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Find video protocols related to scientific articles indexed in Pubmed.
Childhood leprosy: a retrospective descriptive study from Government Medical College, Kozhikode, Kerala, India.
Lepr Rev
PUBLISHED: 09-27-2014
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To assess the profile and describe the clinical presentations and complications of childhood leprosy in a tertiary care hospital in North Kerala, South India during 2003-2012 and to analyse any change in the age-sex profile and the clinical pattern of leprosy in children below the age of 15 years over the 10-year study period.
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Psychiatric morbidity among prisoners.
Indian J Psychiatry
PUBLISHED: 06-04-2014
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There is a considerable lack of scientific estimate of psychiatric morbidity among Indian prisoners.
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Mutational analysis of the helicase domain of a replication initiator protein reveals critical roles of Lys 272 of the B' motif and Lys 289 of the ?-hairpin loop in geminivirus replication.
J. Gen. Virol.
PUBLISHED: 04-11-2014
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Replication initiator protein (Rep) is indispensable for rolling-circle replication of geminiviruses, a group of plant-infecting circular ssDNA viruses. However, the mechanism of DNA unwinding by circular ssDNA virus-encoded helicases is unknown. To understand geminivirus Rep function, we compared the sequence and secondary structure of Rep with those of bovine papillomavirus E1 and employed charged residue-to-alanine scanning mutagenesis to generate a set of single-substitution mutants in Walker A (K227), in Walker B (D261, 262), and within or adjacent to the B' motif (K272, K286 and K289). All mutants were asymptomatic and viral accumulation could not be detected by Southern blotting in both tomato and N. benthamiana plants. Furthermore, the K272 and K289 mutants were deficient in DNA binding and unwinding. Biochemical studies and modelling data based on comparisons with the known structures of SF3 helicases suggest that the conserved lysine (K289) located in a predicted ?-hairpin loop may interact with ssDNA, while lysine 272 in the B' motif (K272) located on the outer surface of the protein is presumably involved in coupling ATP-induced conformational changes to DNA binding. To the best of our knowledge, this is the first time that the roles of the B' motif and the adjacent ?-hairpin loop in geminivirus replication have been elucidated.
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Diffuse large B cell lymphoma in wiskott-Aldrich syndrome: a case report and review of literature.
Indian J Hematol Blood Transfus
PUBLISHED: 03-21-2014
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Wiskott-Aldrich syndrome (WAS) is an X linked rare primary immunodeficiency syndrome with an increased propensity for infection, autoimmunity and malignancy. Here we report a male child, who was diagnosed with WAS at 1 year of age following evaluation for symptomatic thrombocytopenia and eczematous skin lesions. He presented later with lymphadenopathy, which was consistent with diffuse large B cell lymphoma on histopathology. He received 6 cycles of R-CHOP chemotherapy for the same and is presently in remission after 6 months. We review the major publications of lymphoma in WAS and discuss the pathological findings, treatment and prognosis of lymphoma in WAS.
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Genome wide survey and analysis of small repetitive sequences in caulimoviruses.
Infect. Genet. Evol.
PUBLISHED: 02-06-2014
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Microsatellites are known to exhibit ubiquitous presence across all kingdoms of life including viruses. Members of the Caulimoviridae family severely affect growth of vegetable and fruit plants and reduce economic yield in diverse cropping systems worldwide. Here, we analyzed the nature and distribution of both simple and complex microsatellites present in complete genome of 44 species of Caulimoviridae. Our results showed, in all analyzed genomes, genome size and GC content had a weak influence on number, relative abundance and relative density of microsatellites, respectively. For each genome, mono- and dinucleotide repeats were found to be highly predominant and are overrepresented in genome of majority of caulimoviruses. AT/TA and GAA/AAG/AGA was the most abundant di- and trinucleotide repeat motif, respectively. Repeats larger than trinucleotide were rarely found in these genomes. Comparative study of occurrence, abundance and density of microsatellite among available RNA and DNA viral genomes indicated that simple repeats were least abundant in genomes of caulimoviruses. Polymorphic repeats even though rare were observed in the large intergenic region of the genome, indicating strand slippage and/or unequal recombination processes do occur in caulimoviruses. To our knowledge, this is the first analysis of microsatellites occurring in any dsDNA viral genome. Characterization of such variations in repeat sequences would be important in deciphering the origin, mutational processes, and role of repeat sequences in viral genomes.
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The use of a fludarabine-based conditioning regimen in patients with severe aplastic anemia - a retrospective analysis from three Indian centers.
Clin Transplant
PUBLISHED: 09-12-2013
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Between 2001 and 2009, 121 patients with severe aplastic anemia (SAA) underwent hematopoietic stem cell transplantation (HSCT) using a conditioning protocol of fludarabine and cyclophosphamide at three Indian hospitals. Donors were HLA-identical sibling or family donors. Seventy-six patients were considered "high risk" as per criteria. The graft source included peripheral blood stem cells in 109 and G-CSF-stimulated bone marrow in 12. GVHD prophylaxis consisted of cyclosporine and mini-methotrexate. Engraftment occurred in 117 (96.6%) while two had graft failure and two expired in the first two wk. Neutrophil engraftment was seen at 12.3 d (range: 9-19) while platelet engraftment occurred at 12.4 d (range: 8-32). Grade II-IV acute GVHD was seen in 26.7% and grade IV GVHD in 8.6%. Chronic GVHD occurred in 44% and was extensive in 10%. The five-yr overall survival for the entire cohort is 75.8 ± 3.9% with a survival of 95.6 ± 3.1% in the low-risk group (n = 45) and 64.0 ± 5.6% in the high-risk group (n = 76). Conditioning with fludarabine and cyclophosphamide is associated with very good long-term survival in patients undergoing HSCT for SAA.
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Effect of Postremission Therapy before Reduced-Intensity Conditioning Allogeneic Transplantation for Acute Myeloid Leukemia in First Complete Remission.
Biol. Blood Marrow Transplant.
PUBLISHED: 08-19-2013
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The impact of pretransplant (hematopoietic cell transplantation [HCT]) cytarabine consolidation therapy on post-HCT outcomes has yet to be evaluated after reduced-intensity or nonmyeloablative conditioning. We analyzed 604 adults with acute myeloid leukemia in first complete remission (CR1) reported to the Center for International Blood and Marrow Transplant Research who received a reduced-intensity or nonmyeloablative conditioning HCT from an HLA-identical sibling, HLA-matched unrelated donor, or umbilical cord blood donor from 2000 to 2010. We compared transplant outcomes based on exposure to cytarabine postremission consolidation. Three-year survival rates were 36% (95% confidence interval [CI], 29% to 43%) in the no consolidation arm and 42% (95% CI, 37% to 47%) in the cytarabine consolidation arm (P = .16). Disease-free survival was 34% (95% CI, 27% to 41%) and 41% (95% CI, 35% to 46%; P = .15), respectively. Three-year cumulative incidences of relapse were 37% (95% CI, 30% to 44%) and 38% (95% CI, 33% to 43%), respectively (P = .80). Multivariate regression confirmed no effect of consolidation on relapse, disease-free survival, and survival. Before reduced-intensity or nonmyeloablative conditioning HCT, these data suggest pre-HCT consolidation cytarabine does not significantly alter outcomes and support prompt transition to transplant as soon as morphologic CR1 is attained. If HCT is delayed while identifying a donor, our data suggest that consolidation does not increase transplant treatment-related mortality and is reasonable if required.
