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At least 631 records · Page 35Linked to original sources
PubMed2006

Sensory-evoked intrinsic optical signals in the olfactory bulb are coupled to glutamate release and uptake.

Functional imaging signals arise from metabolic and hemodynamic activity, but how these processes are related to the synaptic and electrical activity of neurons is not well understood. To provide insight into this issue, we used in vivo imaging and simultaneous local pharmacology to study how sensory-evoked neural activity leads to intrinsic optical signals (IOS) in the well-defined circuitry of the olfactory glomerulus. Odor-evoked IOS were tightly coupled to release of glutamate and were strongly modulated by activation of presynaptic dopamine and GABA-B receptors. Surprisingly, IOS were independent of postsynaptic transmission through ionotropic or metabotropic glutamate receptors, but instead were inhibited when uptake by astrocytic glutamate transporters was blocked. These data suggest that presynaptic glutamate release and uptake by astrocytes form a critical pathway through which neural activity is linked to metabolic processing and hence to functional imaging signals.

Animals↗
PubMed2004

Isolation and characterization of limonoate and nomilinoate A-ring lactones.

A method combining solid-phase extraction and reversed-phase high-performance liquid chromatography is described for the isolation of two key metabolites in the limonoid biosynthetic pathway critical to citrus quality. Potassium salts of limonoate A-ring lactone and nomilinoate A-ring lactone were isolated from young Chandler pummelo seedlings and characterized on the basis of proton and carbon NMR data.

Chromatography, High Pressure Liquid↗
PubMed2006

Methylmercury-induced toxicity is mediated by enhanced intracellular calcium through activation of phosphatidylcholine-specific phospholipase C.

Methylmercury (MeHg) is a ubiquitous environmental toxicant to which humans can be exposed by ingestion of contaminated food. MeHg has been suggested to exert its toxicity through its high reactivity to thiols, generation of arachidonic acid and reactive oxygen species (ROS), and elevation of free intracellular Ca(2+) levels ([Ca(2+)](i)). However, the precise mechanism has not been fully defined. Here we show that phosphatidylcholine-specific phospholipase C (PC-PLC) is a critical pathway for MeHg-induced toxicity in MDCK cells. D609, an inhibitor of PC-PLC, significantly reversed the toxicity in a time- and dose-dependent manner with concomitant inhibition of the diacylglycerol (DAG) generation and the phosphatidylcholine (PC)-breakdown. MeHg activated the group IV cytosolic phospholipase A(2) (cPLA(2)) and acidic form of sphingomyelinase (A-SMase) downstream of PC-PLC, but these enzymes as well as protein kinase C (PKC) were not linked to the toxicity by MeHg. Furthermore, MeHg produced ROS, which did not affect the toxicity. Addition of EGTA to culture media resulted in partial decrease of [Ca(2+)](i) and partially blocked the toxicity. In contrast, when the cells were treated with MeHg in the presence of Ca(2+) in the culture media, D609 completely prevented cell death with parallel decrease in [Ca(2+)](i). Our results demonstrated that MeHg-induced toxicity was linked to elevation of [Ca(2+)](i) through activation of PC-PLC, but not attributable to the signaling pathways such as cPLA(2), A-SMase, and PKC, or to the generation of ROS.

Animals↗
PubMed2006

Platelet-derived growth factor-BB transactivates the fibroblast growth factor receptor to induce proliferation in human smooth muscle cells.

Platelet-derived growth factor (PDGF) is a major stimulant for smooth muscle cell migration and proliferation, and blockade of PDGF receptors in vivo reduces intimal growth after arterial injury. Signalling by PDGF receptors has been extensively studied and involves multiple signal transduction pathways. These include ras/Extracellular Signal Regulated Kinase (ERK), a pathway critical for controlling cell cycle progression. We have recently discovered that release of fibroblast growth factor 2 and the subsequent activation of fibroblast growth factor receptor 1 are required for maximal induction by PDGF of ERK and of human smooth muscle cell proliferation. This review summarizes our latest findings and discusses the potential implications of this novel signaling mechanism for restenosis.

