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At least 631 records · Page 35Linked to original sources
PubMed2005

Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance.

Despite the beneficial effects of estrogens in women's health, there is a plethora of evidence that suggest an important role for these hormones, particularly 17beta-estradiol (E(2)), in the development and progression of breast cancer. Most estrogenic responses are mediated by estrogen receptors (ERs), either ERalpha or ERbeta, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues (i.e. bone and cardiovascular system) act like estrogens but block estrogen action in others. Tamoxifen is the first SERM that has been successfully tested for the prevention of breast cancer in high-risk women and is currently approved for the endocrine treatment of all stages of ER-positive breast cancer. Raloxifene, a newer SERM originally developed for osteoporosis, also appears to have preventive effect on breast cancer incidence. Numerous studies have examined the molecular mechanisms for the tissue selective action of SERMs, and collectively they indicate that different ER ligands induce distinct conformational changes in the receptor that influence its ability to interact with coregulatory proteins (i.e. coactivators and corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and its target gene promoter also affect SERM biocharacter. This review summarizes the therapeutic application of SERMs in medicine; particularly breast cancer, and highlights the emerging understanding of the mechanism of action of SERMs in select target tissues, and the inevitable development of resistance.

Animals↗
PubMed2004

Oxidative DNA damage and disease: induction, repair and significance.

The generation of reactive oxygen species may be both beneficial to cells, performing a function in inter- and intracellular signalling, and detrimental, modifying cellular biomolecules, accumulation of which has been associated with numerous diseases. Of the molecules subject to oxidative modification, DNA has received the greatest attention, with biomarkers of exposure and effect closest to validation. Despite nearly a quarter of a century of study, and a large number of base- and sugar-derived DNA lesions having been identified, the majority of studies have focussed upon the guanine modification, 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-OH-dG). For the most part, the biological significance of other lesions has not, as yet, been investigated. In contrast, the description and characterisation of enzyme systems responsible for repairing oxidative DNA base damage is growing rapidly, being the subject of intense study. However, there remain notable gaps in our knowledge of which repair proteins remove which lesions, plus, as more lesions identified, new processes/substrates need to be determined. There are many reports describing elevated levels of oxidatively modified DNA lesions, in various biological matrices, in a plethora of diseases; however, for the majority of these the association could merely be coincidental, and more detailed studies are required. Nevertheless, even based simply upon reports of studies investigating the potential role of 8-OH-dG in disease, the weight of evidence strongly suggests a link between such damage and the pathogenesis of disease. However, exact roles remain to be elucidated.

DNA Adducts↗
PubMed2004

Keeping afloat: student nurses' experiences following assignment referral.

The retention of nursing students is an ongoing problem, both within the United Kingdom (UK) and internationally. While there is a plethora of literature relating to student attrition, there is an absence of evidence in relation to the experiences of those students who are struggling to meet the demands of nursing programmes. Using an inductive sociological enquiry based approach, this study sought to examine the experiences of student nurses after referral on the first attempt of a summative assessment. Nursing students who had failed an assignment (n=20) were invited to participate. Data was collected using focus groups, with the emergent themes collapsed into a concise format using thematic content analysis. Four key themes were identified: desire to succeed; acceptance of personal failure; recognition of personal attributes required for success; and responsibility for personal success and failure. Students remained on the programme, despite struggling with financial and personal difficulties, because the desire to become a qualified nurse outweighed transient hardships. This paper will illustrate the benefits of understanding the students' experiences, in order to ensure the support students receive is appropriate to their needs. Understanding the support strategies as perceived by the students may prevent further wastage from nursing programmes.

Adaptation, Psychological↗
PubMed2006

Neurotoxic effects of homocysteine on cerebellar Purkinje neurons in vitro.

