bluuebunny/crossref_metadata_2025 huggingface dataset:
Congenital neutropenia
Authors: Klein Christoph
Published: December 2009

Congenital neutropenia comprises a variety of genetically heterogeneous phenotypic traits. Molecular elucidation of the underlying genetic defects has yielded important insights into the physiology of neutrophil differentiation and function. Non-syndromic variants of congenital neutropenia are caused by mutations in ELA2, HAX1, GFI1, or WAS. Syndromic variants of congenital neutropenia may be due to mutations in genes controlling glucose metabolism (SLC37A4, G6PC3) or lysosomal function (LYST, RAB27A, ROBLD3/p14, AP3B1, VPS13B). Furthermore, defects in genes encoding ribosomal proteins (SBDS, RMRP) and mitochondrial proteins (AK2, TAZ) are associated with congenital neutropenia syndromes. Despite remarkable progress in the field, many patients with congenital neutropenia cannot yet definitively be classified by genetic terms. This review addresses diagnostic and therapeutic aspects of congenital neutropenia and covers recent molecular and pathophysiological insights of selected congenital neutropenia syndromes.
Alpha thalassemia major—new mutations, intrauterine management, and outcomes
Authors: Vichinsky Elliott P.
Published: December 2009

Alpha thalassemia disorders are a group of hereditary anemias caused by absent or decreased production of the alpha chain of hemoglobin. Hemoglobin Bart’s hydrops fetalis is usually a fatal in-utero disease caused by absence of the alpha genes. However, the molecular and genotypic expression of hemoglobin Bart’s varies and increasing numbers of births are being reported. Population screening and prenatal diagnosis of at-risk couples is essential but often not performed. Most affected pregnancies are often undetected, resulting in severe fetal and maternal complications. Noninvasive monitoring by Doppler ultrasonagraphy with intrauterine transfusion therapy has changed the prognosis for this disorder. These advances in intrauterine and postnatal therapy have resulted in ethical dilemmas for the family and the provider.
The role of NOTCH1 signaling in T-ALL
Authors: Ferrando Adolfo A.
Published: December 2009

The identification of activating mutations in NOTCH1 in over 50% of T-cell acute lymphoblastic leukemias (T-ALL) has generated major interest in the elucidation of the mechanisms of transformation downstream of oncogenic NOTCH and in the targeting of the NOTCH signaling pathway in this disease. Small molecule γ-secretase inhibitors (GSIs) block NOTCH1 signaling in T-ALL lymphoblasts, yet the clinical development of GSIs has been held back by the development of gastrointestinal toxicity and their weak antileukemic effects against human T-ALL. However, new therapeutic strategies aiming to optimize the use of anti-NOTCH1 therapies for T-ALL, including combination therapies with molecularly targeted drugs and glucocorticoids, have started to emerge as a result of improved understanding of the molecular mechanisms that mediate the effects of GSIs in leukemic cells and the intestinal epithelium. This review focuses on the molecular basis of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 and clinical significance of NOTCH1 mutations in T-ALL.
Evolving paradigms in the therapy of Philadelphia chromosome–negative acute lymphoblastic leukemia in adults
Authors: Litzow Mark R.
Published: December 2009

Important studies challenging previous approaches to the treatment of adults with Philadelphia chromosome–negative acute lymphoblastic leukemia (ALL) have emerged in the past decade. Donor versus no donor comparisons of allogeneic transplant highlight a potent graft-versus-leukemia effect in ALL, and the application of reduced-intensity conditioning transplants may exploit this effect while reducing non-relapse mortality. The adoption of the use of pediatric intensity-type regimens in adolescents and young adults shows promise to improve outcomes in this population. New therapeutic targets such as mutations in NOTCH1 in T-cell ALL and CD22 in pre-B ALL are being exploited in clinical trials. The application of molecular techniques and flow cytometry to quantitate minimal residual disease will allow further stratification of patients by risk. Although the outcomes of adults with ALL lag behind the stunningly successful results seen in children, new paradigms and new discoveries bring hope that this disparity will steadily lessen.
Optimal induction and post-remission therapy for AML in first remission
Authors: Rowe Jacob M.
Published: December 2009

Approximately 300,000 patients in the world are diagnosed annually with acute myeloid leukemia (AML). The median age at presentation has been steadily increasing over the past few decades and now is approaching 70 years. Although considerable progress has been made over the past 3 decades in the therapy of AML, two thirds of young adults still die of their disease. The therapy of AML, unlike acute lymphoblastic leukemia (ALL), is based on maximally tolerated induction and post-remission therapy, all given within a few months from diagnosis. While complete remission can be achieved in the majority of young patients, ultimate cure of the disease depends on disease eradication through the administration of post-remission therapy. This is most often done with intensive chemotherapy. Harnessing the immunologic effect of graft-versus-leukemia, as in allogeneic transplantation, has further improved the outcome for many patients. Treatment of older adults, representing the majority of patients with AML, remains quite unsatisfactory. While 40% to 50% can achieve a complete remission, less than 10% are long-term survivors, and the cure rate of older patients has only minimally improved over the past three decades. Significant progress in the treatment of this age group is urgently required. New and targeted agents have much promise, but a definitive clinical role for these has yet to be conclusively established.
Monoclonal B-cell lymphocytosis
Authors: Rawstron Andy C.
Published: December 2009