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Providing personalized prognostic information for adult leukemia survivors.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-28-2013
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Prediction of subsequent leukemia-free survival (LFS) and chronic graft-versus-host disease (GVHD) in adults with acute leukemia who survived at least 1 year after allogeneic hematopoietic cell transplantation is difficult. We analyzed 3339 patients with acute myeloid leukemia and 1434 patients with acute lymphoblastic leukemia who received myeloablative conditioning and related or unrelated stem cells from 1990 to 2005. Most clinical factors predictive of LFS in 1-year survivors were no longer significant after 2 or more years. For acute myeloid leukemia, only disease status (beyond first complete remission) remained a significant adverse risk factor for LFS 2 or more years after transplantation. For lymphoblastic leukemia, only extensive chronic GVHD remained a significant adverse predictor of LFS in the second and subsequent years. For patients surviving for 1 year without disease relapse or extensive chronic GVHD, the risk of developing extensive chronic GVHD in the next year was 4% if no risk factors were present and higher if noncyclosporine-based GVHD prophylaxis, an HLA-mismatched donor, or peripheral blood stem cells were used. Estimates for subsequent LFS and extensive chronic GVHD can be derived for individual patients or populations using an online calculator (http://www.cibmtr.org/LeukemiaCalculators). This prognostic information is more relevant for survivors than estimates provided before transplantation.
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A rapid & sensitive liquid chromatography- tandem mass spectrometry method for the quantitation of busulfan levels in plasma & application for routine therapeutic monitoring in haematopoietic stem cell transplantation.
Indian J. Med. Res.
PUBLISHED: 05-25-2013
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Busulfan (Bu) in combination with cyclophosphamide is widely used in myeloablative conditioning regimen prior to haematopoietic stem cell transplantation (HSCT). Its narrow therapeutic range and toxic side effects at high systemic exposure and graft rejection at low exposure emphasize the need for busulfan dose optimization using targeted dose adjustment prior to HSCT. We report here a rapid and sensitive method to quantitate busulfan plasma levels in patients receiving busulfan as part of pre-transplant conditioning.
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Unrelated donor allogeneic transplantation after failure of autologous transplantation for acute myelogenous leukemia: a study from the center for international blood and marrow transplantation research.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-21-2013
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The survival of patients with relapsed acute myelogenous leukemia (AML) after autologous hematopoietic stem cell transplantation (auto-HCT) is very poor. We studied the outcomes of 302 patients who underwent secondary allogeneic hematopoietic cell transplantation (allo-HCT) from an unrelated donor (URD) using either myeloablative (n = 242) or reduced-intensity conditioning (RIC; n = 60) regimens reported to the Center for International Blood and Marrow Transplantation Research. After a median follow-up of 58 months (range, 2 to 160 months), the probability of treatment-related mortality was 44% (95% confidence interval [CI], 38%-50%) at 1-year. The 5-year incidence of relapse was 32% (95% CI, 27%-38%), and that of overall survival was 22% (95% CI, 18%-27%). Multivariate analysis revealed a significantly better overal survival with RIC regimens (hazard ratio [HR], 0.51; 95% CI, 0.35-0.75; P <.001), with Karnofsky Performance Status score ?90% (HR, 0.62; 95% CI, 0.47-0.82: P = .001) and in cytomegalovirus-negative recipients (HR, 0.64; 95% CI, 0.44-0.94; P = .022). A longer interval (>18 months) from auto-HCT to URD allo-HCT was associated with significantly lower riak of relapse (HR, 0.19; 95% CI, 0.09-0.38; P <.001) and improved leukemia-free survival (HR, 0.53; 95% CI, 0.34-0.84; P = .006). URD allo-HCT after auto-HCT relapse resulted in 20% long-term leukemia-free survival, with the best results seen in patients with a longer interval to secondary URD transplantation, with a Karnofsky Performance Status score ?90%, in complete remission, and using an RIC regimen. Further efforts to reduce treatment-related mortaility and relapse are still needed.
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Peripheral dose measurements with diode and thermoluminescence dosimeters for intensity modulated radiotherapy delivered with conventional and un-conventional linear accelerator.
J Med Phys
PUBLISHED: 03-28-2013
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The objective of this paper was to measure the peripheral dose (PD) with diode and thermoluminescence dosimeter (TLD) for intensity modulated radiotherapy (IMRT) with linear accelerator (conventional LINAC), and tomotherapy (novel LINAC). Ten patients each were selected from Trilogy dual-energy and from Hi-Art II tomotherapy. Two diodes were kept at 20 and 25 cm from treatment field edge. TLDs (LiF:MgTi) were also kept at same distance. TLDs were also kept at 5, 10, and 15 cm from field edge. The TLDs were read with REXON reader. The readings at the respective distance were recorded for both diode and TLD. The PD was estimated by taking the ratio of measured dose at the particular distance to the prescription dose. PD was then compared with diode and TLD for LINAC and tomotherapy. Mean PD for LINAC with TLD and diode was 2.52 cGy (SD 0.69), 2.07 cGy (SD 0.88) at 20 cm, respectively, while at 25 cm, it was 1.94 cGy (SD 0.58) and 1.5 cGy (SD 0.75), respectively. Mean PD for tomotherapy with TLD and diode was 1.681 cGy SD 0.53) and 1.58 (SD 0.44) at 20 cm, respectively. The PD was 1.24 cGy (SD 0.42) and 1.088 cGy (SD 0.35) at 25 cm, respectively, for tomotherapy. Overall, PD from tomotherapy was found lower than LINAC by the factor of 1.2-1.5. PD measurement is essential to find out the potential of secondary cancer. PD for both (conventional LINAC) and novel LINACs (tomotherapy) were measured and compared with each other. The comparison of the values for PD presented in this work and those published in the literature is difficult because of the different experimental conditions. The diode and TLD readings were reproducible and both the detector readings were comparable.
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Life events, social support, coping strategies, and quality of life in attempted suicide: A case-control study.
Indian J Psychiatry
PUBLISHED: 02-27-2013
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Though deliberate self-harm encompasses a wide variety of medical and social disciplines some of the important psychosocial variable such as life events, social support, coping strategies, and quality of life have not yet been explored in depth in India.
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Acute nonvariceal upper gastrointestinal bleeding--experience of a tertiary care center in southern India.
Indian J Gastroenterol
PUBLISHED: 02-02-2013
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Over the last few decades, epidemiologic studies from the West have shown changing trends in etiology and clinical outcomes in patients with nonvariceal upper gastrointestinal bleed (NVUGIB). There are limited data from India on the current status of NVUGIB. The aim of this study therefore was to assess the etiological profile and outcomes of patients with NVUGIB at our center.
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Improved clinical outcomes of high risk ? thalassemia major patients undergoing a HLA matched related allogeneic stem cell transplant with a treosulfan based conditioning regimen and peripheral blood stem cell grafts.