Whilst a plethora of studies that describe the toxicity of homocysteine to CNS neurons have been published, the effects of homocysteine on the Purkinje neurons of the cerebellum that play a vital role in motor function remain wholly unexplored. We have therefore established cultures of embryonic cerebellar Purkinje neurons and exposed them to a range of concentrations of homocysteine and determined its effects on their survival. The experiments revealed that all concentrations of homocysteine studied, from 50 to 500microM, caused a significant decrease in cerebellar Purkinje neuron number. This loss could be counteracted by the pan-caspase inhibitor z-VAD-fmk in the first 24h following homocysteine exposure, revealing that the initial loss was apoptotic. However, z-VAD-fmk could not prevent homocysteine-mediated loss of cerebellar Purkinje neurons in the longer term, after 6 days in vitro. In addition to its effects on Purkinje neuron survival, homocysteine markedly reduced both the overall magnitude and the complexity of the neurite arbor extended by the cerebellar Purkinje neurons, following 6 days incubation with this agent in vitro. Taken together our data reveal that homocysteine is toxic to cerebellar Purkinje neurons in vitro, inhibiting both their survival and the outgrowth of neurites.

Amino Acid Chloromethyl Ketones↗
PubMed2006

Synaptic roles of Cdk5: implications in higher cognitive functions and neurodegenerative diseases.

Accumulating evidence indicates that cyclin dependent kinase 5 (Cdk5), through phosphorylating a plethora of pre- and postsynaptic proteins, functions as an essential modulator of synaptic transmission. Recent advances in the field of Cdk5 research have not only consolidated the in vivo importance of Cdk5 in neurotransmission but also suggest a pivotal role of Cdk5 in the regulation of higher cognitive functions and neurodegenerative diseases. In this review, we will discuss the recent findings on the emanating role of Cdk5 as a regulator of synaptic functions and plasticity.

Animals↗
PubMed2006

Seeking a mechanism of action for the novel anticonvulsant lacosamide.

Lacosamide (LCM) is anticonvulsant in animal models and is in phase 3 assessment for epilepsy and neuropathic pain. Here we seek to identify cellular actions for the new drug and effects on recognised target sites for anticonvulsant drugs. Radioligand binding and electrophysiology were used to study the effects of LCM at well-established mammalian targets for clinical anticonvulsants. 10 microM LCM did not bind with high affinity to a plethora of rodent, guinea pig or human receptor sites including: AMPA; Kainate; NMDA (glycine/PCP/MK801); GABA(A) (muscimol/benzodiazepine); GABA(B); adenosine A1,2,3; alpha1, alpha2; beta1, beta2; M1,2,3,4,5; H1,2,3; CB1,2; D1,2,3,4,5; 5HT1A,1B,2A,2C,3,5A,6,7 and KATP. Weak displacement (25%) was evident at batrachotoxin site 2 on voltage gated Na+ channels. LCM did not inhibit neurotransmitter transport mechanisms for norepinephrine, dopamine, 5-HT or GABA, nor did it inhibit GABA transaminase. LCM at 100 microM produced a significant reduction in the incidence of excitatory postsynaptic currents (EPSC's) and inhibitory postsynaptic currents (IPSC's) in cultured cortical cells and blocked spontaneous action potentials (EC50 61 microM). LCM did not alter resting membrane potential or passive membrane properties following application of voltage ramps between -70 to +20 mV. The voltage-gated sodium channel (VGSC) blocker phenytoin potently blocked sustained repetitive firing (SRF) but, in contrast, 100 microM LCM failed to block SRF. No effect was observed on voltage-clamped Ca2+ channels (T-, L-, N- or P-type). Delayed-rectifier or A-type potassium currents were not modulated by LCM (100 microM). LCM did not mimic the effects of diazepam as an allosteric modulator of GABA(A) receptor currents, nor did it significantly modulate evoked excitatory neurotransmission mediated by NMDA or AMPA receptors (n > or = 5). Evidently LCM perturbs excitability in primary cortical cultures but does not appear to do so via a high-affinity interaction with an acknowledged recognition site on a target for existing antiepileptic drugs.

Acetamides↗
PubMed2005

The effect of intravesical Bacillus Calmette-Guerin instillations on the expression of inducible nitric oxide synthase in humans.

