle cell disease (ACHE/ACHE) patients are born, the chances are that in the UK they may end up on a heroin drip. This concentrates the mind, and they listen to me. “One in three of you is a NORM/ACHE. Do you want to end up with ACHE/ACHE children who will be given heroin for pain?” [http://www.konotey- ahulu.com/diagram.asp]

Felix I D Konotey-Ahulu MD(Lond) DSc (UCC) FRCP DTMH FGA FGCPS FAAS FTWAS
Kwegyir Aggrey Distinguished Professor of Human Genetics, University of Cape Coast, Ghana and Consultant Physician Genetic Counsellor, Ten Harley Street, London W1N 1AA, England.

Conflict of interest: None declared

1 Logie D, Leng M. Africans die in pain because of fears of opiate addiction. BMJ 2007; 335: 685

2 Thachil J. The fear of opiate addiction – not unique to Africa. Rapid response BMJ 2007, 8 October.

3 Serjeant GR. Sickle cell disease. Oxford: Oxford university Press, 1992 (Second Edition)

4 Konotey-Ahulu FID. The sickle cell disease patient. London: Macmillan 1991; Waftord: Tetteh-A’Domeno Co, 1996.

5 Konotey-Ahulu FID. Sickle cell disease and the patient. Lancet 2005; 365: 382-383.

6 Konotey-Ahulu FID. Opiates for sickle cell crisis? Lancet 1998; 351: 1438.

7 Konotey-Ahulu FID. Opiates for sickle cell crisis. Lancet 1998; 352: 651-652.

8 Serjeant GR. Sickle cell disease. Oxford. Oxford University Press, 1985, page 204.

9 Serjeant GR. Sickle cell disease. Lancet 1997; 350: 725-730.

10 Ringelhann B, Konotey-Ahulu FID. Hemoglobinopathies and thalassaemias in Mediterranean areas and West Africa: historical and other perspectives 1910 to 1997. Atti dell’Accademia delle Scienze di Ferrara 1998; 74: 267-307.

11 Goodman E. Use of ketorolac in sickle cell disease and vaso- occlusive crisis. Lancet 1991; 338: 641-642.

12 Liesner RJ, Vandenberghe EA, Davies SC. Analgesics in sickle cell disease. Lancet 1993; 341: 188.

13 Konotey-Ahulu FID. Morphine for painful crises in sickle cell disease. BMJ 1991; 302: 1604.

Competing interests: None declared

Link : http://www.bmj.com/cgi/eletters/335/7622/685#177986

There is no mystery [1, 2] about “kwashiorkor”, which is a word from a Ghanaian tribe, my very own Krobo/Dangme/Ga megatribe [3, 4]. Indeed, it was when I was a toddler that the remarkable white woman based at the Princess Marie Louise Hospital in Accra (before the Gold Coast became Ghana) first described the condition which was brought to her attention by my fellow tribes folk [5,6].

Imagine my utter astonishment when, coming over to England to read Medicine in London University, I heard Lecturer after Lecturer state with unwarranted confidence that “kwashiorkor means red hair in an African language”. The word means no such thing in my tribe. Kwashiorkor, as I once pointed out to a British Professor of Paediatrics in this very medical journal “is, primarily, a sibling positional word, which requires careful explanation to the non-native” [3]. It is a reflection of the 'birth position' of the sufferer, before it is a pathology [4], a fact emphasized by Dr Cicely Willams whose descriptions of the condition have not been bettered by anyone [5, 6, 7, 8].

Apart from being a Krobo tribesman, I have a further reason for claiming that I know more about Kwashiorkor than all the non-Ghanaian experts that have written volumes about the syndrome (Cicely Williams excepted). And I say that for this reason: In my tribe, it was said of me (the second child) the day my younger brother was born while I was not yet completely weaned – “afor ese kwasiorkor” [3] which, literally means “it has been born after him kwasiorkor”, stressing my positional risk of being sandwiched between my elder brother, Agbetey, who was just 13 months older than me, and the just arrived sibling who was also just 17 months my junior. See http://www.konotey-ahulu.com/images/generation.jpg for the first 3 children of my parents Rev & Mrs Konotey-Ahulu in Generation VII, and note how closely spaced we were.

The whole tribe expected me to develop kwashiorkor because of the birth of my brother. “The reason I escaped the syndrome first described by Dr Cicely Williams [3, 4] was simply because my educated parents took the same steps that Professor Marsden described from Brazil [9]: I was fed with beans, eggs, milk, minced meat, and Ovaltine” [3]. Less fortunate relatives of my age in my tribe, whose parents also had 3 children in less than 3 years, “and of whom it was also said 'afor ese kwasiorkor' went on to develop kwashiorkor because they could only afford to be fed with maize products such as akasa and k enky” [3].

