Cyclosporine A (CsA) has been widely used in the treatment of aplastic anemia (AA), but the application of CsA was limited in patients who had liver diseases or abnormal liver function due to its liver toxicity. Glycyrrhizin has long been used in China in the treatment of various liver diseases to lower transaminases. In this study, we observed the efficacy and safety of glycyrrhizic acid combined with CsA in the treatment of newly diagnosed patients with non-severe AA (NSAA).A total number of 76 patients with newly diagnosed NSAA were enrolled into the study at our hospital between July 2005 and June 2010. The patients were divided randomly into two groups: the glycyrrhizin-treatment group (group A) and the control group (group B) with 38 patients in each group. All patients received 3 - 5 mg×kg(-1)×d(-1) CsA for at least 4 months and were treated either with or without glycyrrhizin for 4 months.sixty-eight patients were eligible for evaluation. In the control group, 9.09% patients (n = 3) achieved a complete response while 51.52% (n = 17) attained a partial response. The overall response rate was 60.61% (n = 20). The remaining 13 patients (39.39%) did not have any response. In the glycyrrhizin-treatment group, complete response rate was 20% (n = 7) and partial response rate was 62.86% (n = 22). The overall response rate was 82.86% (n = 29) and the non-response rate was 17.14% (n = 6). Response rate was significantly increased with the addition of glycyrrhizin to CsA compared with CsA alone (P < 0.05).The combination of glycyrrhizin and cyclosporine regimen was an effective treatment for NSAA in terms of improvement of response rate, reduction in CsA-related liver injury, and attenuation of severity of nausea and other adverse events in the treatment of patients with NSAA.

: Eosinophilic fasciitis (EF) is a rare entity characterized by symmetrical and painful thickness and induration of the skin, especially localized on forearms and thorax and generally accompanied by eosinophilia. Although several reports indicate the relationship between EF and hematological disorders such as aplastic anemia, polycythemia vera, or myelomonocytic leukemia, the association with lymphomas is extremely rare. Only a few cases of EF have been previously described preceding or concomitant to the Hodgkin disease, peripheral T-cell lymphoma, B-cell lymphoma, and mycosis fungoides. We report for the first time a 76-year-old man with an EF associated with a peripheral T-cell lymphoma not otherwise specified. We review the relationship between both conditions. In conclusion, we present a unique case of EF as a manifestation of a T-cell lymphoma not otherwise specified. The present case demonstrates the importance of clinical and radiological studies in those cases of EF to rule out a visceral, lymph node, or cutaneous lymphoma.

Telomeres are DNA-protein structures that form a protective cap on chromosome ends. As such, they prevent the natural ends of linear chromosomes from being subjected to DNA repair activities that would result in telomere fusion, degradation, or recombination. Both the DNA and protein components of the telomere are required for this essential function, because insufficient telomeric DNA length, loss of the terminal telomeric DNA structure, or deficiency of key telomere-associated factors may elicit a DNA damage response and result in cellular senescence or apoptosis. In the setting of failed checkpoint mechanisms, such DNA-protein defects can also lead to genomic instability through telomere fusions or recombination. Thus, as shown in both model systems and in humans, defects in telomere biology are implicated in cellular and organismal aging as well as in tumorigenesis. Bone marrow failure and malignancy are 2 life-threatening disease manifestations in the inherited telomere biology disorder dyskeratosis congenita. We provide an overview of basic telomere structure and maintenance. We outline the telomere biology defects observed in dyskeratosis congenita, focusing on recent discoveries in this field. Last, we review the evidence of how telomere biology may impact sporadic aplastic anemia and the risk for various cancers.

This study evaluated the feasibility, safety and immunological effects of the intravenous administration of mesenchymal stromal cells (MSCs) from a related donor in patients with refractory aplastic anemia (AA).A mean of 6 × 10(5)/kg (range, 5.0-7.1 × 10(5)) MSCs were injected intravenously to 18 patients, including 14 patients with nonsevere AA and four patients with severe AA who were refractory to prior immunosuppressive treatment. The outcomes of patients treated with MSCs were evaluated and compared with a historic control cohort, including 18 patients with refractory AA.Two patients had injection-related adverse events, including transient fever and headache. No major adverse events were reported during the follow-up period. An immunological analysis revealed an increased proportion of CD4(+)CD25(+) FOXP3(+)regulatory T cells in peripheral mononuclear cells. Following up for 1 year, six of 18 patients (33.3%) achieved a complete response or a partial response to MSC treatment. In six patients, two achieved a complete response including a recovery of three hematopoietic cell lines after MSCs therapy at days 88 and 92, two patients achieved only a red cell recovery with hemoglobin levels >100 g/L at days 30 and 48 and two patients had only a platelet recovery with a platelet count of >60 × 10(9)/L at days 54 and 81. In the control cohort, only one patient (5.56%) achieved a partial response during the follow-up period.The data from the present study suggest that treatment with MSCs from a related donor may be a promising therapeutic strategy for patients with refractory AA. The trial has been registered at ClinicalTrials.gov: identifier NCT01305694.

