Biomedical subjects

Thomas Blank

Publications and source records attributed to Thomas Blank.

9 recordsLinked to original sources

PubMed2006

Understanding treatment decision making: contexts, commonalities, complexities, and challenges.

BACKGROUND: The diagnosis of cancer sets off a cascade of complex decisions at a time when patients feel vulnerable and distressed. Although clinical decisions used to follow one standard, many guidelines now outline several options and include explicit recognition of the need to incorporate patients' preferences to determine the most appropriate treatment. PURPOSE: The purpose of this article is to provide a brief overview of empirical studies about cancer patients' treatment-related decision making, to highlight the areas of congruence and divergence in that empirical literature, and then to generate a framework that points to future interventions and research. METHODS: Through a group discussion with a range of experts in the field, we generated a framework for the critical treatment decisions and key issues within those decisions. Then, we reviewed the literature describing the experiences of cancer patients and evaluating interventions designed to improve the quality of treatment decisions. RESULTS: We identified four major differences that influence decision making across cancers and across individuals with the same diagnosis. We also identified four common themes across situations and people. There is considerable evidence that decision aids can improve the quality of decisions across a range of diseases, although the data for cancer treatment decision making are limited. Other interventions such as navigation-skill training are promising but have little evidence of benefit for cancer decisions. CONCLUSIONS: There are many opportunities for behavioral research to extend and contribute to the understanding and improvement of cancer treatment decision making. Some key areas in need of research include developing taxonomies of disease and patient characteristics and increasing understanding of the lived experiences of cancer survivors, of the influence of time and timing, of the relationship of information and preferences, and of participation in randomized clinical trials.

Comprehension↗

PubMed2004

Molecular determinants mediating effects of acute stress on hippocampus-dependent synaptic plasticity and learning.

The understanding of the molecular events underlying the neuroendocrine and behavioral sequelae of the response to stress has advanced rapidly over recent years. The hippocampus is a target of stress hormones, and we are beginning to dissect the molecular players in the modulation of synaptic plasticity and learning and memory involving this region of the brain. Given the wealth of data obtained from electrophysiological and behavioral experiments and in view of the importance to use identical experimental protocols in order to correlate the results obtained under both experimental conditions, this review focuses primarily on those contributions, which combine both approaches. From these studies it is evident that a single stressful event elicits responses in the hippocampus with different time-spans ranging from rapid changes in glutamatergic neurotransmission (i.e., N-methyl-d-aspartate receptor signaling), activation of second messenger cascades by corticotropin-releasing factor to long-lasting transcriptional changes of acetylcholinesterase. The relative contribution of these molecular targets to the stress response, the relation to hippocampal synaptic plasticity and memory formation, and the possible interaction of the underlying processes are discussed.

Acute Disease↗

PubMed2004

Small conductance Ca2+-activated K+ channels as targets of CNS drug development.

In most central neurons, small conductance Ca(2+)-activated K(+) channels (SK channels) contribute to afterhyperpolarizations (AHPs), which control neuronal excitability. The medium AHP has pharmacological properties similar to recombinant SK channels, consistent with the hypothesis that SK channels generate this afterhyperpolarization component. It is still unclear how recombinant SK channels are functionally related to the slow AHP component. Cloned SK channels are heteromeric complexes of SK channel subunits and calmodulin. The channels are activated by Ca(2+) binding to calmodulin that induces conformational changes resulting in channel opening. Channel deactivation is the reverse process brought about by dissociation of Ca(2+) from calmodulin. In the mammalian brain, the three SK channel subunits (SK1-3) display partially overlapping distributions. Most of the higher brain regions such as the neocortex and hippocampus show expression of both genes encoding SK1 and SK2 channels, whereas phylogenetically older brain regions such as the thalamus, basal ganglia, cerebellum, and brainstem show high levels of SK3 gene expression. At present, it is still unclear whether native SK channels are generated as heteromeric or homomeric channels. Peptide toxins such as apamin and scyllatoxin, as well as organic compounds such as quaternary salts of bicuculline, dequalinium, UCL 1684 and UCL 1848 serve as non-specific SK channel blockers. The only known exceptions so far are the scorpion toxin tamapin and the peptide inhibitor Lei-Dab(7), which bind preferentially to SK2. Electrophysiological and behavioral studies indicate that blockade of SK channels by apamin increases excitability, lowers the threshold for the induction of synaptic plasticity, and facilitates hippocampus-dependent memory. The potential value of pharmacological SK channel modulation in various pathological states such as increased epileptiform activity, cognitive impairment, pain, mood disorders and schizophrenia will be discussed.