The activation of the inducible isoform of nitric oxide synthase (NOS) is associated with the production of large quantities of nitric oxide in response to cytokine stimulation. Bacillus Calmette-Guerin (BCG) mode of action against bladder carcinoma remains unclear, although a plethora of local and systemic events may follow its intravesical instillation. The present study was designed to investigate the expression of inducible NOS in normal and neoplastic urothelium and its alteration following tumor resection and subsequent intravesical immunotherapy. Bladder carcinoma and autologous normal bladder tissue specimens were procured from 36 patients undergoing transurethral resection. Tissue specimens were obtained from the same patients at first cystoscopy following six weekly intravesical instillations. Inducible NOS protein expression was assessed by immunohistochemistry in all tissue specimens. Immunostaining of normal urothelium for iNOS before treatment was negative in all but four cases. BCG treatment induced iNOS expression in tumor-free bladder tissue in 24 cases (66.6%). There were only four early tumor recurrences; interestingly, they corresponded to the cases with tumor cells expressing iNOS before BCG treatment, while novel tumors were also iNOS immunoreactive. BCG upregulated iNOS expression in normal human urothelial cells in vivo suggesting a role for nitric oxide in BCG mediated antitumor activity. Inducible NOS was detected in certain tumor specimens before and after BCG treatment implying a possible involvement in pro-tumor action.

Adjuvants, Immunologic↗
PubMed2005

Gene targeting of presynaptic proteins in synaptic plasticity and memory: across the great divide.

The past few decades have seen an explosion in our understanding of the molecular basis of learning and memory. The majority of these studies in mammals focused on post-synaptic signal transduction cascades involved in post-synaptic long-lasting plasticity. Until recently, relatively little work examined the role of presynaptic proteins in learning and memory in complex systems. The synaptic cleft figuratively represents a "great divide" between our knowledge of post- versus presynaptic involvement in learning and memory. While great strides have been made in our understanding of presynaptic proteins, we know very little of how presynaptically expressed forms of short- and long-term plasticity participate in information processing and storage. The paucity of cognitive behavioral research in the area of presynaptic proteins, however, is in stark contrast to the plethora of information concerning presynaptic protein involvement in neurotransmitter release, in modulation of release, and in both short- and long-term forms of presynaptic plasticity. It is now of great interest to begin to link the extensive literature on presynaptic proteins and presynaptic plasticity to cognitive behavior. In the future there is great promise with these approaches for identifying new targets in the treatment of cognitive disorders. This review article briefly surveys current knowledge on the role of presynaptic proteins in learning and memory in mammals and suggests future directions in learning and memory research on the presynaptic rim of the "great divide."

Adaptor Proteins, Vesicular Transport↗
PubMed2005

Cognitive disruption and altered hippocampus synaptic function in Reelin haploinsufficient mice.

The heterozygote reeler mouse (HRM) shows many neuroanatomical and biochemical features that are also present in some human cognitive disorders, such as schizophrenia. In the present study, hippocampal dependent plasticity and cognitive function of the HRM were characterized in detail in an attempt to reveal phenotypic functional differences that result from Reelin haploinsufficiency. The HRM and wild type mice show similar levels of overall activity, coordination, thermal nociception, startle responses, and anxiety-like behavior. In addition, both genotypes show similar shock threshold, identical cued freezing behavior and comparable spatial learning in Morris water maze tasks. However, a significant reduction in contextual fear conditioned learning was observed in the HRM. Electrophysiological studies in hippocampal CA1 synapses revealed a plethora of differences between genotypes. The HRM exhibits reduced field excitatory postsynaptic potentials in responses to similar synaptic inputs, lowered paired pulse facilitation ratio and impaired long-term depression and tetanus-induced long-term potentiation (LTP). Also, deficits were detected in LTP elicited by theta burst stimulation or by a whole cell pairing protocol. These physiologic differences could not be accounted for by changes in the overall amount of glutamate receptor subunits. In addition, it was determined that network-driven excitatory and inhibitory activities recorded in CA1 pyramidal neurons showed that the HRM had comparable amplitude and frequency of spontaneous excitatory postsynaptic currents, but a marked reduction in spontaneous inhibitory postsynaptic currents. Thus, the HRM exhibits a specific hippocampal-dependent learning deficit accompanied with a pronounced impairment of hippocampal plasticity and functional inhibitory innervation.

Animals↗
PubMed2006

Novel aspects on signal-transduction in the pancreatic beta-cell.