The incidence and presenting features of chronic lymphocytic leukemia (CLL) have changed significantly over the last century. Routine diagnostic techniques can now detect very low levels of CLL phenotype cells. Monoclonal B-cell lymphocytosis (MBL) is a relatively recent diagnostic category encapsulating individuals with an abnormal B-cell population but not meeting the diagnostic criteria for a B-cell malignancy. This review focuses on CLL-type MBL, which represents the majority of MBL cases identified in diagnostic laboratories. CLL-type MBL has a phenotype identical to CLL and shares the same chromosomal abnormalities even at the lowest levels detectable. Recent evidence suggests that the immunoglobulin gene usage plays a key role in whether the abnormal cells will develop in significant numbers. In most cases, CLL-type MBL is a stable condition with only 1% per year among those presenting for clinical attention developing progressive disease requiring treatment, although suppressed immune function may have a more significant impact on outcome.
State-of-the-art treatment of chronic lymphocytic leukemia
Authors: Hallek Michael
Published: December 2009

The last decade has produced rapid progress in the management of chronic lymphocytic leukemia (CLL). Fludarabine, bendamustine and two monoclonal antibodies, alemtuzumab and rituximab, have been approved by the European and/or American regulatory agencies. Several, novel monoclonal antibodies targeting CD20, CD23 or CD40, as well as drugs designed to interfere with proteins regulating the cell cycle, apoptotic machinery, or leukemic microenvironment (eg, flavopiridol, oblimersen, or lenalidomide), are currently being tested in clinical trials. Furthermore, the increased experience with reduced-intensity allogeneic progenitor cell transplantation allows offering this option to physically fit patients. In addition, new prognostic markers that may influence therapeutic decisions have been identified. This review attempts to summarize the current use of these different modalities in CLL therapy.
Asthma and sickle cell disease: two distinct diseases or part of the same process?
Authors: Field Joshua J. , DeBaun Michael R.
Published: December 2009

A physician diagnosis of asthma in children and adults with sickle cell disease (SCD) has been associated with increased rates of pain and acute chest syndrome (ACS) episodes and premature death. Despite the clinical significance of a doctor’s diagnosis of asthma in individuals with SCD, the criteria for a physician diagnosis of asthma are not well defined. Many features of asthma are common in individuals with SCD, including symptoms of wheezing, obstructive lung disease and airway hyper-responsiveness. However, it is not clear if these signs and symptoms of asthma reflect a physician diagnosis of asthma, or if these asthma features are related to SCD. Further complicating the diagnosis of asthma in children with SCD is the significant overlap in clinical manifestations between an asthma exacerbation and an ACS episode. Evidence supporting the concept that asthma and SCD are separate co-morbid conditions includes a similar prevalence of asthma between children with SCD and those in the general population and the observation that asthma is inherited in a familial pattern in the families of children with SCD. In contrast, there is significant evidence that asthma-like features may be associated with SCD without a diagnosis of asthma, including a higher than expected prevalence of airway hyper-responsiveness and obstructive lung disease. Regardless of whether SCD and asthma are distinct or overlapping co-morbid conditions, we recommend a systematic and complete evaluation of asthma when the diagnosis is suspected or when patients have multiple episodes of pain or ACS.
Monitoring disease response to tyrosine kinase inhibitor therapy in CML
Authors: Hughes Timothy P. , Branford Susan
Published: December 2009

The remarkable progress made in the treatment of chronic myeloid leukemia (CML) over the past decade has been accompanied by steady improvements in our capacity to accurately and sensitively monitor response to therapy. After the initial target of therapy, complete cytogenetic response (CCR), is achieved, peripheral blood BCR-ABL transcript levels measured by real-time quantitative reverse transcriptase PCR (RQ-PCR) define the subsequent response targets, major and complete molecular response (MMR and CMR). The majority of patients on first-line imatinib therapy achieve a “safe haven” defined as a confirmed MMR, but 20% to 30% stop imatinib due to intolerance and/or resistance. Many imatinib-resistant patients can be effectively treated with second generation tyrosine kinase inhibitors (TKIs), but the actual drug selected should be based on the resistance profile of each inhibitor, in addition to issues of tolerance and disease phase. The main purpose of monitoring response with cytogenetics and RQ-PCR is to identify patients likely to achieve better long-term outcome if they are switched early to second-line therapy, either another TKI or an allograft. Mutation screening is most valuable in cases of loss of response to imatinib or a second-line TKI, but there are other settings where a high yield of mutations may justify regular mutation screening.
The 2008 WHO classification of lymphomas: implications for clinical practice and translational research
Authors: Jaffe Elaine S.
Published: December 2009

