Paclitaxel associated with cholesterol-rich nanoemulsions promotes atherosclerosis regression in the rabbit

A cholesterol-rich nanoemulsion (LDE) that resembles LDL binds to the LDL receptors and after injection into the blood stream may concentrate in cells with LDL receptor overexpression, as occurs in neoplasias and other proliferative processes. Thus, LDE can be used as vehicle to target drugs against those cells. The current study was designed to verify in rabbits whether LDE concentrates in the lesioned rabbit artery and whether a paclitaxel derivative, paclitaxel oleate, associated to LDE could reduce the atherosclerotic lesions. Sixteen male New Zealand rabbits were fed a 1% cholesterol diet for 60 days. Starting from day 30 under cholesterol feeding, eight animals were treated with four weekly intravenous injections of LDE-paclitaxel (4 mg/kg) and eight with four weekly intravenous saline solution injections for additional 30 days. On day 60, the animals were sacrificed for analysis. The uptake of LDE labeled with [C-14]-cholesteryl oleate by the aortic arch of cholesterol-fed rabbits was twice as much that observed in animals fed only regular chow. LDE-paclitaxel reduced the lesion areas of cholesterol-fed animals by 60% and intima-media ratio fourfold and inhibited the macrophage migration and the smooth muscle cell proliferation and invasion of the intima. LDE-paclitaxel treatment had no toxicity. In conclusion, LDE-paclitaxel produced pronounced atherosclerosis regression without toxicity and has shown remarkable potential in cardiovascular therapeutics. (c) 2008 Published by Elsevier Ireland Ltd.

Malnourished mice display an impaired hematologic response to granulocyte colony-stimulating factor administration

The aim of this Study was to determine if protein-energy malnutrition Could affect the hematologic response to granulocyte colony-stimulating factor (G-CSF). Swiss mice were fled a low-protein diet containing 4% protein, whereas control mice were fed a 20% protein-containing diet. After the malnourished group lost 20% of their original body weight, the mice were subdivided in 2 treatment groups, and hematopoietic parameters were studied. Mice were injected with either 8 mu g/kg per day of G-CSF or saline twice daily for 4 days. Malnourished mice developed anemia with reticulopenia and leukopenia with depletion of granulocytes and lymphocytes. Both malnourished and control mice treated with G-CSF showed a significant increase in neutrophils; however, in the control group, this increase was more pronounced compared to the malnourished group (4.5-fold and 3.4-fold, respectively). Granulocyte colony-stimulating factor administration increased bone marrow blastic (P < .001) and granulocytic (P < .01) compartments in the controls bill had no significant effect oil these hematopoietic compartments in the Malnourished animals (P = .08 and P = .62, respectively). We report that malnourished mice display an impaired response to G-CSF, which contributes to the decreased production of leukocytes in protein-energy malnutrition. (C) 2008 Elsevier Inc. All rights reserved.

An evaluation, using the comet assay and the micronucleus test, of the antigenotoxic effects of chlorophyll b in mice

We investigated the effects of the dietary pigment chlorophyll b (CLb) on cisplatin (cDDP)-induced oxidative stress and DNA damage, using the comet assay in mouse peripheral blood cells and the micronucleus (MN) test in bone marrow and peripheral blood cells. We also tested for thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) in liver and kidney tissues, as well as catalase (CAT) activity and GSH in total blood. CLb (0.2 and 0.5 mg/kg b.w.) was administrated by gavage every day for 13 days. On the 14th day of the experiment, 6 mg/kg cDDP or saline was delivered intraperitoneally. Treatment with cDDP led to a significant decrease in DNA migration and an increase in MN frequency in both cell types, bone marrow and peripheral blood cells. In the kidneys of mice treated with cDDP, TBARS levels were increased, whereas GSH levels were depleted in kidney and liver. In mice that were pretreated with CLb and then treated with cDDP, TBARS levels maintained normal concentrations and GSH did not differ from cDDP group. The improvement of oxidative stress biomarkers after CLb pre-treatment was associated with a decrease in DNA damage, mainly for the highest dose evaluated. Furthermore, CLb also slightly reduced the frequency of chromosomal breakage and micronucleus formation in mouse bone marrow and peripheral blood cells. These results show that pre-treatment with CLb attenuates cDDP-induced oxidative stress, chromosome instability, and lipid peroxidation. (C) 2011 Elsevier B.V. All rights reserved.