PLoS ONE
PUBLISHED: 01-01-2013
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Improving clinical outcomes among high risk Class III ? thalassemia major patients (Class IIIHR) receiving an allogeneic SCT remains a challenge. From October, 2009 a treosulfan based regimen (TreoFluT) was used for all consecutive Class III patients (n = 50). The clinical outcomes were compared with the historical conventional busulfan (BuCy) based regimen (n = 139). Use of TreoFluT was associated with a significantly reduced incidence of sinusoidal obstruction syndrome (SOS) among Class IIIHR cases (78% to 30%; P = 0.000) and early TRM (46% to 13%; p = 0.005). There was also a trend towards better engraftment in the Class IIIHR subset (P = 0.055). However, the use of bone marrow (BM) as source of stem cells along with the TreoFluT regimen was associated with 50% early mixed chimerism which reduced to 8.5% with the use of a peripheral blood stem cell graft (PBSC). Use of a PBSC graft was not associated with a significant increase in the incidence of acute or chronic graft versus host disease (GVHD). The overall and event free survival was significantly better among the Class IIIHR subset with the use of TreoFluT Vs. BuCy (86.6 ± 7.3 Vs. 39.4 ± 6.8%; P = 0.002 and 77.8 ± 8.8 Vs. 32.4 ± 6.5%; P = 0.003 respectively). A TreoFluT conditioning regimen with a PBSC graft can significantly improve clinical outcomes of Class IIIHR patients.
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Clinicopathological features of hepatosplenic T cell lymphoma: a single centre experience from India.
Leuk. Lymphoma
PUBLISHED: 12-05-2011
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In a first series from India, we report 9 cases of hepatosplenic T cell lymphoma (HSTCL) seen in 23 months accounting for 4.2% of all mature T-non-Hodgkin lymphomas (NHLs) in our institution. All patients presented with organomegaly, cytopenias and had evidence of bone marrow involvement. The tumor cells had a blastic (55%) morphology with predominantly intrasinusoidal (33.3%) or intrasinusoidal with an additional interstitial component (33.3%). On flow cytometry, the classical phenotype (CD3+, CD7+, CD4-, CD8-, CD5-, CD56+/-) was seen only in 4 patients. Unusual variations included CD45 (overexpression), CD7 (dim expression), CD3 (overexpression, heterogeneous and dim), CD2 (overexpression), CD5 (heterogeneous), CD8 (heterogeneous or dim or overexpression) and aberrant expression of CD19. Fluoresvent in situ hybridisation (FISH) and karyotyping was abnormal in 5 out of 7 patients evaluated. All of the 5 cases showed abnormalities in chromosome 7 (ring chromosome or isochromosome 7q). Five patients died of disease and related complications in a span of 1-3 months after diagnosis whereas 4 were alive at their last follow up out of which 2 had documented a relapse. In our series, HSTCL was characterized by typical clinical and variable immunophenotypic features and a dismal clinical outcome.
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Treatment of acute promyelocytic leukemia with single-agent arsenic trioxide.
Mediterr J Hematol Infect Dis
PUBLISHED: 10-23-2011
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It is well recognized that arsenic trioxide (ATO) is an efficacious agent for the treatment of acute promyelocytic leukemia (APL). Use of single agent ATO in the treatment of APL leads to remissions which are durable in the majority. ATO is probably the most effective single agent in the treatment of APL and there have been very few reports of primary resistance. It has been used both as a single agent and in combination with other conventional drugs to treat APL. Use of ATO is the accepted standard of care in the management of relapsed APL, where it is often used effectively as a bridge to a stem cell transplant. However, its role in newly diagnosed APL remains controversial. ATO probably has multiple mechanisms of action. Better understanding of its mechanisms of action/s is likely to lead to more rationale use of this agent or its derivatives either alone or in combination with other drugs. There is limited data on the kinetics of leukemia clearance and normal haematopoietic recovery after the administration of single agent ATO for the treatment of APL, preliminary data suggests that it is likely to be different from conventional therapy. There have been a number of concerns of the potential short and long term toxicity of this agent. Most such concerns arise from the toxicity profile noted in people exposed to long term arsenic exposure in the environment. With the therapeutic doses and schedules of administration of ATO in the treatment of malignancies the overall toxicity profile has been favorable. In a resource constrained environments the use of a single agent ATO based regimen is a realistic and acceptable option to treat almost all patients. In the developed world it has the potential in combination with other agents to improve the clinical outcome with reduction of dose intensity of chemotherapy and remains an option for patients who would not tolerate conventional therapy. In this review we focus on the use of single agent ATO for the treatment of APL and summarize our experience and review the literature.
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Clinical Profile of Chikungunya Patients during the Epidemic of 2007 in Kerala, India.
J Glob Infect Dis
PUBLISHED: 09-03-2011
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The association of the present Chikungunya pandemic with a mutation in the Chik virus is already established in many parts of the world, including Kerala. Kerala was one of the worst-affected states of India in the Chikungunya epidemic of 2006-2007. It is important to discuss the clinical features of patients affected by Chikungunya fever in the context of this change in the epidemiology of the disease.
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Cytogenetic analysis of acute myeloid leukemia with t(8;21) from a tertiary care center in India with correlation between clinicopathologic characteristics and molecular analysis.
Leuk. Lymphoma
PUBLISHED: 09-02-2011
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The t(8;21)(q22;q22) is the most common translocation in acute myeloid leukemia (AML). We describe the clinicopathologic and cytogenetic profile of 117 patients with t(8;21) AML. There were 76 males and 88 adults. The median age was 26 years. Most patients (80%) had AML M2. Dysplasia was present in 68% of patients and eosinophilia in 18%. Eight patients had fewer than 20% blasts. Additional chromosomal aberrations were seen in 103 patients (88%) with loss of a sex chromosome (LSC) in 78 patients (66%) and deletion 9q in 21 (18%). The other recurrent abnormalities were trisomies 4, 8 and 15, monosomy 17 and deletion 7q (less than 5% each). Three- or four-way variant t(8;21) were seen in 6% of patients and 3% had tetraploidy. Aberrant expression of CD19 was seen in 54% of patients. FLT3 mutations were seen in 7.5% of patients (3/40) and c-KIT mutations in 6.6% (2/30). None had NPM1 or JAK2 V617F mutations. One patient had a granulocytic sarcoma. Complete remission was achieved in 96% of the 26 newly diagnosed patients after first induction. The median follow-up was 25 months (range 4-68). The overall survival was 69% at 31 months.
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Predictors of osteodystrophy in patients with chronic nonalcoholic pancreatitis with or without diabetes.
Endocr Pract
PUBLISHED: 07-12-2011
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To study bone mineral content (BMC), bone mineral density (BMD), vitamin D status, and bone mineral variables in patients with chronic nonalcoholic pancreatitis and to determine the relationship between pancreatic dysfunction and these variables.
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Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data.
J. Clin. Oncol.
PUBLISHED: 07-19-2010
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PURPOSE We previously reported our results with a single-agent arsenic trioxide (ATO) -based regimen in newly diagnosed cases of acute promyelocytic leukemia (APL). The concern remained about the long-term outcome of this well-tolerated regimen. We report our long-term follow-up data on the same cohort. PATIENTS AND METHODS From January 1998 to December 2004, 72 patients with PML/RARalpha+ APL were enrolled. All patients were treated with a single-agent ATO regimen. Results Overall 62 (86.1%) achieved a hematologic remission (complete remission). After the initial report, an additional seven patients have relapsed for a total of 13 relapses. There were no additional toxicities to report on follow-up. At a median follow-up 60 months, the 5-year Kaplan-Meier estimate (+/- SE) of event-free survival, disease-free survival, and overall survival (OS) was 69% +/- 5.5%, 80% +/- 5.2%, and 74.2% +/- 5.2%, respectively. The OS in the good risk group as defined by us remains 100% over this period. CONCLUSION Single-agent ATO as used in this study in the management of newly diagnosed cases of APL is safe and is associated with durable responses. Results in the low-risk group are comparable to that reported with conventional therapy while additional interventions would probably be required in high-risk cases.
