Inability of dimethyl sulfoxide to increase brain uptake of water-soluble compounds: implications to chemotherapy for brain tumors

There is conflicting evidence as to whether dimethyl sulfoxide (DMSO) can reversibly open the blood-brain barrier and augment brain uptake of water-soluble compounds, including anticancer agents. To investigate this, 125I-human serum albumin, horseradish peroxidase, or the anticancer drug melphalan was administered iv to rats or mice, either alone or in combination with DMSO. Some animals received an additional ip priming dose of DMSO. The regional brain concentrations of each substance were measured after the animals were killed. DMSO administration did not significantly increase the brain uptake of any of the compounds as compared to control uptakes. These results do not support prior reports that DMSO increases the permeability of water-soluble agents across the blood-brain barrier.     

Growth characteristics of circulating hematopoietic progenitor cells from patients with essential thrombocythemia

Peripheral blood mononuclear cells from five patients with essential thrombocythemia (ET) were cultured in vitro to evaluate restricted megakaryocytic (CFU-Meg), myeloid (CFU-GM), and erythroid (BFU-E) progenitor cell development. Varying concentrations of aplastic canine serum served as the source of megakaryocyte colony-stimulating activity, and cultured megakaryocyte ploidy distributions were determined by Feulgen staining and microfluorometry. Megakaryocyte colony growth was strikingly abnormal in all five patients evaluated. Four of the 5 had a marked expansion in the concentration of circulating CFU-Meg and 3 of 4 manifested abnormalities in cultured megakaryocyte colony size (2 unusually large and 1 small). Unstimulated megakaryocyte colony growth was substantially increased in three patients. However, the fraction of megakaryocyte progenitors in cell cycle was near or below normal in all instances. Endomitotic megakaryocyte development was disordered in each of the four ET patients in whom it was evaluable. In normal subjects, mean megakaryocyte ploidy values vary biphasically with aplastic canine serum concentration and peak at 13.2 N following 12 to 15 days of culture. In contrast, day 12 mean ploidy values in cultures from the ET patients remained low at all aplastic canine serum concentrations and reached a maximum averaging only 8.4 N. Three patients were evaluated serially at extended culture durations of up to 21 days. The cultured megakaryocyte ploidy was unchanged during this interval for two of the patients. For the third patient, ploidy increased steadily, reaching abnormally high ploidy values by day 21. Progenitor cell expansion was limited to the megakaryocyte line in three patients. However, two patients had substantial increases in CFU-GM, one of whom also had a marked increase in BFU-E. There was no significant unstimulated colony growth by either CFU-GM or BFU-E. These data indicate that ET is usually characterized by an expansion in the concentration of circulating CFU-Meg in vivo which manifest both disordered replication and endoreduplication in vitro.     

Multilevel Analysis of Women's Empowerment and HIV Prevention: Quantitative Survey Results from a Preliminary Study in Botswana

This preliminary study explored relationships between women's empowerment and HIV prevention on the national and individual level with a focus on Botswana. Among sub-Saharan Africa countries, HIV prevalence was positively correlated with indirect indicators of women's empowerment relating to their education (female enrollment in secondary education and ratio of female to male secondary school enrollment), but not to their economic status (female share of paid employment in industry and services) or political status (women's share of seats in national parliament), while controlling for gross national income, percentage of births attended, and percentage of roads paved. Condom use at last sexual encounter was positively and significantly correlated with both indicators of women's educational empowerment, but was not significantly related to the other two indices. Empowerment at the individual level was explored through a preliminary quantitative survey of 71 sexually active women in Gaborone, Botswana, that was conducted in February 2001. Regression analyses showed that women's negotiating power and economic independence were the factors most strongly related to condom use, and did not show that education was a crucial factor. Economic independence was the factor most strongly related to negotiating power. These results suggest that in Botswana, HIV prevention efforts may need to improve women's negotiating skills and access to income-generating activities.     

Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study

A phase III prospective randomized multicenter study was performed to determine whether quinine could improve the response rate of poor-risk acute leukemias (ALs) to standard chemotherapy including a multidrug resistance (MDR)-related cytotoxic agent. The rationale of the study was based on the negative prognostic value of MDR phenotype in ALs and the ability of quinine to reverse this phenotype both in vitro and ex vivo. Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia (AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia (ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5) and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion beginning 24 hours before MXN infusion). Side effects of quinine were observed in 56 of 161 quinine-treated patients and disappeared in all but four cases after one or two 20% dose decreases. Sera from quinine-treated patients showed increased MXN uptake in an MDR-positive cell line compared with matched sera obtained before quinine infusion. Quinine induced a significant increase in the incidence of nausea, vomiting, mucositis, and cardiac toxicity. A complete response (CR) was observed in 85 of 161 patients (52.8%) from the quinine-treated group versus 70 of 154 patients (45.5%) in the control group (P = .19). The most important differences between quinine and control group CR rates were observed in patients with refractory AMLs and blastic transformation of MDS and MPS. The CR rate was higher in P-glycoprotein-positive cases, although the difference was not significant. Failure of the regimen due to blastic persistence or blast number increase was higher in the control group (61 of 154 patients) than in the quinine group (45 of 161, P = .04). Early death was observed in eight cases (four in each arm) and death in aplasia in 27 cases (20 in quinine group v seven in control group, P = .01). The significant increase of toxicity in the quinine arm could have masked the clinical benefit of MDR reversion in poor- risk ALs.     

Age-related impairment of cerebral blood flow response to KATP channel opener in Alzheimer’s disease mice with presenilin-1 mutation

Local cerebral blood flow (CBF) responses to neuronal activity are essential for cognition and impaired CBF responses occur in Alzheimer’s disease (AD). In this study, regional CBF (rCBF) responses to the K_ATP channel opener diazoxide were investigated in 3xTgAD, WT and mutant Presenilin 1(PS1_M146V) mice from three age groups using Laser-Doppler flowmetry. The rCBF response was reduced early in young 3xTgAD mice and almost absent in old 3xTgAD mice, up to 30%–40% reduction with altered CBF velocity and mean arterial pressure versus WT mice. The impaired rCBF response in 3xTgAD mice was associated with progression of AD pathology, characterized by deposition of intracellular and vascular amyloid-β (Aβ) oligomers, senile plaques and tau pathology. The nitric oxide synthase (NOS) inhibitor N^ω-nitro-L-arginine abolished rCBF response to diazoxide suggesting NO was involved in the mediation of vasorelaxation. Levels of phosphor-eNOS (Ser1177) diminished in 3xTgAD brains with age, while the rCBF response to the NO donor sodium nitroprusside remained. In PS1_M146V mice, the rCBF response to dizoxide reduced and high molecular weight Abeta oligomers were increased indicating PS1_M146V contributed to the dysregulation of rCBF response in AD mice. Our study revealed an Aβ oligomer-associated compromise of cerebrovascular function in rCBF response to diazoxide in AD mice with PS1_M146V mutation.     

Beneficial effects of SK&F 105809, a novel cytokine-suppressive agent, in murine models of endotoxin shock.

SK&F 105809 is a structurally novel dual inhibitor of lipoxygenase and cyclooxygenase-mediated arachidonic acid (AA) metabolism, which has demonstrated antiinflammatory activity in rodent models of inflammation. In addition, the active metabolite of this compound, SK&F 105561, has been shown in vitro to inhibit the production of the inflammatory cytokine interleukin-1 (IL-1) in human monocytes stimulated with lipopolysaccharide (LPS). We report here that in vitro SK&F 105561 also blocks the production of tumor necrosis factor (TNF) from human monocytes (IC50 0.8-3 microM). Furthermore, in a murine model of endotoxin shock in which animals are injected with LPS in combination with D-galactosamine (D-gal), SK&F 105809 (10, 30, and 100 mg/kg p.o.), delivered 30 min prior to LPS/D-gal, caused a dramatic reduction in serum TNF (40-90%) and protected the animals from the lethal effects of this treatment. Similar results were obtained in a second model of endotoxin shock in which mice were sensitized with Propionibacterium acnes 10 days prior to LPS injection. In this system 100-fold higher levels of serum TNF are elicited than with the LPS/D-gal model. Treatment with SK&F 105809 (30 and 100 mg/kg p.o.) delivered 30 min prior to LPS resulted in 90-100% inhibition of serum TNF. Protection from the lethal effects of LPS was observed at these doses in the P. acnes/LPS model.     

