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Objectives Human population totals are used for generating burden of disease estimates at global, continental and national scales to help guide priority setting in international health financing. These exercises should be aware of...
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Objectives Human population totals are used for generating burden of disease estimates at global, continental and national scales to help guide priority setting in international health financing. These exercises should be aware of the accuracy of the demographic information used. Methods The analysis presented in this paper tests the accuracy of five large-area, public-domain human population distribution data maps against high spatial resolution population census data enumerated in Kenya in 1999. We illustrate the epidemiological significance, by assessing the impact of using these different human population surfaces in determining populations at risk of various levels of climate suitability for malaria transmission. We also describe how areal weighting, pycnophylactic interpolation and accessibility potential interpolation techniques can be used to generate novel human population distribution surfaces from local census information and evaluate to what accuracy this can be achieved. Results We demonstrate which human population distribution surface performed best and which population interpolation techniques generated the most accurate bespoke distributions. Despite various levels of modelling complexity, the accuracy achieved by the different surfaces was primarily determined by the spatial resolution of the input population data. The simplest technique of areal weighting performed best. Conclusions Differences in estimates of populations at risk of malaria in Kenya of over 1 million persons can be generated by the choice of surface, highlighting the importance of these considerations in deriving per capita health metrics in public health. Despite focussing on Kenya the results of these analyses have general application and are discussed in this wider context.
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OBJECTIVE: Bioactive food ingredients influence energy balance by exerting weak thermogenic effects. We studied whether the thermogenic effect of a combination of capsaicin, green tea extract (catechins and caffeine), tyrosine, an...
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OBJECTIVE: Bioactive food ingredients influence energy balance by exerting weak thermogenic effects. We studied whether the thermogenic effect of a combination of capsaicin, green tea extract (catechins and caffeine), tyrosine, and calcium was maintained after 7-day treatment and whether local effects in the gastric mucosa were involved in the efficacy. DESIGN: The present study was designed as a 3-way crossover, randomised, placebo-controlled, double-blinded intervention.SETTING: Department of Human Nutrition, RVAU, Denmark. SUBJECTS: A total of 19 overweight to obese men (BMI: 28.0+/-2.7 kg/m2) were recruited by advertising locally. INTERVENTION: The subjects took the supplements for a period of 7 days. The supplements were administrated as a simple supplement with the bioactive ingredients, a similar enterocoated version, or placebo. In all, 24-h energy expenditure (EE), substrate oxidations, spontaneous physical activity (SPA), and heart rate were measured in respiration chambers on the seventh dayof each test period.Results:After adjustment for changes in body weight and SPA, 24-h EE was increased by 160 kJ/day (95% CI: 15-305) by the simple preparation as compared to placebo, whereas the enterocoated preparation had no such effect (53 kJ/day, -92 to 198); simple vs enterocoated versions (P=0.09). The simple preparation produced a deficit in 24-h energy balance of 193 kJ/day (49-338, P=0.03). Fat and carbohydrate oxidation were equally increased by the supplements.CONCLUSION: A supplement containing bioactive food ingredients increased daily EE by approximately 200 kJ or 2%, without raising the heart rate or any observed adverse effects. The lack of effect of the enterocoated preparation suggests that a local action of capsaicin in the gastric mucosa is a prerequisite for exerting the thermogenic effect.
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Many anesthetics evoke electroencephalogram (EEG) burst suppression activity in humans and animals during anesthesia, and the mechanisms underlying this activity remain unclear. The present study used a rat neocortical brain slice...
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Many anesthetics evoke electroencephalogram (EEG) burst suppression activity in humans and animals during anesthesia, and the mechanisms underlying this activity remain unclear. The present study used a rat neocortical brain slice EEG preparation to investigate excitatory synaptic mechanisms underlying anesthetic-induced burst suppression activity. Excitatory synaptic mechanisms associated with burst suppression activity were probed using glutamate receptor antagonists (CNQX and APV), GABA receptor antagonists, and simultaneous whole cell patch clamp and microelectrode EEG recordings. Clinically relevant concentrations of thiopental (50--70 microM), propofol (5--10 microM) or isoflurane (0.7--2.1 vol%, 0.5--1.5 rat minimum aveolar concentration (MAC), 200--700 microM) evoked delta slow wave activity and burst suppression EEG patterns similar to in vivo responses. These effects on EEG signals were blocked by glutamate receptor antagonists CNQX (8.6 microM) or APV (50 microM). Depolarizing intracellular bursts (amplitude=34.7+/-4.5 mV; half width=132+/-60 ms) always accompanied EEG bursts, and hyperpolarization increased intracellular burst amplitudes. Barrages of glutamate-mediated excitatory events initiated EEG bursting activity. Glutamate-mediated excitatory postsynaptic currents were significantly depressed by higher anesthetic concentrations that depressed burst suppression EEG activity. A GABA(A) agonist produced a similar EEG effect to the anesthetics. It appears that anesthetic effects at both glutamate and GABA synapses contribute to EEG patterns seen during anesthesia.