Becaplermin↗
PubMed2002

Molecular characterization of human meningiomas by gene expression profiling using high-density oligonucleotide microarrays.

Meningiomas are common central nervous system neoplasms that exhibit remarkably diverse histopathology and biological behavior. Compared to astrocytomas, the most common central nervous system tumor, little is known about the molecular pathways critical for meningioma tumor formation and malignant progression. As an initial step toward characterizing the genetic basis of meningioma pathogenesis, we assessed cancer-related gene expression profiles of nonneoplastic leptomeningeal specimens and human meningiomas of varying World Health Organization (WHO) grade using high-density oligonucleotide microarrays. Although expression profile differences between nonneoplastic and meningioma specimens were readily discernible, the expression profile of a subset of genes could also distinguish WHO grade I from WHO grades II and III tumors. Altered expression levels of several genes identified in this study have been previously noted in meningiomas (eg, growth hormone receptor, IGFBP-7, endothelin receptor A, IGF2). However, we also identified a number of novel genes whose expression was associated with WHO grade and was confirmed by reverse transcriptase-polymerase chain reaction in a larger, independent set of meningeal tumors (n = 47). This report represents the first gene expression profiling studies of meningiomas and identifies some initial candidate genes that may provide further insights into the genetic basis for meningioma pathogenesis.

Carrier Proteins↗
PubMed1986

D-ribose inhibits DNA repair synthesis in human lymphocytes.

D-ribose is cytotoxic for quiescent human lymphocytes and severely inhibits their PHA-induced proliferation at concentrations (25-50 mM) at which other simple sugars are ineffective. In order to explain these effects, DNA repair synthesis was evaluated in PHA-stimulated human lymphocytes treated with hydroxyurea and irradiated. D-ribose, in contrast to other reducing sugars, did not induce repair synthesis and therefore did not apparently damage DNA in a direct way, although it markedly inhibited gamma ray-induced repair. Taking into account that lymphocytes must rejoin physiologically-formed DNA strand breaks in order to enter the cell cycle, we suggest that D-ribose exerts its cytotoxic activity by interfering with metabolic pathways critical for the repair of DNA breaks.

Arabinose↗
PubMed2000

Descending projections of infralimbic cortex that mediate stimulation-evoked changes in arterial pressure.

The infralimbic cortex (IL) of the rat can modify autonomic nervous system activity, but the critical pathway(s) that mediate this influence are unclear. To define the potential pathways, the first series of experiments characterizes the descending projections of IL and the neighboring cortical areas using Phaseolus vulgaris leucoagglutinin (PHA-L). IL has prominent projections to the central nucleus of the amygdala (Ce), the mediodorsal nucleus of the thalamus (MD), the lateral hypothalamic area (LHA), the periaqueductal gray (PAG), the parabrachial nucleus (Pb), and the nucleus of the solitary tract (NTS). The density and selectivity of these projections suggest that the LHA and the PAG mediate the ability of the IL to regulate cardiovascular function. The second series of experiments demonstrates that locally anesthetizing neurons in either the LHA or PAG with lidocaine attenuates the hypotensive effects produced by electrical stimulation of the IL. Similarly, microinjections of cobalt chloride (a neurotransmission blocker) into the anterior portion of the LHA also decrease the arterial pressure responses to IL stimulation, suggesting that the ability of lidocaine to reversibly block the evoked response is due to inactivation of neurons in the LHA. These data indicate that hypotension evoked by stimulation of IL is mediated, at least in part, by direct or indirect projections to the LHA and through the PAG.

Animals↗
PubMed1997

c-Ras is required for the activation of the matrix metalloproteinases by concanavalin A in 3Y1 cells.

Concanavalin A (Con A) is known to trigger augmented secretion and proteolytic activation of the matrix metalloproteinases (MMPs) in fibroblasts. To study the signaling pathway critical for the activation of MMPs in fibroblasts, we examined the effects of dominant negative ras (S17N ras) expression under the control of conditionally inducible promoter in Con A-activated 3Y1 cells. We found that augmented secretion and proteolytic activation of MMP-2 and MMP-9 together with expression of MT1-MMP in Con A-activated 3Y1 were dramatically suppressed by S17N ras expression. These results strongly suggest that c-Ras plays a critical role in the augmented expression and proteolytic activation of MMPs in fibroblasts.