I went on to make the point that: “The sibling positional word became almost invariably associated with the syndrome Cicely Williams was investigating, and although the term kwashiorkor was occasionally attached to a child who never went on to get the disease ” (just as in my own case), whenever the the syndrome kwashiorkor was seen in a child there was, more likely than not, very close proximity to a younger sibling” [3]. Exceptions, of course, occurred, “when children were orphaned” (as would be the case in Malawi ravaged with AIDS), regardless of sibling positioning, or multiple births. Indeed, I described such children (with photographs) on my AIDS tour of African countries [Ref 10 – See Figure 6.14, page 124]. I also described in a man who was mistaken for suffering from HIV-AIDS [Ref 10, photographs on pages 80-82] what has been called the Adult Kwashiorkor syndrome “in which diarrhoea, pitting oedema, hepatomegaly, dermatopathy, mental apathy, and hair changes result from protein energy malnutrition as, for example, in the creatorrhoea and steatorrhoea of severe alcoholic chronic pancreatitis”. This syndrome was completely reversible in the man described [10] when his alcoholism [he was on one litre and half of gin a day] was treated, diabetes reversed, pancreatin supplied, and protein supplements given [See remarkable change in just 6 months – Ref 10]. Should we have spent research funds finding out how much antioxidants this man's diet contained?

I had the enormous privilege of meeting up with 93-year old Dame Cicely Williams in Oxford in 1986 when we were photographed together[See The Lancet, Ref 4 for what she looked like at 93!]. I thanked her profusely for all that she did in my tribe in those colonial days wihout electron microscopes and sophisticated analysers. We both were greatly baffled why many of today's experts (especially those who have little experience of a tropical sojourn)find it difficult to accept that “Kwashiorkor is the result of a social pathology before it is the outcome of a biochemical pathology” [4]. Clinical epidemiology ie answering the questions Who? Which? Where? When? Why? What? and How? is far and away the best tool to investigate a tropical phenomenon such as kwashiorkor, and Cicely Williams gets my Full Marks for employing that tool with hardly any funds for medical research.

I repeat what I said a decade or so ago in The Lancet: “Those of us who grew up in the kwashiorkor belt and who have also had the benefit of an excellent medical education cannot but caution our ministries of health and social welfare about the danger of missing the social pathology wood for the trees of free radicals and leukotrienes”.

Nothing to declare, except that Kwashiorkor is my tribal language.

References

1 Fuchs GJ. Antioxidants for children with kwashiorkor. Brit Med J 2005; 330: 1095-1096.

2 Ciliberto H, Ciliberto M, Briend A, Ashorn P, Bier D, Manary M. Antioxidant supplementation for the prevention of kwashiorkor in Malawian children: randomised, double blind, placebo controlled trial. Brit Med J 2005; 330: 1109-1111.

3 Konotey-Ahulu FID. Kwashiorkor. Brit Med J 1991; 302: 180-181.

4 Konotey-Ahulu FID. Issues in kwashiorkor. Lancet 1994; 343: 548.

5 Williams CD. A nutritional disease of childhood associated with a maize diet. Arch Dis Child 1933; 8: 423-8.

6 Williams CD. Kwashiorkor – a nutritional disease of children associated with a maize diet. Lancet 1935; 2: 1151-52.

7 Williams CD. Kwashiorkor. JAMA 1953; 1280-85.

8 Williams CD. Social Medicine in Developing Countries (Millroy Lecture, Royal College of Physicians). Lancet 1958; 863-66.

9 Marsden PD. Kwashiorkor. Brit Med J 1990; 301: 1036-37.

10 Konotey-Ahulu FID. What Is AIDS? T-A'D Co. Watford 1996.

Competing interests: None declared

Source Link as http://www.bmj.com/cgi/eletters/330/7500/1095#106854 14 May 2005

BMJ  2007;335:210-211 (28 July), doi:10.1136/bmj.39268.553021.47

Views & reviews

Personal views

The perils of unmasking scientific truths

Felix I D Konotey-Ahulu, consultant physician

London W1N 1AA

felix@konotey-ahulu.com

To be chosen to deliver the keynote address at the Martin LutherKing Jr Foundation's award banquet took me completely by surprise—andto find that four bodyguards had been assigned me shook me rigid.Nobel laureates Linus Pauling and Max Perutz, along with HermannLehmann, Roland Scott, A C Allison, Graham Serjeant, and I,were among a select few invited to Philadelphia to receive anaward “for outstanding research in sickle cell anaemia.” Butwhy was I asked to deliver the keynote address, with Paulingand other abnormal haemoglobin heavyweights on the platform?