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The bisbenzylisoquinoline alkaloid cepharanthine, which has been considered to exhibit antiperoxidation activity due to its membrane stabilizing effect, was found to scavenge radicals such as .OH and DPPH (1,1-diphenyl-2-picrylhyd...
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The bisbenzylisoquinoline alkaloid cepharanthine, which has been considered to exhibit antiperoxidation activity due to its membrane stabilizing effect, was found to scavenge radicals such as .OH and DPPH (1,1-diphenyl-2-picrylhydrazyl) in solution, and to inhibit lipid peroxidation in mitochondria and liposomes by Fe2+/ADP. The antiperoxidation activity of cepharanthine in rat liver mitochondria initiated by Fe2+/ADP at pH 7.4 was much greater than that of alpha-tocopherol, its half-inhibitory concentration being about 23 microM. However, cepharanthine was effective only at neutral pH values such as pH 7.4, not in a moderately acidic pH region below pH 6.5. Accordingly, the neutral form of the deprotonated amine moiety in the tetrahydroisoquinoline ring is concluded to be responsible for the radical scavenging activity of cepharanthine. There are two amine moieties in the cepharanthine molecule, but we specified the effective amine moiety from the antiperoxidation activities of the imine analogs of cepharanthine.
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We previously showed that prostaglandin (PG) E1 stimulates the synthesis of interleukin-6 (IL-6) through activation of protein kinase (PK) A in osteoblast-like MC3T3-E1 cells and that PGF2alpha induces IL-6 synthesis through PKC a...
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We previously showed that prostaglandin (PG) E1 stimulates the synthesis of interleukin-6 (IL-6) through activation of protein kinase (PK) A in osteoblast-like MC3T3-E1 cells and that PGF2alpha induces IL-6 synthesis through PKC activation. In other studies, we demonstrated that thrombin stimulates IL-6 synthesis, which depends on intracellular Ca2+ mobilisation in these cells and that tumour necrosis factor-alpha (TNF) induces IL-6 synthesis through sphingosine 1-phosphate, a product of sphingomyelin turnover. In the present study, among sphingomyelin metabolites, we examined the effect of ceramide on the IL-6 synthesis induced by various agonists in MC3T3-E1 cells. C2-ceramide, a cell-permeable ceramide analogue, suppressed the PGE1-induced IL-6 synthesis. C2-ceramide inhibited the IL-6 synthesis induced by PGF2alpha or 12-O-tetradecanoylphorbol-13-acetate, an activator of PKC. C2-ceramide reduced the IL-6 synthesis induced by cholera toxin, forskolin or dibutyryl cAMP. C2-ceramide inhibited the IL-6 synthesis induced by thrombin. The IL-6 synthesis stimulated by thapsigargin, which is known to stimulate Ca2+ mobilisation from intracellular Ca2+ stores, or A23187, a Ca-ionophore, was also inhibited by C2-ceramide. C2-ceramide did not affect the IL-6 synthesis induced by interleukin-1. On the contrary, C2-ceramide enhanced the TNF-induced IL-6 synthesis. D,L-threo-dihydrosphingosine, an inhibitor of sphingosine kinase, inhibited the enhancement by C2-ceramide as well as the TNF-effect. These results strongly suggest that ceramide modulates the IL-6 synthesis stimulated by various agonists in osteoblasts.
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Correct attribution is an important part of science and allows us to understand the evolution of ideas and discovery. So it is with some shame that we start this article with a quote that comes from Niels Bohr but may have origina...
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Correct attribution is an important part of science and allows us to understand the evolution of ideas and discovery. So it is with some shame that we start this article with a quote that comes from Niels Bohr but may have originated with Mark Twain 'Prediction is very difficult especially about the future'. The task in trying to write an article about the future of pharmacology is made more difficult by Lao Tzo, a poet from 6th century China who declared that "Those who have knowledge don't predict, and those who predict don't have knowledge". Looking back, the use of herbal and animal extracts and minerals has been with us for thousands of years as a very early form of therapeutics. Indeed, Cladius Galen could be considered as one of the first practitioners of pharmacology as early as 150AD when he recognised the importance of experimentation and theory in the rational use of medicines (Galen on Pharmacology). The Swiss physician, Paracelsus, provided the early momentum for pharmacology by investigating the active principles/ingredients of many medieval preparations.
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The effect of organic solvents (n-propanol, isopropanol, dimethylformamide and dimethylsulfoxide) on the structure, activity and stability of thermolysin was the focus of this investigation. Results show the ability of the solvent...
