Describing the process of creating an intellectual capital management framework: An interventionist case study

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Treatment of migraine attacks based on the interaction with the trigemino-cerebrovascular system

Primary headaches such as migraine are among the most prevalent neurological disorders, affecting up to one-fifth of the adult population. The scientific work in the last decade has unraveled much of the pathophysiological background of migraine, which is now considered to be a neurovascular disorder. It has been discovered that the trigemino-cerebrovascular system plays a key role in migraine headache pathophysiology by releasing the potent vasodilator calcitonin gene-related peptide (CGRP). This neuropeptide is released in parallel with the pain and its concentration correlates well with the intensity of the headache. The development of drugs of the triptan class has provided relief for the acute attacks but at the cost of, mainly cardiovascular, side effects. Thus, the intention to improve treatment led to the development of small CGRP receptor antagonists such as olcegepant (BIBN4096BS) and MK-0974 that alleviate the acute migraine attack without acute side events. The purpose of this review is to give a short overview of the pathological background of migraine headache and to illustrate the mechanisms behind the actions of triptans and the promising CGRP receptor blockers

Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients

Calcitonin gene-related peptide (CGRP)-containing nerves are closely associated with cranial blood vessels. CGRP is the most potent vasodilator known in isolated cerebral blood vessels. CGRP can induce migraine attacks, and two selective CGRP receptor antagonists are effective in the treatment of migraine attacks. It is therefore important to investigate its mechanism of action in patients with migraine. We here investigate the effects of intravenous human alpha-CGRP (hαCGRP) on intracranial hemodynamics. In a double-blind, cross-over study, the effect of intravenous infusion of hαCGRP (2 μg/min) or placebo for 20 min was studied in 12 patients with migraine without aura outside attacks. Xenon-133 inhalation SPECT-determined regional cerebral blood flow (rCBF) and transcranial Doppler (TCD)-determined blood velocity (Vmean) in the middle cerebral artery (MCA), as well as the heart rate and blood pressure, were the outcome parameters. No change of rCBF was observed at the end of infusion [1.2% ± 1.7 with hαCGRP, vs. −1.6% ± 3.1 with placebo (mean ± SD)] (P = 0.43). Vmean in MCA decreased to 13.5% ± 3.6 with hαCGRP versus 0.6% ± 1.8 with placebo (P < 0.005). Since rCBF was unchanged, this indicates a dilation of the MCA. hαCGRP induced a decrease in MAP (12%) (P < 0.005) and an increase in heart rate (58%) (P < 0.0001). CGRP dilates cerebral arteries, but the effect is so small that it is unlikely to be the only mechanism of CGRP-induced migraine

Search for the electric dipole moment of the electron with thorium monoxide

The electric dipole moment of the electron (eEDM) is a signature of CP-violating physics beyond the Standard Model. We describe an ongoing experiment to measure or set improved limits to the eEDM, using a cold beam of thorium monoxide (ThO) molecules. The metastable $H {}^3\Delta_1$ state in ThO has important advantages for such an experiment. We argue that the statistical uncertainty of an eEDM measurement could be improved by as much as 3 orders of magnitude compared to the current experimental limit, in a first-generation apparatus using a cold ThO beam. We describe our measurements of the $H$ state lifetime and the production of ThO molecules in a beam, which provide crucial data for the eEDM sensitivity estimate. ThO also has ideal properties for the rejection of a number of known systematic errors; these properties and their implications are described.Comment: v2: Equation (11) correcte

Cigarette Smoke Upregulates Rat Coronary Artery Endothelin Receptors In Vivo

Background: Cigarette smoking is a strong cardiovascular risk factor and endothelin (ET) receptors are related to coronary artery diseases. The present study established an in vivo secondhand smoke (SHS) exposure model and investigated the hypothesis that cigarette smoke induces ET receptor upregulation in rat coronary arteries and its possible underlying mechanisms. Methodology/Principal Findings: Rats were exposed to SHS for 200 min daily for 8 weeks. The coronary arteries were isolated and examined. The vasoconstriction was studied by a sensitive myograph. The expression of mRNA and protein for receptors was examined by real-time PCR, Western blot and immunofluorescence. Compared to fresh air exposure, SHS increased contractile responses mediated by endothelin type A (ETA) and type B (ETB) receptors in coronary arteries. In parallel, the expression of mRNA and protein for ETA and ETB receptors of smoke exposed rats were higher than that of animals exposed to fresh air, suggesting that SHS upregulates ET A and ET B receptors in coronary arteries in vivo. Immunofluorescence staining showed that the enhanced receptor expression was localized to the smooth muscle cells of coronary arteries. The protein levels of phosphorylated (p)-Raf-1 and p-ERK1/2 in smoke exposed rats were significantly higher than in control rats, demonstrating that SHS induces the activation of the Raf/ERK/MAPK pathway. Treatment with Raf-1 inhibitor GW5074 suppressed SHS-induced enhanced contraction mediated by ET A receptors, and inhibited th

Human Resources and the Resource Based View of the Firm

The resource-based view (RBV) of the firm has influenced the field of strategic human resource management (SHRM) in a number of ways. This paper explores the impact of the RBV on the theoretical and empirical development of SHRM. It explores how the fields of strategy and SHRM are beginning to converge around a number of issues, and proposes a number of implications of this convergence