Was it, perhaps, because a foundation commemorating a blackperson wanted to “show off” the only black African among thosereceiving the award? Was it, perhaps, because I was then directorof the largest sickle cell disease clinic in the world? Or wasit because I was the only person to have traced hereditary diseasein his forebears, with named patients, generation by generationback more than three centuries? Or was it the statement madea few weeks back in New York by Professor Helen Ranney of theAlbert Einstein University College of Medicine: “There is nosingle clinical experience in the United States comparable tothat of Dr Konotey-Ahulu”?

Such “perhaps hypotheses” competed in my brain when I arrivedin Philadelphia, that day in 1972. I walked out of the hotelto post a letter to my wife in Ghana. Just as I was about tocross a road, I heard a voice behind me: “Doctor! Doctor!! DoNOT cross that road. Where are you going?” The hugely builtAmerican (black) took the letter from me before dropping thebombshell: “I am one of your four bodyguards.”

The award organisers, who came within minutes of my call, explainedthat the text of my lecture alerted them to several problems.I had distinguished between sickle cell trait and sickle celldisease (sickle cell anaemia) because the terms were being usedinterchangeably, with disastrous consequences, by people whoshould know better. People with the trait (one abnormal gene)cope better than people with two normal genes with falciparummalaria, which kills sickle cell disease patients (two abnormalgenes) quicker than people with two normal genes. I had questionedpublished work which claimed that black Army recruits exercisingat an altitude of 4000 ft collapsed and died because of sicklecell trait. I had asked: “How could black sickle cell traitsrun and beat the whole world at the Olympic Games at MexicoCity, at an altitude of 8000 ft (double the altitude at whichpeople with sickle traits had been said to perish)?”

Why did I need four bodyguards? The award organisers thoughtI needed protection because I used data from an article by JamesBowman, who had named seven insurance companies in the UnitedStates which loaded the premium of black people with sicklecell trait, thus making lots of money on healthy people, whoneeded to pay 150% for health insurance. I explained that insouthern Ghana, where one person in five has the sickle celltrait, one in five sudden deaths in adults from whatever causewould be in people with sickle trait. Moreover, to make insurancerecommendations for only “black” sickle cell trait, withoutmention of “white” sickle trait in people from Greece, Cyprus,Turkey, India, and Saudi Arabia—many of whom lived inthe United States—was not medical science.

The award organisers advised me to leave names of the insurancecompanies out of my lecture. Even so, they could not run therisk that I would be bumped off before the lecture. I cannotremember being able to eat anything at the banquet, but I wasglad to be able to shake hands later with the great and good.I left Philadelphia immediately afterwards—no sight seeingfor me.

How dangerous is it these days to stand firm for scientifictruth—or rather, how risky is it to criticise scientificuntruths? The Ghanaian herbalist Nana Drobo was found with bulletholes in his head, not long after successfully treating a dyingFrench man with AIDS who was sent to him from the Ivory Coast.And how safe is it to point out that some of the prescribedprotocols for global malaria control are not the best answerto the problem? How many bodyguards would be adequate protection,when huge amounts of money are at stake in global health protocols?Money in itself is not sinful—rather, as it says in theBible: “The love of money is the root of all evil.”

Published : BMJ [www.bmj.com]

Sickle-cell anaemia, “SS”, is just one of the 4 common phenotypes comprising sickle-cell disease, defined as possession of 2 globin gene variants at least one of which is the sickle gene.¹ The others are sickle-cell Haemoglobin C disease, “SC”, sickle-cell beta-thalassaemia, “Sβ-Thal”, and sickle-cell hereditary persistence of Fetal Haemoglobin, “SF_hereditary”. Ghana abounds in beta globin gene defects (qualitative and quantitative), which allowed me to study the clinical epidemiology of these 4 common phenotypes contemporaneously.² For non-technical readers I use the term AcheAche for Sickle Cell Disease in all its forms, ie the possession of an ‘Ache’ gene from both father and mother.