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The effect of organic solvents (n-propanol, isopropanol, dimethylformamide and dimethylsulfoxide) on the structure, activity and stability of thermolysin was the focus of this investigation. Results show the ability of the solvents to cause mixed inhibition of thermolysin, which was indicated by kinetic and structural studies (near-UV CD spectra and intrinsic fluorescence). Inhibitory effect of the solvents increased with increments in solvents logP. Thermoinactivation of thermolysin was studied at 80 degrees C in 50% of solvents and showed that with the increase in solvent hydrophobicity, thermal stability of the enzyme decreased. For the stabilization of thermolysin at high temperature, additives such as glycerol, sorbitol and trehalose were employed. In the presence of DMF with a relatively low logP, trehalose was shown to be a good stabilizer, whereas glycerol had a marked stabilization effect in the presence of n-propanol and isopropanol with a relatively high logP. Consequently, it was concluded that the stabilizing effect of additives can be correlated with the logP of solvents.
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The effect of organic solvents (n-propanol, isopropanol, dimethylformamide and dimethylsulfoxide) on the structure, activity and stability of thermolysin was the focus of this investigation. Results show the ability of the solvent...
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The effect of organic solvents (n-propanol, isopropanol, dimethylformamide and dimethylsulfoxide) on the structure, activity and stability of thermolysin was the focus of this investigation. Results show the ability of the solvents to cause mixed inhibition of thermolysin, which was indicated by kinetic and structural studies (near-UV CD spectra and intrinsic fluorescence). Inhibitory effect of the solvents increased with increments in solvents logP. Thermoinactivation of thermolysin was studied at 80 degrees C in 50% of solvents and showed that with the increase in solvent hydrophobicity, thermal stability of the enzyme decreased. For the stabilization of thermolysin at high temperature, additives such as glycerol, sorbitol and trehalose were employed. In the presence of DMF with a relatively low logP, trehalose was shown to be a good stabilizer, whereas glycerol had a marked stabilization effect in the presence of n-propanol and isopropanol with a relatively high logP. Consequently, it was concluded that the stabilizing effect of additives can be correlated with the logP of solvents.
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In mouse embryo NIH 3T3 fibroblasts, ethanol (60-80 mM) was found to enhance the stimulatory effects of sphingosine 1-phosphate (S1P) on both DNA synthesis and cell proliferation. Well-detectable potentiating effects of ethanol on...
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In mouse embryo NIH 3T3 fibroblasts, ethanol (60-80 mM) was found to enhance the stimulatory effects of sphingosine 1-phosphate (S1P) on both DNA synthesis and cell proliferation. Well-detectable potentiating effects of ethanol on S1P-induced mitogenesis required the presence of calcium (>1 mM) and zinc (20-40 microM) in the incubation medium. The amphibian tetrapeptide bombesin, which is known to mobilize intracellular calcium in fibroblasts, had no effect alone, but it approximately doubled the combined stimulatory effects of ethanol and S1P on DNA synthesis. The synergistic mitogenic effects of ethanol and S1P were also slightly enhanced, rather than inhibited, by the alcohol dehydrogenase inhibitor 4-methylpyrazole (5 mM). Of the various growth regulatory enzymes examined, ethanol detectably enhanced the stimulatory effects of S1P on the phosphosphorylation (activation) of p42/p44 mitogen-activated protein (MAP) kinases, but not of p38 MAP kinase. Cotreatment of fibroblasts with ethanol for 10 min also enhanced the stimulatory effects of S1P on the activities of c-Raf-1 kinase and p70 S6 kinase, but neither S1P nor ethanol had effects on phosphatidylinositol 3'-kinase and Akt/PKB kinase activities. Ethanol-plus-S1P-induced DNA synthesis was partially inhibited by both PD 98059 (50 microM) and rapamycin (10 nM), inhibitors of p42/p44 MAP kinase kinase and mTOR/p70 S6 kinases, respectively. The results indicate that in NIH 3T3 fibroblasts, ethanol can enhance the mitogenic effects of S1P by a zinc- and calcium-dependent mechanism involving both the rapamycin-sensitive p70 S6 kinase-dependent and the c-Raf-1/MAP kinase-dependent growth regulatory pathways. Copyright 1999 Academic Press.
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Some venom and mammalian-secreted phospholipases A2 (sPLA2) have been described to exert an anticoagulant effect. This review will discuss and compare phospholipid-dependent versus protein-dependent mechanisms of action of these s...
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Some venom and mammalian-secreted phospholipases A2 (sPLA2) have been described to exert an anticoagulant effect. This review will discuss and compare phospholipid-dependent versus protein-dependent mechanisms of action of these sPLA2 on the coagulation cascade. The importance of venom proteins, and of the study of their pharmacological effects, to explore the physiological functions of homologous mammalian proteins is also pointed out. Copyright < copyright > 2002 S. Karger AG, Basel.
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