This Week In Sickle Cell News

Hello!

This week's selection of the latest in Sickle Cell Disease research features further strides being made towards understanding the complexities of the disease. They range from drug trials to unveiling molecular mechanisms of both SCD and other hemoglobinopathies.




Patient Care

Genomic Counseling in the Newborn Period: Experiences and Views of Genetic Counselors


Research

Molecular mechanisms underlying synergistic adhesion of sickle red blood cells by hypoxia and 
low nitric oxide bioavailability

Cellular, pharmacological, and biophysical evaluation of explanted lungs from a patient with sickle cell disease and severe pulmonary arterial hypertension.

Erythro-megakaryocytic transcription factors associated with hereditary anemia.

Ex-Vivo Cytoadherence Phenotypes of Plasmodium falciparum Strains from Malian Children with Hemoglobins A, S, and C

Subchronic Oral Toxicity Study of Decitabine in Combination with Tetrahydrouridine in CD-1 Mice

Methods and Compositions for Treatment of a Genetic Condition (Patent Application Publication)

A phase 2 trial of HQK-1001 in HbE-β thalassemia demonstrates HbF induction and reduced anemia (Letter to the Editor)

This Week In Sickle Cell News

Hello all!

Another week ends with more interesting revelations from the world of Sickle Cell Research. The potential translation of findings into useful clinical practices remains a key goal and driving force behind health sciences research. This week we offer publications relevant to patient care, as well as more basic science research findings related to Sickle Cell Disease and other hemoglobinopathies.


Patient Care

 An update on sickle cell nephropathy

Descriptive approach for sickle cell disease in Eastern of Algeria

The Utility of Routine Electrolytes in Patients with Sickle Cell Anemia Presenting with an Acute Pain Crisis

An Official American Thoracic Society Clinical Practice Guideline: Diagnosis, Risk Stratification, and Management of Pulmonary Hypertension of Sickle Cell Disease

Clinical potential of gene therapy: towards meeting the demand

Reticulocyte parameters: why should clinical laboratories evaluate and report them?

Sickle cell disease in sub-Saharan Africa: stakes and strategies for control of the disease.


Preoperative transfusion in patients with sickle cell disease to prevent perioperative complications: A systematic review and meta-analysis

Pediatric Hematology Providers on Referral for Transplant Evaluation for Sickle Cell Disease: A Regional Perspective

Research

A Short-Term Trial of Butyrate to Stimulate Fetal-Globin-Gene Expression in the ß-Globin Disorders

Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease

Hydroxycarbamide decreases sickle reticulocyte adhesion to resting endothelium by inhibiting endothelial Lu/BCAM through phosphodiesterase 4A activation

Excess adenosine A2B receptor signaling contributes to priapism through HIF-1α mediated reduction of PDE5 gene expression

Prevalence of Deletional Alpha Thalassemia and Sickle Gene in a Tribal Dominated Malaria Endemic Area of Eastern India

AKAP-Dependent Modulation of BCAM/Lu Adhesion on Normal and Sickle Cell Disease RBCs Revealed by Force Nanoscopy

This Week in Sickle Cell News

Another week and more exciting finds!

Publications

• First recorded case of haemoglobin SC in Sudan

          Excerpt:

Hb S is known to be prevalent in Sudan and was suggested to be more common in populations from Western tribes. On the other hand, Hb C is not as well documented as HbS in Sudan, but was recently reported in 2008  Interestingly, the current study showed two schoolgirls with HbSC, as their parents are carriers of HbAS and HbAC.

• α-Thalassemia Does Not Seem to Influence Erythrocyte Deformability in Sickle Cell Trait Carriers 

          Excerpt

 When compared with controls, sickle cell trait carriers showed no differences for any of the biochemical parameters analyzed (p > 0.05), but significantly lower hemoglobin (Hb) (p = 0.003), mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) (p < 0.001) levels, although no differences in erythrocyte deformability were observed at any of the shear stresses tested (p > 0.05). When comparing sickle cell trait carriers, with and without α-thal, no differences in erythrocyte deformability were observed (p > 0.05), in spite of the former showing lower MCV and MCH (p < 0.05) levels.

• Screening and Molecular Characterization of β-Thalassaemia Mutations in Parents and Siblings of β-Thalassaemia Major Patients.

          Excerpt

 The β-thalassaemic population (3–17%) in India has been used to reflect on blood safety. The prevalence of HIV-1/2, HCV and HBV in the Indian donor population, the limitations in accessing safe donors, quality of serological tests and the impact on repeat recipients is evaluated. The reports point to prevalence of ˜2% of viral diseases in the blood donor population, and the insufficiency of serology testing resulting in up to 45% TTIs in thalassaemics.

