Pharmacokinetics of ICG and HPPH-car for the detection of normal and tumor tissue using fluorescence, near-infrared reflectance imaging: a case study.

We present in vivo fluorescent, near-infrared (NIR), reflectance images of indocyanine green (ICG) and carotene-conjugated 2-devinyl-2-(1-hexyloxyethyl) pyropheophorbide (HPPH-car) to discriminate spontaneous canine adenocarcinoma from normal mammary tissue. Following intravenous administration of 1.0 mg kg-1 ICG or 0.3 mg kg-1 HPPH-car into the canine, a 25 mW, 778 nm or 70 mW, 660 nm laser diode beam, expanded by a diverging lens to approximately 4 cm in diameter, illuminated the surface of the mammary tissue. Successfully propagating to the tissue surface, ICG or HPPH-car fluorescence generated from within the tissue was collected by an image-intensified, charge-coupled device camera fitted with an 830 or 710 nm bandpass interference filter. Upon collecting time-dependent fluorescence images at the tissue surface overlying both normal and diseased tissue volumes, and fitting these images to a pharmacokinetic model describing the uptake (wash-in) and release (wash-out) of fluorescent dye, the pharmacokinetics of fluorescent dye was spatially determined. Mapping the fluorescence intensity owing to ICG indicates that the dye acts as a blood pool or blood persistent agent, for the model parameters show no difference in the ICG uptake rates between normal and diseased tissue regions. The wash-out of ICG was delayed for up to 72 h after intravenous injection in tissue volumes associated with disease, because ICG fluorescence was still detected in the diseased tissue 72 h after injection. In contrast, HPPH-car pharmacokinetics illustrated active uptake into diseased tissues, perhaps owing to the overexpression of LDL receptors associated with the malignant cells. HPPH-car fluorescence was not discernable after 24 h. This work illustrates the ability to monitor the pharmacokinetic delivery of NIR fluorescent dyes within tissue volumes as great as 0.5-1 cm from the tissue surface in order to differentiate normal from diseased tissue volumes on the basis of parameters obtained from the pharmacokinetic models.

Remembering more nouns than verbs in lists of foreign-language words as an indicator of syntactic phonetic symbolism.

In lists with words from languages not known to the subjects (students of the University of Essen, Germany, and in one experiment Polish teachers in North Poland), nouns were remembered more often than verbs, and the effect was not dependent on the length of the words. The effect was clearer with languages with a strong (Swahili) or medium (Hungarian, Turkish) tendency to marcation and less with languages with a tendency for weak marcation (Japanese). We interpreted this effect as influenced by syntactic phonetic symbolism, assuming there is a phonologic and prosodic difference between nouns and verbs.

Spatial restriction of spontaneous activity towards the rostral primary initiating zone during development of the embryonic mouse hindbrain.

In the developing embryonic mouse hindbrain, we have previously shown that synchronized spontaneous activity is driven by midline serotonergic neurons at E11.5. This is mediated, at least in part, by the 5-HT2A receptor, which is expressed laterally in the hindbrain. Activity at E11.5 is widespread within the hindbrain tissue, propagating from the midline to more lateral regions. Using rapid acquisition of [Ca2+]i events along the midline, we now show that the rostral midline, primarily in the region of former rhombomere r2, is the primary initiating zone for this activity. We propose that at E11.5, the combined events along the rostral-caudal axis in combination with events propagating along the medial-lateral axis could assign positional information to developing neurons within the hindbrain. With further development, to E13.5, both the lateral and caudal dimensions of spontaneous activity retract to the rostral midline, occupying an area only 14% of that exhibited at E11.5. We also show that increased levels of [K+]o (to 8 mM) at E13.5 are able to increase the spread of spontaneous activity laterally and rostro-caudally. This suggests that spontaneous activity in the hindbrain depends in a dynamic way on the dominant initiating zone of the rostral midline, and that this relationship changes over development.

Primary role of the serotonergic midline system in synchronized spontaneous activity during development of the embryonic mouse hindbrain.

