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PubMed2004

Simultaneous determination of semivolatile organic compounds in indoor air by gas chromatography-mass spectrometry after solid-phase extraction.

A method is described for simultaneous determination of semivolatile organic compounds (SVOCs) in indoor air by gas chromatography-mass spectrometry (GC-MS). The selected 73 SVOCs were collected using combined adsorbents (quartz fiber filter disk and Empore disk) for 24 h at a 5.0 l/min flow rate. The SVOCs collected were extracted with acetone, concentrated, then analyzed by an internal standard method. Forty compounds (19 plasticizers and flame retardants; 19 insecticides; 1 synergist; and 1 fungicide) among the target SVOCs were determined accurately and precisely. The method of detection limits for these compounds were approximately 0.5 ng/m3 for most of the SVOCs. The collected SVOC samples could be stored for up to 1 month at 4 C in the refrigerator.

Calibration↗

PubMed2004

Dendritic cell-based vaccination against opportunistic fungi.

Efficient responses to the different forms of fungi require different mechanisms of immunity. Dendritic cells (DCs) are uniquely able to decode the fungus-associated information and translate it in qualitatively different T helper (Th) immune responses, in vitro and in vivo. DCs sense fungi in a morphotype-specific manner, through the engagement of distinct recognition receptors ultimately affecting cytokine production and costimulation. Adoptive transfer of different types of DCs activates protective and non-protective Th cells as well as regulatory T cells and affects the outcome of the infections. DCs transfected with fungal RNA also restore antifungal resistance in hematopoietic transplantation. Thus, the remarkable functional plasticity of DCs in response to fungi can be exploited for the deliberate targeting of cells and pathways of cell-mediated immunity in response to fungal vaccines.

Animals↗

PubMed2000

Effects of adverse experiences for brain structure and function.

Studies of the hippocampus as a target of stress and stress hormones have revealed a considerable degree of structural plasticity in the adult brain. Repeated stress causes shortening and debranching of dendrites in the CA3 region of the hippocampus and suppresses neurogenesis of dentate gyrus granule neurons. Both forms of structural remodeling of the hippocampus appear to be reversible and are mediated by glucocorticoid hormones working in concert with excitatory amino acids (EAA) and N-methyl-D-aspartate (NMDA) receptors, along with transmitters such as serotonin and the GABA-benzodiazepine system. Glucocorticoids, EAA, and NMDA receptors are also involved in neuronal damage and death that is caused in pyramidal neurons by seizures and by ischemia. A similar mechanism may be involved in hippocampal damage caused by severe and prolonged psychosocial stress. Studies using magnetic resonance imaging have shown that there is a selective atrophy of the human hippocampus in a number of psychiatric disorders, as well as during aging in some individuals, accompanied by deficits in declarative, spatial, and contextual memory performance. It is therefore important to appreciate how hippocampal dysfunction may play a role in the symptoms of the psychiatric illness and, from a therapeutic standpoint, to distinguish between a permanent loss of cells and a reversible remodeling to develop treatment strategies to prevent or reverse deficits. Remodeling of the hippocampus may be only the tip of the iceberg; other brain regions may also be affected.

Adult↗

PubMedDate not supplied

Sex, stress and the hippocampus: allostasis, allostatic load and the aging process.

The adaptive responses of the body that maintain homeostasis in response to stressors can be called "allostasis", meaning "achieving stability through change". Mediators produced by the immune system, autonomic nervous system (ANS) and hypothalamo-pituitary-adrenal(HPA) axis produce allostasis. The brain also shows allostasis, involving the activation of nerve cell activity and the release of neurotransmitters. When the individual is challenged repeatedly or when the allostatic systems remain turned on when no longer needed, the mediators of allostasis can produce a wear and tear on the body and brain that has been termed "allostatic load". Examples of allostatic load include the accumulation of abdominal fat, the loss of bone minerals and the atrophy of nerve cells in the hippocampus. Studies of the hippocampus as a target of stress and sex hormones have revealed a considerable degree of structural plasticity and remodeling in the adult brain that differs between the sexes. Three forms of hippocampal structural plasticity are affected by circulating hormones: (1) repeated stress causes remodeling of dendrites in the CA3 region; (2) different modalities of stress suppress neurogenesis of dentate gyrus granule neurons; (3) ovarian steroids regulate synapse formation during the estrous cycle of female rats. All three forms of structural remodeling of the hippocampus are mediated by hormones working in concert with excitatory amino acids (EAA) and NMDA receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures, by ischemia and by severe and prolonged psychosocial stress. The aging brain seems to be more vulnerable to such effects, although there are considerable individual differences in vulnerability that can be developmentally determined. Moreover, the brain retains considerable resilience in the face of stress, and estrogens appear to play a role in this resilience. "Resilience is an example of successful allostasis in which wear and tear is minimized, and estrogens exemplify the type of agent that works against the allostatic load associated with aging." This review discusses the current status of work on underlying mechanisms for protection and damage.

