High potency dipeptide sweeteners. 1. L-aspartyl-D-phenylglycine esters

Twenty esters of L-aspartyl-D-phenylglycine, as well as two substituted analogues, an o-fluoro and a p-hydroxy-phenylglycine ester, were prepared. The L-aspartyl-D-phenylglycine (-)-alpha- and (+)-beta-fenchyl esters had the highest sweetness potency at 1200 and 3700 times that of sucrose, respectively. The high potency of these sweeteners is surprising as the phenyl group occupies a position previously believed to accommodate only much smaller groups.     

HIV-1 plasma RNA level and CD4 cell count in a large urban HIV-1-infected patient population from 1997 to 2000

We evaluated the change in plasma HIV-1 RNA level and CD4 cell counts in an HIV-1-infected population between 1997 and 2000. Both the mean and the median values of plasma HIV-1 RNA level decreased with time with the exception of 1998. The mean and medians for CD4 cell count appear to be fairly stable. While the percentage of patients with plasma HIV-1 RNA level <400 copies/mL increased from 29.12% in 1997 to 41.31% in 2000, the percentage of patients with plasma HIV-1 RNA level >100,000 copies/mL remained fairly constant. The availability of HAART had impacted the level of plasma HIV-1 RNA, although many patients still have plasma HIV-1 RNA level >100,000 copies/mL. Most patients with plasma HIV-1 RNA level >400 copies/mL in 1997 still have plasma HIV-1 RNA level >400 copies/mL in 2000. These laboratory findings, however, do not necessarily mean that there had been a lack of clinical benefit.     

Involvement of the peripheral benzodiazepine receptor in the development of cutaneous pathology in Mrl/Lpr mice

Mrl/Lpr mice develop inflammatory pathologies similar to human lupus erythematosus (LE). In that model, we showed a protective effect of different peripheral benzodiazepine receptor (PBR) ligands: PK 11195, Ro5-4864 and the newly described SSR180575 on the development of the cutaneous lesions. Specifically, we evidenced that a chronic treatment at 3 mg/kg per i.p. for 30 days prevented acanthosis, hyperkeratosis and generation of dermal infiltrates as compared with control untreated mice. In addition, using a specific polyclonal anti mouse PBR antibody, we characterized PBR expression in the skin lesions, and we observed that PBR expression in the epidermal component was increased when Mrl/Lpr mice developed the pathology and diminished upon PBR ligand treatment. PBR expression modulation together with the protective effects of its ligands further reinforce the role that PBR may play in the regulation of inflammation processes. Provided the exact mechanism of action that accounts for PBR action in that process is elucidated, these data support new therapeutic applications for specific potent PBR ligands.     

Neurotensin stimulates both calcium mobilization from inositol trisphosphate-sensitive intracellular stores and calcium influx through membrane channels in frog pituitary melanotrophs

Neurotensin (NT) is a potent stimulator of electrical and secretory activities in frog pituitary melanotrophs. The aim of the present study was to characterize the transduction pathways associated with activation of NT receptors in frog melanotrophs. Application of synthetic frog NT (fNT) increased the cytosolic calcium concentration ([Ca2+]c) and stimulated the formation of inositol trisphosphate (IP3). The phospholipase C inhibitor U-73122 blocked the electrophysiological and secretory effects of fNT. Intracellular application of the IP3 receptor antagonist heparin abolished fNT-induced electrical activity. Suppression of Ca2+ in the incubation medium markedly reduced the effect of NT on [Ca2+]c, firing rate, and alpha-melanocyte-stimulating hormone (alphaMSH) secretion. Similarly, the inhibitor of IP3-induced Ca2+ release and store-operated Ca2+ channels, 2-Aminoethoxydiphenylborane, and the nonselective Ca2+ channel blockers GdCl3 and NiCl2, attenuated the [Ca2+]c increase and the electrical and secretory responses evoked by fNT. Coapplication of the L- and N-type Ca2+ channel blockers nifedipine and omega-CgTx GVIA reduced the effects of fNT on action potential discharge, [Ca2+]c increase, and alphaMSH release. The protein kinase C (PKC) inhibitors, PKC-(19-31) and chelerythrine, reduced the electrophysiological and secretory responses induced by iterative applications of fNT. Collectively, these results demonstrate that, in frog melanotrophs, NT stimulates the phospholipase C/PKC pathway and increases [Ca2+]c. Both Ca2+ release from intracellular stores and Ca2+ influx through L- and N-type Ca2+ channels are involved in fNT-induced alphaMSH secretion. In addition, the present data indicate that PKC plays a crucial role in maintenance of the responsiveness of melanotrophs to NT.     

Immunogenic measles antigens expressed in plants: role as an edible vaccine for adults

Vaccine-induced immunity against measles is less robust than natural immunity. Waning of immunity in vaccines may eventually require a revaccination of adults. Measles antigens expressed in plants have been shown to be antigenic and immunogenic both after invasive and oral vaccination. Strategies for the vaccination of adults, the potential of an oral measles vaccine produced in edible plants and the design of suitable antigens are discussed.     

The role of dietary macronutrients in optimizing endurance performance

We have evaluated the evidence underlying certain key nutritional recommendations for endurance sporting activities. A relatively high daily carbohydrate (CHO) intake (> 6 g/kg/d) and CHO ingestion (30-60 g/h) during exercise appears to delay the onset of fatigue. However, the mechanisms of this effect are governed in part by an attenuation of effort perception, rather than solely as a consequence of delaying an impending energy crisis. CHO loading and ingestion also impart some neuroprotection from fatigue during prolonged exercise, as well as high-intensity, intermittent exercise. In addition, the individual response to short-term (5- to 6-day) ingestion of a high-fat diet (> 60% of calories from fat) followed by 1-day CHO loading seems to vary widely, and is most likely to be of benefit only during ultra-endurance activities. Furthermore, CHO and protein intake in the postexercise period aid in protein synthesis and restoration of muscle glycogen stores. However, athletes and their advisors must be prepared to try various nutritional strategies in order to optimize both performance and training.     

Chemotherapy prior to autologous bone marrow transplantation impairs long-term engraftment in mice

OBJECTIVE: Autologous bone marrow transplantation in cancer patients is often preceded by multiple cycles of chemotherapy. In this study, we assessed in a mouse model whether stem cells were affected by prior chemotherapy. METHODS: Donor mice were treated with three consecutive injections of 150 mg/kg 5-fluorouracil (5-FU). Peripheral blood counts were allowed to recover before the subsequent dose of 5-FU was given. Mice recovered from three doses of 5-FU and showed normal steady-state hematopoiesis. Bone marrow cells from these mice were mixed with congenic competitor cells and transplanted into lethally irradiated recipients. RESULTS: Although in vivo homing of cells from these mice was not impaired, donor leukocyte contribution steadily decreased posttransplantation. In contrast to in vivo homing, both in vitro migration toward stromal-derived factor (SDF)-1 and the average CXC chemokine receptor-4 (CXCR4) expression were lower in 5-FU-treated cells. Moderate reductions in L-selectin and CD11a expression were observed on stem cells of 5-FU-treated mice. CD43, CD44, CD49d, and CD49e were normally expressed and could thus not explain the reduced engraftment of these cells. CONCLUSION: We therefore conclude that 5-FU either directly damages stem cells or that the replicative stress induced by 5-FU causes a decline in stem cell reconstitution potential resulting in lower chimerism levels posttransplantation, that declines in time.