Animals↗
PubMed2002

Thermally responsive polymer-grafted surfaces facilitate patterned cell seeding and co-culture.

Tissue engineering constructs that effectively duplicate natural tissue function must also maintain tissue architectural and organization features, particularly the integration of multiple cell types preserving distinct, integrated phenotypes. Cell-cell communication and biochemical cross-talk have been shown to be essential for the maintenance of differentiated cell functions in tissues and organs. Current limitations of cell-culture hinder progress in understanding the features and dynamics of heterotypic cell communication pathways critical to developing more sophisticated or effective tissue-engineered devices. We describe a method to conveniently electron-beam pattern cell culture surfaces with thermo-responsive polymer chemistry that exploits changes in cell-polymer adhesive interactions over a temperature window amenable for high-throughput cell culture. Cells seeded on these patterned surfaces at 20 degrees C adhere only to surface areas lacking thermo-responsive grafting chemistry; grafted domains at 20 degrees C are hydrophilic and non-cell adhesive. The culture temperature is then increased to 37 degrees C collapsing the hydrated grafted chemistry. A second cell type is added to the culture and adheres only to these exposed relatively hydrophobic grafted patterns. Both cell types can then be effectively co-cultured at 37 degrees C under multiple conditions. Long-term cell pattern fidelity and differentiated cell functions characteristic of each co-planar cell type are observed. This method is simple and has few limitations, compared with other existing co-culture methods.

Animals↗
PubMed2003

Absence of cadmium excretion and high assimilation result in cadmium biomagnification in a wolf spider.

Cd biomagnification in the terrestrial food chain appears to be dependent on the physiological properties of the organisms rather than on their trophic level. Although high Cd body burdens in spiders from the field have been reported many times, experimental verification of the key factors that determine the rate of cadmium accumulation is lacking. We investigated the cadmium assimilation rate in the common wolf spider Pirata piraticus fed with contaminated fruit flies. Spiders were fed for 42 days with contaminated flies, followed by a detoxicification period of 28 days. Every 14 days, a subsample of spiders and flies was taken for Cd determination. It was demonstrated that a high cadmium assimilation (69.5%) and an excretion rate approaching zero resulted in high Cd concentration factors. The results indicate the importance of spiders in cadmium biomagnification along critical pathways.

Animals↗
PubMedDate not supplied

Functional status instruments: outcome measure in the evaluation of patients with chronic obstructive pulmonary disease.

The purpose of this article is to review the instruments developed to measure functional status in patients with chronic obstructive pulmonary disease. Because the ability to carry out day-to-day activities is of primary importance to patients with chronic obstructive pulmonary disease, it is necessary for clinicians to understand which instruments provide the best measures of patient activity levels. Furthermore, as a critical outcome in managed care services, pulmonary critical pathways, and patient disability, the measurement of functional status in clinical practice assumes greater relevance. Functional status instruments in this review will refer to questionnaires measuring the day-to-day activities of patients. Questionnaires reviewed will include those that provide measures of general health status with activity-specific items, as well as questionnaires specifically designed to evaluate patients with pulmonary disease. The psychometric strengths, reliability and validity, and clinical utility of the instruments will be presented.

Activities of Daily Living↗
PubMed1999

Strategies for early discharge of the hospitalized patient with community-acquired pneumonia.