Adaptation, Physiological↗

PubMed2005

Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion.

Neurotransmitter release is triggered by an increase in the cytosolic Ca2+ concentration ([Ca2+]i), but it is unknown whether the Ca2+-sensitivity of vesicle fusion is modulated during synaptic plasticity. We investigated whether the potentiation of neurotransmitter release by phorbol esters, which target presynaptic protein kinase C (PKC)/munc-13 signalling cascades, exerts a direct effect on the Ca2+-sensitivity of vesicle fusion. Using direct presynaptic Ca2+-manipulation and Ca2+ uncaging at a giant presynaptic terminal, the calyx of Held, we show that phorbol esters potentiate transmitter release by increasing the apparent Ca2+-sensitivity of vesicle fusion. Phorbol esters potentiate Ca2+-evoked release as well as the spontaneous release rate. We explain both effects by an increased fusion 'willingness' in a new allosteric model of Ca2+-activation of vesicle fusion. In agreement with an allosteric mechanism, we observe that the classically high Ca2+ cooperativity in triggering vesicle fusion (approximately 4) is gradually reduced below 3 microM [Ca2+]i, reaching a value of <1 at basal [Ca2+]i. Our data indicate that spontaneous transmitter release close to resting [Ca2+]i is a consequence of an intrinsic property of the molecular machinery that mediates synaptic vesicle fusion.

Allosteric Regulation↗

PubMed2006

Triclosan and antimicrobial resistance in bacteria: an overview.

Triclosan is a widely used biocide that is considered as an effective antimicrobial agent against different microorganisms. It is included in many contemporary consumer and personal health-care products, like oral and dermal products, but also in household items, including plastics and textiles. At bactericidal concentrations, triclosan appears to act upon multiple nonspecific targets, causing disruption of bacterial cell wall functions, while at sublethal concentrations, triclosan affects specific targets. During the 1990s, bacterial isolates with reduced susceptibility to triclosan were produced in laboratory experiments by repeated exposure to sublethal concentrations of the agent. Since 2000, a number of studies have verified the occurrence of triclosan resistance amongst dermal, intestinal, and environmental microorganisms, including some of clinical relevance. Of major concern is the possibility that triclosan resistance may contribute to reduced susceptibility to clinically important antimicrobials, due to either cross-resistance or co-resistance mechanisms. Although the number of studies elucidating the association between triclosan resistance and resistance to other antimicrobials in clinical isolates has been limited, recent laboratory studies have confirmed the potential for such a link in Escherichia coli and Salmonella enterica. Thus, widespread use of triclosan may represent a potential public health risk in regard to development of concomitant resistance to clinically important antimicrobials.

Anti-Bacterial Agents↗

PubMed2006

Validity of melanoma diagnosis in a community-based screening program.

Although screening for melanoma is intuitively attractive, evidence of the effectiveness of screening programs for skin cancer is lacking. Since 1990, the Lions Cancer Institute has conducted clinics in Western Australia in which volunteer plastic surgeons and dermatologists undertake full-body skin screens. Advertisements for attendees target people with risk factors for skin cancer. Each person screened between 1994 and 2002 (n = 7,436) completed a questionnaire including basic demographic information, on which the physician added provisional diagnoses. Attendees' details were linked with the Western Australian Cancer Registry to determine the number of diagnosed melanomas up to 1 and 2 years after screening. The positive predictive value of a screening diagnosis of "any lesion" at a particular body site was 1.5% and that of a screening diagnosis of "melanoma" was 10.0%. The 1-year specificity of the screening test ranged from 95.1% to 99.5%, and 1-year sensitivity ranged from 63.6% to 81.8%. Two-year sensitivity was lower. If body site was not taken into account, the sensitivities were higher and the specificities lower. Findings suggest that the validity of skin screening diagnoses in the general population is reasonable. Body site of the lesion should be taken into account when calculating validity of these diagnoses.

Adult↗

PubMed1998

Improvement in resource utilization after development of a clinical pathway for patients with pressure ulcers.

