Laparoscopic en bloc excision of gastrointestinal stromal tumors of the rectum after neoadjuvant imatinib therapy: anteriorly extended intersphincteric resection combined with partial resection of the prostate.

We herein present a novel technique for laparoscopic en bloc excision involving anteriorly extended intersphincteric resection with partial resection of the posterior lobe of the prostate for large rectal gastrointestinal stromal tumors (GISTs). The sequence of neoadjuvant imatinib therapy and this less invasive surgery for marginally resectable rectal GISTs has the potential to obviate the need for urinary reconstruction and permanent stomas without jeopardizing the tumor margin status.

Interferon-γ/CCR5 expression in invariant natural killer T cells and CCL5 expression in capillary veins of dermal papillae correlate with development of psoriasis vulgaris.

BACKGROUND: There have been extensive studies regarding which types of T lymphocytes are involved in psoriasis vulgaris (PV). However, it has remained unclear which types of T lymphocytes might directly contribute to psoriasiform epidermal and vascular hyperplasia. OBJECTIVES: To understand the role of T-cell receptor (TCR)Vα24+ invariant natural killer (iNK)T cells in the development of PV. METHODS: Seventeen patients were enrolled in this study. Using biopsy samples of PV plaques, TCRVα24(+) iNKT cells were investigated regarding their cytokine production to understand their roles in development of disease. RESULTS: The number of interferon (IFN)-γ+ iNKT cells correlated with the length of the psoriasiform hyperplasia rete ridge and the Psoriasis Area and Severity Index. IFN-γ+ iNKT cells in psoriatic skin exhibited higher C-C chemokine receptor (CCR)5 expression, and the amount of C-C chemokine ligand (CCL)5, a ligand for CCR5, was increased in capillary veins of psoriasis plaques. CCR5+ iNKT-cell numbers significantly correlated with the number of capillary vein endothelial cells expressing CCL5 in PV. Furthermore, the number of CCL5+ capillary veins correlated with the maximum rete ridge length. CONCLUSIONS: IFN-γ/CCR5 expression in iNKT cells and CCL5 expression in vessels of dermal papillae correlate with the development of psoriasiform hyperplasia and microabscess. We propose that these iNKT cells may become useful targets for development of novel therapeutic approaches to PV.

Wilson ratio of a Tomonaga-Luttinger liquid in a spin-1/2 Heisenberg ladder.

Using micromechanical force magnetometry, we have measured the magnetization of the strong-leg spin-1/2 ladder compound (C(7)H(10)N)(2)CuBr(2) at temperatures down to 45 mK. Low-temperature magnetic susceptibility as a function of field exhibits a maximum near the critical field H(c) at which the magnon gap vanishes, as expected for a gapped one-dimensional antiferromagnet. Above H(c) a clear minimum appears in the magnetization as a function of temperature, as predicted by theory. In this field region, the susceptibility in conjunction with our specific-heat data yields the Wilson ratio R(W). The result supports the relation R(W)=4K, where K is the Tomonaga-Luttinger-liquid parameter.

Gigantic optical nonlinearity in one-dimensional Mott-Hubbard insulators

The realization of all-optical switching, modulating and computing devices is an important goal in modern optical technology. Nonlinear optical materials with large third-order nonlinear susceptibilities (chi(3)) are indispensable for such devices, because the magnitude of this quantity dominates the device performance. A key strategy in the development of new materials with large nonlinear susceptibilities is the exploration of quasi-one-dimensional systems, or 'quantum wires'--the quantum confinement of electron-hole motion in one-dimensional space can enhance chi(3). Two types of chemically synthesized quantum wires have been extensively studied: the band insulators of silicon polymers, and Peierls insulators of pi-conjugated polymers and platinum halides. In these systems, chi(3) values of 10(-12) to 10(-7) e.s.u. (electrostatic system of units) have been reported. Here we demonstrate an anomalous enhancement of the third-order nonlinear susceptibility in a different category of quantum wires: one-dimensional Mott insulators of 3d transition-metal oxides and halides. By analysing the electroreflectance spectra of these compounds, we measure chi(3) values in the range 10(-8) to 10(-5) e.s.u. The anomalous enhancement results from a large dipole moment between the lowest two excited states of these systems.