Curcumin could prevent methemoglobinemia induced by dapsone in rats

The curcumin`s effect given orally by gavage in single- or multiple-dose regimens on methemoglobinemia induced by dapsone (DDS) was investigated in male Wistar rats. In the single-dose regimen, groups of 10 rats received either vehicle alone, or curcumin at 0.1, 1.0, 10, or 30 mg/kg body weight (bw), or curcumin at 0.02, 0.1, 1, 10, or 30 mg/kg bw plus DDS at 40 mg/kg bw, intraperitoneally (i.p.), 2 hours after. In the multiple-dose regimen, groups of 10 rats received either vehicle alone, or curcumin at 0.1, 1.0, 10, or 30 mg/kg bw for 5 days, with or without DDS (40 mg/kg bw, i.p.) 2 hours after on the fifth day. In both regimens, further groups of 10 rats were given DDS alone (positive controls) or normal saline (negative controls) i.p. Single-dose treatment with curcumin at 0.02 and 0.1 mg/kg bw significantly reduced DDS-induced methemoglobin formation, while the higher doses showed a pro-oxidant effect, significantly increasing DDS-induced methemoglobinemia. In the multiple-dose regimen, treatment with curcumin at 0.1 mg/kg bw significantly reduced DDS-induced methemoglobin formation, but the higher doses were without significant effect compared to DDS alone. It is concluded that curcumin at low doses mitigates methemoglobinemia induced by dapsone in rats, both in single- and multiple-dose regimens. (C) 2011 Elsevier Ltd. All rights reserved.

Metal embryotoxicity from urban particles in Sao Paulo city: An experimental study in chicken embryos

Chicken eggs were inoculated with suspensions of ambient air particles (<= 10 mu m, PM(10)) from Sao Paulo city in 3, 0.3 or 0.03 mu g doses on one of the four early days of embryo development. On the eleventh day of development alterations were observed on embryos inoculated with PM(10) 3 mu g on the third day. Particles analysis showed high content of metals. Hence, embryos were also inoculated with PM(10) (3 mu g) combined with metal chelating EDTA. PM(10) (3 mu g) embryos presented underdevelopment (stage 29.44 +/- 11.4) compared to vehicle and positive controls (stage 36.44 +/- 0.51 Saline and stage 31.20 +/- 9.7 Cyclophosphamide, p <= 0.05); higher (47%) mortality rate (23% Saline and 42% Cyclophosphamide) and low (68%) viability (100% Saline and 70% Cyclophosphamide, p = 0.04). Effects were attenuated when embryos received PM(10) + EDTA (stage 33.63 +/- 0.94, 18.9% mortality rate and 82% viability). PM(10) from Sao Paulo city is embryotoxic and metal may be implicated in the toxic mechanism. (C) 2010 Elsevier Inc. All rights reserved.

Growth Response of Various Perennial Grasses to Increasing Salinity

Although the effect of salinity on plant growth has been the focus of a substantive research effort, much of this research has failed to adequately separate the various growth limiting aspects of salinity; thus the results are confounded by multiple factors. Eight perennial grass species were grown in a sand culture system dominated by NaCl (electrical conductivities (ECs) between 1.4 and 38 dS m 1), with sufficient Ca added to each treatment to ensure that Na-induced Ca deficiency did not reduce growth. Of the eight perennial grass species examined, Chloris gayana cv. Pioneer (Rhodes grass) was the most salt tolerant species, whilst in comparison, Chrysopogon zizanioides cv. Monto (vetiver) was of only moderate tolerance. However, observed salinity tolerances tended to be lower than those expected from published values based on the threshold salinity model (bent stick model). This discrepancy may be due in part to differences in the evapotranspirational demand between studies; an increase in demand accelerating the accumulation of Na in the shoots and hence decreasing apparent salinity tolerance. It was also observed that the use of a non-saline growth period to allow seed germination and establishment results in the overestimation of vegetative salinity tolerance if not taken into consideration. This is particularly true for species of low salt tolerance due to their comparatively rapid growth in the non-saline medium compared to that at full salinity.

