Alok Srivastava

Cells responding to dramatic environmental changes or undergoing a developmental switch typically change the expression of numerous genes. In bacteria, sigma factors regulate much of this process, whereas in eukaryotes, four RNA polymerases and a multiplicity of generalized transcription factors (GTFs) are required. Here, by using a systems approach, we provide experimental evidence (including protein-coimmunoprecipitation, ChIP-Chip, GTF perturbation and knockout, and measurement of transcriptional changes in these genetically perturbed strains) for how archaea likely accomplish similar large-scale transcriptional segregation and modulation of physiological functions. We are able to associate GTFs to nearly half of all putative promoters and show evidence for at least 7 of the possible 42 functional GTF pairs. This report represents a significant contribution toward closing the gap in our understanding of gene regulation by GTFs for all three domains of life and provides an example for how to use various experimental techniques to rapidly learn significant portions of a global gene regulatory network of organisms for which little has been previously known.

It has been long recognized that 10 to 15% of patients with "phenotypically characterized" severe hemophilia (< 1% clotting factor activity) have relatively mild disease clinically. Not all these patients have frequent spontaneous bleeding, and even among those who bleed, the extent of joint damage tends to vary considerably. The basis for this difference has not been completely understood. This article reviews the literature on possible determinants of phenotypic variation in patients with severe hemophilia. Apart from the well-recognized associations of the level of residual clotting factor activity, pharmacokinetics of administered clotting factor concentrates, and presence of prothrombotic markers, there is evidence to suggest that variations in other coagulation proteins as assessed in tests of global hemostasis as well as the fibrinolytic system can affect the clinical severity of bleeding. We also hypothesize that mediators of the inflammatory response in the synovium are likely to impact the severity of joint damage in these patients. One of the major issues in the management of hemophilia today is to decide on ways in which therapy, particularly the initiation and intensity of prophylaxis, can be individualized. A detailed understanding of all factors that may contribute to joint damage in severe hemophilia could help us in tailoring therapy for these individuals.

BACKGROUND: Limited data exists on the long-term treatment outcome and prognosis of childhood ALL in India. PROCEDURE: Three hundred and seven children (1-14 years) with acute lymphoblastic leukemia (ALL) were treated with a modified BFM protocol 76/79 between 1985 and 2003. Treatment outcome and prognostic factors were evaluated. RESULTS: The median age was 6 years; 78% had B lineage acute lymphoblastic leukemia and 22% had T lineage disease. Good prednisolone response was observed in 82% of cases. Two hundred and seventy-three children (91.6%) achieved complete remission; with 2% induction-related mortality and 6.4% having resistant disease. 52% of all evaluable patients and 56.8% of complete responders are in continuous complete remission (CCR) at a median follow up of 62 months (30-194 months). The median event free survival (EFS) was 114 months. The estimated 5 year overall survival, EFS and disease free survival was 59.8%, 56%, and 53.9%, respectively. The prognostic factors adversely affecting the EFS were poor prednisolone response, resistant disease and WBC count greater than 20 x 10(9)/L at diagnosis. The 5 year EFS in the favorable risk group (age 1-9 years, WBC count less than 20 x 10(9)/L and prednisolone good response) was 73.1 +/- 4.9%. CONCLUSION: This report examines a cohort of children with ALL treated with a BFM protocol in India with adequate follow up and demonstrates the need for cost effective improvements.