The treatment of the hospitalized patient with uncomplicated CAP is changing, to include a brief period of intravenous antibiotics followed by oral therapy. The Classification of Community-Acquired Pneumonia or CoCAP is a stratification tool that categorizes patients as low-risk pneumonia, unstable pneumonia, or complicated pneumonia. Use of validated hospital admission criteria, combined with the CoCAP algorithm and evolving criteria for switching patients from intravenous to oral therapy provides a structure for organizing treatment of patients with CAP for caregivers. Patients who can be discharged early are those from the unstable pneumonia group, which includes patients who have had reversal of their metabolic problems and stabilization of comorbid conditions, and who have not developed any serious pneumonia-related complications. Prolonged courses of intravenous antibiotic therapy are being replaced with 2 to 3 day courses of intravenous hydration and antibiotics; a switch to oral therapy and hospital discharge can be achieved after the patient tolerates one dose of oral therapy. Parameters to watch include vital signs and white blood cell count. Provided these parameters are improving, although they may not have returned to normal, the patient can be switched to oral therapy. Although patient treatment guidelines and critical pathways are becoming widespread in disease management, CAP is one disease in which prospective studies have demonstrated that a reduction in hospital stay is safe. Patients, caregivers, and administrators are happy with the reduction in hospital LOS. Other treatment protocols are being explored, including a single dose of intravenous antibiotic prior to oral switch and all-oral regimens employing the newer fluoroquinolones.

Administration, Oral↗
PubMed2000

Bilateral lesions of the central but not anterior or posterior parts of the piriform cortex retard amygdala kindling in rats.

The piriform cortex is thought to be involved in temporal lobe seizure propagation, such as that occurring during kindling of the amygdala or hippocampus. A number of observations suggested that the circuits of the piriform cortex might act as a critical pathway for limbic seizure discharges to assess motor systems, but direct evidence for this suggestion is scarce. Furthermore, the piriform cortex is not a homogeneous structure, which complicates studies on its role in limbic epileptogenesis. We have previously reported data indicating that the central part of the piriform cortex might be particularly involved during amygdala kindling. In order to further evaluate the role of different parts of the piriform cortex during kindling development, we bilaterally destroyed either the central, anterior or posterior piriform cortex by microinjections of ibotenate two weeks before onset of amygdala kindling. Lesions of the anterior piriform cortex hardly affected kindling acquisition, except that fewer animals exhibited stage 3 (unilateral forelimb) seizures compared to sham controls. Lesions of the central piriform cortex significantly retarded kindling, which was due to a decreased progression from stage 3 to stage 4/5 seizures, i.e. the lesioned rats needed significantly longer for the acquisition of generalized clonic seizures in the late stages of kindling development. Lesions of the posterior piriform cortex did not significantly affect kindling development. The data demonstrate that different parts of the piriform cortex mediate qualitatively different effects on amygdala kindling. The central piriform cortex seems to be a neural substrate involved in the continuous development of kindling from stage 3 to stages 4/5, indicating that this part of the piriform cortex may have preferred access, either directly or indirectly, to structures capable of supporting generalized kindled seizure expression.

Amygdala↗
PubMed1998

Inhibition of the cAMP signaling cascade via cannabinoid receptors: a putative mechanism of immune modulation by cannabinoid compounds.

Immune modulation by cannabinoids has been widely established over the past three decades. In spite of this, the mechanism of action responsible for immune modulation and other well described biological effects attributed to cannabinoid compounds has been elusive. The identification and cloning of two novel G protein coupled receptors, CB1 and CB2, both of which bind cannabimimetic agents has served as the basis for a putative mechanism of action. CB1, which is also referred to as the central cannabinoid receptor is the primary form expressed within the central nervous system (CNS). Conversely, the peripheral cannabinoid receptor, CB2, does not appear to be expressed within the CNS but is the predominant form of the receptor expressed within the immune system. Both CB1 and CB2 negatively regulate adenylate cyclase activity through a pertussis toxin sensitive GTP-binding protein. Recent investigations addressing the mechanism by which cannabinoids disrupt leukocyte function have demonstrated that in the presence of cannabinoids the cAMP signaling cascade is markedly inhibited as evidenced by decreased adenylate cyclase and protein kinase A activity and decreased DNA binding by cAMP response element binding proteins. The focus of this discussion will be on the effects cannabinoids elicit on events within the cAMP cascade and related signaling pathways critical to the regulation of cytokine genes.

Animals↗
PubMed1999

Early use of coronary angiography and intervention.

