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Medical Specialties / Hematology / Anemia


Exome Sequencing and Unrelated Findings in the Context of Complex Disease Research: Ethical and Clinical Implications

Abstract: Exome sequencing has identified the causes of several Mendelian diseases, although it has rarely been used in a clinical setting to diagnose the genetic cause of an idiopathic disorder in a single patient. We performed exome sequencing on a pedigree with several members affected with attention deficit/hyperactivity disorder (ADHD), in an effort to identify candidate variants predisposing to this complex disease. While we did identify some rare variants that might predispose to ADHD, we have not yet proven the causality for any of them. However, over the course of the study, one subject was discovered to have idiopathic hemolytic anemia (IHA), which was suspected to be genetic in origin. Analysis of this subject's exome readily identified two rare non-synonymous mutations in PKLR gene as the most likely cause of the IHA, although these two mutations had not been documented before in a single individual. We further confirmed the deficiency by functional biochemical testing, consistent with a diagnosis of red blood cell pyruvate kinase deficiency. Our study implies that exome and genome sequencing will certainly reveal additional rare variation causative for even well-studied classical Mendelian diseases, while also revealing variants that might play a role in complex diseases. Furthermore, our study has clinical and ethical implications for exome and genome sequencing in a research setting; how to handle unrelated findings of clinical significance, in the context of originally planned complex disease research, remains a largely uncharted area for clinicians and researchers. ... Read more

Neurorestorative Treatments for Traumatic Brain Injury

Abstract: Traumatic brain injury (TBI) remains a major cause of death and permanent disability worldwide, especially in children and young adults. A total of 1.5 million people experience head trauma each year in the United States, with an annual economic cost exceeding $56 billion. Unfortunately, almost all Phase III TBI clinical trials have yet to yield a safe and effective neuroprotective treatment, raising questions regarding the use of neuroprotective strategies as the primary therapy for acute brain injuries. Recent preclinical data suggest that neurorestorative strategies that promote angiogenesis (formation of new blood vessels from pre-existing endothelial cells), axonal remodeling (axonal sprouting and pruning), neurogenesis (generation of new neurons) and synaptogenesis (formation of new synapses) provide promising opportunities for the treatment of TBI. This review discusses select cell-based and pharmacological therapies that activate and amplify these endogenous restorative brain plasticity processes to promote both repair and regeneration of injured brain tissue and functional recovery after TBI. ... Read more

New Classification of Acute Myeloid Leukemia and Precursor-related Neoplasms: Changes and Unsolved Issues

Abstract: The World Health Organization (WHO) classification of lympho-hematopoietic neoplasms is increasingly based on genetic criteria. Here, we focus on changes that, as compared to the 2001 edition, were introduced into the 2008 WHO classification of acute myeloid leukemia (AML) and related precursor neoplasms. The category of AML with recurrent genetic abnormalities was expanded to account for 60% of AML by adding three distinct entities, i.e., AML with t(6,9), inv(3), or t(1;22), and two provisional entities, i.e., AML with mutated NPM1 or CEBPA. These changes have greatly modified the approaches to diagnosis and prognostic stratification of AML patients. To emphasize the need of various parameters for diagnosis, including myelodysplasia (MD)-related cytogenetic abnormalities, history of myelodysplasia or myelodysplasia/myeloproliferative neoplasm, and multilineage dysplasia, the category of "AML with multilineage dysplasia" was re-named AML with MD-related changes. Finally, we describe the unique characteristics of myeloid proliferations associated with Down syndrome and blastic plasmacytoid dendritic cell neoplasm. ... Read more

A Molecular Trojan Horse: Hijacking the Bone Marrow to Treat Autoimmune Diseases

Abstract: Autoimmune diseases such as multiple sclerosis, type 1 diabetes, systemic sclerosis, and rheumatoid arthritis affect approximately 5% of the population and are characterized by a destructive immune response directed to self-tissues. Treatments are often designed to dampen the immune system and are therefore associated with unwanted side effects. A major challenge is to find a cure that does not compromise normal immune function. From our understanding of how the immune system develops, it is clear that mechanisms designed to eliminate or maintain control over self-reactive clones are critical for normal health. These key concepts form the crux of many experimental strategies currently aimed at abrogating the autoimmune response. In this review, we focus on the strategy of harnessing the bone marrow compartment through genetic manipulation directed at promoting ectopic autoantigen expression. Our experience with this strategy is presented in the context of reports in the literature and we argue for the potential benefit of translating this approach to the treatment of human autoimmune disease. ... Read more