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Oseltamivir resistance in adult oncology and hematology patients infected with pandemic (H1N1) 2009 virus, Australia.
Emerging Infect. Dis.
PUBLISHED: 07-01-2010
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We describe laboratory-confirmed influenza A pandemic (H1N1) 2009 in 17 hospitalized recipients of a hematopoietic stem cell transplant (HSCT) (8 allogeneic) and in 15 patients with malignancy treated at 6 Australian tertiary centers during winter 2009. Ten (31.3%) patients were admitted to intensive care, and 9 of them were HSCT recipients. All recipients of allogeneic HSCT with infection <100 days posttransplantation or severe graft-versus-host disease were admitted to an intensive care unit. In-hospital mortality rate was 21.9% (7/32). The H275Y neuraminidase mutation, which confers oseltamivir resistance developed in 4 of 7 patients with PCR positive for influenza after > or = 4 days of oseltamivir therapy. Three of these 4 patients were critically ill. Oseltamivir resistance in 4 (13.3%) of 30 patients who were administered oseltamivir highlights the need for ongoing surveillance of such resistance and further research on optimal antiviral therapy in the immunocompromised.
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Breeding patterns of Aedes stegomyia albopictus in periurban areas of Calicut, Kerala, India.
Southeast Asian J. Trop. Med. Public Health
PUBLISHED: 06-29-2010
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Aedes albopictus has been shown to be a vector for diseases which have been on the increase, such as dengue fever and chikungunya infection. We conducted a study of 100 homes from 2006-2009 to determine the breeding sites for Ae. albopictus mosquitoes in Calicut, Kerala, India. We found the larvae of Ae. albopictus mosquitoes most often in coconut shells and plastic waste, followed by tires, flower pots, glass products, egg shells and dumped grinding stones. Ae. albopictus control programs in Calicut, Kerala, India should target these objects as part of a control program.
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Comparison of outcomes after transplantation of G-CSF-stimulated bone marrow grafts versus bone marrow or peripheral blood grafts from HLA-matched sibling donors for patients with severe aplastic anemia.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-18-2010
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We compared outcomes of patients with severe aplastic anemia (SAA) who received granulocyte-colony stimulating factor (G-CSF)-stimulated bone marrow (G-BM) (n = 78), unstimulated bone marrow (BM) (n = 547), or peripheral blood progenitor cells (PBPC) (n = 134) from an HLA-matched sibling. Transplantations occurred in 1997 to 2003. Rates of neutrophil and platelet recovery were not different among the 3 treatment groups. Grade 2-4 acute graft-versus-host disease (aGVHD) (relative risk [RR] = 0.82, P = .539), grade 3-4 aGVHD (RR = 0.74, P = .535), and chronic GVHD (cGVHD) (RR = 1.56, P = .229) were similar after G-BM and BM transplants. Grade 2-4 aGVHD (RR = 2.37, P = .012) but not grade 3-4 aGVHD (RR = 1.66, P = .323) and cGVHD (RR = 5.09, P < .001) were higher after PBPC transplants compared to G-BM. Grade 2-4 (RR = 2.90, P < .001), grade 3-4 (RR = 2.24, P = .009) aGVHD and cGVHD (RR = 3.26, P < .001) were higher after PBPC transplants compared to BM. Mortality risks were lower after transplantation of BM compared to G-BM (RR = 0.63, P = .05). These data suggest no advantage to using G-BM and the observed higher rates of aGVHD and cGVHD in PBPC recipients warrants cautious use of this graft source for SAA. Taken together, BM is the preferred graft for HLA-matched sibling transplants for SAA.
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The t(6;9)(p22;q34) in myeloid neoplasms: a retrospective study of 16 cases.
Cancer Genet. Cytogenet.
PUBLISHED: 04-26-2010
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Among patients with acute myeloid leukemia (AML), the t(6;9) (p22;q34) is a rare but defined subset with a poor prognosis. We report 16 patients with the t(6;9), of whom 13 had AML, 2 had myelodysplastic syndrome (MDS), and 1 had chronic myeloid leukemia in myeloid blast crisis (CML-BC). All except for one were evaluated at diagnosis. The median age was 34.5 (range: 7-62 years), with 12 adults and 12 males. Trilineage dysplasia was present in 13 (81%). Marrow basophilia was seen in only two patients, one of whom had CML-BC. HLA-DR was positive in all 12 patients assessed, CD33 in 11, CD13 in 10, and CD34 in seven. Four patients had one other abnormality apart from the t(6;9). These were the t(9;22) in the patient with CML and deletion 9q, addition 13q, and an isochromosome 8q in the other three patients. There were no complex karyotypes. Fms-related tyrosine kinase 3--internal tandem duplication (FLT3-ITD) mutations were seen in seven of 13 patients. Follow-up details were available for six patients. Three received palliative care, and follow-up details were not available for the other seven. The response to chemotherapy was poor in the remaining patients. The only patients who survived were three out of the four who had allogeneic hematopoietic stem cell transplantation (HSCT).
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The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission.
Blood
PUBLISHED: 04-19-2010
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We examined the efficacy of reduced-intensity conditioning (RIC) and compared outcomes of 93 patients older than 16 years after RIC with 1428 patients receiving full-intensity conditioning for allografts using sibling and unrelated donors for Philadelphia-negative acute lymphoblastic leukemia (ALL) in first or second complete remission. RIC conditioning included busulfan 9 mg/kg or less (27), melphalan 150 mg/m(2) or less (23), low-dose total body irradiation (TBI; 36), and others (7). The RIC group was older (median 45 vs 28 years, P < .001) and more received peripheral blood grafts (73% vs 43%, P < .001) but had similar other prognostic factors. The RIC versus full-intensity conditioning groups had slightly, but not significantly, less acute grade II-IV graft-versus-host disease (39% vs 46%) and chronic graft-versus-host disease (34% vs 42%), yet similar transplantation-related mortality. RIC led to slightly more relapse (35% vs 26%, P = .08) yet similar age-adjusted survival (38% vs 43%, P = .39). Multivariate analysis showed that conditioning intensity did not affect transplantation-related mortality (P = .92) or relapse risk (P = .14). Multivariate analysis demonstrated significantly improved overall survival with: Karnofsky performance status more than 80, first complete remission, lower white blood count, well-matched unrelated or sibling donors, transplantation since 2001, age younger than 30 years, and conditioning with TBI, but no independent impact of conditioning intensity. RIC merits further investigation in prospective trials of adult ALL.
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Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome.