Long-term potentiation: evidence against an increase in transmitter release probability in the CA1 region of the hippocampus.

It is widely accepted that N-methyl-D-aspartate (NMDA)-receptor-dependent long-term potentiation (LTP) in the CA1 region of the hippocampus is triggered postsynaptically, but there is considerable debate as to the site at which the increase in synaptic strength is expressed. The irreversible open-channel blocking action of the NMDA receptor antagonist MK-801 has been used to test whether the probability of transmitter release (Pr) is increased during LTP. Although the rate of decline of the amplitude of the NMDA receptor-mediated excitatory postsynaptic current (EPSC) in the presence of MK-801 strongly depends on Pr, the rate of decline of the EPSC evoked at synapses expressing LTP is identical to that observed at synapses not expressing LTP. These findings are difficult to reconcile with models in which the expression of LTP is due to an increase in Pr.

Release of adenosine by activation of NMDA receptors in the hippocampus.

Adenosine is present in the mammalian brain in large amounts and has potent effects on neuronal activity, but its role in neural signaling is poorly understood. The glutamate receptor agonist N-methyl-D-aspartate (NMDA) caused a presynaptic depression of excitatory synaptic transmission in the CA1 region of guinea pig hippocampal slices. This depression was blocked by an adenosine A1 receptor antagonist, which suggests that activation of the NMDA subtype of glutamate receptor raises the concentration of extracellular adenosine, which acts on presynaptic inhibitory A1 receptors. Strong tetanic stimulation caused a heterosynaptic inhibition that was blocked by both NMDA and A1 receptor antagonists. Enkephalin, which selectively inhibits interneurons, antagonized the heterosynaptic inhibition. These findings suggest that synaptically released glutamate activates NMDA receptors, which in turn releases adenosine, at least in part from interneurons, that acts at a distance to inhibit presynaptically the release of glutamate from excitatory synapses. Thus, interneurons may mediate a widespread purinergic presynaptic inhibition.

Harmonic-sensitive neurons in the auditory cortex of the mustache bat.

Human speech and animal sounds contain phonemes with prominent and meaningful harmonics. The biosonar signals of the mustache bat also contain up to four harmonics, and each consists of a long constant-frequency component followed by a short frequency-modulated component. Neurons have been found in a large cluster within auditory cortex of this bat whose responses are facilitated by combinations of two or more harmonically related tones. Moreover, the best frequencies for excitation of these neurons are closely associated with the constant-frequency components of the biosonar signals. The properties of these neurons make them well suited for identifying the signals produced by other echolocating mustache bats. They also show how meaningful components of sound are assembled by neural circuits in the central nervous system and suggest a method by which sounds with important harmonics (or formants) may be detected and recognized by the brain in other species, including humans.

Presynaptic long-term depression at the hippocampal mossy fiber-CA3 synapse.

Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength may underlie learning and memory in the brain. The induction of LTP occurs in postsynaptic cells in the hippocampal CA1 region but is presynaptic in CA3. LTD is also well characterized in CA1 but not in CA3. Low-frequency stimulation of mouse hippocampal slices caused homosynaptic LTD at the mossy fiber-CA3 synapse, which may be induced presynaptically by activation of metabotropic glutamate receptors. Thus, the efficacy of mossy fiber-CA3 synapses can be regulated bidirectionally, which may contribute to neuronal information processing.

Aural representation in the Doppler-shifted-CF processing area of the auditory cortex of the mustache bat.