In this article we have outlined the current rationale and role of invasive management in ACS. For the majority of patients with ACS, who are either at high risk or unstable, invasive management is a critical element in breaking the sequence of recurrent ischemia leading to early cardiac events (Fig. 11). Secular trends in the care of cardiovascular patients predict even more sophisticated, invasive methods of treating coronary occlusion in the future. A futurist's view on this subject may envision the following type of scenario. A patient with prior CAD experiences persistent chest pain and notifies the emergency medical system. The paramedics arrive, and perform a rapid fingerstick cardiac biomarker panel and ECG. The results are interpreted by an emergency physician via a telecommunication system, and the patient is determined to be at high risk. He or she is triaged to a center capable of angioplasty and bypass surgery. On the way to the hospital, the patient is treated with aspirin, IV heparin, and an IV glycoprotein IIb/IIIa inhibitor. The patient undergoes triage angiography within 1 hour of hospital arrival, culprit lesion(s) are identified, and a revascularization plan is made--setting a critical pathway that is definitive. This vision is not far off on the horizon. We anticipate additional clinical trial results will help form the decision points in this optimal treatment scenario, which for a large proportion of patients will involve invasive management.

Angina, Unstable↗
PubMedDate not supplied

Delay in thrombolysis administration: causes of extended door-to-drug times and the asymptote effect.

We retrospectively analyzed medical records and critical pathway data forms of all patients who received thrombolytic therapy for acute myocardial infarction (AMI) over a 2 1/2-year period. The time spent by each patient in the emergency department (ED) prior to receiving thrombolytic therapy (the door-to-drug time) was determined. Records of those patients with door-to-drug times exceeding the median were closely examined to determine the cause of treatment delays. Results indicated that treatment delays resulted from delays in obtaining the initial electrocardiogram (24%), atypical presentations (11%), the need to rule out a potential contraindication (11%), the need to confirm the diagnosis (14%), and miscellaneous causes (8%). Many patients had no identifiable reason for their delay (32%). A certain population of AMI patients either do not satisfy thrombolytic criteria upon initial ED presentation or require prolonged evaluation to investigate possible contraindications to thrombolysis such as aortic dissection. The inclusion of patients in this separate population in a general analysis of median door-to-drug times results in an artificial asymptote effect and may confound quality initiatives.

Electrocardiography↗
PubMed2001

Potential biologic agents for treating rheumatoid arthritis.

The encouraging clinical results observed in trials using anti-TNF therapy clearly warrant further studies to determine whether TNF inhibitors are capable of modifying the destructive component of this disease in long-term follow-up studies as well as to assess the safety of long-term use (see the article by Keystone in this issue). It is also reasonable to propose that interfering with the cytokine cascade earlier in the course of disease may be of even greater therapeutic benefit. As the pathogenetic mechanisms in RA are more clearly defined, especially in early disease and in those individuals destined to develop severe disease, the potential of other biologic agents to specifically inhibit these critical pathways may provide better treatments for our patients. Many potential targets in the immune-mediated process of RA are currently being rigorously evaluated in clinical trials. Use of combinations of biologic therapies, perhaps in human patients with RA, should be of considerable interest in future trials.

Arthritis, Rheumatoid↗
PubMed1998

Calmodulin mediates calcium-dependent inactivation of N-methyl-D-aspartate receptors.

Ca2+ influx through N-methyl-D-aspartate (NMDA) receptors activates signal transduction pathways critical for many forms of synaptic plasticity in the brain. NMDA receptor-mediated Ca2+ influx also downregulates the gating of NMDA channels through a process called Ca2+-dependent inactivation (CDI). Recent studies have demonstrated that the calcium binding protein calmodulin directly interacts with NMDA receptors, suggesting that calmodulin may play a role in CDI. We report here that the mutation of a specific calmodulin binding site in the CO region of the NR1 subunit of the NMDA receptor blocks CDI. Moreover, intracellular infusion of a calmodulin inhibitory peptide markedly reduces CDI of both recombinant and neuronal NMDA receptors. Furthermore, this inactivating effect of calmodulin can be prevented by coexpressing a region of the cytoskeletal protein alpha-actinin2 known to interact with the CO region of NR1. Taken together, these results demonstrate that the binding of Ca2+/calmodulin to NR1 mediates CDI of the NMDA receptor and suggest that inactivation occurs via Ca2+/calmodulin-dependent release of the receptor complex from the neuronal cytoskeleton.

Actinin↗