Lipid-soluble smoke particles damage endothelial cells and reduce endothelium-dependent dilatation in rat and man

BACKGROUND: Cigarette smoking is a strong risk factor for vascular disease and known to cause dysfunction of the endothelium. However, the molecular mechanisms involved are still not fully understood. METHODS: In order to reveal the direct effects of lipid-soluble smoke particles on the endothelium, ring segments isolated from rat mesenteric arteries and human middle cerebral arteries (MCA) obtained at autopsy were incubated for 6 to 48 hrs in the presence of dimethylsulphoxide (DMSO)-soluble particles from cigarette smoke (DSP), i.e. lipid-soluble smoke particles. The endothelial microstructure was examined by transmission electron microscopy. The endothelial function was evaluated by acetylcholine (ACh)-induced endothelium-dependent vasodilatation, using a sensitive myograph. RESULTS: After DSP treatment, the arterial endothelium was swollen and loosing its attachment. In functional tests, the total ACh-induced dilatation, the nitric oxide (NO)-mediated and the endothelium-derived hyperpolarization factor (EDHF)-mediated dilatations were significantly decreased by DSP in a time- and concentration-dependent manner (p < 0.05). Nicotine, an important compound in cigarette smoke had, in an equivalent concentration as in DSP, no such effects (p > 0.05). Similar results were obtained in the human MCA. CONCLUSION: Thus, we demonstrate that the lipid-soluble smoke particles, but not nicotine, caused damage to arterial endothelium and reduced the endothelium-dependent dilatation in man and rat

Web Based Postgraduate Thesis/Dessertation System - A Prototype

With the advancement of information communication technology in Malaysia, education field should take advantage to upgrade their learning and management techniques. Students should be allowed to learn anytime, anywhere and at their own place. However administration and lecture should be able to manage their work more effective and flexible. The web-based system is effective way to learning and managing education works. This report outlines the development of a web-based postgraduate thesis/dissertation management system (WPTS), which aimed to assist thesis/dissertation administration, supervisor and students in the better integration during students doing the thesis/dissertation works. This prototype system base on case study with a group of MSC(IT), administration, lecturer and students who participate in thesis/dissertation management activities. This report also presenting the tests conducted with users, it also contributed some perspective regarding benefits that gain by administration, supervisor and students, and recommends future application of the approach

Effect of CGRP and sumatriptan on the BOLD response in visual cortex

To test the hypothesis that calcitonin gene-related peptide (CGRP) modulates brain activity, we investigated the effect of intravenous CGRP on brain activity in response to a visual stimulus. In addition, we examined if possible alteration in brain activity was reversed by the anti-migraine drug sumatriptan. Eighteen healthy volunteers were randomly allocated to receive CGRP infusion (1.5 μg/min for 20 min) or placebo. In vivo activity in the visual cortex was recorded before, during and after infusion and after 6 mg subcutaneous sumatriptan by functional magnetic resonance imaging (3 T). 77% of the participants reported headache after CGRP. We found no changes in brain activity after CGRP (P = 0.12) or after placebo (P = 0.41). Sumatriptan did not affect brain activity after CGRP (P = 0.71) or after placebo (P = 0.98). Systemic CGRP or sumatriptan has no direct effects on the BOLD activity in visual cortex. This suggests that in healthy volunteers both CGRP and sumatriptan may exert their actions outside of the blood–brain barrier

Inhibition of cerebrovascular raf activation attenuates cerebral blood flow and prevents upregulation of contractile receptors after subarachnoid hemorrhage

<p>Abstract</p> <p>Background</p> <p>Late cerebral ischemia carries high morbidity and mortality after subarachnoid hemorrhage (SAH) due to reduced cerebral blood flow (CBF) and the subsequent cerebral ischemia which is associated with upregulation of contractile receptors in the vascular smooth muscle cells (SMC) via activation of mitogen-activated protein kinase (MAPK) of the extracellular signal-regulated kinase (ERK)1/2 signal pathway. We hypothesize that SAH initiates cerebrovascular ERK1/2 activation, resulting in receptor upregulation. The raf inhibitor will inhibit the molecular events upstream ERK1/2 and may provide a therapeutic window for treatment of cerebral ischemia after SAH.</p> <p>Results</p> <p>Here we demonstrate that SAH increases the phosphorylation level of ERK1/2 in cerebral vessels and reduces the neurology score in rats in additional with the CBF measured by an autoradiographic method. The intracisternal administration of SB-386023-b, a specific inhibitor of raf, given 6 h after SAH, aborts the receptor changes and protects the brain from the development of late cerebral ischemia at 48 h. This is accompanied by reduced phosphorylation of ERK1/2 in cerebrovascular SMC. SAH per se enhances contractile responses to endothelin-1 (ET-1), 5-carboxamidotryptamine (5-CT) and angiotensin II (Ang II), upregulates ET_B, 5-HT_1Band AT₁receptor mRNA and protein levels. Treatment with SB-386023-b given as late as at 6 h but not at 12 h after the SAH significantly decreased the receptor upregulation, the reduction in CBF and the neurology score.</p> <p>Conclusion</p> <p>These results provide evidence for a role of the ERK1/2 pathway in regulation of expression of cerebrovascular SMC receptors. It is suggested that raf inhibition may reduce late cerebral ischemia after SAH and provides a realistic time window for therapy.</p