In the mustache bat (Pteronotus pamellii rubiginosus) the frequency and amplitude of an acoustic signal are represented in the coordinates parallel to the surface of the Doppler-shifted-CF (constant frequency) processing area ofthe primary auditory cortex. In this area all cortical neurons studied were excited by contralateral stimuli, and almost all of them were either excited or inhibited by ipsilateral stimuli. These are called E-E (ipsilateral and contralateral excitatory) and I-E (ipsilateral inhibitory and contralateral excitatory) neurons, respectively. The I-E neurons are directionally sensitive, while the E-E neurons are not. The E-E neurons are equally sensitive to echoes between 30 degrees contralateral and 30 degrees ipsilateral. Of the electrode penetrations orthogonal to the Doppler-shifted-CF processing area, 57 percent were characterized by either E-E or I-E neurons. Thus, there are at least two types of binaural columns: E-E columns, mainly located in a ventral part of the Doppler-shifted-CF processing area, where neurons are tuned to weak echoes; and IE columns, mainly distributed in a dorsal part, where neurons are tuned to moderate to intense echoes. Therefore, neurons tuned to weaker echoes integrate or even multiply faint signals from both ears for effective detection of a distant small target, while neurons tuned to moderate to intense echoes are suited for processing directional information and are stimulated when a bat approaches a target at short range. The Doppler-shifted-CF processing area may be considered to consist of two functional subdivisions.

Cortical neurons sensitive to combinations of information-bearing elements of biosonar signals in the mustache bat.

The auditory cortex of the mustache bat, Pteronotus parnellii rubiginosus, is composed of functional divisions which are differently organized to be suited for processing the elements of its biosonar signal according to their biological significance. Unlike the Doppler-shifted-CF (constant frequency) processing area, the area processing the frequency-modulated components does not show clear tonotopic and amplitopic representations, but consists of several clusters of neurons, each of which is sensitive to a particular combination (or combinations) of information-bearing elements of the biosonar signal and echoes. The response properties of neurons in the major clusters indicate that processing of information carried by the frequency-modulated components of echoes is facilitated by the first harmonic of the emitted biosonar signal. The properties of some of these neurons suggest that they are tuned to a target which has a particular cross-sectional area and which is located at a particular distance.

Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1.

Extracellular levels of the excitatory neurotransmitter glutamate in the nervous system are maintained by transporters that actively remove glutamate from the extracellular space. Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury. These effects can be attributed to elevated levels of residual glutamate in the brains of these mice.

Impairment of hippocampal mossy fiber LTD in mice lacking mGluR2.

Subtype 2 of the metabotropic glutamate receptor (mGluR2) is expressed in the presynaptic elements of hippocampal mossy fiber-CA3 synapses. Knockout mice deficient in mGluR2 showed no histological changes and no alterations in basal synaptic transmission, paired-pulse facilitation, or tetanus-induced long-term potentiation (LTP) at the mossy fiber-CA3 synapses. Long-term depression (LTD) induced by low-frequency stimulation, however, was almost fully abolished. The mutant mice performed normally in water maze learning tasks. Thus, the presynaptic mGluR2 is essential for inducing LTD at the mossy fiber-CA3 synapses, but this hippocampal LTD does not seem to be required for spatial learning.

Effects of seed- and pollen-mediated gene dispersal on genetic structure among Quercus salicina saplings.

We evaluated the effects of seed- and pollen-mediated gene dispersal on genetic structure among Quercus salicina saplings. Parentage analysis using 10 microsatellite markers indicated that the 111 adult trees located within a 11.56 ha plot in the Tatera Forest Reserve, Japan, included only one parent of 44.2% and both parents of 40.7% of the 226 saplings located in a 1-ha core plot at its center. Coancestry (F(ij)) estimates indicated that there was strong genetic structure among the saplings. The numbers of pairs of full- and half-siblings were high among neighboring saplings, suggesting that there was strong maternal half-sibling family structure among the saplings around their seed parents, probably generated by the spatially limited seed dispersal and the small extent of overlapping seed shadows owing to the low density of adults. The frequencies also suggest that the maternal half-sibling families are interspersed with full-siblings, produced by correlated mating, probably because pollination frequency depends on the distance between parents. The frequencies of pairs of half-siblings decreased as the distance between saplings increased, but did not fall to zero even at distances up to the 90-95 m class, suggesting that paternal half-siblings originating from correlated paternity were widely distributed owing to extensive pollen flow. We separately examined the genetic structure for maternal and paternal alleles in the saplings. Unsurprisingly, very strong genetic structure was detected for maternal alleles. However, weak (but significant) genetic structure was also detected for paternal alleles. Therefore, pollen dispersal may affect the extent of genetic structure as well as seed dispersal.

