Summary:chemotherapy does not exceed 5-10%. Advanced age (median, 65 years), renal function impairment and hematoThis report summarizes 2 years experience in perpoietic stem cell compromise due to prolonged alkylating forming 336 autotransplant procedures in 251 consecuagent therapy have delayed evaluation of high-dose chemotive patients with multiple myeloma, using high-dose therapy in MM, an approach that has proven to be successmelphalan at 200 mg/m 2 in the context of a tandem ful in the management of lymphomas. 2 Pilot studies in the transplant program. A total of 91 patients received 118 early 1980s revealed that drug-resistance in advanced MM transplants as outpatients while the remaining 160 could be overcome by dose-escalation of alkylating patients received 218 transplants as inpatients. Outagents. 3,4 As a result, numerous clinical trials have patients were more often younger, with better stem cell employed autologous stem cells, as well as colony-stimulatproducts, normal serum albumin and ␤-2-microglobuing factors, to support myeloablative therapy for MM. 5-9 A lin levels as well as chemotherapy-sensitive disease comrandomized clinical trial by French investigators has shown pared to inpatients. There were no differences in hemaautotransplant to be superior to standard chemotherapy in topoietic recovery and non-hematologic toxicities the management of newly diagnosed symptomatic myeloma between outpatient and inpatient transplant recipients.patients. 10 In the interest of offering this promising treatPost-transplant febrile neutropenia and most other ment strategy to a larger MM patient population, outpatient post-transplant toxicities were managed successfully in transplants were initiated at our institution and their safety, an ambulatory setting. Although liberal criteria were efficacy, and cost-effectiveness were examined. developed for hospitalization of outpatients, including High-dose melphalan was chosen as cytoreductive regiclinical parameters as well as patient desire and men because of its relative lack of extra-medullary toxicity, physician/nurse judgment, only 21% of outpatients even at 200 mg/m 2 . 11,12 The initiation of outpatient transrequired admission after transplantation. Median hosplants required a high degree of proficiency on the part of pital stay for these outpatients was 9 days, while inpathe transplant team and an adequate outpatient nursing and tients were hospitalized for a median of 15 days (P ‫؍‬ pharmacy infrastructure to ensure continuity of care, even 0.0001). After adjusting for differences in disease and at weekends. Because only two outpatient autotransplant host features, our study showed outpatient management procedures could be accommodated per week, patient perresulted in significant financial savings due to lower formance status and preference, as well as third-party pharmacy (42%), hospitalization (50%) and insurance payments influenced whether or not a patient was pathology/laboratory charges (36%). We conclude that accepted for outpatient transplantation....

Sphingolipids, a family of membrane lipids, are bioactive molecules that participate in diverse functions controlling fundamental cellular processes such as cell division, differentiation, and cell death. Given that most of these cellular processes form the basis for several pathologies, it is not surprising that sphingolipids are key players in several pathological processes. This review discusses the role of the sphingolipid metabolic pathway in diabetes, Alzheimer's disease, and hepatocellular carcinoma, with a special emphasis on the changes in gene expression pattern in these disease conditions. For convenience, the sphingolipid metabolic pathway is divided into hypothetical compartments (modules) with each compartment representing a physiological process and changes in gene expression pattern are mapped to each of these modules. It appears that alterations in the gene expression pattern in these disease conditions are biased to manipulate the system in order to result in a particular disease.