Hypothalamic dopamine D1 receptors are involved in the stimulation of prolactin secretion by high environmental temperature in the female sheep

Recent evidence suggests that dopamine, acting via its D1 receptors, may function as a neurotransmitter in intrahypothalamic pathways involved in the stimulation of prolactin secretion. Functional dopamine D1 receptors are present in the ventromedial hypothalamic nucleus (VMH) and we hypothesized that they might be part of a prolactin-stimulatory pathway activated by stress. We tested this hypothesis in a series of experiments on sheep involving two different forms of stressors, audiovisual (barking dog) and high environmental temperature. We attempted to block the stimulation of prolactin secretion by infusion into the VMH of an antagonist specific for the D1 receptor. Ovariectomised, oestradiol-implanted merino ewes were surgically implanted with bilateral guide tubes directed at the VMH. After a 180 min pretreatment period, the ewes either were or were not exposed to a stressor (30 min of barking dog or 120 min at 35 degrees C, 65% relative humidity). D1 receptor antagonist, SCH23390 or vehicle (0.9% saline) was infused into the VMH (1.7 mu l/h, 120 nmol/h) for 60 min prior to and during the stressor period. Blood was sampled every 15 min via jugular cannulae and the plasma was assayed for prolactin, cortisol and growth hormone (GH). Both stressors significantly increased prolactin concentrations over control levels. SCH23390 infusion significantly attenuated the prolactin response to high environmental temperature, but had no effect on the prolactin response to audiovisual stress. Cortisol concentrations were significantly increased by audiovisual stress only and were not affected by SCH23390, GH concentrations were not changed by either stressor or infusion. Drug infusion alone did not affect the concentration of the hormones. The data suggest that the VMH D1 receptors are involved in a prolactin stimulatory pathway in response to high environmental temperature. The inability of the D1 antagonist to affect the response to the barking dog indicates that this pathway is stress-specific, implying that there is more than one mechanism or pathway involved in the prolactin response to different stressors.

Geochemical mass-balance and oxygen-isotope constrains on silcrete formation and its paleoclimatic implications in Southern Australia

Two geographically distinct silcrete associations are present in southern Australia, inland and eastern; these were sampled in central South Australia and central Victoria, respectively, At each site, both silicified and immediately adjacent unsilicified parent material were collected. Analytical data from these pairs were used to construct isocons, assuming Zr immobility, and to calculate the volume change and amount of silica introduced during silicification, These results, together with whole-rock oxygen isotope compositions, were used to determine the delta(18)O of th, introduced silica, The results show that the eastern silcretes in central Victoria are probably linked genetically to the associated basalts, weathering of which supplied the introduced silica, This conclusion is based on the close spatial connection between the two, as well as the substantial amount of introduced silica in the silcretes (greater than in the inland silcretes), resulting in volume increases in some eastern silcretes, Oxygen isotopic calculations for the silcretes indicate that the silica precipitated from groundwaters at temperatures slightly higher than present conditions. Silcrete formation apparently occurred during the Miocene and Pliocene (basalts in Victoria younger than Pliocene lack associated silcrete) and may reflect the much wetter climate in southeastern Australia at that time. The inland silcretes of central South Australia can be divided into pedogenic (the most common) and groundwater varieties. The pedogenic silcretes, which show typical soil features like columnar and nodular textures, contain moderate amounts of introduced silica that precipitated by evaporation from saline groundwaters, For the groundwater silcretes, which have massive textures and formed at or close to the water table, insufficient data are available to determine the mode of formation. The inland pedogenic silcretes have probably been farming from the Eocene-Miocene to the present, implying that conditions of seasonally high evaporation have occurred in central Australia during this time period. Thus silcrete formation depends on a complex interplay between climate and silica supply, and it is impossible to generalize that the presence of silcrete is indicative of a particular climate. Likewise, the elemental composition of silcretes, particularly Ti content, is not necessarily of climatic significance, Nevertheless, detailed geochemical and oxygen isotopic studies of a silcrete and its parent material can elucidate the mechanisms of silcrete formation, and if evaporation is indicated as a major factor in silcrete formation, then the climate at the time was likely to have been at least seasonally arid.