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes.

Chemokines and their receptors are essential for leukocyte trafficking, and also implicated in cancer metastasis to specific organs. We have recently demonstrated that CXCR3 plays a critical role in metastasis of mouse melanoma cells to lymph nodes. Here, we show that some human colon cancer cell lines express CXCR3 constitutively. We constructed cells that expressed CXCR3 cDNA ('DLD-1-CXCR3'), and compared with nonexpressing controls by rectal transplantation in nude mice. Although both cell lines disseminated to lymph nodes at similar frequencies at 2 weeks, DLD-1-CXCR3 expanded more rapidly than the control in 4 weeks. In 6 weeks, 59% of mice inoculated with DLD1-CXCR3 showed macroscopic metastasis in para-aortic lymph nodes, whereas only 14% of those with the control (P<0.05). In contrast, metastasis to the liver or lung was rare, and unaffected by CXCR3 expression. In clinical colon cancer samples, we found expression of CXCR3 in 34% cases, most of which had lymph node metastasis. Importantly, patients with CXCR3-positive cancer showed significantly poorer prognosis than those without CXCR3, or those expressing CXCR4 or CCR7. These results indicate that activation of CXCR3 with its ligands stimulates colon cancer metastasis preferentially to the draining lymph nodes with poorer prognosis.

A rise in postsynaptic Ca2+ potentiates miniature excitatory postsynaptic currents and AMPA responses in hippocampal neurons.

We have investigated the site of expression of the potentiation of excitatory postsynaptic currents (EPSCs) induced by the activation of postsynaptic voltage-sensitive Ca2+ channels, by examining the effect of depolarizing pulses on miniature (m) EPSCs and responses to AMPA. Application of voltage pulses caused a approximately 2.5-fold increase in the mean amplitude of mEPSCs. This NMDA receptor-independent potentiation of mEPSC amplitudes was transient, returning to control values within 30-40 min. The potentiation was associated with a decrease in the number of small amplitude events and an increase in the number, as well as the maximum amplitude, of the larger events, with no apparent change in mEPSC kinetics. Accompanying the increase in mEPSC amplitudes, there was a 1.6-fold increase in the apparent frequency of events. Voltage pulse-induced potentiation was completely blocked by the inclusion of the Ca2+ chelator BAPTA in the recording pipette. Responses to repeated applications of AMPA were also potentiated following the application of voltage pulses, and the time course of this potentiation was similar to that observed with the mEPSCs. Our data indicate that rises in intracellular Ca2+ that occur independently of NMDA receptor activation can result in a potentiation of quantal size, which is due to an increase in the postsynaptic sensitivity of non-NMDA receptors.

Ca2+ entry via postsynaptic voltage-sensitive Ca2+ channels can transiently potentiate excitatory synaptic transmission in the hippocampus.

We have studied the role of Ca2+ entry via voltage-sensitive Ca2+ channels in long-term potentiation (LTP) in the CA1 region of the hippocampus. Repeated depolarizing pulses, in the presence of the NMDA receptor antagonist D-APV and without synaptic stimulation, resulted in a potentiation of excitatory postsynaptic potentials (EPSPs) or currents (EPSCs). This depolarization-induced potentiation was augmented in raised extracellular Ca2+ and was blocked by intracellular BAPTA, a Ca2+ chelator, or by nifedipine, a Ca2+ channel antagonist, indicating that the effect was mediated by Ca2+ entry via voltage-sensitive Ca2+ channels. Although the peak potentiation could be as large as 3-fold, the EPSP(C)s decayed back to baseline values within approximately 30 min. However, synaptic activation paired with depolarizing pulses in the presence of D-APV converted the transient potentiation into a sustained form. These results indicate that a rise in postsynaptic Ca2+ via voltage-sensitive Ca2+ channels can transiently potentiate synaptic transmission, but that another factor associated with synaptic transmission may be required for LTP.

