Status report. Canadian strategy for cancer control.

The Canadian Strategy for Cancer Control is a stakeholder-driven initiative, led by a partnership between the Canadian Cancer Society, National Cancer Institute of Canada, Canadian Association of Provincial Cancer Agencies and Health Canada. The planning process began in January 1999 and currently involves more than 130 health professionals and community representatives who are volunteering their time, experience and expertise. A crucial aspect of the strategy's successful implementation is early participation of the provincial/territorial ministries of health in the planning process. Working groups are addressing 11 areas of the cancer continuum: prevention, screening, diagnosis, treatment, supportive care/rehabilitation, palliative care, pediatric cancer, research, human resource planning, surveillance and informatics/technology. Two stakeholder conferences will engage all cancer stakeholders in helping develop recommendations and establishing priorities for cancer control in Canada.

Inhibition evoked from primary afferents in the electrosensory lateral line lobe of the weakly electric fish (Apteronotus leptorhynchus).

Inhibition evoked from primary afferents in the electrosensory lateral line lobe of the weakly electric fish (Apteronotus leptorhynchus). J. Neurophysiol. 80: 3173-3196, 1998. The responses of two types of projection neurons of the electrosensory lateral line lobe, basilar (BP) and nonbasilar (NBP) pyramidal cells, to stimulation of primary electrosensory afferents were determined in the weakly electric fish, Apteronotus leptorhynchus. Using dyes to identify cell type, the response of NBP cells to stimulation of primary afferents was inhibitory, whereas the response of BP cells was excitation followed by inhibition. gamma-Aminobutyric acid (GABA) applications produced biphasic (depolarization then hyperpolarization) responses in most cells. GABAA antagonists blocked the depolarizing effect of GABA and reduced the hyperpolarizing effect. The GABAB antagonists weakly antagonized the hyperpolarizing effect. The early depolarization had a larger increase in cell conductance than the late hyperpolarization. The conductance changes were voltage dependent, increasing with depolarization. In both cell types, baclofen produced a slow small hyperpolarization and reduced the inhibitory postsynaptic potentials (IPSPs) evoked by primary afferent stimulation. Tetanic stimulation of primary afferents at physiological rates (100-200 Hz) produced strongly summating compound IPSPs (approximately 500-ms duration) in NBP cells, which were usually sensitive to GABAA but not GABAB antagonists; in some cells there remained a slow IPSP that was unaffected by GABAB antagonists. BP cells responded with excitatory or mixed excitatory + inhibitory responses. The inhibitory response had both a fast (approximately 30 ms, GABAA) and long-lasting slow phase (approximately 800 ms, mostly blocked by GABAA antagonists). In some cells there was a GABAA antagonist-insensitive slow IPSP (approximately 500 ms) that was sensitive to GABAB antagonists. Application of glutamate ionotropic receptor antagonists blocked the inhibitory response of NBP cells to primary afferent stimulation and the excitatory response of BP cells but enhanced the BP cell slow IPSP; this remaining slow IPSP was reduced by GABAB antagonists. Unit recordings in the granule cell layer and computer simulations of pyramidal cell inhibition suggested that the duration of the slow GABAA inhibition reflects the prolonged firing of GABAergic granule cell interneurons to primary afferent input. Correlation of the results with known GABAergic circuitry in the electrosensory lobe suggests that the GABAergic type 2 granule cell input to both pyramidal cell types is via GABAA receptors. The properties of the GC2 GABAA input are well suited to their putative role in gain control, regulation of phasicness, and coincidence detection. The slow GABAB IPSP evoked in BP cells is likely due to ovoid cell input to their basal dendrites.

Interaction of GABAB-mediated inhibition with voltage-gated currents of pyramidal cells: computational mechanism of a sensory searchlight.