The 4th edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues published in 2008 builds upon the success of the 2001 3rd edition; new entities are defined, and solutions for problematic categories are sought. Recent studies have drawn attention to the biological overlap between classical Hodgkin lymphoma (CHL) and diffuse large B-cell lymphomas (DLBCL). Similarly, there is a greater appreciation of the borderlands between Burkitt lymphoma and DLBCL. Strategies for the management of these borderline lesions are proposed. Additionally, age-specific and site-specific factors play an important role in the definition of several new entities, which also have biological underpinnings. Among the peripheral T-cell lymphomas (PTCL), more precise definitions were introduced for several entities, including anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, enteropathy-associated T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. Several new variants of primary cutaneous T-cell lymphomas are proposed. Finally, the subclassification and categorization of the most common lymphoma subtypes, follicular lymphoma (FL) and DLBCL, were altered to enhance diagnostic accuracy and aid in clinical management. The 2008 WHO classification also draws attention to early events in lymphomagenesis. These lesions help delineate the earliest steps in neoplastic transformation and generally mandate a conservative therapeutic approach. The 2001 classification was rapidly adopted for clinical trials and successfully served as a common language for scientists comparing genetic and functional data. The modifications made in the 2008 classification are the result of this successful partnership among pathologists, clinicians, and biologists, but are only a stepping stone to the future.
Current treatment standards and emerging strategies in mantle cell lymphoma
Authors: Dreyling Martin , Hiddemann Wolfgang ,   for The European MCL Network
Published: December 2009

Mantle cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphomas characterized by the chromosomal translocation t(11;14)(q13;q32) and nuclear cyclin D1 overexpression in the vast majority of cases. Most patients present with advanced stage disease, often with extranodal dissemination, and pursue an aggressive clinical course in the majority of cases. Recent improvement has been achieved by the successful introduction of monoclonal antibodies and dose-intensified approaches including autologous stem cell transplantation (ASCT) strategies. With the exception of allogeneic hematopoietic stem cell transplantation, current treatment approaches are non-curative and the corresponding survival curves are characterized by a delayed, but continuous decline and a median survival of 4 to 6 years. However, recently a subset (15%) of long-term survivors have been identified with a rather indolent clinical course even after conventional treatment strategies only. Emerging strategies such as proteasome inhibitors, IMIDs, mTOR inhibitors and others are based on the dysregulated control of cell cycle machinery and impaired apoptotic pathways. Monotherapy of these compounds achieves efficacy comparable to conventional chemotherapy in relapsed MCL, and combination strategies are currently being investigated in numerous trials; however, their introduction into clinical practice and current treatment algorithms remains a challenge.
Transplantation in adult ALL
Authors: Goldstone Anthony H. , Rowe Jacob M.
Published: December 2009

The value of the allogeneic graft-versus-leukemia effect in adult acute lymphoblastic leukemia (ALL) has now been conclusively demonstrated and confirmed. While this is true for adults in all age groups, it may not be the best clinical option for young adults for whom increasingly intensive pediatric protocols are clearly of benefit. On the other hand, there is potentially wider applicability of allogeneic donor transplantation for adults 25 to 45 years old, for whom matched unrelated donors may be as safe and effective as sibling donors, and for the patient older than 45 years for whom reduced-intensity conditioning may be a promising way forward.

Since the treatment-related mortality of allogeneic transplantation remains significant, careful selection of patients is mandatory. Patients with the Philadelphia chromosome, those with t(4;11) and those with a complex karyotype remain transplant candidates, and allogeneic transplantation remains the best option for salvage, where achievable, in a remission beyond first.

As in childhood ALL minimal residual disease studies may be extremely useful in predicting outcome and, therefore, strategy, but at present there are less definite data in adults. Clinical indications to harness the allogeneic effect will mature as the true value of pediatric protocols in adult patients and the safety and efficacy of a sibling, unrelated and reduced intensity transplant emerge in this disease.
Allotransplantation for chronic lymphocytic leukemia
Authors: Dreger Peter
Published: December 2009

Efforts to develop curative treatment strategies for chronic lymphocytic leukemia (CLL) in recent years have focused on allogeneic stem cell transplantation (alloSCT). The crucial anti-leukemic principle of alloSCT in CLL appears to be the immune-mediated anti-host activities conferred with the graft (graft-versus-leukemia effects, GVL). Evidence for GVL in CLL is provided by studies analyzing the kinetics of minimal residual disease on response to immune modulation after transplantation, suggesting that GVL can result in complete and durable suppression of the leukemic clone. AlloSCT from matched related or unrelated donors can overcome the treatment resistance of poor-risk CLL, ie, purine analogue refractory disease and CLL with del 17p-. Even with reduced-intensity conditioning, alloSCT in CLL is associated with significant mortality and morbidity due to graft-versus-host disease, which has to be weighed against the risk of the disease when defining the indication for transplantation. Therefore, it can be regarded as a reasonable treatment option only for eligible patients who fulfill accepted criteria for poor-risk disease. If alloSCT is considered, it should be performed before CLL has advanced to a status of complete refractoriness to assure an optimum chance for a successful outcome. Prospective trials are underway to prove whether allo-SCT can indeed change the natural history of poor-risk CLL.
Allogeneic stem cell transplantation in follicular lymphoma: recent progress and controversy
Authors: van Besien Koen
Published: December 2009

