Caffeine tolerance is incomplete: persistent blood pressure responses in the ambulatory setting.

Background: Caffeine in dietary doses is a well-established pressor agent. Tolerance to this pressor effect occurs in only about half of regular consumers in acute laboratory tests. The clinical significance of this incomplete tolerance depends on whether the pressor effect is maintained throughout the day with repeated intake.

Integral equation theory for two-dimensional polymer melts.

The polymer reference interaction site model theory is investigated for two-dimensional polymer melts composed of freely-jointed hard disk chains and tangent-disk rods. Exact results for the intramolecular pair correlation functions are input into the theory, and predictions of the theory for the intermolecular pair correlation functions are tested via comparison with simulation. The theory is not as accurate for this system as it is for three-dimensional polymer melts, and the quantitative predictions are not good except at the highest area fractions.

Spinal glucocorticoid receptors contribute to the development of morphine tolerance in rats.

Background: Opioid analgesic tolerance is a pharmacologic phenomenon involving the mechanisms of cellular adaptation. Central glucocorticoid receptors (GRs) have been implicated in the cellular mechanism of neuronal plasticity that has many cellular steps in common with the mechanism of opioid tolerance. In a rat model of morphine tolerance, the authors examined the hypothesis that spinal GRs would play a significant role in the development of tolerance to the antinociceptive effect of morphine.

Evidence for a long-term influence on morphine tolerance after previous morphine exposure: role of neuronal glucocorticoid receptors.

Opioid analgesic tolerance is a pharmacological phenomenon that overtime diminishes the opioid analgesic effect. However, it remains unknown as to whether a previous opioid exposure would have a long-term influence on opioid tolerance upon subsequent opioid administration. Here, we show that the onset and degree of antinociceptive tolerance to a subsequent cycle of morphine exposure were substantially exacerbated in rats made tolerant to and then recovered from previous morphine administration, indicating a long-term influence from a previous morphine exposure on the development of morphine tolerance.

Central glucocorticoid receptors modulate the expression and function of spinal NMDA receptors after peripheral nerve injury.

Central glucocorticoid receptors (GRs) and NMDA receptors (NMDARs) have been shown to play a significant role in the mechanisms of neuropathic pain after peripheral nerve injury; however, how central GRs and NMDARs interact in this process remains unknown. Here we show that the expression and function of spinal NMDARs after peripheral nerve injury were modulated by central GRs. Chronic constriction nerve injury (CCI) in rats induced a time-dependent upregulation of NR1 and NR2 subunits of the NMDAR within the spinal cord dorsal horn ipsilateral to CCI.

Modulation of PPAR in aging, inflammation, and calorie restriction.

Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily of transcription factors, are key regulators in various pathophysiological processes related to energy metabolism including lipid, carbohydrate metabolism, and inflammation. At present, little information is on the effect of age and calorie restriction (CR) on PPARs. In the present study, we investigated how age and CR (60% of the ad libitum intake) modulate PPARs in kidneys obtained from Fischer 344 rats, ages 13 and 25 months.

Expression of central glucocorticoid receptors after peripheral nerve injury contributes to neuropathic pain behaviors in rats.

Peripheral glucocorticoid receptors (GRs) play a significant role in the anti-inflammatory effects of glucocorticoids; however, the role of central GRs in nociceptive behaviors after peripheral nerve injury (neuropathic pain behaviors) remains unknown. Here we show that the development of neuropathic pain behaviors (thermal hyperalgesia and mechanical allodynia) induced by chronic constriction nerve injury (CCI) in rats was attenuated by either the GR antagonist RU38486 (4 = 2 > 1 = 0.5 microg) or a GR antisense oligonucleotide administered intrathecally twice daily for postoperative days 1-6.

Proteomic analysis of post-mitochondrial fractions of young and old rat kidney.