Clinical pathways are interdisciplinary patient care plans intended to reduce variance and improve quality of care while lowering health care cost. This study was undertaken to determine whether the development of a clinical pathway for care of patients with pressure ulcers can indeed decrease health care costs while preserving quality of care. A clinical pathway for surgical reconstruction of pressure ulcers was developed by standardizing the current practices of our plastic surgeon group. The pathway provided direction in optimal scheduling of physician interventions along with nursing, physical and occupational therapies, and spinal cord rehabilitation interventions. It covered all potential elements of patient care, including laboratory, radiology, dietary services, intravenous fluids, and use of specialty beds. It defined patient outcomes and outlined discharge planning. Pathways were distributed throughout all services caring for patients with pressure ulcers. Patient charts and billing data were reviewed for the 16-month periods before and after initiation of the pathway. No other significant changes in treatment occurred during this time frame. Ninety-seven patient charts were examined (54 before pathway and 43 after pathway implementation). Parameters evaluated included length of stay and total charges (including bed use, medications, laboratory tests, and radiology). Patient readmission rate was also examined. A significant reduction in patient length of stay and total charges was achieved after implementation of the clinical pathway. Reduction was seen not only for patients treated with flaps by plastic surgery but also for patients with pressure ulcers who were not specifically targeted such as those from other services. The readmission rate decreased slightly, although not significantly, after the pathway inception. Total cost saving was almost $11,000 per patient (23 percent). In conclusion, implementation of a clinical pathway, because it standardizes care and reduces variations and duplication of care, can reduce health care cost without impairing quality of care in the treatment of decubitus ulcer patients.

Costs and Cost Analysis↗

PubMed1998

Sex-steroid actions on neurotransmission.

Although it is well recognized that sex-steroids exert both developmental and activational influences on the brain, the cellular and molecular mechanisms underlying their actions are less well understood. Progress is rapid, however, and this paper reviews recent insights gained through manipulation of sex-steroid receptor genes, identification of phenotypes expressing these receptors and how these proteins may also be activated to regulate transcription by ligand-independent pathways. Advances in our understanding of more rapid actions of sex-steroids and the molecular targets involved are also reviewed, as are new studies describing effects on synaptic plasticity and the recent excitement regarding the neuroprotective effects of oestrogen replacement therapy in Alzheimer's disease.

Aged↗

PubMed2004

Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells.

BACKGROUND: Stroke is a leading cause of death and disability worldwide; however, no effective treatment currently exists. METHODS AND RESULTS: Rats receiving subcutaneous granulocyte colony-stimulating factor (G-CSF) showed less cerebral infarction, as evaluated by MRI, and improved motor performance after right middle cerebral artery ligation than vehicle-treated control rats. Subcutaneous administration of G-CSF enhanced the availability of circulating hematopoietic stem cells to the brain and their capacity for neurogenesis and angiogenesis in rats with cerebral ischemia. CONCLUSIONS: G-CSF induced increases in bone marrow cell mobilization and targeting to the brain, reducing the volume of cerebral infarction and improving neural plasticity and vascularization.

Animals↗

PubMed1999

Ca(2+)-permeable AMPA receptors induce phosphorylation of cAMP response element-binding protein through a phosphatidylinositol 3-kinase-dependent stimulation of the mitogen-activated protein kinase signaling cascade in neurons.

Ca(2+)-permeable AMPA receptors may play a key role during developmental neuroplasticity, learning and memory, and neuronal loss in a number of neuropathologies. However, the intracellular signaling pathways used by AMPA receptors during such processes are not fully understood. The mitogen-activated protein kinase (MAPK) cascade is an attractive target because it has been shown to be involved in gene expression, synaptic plasticity, and neuronal stress. Using primary cultures of mouse striatal neurons and a phosphospecific MAPK antibody we addressed whether AMPA receptors can activate the MAPK cascade. We found that in the presence of cyclothiazide, AMPA caused a robust and direct (no involvement of NMDA receptors or L-type voltage-sensitive Ca(2+) channels) Ca(2+)-dependent activation of MAPK through MAPK kinase (MEK). This activation was blocked by GYKI 53655, a noncompetitive selective antagonist of AMPA receptors. Probing the mechanism of this activation revealed an essential role for phosphatidylinositol 3-kinase (PI 3-kinase) and the involvement of a pertussis toxin (PTX)-sensitive G-protein, a Src family protein tyrosine kinase, and Ca(2+)/calmodulin-dependent kinase II. Similarly, kainate activated MAPK in a PI 3-kinase-dependent manner. AMPA receptor-evoked neuronal death and arachidonic acid mobilization did not appear to involve signaling through the MAPK pathway. However, AMPA receptor stimulation led to a Ca(2+)-dependent phosphorylation of the nuclear transcription factor CREB, which could be prevented by inhibitors of MEK or PI 3-kinase. Our results indicate that Ca(2+)-permeable AMPA receptors transduce signals from the cell surface to the nucleus of neurons through a PI 3-kinase-dependent activation of MAPK. This novel pathway may play a pivotal role in regulating synaptic plasticity in the striatum.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2000