Animals↗

PubMed2003

The corticotropin-releasing factor receptor 1 antagonist CP-154,526 reverses stress-induced learning deficits in mice.

The neuropeptide corticotropin-releasing factor (CRF) coordinates the endocrine responses to stress as a major physiological regulator of the hypothalamic-pituitary-adrenal axis. We assessed the effect of the non-peptidergic CRF receptor 1 antagonist CP-154,526 on stress-induced changes in context-dependent fear conditioning and hippocampal synaptic plasticity. The learning impairment of mice trained immediately after 1 h immobilization could be overcome by preinjection of CP-154,526 before exposure to immobilization. Exposure to acute stress reduced the amount of autophosphorylated Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in the hippocampal CA1 area. When animals were pretreated with CP-154,526 before immobilization, the amount of hippocampal autophosphorylated CaMKII was elevated. Electrophysiological studies in the hippocampal CA1 region of stressed animals revealed no significant effects of the CP-154,526 pretreatment on long-term potentiation but a significant elevation of paired-pulse facilitation (PPF) was observed. The CP-154,526-induced enhancements in fear conditioning and PPF could be prevented by the selective CaMKII inhibitor KN-62. Our results demonstrated that learning impairment after acute stress was antagonized by CP-154,526 pretreatment.

Animals↗

PubMed2003

Corticotropin-releasing factor receptors couple to multiple G-proteins to activate diverse intracellular signaling pathways in mouse hippocampus: role in neuronal excitability and associative learning.

Corticotropin-releasing factor (CRF) exerts a key neuroregulatory control on stress responses in various regions of the mammalian brain, including the hippocampus. Using hippocampal slices, extracts, and whole animals, we investigated the effects of human/rat CRF (h/rCRF) on hippocampal neuronal excitability and hippocampus-dependent learning in two mouse inbred strains, BALB/c and C57BL/6N. Intracellular recordings from slices revealed that application of h/rCRF increased the neuronal activity in both mouse inbred strains. Inhibition of protein kinase C (PKC) by bisindolylmaleimide I (BIS-I) prevented the h/rCRF effect only in hippocampal slices from BALB/c mice but not in slices from C57BL/6N mice. Inhibition of cAMP-dependent protein kinase (PKA) by H-89 abolished the h/rCRF effect in slices from C57BL/6N mice, with no effect in slices from BALB/c mice. Accordingly, h/rCRF elevated PKA activity in hippocampal slices from C57BL/6N mice but increased only PKC activity in the hippocampus of BALB/c mice. These differences in h/rCRF signal transduction were also observed in hippocampal membrane suspensions from both mouse strains. In BALB/c mice, hippocampal CRF receptors coupled to G(q/11) during stimulation by h/rCRF, whereas they coupled to G(s), G(q/11), and G(i) in C57BL/6N mice. As expected on the basis of the slice experiments, h/rCRF improved context-dependent fear conditioning of BALB/c mice in behavioral experiments, and BIS-I prevented this effect. However, although h/rCRF increased neuronal spiking in slices from C57BL/6N mice, it did not enhance conditioned fear. These results indicate that the CRF system activates different intracellular signaling pathways in mouse hippocampus and may have distinct effects on associative learning depending on the mouse strain investigated.

Animals↗

PubMed2003

Small-conductance, Ca2+-activated K+ channel SK3 generates age-related memory and LTP deficits.