J. Clin. Oncol.
PUBLISHED: 03-08-2010
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PURPOSE Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) primarily afflict older individuals. Hematopoietic cell transplantation (HCT) is generally not offered because of concerns of excess morbidity and mortality. Reduced-intensity conditioning (RIC) regimens allow increased use of allogeneic HCT for older patients. To define prognostic factors impacting long-term outcomes of RIC regimens in patients older than age 40 years with AML in first complete remission or MDS and to determine the impact of age, we analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR). PATIENTS AND METHODS We reviewed data reported to the CIBMTR (1995 to 2005) on 1,080 patients undergoing RIC HCT. Outcomes analyzed included neutrophil recovery, incidence of acute or chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, disease-free survival (DFS), and overall survival (OS). RESULTS Univariate analyses demonstrated no age group differences in NRM, grade 2 to 4 acute GVHD, chronic GVHD, or relapse. Patients age 40 to 54, 55 to 59, 60 to 64, and > or = 65 years had 2-year survival rates as follows: 44% (95% CI, 37% to 52%), 50% (95% CI, 41% to 59%), 34% (95% CI, 25% to 43%), and 36% (95% CI, 24% to 49%), respectively, for patients with AML (P = .06); and 42% (95% CI, 35% to 49%), 35% (95% CI, 27% to 43%), 45% (95% CI, 36% to 54%), and 38% (95% CI, 25% to 51%), respectively, for patients with MDS (P = .37). Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS (all P > .3). Greater HLA disparity adversely affected 2-year NRM, DFS, and OS. Unfavorable cytogenetics adversely impacted relapse, DFS, and OS. Better pre-HCT performance status predicted improved 2-year OS. CONCLUSION With these similar outcomes observed in older patients, we conclude that older age alone should not be considered a contraindication to HCT.
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Allogeneic hematopoietic stem cell transplantation is superior to immunosuppressive therapy in Indian children with aplastic anemia--a single-center analysis of 100 patients.
Pediatr Hematol Oncol
PUBLISHED: 03-06-2010
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The authors compared the outcome in 100 children (61 boys, 39 girls; median age of 10.1 +/- 3.4 years) with aplastic anemia who underwent either immunosuppressive therapy (IST; n = 70) or hematopoietic stem cell transplantation (HSCT; n = 30) between 1998 and 2007. Conditioning regimes for HSCT were a combination of either cyclophosphamide (Cy) with antilymphocyte globulin (ALG) or fludarabine (Flu) with Cy or busulfan (Bu) +/- antithymocyte globulin (ATG). Stem cell source was bone marrow in 20 and peripheral blood stem cells (PBSCs) in 10. Patients undergoing IST received either equine ALG or ATG in combination with steroids and cyclosporine. Primary engraftment was seen in 25 children (83.3%), with acute graft-versus-host disease (aGvHD) in 5 (16.6%). The day 100 transplant-related mortality (TRM) was 30% and at a median follow up of 36 months (range: 6-197), the overall and disease-free survival is 70%. Among children who received IST, 60 children received ALG while 10 received ATGAM. Responses were seen in 27 children (43.5%), which was complete (CR) in 12 and partial (PR) in 15. At a median follow up of 38 months (range: 1-84), the overall survival is 37.1%, with 81.4% survival among responders and <10% survival among non-responders. HSCT would be the treatment of choice in children with severe aplastic anemia who have a human leukocyte antigen (HLA)-matched related donor and is superior to IST in this series from India.
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The Clinical Impact of Infection with Swine Flu (H1N109) Strain of Influenza Virus in Hematopoietic Stem Cell Transplant Recipients.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-26-2010
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There are limited data on the impact of H1N109 infection in patients undergoing hematopoietic stem cell transplantation (HSCT). We reviewed individual medical records of patients who underwent HSCT or were on follow-up post-HSCT between May and September 2009. Thirteen patients with H1N109 infection were identified: 2 <100 days post-HSCT, 7 >100 days post-HSCT, and 4 just prior to HSCT. Five (38.7%) had lower respiratory tract involvement (LRTI), whereas the remainder had upper respiratory tract involvement (URTI). LRTI occurred in patients who were profoundly neutropenic post-HSCT or on potent immunosuppression for chronic graft-versus-host disease (cGVHD). At 100 days post-H1N109 infection, only 1 patient with LRTI survived, whereas all with URTI are alive. Four patients successfully treated for H1N109 infection prior to HSCT underwent the procedure after 4 to 6 weeks without any complications. Another 6 patients received oseltamivir prophylaxis during conditioning and none developed H1N109 infection. In conclusion, H1N109 infection was associated with LRTI in HSCT recipients who were profoundly neutropenic or immunosuppressed. Prior H1N109 infection did not affect the successful outcome of HSCT and oseltamivir prophylaxis in a small group of recipients resulted in no infection. Further studies are required.
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Dendritic cell count in the graft predicts relapse in patients with hematologic malignancies undergoing an HLA-matched related allogeneic peripheral blood stem cell transplant.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-21-2010
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We investigated the impact of the number of infused and reconstituted immunocompetent cells including dendritic cells (DCs) on clinical outcome of patients with hematologic malignancies undergoing an allogeneic peripheral blood stem cell transplantation. Sixty-nine consecutive patients with hematologic malignancies were included in the analysis. The median age of the cohort was 32 years (range: 2-62 years) and there were 39 (57%) males. Twenty-one (30%) patients relapsed with a cumulative incidence of 44 % +/- 14% at a median follow up of 28 months. On a multivariate analysis, a high plasmacytoid dendritic cell (PC) content in the graft was associated with higher risk of relapse. The patients were further categorized based on the median PC counts in the graft as high (> or =2.3 x 10(6)/kg) and low (<2.3 x 10(6)/kg) groups. The baseline characteristics of these 2 groups were comparable. The group that had a high PC content in the graft had significantly higher risk of relapse and lower overall survival (OS) and event-free survival (EFS). Our data suggests that PC content in the graft predicts clinical outcomes such as relapse and survival in patients with hematologic malignancies undergoing an allogeneic HLA matched related peripheral blood stem cell transplantation. There is potential for pretransplant manipulation of this cellular subset in the graft.
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Transcriptional coactivator p300 regulates glucose-induced gene expression in endothelial cells.
Am. J. Physiol. Endocrinol. Metab.
PUBLISHED: 11-10-2009
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Sustained hyperglycemia in diabetes causes alteration of a large number of transcription factors and mRNA transcripts, leading to tissue damage. We investigated whether p300, a transcriptional coactivator with histone acetyl transferase activity, regulates glucose-induced activation of transcription factors and subsequent upregulation of vasoactive factors and extracellular matrix (ECM) proteins in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated in varied glucose concentrations and were studied after p300 small interfering RNA (siRNA) transfection, p300 overexpression, or incubation with the p300 inhibitor curcumin. Histone H2AX phosphorylation and lysine acetylation were examined for oxidative DNA damage and p300 activation. Screening for transcription factors was performed with the Luminex system. Alterations of selected transcription factors were validated. mRNA expression of p300, endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), and fibronectin (FN) and its splice variant EDB(+)FN and FN protein production were analyzed. HUVECs in 25 mmol/l glucose showed increased p300 production accompanied by increased binding of p300 to ET-1 and FN promoters, augmented histone acetylation, H2AX phosphorylation, activation of multiple transcription factors, and increased mRNA expression of vasoactive factors and ECM proteins. p300 overexpression showed a glucose-like effect on the mRNA expression of ET-1, VEGF, and FN. Furthermore, siRNA-mediated p300 blockade or chemical inhibitor of p300 prevented such glucose-induced changes. Similar mRNA upregulation was also seen in the organ culture of vascular tissues, which was prevented by p300 siRNA transfection. Data from these studies suggest that glucose-induced p300 upregulation is an important upstream epigenetic mechanism regulating gene expression of vasoactive factors and ECM proteins in endothelial cells and is a potential therapeutic target for diabetic complications.