In the developing embryonic mouse hindbrain, we have shown that previously widespread synchronized spontaneous activity at E11.5 retracts to the initiating zone of the rostral hindbrain by E13.5, and ceases completely by E14.5. We now confirm that at E11.5 and E13.5, the primary driver of spontaneous activity is serotonergic input, while other transmitters (GABA, glutamate, NE, and ATP) have only modulatory roles. Using immunocytochemistry, we also show that at E13.5, 5-HT-positive neurons in the midline extend over a larger rostro-caudal distance than at E11.5, and that in the presumptive initiating zone, cell bodies occupy a band that extends 200 microm laterally on each side of the midline, with extensive axonal processes. The 5-HT2A receptor retains expression in lateral tissue over this developmental time. We find that in addition to being sensitive to 5-HT receptor antagonists, spontaneous activity is also abolished by blockers of gap junctions, and is increased in frequency and lateral spread by application of ammonium, presumably via increased intracellular pH augmenting gap junction conductance. Thus, 5-HT neurons of the midline remain the primary drivers of spontaneous activity at several stages of development in the hindbrain, relying in part on gap junctional communication during initiation of activity.

Measures of impairment for children and adolescents.

Measuring the degree of impairment in children and adolescents due to emotional or behavioral disorders is a recent development that will become increasingly important to states and their mental health administrators. A survey of the 50 states was conducted to identify impairment measures that were used on a statewide basis. The results of the survey are presented; five measures were found to be used consistently. The three global measures and two multidimensional measures identified in the survey are reviewed here. Each measure is described and its pertinent psychometric data are presented. The implications for mental health administrators in terms of implementing statewide procedures to assess impairment are considered.

Lack of geographic structure in mitochondrial DNA sequences of Bering Sea walleye pollock, Theragra chalcogramma.

We compared 511 nucleotides of mitochondrial DNA from 162 walleye pollock from 32 locations in the Bering Sea, the Shelikof Strait, and the Gulf of Alaska to learn about population structuring in this economically important species. Specifically, we tested for evidence of genetic heterogeneity among three sequence data sets: a 76-bp spacer, the control region, and spacers and control regions combined among six geographic regions: southwest Bering Sea, northern Bering Sea, western Aleutians, eastern Aleutians, the Donut Hole, and the Gulf of Alaska. No significant genetic heterogeneity was detected among spacer sequences or control regions, or spacers and control regions combined among areas of the Bering Sea. Slight genetic heterogeneity was detected when a "Western Bering" sample (southwest Bering and northern Bering) and an "Eastern Bering" sample (western Aleutians and eastern Aleutians) were compared. Presence of an abundant and widespread haplotype suggests recent establishment of the walleye pollock population in the Bering Sea. However, the ratio of nucleotide transitions to transversions in these pollock is extremely low, suggesting that the population may be old. Presence of a widespread and abundant haplotype, together with numerous rare ones, suggests a high variance in reproductive success for relatively few females, which may be disproportionately contributing to the survival of individual haplotypes. Sequencing of control regions in pollock may be less informative than conventional analysis of restriction fragment length polymorphisms or RFLP analysis of amplified variable sites.

Development of synchronized activity of cranial motor neurons in the segmented embryonic mouse hindbrain.

Spontaneous electrical activity synchronized among groups of related neurons is a widespread and important feature of central nervous system development. Among the many places from which spontaneous rhythmic activity has been recorded early in development are the cranial motor nerve roots that exit the hindbrain, the motor neuron pool that, at birth, will control the rhythmic motor patterns of swallow, feeding and the oral components of respiratory behaviour. Understanding the mechanism and significance of this hindbrain activity, however, has been hampered by the difficulty of identifying and recording from individual hindbrain motor neurons in living tissue. We have used retrograde labelling to identify living cranial branchiomeric motor neurons in the hindbrain, and [Ca2+]i imaging of such labelled cells to measure spontaneous activity simultaneously in groups of motor neuron somata. We find that branchiomeric motor neurons of the trigeminal and facial nerves generate spontaneous [Ca2+]i transients throughout the developmental period E9.5 to E11.5. During this two-day period the activity changes from low-frequency, long-duration events that are tetrodotoxin insensitive and poorly coordinated among cells, to high-frequency short-duration events that are tetrodotoxin sensitive and tightly coordinated throughout the motor neuron population. This early synchronization may be crucial for correct neuron-target development.