The glucose-stimulus/insulin-secretion-coupling by the pancreatic beta-cell, which guarantees the maintenance of glucose homeostasis in man, is regulated by a sophisticated interplay between glucose and a plethora of additional factors. Besides other nutrients, incretins, nerval innervation, systemic growth factors as well as autocrine and paracrine regulatory loops within the islet of Langerhans modulate the function of the insulin-producing beta-cell. Although the modulatory role of these factors is well appreciated, the underlying molecular mechanisms involved remain poorly understood. However, in most cases beta-cell membrane receptors coupled primarily to either G-proteins or tyrosine kinases, which subsequently activate respective second messenger cascades, are involved. In the present mini-review we will discuss the role of signaling through some of these receptor-operated effector systems in the light of pancreatic beta-cell signal-transduction.

Diabetes Mellitus↗
PubMed2004

Hypercalcemic hypocalciuria: a critical differential diagnosis for hyperparathyroidism.

A differential diagnosis for hyperparathyroidism includes all causes of hypercalcemia; the primary causes of which are primary hyperparathyroidism and humoral hypercalcemia of malignancy. Benign familial hypocalciuric hypercalcemia is a rare condition of primary importance because failure to recognize this entity leads to unnecessary surgery. There are a plethora of other rare causes of hypercalcemia that can be distinguished from primary hyperparathyroidism by history and laboratory profiles. This article discusses the main and less common causes of hypercalcemia and provides guidance for distinguishing among them.

Calcium↗
PubMedDate not supplied

Critical thinking and patient outcomes: a review.

There has been a multidisciplinary plethora of critical thinking definitions stemming from educators in 1912 1 through and inclusive of today. As nurses' roles change in response to the dynamics of managed care and an increase in use of biotechnology in health care, more is expected of them both in terms of psychomotor and cognitive skills. The American Association for Colleges of Nursing requires that critical thinking be reflected within academic nursing programs as a core competency for program accreditation. 2 Although critical thinking has been associated with and evaluated in regard to learning outcomes, little information exists which links critical thinking to patient outcomes. The purpose of this article is to provide a literature review of critical thinking and to explore a possible link between nurses' critical thinking and patient outcomes.

Accreditation↗
PubMedDate not supplied

Cultivating interpretive thinking through enacting narrative pedagogy.

Teachers and educational researchers in nursing have persisted in their attempts to teach students critical thinking and to evaluate the effectiveness of these efforts. Yet, despite the plethora of studies investigating critical thinking, there is a paucity of research providing evidence that teachers' efforts improve students' thinking. The purpose of this interpretive phenomenological study is to explicate how students' thinking can be extended when teachers use Narrative Pedagogy. Specifically, the theme Cultivating Interpretive Thinking refers to how teachers' use of Narrative Pedagogy moves beyond the critical thinking movement's emphasis on analytical thinking (i.e., problem solving). Cultivating Interpretive Thinking offers an innovative approach for teaching and learning thinking that attends to students' embodied, reflective, and pluralistic thinking experiences. Teachers who cultivate interpretive thinking add complexity to students' thinking to better prepare them for challenging, complex, and unpredictable clinical environments.

Attitude of Health Personnel↗
PubMed2004

Cell expansion in roots.

Cell expansion in roots is crucial for the exploration and exploitation of the soil substrate and the plethora of activities that roots engage in. Expansion requires the coordinated activities of many cell processes. Central to this is the control of ion transport during vacuolar growth, which mediates the increase in cell size and the concomitant production of new wall and membrane at the surface of growing cells. The cytoskeleton plays an important role in growth and the control of growth direction. Evidence is accumulating to show that plant hormones also coordinate cell expansion throughout the plant by controlling the activities of growth-regulating DELLA proteins.

Arabidopsis↗
PubMed2006

F-box proteins everywhere.

The ubiquitin proteasome system is a key regulator of many biological processes in all eukaryotes. This mechanism employs several types of enzymes, the most important of which are the ubiquitin E3 ligases that catalyse the attachment of polyubiquitin chains to target proteins for their subsequent degradation by the 26S proteasome. Among the E3 families, the SCF is the best understood; it consists of a multi-protein complex in which the F-box protein plays a crucial role by recruiting the target substrate. Strikingly, nearly 700 F-box proteins have been predicted in Arabidopsis, suggesting that plants have the capacity to assemble a multitude of SCF complexes, possibly controlling the stability of hundreds of substrates involved in a plethora of biological processes. Interestingly, viruses and even pathogenic bacteria have also found ways to hijack the plant SCF and to reprogram it for their own purposes.