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25 (OH) vitamin D level in Crohns disease: association with sun exposure & disease activity.
Indian J. Med. Res.
PUBLISHED: 10-03-2009
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Western studies show that up to 65 per cent of patients with Crohns disease have low serum 25-hydroxy vitamin D concentrations, and 45 per cent of these patients have metabolic bone disease. No data are available from India or from any country with comparable climatic conditions or ethnicity. We carried out this study to measure the serum 25 (OH) vitamin D levels of Crohns disease patients and compare with matched controls and to assess the consequences of low 25 (OH) vitamin D levels on bone and mineral metabolism in these patients.
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Impact of pretransplant splenectomy on patients with beta-thalassemia major undergoing a matched-related allogeneic stem cell transplantation.
Pediatr Transplant
PUBLISHED: 09-08-2009
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Impact of pretransplant splenectomy in patients with beta-thalassemia major undergoing an allogeneic SCT has never been addressed. Twenty-seven class III patients (29 transplants) had a pretransplant splenectomy. The outcome of these 29 transplants was compared with 76 transplants in class III who did not have a splenectomy. Patients in the splenectomy group were older (11.7 +/- 5.0 vs. 8.5 +/- 3.5 yr; p = 0.003) and had a larger liver size (5.7 +/- 1.8 vs. 4.4 +/- 1.6 cm; p = 0.000). Splenectomized patients had a significantly faster time to ANC >500/mm(3) (15.4 +/- 5.9 vs. 17.5 +/- 4 days; p = 0.002) and platelet >20 000/mm(3) (22.5 +/- 6.7 vs. 32.5 +/- 13.6 days; p = 0.000). The splenectomized group had a significantly reduced requirement of blood transfusion in the first 100 days post-transplant (5.5 +/- 5.1 vs. 7.2 +/- 5.4 units; p = 0.017). There were significantly more deaths related to peri-transplant infections in the post-splenectomy group (24% vs. 5.3%; p = 0.0001). The graft rejections were comparable between the two groups (20.7% vs. 14.5%; p = 0.55). The incidence of acute and chronic GVHD, late infections, and deaths from RRT was not significantly different between the two groups. The five-yr EFS (31.0 +/- 8.6 vs. 60.8 +/- 5.98; p = 0.003) and OS (39.7 +/- 9.3 vs. 71.8 +/- 5.5; p = 0.002) was significantly worse in the splenectomized group. In conclusion, pretransplant splenectomy among patients with beta-thalassemia major was associated with faster engraftment, reduced transfusion support, a higher incidence of peri-transplant infection related deaths, and a reduced EFS and OS.
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Frequency of TPMT alleles in Indian patients with acute lymphatic leukemia and effect on the dose of 6-mercaptopurine.
Med. Oncol.
PUBLISHED: 06-24-2009
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Functional polymorphisms in the thiopurine methyl transferase (TPMT) gene have been associated with varying levels of enzyme activity and the occurrence of toxicity related to thiopurines. A total of 98 patients (66 pediatric and 32 adults) with precursor B acute lymphoblastic leukemia (Pre-B ALL) were evaluated for TPMT gene polymorphisms. The inability to tolerate 6-mercaptopurine (6-MP) at conventional doses was considered as a surrogate marker of hematologic toxicity. The allele frequency of TPMT*2, *3A, *3B and *3C in the study population was 0.5, 0, 0 and 2.6%, respectively, similar to the frequency observed in other Asian populations. Five patients were heterozygous for TPMT*3C variant allele, and one of these patients was compound heterozygous with TPMT*2 variant as the other allele. The impact of TPMT polymorphisms on the toxicity and treatment outcome was assessed in 66 pediatric patients only, as there was no variant TPMT detected in the adult patients. Three of the 5 patients (60%) heterozygous for TPMT*2 or TPMT*3C polymorphisms and 12/61 patients (20%) with wild type TPMT genotype had more than 10% of reduction of 6-MP dose (P=0.07). The presence of TPMT polymorphisms did not seem to completely explain the variation in 6-MP toxicity in this small group of patients. Other novel variants in TPMT or variations in the genes involved in transport and biotransformation of 6-MP need to be evaluated in the Indian population.
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Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-02-2009
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In patients with relapsed acute promyelocytic leukemia (APL), the best consolidation regimen following induction of remission with arsenic trioxide (ATO) remains to be defined. Since January 2000, 37 patients with relapsed APL were treated at our center. The median age was 34 years (range, 6-57 years), and there were 20 males (54.1%). The median duration of first remission was 20.3 months (range, 2.9-81.2 months). Relapse was treated with single-agent ATO in 22 patients (59.5%), ATO+ATRA in 5 patients (13.5%), and ATO+ATRA + anthracycline in 10 patients (27%). Thirty-three patients (89%) achieved molecular remission after induction and a consolidation course. Fourteen patients opted to undergo autologous stem cell transplantation (SCT), and the remaining 19 patients received monthly cycles of ATO as a single agent (n=13) or ATO+ATRA (n=6) for 6 months. At a median follow-up of 32 months, the 5-year Kaplan-Meier estimate of event-free survival (EFS) was 83.33% +/- 15.21% in those who underwent autologous SCT versus 34.45% +/- 11.24% in those who did not (P=.001; log-rank test). Following remission induction with ATO-based regimens in patients with relapsed APL, consolidation with autologous SCT is associated with a significantly superior clinical outcome compared with ATO- and ATO+ATRA-based maintenance regimens.
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Fludarabine-based reduced intensity conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with aplastic anemia and fungal infections.
Clin Transplant
PUBLISHED: 04-30-2009
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Eighteen patients (12 men and 6 women) with aplastic anemia and active fungal infections (10 proven/probable; 8 possible) underwent stem cell transplantation using fludarabine combined with cyclophosphamide or total body irradiation. Peripheral blood stem cells (PBSC) were the main graft source and a combination of cyclosporine with either methotrexate or methylprednisolone was used for graft versus host disease prophylaxis. Fourteen patients (77.8%) achieved neutrophil engraftment after a median time of 11 d, while four died of fungal sepsis. Resolution of fungal infection occurred in 60% of patients with proven/probable infections and in 100% with possible fungal infections. At a median follow up of 30 months, 11 patients (61.1%) were alive and well. Fludarabine-based conditioning regimens with PBSC transplantation can be used successfully in patients with aplastic anemia and fungal infections.
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Leptin and endothelin-1 mediated increased extracellular matrix protein production and cardiomyocyte hypertrophy in diabetic heart disease.
Diabetes Metab. Res. Rev.
PUBLISHED: 04-25-2009
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We investigated the role of leptin and its interaction with endothelin 1 (ET-1) in fibronectin (FN) synthesis and cardiomyocyte hypertrophy, two characteristic features of diabetic cardiomyopathy.
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Extracellular matrix proteins in epiretinal membranes and in diabetic retinopathy.
Curr. Eye Res.