Allogeneic stem cell transplantation (allo HCT) is a curative treatment for follicular lymphoma, but is hampered by a relatively high treatment-related mortality and by difficulties in identifying high-risk groups for whom transplant is warranted. Results with myeloablative conditioning have improved, but the field has shifted largely to reduced-intensity conditioning and non-myeloablative transplantation, though morbidity and mortality are also substantial. Some groups have investigated T cell–depleted transplantation, which results in a low rate of chronic graft-versus-host disease (GVHD) and, in most studies, excellent rates of disease control. Overall, outcome after alloHCT for follicular lymphoma correlates more with disease status, with performance status and with comorbidities than with any particular conditioning regimen used. For patients with chemotherapy-sensitive disease, the treatment-related mortality has stabilized in the 15% to 20% range and, depending on the method of GVHD prophylaxis and the donor type, there is an additional 20% to 60% incidence of chronic GVHD. For patients with chemotherapy-refractory disease, both treatment-related mortality and recurrence rates are much higher, but their prognosis is dismal with other treatments and some may be cured, particularly with myeloablative transplants. Ongoing studies focus on improving conditioning regimens, on prevention of disease recurrence and on decreasing chronic GVHD.
Therapeutic potential of JAK2 inhibitors
Authors: Verstovsek Srdan
Published: December 2009

The discovery of an activating tyrosine kinase mutation JAK2V617F in myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) has resulted in the development of JAK2 inhibitors, of which several are being evaluated in phase I/II clinical studies. It is important to recognize that because the V617F mutation is localized in a region outside the adenosine triphosphate (ATP)-binding pocket of JAK2 enzyme, ATP-competitive inhibitors of JAK2 kinase (like the current JAK2 inhibitors in the clinic) are not likely to discriminate between wild-type and mutant JAK2 enzymes. Therefore, JAK2 inhibitors, by virtue of their near equipotent activity against wild-type JAK2 that is important for normal hematopoiesis, may have adverse myelosuppression as an expected side effect, if administered at doses that aim to completely inhibit the mutant JAK2 enzyme. While they may prove to be effective in controlling hyperproliferation of hematopoietic cells in PV and ET, they may not be able to eliminate mutant clones. On the other hand, JAK inhibitors may have great therapeutic benefit by controlling the disease for patients with MPNs who suffer from debilitating signs (eg, splenomegaly) or constitutional symptoms (which presumably result from high levels of circulating cytokines that signal through JAK enzymes). Indeed, the primary clinical benefits observed so far in MF patients have been significant reduction is splenomegaly, elimination of debilitating disease-related symptoms, and weight gain. Most importantly, patients with and without the JAK2V617F mutation appear to benefit to the same extent. In this review we summarize current clinical experience with JAK2 inhibitors in MPNs.
The changing classification of myelodysplastic syndromes: what’s in a name?
Authors: Steensma David P.
Published: December 2009

What is the most sensible way of organizing the disorderly spectrum of acquired marrow failure states collectively known as the myelodysplastic syndromes (MDS)? While the 2008 version of the World Health Organization classification is the current standard, the recent proliferation of MDS prognostic tools illustrates the usefulness of supplemental information for clinical purposes. Many cases of acquired bone marrow failure do not fit cleanly into established MDS categories, yet an alternative diagnosis is not apparent. The term “idiopathic cytopenias of undetermined significance” (ICUS) has been proposed to describe these cases, but there is a paucity of information about the natural history of ICUS. New data on the natural history of MDS associated with a broad range of cytogenetic abnormalities that were not included in the International Prognostic Scoring System (IPSS), as well as the emerging picture of karyotypically occult DNA changes, promise to inform future classifications.
Supportive care and chelation therapy in MDS: are we saving lives or just lowering iron?
Authors: Leitch Heather A. , Vickars Linda M.
Published: December 2009

The myelodysplastic syndromes (MDS) are characterized by cytopenias and risk of transformation to acute myeloid leukemia (AML). Although new treatments are available, a mainstay in MDS remains supportive care, which aims to minimize the impact of cytopenias and transfusion of blood products. Red blood cell (RBC) transfusions place patients at risk of iron overload (IOL). In beta-thalassemia major (BTM), IOL from chronic RBC transfusions inevitably leads to organ dysfunction and death. With iron chelation therapy (ICT), survival in BTM improved from the second decade to near normal and correlated with ICT compliance. Effects of ICT in BTM include reversal of cardiac arrhythmias, improvement in left ventricular ejection fraction, arrest of hepatic fibrosis, and reduction of glucose intolerance.

It is not clear whether these specific outcomes are applicable to MDS. Although retrospective, recent studies in MDS suggest an adverse effect of transfusion dependence and IOL on survival and AML transformation, and that lowering iron minimizes this impact. These data raise important points that warrant further study. ICT is potentially toxic and cumbersome, is costly, and in MDS patients should be initiated only after weighing potential risks against benefits until further data are available to better justify its use. Since most MDS patients eventually require RBC transfusions, the public health implications both of transfusion dependence and ICT in MDS are considerable. This paper summarizes the impact of cytopenias in MDS and treatment approaches to minimize their impact, with a focus on RBC transfusions and their complications, particularly with respect to iron overload.
Overview of gene therapy clinical progress including cancer treatment with gene-modified T cells
Authors: Brenner Malcolm K. , Okur Fatma V.
Published: December 2009