Interaction of GABAB-mediated inhibition with voltage-gated currents of pyramidal cells: computational mechanism of a sensory searchlight. J. Neurophysiol. 80: 3197-3213, 1998. This study examines, in the in vitro electrosensory lateral line lobe (ELL) slice preparation, mono- and disynaptic inhibition in pyramidal cells evoked by stimulation of the direct descending pathway from nucleus praeminentialis (Pd). The pathway forms the stratum fibrosum (StF) in the ELL and consists of excitatory fibers from Pd stellate cells that make monosynaptic contact with pyramidal cells and disynaptic inhibitory contacts via local interneurons and of GABAergic inhibitory fibers from Pd bipolar cells. Single or tetanic stimulation (physiological rates of 100-200 Hz) of the StF produced excitatory postsynaptic potentials (EPSPs) or compound EPSPs in ELL pyramidal cells. Slow (>600 ms) and fast inhibitory postsynaptic potentials (IPSPs; 5-50 ms) also were evoked. Application of gamma-aminobutyric acid-A (GABAA) antagonists blocked the fast inhibition and dramatically increased the firing rate response to StF tetanic stimuli. GABAA antagonists also increased the amplitude of the slow IPSP. The slow IPSP was reduced by GABAB antagonists. Blockade of excitatory amino acid (EAA) synaptic transmission allowed the monosynaptic bipolar-cell-mediated inhibition to be studied in isolation: EAA antagonists blocked most of the EPSP response to StF stimulation leaving fast and (an increased amplitude) slow IPSP components. The bipolar-cell IPSPs were mediated by GABAA and GABAB receptors as they were sensitive to GABAA and GABAB antagonists. The bipolar-cell IPSPs scaled with stimulation rate (20-400 Hz), reaching a maximum amplitude at 200 Hz. Inhibitory efficacy of bipolar-cell slow IPSPs were tested by their ability to reduce spiking in the face of sustained or brief current pulses. Established spike trains (by sustained injected current) were little affected by the onset of the slow IPSP. Weak brief currents injected during the slow IPSP were strongly inhibited. Strong brief currents could overcome the slow IPSP inhibitory effect. Inhibition was observed to interact with the intrinsic IA-like K+ currents to produce a complex control of cell spiking. Hyperpolarizing inhibition removes inactivation of IA to prevent subsequent inputs from driving the cell to threshold. Established depolarizing inputs, having allowed IA to inactivate, enable the cell to be highly sensitive to further depolarizing input. The term "conditional inhibition" is proposed to describe the general phenomenon where synaptic inhibition interacts with voltage-sensitive intrinsic currents.

Distal versus proximal inhibitory shaping of feedback excitation in the electrosensory lateral line lobe: implications for sensory filtering.

Distal versus proximal inhibitory shaping of feedback excitation in the electrosensory lateral line lobe: implications for sensory filtering. J. Neurophysiol. 80: 3214-3232, 1998. The inhibition controlling the indirect descending feedback (parallel fibers originating from cerebellar granule cells in the eminentia posterior pars granularis) to electrosensory lateral line lobe (ELL) pyramidal cells was studied using intracellular recording techniques in vitro. Parallel fibers (PF) contact stellate cells and dendrites of ventral molecular layer (VML) GABAergic interneurons. Stellate cells provide local input to pyramidal cell distal dendrites, whereas VML cells contact their somata and proximal dendrites. Single-pulse stimulation of PF evoked graded excitatory postsynaptic potentials (EPSPs) that were blocked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl--aspartate (NMDA) antagonists. The EPSPs peaked at 6.4 +/- 1.8 ms (mean +/- SE; n = 11) but took >50 ms to decay completely. Tetanic stimulation (100 ms, 100 Hz) produced a depolarizing wave with individual EPSPs superimposed. The absolute amplitude of the individual EPSPs decreased during the train. Spike rates, established by injected current, mostly were increased, but in some cells were decreased, by tetanic stimulation. Global application of a gamma-aminobutyric acid-A (GABAA) antagonist to the recorded cell's soma and apical dendritic region increased the EPSP peak and decay phase amplitudes. Tetanic stimulation always increased current-evoked spike rates after GABAA blockade during, and for several hundred milliseconds after, the stimulus. Application of a GABAB antagonist did not have any significant effects on the PF-evoked response. This, and the lack of any long hyperpolarizing inhibitory postsynaptic potentials, suggests that VML and stellate cell inhibition does not involve GABAB receptors. Focal GABAA antagonist applications to the dorsal molecular layer (DML) and pyramidal cell layer (PCL) had contrasting effects on PF-evoked EPSPs. DML GABAA blockade significantly increased the EPSP peak amplitude but not the decay phase of the EPSP, whereas PCL GABAA-blockade significantly increased the decay phase, but not the EPSP peak, amplitude. The order of antagonist application did not affect the outcome. On the basis of the known circuitry of the ELL, we conclude that the distal inhibition originated from GABAergic molecular layer stellate cells and the proximal inhibition originated from GABAergic cells of the ventral molecular layer (VML cells). Computer modeling of distal and proximal inhibition suggests that intrinsic differences in IPSP dynamics between the distal and proximal sites may be amplified by voltage-dependent NMDA receptor and persistent sodium currents. We propose that the different time courses of stellate cell and VML cell inhibition allows them to act as low- and high-pass filters respectively on indirect descending feedback to ELL pyramidal cells.

