Modified LSA2-L2 treatment in 53 children with E-rosette-positive T- cell leukemia: results and prognostic factors (a Pediatric Oncology Group Study)

In an attempt to improve the poor outlook for children with T-cell leukemia (T-ALL), the Southwest Oncology Group, Pediatric Division, used a modified LSA2-L2 multidrug regimen to treat 53 patients with E- rosette-positive T-ALL. This regimen was chosen because of its demonstrated efficacy in T-cell (mediastinal) non-Hodgkin's lymphoma. Complete remission (CR) rate was 88%. Range of follow-up for those patients remaining in CR is 24-49 mo (median 39 mo). Life table analysis estimates that 40% (SE 8.3%) of all patients who started induction therapy will remain failure-free at 3 yr. For patients achieving CR, 46% (SE 9%) are projected to remain in both marrow and extramedullary CR at 3 yr. Median failure-free duration was 13 mo, but only 1 patient has relapsed beyond 16 mo. Twenty-nine percent of initial relapses were isolated CNS relapses. The following presenting factors did not relate significantly to outcome: hemoglobin, platelet count, uric acid, race, and mediastinal mass. Age greater than 10 yr was a poor prognosis indicator only in the less than 50,000/microliter WBC group. Sex was not a significant factor after adjusting for WBC. WBC was the most important prognostic factor: 19% (SE 8%) of patients with WBC greater than 50,000/microliter are projected to remain failure- free at 3 yr as compared to 67% (SE 11%) of patients with WBC less than 50,000/microliter. Although the overall results are better than those previously reported for pediatric patients with T-ALL, the long-term failure-free rate remains low for patients presenting with greater than 50,000/microliter WBC.     

Spontaneous generation and survival of blood dendritic cells in mononuclear cell culture without exogenous cytokines

Studies on purified blood dendritic cells (DCs) are hampered by poor viability in tissue culture. We, therefore, attempted to study some of the interactions/relationships between DCs and other blood cells by culturing unseparated peripheral blood mononuclear cell (PBMC) preparations in vitro. Flow cytometric techniques were used to undertake a phenotypic and functional analysis of DCs within the cultured PBMC population. We discovered that both the CD11c(+) and CD11c(-) CD123(hi) DC subsets maintained their viability throughout the 3-day culture period, without the addition of exogenous cytokines. This viability was accompanied by progressive up-regulation of the surface costimulatory (CD40, CD80, CD86) and activation (CMRF-44, CMRF-56, CD83) molecules. The survival and apparent production of DCs in PBMC culture (without exogenous cytokines) and that of sorted DCs (with cytokines) were evaluated and compared by using TruCOUNT analysis. Absolute DC counts increased (for CD123(hi) and CD11c(+) subsets) after overnight culture of PBMCs. Single-cell lineage depletion experiments demonstrated the rapid and spontaneous emergence of "new" in vitro generated DCs from CD14(+)/CD16(+) PBMC radioresistant precursors, additional to the preexisting ex vivo DC population. Unlike monocyte-derived DCs, blood DCs increased dextran uptake with culture and activation. Finally, DCs obtained after culture of PBMCs for 3 days were as effective as freshly isolated DCs in stimulating an allogeneic mixed leukocyte reaction.     

Plasmic degradation of crosslinked fibrin. I. Structural analysis of the particulate clot and identification of new macromolecular-soluble complexes

Plasmic degradation of crosslinked fibrin has been studied to identify the proteolytic cleavages that convert the clot into a soluble lysate and also to identify the derivatives that are likely to circulate during clot dissolution. Initial polypeptide chain cleavages do not disrupt the solid clot matrix. With continued exposure to plasmin, high molecular weight derivatives are produced that remain attached to the clot by noncovalent forces. Further degradation then results in the liberation into solution of several large, noncovalently bound complexes. Progressive degradation of the largest, initially liberated complexes to the terminal derivatives, DD/E, DD, and E, occurs in solution after their release from the clot. As the fibrin clot is exposed to plasmin for longer intervals, progressive dissolution occurs, but the structure of the covalently bound insoluble fibrin core, the noncovalently attached derivatives, and the liberated complexes remains constant. Since much of the initially liberated protein is in complexes larger than DD/E, these derivatives probably represent the more prevalent plasmic degradation products of crosslinked fibrin in vivo.     

The effect of cycling deflection on the injection-molded thermoplastic denture base resins

Objective. The aim of this study was to evaluate the effect of cycling deflection on the flexural behavior of injection-molded thermoplastic resins. Materials and methods. Six injection-molded thermoplastic resins (two polyamides, two polyesters, one polycarbonate, one polymethyl methacrylate) and, as a control, a conventional heat-polymerized denture based polymer of polymethyl methacrylate (PMMA) were used in this study. The cyclic constant magnitude (1.0 mm) of 5000 cycles was applied using a universal testing machine to demonstrate plasticization of the polymer. Loading was carried out in water at 23ºC with eight specimens per group (n = 8). Cycling load (N) and deformation (mm) were measured. Results. Force required to deflect the specimens during the first loading cycle and final loading cycle was statistically significantly different (p < 0.05) with one polyamide based polymer (Valplast) and PMMA based polymers (Acrytone and Acron). The other polyamide based polymer (LucitoneFRS), polyester based polymers (EstheShot and EstheShotBright) and polycarbonate based polymer (ReigningN) did not show significant differences (p > 0.05). None of the materials fractured during the loading test. One polyamide based polymer (Valplast) displayed the highest deformation and PMMA based polymers (Acrytone and Acron) exhibited the second highest deformation among the denture base materials. Conclusion. It can be concluded that there were considerable differences in the flexural behavior of denture base polymers. This may contribute to the fatigue resistance of the materials.     