It is now twenty years since the first legal gene transfer studies were approved, and there has been considerable disappointment in the slow rate of progress that followed the initial studies. Gradually, however, as the limitations of available vectors are acknowledged and overcome, and with advances in our understanding of the molecular and cell biology of genetic diseases and of cancer, unequivocal successes are now being reported. In this paper we describe the remaining major roadblocks to successful gene therapy and outline approaches to overcome them. We also illustrate how genetically modified immune system cells are already being used for the effective treatment of hematological and other malignancies, and how these approaches are being modified so that they can be effective in treating a broader range of malignancies.
Ten years of gene therapy for primary immune deficiencies
Authors: Aiuti Alessandro , Roncarolo Maria Grazia
Published: December 2009

Gene therapy with hematopoietic stem cells (HSC) is an attractive therapeutic strategy for several forms of primary immunodeficiencies. Current approaches are based on ex vivo gene transfer of the therapeutic gene into autologous HSC by vector-mediated gene transfer. In the past decade, substantial progress has been achieved in the treatment of severe combined immundeficiencies (SCID)-X1, adenosine deaminase (ADA)-deficient SCID, and chronic granulomatous disease (CGD). Results of the SCID gene therapy trials have shown long-term restoration of immune competence and clinical benefit in over 30 patients. The inclusion of reduced-dose conditioning in the ADA-SCID has allowed the engraftment of multipotent gene-corrected HSC at substantial level. In the CGD trial significant engraftment and transgene expression were observed, but the therapeutic effect was transient. The occurrence of adverse events related to insertional mutagenesis in the SCID-X1 and CGD trial has highlighted the limitations of current retroviral vector technology. For future applications the risk-benefit evaluation should include the type of vector employed, the disease background and the nature of the transgene. The use of self-inactivating lentiviral vectors will provide significant advantages in terms of natural gene regulation and reduction in the potential for adverse mutagenic events. Following recent advances in preclinical studies, lentiviral vectors are now being translated into new clinical approaches, such as Wiskott-Aldrich Syndrome.
Application of semiconductor and metal nanostructures in biology and medicine
Authors: Walkey Carl , Sykes Edward A. , Chan Warren C. W.
Published: December 2009

Advances in nanotechnology research have led to the creation of new generation of contrast agents, therapeutics, and delivery systems. These applications are expected to significantly improve the diagnosis and treatment of a variety of diseases. Two nanotechnologies—semiconductor and metallic nanostructures—are the most advanced in this young field and have been extensively investigated for clinical use. These nanostructures are currently the “model” for the developments of many novel nanostructures. This review describes their chemical design, tunable properties, and utility in medicine. Furthermore, we will describe the current understanding of their toxicity, which could be barriers to their use for human.
Dendrimer-based nanoparticles for cancer therapy
Authors: Baker James R.
Published: December 2009

Recent work has suggested that nanoparticles in the form of dendrimers may be a keystone in the future of therapeutics. The field of oncology could soon be revolutionized by novel strategies for diagnosis and therapy employing dendrimer-based nanotherapeutics. Several aspects of cancer therapy would be involved. Diagnosis using imaging techniques such as MRI will be improved by the incorporation of dendrimers as advanced contrast agents. This might involve novel contrast agents targeted specifically to cancer cells. Dendrimers can also be being applied to a variety of cancer therapies to improve their safety and efficacy. A strategy, somewhat akin to the “Trojan horse,” involves targeting anti-metabolite drugs via vitamins or hormones that tumors need for growth. Further applications of dendrimers in photodynamic therapy, boron neutron capture therapy, and gene therapy for cancer are being examined. This presentation will cover the fundamentals of research utilizing dendrimers for cancer diagnosis and therapy. An evaluation of this new technologies will detail what advantage dendrimer based therapeutics might have over conventional cancer drugs.
Drug-induced immune hemolytic anemia
Authors: Garratty George
Published: December 2009

Drug-induced immune hemolytic anemia (DIIHA) is rare, and a specialized laboratory is often required to provide the optimal serological tests to confirm the diagnosis. The most common drugs associated with DIIHA and the hypotheses for the mechanisms thought to be involved have changed during the last few decades. The drugs most frequently associated with DIIHA at this time are cefotetan, ceftriaxone, and piperacillin. DIIHA is attributed most commonly to drug-dependent antibodies that can only be detected in the presence of drug (eg, cephalosporin antibodies). DIIHA can also be associated with drug-independent antibodies; such antibodies do not need drug to be present to obtain in vitro reactions (eg, fludarabine). In these latter cases, the drug affects the immune system, causing production of red cell (RBC) autoantibodies; the clinical and laboratory findings are identical to autoimmune hemolytic anemia (AIHA), other than the remission associated with discontinuing the drug. Some of the mechanisms involved in DIIHA are controversial. The most acceptable one involves drugs, like penicillin, that covalently bind to proteins (eg, RBC membrane proteins); RBCs become coated with drug in vivo and, a drug antibody (usually IgG) attaches to the drug-coated RBCs that are subsequently cleared by macrophages. The most controversial is the so-called immune complex mechanism, which has been revised to suggest that most drugs are capable of binding to RBC membrane proteins, but not covalently like penicillins. The combined membrane plus drug can create an immunogen; the antibodies formed can be IgM or IgG and often activate complement, leading to acute intravascular lysis and sometimes renal failure; fatalities are more common in this group. It is still unknown why and how some drugs induce RBC autoantibodies, sometimes causing AIHA.
Immune hemolytic anemia—selected topics
Authors: Hoffman Philip C.
Published: December 2009

Autoimmune hemolytic anemia (AIHA) is most often idiopathic. However, in recent years, AIHA has been noted with increased incidence in patients receiving purine nucleoside analogues for hematologic malignancies; it has also been described as a complication of blood transfusion in patients who have also had alloimmunization. As the technology of hematopoietic stem cell transplantation has become more widespread, immune hemolysis in the recipients of ABO-mismatched products has become better recognized. The syndrome is caused by passenger lymphocytes transferred from the donor and, although transient, can be quite severe. A similar syndrome has been observed in recipients of solid organ transplants when there is ABO-incompatibility between donor and recipient.