When Is Enough Enough? The Need for a Robust Pipeline of High-quality Antimalarials

Abstract: Malaria kills an estimated one million people a year -- mostly children under 5. State-of-the-art medicines known as artemisinin combination therapies (ACTs) are available, and successfully cure up to 99% of patients. Additionally, insecticide-treated bed nets and insecticide spraying are helping to prevent the disease, while a vaccine is in clinical development. With all these tools at hand, you might ask why we need more new medicines. Why not just concentrate on improving the distribution of existing ones? Whilst access to medicines is clearly a major challenge, there are several reasons why new antimalarials are urgently needed -- and will continue to be needed until we have finally defeated the parasite. First, the emergence of drug resistance to any infectious disease treatment is inevitable. A range of medicines with varying mechanisms of action are needed to stem the tide of drug resistance as well as fill the gap when it takes hold. Second, malaria is a disease predominantly affecting children and expectant mothers. These vulnerable patient groups require medicines tailored to their needs with robust safety profiles. Third, of the five species of malarial parasites that infect humans, two can relapse, and there is currently no safe medicine to combat the relapse for all patients. Finally, in order to ultimately eradicate malaria, medicines are needed that go a step beyond simple treatment and break the transmission of the parasite from patient to patient. ... Read more

Hypoxia-inducible EPO production, a new approach to treating anemia

Anemia is a common disease in which the supply of red blood cells (RBCs) is inadequate. An important mechanism of anemia is the inadequate production of erythropoietin (EPO), the regulator of production of RBCs. A UK group developed a gene therapy protocol in which the murine Epo gene expression was controlled by a hypoxia-inducible element (HRE), and was tested in a transgenic mouse model (the first synopsis on this page). They hoped that their new methodology could be applied to human patients as an alternative or complementary therapy to the current treatment for anemia — life-long supplying of EPO protein ... Read more

Biotech and pharma shares hit a valley, came out ahead

U.S. financial markets accelerated on their downward trajectory in the period from mid-September to mid-October (2002). Dow Jones Industrial Average and S&P 500 reached their 5-year lows and the Nasdaq Composite Index touched a 6-year low. Investors fled from stocks like from the plague. Toward mid-October, U.S. shares rebounded strongly after mega-corporations like Citigroup, IBM, and Microsoft reported better than expected earnings and an affirmed outlook.

Biopharmaceutical companies “piggy-backed” the v-shaped ride along with the markets, with Amgen and Idec Pharmaceuticals leading the pack. Idec reported better than expected operational results on Oct. 16th owing to strong sales of its Rituxan, ... Read more

Pharmaceutical companies need to turn to biotech firms for growth opportunities

Pharmaceutical companies show frailty of their own research efforts. All noises aside, the real problem for big pharmaceutical companies right now is that they do not have new drugs with blockbuster potential going into the market to replace old ones, which are ceding or will cede sales to generics due to the loss of patent protection. But some former executives of pharmaceutical companies think there’s a solution: pharmaceutical companies should turn to biotech companies for opportunities.

Pharmaceutical companies may still be gun-shy lately, watching in tremor of the implosion of Bristol-Myers Squibb’s $2 billion partnership with ImClone [Discovery Medicine 1(1):4, Nov. ... Read more

News and quotes: Johnson and Johnson, Dr. Julie Gerberding, and Dr. Mark McClellan

Johnson & Johnson said in a letter to European physicians that there have so far been 141 cases of pure red blood cell aplasia after using Eprex, the company’s European version of Epogen (an Amgen brand). This side effect whereby the bone marrow stops making red blood cells is the condition that Eprex intends to help, not cause! Patients with this side effect have to rely on repeated transfusions to survive.

Johnson & Johnson said it does not know the cause of the side effect. It noted that most of the cases are associated with patients who received Eprex through skin ... Read more

Amgen's Aranesp is approved by the US; sets the stage for marketing battle with Johnson and Johnson

On September 19, US FDA approved Amgen’s anemia drug Aranesp for marketing in the US. The approval is great news for anemia patients, but also sets the stage for the new round of entrenched battle between Amgen and Johnson and Johnson.

Aranesp is the second generation drug of erythropoietin, a natural glycoprotein produced in kidney, which stimulates the production of red blood cells. Molecularly, Aranesp differs from its first generation drug Epogen (and Procrit) in that the 165-amino acid protein carries 5 N-linked oligosaccharide chains compared to 3 carried by Epogen. The 2 additional N-glycosylation sites are created from amino acid ... Read more

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