Dr Pavlü and colleagues wrote an article about a 50 year old lady (Jan 20 2007, p 246)³ which is inadvertently misleading because although sickle cell anaemia ‘SS’’ (which their patient has) is sickle-cell disease, not all sickle cell disease is sickle cell anaemia. In over one thousand consecutive sickle cell disease patients that I have personally followed up, although ECG changes occurred frequently during sickle crises in all 4 phenotypes it is my “impression that signs of acute coronary occlusion and myocardial infarction, reversible after crisis, are more a feature of Hb SC disease where blood viscosity is greater than Hb SS disease (Figs 25.4 and 25.5; Case Histories 84 and 85)”.²   

     One reason their 50-year-old woman developed myocardial infarction could be because of increased red cell mass from “intermittently needed exchange transfusion”.³ What was the low-level haematocrit that determined need for transfusion, and what was the upper level attained afterwards? In my opinion the 110 g/L Hb level that many haematologists in the UK and USA feel “SS” patients required for their steady state does more harm than good^{1 2 4}. I have both a sickle-cell anaemia (“SS”) patient who required to be bled to keep Hb level below 90 g/L otherwise he had thrombotic episodes² (Case history 21, page 482) and a “Sβ-Thal” adult whom I once sent to Professor Lucio Luzzatto for a second opinion, and who demanded periodic venesections (removal of blood) to get Hb level below 850 g/L to abort incipient sickle crisis. Therefore, when was this 50-year-old last transfused before her myocardial infarction? What was her serum Ferritin level?

     While I totally agree with the authors “myocardial infarction should be included in the differential diagnosis of chest pain in sickle-cell disease despite normal coronary angiography”³ I want information that can help prevent myocardial infarction in my patients. Circumstances are crucial in the welfare of sickle-cell disease patients.⁴ What, then, were the circumstances of this particular episode? What was this lady’s alcohol intake like? A 44-year-old Hb SC man I once described (Case history 85, page 503)² “drank Campari and brandy continuously for about 8 hours having had little to eat before going to bed. At 4 am the next morning (12.6.67) he was woken up with severe retrosternal pain ..”². Cardiologist Professor Silas Dodu not only confirmed myocardial infarction (ECG’s on pages 504 to 508 of my book)² but also made the correct phenotype diagnosis of Hb SC disease even before electrophoresis report arrived.² Warned off alcohol, he abstained for 12 months but “the patient died at home after a history of drinking spirits”.² Alcohol effect on the heart and lungs has been described in sickle-cell states⁵ so we need to know more about this lady.

Incidentally, insisting on raising transfusion levels of sickle cell disease patients to 110 g/dL (ie 11 grams per deciitre) as sometimes happens in the UK, continental Europe, and the USA can cause what I have come to call “hyperviscosity encephalopathy” which manifests itself with severe headaches, disorietaition, fits, and sometimes such mental symptoms as make doctors call in a psychiatrist. Not necessary. Just quickly remove a substantial amount of the transfused blood, to get the haemoglobin down to between 8 grams and 9 grams per decilitre. Watch the patient, more than you watch the patient’s blood.               

I declare that I have no conflict of interest except that I have a book ‘The Sickle Cell Disease Patient’ (Home Page) and I had 2 brothers and 1 sister with Sickle Cell Disease. My conflict of interest lies in the fact that any time I read about patients given Heroin or Morphine, or over-transfused, and causing complications, I assume them to be my own brothers and sisters. 

Felix I D Konotey-Ahulu

felix@konotey-ahulu.com

Kwegyir Aggrey Distinguished Professor of Human Genetics, Faculty of Science, University of Cape Coast, Ghana, and Consultant Physician & Haemoglobinopathy Genetic Counsellor, 10 Harley Street, London W1N 1AA, England

1    Ringelhann B, Konotey-Ahulu FID. Haemoglobinopathies and thalassaemias in  

     Mediterranean areas and in West Africa: historical and other perspectives 1910–1997 A

     Century Review. Atti  del’Accademia  della Science di Ferrara 1996; 74: 267-307.

2   Konotey-Ahulu FID. The sickle cell disease patient: natural history from a clinico-

     epidemiological study of the first 1550 patients of Korle Bu Hospital Sickle Cell Clinic. Watford:  

     Tetteh-A’Domeno, 1996.

3    Pavlü J, Ahmed RE, O’Regan DP, Patridge J, LefroyDC, Layton DM. Myocardial infarction in  

       sickle-cell disease. Lancet 2007; 369: 246.

4    Konotey-Ahulu FID. Sickle-cell disease and the patient. Lancet 2005; 365: 382-83.

5    Rubler S, Fleischer RA. Sudden death due to pulmonary thrombosis and infarction. Am J

      Cardiol  1967; 19: 867-73.