Venous thromboembolism is a little-recognized, though likely common, complication of AIHA, and may in some instances be related to coexistent antiphospholipid antibodies. While AIHA is a well-documented complication of malignant lymphoproliferative disorders, lymphoproliferative disorders may also paradoxically appear as a consequence of AIHA.

A number of newer options are available for treatment of AIHA in patients refractory to corticosteroids and splenectomy. Newer immunosuppressives such as mycophenolate mofetil may have a role in such cases. Considerable experience has been accumulating in the last few years with monoclonal antibody therapy, mainly rituximab, in difficult AIHA cases; it appears to be a safe and effective option.
Malaria, erythrocytic infection, and anemia
Authors: Haldar Kasturi , Mohandas Narla
Published: December 2009

Malaria is a major world health problem. It results from infection of parasites belonging to the genus Plasmodium. Plasmodium falciparum and Plasmodium vivax cause the major human malarias, with P falciparum being the more virulent. During their blood stages of infection, both P falciparum and P vivax induce anemia. Severe malarial anemia caused by P falciparum is responsible for approximately a third of the deaths associated with disease. Malarial anemia appears to be multi-factorial. It involves increased removal of circulating erythrocytes as well as decreased production of erythrocytes in the bone marrow. The molecular mechanisms underlying malarial anemia are largely unknown. Over the last five years, malaria parasite ligands have been investigated for their remodeling of erythrocytes and possible roles in destruction of mature erythrocytes. Polymorphisms in cytokines have been associated with susceptibility to severe malarial anemia: these cytokines and malaria “toxins” likely function by perturbing erythropoiesis. Finally a number of co-infections increase susceptibility to malarial anemia, likely because they exacerbate inflammation caused by malaria. Because of the complexities involved, the study of severe malarial anemia may need a “systems approach” to yield comprehensive understanding of defects in both erythropoiesis and immunity associated with disease. New and emerging tools such as (i) mathematical modeling of the dynamics of host control of malarial infection, (ii) ex vivo perfusion of human spleen to measure both infected and uninfected erythrocyte retention, and (iii) in vitro development of erythroid progenitors to dissect responsiveness to cytokine imbalance or malaria toxins, may be especially useful to develop integrated mechanistic insights and therapies to control this major and fatal disease pathology.
Factor XI deficiency—resolving the enigma?
Authors: Bolton-Maggs Paula H. B.
Published: December 2009

The management of factor XI deficiency is not straightforward for three reasons: firstly, the role of this factor in the coagulation pathway is not clearly understood; secondly, the bleeding tendency, although mild, is unpredictable and does not clearly relate to the factor XI level; and thirdly, all treatment products, although available, have some potentially serious side effects. These factors (or enigmas) contribute to the variable management of patients with this coagulation factor deficiency, but recent research is helping to clarify some of these areas.
Free HTLV-1 induces TLR7-dependent innate immune response and TRAIL relocalization in killer plasmacytoid dendritic cells
Authors: Colisson Renaud , Barblu Lucie , Gras Christophe , Raynaud Françoise , Hadj-Slimane Reda , Pique Claudine , Hermine Olivier , Lepelletier Yves , Herbeuval Jean-Philippe
Published: December 2009

A recent report demonstrated that free human T-cell leukemia virus 1 (HTLV-1) could infect plasmacytoid dendritic cells (pDCs). The major role of pDCs is to secrete massive levels of interferon-α (IFN-α) upon virus exposure; however, the induction of IFN-α by HTLV-1 remains unknown. We demonstrate here that cell-free HTLV-1 generated a pDC innate immune response by producing massive levels of IFN-α that were inhibited by anti–HTLV-1 antibodies. HTLV-1 induced costimulatory molecules and rapid expression of the apoptotic ligand tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Furthermore, HTLV-1 stimulated pDC-induced apoptosis of CD4+ T cells expressing DR5, transforming pDCs into IFN-producing killer pDCs. We also observed that an endosomal acidification inhibitor and a Toll-like receptor-7 (TLR7)–specific blocker drastically inhibited pDC response to HTLV-1. Three-dimensional microscopy analysis revealed that unstimulated pDCs were “dormant” IFN-producing killer pDCs with high levels of intracellular TRAIL that could be rapidly mobilized to the surface in response to TLR7 activation. Inhibition of viral degradation in endosomes by chloroquine maintained viral integrity, allowing virus detection by 3-dimensional microscopy. We demonstrate that pDCs respond to cell-free HTLV-1 by producing high levels of IFN-α and by mobilizing TRAIL on cell surface after TLR7 triggering. This is the first demonstration of an innate immune response induced by free HTLV-1.
Emergence of BCR-ABL–specific cytotoxic T cells in the bone marrow of patients with Ph+ acute lymphoblastic leukemia during long-term imatinib mesylate treatment
Authors: Riva Giovanni , Luppi Mario , Barozzi Patrizia , Quadrelli Chiara , Basso Sabrina , Vallerini Daniela , Zanetti Eleonora , Morselli Monica , Forghieri Fabio , Maccaferri Monica , Volzone Francesco , Del Giovane Cinzia , D'Amico Roberto , Locatelli Franco , Torelli Giuseppe , Comoli Patrizia , Potenza Leonardo
Published: December 2009