Rotavirus NSP4 is a multifunctional endoplasmic reticulum (ER)-resident nonstructural protein with the N terminus anchored in the ER and about 131 amino acids (aa) of the C-terminal tail (CT) oriented in the cytoplasm. Previous studies showed a peptide spanning aa 114 to 135 to induce diarrhea in newborn mouse pups with the 50% diarrheal dose approximately 100-fold higher than that for the full-length protein, suggesting a role for other regions in the protein in potentiating its diarrhea-inducing ability. In this report, employing a large number of methods and deletion and amino acid substitution mutants, we provide evidence for the cooperation between the extreme C terminus and a putative amphipathic ␣-helix located between aa 73 and 85 (AAH [73][74][75][76][77][78][79][80][81][82][83][84][85] ) at the N terminus of ⌬N72, a mutant that lacked the N-terminal 72 aa of nonstructural protein 4 (NSP4) from Hg18 and SA11. Cooperation between the two termini appears to generate a unique conformational state, specifically recognized by thioflavin T, that promoted efficient multimerization of the oligomer into high-molecular-mass soluble complexes and dramatically enhanced resistance against trypsin digestion, enterotoxin activity of the diarrhea-inducing region (DIR), and double-layered particle-binding activity of the protein. Mutations in either the C terminus, AAH 73-85 , or the DIR resulted in severely compromised biological functions, suggesting that the properties of NSP4 are subject to modulation by a single and/or overlapping highly sensitive conformational domain that appears to encompass the entire CT. Our results provide for the first time, in the absence of a three-dimensional structure, a unique conformation-dependent mechanism for understanding the NSP4-mediated pleiotropic properties including virus virulence and morphogenesis.Rotavirus is the most common cause of life-threatening, severe dehydrating diarrhea in children and animals (50). Rotavirus infection can be either symptomatic or asymptomatic. But the genetic/molecular basis for rotavirus virulence is not yet clearly understood. The recent identification of the nonstructural protein 4 (NSP4) as the first viral enterotoxin has attracted considerable attention toward understanding its structure and function. But analysis of NSP4 sequences from more than 175 strains failed to reveal any sequence motifs or amino acids that segregated with the virulence phenotype of the virus. Furthermore, a peptide spanning amino acids (aa) 114 to 135 was reported to induce diarrhea at an approximately 100-fold molar excess compared to the full-length protein (6). This suggested that other regions in the protein might influence its diarrhea-inducing potential. Also, the extreme C terminus, including the terminal methionine, was shown to be important for double-layered particle (DLP)-binding activity. NSP4 is 175 aa in length, with the N-terminal region anchored in the endoplasmic reticulum (ER) and approximately 131 aa of the C terminus oriented in the cytoplasm. The...

In an epidemiological study of symptomatic human rotaviruses in Mysore, India during 1993 and 1994, isolates MP409 and MP480 were isolated from two children suffering from severe, acute dehydrating diarrhea. Both isolates exhibited 'long' RNA pattern and subgroup I specificity suggesting the likelihood of their animal origin. Both isolates did not react with monoclonal antibodies (MAbs) specific for serotypes G1 to G6 as well as G10. To determine the genetic origin of these isolates, complete nucleotide sequences of genes encoding the outer capsid proteins VP4 and VP7, nonstructural proteins NSP1 and NSP3 and viral enterotoxin protein NSP4 from MP409 and partial sequences of genes from MP480 were determined. Comparison of the 5' and 3' terminal sequences of 250 nucleotides revealed complete identity of the gene sequences in both strains suggesting that MP409 and MP480 are two different isolates of a single strain. Comparison of the nucleotide and deduced amino acid sequences of VP4, VP7, NSP1 and NSP3 of MP409 with published sequences of strains belonging to different serotypes revealed that both outer capsid proteins VP4 and VP7 and NSPI are highly related to the respective proteins from the P6[1], G8 type bovine rotavirus A5 isolated from a calf with diarrhoea in Thailand and that the NSP3 is highly homologous to that of bovine rotaviruses. The NSP4 protein showed greatest sequence identity with NSP4s belonging to the KUN genetic group to which NSP4s from human G2 type strains and bovine rotaviruses belong. MP409 and MP480 likely signify interspecies transmission of P6[1], G8 type strains from cattle to humans and represent the first P6[1] type rotaviruses isolated in humans. These and our previous studies on the asymptomatic neonatal strain 1321 are of evolutionary and epidemiological significance in the context of close association of majority of the Indian population with cattle.