Administration of growth hormone or IGF-I to pregnant rats on a reduced diet throughout pregnancy does not prevent fetal intrauterine growth retardation and elevated blood pressure in adult offspring

Increasing evidence from human epidemiological studies suggests that poor growth before birth is associated with postnatal growth retardation and the development of cardiovascular disease in adulthood. We have shown previously that nutritional deprivation in the pregnant rat leads to intrauterine growth retardation (IUGR), postnatal growth failure, changes in the endocrine parameters of the somatotrophic axis, and to increased blood pressure in later life. In the present study, we investigated whether administration of insulin-like growth factor-I (IGF-I) or bovine growth hormone (GH) during pregnancy could prevent IUGR and/or alter long-term outcome. Dams h-om day 1 of pregnancy throughout gestation received a diet of nd libitum available food or a restricted dietary intake of 30% of ad libitum fed dams. From day 10 of gestation, dams were treated for 10 days with three times daily subcutaneous injections of saline (100 mu l), IGF-I (2 mu g/g body weight) or GH (2 mu g/g body weight). Maternal weight gain was significantly increased (P

Sensitivity of multiple frequency bioelectrical impedance analysis to changes in ion status

Bioelectrical impedance analysis has found extensive application as a simple noninvasive method for the assessment of body fluid volumes, The measured impedance is, however, not only related to the volume of fluid but also to its inherent resistivity. The primary determinant of the resistivities of body fluids is the concentration of ions. The aim of this study was to investigate the sensitivity of bioelectrical impedance analysis to bodily ion status. Whole body impedance over a range of frequencies (4-1012 kHz) of rats was measured during infusion of various concentrations of saline into rats concomitant with measurement of total body and intracellular water by tracer dilution techniques. Extracellular resistance (R-o), intracellular resistance (R-i) and impedance at the characteristic frequency (Z(c)) were calculated. R-o and Z(c) were used to predict extracellular and total body water respectively using previously published formulae. The results showed that whilst R-o and Z(c) decreased proportionately to the amount of NaCl infused, R-i increased only slightly. Impedances at the end of infusion predicted increases iu TBW and ECW of approximately 4-6% despite a volume increase of less than 0.5% in TBW due to the volume of fluid infused. These data are discussed in relation to the assumption of constant resistivity in the prediction of fluid volumes from impedance data.

Regional-scale investigation of the spatial distribution and origin of soluble salts in central north Queensland

A method for regional assessment of the distribution of saline outbreaks is demonstrated for a large area (68 000 km(2)) in north Queensland, Australia. Soil samples were used in conjunction with a digital elevation model and a map of potentially saline discharge zones to examine the landscape distribution of soluble salts in the region. The hypothesis of atmospheric accession of salt was tested for the topographically defined catchment regions feeding into each potentially saline discharge area. Most catchments showed a salt distribution consistent with this hypothesis, i.e. %TSS was large near the discharge areas and decreased rapidly with distance uphill from the discharge areas. In some catchments, however, local saline outbreaks were apparent at significant distances uphill from discharge areas. The possibility of geological sources of this salt was examined by comparing random point distributions with the location of saline points with distance downhill from geological units (excluding points near discharge zones). The distribution of some saline outbreaks was consistent with the occurrence of Cambro-Ordovician metasediments, Devonian limestone, Upper Devonian-Lower Carboniferous volcanics, and Triassic sediments. Copyright (C) 2000 John Wiley & Sons, Ltd.

Systemic administration of antisense p75(NTR) oligodeoxynucleotides rescues axotomised spinal motor neurons

The 75 kD low-affinity neurotrophin receptor (p75(NTR)) is expressed in developing and axotomised spinal motor neurons. There is now convincing evidence that p75NTR can, under some circumstances, become cytotoxic and promote neuronal cell death. We report here that a single application of antisense p75(NTR) oligodeoxynucleotides to the proximal nerve stumps of neonatal rats significantly reduces the loss of axotomised motor neurons compared to controls treated with nonsense oligodeoxynucleotides or phosphate-buffered saline. Our investigations also show that daily systemic intraperitoneal injections of antisense p75(NTR) oligodeoxynucleotides for 14 days significantly reduce the loss of axotomised motor neurons compared to controls. Furthermore, we found that systemic delivery over a similar period continues to be effective following axotomy when intraperitoneal injections were 1) administered after a delay of 24 hr, 2) limited to the first 7 days, or 3) administered every third day. In addition, p75(NTR) protein levels were reduced in spinal motor neurons following treatment with antisense p75(NTR) oligodeoxynucleotides. There were also no obvious side effects associated with antisense p75(NTR) oligodeoxynucleotide treatments as determined by behavioural observations and postnatal weight gain. Our findings indicate that antisense-based strategies could be a novel approach for the prevention of motor neuron degeneration associated with injuries or disease. (C) 2001 Wiley-Liss, Inc.