Imatinib mesylate has been demonstrated to allow the emergence of T cells directed against chronic myeloid leukemia cells. A total of 10 Philadelphia chromosome–positive acute lymphoblastic leukemia patients receiving high-dose imatinib mesylate maintenance underwent long-term immunological monitoring (range, 2-65 months) of p190BCR-ABL–specific T cells in the bone marrow and peripheral blood. p190BCR-ABL–specific T lymphocytes were detected in all patients, more frequently in bone marrow than in peripheral blood samples (67% vs 25%, P < .01) and resulted significantly associated with lower minimal residual disease values (P < .001), whereas absent at leukemia relapse. Specific T cells were mainly effector memory CD8+ and CD4+ T cells, producing interferon-γ, tumor necrosis factor-α, and interleukin-2 (median percentage of positive cells: 3.34, 3.04, and 3.58, respectively). Cytotoxic subsets able to lyse BCR-ABL–positive leukemia blasts also were detectable. Whether these autologous p190BCR-ABL–specific T cells may be detectable under other tyrosine-kinase inhibitors, expanded ex vivo, and exploited for immunotherapy remains to be addressed.
Crystal structure and collagen-binding site of immune inhibitory receptor LAIR-1: unexpected implications for collagen binding by platelet receptor GPVI
Authors: Brondijk T. Harma C. , de Ruiter Talitha , Ballering Joost , Wienk Hans , Lebbink Robert Jan , van Ingen Hugo , Boelens Rolf , Farndale Richard W. , Meyaard Linde , Huizinga Eric G.
Published: December 2009

Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1), one of the most widely spread immune receptors, attenuates immune cell activation when bound to specific sites in collagen. The collagen-binding domain of LAIR-1 is homologous to that of glycoprotein VI (GPVI), a collagen receptor crucial for platelet activation. Because LAIR-1 and GPVI also display overlapping collagen-binding specificities, a common structural basis for collagen recognition would appear likely. Therefore, it is crucial to gain insight into the molecular interaction of both receptors with their ligand to prevent unwanted cross-reactions during therapeutic intervention. We determined the crystal structure of LAIR-1 and mapped its collagen-binding site by nuclear magnetic resonance (NMR) titrations and mutagenesis. Our data identify R59, E61, and W109 as key residues for collagen interaction. These residues are strictly conserved in LAIR-1 and GPVI alike; however, they are located outside the previously proposed GPVI collagen-binding site. Our data provide evidence for an unanticipated mechanism of collagen recognition common to LAIR-1 and GPVI. This fundamental insight will contribute to the exploration of specific means of intervention in collagen-induced signaling in immunity and hemostasis.
Identification of known and novel pancreas genes expressed downstream of Nkx2.2 during development
Authors: Anderson Keith R , White Peter , Kaestner Klaus H , Sussel Lori
Published: December 2009

Background

The homeodomain containing transcription factor Nkx2.2 is essential for the differentiation of pancreatic endocrine cells. Deletion of Nkx2.2 in mice leads to misspecification of islet cell types; insulin-expressing β cells and glucagon-expressing α cells are replaced by ghrelin-expressing cells. Additional studies have suggested that Nkx2.2 functions both as a transcriptional repressor and activator to regulate islet cell formation and function. To identify genes that are potentially regulated by Nkx2.2 during the major wave of endocrine and exocrine cell differentiation, we assessed gene expression changes that occur in the absence of Nkx2.2 at the onset of the secondary transition in the developing pancreas.

Results

Microarray analysis identified 80 genes that were differentially expressed in e12.5 and/or e13.5 Nkx2.2-/-embryos. Some of these genes encode transcription factors that have been previously identified in the pancreas, clarifying the position of Nkx2.2 within the islet transcriptional regulatory pathway. We also identified signaling factors and transmembrane proteins that function downstream of Nkx2.2, including several that have not previously been described in the pancreas. Interestingly, a number of known exocrine genes are also misexpressed in the Nkx2.2-/-pancreas.

Conclusions

Expression profiling of Nkx2.2-/-mice during embryogenesis has allowed us to identify known and novel pancreatic genes that function downstream of Nkx2.2 to regulate pancreas development. Several of the newly identified signaling factors and transmembrane proteins may function to influence islet cell fate decisions. These studies have also revealed a novel function for Nkx2.2 in maintaining appropriate exocrine gene expression. Most importantly, Nkx2.2 appears to function within a complex regulatory loop with Ngn3 at a key endocrine differentiation step.
Gene socialization: gene order, GC content and gene silencing in Salmonella
Authors: Papanikolaou Nikolas , Trachana Kalliopi , Theodosiou Theodosios , Promponas Vasilis J , Iliopoulos Ioannis
Published: December 2009

Background

Genes of conserved order in bacterial genomes tend to evolve slower than genes whose order is not conserved. In addition, genes with a GC content lower than the GC content of the resident genome are known to be selectively silenced by the histone-like nucleoid structuring protein (H-NS) in Salmonella.