Tumor necrosis factor alpha-induced endothelial tissue factor is located on the cell surface rather than in the subendothelial matrix

Because there is no consensus regarding the precise distribution of induced endothelial tissue factor (TF), we studied TF activity in and on tumor necrosis factor alpha-stimulated cultured human umbilical vein endothelial cells (ECs) and their underlying matrix. TF was mainly expressed on the cell surface. Only small traces were found on the apical surface suggesting that TF is predominantly located on the basolateral side of the cell membrane. The presence of TF on the cell surface was confirmed by flow cytometry. Subendothelial TF activity appeared to be dependent upon the procedure used to remove the stimulated EC monolayer. Whereas ammonium hydroxide or hypotonic lysis resulted in relatively high levels of matrix-associated TF, virtually no TF was found on the matrix after mild enzymatic detachment of stimulated ECs. Cell removal with EDTA resulted in intermediate levels of matrix-associated TF. Neither the enzymatic treatment nor EDTA degraded or removed this TF activity. Similar patterns were observed for matrix-associated TF antigen and EC surface markers. Electron microscopic analysis showed cell fragments on the matrix after monolayer lysis. The findings strongly suggest that induced endothelial TF associated with the subendothelial matrix actually represents TF on EC remnants.     

Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques

In 2012, a novel betacoronavirus, designated Middle East respiratory syndrome coronavirus or MERS-CoV and associated with severe respiratory disease in humans, emerged in the Arabian Peninsula. To date, 108 human cases have been reported, including cases of human-to-human transmission. The availability of an animal disease model is essential for understanding pathogenesis and developing effective countermeasures. Upon a combination of intratracheal, ocular, oral, and intranasal inoculation with 7 × 10⁶ 50% tissue culture infectious dose of the MERS-CoV isolate HCoV-EMC/2012, rhesus macaques developed a transient lower respiratory tract infection. Clinical signs, virus shedding, virus replication in respiratory tissues, gene expression, and cytokine and chemokine profiles peaked early in infection and decreased over time. MERS-CoV caused a multifocal, mild to marked interstitial pneumonia, with virus replication occurring mainly in alveolar pneumocytes. This tropism of MERS-CoV for the lower respiratory tract may explain the severity of the disease observed in humans and the, up to now, limited human-to-human transmission.In June of 2012, a novel betacoronavirus, associated with severe respiratory disease in humans emerged in the Middle East (1, 2), which is closely related to betacoronaviruses circulating in bats (3, 4). The first isolate of Middle East respiratory coronavirus (MERS-CoV) (5), HCoV-EMC/2012, was obtained from a patient with a fatal pneumonia and acute renal failure. To date, 107 additional human cases have been identified, of which 49 were fatal (6). Aside from cases in Saudi Arabia, Qatar, Jordan, and the United Arab Emirates, imported cases have been identified in the United Kingdom, Germany, France, Tunisia, and Italy (6). Although no information is available on the source or route of primary transmission of MERS-CoV, human-to-human transmission has been recorded (7–9). Clinical data on human cases of MERS-CoV infection are currently sparse, but it appears that this virus mainly causes severe lower respiratory tract disease, occasionally accompanied by renal disease. The severity of disease distinguishes MERS-CoV from other coronaviruses circulating in the human population, HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, which are generally associated with upper respiratory tract infections. Instead, MERS-CoV appears to be more similar to the severe respiratory disease caused by severe acute respiratory syndrome (SARS)-CoV.In vitro studies have shown that MERS-CoV replicates efficiently in nonciliated cells in the primary human airway epithelium (10), and in ex vivo human lung cultures MERS-CoV replicated in bronchial, bronchiolar, and alveolar epithelial cells (11), in line with the observed respiratory disease in humans. The recently defined receptor for MERS-CoV, dipeptidylpeptidase 4 (DPP4), is generally expressed in endothelial and epithelial cells and has been shown to be present on cultured human nonciliated bronchiolar epithelium cells (12), providing further information on the respiratory tropism of MERS-CoV.Animal models that recapitulate human disease are essential for understanding pathologic processes involved in disease progression. Moreover, these models are instrumental for the development of prophylactic and therapeutic countermeasures. We have previously shown that rhesus macaques inoculated with a high dose of MERS-CoV isolate HCoV-EMC/2012 developed a respiratory disease reminiscent of that observed in humans (13). To increase our understanding of the pathogenesis of MERS-CoV in the absence of clinical and pathological data from human patients, we present herein a more detailed analysis of the extent of virus replication, the histopathological changes in the respiratory tract and changes in systemic (peripheral blood mononuclear cell, PBMC) and local (lung tissue) gene expression of MERS-CoV–infected rhesus macaques.     

Indian Systems of Medicine: A Brief Profile

Medicinal plants based traditional systems of medicines are playing important role in providing health care to large section of population, especially in developing countries. Interest in them and utilization of herbal products produced based on them is increasing in developed countries also. To obtain optimum benefit and to understand the way these systems function, it is necessary to have minimum basic level information on their different aspects. Indian Systems of Medicine are among the well known global traditional systems of medicine. In this review, an attempt has been made to provide general information pertaining to different aspects of these systems. This is being done to enable the readers to appreciate the importance of the conceptual basis of these system in evolving the material medica. The aspects covered include information about historical background, conceptual basis, different disciplines studied in the systems, Research and Development aspects, Drug manufacturing aspects and impact of globalization on Ayurveda. In addition, basic information on Siddha and Unani systems has also been provided.