Anti fi larial potential of the fruits and leaves extracts of Pongamia pinnata on cattle filarial parasite Setaria cervi

The effect of aqueous and alcohol extracts of the fruits and leaves of Pongamia pinnata (Linn.) Merr. (Syn. Pongamia glabra Vent, leguminosae) on the spontaneous movements of both the whole worm and the nerve-muscle preparation of Setaria cervi and on the survival of micro fi lariae in vitro was studied. The aqueous and alcohol extracts of fruits and the alcohol extract of leaves caused an inhibition of spontaneous movements of the whole worm and the nerve-muscle preparation of S. cervi. The initial stimulatory effect was not observed with the aqueous extract of fruits on the nerve-muscle preparation. The concentration required to inhibit the movements of the whole worm preparation was 250 micro g/mL for aqueous, 120 micro g/mL for alcohol extract of fruits and 270 microgram/mL for alcohol extracts of the leaves. The concentrations of P. pinnata extracts required to produce an equivalent effect on the nerve-muscle preparation were 25 micro g/mL, 5 micro g/mL and 20 micro g/mL, respectively, suggesting a cuticular permeability barrier.     

Physiologic Transdermal Estradiol Replacement Mimics Effects of Endogenous Estrogen on Bone Outcomes in Hypoestrogenic Women with Anorexia Nervosa

Background: While physiologic estrogen replacement results in increases in areal bone mineral density (aBMD) in hypoestrogenic adolescent girls and young adult women with AN, data are lacking regarding its impact on measures of volumetric BMD (vBMD), bone geometry, and structure. Methods: 23 young women with anorexia nervosa (AN) and 27 normal-weight healthy controls (HC) between 14–25 years old were followed for 12 months. AN participants received transdermal 17β-estradiol (continuously) with 10 days of cyclic oral progesterone (100 mg daily) every month for the study duration (AN-E+). DXA was used to measure aBMD and body composition, high resolution peripheral quantitative CT (HRpQCT) to assess vBMD, bone geometry and structure at the distal radius and tibia, and microfinite element analysis to estimate strength. Results: Groups did not differ for age. Median baseline BMI z-scores were −1.13 (−1.58, −0.38) in AN-E+ vs. 0.08 (−0.40, 0.84) in HC (p < 0.0001). For most HRpQCT parameters and strength estimates, young women with AN receiving physiologic estrogen replacement demonstrated similar changes over 12 months as did normoestrogenic HC. Additionally, radial cortical tissue mineral density, cortical vBMD, and failure load increased (p = 0.01; p = 0.02; p = 0.004 respectively) over 12 months in AN-E+ compared to HC. Conclusions: With physiologic estrogen replacement, bone accrual improved in AN to approximate changes observed in normoestrogenic controls followed without any intervention, with additional benefits observed for cortical tissue mineral density, cortical vBMD, and failure load at the radius in AN vs. controls. Thus, this strategy for estrogen replacement effectively mimics the effects of endogenous estrogen on bone structure and estimated strength.     

The Impact of Hot Melt Extrusion and Spray Drying on Mechanical Properties and Tableting Indices of Materials Used in Pharmaceutical Development

The impact of melt extrusion (HME) and spray drying (SD) on mechanical properties of hypromellose acetate succinate (HPMCAS), copovidone, and their formulated blends was studied and compared with that of reference excipients. Tensile strength (TS), compression pressure (CP), elastic modulus (E), and dynamic hardness (H_d) were determined along with Hiestand indices using compacts prepared at a solid fraction of ～0.85. HPMCAS and copovidone exhibited lower H_d, lower CP, and lower E than the reference excipients and moderate TS. HPMCAS was found to be highly brittle based on brittle fracture index values. The CP was 24% and 61% higher for HPMCAS after SD and HME, respectively, than for unprocessed material along with a higher H_d. Furthermore, the TS of HPMCAS and copovidone decreased upon HME. Upon blending melt-extruded HPMCAS with plastic materials such as microcrystalline cellulose, the TS increased. These results suggest that SD and HME could impact reworkability by reducing deformation of materials and in case of HME, likely by increasing density due to heating and shear stress in a screw extruder. A somewhat similar effect was observed for the dynamic binding index (BI_d) of the excipients and formulated blends. Such data can be used to quantitate the impact of processing on mechanical properties of materials during tablet formulation development.     