• Modulation of gamma globin genes expression by histone deacetylase Inhibitors: an in vitro study

         Excerpt

Increased levels of HbF can ameliorate the severity of the β-haemoglobin disorders, such as SCD and β-thalassaemia, which are major sources of morbidity and mortality worldwide. As a result, there has been a longstanding interest in developing therapeutic approaches for inducing HbF. Different classes of pharmacological agents (hypomethylating agents: 5-Azacytidine; HDAC inhibitors: butyrate and its derivatives; HC) have been tested both in vitro and in vivo (Atweh & Loukopoulos, 2001; Testa, 2009). Although the clinical outcome of SCD patients has improved considerably since the approval of HC for the treatment of SCD in 1998 (Platt, 2008), the impact of these new therapies on the natural history of β-thalassaemia was of only limited efficacy.

This Week in Sickle Cell News

Hello All!

The AfroSickleNet Project is one cog in the very large wheel that is the machinery of Sickle Cell Disease research. Every week, we will offer up a serving of news articles, papers, events and findings related to the disease from around the world.

This weeks selection:


Events

• Fifth International Symposium on Sickle Cell Disease in Central Africa: Hosted by the Global Sickle Cell Disease Network, under the theme  "Sickle Cell Disease in Central Africa: Clinics, Genetics and Environment"
  

Publications

•  Prediction of Fetal Hemoglobin in Sickle Cell Anemia Using an Ensemble of Genetic Risk Prediction Models.
•  Craniofacial features of patients with sickle cell anemia and sickle cell trait
• Infection in sickle cell disease: A review
• Current sickle cell disease management practices in Nigeria
• Beyond Malaria — Causes of Fever in Outpatient Tanzanian Children

The Challenges of Research in Africa: Expert Perspectives

Hello and welcome to the AfroSickleNet Blog!

Following the inception of the AfroSickleNet Project in October 2013, a lively debate occurred between the various investigators in the US and those of the collaborating centers in Ghana, Nigeria, Cameroon and Kenya. This debate focused on the  challenges associated with carrying out research on the African continent, and explored ideas to move the practice forward, as well as on how to make the essential step of translating research findings to patient care. Following is a transcript of the conversation:

02/04/2014

Dear Colleagues, 

I hesitate to speak up first as a person who is still planning his first trip to Africa, but I suggest that highest priority studies to be conducted in Africa should be those that lead quickly to better treatment of sickle cell disease. The huge numbers of sickle cell patients and resource-poor collaborating centers should gain direct health benefits from research. I certainly value basic and translational research and I devoted a lot of my career to bench research. However, I think that basic and translational studies can be ancillary to clinical work or clinical trials. 

Sincerely,

Lewis Hsu, MD, PhD  

   

Lewis, 

First, let me say I appreciate you this on the table.  There could be no better use for this forum than to discuss this issue.  It’s simply intellectually dishonest and morally inexcusable not to struggle with this question.

Let me try not to wrap my argument up into some convoluted logic.   Most people on this list are biomedical scientists, and we make our living off of NIH grants.  We hope, at least in the long run, that our work does something to improve health, but in truth most of us - aside from trials - see very little of that.  I have spent a lot of time studying the genetics of hypertension in Africa. .  to what end?   But at the same time most of us don't have access to any financial resources other than grants.  So - speaking again for myself - the choice is to try to do as much as we can to improve the science and practice of public health and medicine in Africa at the margins of our grants - that is, some training of new scientists, building awareness through papers, professional organizations, etc.  But we know that has little impact.  At the session on sickle cell organized by the NIH 2 yrs. ago at ASH in San Diego I tried to make the point that research in Africa that would make a difference must take on the task of improving care - if just to make it possible to collect high quality data.  Some of you who were there may remember that the NIH Director rose immediately to make it clear to those with any delusions, that job is not the NIH's mission. We could just step off the NIH treadmill, but then what do we bring to the table?  Some of us will have the resources, the clinical skills, and political influence that make it possible to improve patient care, but most of us don't.  And there are innumerable small scale volunteer organizations operating in Africa, and on the whole they do a lot of good, I don't see that as our role.

In the end, I think - most of us at least - will have to contribute with the skills and influence we have - namely biomedical research.  We need to use whatever influence and resources we get through that means to make a lot of noise and put sickle cell much more on the agenda.   At the same time, I agree entirely - we should challenge ourselves to use our privileged positions to do more.  From what I know - I think the work that David Weatherall has done for inherited anemias is an excellent example.  Or Graham Serjeant's contribution in Jamaica.  The work that KOF and others are doing on newborn screening and studies of infection in Ghana are in the same category.  The Doris Duke trial in Ibadan should make some small impact on patient care and the work now started in Kumasi should have an even bigger pay-off for patient care.