Proteomic analysis is defined as the characterization of the entire set of proteins encoded by a genome. Two-dimensional (2D) electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) are key technologies used in proteomic analysis to gain information about protein expression profiles and post-translational modifications. Knowledge about aging processes can be gained by recognizing changes in protein expression.

Growth responses of Cassia obtusifolia toward human intestinal bacteria.

1,2-Dihydroxyanthraquinone (1) was isolated from the seed of Cassia obtusifolia through bioassay-guided fractionation. 1,2-Dihydroxyanthraquinone strongly inhibited the growth of Clostridium perfringens and Escherichia coli. Structure-activity relationship revealed that 1,4-dihydroxyanthraquinone (2) and 1,8-dihydroxyanthraquinone (3) had strong growth-inhibition against C.

Acridine orange staining method to reveal the characteristic features of an intravascular threadlike structure.

A threadlike structure in blood vessels that is considered part of the Bohghan duct system was first reported about 40 years ago. This structure has remained elusive since then due to the inability of other researchers to duplicate the original identification. In this study we identified the characteristic features of this threadlike structure in rats by the use of fluorescent microscope imaging of nuclei stained by acridine orange perfusion.

NF-kappaB activation mechanism of 4-hydroxyhexenal via NIK/IKK and p38 MAPK pathway.

4-Hydroxyhexenal (HHE) is known to affect redox balance during aging, included are vascular dysfunctions. To better understand vascular abnormality through the molecular alterations resulting from HHE accumulation in aging processes, we set out to determine whether up-regulation of mitogen-activated protein kinase (MAPK) by HHE is mediated through nuclear factor kappa B (NF-kappaB) activation in endothelial cells. HHE induced NF-kappaB activation by inhibitor of kappaB (IkappaB) phosphorylation via the IkappaB kinase (IKK)/NF-kappaB inducing kinase (NIK) pathway.

Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125.

The c-jun N-terminal kinase (JNK) signaling pathway is regulated by JNK-interacting protein-1 (JIP1), which is a scaffolding protein assembling the components of the JNK cascade. Overexpression of JIP1 deactivates the JNK pathway selectively by cytoplasmic retention of JNK and thereby inhibits gene expression mediated by JNK, which occurs in the nucleus. Here, we report the crystal structure of human JNK1 complexed with pepJIP1, the peptide fragment of JIP1, revealing its selectivity for JNK1 over other MAPKs and the allosteric inhibition mechanism.

Peripherally administered amitriptyline derivatives have differential anti-allodynic effects in a rat model of neuropathic pain.

We assessed if derivatives of amitriptyline could alleviate mechanical allodynia in a rat model of neuropathic pain. N-methyl amitriptyline (NMA), and amitriptyline HCl (AHC) were compared to evaluate the antiallodynic effects produced by systemic and peripheral administration. Under general anesthesia with halothane, neuropathic injury was produced in rats by tightly ligating the left L5 and L6 spinal nerves.

Blood pressure response to caffeine shows incomplete tolerance after short-term regular consumption.

Caffeine acutely raises blood pressure (BP). The clinical significance of this effect depends on whether BP responses persist in persons who consume caffeine on a daily basis. Accordingly, the ability of caffeine to raise BP after 5 days of regular daily intake was tested in a randomized controlled trial.

Human cytomegalovirus (HCMV) IE1 plays role in resistance to apoptosis with etoposide in cancer cell line by Cdk2 accumulation.

Human cytomegalovirus (HCMV) has many strategies to survive the attack of the host. HCMV infection of host cells induces cellular activation and disturbance of the cell cycle. It is possible that HCMV modulates the behavior of certain cancer cells that are susceptible to HCMV infection.

Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats.

Exogenous cannabinoids are effective in attenuating neuropathic pain behaviors induced by peripheral nerve injury, but the mechanisms of their effectiveness remain unclear. Here we examined the expression of spinal cannabinoid-1-receptors (CB1Rs) following chronic constriction sciatic nerve injury (CCI) and its relation to the effects of a CBR agonist (Win 55,212-2) on neuropathic pain in rats. CCI induced a time-dependent upregulation of spinal CB1Rs primarily within the ipsilateral superficial spinal cord dorsal horn as revealed by both Western blot and immunohistochemistry.

Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules.

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue.

A recombinant human G-CSF/GM-CSF fusion protein from E. coli showing colony stimulating activity on human bone marrow cells.

Granulocyte-Macrophage colony stimulating factor (GM-CSF) and Granulocyte colony stimulating factor (G-CSF) are cytokines involved in the differentiation of bone marrow progenitor cells into myeloid cells. They also activate mature myeloid cells to mediate a variety of antimicrobial activities and inflammatory responses. Recombinant GM-CSF and G-CSF proteins have been used to treat various diseases including cancer and hematopoietic diseases and to isolate peripheral blood progenitor cells for bone marrow transplantation.

Increases in spinal vasoactive intestinal polypeptide and neuropeptide Y are not sufficient for the genesis of neuropathic pain in rats.

We tested the hypothesis that increases in the spinal levels of vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) were related to the development of neuropathic pain. To this aim, we compared two groups of rats. One group showed well-developed neuropathic pain in the tail following unilateral transection of the inferior and superior caudal trunks between the S1 and S2 spinal nerves, and the other group showed poorly-developed neuropathic pain despite the same nerve injury.

Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats.

The central glutamatergic system has been implicated in the pathogenesis of neuropathic pain, and a highly active central glutamate transporter (GT) system regulates the uptake of endogenous glutamate. Here we demonstrate that both the expression and uptake activity of spinal GTs changed after chronic constriction nerve injury (CCI) and contributed to neuropathic pain behaviors in rats. CCI induced an initial GT upregulation up to at least postoperative day 5 primarily within the ipsilateral spinal cord dorsal horn, which was followed by a GT downregulation when examined on postoperative days 7 and 14 by Western blot and immunohistochemistry.

Minimization of the Escherichia coli genome using a Tn5-targeted Cre/loxP excision system.

An increasing number of microbial genomes have been completely sequenced, and functional analyses of these genomic sequences are under way. To facilitate these analyses, we have developed a genome-engineering tool for determining essential genes and minimizing bacterial genomes. We made two large pools of independent transposon mutants in Escherichia coli using modified Tn5 transposons with two different selection markers and precisely mapped the chromosomal location of 800 of these transposons.

Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity.

Tolerance to the analgesic effects of an opioid occurs after its chronic administration, a pharmacological phenomenon that has been associated with the development of abnormal pain sensitivity such as hyperalgesia. In the present study, we examined the role of spinal glutamate transporters (GTs) in the development of both morphine tolerance and associated thermal hyperalgesia. Chronic morphine administered through either intrathecal boluses or continuous infusion induced a dose-dependent downregulation of GTs (EAAC1 and GLAST) in the rat's superficial spinal cord dorsal horn.

Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism.

Tolerance to the analgesic effect of an opioid is a pharmacological phenomenon that occurs after its prolonged administration. Activation of the NMDA receptor (NMDAR) has been implicated in the cellular mechanisms of opioid tolerance. However, activation of NMDARs can lead to neurotoxicity under many circumstances.

A mouse model for peripheral neuropathy produced by a partial injury of the nerve supplying the tail.

We attempted to develop a mouse model for peripheral neuropathy by a partial injury of the nerve supplying the tail. Under enflurane anesthesia, the unilateral superior caudal trunk was resected between the S3 and S4 spinal nerves. Tests for thermal allodynia were conducted by immersing the tail into 4 or 38 degrees C water.

Caffeine and stress: implications for risk, assessment, and management of hypertension.

Caffeine use is widespread, and its consumption increases during periods of stress. Caffeine raises blood pressure by elevating vascular resistance, and this effect is larger and more prolonged in hypertensive patients than in normotensive. The pressor response to caffeine occurs equally in persons at rest and under stress.