PUBLISHED: 02-17-2009
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Non-vascular epiretinal membranes (ERM) and neovascular membrane in proliferative diabetic retinopathy (PDR) are recognized causes of visual impairment. Both ERMs and neovascular membranes in PDR consist of cellular components and extracellular matrix (ECM) proteins such as fibronectin (FN) and collagen. Transforming growth factor-beta (TGF-beta) and endothelin-1 (ET-1) regulate ECM protein production. In this study, we investigated ECM proteins and their regulators in ERMs and vitreous from PDR subjects and non-diabetic subjects undergoing vitrectomy.
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Aetiology of paediatric portal hypertension - experience of a tertiary care centre in South India.
Trop Doct
PUBLISHED: 02-13-2009
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The aetiological profile of paediatric portal hypertension in our hospital, a tertiary care centre in South India, showed that the commonest causes were extrahepatic portal venous obstruction (EHPVO) and cirrhosis. Wilsons disease was the most common cause of cirrhosis.
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Cellular immune reconstitution and its impact on clinical outcome in children with beta thalassemia major undergoing a matched related myeloablative allogeneic bone marrow transplant.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-26-2009
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We have prospectively analyzed cellular immune reconstitution (IR) in 63 consecutive pediatric patients with beta thalassemia major who underwent an HLA matched related allogeneic bone marrow transplant (BMT). Samples from bone marrow graft and posttransplant peripheral blood samples from recipients at specified time points were assessed for IR of cellular subsets. The median age of the cohort was 7 years, and there were 37 (59%) males. A CD34 cell dose above the median value of 7.3 x 10(6)/kg had a lower incidence of bacterial (P = .003) and fungal (P = .003) infections in the posttransplant period, and was not associated with an increased risk of graft-versus-host disease (GVHD). Among cases that did develop grade II-IV GVHD the absolute CD8 (116 versus 52 cells/microL, P = .012), CD8 naïve (74 versus 9 cells/microL, P = .005), and CD8 memory counts (44 versus 21 cells/microL, P = .010) were significantly higher on day 15. Fifteen patients (24%) rejected their graft (7 primary and 8 secondary). The day 28 natural killer (NK) cell count was significantly associated with secondary graft rejection, event-free survival (EFS), and overall survival (OS) (P = .044, .013, and .034, respectively). On a multivariate analysis, patients with a day 28 NK cell count below the median value of 142/microL had a significantly higher rejection rate (hazard ratio [HR] = 11.1, P = .038) and a lower EFS (HR = 16.3, P = .034).
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Fluorescence in situ hybridization patterns of BCR/ABL1 fusion in chronic myelogenous leukemia at diagnosis.
Indian J Pathol Microbiol
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Chronic myelogenous leukemia (CML) is characterised by the t(9;22)(q34;q11.2) which results in the formation of the BCR/ABL1 fusion gene. Occasionally, the t(9;22) may be associated with submicroscopic deletions of chromosomes 9 and/or 22 which appear to be associated with a worse prognosis. Three or four-way variant t(9;22) may also occur. All these changes as well as gain of the Philadelphia chromosome which represents disease progression can be detected by fluorescence in situ hybridization (FISH) analysis. FISH analysis at presentation is used to determine the number of cells with BCR/ABL1 fusion and establish whether the patterns are typical or atypical. Response to therapy can then be monitored by serial testing.
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Carbonyl reductase 1 expression influences daunorubicin metabolism in acute myeloid leukemia.
Eur. J. Clin. Pharmacol.
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The present study aimed to investigate the role of expression of daunorubicin-metabolizing enzymes carbonyl reductase 1 and 3 (CBR1 and CBR3) on the in vitro cytotoxicity of daunorubicin in primary acute myeloid leukemia (AML) cells and the effect of genetic variants in CBR1 and CBR3 on the plasma pharmacokinetics of daunorubicin and daunorubicinol (DOL) in AML patients.
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Standardizing minimal residual disease by flow cytometry for precursor B lineage acute lymphoblastic leukemia in a developing country.
Cytometry B Clin Cytom
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In addition to standard risk criteria at diagnosis, minimal residual disease (MRD) following initiation of therapy is a well-recognized risk factor to predict relapse. Literature from developing countries addressing therapeutic or laboratory practices related to MRD, is largely lacking. In a first paper from India, we describe our experience in establishing a flow cytometry-based MRD assay for precursor B lineage ALL (BCP-ALL) with emphasis on the assay standardization and cost.
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Allogeneic hematopoietic cell transplantation for advanced polycythemia vera and essential thrombocythemia.
Biol. Blood Marrow Transplant.
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Allogeneic hematopoietic cell transplantation (HCT) is curative for selected patients with advanced essential thrombocythemia (ET) or polycythemia vera (PV). From 1990 to 2007, 75 patients with ET (median age 49 years) and 42 patients with PV (median age 53 years) underwent transplantations at the Fred Hutchinson Cancer Research Center (FHCRC; n = 43) or at other Center for International Blood and Marrow Transplant Research (CIBMTR) centers (n = 74). Thirty-eight percent of the patients had splenomegaly and 28% had a prior splenectomy. Most patients (69% for ET and 67% for PV) received a myeloablative (MA) conditioning regimen. Cumulative incidence of neutrophil engraftment at 28 days was 88% for ET patients and 90% for PV patients. Acute graft-versus-host disease (aGVHD) grades II to IV occurred in 57% and 50% of ET and PV patients, respectively. The 1-year treatment-related mortality (TRM) was 27% for ET and 22% for PV. The 5-year cumulative incidence of relapse was 13% for ET and 30% for PV. Five-year survival/progression-free survival (PFS) was 55%/47% and 71%/48% for ET and PV, respectively. Patients without splenomegaly had faster neutrophil and platelet engraftment, but there were no differences in TRM, survival, or PFS. Presence of myelofibrosis (MF) did not affect engraftment or TRM. Over 45% of the patients who undergo transplantations for ET and PV experience long-term PFS.
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HLA DR15 antigen status does not impact graft-versus-host disease or survival in HLA-matched sibling transplantation for hematologic malignancies.
Biol. Blood Marrow Transplant.
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The HLA class II DRB1 antigen DR15 is an important prognostic marker in immune-mediated marrow failure states. DR15 has also been associated with favorable outcomes (reduced acute graft-versus-host disease [aGVHD] and relapse) after allogeneic hematopoietic cell transplant. To elucidate the impact of DR15 on transplantation outcomes, we conducted a retrospective study of 2891 recipients of first allogeneic stem cell transplant from HLA-matched sibling donors for the treatment of acute leukemia, chronic myeloid leukemia, or myelodysplastic syndrome (MDS) between 1990 and 2007. All patients received conventional myeloablative conditioning, T-replete grafts, and cyclosporine plus methotrexate-based GVHD prophylaxis. DNA-based HLA typing allowed categorization of 732 patients (25.3%) as positive and 2159 patients (74.7%) as negative for DRB1*15:01 or *15:02 (DR15). There were no significant differences in baseline characteristics between the HLA DR15 positive and negative groups. In univariate analysis, HLA-DR15 status had no impact on neutrophil engraftment, aGVHD, chronic GVHD (cGVHD), treatment-related mortality, relapse, disease-free survival, or overall survival (OS). In multivariate analysis, DR15 status showed no significant difference in aGVHD, cGVHD, OS, or relapse. In conclusion, DR15 status had no impact on major HLA-matched sibling donor hematopoietic cell transplant outcomes in this large and homogenous cohort of patients with leukemia and MDS.