Human Parvovirus B19 has been linked to a variety of diseases. One of the most common complications is transient aplastic crisis in patients with chronic hemolytic anemia. Very few case reports have implicated this virus as a putative etiology behind hepatitis and severe aplastic anemia in immuno competent individuals. We report a case of severe aplastic anemia in a previously healthy adult female due to acute parvovirus B19 infection. Laboratory examination showed pancytopenia in peripheral blood and severe hypoplastic bone marrow on biopsy. Serological analysis (ELISA) revealed acute Parvovirus B19 infection. In the face of unavailable HLA matched bone marrow donor, immuno-supressive therapy was contemplated, but could not be given because of financial constraints. Pancytopenia persists till date, 4 months after the diagnosis, with the patient requiring repeated packed red cell and irradiated platelet transfusions. Thus, acute infection with this virus must be considered a cause of acquired aplastic anemia even in individuals without underlying disease.

Seronegative hepatitis-non-A, non-B, non-C, non-D, non-E hepatitis-is poorly characterized but strongly associated with serious complications. We collected 92 sera specimens from patients with non-A-E hepatitis in Chongqing, China between 1999 and 2007. Ten sera pools were screened by Solexa deep sequencing. We discovered a 3,780-bp contig present in all 10 pools that yielded BLASTx E scores of 7e-05-0.008 against parvoviruses. The complete sequence of the in silico-assembled 3,780-bp contig was confirmed by gene amplification of overlapping regions over almost the entire genome, and the virus was provisionally designated NIH-CQV. Further analysis revealed that the contig was composed of two major ORFs. By protein BLAST, ORF1 and ORF2 were most homologous to the replication-associated protein of bat circovirus and the capsid protein of porcine parvovirus, respectively. Phylogenetic analysis indicated that NIH-CQV is located at the interface of Parvoviridae and Circoviridae. Prevalence of NIH-CQV in patients was determined by quantitative PCR. Sixty-three of 90 patient samples (70%) were positive, but all those from 45 healthy controls were negative. Average virus titer in the patient specimens was 1.05 e4 copies/µL. Specific antibodies against NIH-CQV were sought by immunoblotting. Eighty-four percent of patients were positive for IgG, and 31% were positive for IgM; in contrast, 78% of healthy controls were positive for IgG, but all were negative for IgM. Although more work is needed to determine the etiologic role of NIH-CQV in human disease, our data indicate that a parvovirus-like virus is highly prevalent in a cohort of patients with non-A-E hepatitis.

Current diagnostic approaches that characterize T-cell deficiency by analyzing diversity of T-cell receptor sequences effectuate limited informational gain about the actual restrictiveness. For deeper insight into T-cell receptor repertoires we developed next-generation-sequencing-spectratyping, which employs high coverage Roche/454 sequencing of T-cell receptor β-chain amplicons. For automated analysis of high-throughput-sequencing data, we developed a freely available software, the TCR profiler. Gene usage, length, encoded amino acid sequence and sequence diversity of the complementarity determining region 3 were determined and comprehensively integrated into a novel complexity score. Repertoires of CD8+ T-cells from children with idiopathic or hepatitis-induced very severe aplastic anemia (n=7), children two months after bone marrow transplantation (n=7) and healthy controls (children n=5, adults n=5) were analyzed. Complexity scores clearly distinguished between healthy and diseased, and even between different immune deficiency states. The repertoire of aplastic anemia patients was dominated by public (i.e. present in more than one person) T-cell receptor clonotypes, whereas only 0.2% or 1.9% were public in normal children and adults, respectively. The CDR3 sequence ASSGVGFSGANVLT was highly prevalent in three cases of hepatitis-induced anemia (15-32% of all sequences), but was only low expressed in idiopathic aplastic anemia (2-5%, n=4) or healthy controls (<1%). 15 high frequent sequences were present exclusively in aplastic anemia patients. Next-generation-sequencing-spectratyping allows in-depth analysis of T-cell receptor repertoires and their restriction in clinical samples. A dominating clonotype was identified in hepatitis-induced anemia that may be associated with disease pathogenesis and several aplastic-anemia-associated, putatively autoreactive clonotypes were sequenced.

Aplastic anemia is a bone marrow failure syndrome that causes pancytopenia and can lead to life-threatening complications. Bone marrow transplantation remains the standard of care for younger patients and those with a good performance status but many patients may not have a suitable donor. Immunosuppressive therapy is able to resolve cytopenias in a majority of patients with aplastic anemia but relapses are not uncommon and some patients remain refractory to this approach. Patients may require frequent blood and platelet transfusion support which is expensive and inconvenient. Life-threatening bleeding complications still occur despite prophylactic platelet transfusion. Thrombopoietin (TPO) mimetics, such as romiplostim and eltrombopag, were developed to treat patients with refractory immune thrombocytopenia but are now being investigated for the treatment of bone marrow failure syndromes. TPO is the main regulator for platelet production and its receptor (c-Mpl) is present on megakaryocytes and hematopoietic stem cells. Trilineage hematopoietic responses were observed in a recent clinical trial using eltrombopag in patients with severe aplastic anemia refractory to immunosuppression suggesting that these agents can provide a new therapeutic option for enhancing blood production. In this review, we discuss these recent results and ongoing investigation of TPO mimetics for aplastic anemia and other bone marrow failure states like myelodysplastic syndromes. Clonal evolution or progression to acute myeloid leukemia remains a concern when using these drugs in bone marrow failure and patients should only be treated in the setting of a clinical trial.