But this group was assembled to write a grant. . or 2 or 3.  Within that structure, as originally conceived, attempts to directly improve care will remain at the margin.  How do we change that, and where could we get resources to do more?  Without an organizational base, say in a professional society, or some formal program, like PEPFAR, I'm not sure what we can do.

But I am sure that others on this list will have useful ideas about how we could do more.  The best I can come up with is to try to create "Centers of Excellence" at the universities where we are connected to improve training, build the capacity to deliver  - as close as possible - standard of care as practiced in the US and elsewhere, and develop lab capacity.  I know in other field’s conferences and short courses in clinical up-dates have been used, and if we had the funds we could do that.  Personally I favor putting effort into Centers of Excellence first.

But, having said all that, I think it is patently obvious that I am not the person best qualified to address the question you raise.  I very much agree that the best outcome would be to move forward on 2 parallel tracks - one based on NIH-funded research and one devoted to improving diagnosis and care.  I think I can do something useful about the former, but not the latter.

Open for comments  . . .

Richard Cooper, MD 

Hello ALL: 

I just arrived from Ghana yesterday to be welcomed by yet another snow storm to hit the northeast. Solomon and Kofi Anie arrived in Ghana to continue research planning with Ellis just as I was getting ready to leave. They deserve their escape from Pittsburgh freeze and London cold rain, respectively.

In this chill, I am warmed by this lively discussion. Lewis' point is well taken but I believe the responsibility of research investigators is to pursue questions that ultimately lead to improved health care. Sometimes, research investigators get the opportunity to conduct clinical trials the results of which may lead to improvement in clinical care.

From my knowledge, the major problem facing people with SCD in Africa is failure of governments to see SCD as a major public health issue. For example, newborn screening and anti-microbial prophylaxis of young children with SCD are interventions by most African countries. The fact that no African country has fully implemented these interventions is because the public health services have failed to recognize the impact of SCD on child mortality. That situation can hardly be blamed on the biomedical research community.

It clearly takes another set of skills and tolerance to convince a Minister of Health that an intervention such as newborn screening for SCD is as important as HIV prevention. HIV prevention comes with millions of cash, dozens of vehicles and other perks from international donors; newborn screening for SCD is not supported by any major international donor organizations. Perhaps we could recruit marketing experts to find ways to sell such proven interventions to African governments.

It is always difficult to target the outcome of basic research as important findings often lead to unintended and unexpected benefits. Most clinicians in Africa do not implement penicillin prophylaxis because they are either unaware of the published research on the subject or, they do not believe that the findings of a study conducted in the US apply to Africa. Is it the responsibility of the NIH to "sell" the results of the Penicillin Prophylaxis Study to developing countries? Perhaps, but, soccer fans in Ghana are as fanatic about the English Premier League as are the diehard fans living in Liverpool. One would expect that SCD fans in the clinician communities in Africa would devour research findings applicable to their patients as much the soccer fans do the scores and intricacies of the EPL.

Engaging young Africans in biomedical research - basic, translational, or clinical - can help enhance the atmosphere that will encourage African clinicians to see directly the benefits of research in their work. If research is conducted only by "foreign" scientists, it is likely that African clinicians will believe that their work derives no fruits from research no matter how low those fruits may be hanging.

I would urge us to proceed on all fronts of biomedical research as long as we include African collaborators in planning and execution of projects, African subjects in clinical trials, and African trainees to learn how research questions are developed and answered. The reality on the ground will dictate how public health services will be provided.

Lewis, you are welcome to visit Ghana where I am working with the 16th Minister of Health in 18 years of developing the newborn screening program! That is a challenge beyond all of us.

Kwaku Ohene-Frempong, MD 

This is a great discussion.

NIH mission is clear. Labs based outside Africa have set their missions too. A network such as this is being pooled together to write a research grant. I believe the idea should proceed considering the mission of the potential funding sources. 

As researchers from Africa, we should set our mission considering our potentials. Having a common mission, can enable us work with other collaborators outside Africa. As a network, we can also be able to apply for grants that may have direct benefit to the people from other foundations.