Liver-derived fetal hematopoietic stem cells selectively and preferentially home to the fetal bone marrow

In the course of ontogeny, the homing site for the hematopoietic stem cells (HSC) moves with certain predictability from the yolk sac to the liver/spleen and then to the marrow. The pattern of this migration has thus far been established mostly on a morphologic basis. To delineate further the course of this migration and to gain insight into its possible mechanism, we used in utero transplantation of allogeneic or xenogeneic HSC in preimmune sheep fetuses. Sex chromosome, type of hemoglobin, and species-specific surface markers were used to follow the path of transplanted cells in the fetus. Before the development of the bone marrow, transplanted HSC (liver- or marrow-derived) homed exclusively to the liver/spleen. With the development of marrow, around day 60 of gestation (term, 145 days), homing occurred also in the nascent marrow and by day 80 transplanted cells homed exclusively to the marrow. This suggests that there may be a hierarchy in homing sites, with those of the marrow having higher affinity than those of liver/spleen. Interestingly, despite a change in homing that was followed by the expansion of the marrow compartment of HSC (ie, HSC proliferation), these cells did not participate actively in blood cell formation during most of the prenatal period. Liver remained the major hematopoietic organ throughout the gestation. It was only during the perinatal period that this organ assumed the function of hematopoiesis from the liver. This lack of expression of HSC in fetal marrow can possibly be attributable to the immaturity of marrow stroma required for differentiation and maturation of progenitors and the orderly egress of mature cells into the blood stream. The availability of this model allows us to begin studies in the molecular mechanism of stem cell homing in vivo during ontogeny.     

TEMPORAL PATTERN OF KINESIOLOGY TAPE EFFICACY ON HAMSTRING EXTENSIBILITY

Background

Kinesiology tape has been advocated as a means of improving muscle flexibility, a potential modifiable risk factor for injury, over time. The epidemiology and etiology of hamstring injuries in sport have been well documented.

Purpose

To compare the temporal pattern of efficacy of kinesiology tape and traditional stretching techniques on hamstring extensibility over a five day period.

Study Design

Controlled laboratory study.

Methods

Thirty recreationally active male participants (Mean ± SD: age 20.0 ± 1.55 years; height 179.3 ± 4.94 cm; mass 76.9 ± 7.57 kg) completed an active knee extension assessment (of the dominant leg) as a measure of hamstring extensibility. Three experimental interventions were applied in randomized order: Kinesiology tape (KT), static stretch (SS), proprioceptive neuromuscular facilitation (PNF). Measures were taken at baseline, +1min, + 30mins, + 3days and +5days days after each intervention. The temporal pattern of change in active knee extension was modelled as a range of regression polynomials for each intervention, quantified as the regression coefficient.

Results

Hamstring ROM with KT application at +3days was significantly greater than baseline (129.18 ± 15.46%, p = 0.01), SS (106.99 ± 9.84%, p = 0.03) and PNF (107.42 ± 136.13%, p = 0.03) interventions. The temporal pattern of changes in ROM for SS and PNF were best modelled by a negative linear function, although the strength of the correlation was weak in each case. In contrast, the KT data was optimised using a quadratic polynomial function (r² = 0.60), which yielded an optimum time of 2.76 days, eliciting a predicted ROM of 129.6% relative to baseline.

Conclusion

Each intervention displayed a unique temporal pattern of changes in active knee extension. SS was best suited to immediate improvements, and PNF to +30 minutes in hamstring extensibility, whereas kinesiology tape offered advantages over a longer duration, peaking at 2.76 days. These findings have implications for the choice of intervention, timing and duration to assist clinicians in both a sporting and clinical context.

Level of evidence

2c