Haploidentical vs autologous hematopoietic stem cell transplantation in patients with acute leukemia beyond first remission

This is a retrospective comparison of partially mismatched related donor transplantation (PMRDT) and autotransplantation (ABMT) in advanced acute leukemia. Patients underwent T-cell-depleted PMRDT (n=164) or ABMT (n=131) for acute myeloid leukemia (n=130) or acute lymphoblastic leukemia (n=165). Fewer PMRDT patients were in remission (29 vs 85%; P<0.0001). The 5-year cumulative incidence of transplant-related mortality (TRM) was 52% after PMRDT and 16% after ABMT (P<0.0001). The 5-year cumulative incidence of relapse was 32% after PMRDT and 54% after ABMT (P=0.006). The actuarial unadjusted 5-year disease-free survival (DFS) was 16% after PMRDT and 30% after ABMT. In Cox's regression analysis, PMRDT (P<0.0001) and age >15 years (P=0.002) were associated with higher TRM, active disease (P=0.0021), ABMT (P=0.0074) and male sex (P=0.011) with higher relapse, and age >15 years (P=0.0007) and PMRDT (P=0.047) with lower DFS. Amongst second remission patients, TRM was higher after PMRDT (P=0.0003), relapse was higher after ABMT (P=0.034), and 5-year DFS was comparable (32% ABMT and 25% PMRDT). ABMT, if feasible, may be preferable to PMRDT in advanced acute leukemia patients since lower relapse after PMRDT is offset by higher TRM. If an autograft is not feasible because of nonavailability of autologous cells or very advanced disease, PMRDT is a potential alternative.     

Impact of cytogenetics on the outcome of autotransplantation for acute myeloid leukemia in first remission: is the benefit of intensive pretransplant therapy limited to patients with good karyotypes?

A total of 81 adults with acute myeloid leukemia (AML) (47% favorable karyotypes) were autografted in first remission after melphalan-total body irradiation, having received 0 (n=7), 1 (n=19), 2 (n=51), or 3 (n=4) consolidation chemotherapy cycles before harvest. The cumulative 5-year incidences of relapse and transplant-related mortality were 37 and 17%, respectively. The actuarial 5-year probability of disease-free survival (DFS) was 46%. In Cox analysis, favorable karyotypes, increasing numbers of consolidation cycles (0 vs > or =1 or 1 vs >1), and higher nucleated cell doses were associated with lower relapse rates and higher DFS. Patients with favorable karyotypes benefited from every additional cycle of consolidation therapy (0 vs > or =1 as well as 1 vs >1). Among patients with other karyotypes, while the benefit of one cycle of consolidation was clear (0 vs > or =1), there was no obvious beneficial impact of further consolidation therapy (1 vs >1). Administration of consolidation chemotherapy prior to harvest is essential in AML. While it is possible to enhance the benefit of consolidation with favorable karyotypes by delivering two cycles, its usefulness is limited in others. In them, it may be worthwhile exploring alternatives not normally used in AML (eg high-dose cyclophosphamide) that could have antileukemic effects while permitting mobilization of stem cells.     

Collection of peripheral blood stem cells in newly diagnosed myeloma patients without any prior cytoreductive therapy: the first step towards an 'operational cure'?