Cognitive deficits are among the most devastating changes associated with the aging process. Age-related decrement in performance on learning tasks is correlated with substantial changes in neuronal signal processing in the hippocampus. Here we show that elevated expression of small-conductance Ca2+-activated K+ channels (SK channels) of the SK3 type in hippocampi of aged mice contributes to reduced long-term potentiation (LTP) and impaired trace fear conditioning, a hippocampus-dependent learning task.

Aging↗

PubMed2002

Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning.

In the present experiments, we characterized the action of human/rat corticotropin-releasing factor (h/rCRF) and acute stress (1 hr of immobilization) on hippocampus-dependent learning and on synaptic plasticity in the mouse hippocampus. We first showed that h/rCRF application and acute stress facilitated (primed) long-term potentiation of population spikes (PS-LTP) in the mouse hippocampus and enhanced context-dependent fear conditioning. Both the priming of PS-LTP and the improvement of context-dependent fear conditioning were prevented by the CRF receptor antagonist [Glu(11,16)]astressin. PS-LTP priming and improved learning were also reduced by the protein kinase C inhibitor bisindolylmaleimide I. Acute stress induced the activation of Ca2+/calmodulin-dependent kinase II (CaMKII) 2 hr after the end of the stress session. The CaMKII inhibitor KN-62 antagonized the stress-mediated learning enhancement, however, with no effect on PS-LTP persistence. Thus, long-lasting increased neuronal excitability as reflected in PS-LTP priming appeared to be essential for the enhancement of learning in view of the observation that inhibition of PS-LTP priming was associated with impaired learning. Conversely, it was demonstrated that inhibition of CaMKII activity reduced contextual fear conditioning without affecting PS-LTP priming. This observation suggests that priming of PS-LTP and activation of CaMKII represent two essential mechanisms that may contribute independently to long-term memory.

Action Potentials↗

PubMed2002

In vivo CREB phosphorylation mediated by dopamine and NMDA receptor activation in mouse hippocampus and caudate nucleus.

The pattern of CREB phosphorylation was investigated in the caudate nucleus and hippocampus 10 min or 3 h after i.p. injection of dopamine or NMDA receptor agonists alone, or in combination with antagonists. Ten minutes after C57BL/6 J mice were injected with either the dopamine D1 receptor agonist SKF-38393 hydrobromide or NMDA, immunoreactivity of phosphorylated CREB (pCREB) was significantly increased in all parts of the caudate nucleus but not in hippocampal regions. However, 3 h after the injection of SKF-38393, pCREB levels in the caudate nucleus did not differ significantly from the pCREB levels in control animals, whereas pCREB levels were still elevated 3 h after NMDA injection. Except for the D1 receptor antagonist SCH-23390, which induced CREB phosphorylation in the caudate nucleus, dopamine and NMDA receptor antagonists had little effect on pCREB levels by themselves. However, the NMDA receptor antagonist CGS-19755 injected i.p. blocked both the NMDA- and SKF-38393-induced rise of pCREB levels in the caudate nucleus. Similarly, the D1 receptor antagonist SCH-23390 inhibited the effects produced by SKF-38393 or NMDA. Interestingly, the D2 receptor antagonist sulpiride also blocked the SKF-38393-triggered rise of pCREB. The results demonstrated that NMDA and dopamine receptors modulate pCREB levels in the caudate nucleus and suggest mutual permissive roles for both receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2001

R$\rm{^{{\ast}}_{4}}$Tl(3)Cl and R$\rm{^{{\ast}}_{6}}$Tl(6)Cl(2) (R*=SitBu(3))-The First Compounds with Larger Clusters Containing Covalently Linked Thallium Atoms Compounds of Silicon, Part 143. Supersilyl Compounds of Boron and Its Homologues, Part 12. This work was supported by the Deutsche Forschungsgemeinschaft and by the Fonds der Chemischen Industrie. Part 42: N. Wiberg, W. Niedermayer, J. Organomet. Chem. 2001, in press; Part 11. M. Kehrwald, W. Köstler, A. Rodig, G. Linti, T. Blank, N. Wiberg, Organometallics 2001, in press.

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Journal Article↗