[Prospects of Research on Bone Marrow Mesenchymal Stem Cells]

Besides hematopoietic stem cells, bone marrow also contains another type of stem cells called mesenchymal stem cells (MSCs). With different induced conditions, MSCs have the ability to differentiate into a variety of nonhematopoietic tissue cells, including osteoblasts, chondroblast, adipocytes, myoblasts, astrocytes, and so on. MSCs can be readily obtained from bone marrow by their adhesion to plastic and expansion in culture. Also they can be genetically engineered by transduced target genes. MSCs may be the farget cells for both cell therapy and gene therapy for diseases derived from many different nonhematopoietic tissues.

Journal Article↗

PubMed2003

Switching mechanisms of cell death in mdm2- and mdm4-null mice by deletion of p53 downstream targets.

The p53 tumor suppressor ensures maintenance of genome integrity by initiating either apoptosis or cell cycle arrest in response to DNA damage. Deletion of either mdm2 or mdm4 genes, which encode p53 inhibitors, results in embryonic lethality. The lethal phenotypes are rescued in the absence of p53, which indicates that increased activity of p53 is the cause of lethality in the mdm2- and mdm4-null embryos. Here we show that mdm2-null embryos die because of apoptosis initiated at 3.5 days postcoitum (dpc). Partial rescue of mdm2-null embryos by deletion of bax allows survival to 6.5 dpc and alters the mechanism of death from apoptosis to cell cycle arrest, indicating that bax is a critical component of the p53 pathway in early embryogenesis. The death of mdm4-null embryos is due to p53-initiated cell cycle arrest at 7.5 dpc. Deletion of p21(p21(waf1/cip1)), a p53 downstream target partially responsible for cell cycle arrest, does not rescue this phenotype; however, deletion of p21 alters the mechanism of cell death from lack of proliferation to apoptosis. Thus, in both examples, deletion of a p53 downstream target gene allows p53 to redirect its efforts, highlighting a high degree of plasticity in p53 function.

Animals↗

PubMed1982

Natural cytotoxic activity in human lungs.

Disease-free surgical lung specimens from 13 patients with neoplastic or infectious diseases and from three subjects with non-neoplastic, non-infectious pathology were mechanically disaggregated. Natural cytotoxicity was tested against 51Cr-labelled K562 target cells. Unseparated lung cells had little cytotoxicity against K562 cells. Removal of plastic and nylon-wool-adherent cells resulted in cell preparations (morphologically 80% lymphoid) with increased cytolytic activity against K562 but cytotoxicity levels were considerably lower than those of blood lymphocytes tested in parallel. Similar results were obtained when phagocytic adherent cells were removed with carbonyl iron. The NK-resistant murine TU5 and human Raji lines were not affected by lung effector cells. In vitro exposure to partially purified fibroblast interferon enhanced the cytotoxicity of unseparated or non-adherent lung cells. Thus, unlike in mouse pulmonary tissue, low levels of natural cytotoxic activity are associated with the humans lung.

Cell Survival↗

PubMed1995

Neural regeneration in gastropod molluscs.

Snails recover function following a variety of neural injuries. They grow new tentacles with associated tentacle ganglia, selectively reinnervate peripheral targets, repair central connections and may even replace lost neurons and ganglia. The plasticity revealed in their responses to neural injury is an extreme expression of the adaptability observed in studies of learning and age-related changes in the nervous system. Recent information on neurogenesis in gastropods is providing a basis for comparing developmental events with neural regeneration. Studies of neural regeneration in gastropods have capitalized on our ability to identify many gastropod neurons individually and characterize the cellular properties and network properties that generate output patterns that underlie behaviors. The robustness of the model systems formed by cultured gastropod neurons is apparent in the similarity of the activity patterns in circuits formed in vitro and in vivo. Cell membrane repair, activation of an altered pattern of protein synthesis, and observation of the searching action of the growth cones can be studied under defined conditions that promote or inhibit the processes. Basic properties of growth cones, the molecular binding and second messenger systems underlying adhesion, sprouting and pathfinding, and events in synaptogenesis are accessible to analysis. Rules that govern selection of synaptic partners are being evaluated on the basis of cellular characteristics such as transmitter and receptor expression and ganglion of origin. The conservation of the molecular language that governs growth and communication between cells suggest that information gained in such studies may some day be applied to promote neural regeneration in mammals.