Results

In this study, we use a comparative genomics approach to demonstrate that in Salmonella, genes whose order is not conserved (or genes without homologs) in closely related bacteria possess a significantly lower average GC content in comparison to genes that preserve their relative position in the genome. Moreover, these genes are more frequently targeted by H-NS than genes that have conserved their genomic neighborhood. We also observed that duplicated genes that do not preserve their genomic neighborhood are, on average, under less selective pressure.

Conclusions

We establish a strong association between gene order, GC content and gene silencing in a model bacterial species. This analysis suggests that genes that are not under strong selective pressure (evolve faster than others) in Salmonella tend to accumulate more AT-rich mutations and are eventually silenced by H-NS. Our findings may establish new approaches for a better understanding of bacterial genome evolution and function, using information from functional and comparative genomics.
Destructive arthritis in a patient with chikungunya virus infection with persistent specific IgM antibodies
Authors: Malvy Denis , Ezzedine Khaled , Mamani-Matsuda Maria , Autran Brigitte , Tolou Hugues , Receveur Marie-Catherine , Pistone Thierry , Rambert Jérome , Moynet Daniel , Mossalayi Djavad
Published: December 2009

Background

Chikungunya fever is an emerging arboviral disease characterized by an algo-eruptive syndrome, inflammatory polyarthralgias, or tenosynovitis that can last for months to years. Up to now, the pathophysiology of the chronic stage is poorly understood.

Case presentation

We report the first case of CHIKV infection with chronic associated rheumatism in a patient who developed progressive erosive arthritis with expression of inflammatory mediators and persistence of specific IgM antibodies over 24 months following infection.

Conclusions

Understanding the specific features of chikungunya virus as well as how the virus interacts with its host are essential for the prevention, treatment or cure of chikungunya disease.
Whole pelvic helical tomotherapy for locally advanced cervical cancer: technical implementation of IMRT with helical tomothearapy
Authors: Hsieh Chen-Hsi , Wei Ming-Chow , Lee Hsing-Yi , Hsiao Sheng-Mou , Chen Chien-An , Wang Li-Ying , Hsieh Yen-Ping , Tsai Tung-Hu , Chen Yu-Jen , Shueng Pei-Wei
Published: December 2009

Background

To review the experience and to evaluate the treatment plan of using helical tomotherapy (HT) for the treatment of cervical cancer.

Methods

Between November 1st, 2006 and May 31, 2009, 10 cervical cancer patients histologically confirmed were enrolled. All of the patients received definitive concurrent chemoradiation (CCRT) with whole pelvic HT (WPHT) followed by brachytherapy. During WPHT, all patients were treated with cisplatin, 40 mg/m2 intravenously weekly. Toxicity of treatment was scored according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0).

Results

The mean survival was 25 months (range, 3 to 27 months). The actuarial overall survival, disease-free survival, locoregional control and distant metastasis-free rates at 2 years were 67%, 77%, 90% and 88%, respectively. The average of uniformity index and conformal index was 1.06 and 1.19, respectively. One grade 3 of acute toxicity for diarrhea, thrombocytopenia and three grade 3 leucopenia were noted during CCRT. Only one grade 3 of subacute toxicity for thrombocytopenia was noted. There were no grade 3 or 4 subacute toxicities of anemia, leucopenia, genitourinary or gastrointestinal effects. Compared with conventional whole pelvic radiation therapy (WPRT), WPHT decreases the mean dose to rectum, bladder and intestines successfully.

Conclusion

HT provides feasible clinical outcomes in locally advanced cervical cancer patients. Long-term follow-up and enroll more locally advanced cervical carcinoma patients by limiting bone marrow radiation dose with WPHT technique is warranted.
Investigation of the cerebral blood flow of an Omani man with supposed ‘spirit possession’ associated with an altered mental state : a case report
Authors: Guenedi Amr A , Al Hussaini Ala'Alddin , Obeid Yousif A , Hussain Samir , Al-Azri Faisal , Al-Adawi Samir
Published: December 2009

Introduction

The view that spirits may possess humans is found in 90% of the world population, including Arab/Islamic societies. Despite the association between possessive states and various neurological and psychiatric disorders, the available literature has yet to correlate possessive states with functional brain imaging modalities such as single-photon-emission computed tomography.

Case presentation

This paper describes the clinical case of a 22-year-old male Omani patient who presented to us with an altered state of consciousness that his caregiver attributed to possession. We examined whether the patient's mental state correlated with neuro-imaging data. The patient's distress was invariably associated with specific perfusion in the left temporal lobe and structural abnormality in the left basal ganglia.

Conclusion

We discuss the case in the context of possession as a culturally sanctioned idiom of distress, and highlight the importance of studying cross-cultural presentations of altered states of consciousness within biomedical models.