Excitatory amino acid receptors at a feedback pathway in the electrosensory system: implications for the searchlight hypothesis.

The electrosensory lateral line lobe (ELL) of the South American gymnotiform fish Apteronotus leptorhynchus has a laminar structure: electroreceptor afferents terminate ventrally whereas feedback input distributes to a superficial molecular layer containing the dendrites of the ELL principle (pyramidal) cells. There are two feedback pathways: a direct feedback projection that enters the ELL via a myelinated tract (stratum fibrosum, StF) and terminates in the ventral molecular layer (VML) and an indirect projection that enters as parallel fibers and terminates in the dorsal molecular layer. It has been proposed that the direct feedback pathway serves as a "searchlight" mechanism. This study characterizes StF synaptic transmission to determine whether the physiology of the direct feedback projection is consistent with this hypothesis. We used field and intracellular recordings from the ELL to investigate synaptic transmission of the StF in an in vitro slice preparation. Stimulation of the StF produced field potentials with a maximal negativity confined to a narrow band of tissue dorsal to the StF. Current source density analysis revealed two current sinks: an early sink within the StF and a later sink that corresponded to the anatomically defined VML. Field potential recordings from VML demonstrated that stimulation of the StF evoked an excitatory postsynaptic potential (EPSP) that peaked at a latency of 4-7 ms with a slow decay ( approximately 50 ms) to baseline. Intracellular recordings from pyramidal cells revealed that StF-evoked EPSPs consisted of at least two components: a fast gap junction mediated EPSP (peak 1.2-1.8 ms) and a chemical synaptic potential (peak 4-7 ms) with a slow decay phase ( approximately 50 ms). The amplitudes of the peak and decay phases of the chemical EPSP were increased by depolarizing current injection. Pharmacological studies demonstrated that the chemical EPSP was mainly due to ionotropic glutamate receptors with bothN-methyl--aspartate (NMDA) and non-NMDA components. NMDA receptors contributed substantially to both the early and late phase of the EPSP, whereas non-NMDA receptors contributed mainly to the early phase. Stimulation of the StF at physiological rates (100-200 Hz, 100 ms) produced an augmenting depolarization of the membrane potential of pyramidal cells. Temporal summation and a voltage-dependent enhancement of later EPSPs in the stimulus train permitted the compound EPSP to reach spike threshold. The nonlinear behavior of StF synaptic potentials is appropriate for the putative role of the direct feedback pathway as part of a searchlight mechanism allowing these fish to increase the electrodetectability of scanned objects.

Inositol 1,4,5-trisphosphate receptor localization in the brain of a weakly electric fish (Apteronotus leptorhynchus) with emphasis on the electrosensory system.