Animals↗

PubMed1996

Recent advances related to basic mechanisms of epileptogenesis.

A variety of clinical observations suggest that certain forms of epilepsy are due to long-term, progressive changes in neural networks that eventually provoke spontaneous and recurring seizures. This process of network transformation, known as epileptogenesis, is a potentially important therapeutic target and also serves as an extremely interesting model of central nervous system plasticity. This article reviews some of the significant, recent advances in our understanding of mechanisms underlying epileptogenesis in different forms of epilepsy. The most substantial progress has been made in work related to temporal lobe epilepsy (TLE), where the biochemical, electrophysiological and anatomical changes in the hippocampus have been intensively studied. This has led to a number of cogent and testable hypotheses, including the concept that dentate granule cell hyperexcitability in TLE is due to a selective loss of hilar neurons that renders inhibitory cells 'dormant.' Studies of other forms of focal epilepsy suggest that a seizure focus may develop as a result of axonal reorganization or immune-mediated effects on membrane channels. Epileptogenesis in generalized epilepsies remains poorly understood, although recent work using models of absence epilepsy point to the critical role of GABAB or T-type calcium channels in the thalamus. Also, new transgenic mouse lines with epilepsy phenotypes have introduced candidate genes, such as those encoding the serotonin 5-HT2C receptor or the alpha subunit of calcium/calmodulin kinase II, that may be responsible for epileptogenesis. Finally, a large amount of investigation has focused on seizure-induced gene expression and it is now clear that seizures can cause a cascade of changes in the expression of gene products that are likely to play a role in network plasticity. Progress in developing 'anti-epileptogenic' therapies will require further advances in understanding the mechanistic roles of these various biochemical and anatomical changes in the transformation of normal to hyperexcitable neural networks.

Animals↗

PubMed2006

Faulty regulation of tau phosphorylation by the reelin signal transduction pathway is a potential mechanism of pathogenesis and therapeutic target in Alzheimer's disease.

Hyperphosphorylated tau protein is the basic structural component of the neurofibrillary tangle, a histopathological hallmark of Alzheimer's disease. The formation of hyperphosphorylated tau protein may impair learning and the synaptic plasticity of neurons. Tau is a protein that is associated with and stabilizes microtubules; hyperphosphorylated tau protein is unable to perform this stabilization function. The transduction of reelin, a protein that is crucial to neuronal migration and the formation of synaptic connections in the fetal brain, may have an equally important role in regulating at least some forms of learning and synaptic plasticity in the fully developed mature brain. Reelin transduction is mediated by receptors in the brain that are members of the superfamily of low-density lipoprotein receptors. An important downstream target of reelin signal transduction appears to be inhibition of an enzyme involved in the regulation of tau phosphorylation. The faulty transduction of the reelin signal may be a pathological mechanism leading to hyperphosphorylation of tau protein. Ultimately, inhibition of tau phosphorylation may be an important therapeutic target in Alzheimer's disease and other neuropsychiatric disorders.

Alzheimer Disease↗

PubMed2006

[Apoptosis and its role in plastic surgery].

Apoptosis and cell proliferation are the main mechanisms of cell homeostasis. The pathogenesis of approximately 70 % of all diseases results from an imbalance between these two counterparts. Therefore, research on apoptosis is a main target in biological and clinical fields. Many signalling pathways and proteins involved in their regulation have been characterized. In order to evaluate the relevance of apoptosis in plastic surgery, the literature was reviewed for its impact on ischemia and reperfusion concerning flap surgery as well as wound healing and angiogenesis. Furthermore, the relevance of apoptosis in ageing, allotransplantation and tumors was investigated. In all subsections of plastic surgery, a high impact was identified. More studies on the influence and regulation of apoptosis can bring further understanding on the disease patterns of plastic surgery and other specialties as well as the development of new therapeutic options. Research focusing on apoptosis is therefore an essential means for the advancement of and future trends in plastic surgery.

Aging↗