I just feel that as researchers from Africa, we should do more to demonstrate our commitments. One way is to start "A Regional Centers of Excellence" and this center can collaborate or sign a MOU with any local university and hospital to offer short courses such as a genetic counseling or medical genetics. Starting a program like this will have a huge benefit to the people in terms of prevention of genetic conditions, with a center working closely with the hospital and university; we can also be actively involved in biomedical research that fits the mission of NIH and others.

I am really keen to know what is going on in Ghana and Nigeria and other African countries as far as their own initiatives are concern. Sharing this can enable us come up with a common mission. I am very sorry to say that we have done very little in Kenya.

I am also keen to know thoughts on starting some  "Centers of Excellence".  What could be the structure of this center so that it remains focused on its mission?

As noted, research aims at improving patient’s conditions and I feel selection and population genetics have not been exploited to identify drug targets for sickle cell disease and I feel idea in the first discussion paper has a lot of potentials.

George Ayodo 

Dear all,

A few personal anecdotes: when I met Stylianos Antonarakis (that  described the origin sickle haplotypes...) for an interview as medical genetic intern, he asked me if African/Cameroon doesn't had others priorities than Medical genetics specialists...My answer  was 'if genetics was good for Switzerland it should be good for anywhere...in addition, he will need to train me so that I could appropriately evaluate the need of medical genetics in Africa'...he smiled and said you have the position...

Our first lab in Yaoundé was developed on the back of HIV prevention program; we couldn't convince the Minister to have a lab for molecular diagnosis of monogenic disease..., but he was ready to fund a lab to apply molecular technology for diagnosis of HIV in the scheme of prevention of vertical transmission and transfusion security...

We then used the available equipment (for HIV initially) to develop the molecular diagnosis of SCD before birth, as a point of entry of genetic Medicine in Cameroon. The Genetic unit, created in 2007, has developed beyond the HIV molecular detection and SCD, at   least two other on-going programs that have a direct impact on prevention and treatment of diseases (National urogenital malformation program and congenital of hearing loss program...).  On the training front at least 10 MD thesis, and three current trainees in Genetic medicine to ensure sustainability...Of course this is a very modest experience and not always easy journey,  as we were forced by the circumstances to  strategically retreat to South Africa, but keeping in mine our ultimate goals...

I'm strongly convinced that equipping Africa and African based scientist with advance skills in biomedical research, to serve the purpose of public health priority like SCD, will have a direct impact on care and prevention non only of SCD but of various other conditions...Biomedical research will not solve the all problems of care SCD patients in Africa, but without biomedical research many problems of SCD care will not be solved in Africa.

The critical issue here will be to make sure that, at all the stages, capacity is built and the community is engaged in each and all the performance sites. Civil society is full of vibrant and very committed people here, who could serve our SCD advocacy cause. Training and Community Engagement should be budgeted from the early beginning to ensure this endeavour. The NIH and other funders should be sensible to this.

Prof. Ambroise Wonkam, MD, DmedSc 

02/05/2014

Great point about engaging young Africans in all of our research.

Victor R. Gordeuk, MD 

02/06/2014

Ambroise, 

That's more than an anecdotes, it’s a short story that captures much of

the reality of this experience.  I certainly agree, and it is obvious

that much of the progress, certainly in genetics, has come from engaging

young African scientists.

At this point we have progressed well beyond Lewis's opening remarks.  I

think the point was well made by KOF, however, that progress in

advancing patient care will be slow.  We need to constantly look for

opportunities but accept reality and be patient.  I think one of the

useful things we can do immediately is provide training for clinical

care, such as ultrasound etc.  But that will have to be supported by

each of our institutions somehow.

It may be premature but I think it should be possible to spell out the

concept of a Center of Excellence as George discussed.  If there are

volunteers who would like to join me we could pull together a draft

statement on what that would look like.  I think we already have the

pieces, but they are scattered across the clinical sites and there is no

immediate candidate for such a Center at the moment.  But having a clear

idea of the concept would help - who knows, we might sit next to Bill

Gates on the plane someday.  (Oh, that's right; I guess he flies in his

own plane.)

One other idea I would like to propose. I know there are several

projects that have been discussed that are at a point where a small

scale or pilot study could be started.  (E.g., Neil's idea about selection

and SS, assessing HRQL, assessing hemolysis physiology).  If someone

wants to come forward as the leader/PI of a pilot I think we at Loyola

could handle the logistics (IRB, sample collection etc.).

Finally, Ambroise makes the point that we need to involve new young

eager scientists/clinicians.  Can I ask those of you at clinical sites

to think hard and see if you have a candidate?  If you did, we should

form a separate group to discuss their training needs and see if we can

invent a plan to help them win that trip to Switzerland like Ambroise

did. 

Richard Cooper, MD