Inositol 1,4,5-trisphosphate is a widespread intracellular second messenger that mobilizes intracellular Ca2+ stores. The inositol 1,4,5-trisphosphate receptor involved is associated with the endoplasmic reticulum in neurons. In mammalian brain, inositol 1,4,5-trisphosphate receptor-containing neurons are found in many diverse regions, with cerebellar Purkinje cells containing the highest density of these receptors. We used immunohistochemical methods to identify the distribution of inositol 1,4,5-trisphosphate receptor-containing neurons in the brain of the weakly electric fish and Western blotting to confirm that a protein similar to the inositol 1,4,5-trisphosphate receptor of mammalian brain was recognized in the fish brain. In the telencephelon, the dorsal forebrain regions had low amounts of inositol 1,4,5-trisphosphate receptor. In the diencephalon, only the nucleus tuberis posterior was moderately immunoreactive. In the mesencephalon, only the optic tectum contained cells with intense immunoreactivity, similar to our findings for the ryanodine receptor (G.K.H. Zupanc, J.A. Airey, L. Maler, J. Sutko, and M.H. Ellisman, 1992, J. Comp. Neurol. 325:135-151), which also mobilizes intracellular calcium. In the rhombencephalon, a subset of the pyramidal cells of the electrosensory lateral line lobe contained inositol 1,4,5-trisphosphate receptor. These cells have been shown to contain ryanodine receptor (Zupanc et al., 1992). However, unlike the ryanodine receptor, the distribution of inositol 1,4,5-trisphosphate receptor in these cells is constrained to the soma and proximal dendrites. This compartmentalization may indicate the limit of the range of second-messenger action. Other regions containing immunoreactive cells were the nucleus praeminentialis dorsalis (multipolar and boundary cells), nucleus medialis and crista cerebellaris, and the cerebellum, whose Purkinje cells were the most intensely labeled. The functional implications of inositol 1,4,5-trisphosphate receptor localization in the electrosensory lateral line lobe are discussed.

Mechanisms of inhibition in cat visual cortex.

1. Neurones from layers 2-6 of the cat primary visual cortex were studied using extracellular and intracellular recordings made in vivo. The aim was to identify inhibitory events and determine whether they were associated with small or large (shunting) changes in the input conductance of the neurones. 2. Visual stimulation of subfields of simple receptive fields produced depolarizing or hyperpolarizing potentials that were associated with increased or decreased firing rates respectively. Hyperpolarizing potentials were small, 5 mV or less. In the same neurones, brief electrical stimulation of cortical afferents produced a characteristic sequence of a brief depolarization followed by a long-lasting (200-400 ms) hyperpolarization. 3. During the response to a stationary flashed bar, the synaptic activation increased the input conductance of the neurone by about 5-20%. Conductance changes of similar magnitude were obtained by electrically stimulating the neurone. Neurones stimulated with non-optimal orientations or directions of motion showed little change in input conductance. 4. These data indicate that while visually or electrically induced inhibition can be readily demonstrated in visual cortex, the inhibition is not associated with large sustained conductance changes. Thus a shunting or multiplicative inhibitory mechanism is not the principal mechanism of inhibition.

Adaptation and bursting in neocortical neurones may be controlled by a single fast potassium conductance.

We have used computer simulation of a model neurone and in vitro intracellular recording to demonstrate that the adaptation of repetitive discharge in neocortical neurones can be explained by a fast potassium current whose inactivation is retarded by intracellular calcium. The maximum amplitude of this current determines whether the neurone will discharge in regular or burst mode.

Trends in arthropod defensive secretions, an aquatic predator assay.

Twenty-five arthropod defensive chemicals were tested on a potential fish predator to assay basic repellency, interniche effectiveness and mimetic interactions among repellents, and predator tolerance to repellents.The defensive secretions of aquatic arthropods are more effective repellents than those of terrestrial or cryptozoic arthropods. Phenolic compounds are more effective than carbonylic or acidic compounds. Repellency is most effective in compounds of reduced water solubility. Repeated exposure to gradually increasing molar concentrations of benzoic acid resulted in a greater acceptability of this compound to fish predators. It is suggested that Mullerian mimicry systems based on large numbers of species may be susceptible to dilution effects in terms of effectiveness.