F-Box Proteins↗
PubMedDate not supplied

Deciphering the mechanisms of homeostatic plasticity in the hypothalamo-neurohypophyseal system--genomic and gene transfer strategies.

The hypothalamo-neurohypophyseal system (HNS) is the specialised brain neurosecretory apparatus responsible for the production of a peptide hormone, vasopressin, that maintains water balance by promoting water conservation at the level of the kidney. Dehydration evokes a massive increase in the regulated release of hormone from the HNS, and this is accompanied by a plethora of changes in morphology, electrical properties and biosynthetic and secretory activity, all of which are thought to facilitate hormone production and delivery, and hence the survival of the organism. We have adopted a functional genomic strategy to understand the activity dependent plasticity of the HNS in terms of the co-ordinated action of cellular and genetic networks. Firstly, using microarray gene-profiling technologies, we are elucidating which genes are expressed in the HNS, and how the pattern of expression changes following physiological challenge. The next step is to use transgenic rats to probe the functions of these genes in the context of the physiological integrity of the whole organism.

Animals↗
PubMedDate not supplied

Long-term safety of antihypertensive therapy.

Lowering blood pressure (BP) in hypertensive patients reduces morbidity and mortality. However the long-term safety of some antihypertensive agents was a matter of concern. Diuretic, the gold standard treatment in hypertension may impair glucose tolerance and thereby accelerate the development of diabetes mellitus. It was also associated with increased cardiovascular mortality in diabetic patients. However, recent evidence showed that low-medium dose of thiazide diuretic especially when given in combination with potassium sparing agent is effective in reducing BP and cardiovascular morbidity and mortality. Beta blockers are less effective than other antihypertensive agents in the elderly. Therefore they may be appropriate as a first choice in young and middle-age hypertensives, and in those with fast heart rate, but they should not be considered appropriate as the first-line therapy in the elderly with uncomplicated hypertension. Several years ago a plethora of publications showed that short-acting calcium antagonists may increase the risk for myocardial infarction and cancer. A few years ago two studies showed that calcium antagonists are less effective than angiotensin converting enzyme inhibitors in preventing cardiovascular events in diabetic hypertensive patients. However, recent results from large prospective randomized studies showed that calcium antagonists reduce cardiovascular morbidity and mortality in diabetic and non-diabetic hypertensive patients. Some investigators have suggested that angiotensin receptor blockers (ARBs) may increase the risk of myocardial infarction in hypertensive patients. However, recent meta analyses refuted this conclusions and showed that ARBs are probably as effective as other antihypertensive agents in prevention of myocardial infarction. Despite the concern that has been raised regarding the long-term safety of some antihypertensive agents, it is clear that lowering BP is safe and beneficial.

Adrenergic alpha-Antagonists↗
PubMed2005

Production of constitutively acetylated recombinant p53 from yeast and Escherichia coli by tethered catalysis.

Post-translational modification of proteins is a dynamic way of generating new protein-protein interaction interfaces that are critical for signaling networks in diverse cellular functions. Purified recombinant proteins frequently lack these signature modifications. Using the tumor suppressor p53 as the model protein, we present here a tethered catalysis approach for the production of acetylated p53 in vivo. P53 is a major tumor suppressor protein that protects the cell from various oncogenic stresses. Upon DNA damage, p53 is stabilized and activated by a plethora of post-translational modifications, including acetylation. Here, we show that constitutively acetylated p53 can be expressed and purified from both yeast and Escherichia coli. This method is highly suitable for studying protein-protein interactions in the conventional yeast two-hybrid screen that requires a constitutively acetylated state of p53. Furthermore, effective production and purification of acetylated p53 from E. coli supports future biochemical and structural characterization. The method described in this work can be applied to other proteins and modifications, and thus has widespread use in the fields of signal transduction and proteomic research.

Acetylation↗