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HLA-matched sibling transplantation for severe aplastic anemia: impact of HLA DR15 antigen status on engraftment, graft-versus-host disease, and overall survival.
Biol. Blood Marrow Transplant.
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The HLA class II DRB1 antigen DR15 (common alleles *1501, *1502) is an important marker in the pathobiology of severe aplastic anemia (SAA). We studied 1204 recipients of HLA-matched sibling bone marrow transplantation for SAA to determine whether HLA DR15 status (as determined by allele-level typing) affected hematopoietic recovery, graft-versus-host disease (GVHD), or overall survival (OS). In multivariate analysis, secondary graft failure rate at 2 years was lower in patients who were HLA DR15+ (hazard ratio = 0.46, P = .01). However, neutrophil recovery at day -28, platelet recovery at day -100, acute GVHD, chronic GVHD, and overall mortality were independent of DR15 status. The 5-year probabilities of OS, after adjusting for age, race, performance score, transplant-conditioning regimen, and year of transplantation, were 78% and 81% for patients who were HLA DR15+ and HLA DR15-, respectively (P = .35). In conclusion, DR15 status is associated with secondary graft failure after HLA-matched sibling bone marrow transplantation for SAA but has no significant impact on survival.
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Role of minimal residual disease monitoring in acute promyelocytic leukemia treated with arsenic trioxide in frontline therapy.
Blood
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Data on minimal residual disease (MRD) monitoring in acute promyelocytic leukemia (APL) are available only in the context of conventional all-trans retinoic acid plus chemotherapy regimens. It is recognized that the kinetics of leukemia clearance is different with the use of arsenic trioxide (ATO) in the treatment of APL. We undertook a prospective peripheral blood RT-PCR-based MRD monitoring study on patients with APL treated with a single agent ATO regimen. A total of 151 patients were enrolled in this study. A positive RT-PCR reading at the end of induction therapy was significantly associated on a multivariate analysis with an increased risk of relapse (relative risk = 4.9; P = .034). None of the good risk patients who were RT-PCR negative at the end of induction relapsed. The majority of the relapses (91%) happened within 3 years of completion of treatment. After achievement of molecular remission, the current MRD monitoring strategy was able to predict relapse in 60% of cases with an overall sensitivity and specificity of 60% and 93.2%, respectively. High-risk group patients and those that remain RT-PCR positive at the end of induction are likely to benefit from serial MRD monitoring by RT-PCR for a period of 3 years from completion of therapy.
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Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia.
Pharmacogenomics
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Cytidine deaminase (CDA) irreversibly deaminates cytarabine (Ara-C), a key component of acute myeloid leukemia (AML) induction and consolidation therapy. CDA overexpression results in Ara-C resistance, while decreased expression is associated with toxicity. We evaluated factors influencing variation in CDA mRNA expression in adult AML patients and normal controls, and how they contributed to Ara-C cytotoxicity in AML cells.
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Polymorphisms in the immunoregulatory genes are associated with hematopoietic recovery and increased susceptibility to bacterial infections in patients with thalassaemia major undergoing matched related hematopoietic stem cell transplantation.
Biol. Blood Marrow Transplant.
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In this study, the impact of polymorphisms in the genes of proinflammatory (IL-?, TNF-?, IL-6, IFN-?), anti-inflammatory (transforming growth factor [TGF]-?, IL-10, IL-Ra), and other immunoregulatory factors (Fc?RIIa, NOS3) along with the conventional risk factors on the rate of hematopoietic recovery and first episodes of bacterial, viral, or invasive fungal infections in 102 patients with ?-thalassaemia major who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with relatively uniform protocols at our center from June 1995 to June 2004 with a minimum follow-up of at least 2 years were studied retrospectively for 180 days after hematopoietic stem cell transplantation (HSCT). Our data show that (1) donor IL-1RN?2/2 (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.17-5.09; P = .018) and FC?RIIA +4481G/G genotypes (HR, 3.1; 95% CI, 1.56-6.31; P = .001) increased the incidence of bacterial infection; (2) fungal infection was increased in recipients with whose donors had IFN-? +874T/T genotype (HR, 3.8; 95% CI, 1.08-13.62; P = .037); (3) time to neutrophil recovery was shorter in splenectomized patients (HR, 3.1; 95% CI, 1.70-5.64; P < .001), donors without IL-10 -1082A, -819T, and -592A haplotype (HR, 1.6; 95% CI, 1.02-2.39; P = .039), and recipients with IFN-? +874A/A genotype (HR, 1.6; 95% CI, 1.05-2.56; P = .029); and (4) time to platelet recovery was shorter in patients with IL-10 -1082A/A genotype (HR, 1.8; 95% CI, 1.14-2.68; P = .010) and with donors having TNF-? -308G/G genotypes (HR, 1.8; 95% CI, 1.06-2.93; P = .028). These data suggest that outcome after allogeneic stem cell transplantation could be affected by many factors. The mechanisms by which they bring about such impact needs further evaluation.
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International reporting scale of BCR-ABL1 fusion transcript in chronic myeloid leukemia: first report from India.
Acta Haematol.
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Achieving a major molecular response (MMR) is an important predictor of progression-free survival in chronic myeloid leukemia patients treated with imatinib. This requires accurate measurement of BCR-ABL1 transcripts normalized to a control gene, as well as defining a level (BCR-ABL1/control gene ratio) that will correlate with sustained clinical response. To make these measurements comparable between laboratories, an international scale (IS) is necessary. A BCR-ABL1/control gene ratio of 0.10% represents MMR in the IS. In collaboration with an international reference laboratory in Adelaide, S.A., Australia, we have established and validated a lab-specific conversion factor for expressing BCR-ABL1 transcript levels in the IS. In this report, we explain the process and steps involved in obtaining a valid lab-specific conversion factor for expressing BCR-ABL1 transcript levels in the IS.
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A novel 26 bp deletion [HBB: c.20_45del26bp] in exon 1 of the ?-globin gene causing ?-thalassemia major.
Hemoglobin
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Molecular characterization of ?-thalassemia (?-thal) is essential in prevention and in understanding the biology of the disease. Deletion mutations are relatively uncommon in ?-thal. In this report, we describe a novel 26 bp deletion from codon 6 to codon 14 in the ?-globin in a consanguineous family from Tamil Nadu, India. This novel mutation causes a shift in the normal reading frame of the ?-globin coding sequence, and consequently, a premature chain termination of translation due to the creation of a stop codon at the position of codon 21. The identification of this novel deletional mutation adds to the repertoire of ?-thal mutations in India.
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Genotoxic stress and activation of novel DNA repair enzymes in human endothelial cells and in the retinas and kidneys of streptozotocin diabetic rats.
Diabetes Metab. Res. Rev.
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Mammalian excision repair cross-complementing 1 (ERCC1) and ERCC4 (a.k.a xeroderma pigmentosum complementation group F) are nucleotide excision repair enzymes, which excise the 5 end of damaged DNA. ERCC1 and ERCC4 have an interactive relationship with poly (adenosine diphosphate ribose) polymerase (PARP). We studied the role of ERCC1 and ERCC4 in glucose-induced extracellular matrix protein production in human endothelial cells and in the retinas and kidneys of streptozotocin diabetic rats.
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