Pathway-specific targeting of GAB(A) a receptor subtypes to somatic and dendritic synapses in the central amygdala

Neurons in the central amygdala express two distinct types of ionotropic GABA receptor. One is the classical GABA(A) receptor that is blocked by low concentrations of bicuculline and positively modulated by benzodiazepines. The other is a novel type of ionotropic GABA receptor that is less sensitive to bicuculline but blocked by the GABA(C) receptor antagonist (1,2,5,6-tetrohydropyridine-4-yl) methylphosphinic acid (TPMPA) and by benzodiazepines. In this study, we examine the distribution of these two receptor types. Recordings of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) showed a wide variation in amplitude. Most events had amplitudes of 100 pA. Large-amplitude events also had rise times faster than small-amplitude events. Large-amplitude events were fully blocked by 10 muM bicuculline but unaffected by TPMPA. Small amplitude events were partially blocked by both bicuculline and TPMPA. Focal application of hypertonic sucrose to the soma evoked large-amplitude mIPSCs, whereas focal dendritic application of sucrose evoked small-amplitude mIPSCs. Thus inhibitory synapses on the dendrites of neurons in the central amygdala express both types of GABA receptor, but somatic synapses expressed purely GABA(A) receptors. Minimal stimulation revealed that inhibitory inputs arising from the laterally located intercalated cells innervate dendritic synapses, whereas inhibitory inputs of medial origin innervated somatic inhibitory synapses. These results show that different types of ionotropic GABA receptors are targeted to spatially and functionally distinct synapses. Thus benzodiazepines will have different modulatory effects on different inhibitory pathways in the central amygdala.

Tubular system volume changes in twitch fibres from toad and rat skeletal muscle assessed by confocal microscopy

The volume of the extracellular compartment (tubular system) within intact muscle fibres from cane toad and rat was measured under various conditions using confocal microscopy. Under physiological conditions at rest, the fractional volume of the tubular system (t-sys(Vol)) was 1.38 +/- 0.09% (n = 17),1.41 +/- 0.09% (n = 12) and 0.83 +/- 0.07% (n = 12) of the total fibre volume in the twitch fibres from toad iliofibularis muscle, rat extensor digitorum longus muscle and rat soleus muscle, respectively. In toad muscle fibres, the t-sys(Vol) decreased by 30% when the tubular system was fully depolarized and decreased by 15% when membrane cholesterol was depleted from the tubular system with methyl-beta-cyclodextrin but did not change as the sarcomere length was changed from 1.93 to 3.30 mum. There was also an increase by 30% and a decrease by 25% in t-sys(Vol) when toad fibres were equilibrated in solutions that were 2.5-fold hypertonic and 50% hypotonic, respectively. When the changes in total fibre volume were taken into consideration, the t-sys(Vol) expressed as a percentage of the isotonic fibre volume did actually decrease as tonicity increased, revealing that the tubular system in intact fibres cannot be compressed below 0.9% of the isotonic fibre volume. The results can be explained in terms of forces acting at the level of the tubular wall. These observations have important physiological implications showing that the tubular system is a dynamic membrane structure capable of changing its volume in response to the membrane potential, cholesterol depletion and osmotic stress but not when the sarcomere length is changed in resting muscle.

Plant growth limitation and nutrient loss following piled burning in slash and burn agriculture

In the forest zone of Cameroon, small-scale family farmers practicing traditional slash and burn practices achieve a clear field by piled burning of the branches and trunks of cleared vegetation. Plant growth inhibition on ash patches, and the risk of nutrient loss from these areas, was evaluated on field plots on which 0.5 t m(-2) or 1.0 t m(-2) of wood was piled and burnt, and in laboratory studies. The ash produced by burning was strongly alkaline, and laboratory bio-assessment studies showed that the saline, high pH conditions produced in ash patches prevented germination and plant growth for up to two wet seasons, as is observed in the field. Field and laboratory studies demonstrated rapid release (1 wet season) of K and S from the ash and the loss of a substantial portion of these nutrients from the soil profile by leaching. In contrast, leaching carries Mg from the ash gradually (3 to 4 wet seasons), while Ca, Cu, Zn and P are leached slowly. The nutrients contained in ash patches are considered at risk of loss both through leaching (K and S) and by erosion of ash (Ca, Mg, Cu, Zn and P). Farmers should be encouraged to spread ash patches prior to cultivation in order to exploit the nutrient content of ash and to lessen the risk of nutrient loss.