We have shown that primary therapy with non-myeloablative (140 mg/m(2)) high-dose melphalan (HDM) without hematopoietic support results in high response rates in untreated myeloma and very long-term survival of some patients. This study was designed to see if sufficient CD34 (+) cells can be harvested at presentation in newly diagnosed patients to administer myeloablative HDM (200 mg/m(2); HDM200) with autograft as primary therapy. This may improve outcome by rapid achievement of complete remission (CR) and possible avoidance of late myelodysplasia as a consequence of non-transplant induction chemotherapy. Thirty untreated patients received 1 g/m(2) methylprednisolone daily (days 1-6) and 12-16 micro g/kg G-CSF daily (days 3-6), and underwent leukapheresis on days 6 and 7. The median CD34(+) cell yield was 1.31 x10(6)/kg (range, 0.23-5.63), and was > or =1 x10(6)/kg in 73%. Cell yields were significantly lower than in 82 historical controls apheresed after completion of induction chemotherapy (median 2.16 x 10(6)/kg), and improved in patients who were apheresed again after induction chemotherapy. Three patients received primary therapy with HDM200 and autograft using these cells and attained CR. We conclude that it is possible to harvest stem cells in three-quarters of untreated myeloma patients. Increasing the number of apheresis procedures is needed to improve the number of CD34(+) cells collected.     

Decreased expression of phospholipase C-beta 2 isozyme in human platelets with impaired function

Platelets from a patient with a mild inherited bleeding disorder and abnormal platelet aggregation and secretion show reduced generation of inositol 1,4,5-trisphosphate, mobilization of intracellular Ca2+, and phosphorylation of pleckstrin in response to several G protein mediated agonists, suggesting a possible defect at the level of phospholipase C (PLC) activation (see accompanying report). A procedure was developed that allows quantitation of platelet PLC isozymes. After fractionation of platelet extracts by high-performance liquid chromatography, 7 out of 10 known PLC isoforms were detected by immunoblot analysis. The amount of these isoforms in normal platelets decreased in the order PLC- gamma 2 > PLC-beta 2 > PLC-beta 3 > PLC-beta 1 > PLC-gamma 1 > PLC- delta 1 > PLC-beta 4. Compared with normal platelets, platelets from the patient contained approximately one-third the amount of PLC-beta 2, whereas PLC-beta 4 was increased threefold. These results suggest that the impaired platelet function in the patient in response to multiple G protein mediated agonists is attributable to a deficiency of PLC-beta 2. They document for the first time a specific PLC isozyme deficiency in human platelets and provide an unique opportunity to understand the role of different PLC isozymes in normal platelet function.     

Impact of previous high-dose therapy on outcome after allografting for multiple myeloma

We describe a single centre experience of 33 patients allografted for multiple myeloma, of which 28 received matched sibling marrow, one haploidentical family donor marrow and four matched but unrelated donor marrow. Median follow-up after transplant is 27 months, and 13 patients are currently alive. One out of four patients with an unrelated donor survives and 12 out of 28 (42.8%) with matched sibling donors. Four patients were unevaluable because of early death (相似文献   

Human platelet signaling defect characterized by impaired production of inositol-1,4,5-triphosphate and phosphatidic acid and diminished Pleckstrin phosphorylation: evidence for defective phospholipase C activation

Signal transduction on platelet activation involves phosphoinositide- specific phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositides and formation of inositol-1,4,5-triphosphate [I(1,4,5)P3], which mediates Ca2+ mobilization, and diacylglycerol (DG), which activates protein kinase C (PKC) to phosphorylate a 47-kD protein (Pleckstrin). We studied these events in two related patients previously reported (Blood 74:664, 1989) to have abnormal aggregation and 14C-serotonin secretion, and impaired intracellular Ca2+ mobilization in response to several agonists. Thrombin-induced I(1,4,5)P3 and phosphatidic acid formation were diminished. Pleckstrin phosphorylation was impaired on activation with thrombin, platelet- activating factor, and ionophore A23187, but was normal with PKC activator 1,2-dioctonyl-sn-glycerol (DiC8). Ca2+ mobilization induced by guanosine triphosphate (GTP) analog guanosine 5'-0-(3 thiotriphosphate) (GTP gamma S) was diminished. Pretreatment with either A23187 or DiC8 did not correct the impaired adenine diphosphate- induced secretion; however, upon stimulation with A23187 plus DiC8, pleckstrin phosphorylation and secretion were normal, indicating that both PKC activation and Ca2+ mobilization are essential for normal secretion. We conclude that these patients have a unique inherited platelet defect in formation of two key intracellular mediators [I(1,4,5)P3 and DG] and in the responses mediated by them due to a defect in postreceptor mechanisms of PLC activation.