Role of the carboxy-terminal region of the GluR epsilon2 subunit in synaptic localization of the NMDA receptor channel.

The synaptic localization of the N-methyl-D-aspartate (NMDA) type glutamate receptor (GluR) channel is a prerequisite for synaptic plasticity in the brain. We generated mutant mice carrying the carboxy-terminal truncated GluR epsilon2 subunit of the NMDA receptor channel. The mutant mice died neonatally and failed to form barrelette structures in the brainstem. The mutation greatly decreased the NMDA receptor-mediated component of hippocampal excitatory postsynaptic potentials and punctate immunofluorescent labelings of GluR epsilon2 protein in the neuropil regions, while GluR epsilon2 protein expression was comparable. Immunostaining of cultured cerebral neurons showed the reduced punctate staining of the truncated GluR epsilon2 protein at synapses. These results suggest that the carboxy-terminal region of the GluRepsilon2 subunit is important for efficient clustering and synaptic localization of the NMDA receptor channel.

Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice.

Multiple epsilon subunits are major determinants of the NMDA receptor channel diversity. Based on their functional properties in vitro and distributions, we have proposed that the epsilon 1 and epsilon 2 subunits play a role in synaptic plasticity. To investigate the physiological significance of the NMDA receptor channel diversity, we generated mutant mice defective in the epsilon 2 subunit. These mice showed no suckling response and died shortly after birth but could survive by hand feeding. The mutation hindered the formation of the whisker-related neuronal barrelette structure and the clustering of primary sensory afferent terminals in the brainstem trigeminal nucleus. In the hippocampus of the mutant mice, synaptic NMDA responses and longterm depression were abolished. These results suggest that the epsilon 2 subunit plays an essential role in both neuronal pattern formation and synaptic plasticity.

L3/Lhx8 is a pivotal factor for cholinergic differentiation of murine embryonic stem cells.

L3/Lhx8 is a member of the LIM-homeobox gene family. Previously, we demonstrated that L3/Lhx8-null mice specifically lacked cholinergic neurons in the basal forebrain. In the present study, we conditionally suppressed L3/Lhx8 function during retinoic acid-induced neural differentiation of a murine embryonic stem (ES) cell line using an L3/Lhx8-targeted small interfering RNA (siRNA) produced by an H1.2 promoter-driven vector. Our culture conditions induced efficient differentiation of the ES cells into neurons and astrocytes, but far less efficient differentiation into oligodendrocytes. Suppression of L3/Lhx8 expression by siRNA led to a dramatic decrease in the number of cells positive for the cholinergic marker ChAT, and overexpression of L3/Lhx8 recovered this effect. However, no significant changes were observed in the number of Tuj1+ neurons and GABA+ cells. These results strongly suggest that L3/Lhx8 is a key factor in the cholinergic differentiation of murine ES cells and is involved in basal forebrain development.

Integrin-linked kinase activity is associated with interleukin-1 alpha-induced progressive behavior of pancreatic cancer and poor patient survival.

Cancer cell adhesion and invasion into extracellular matrix are regulated by integrin-linked kinase (ILK) activity in a phosphatidylinositol 3-kinase (PI3-K)-dependent manner. In this study, we demonstrated that ILK and beta(1)-integrin play important roles in interleukin (IL)-1alpha-induced enhancement of adhesion and invasion of pancreatic cancer cells through p38 mitogen-activated protein kinase (MAPK) signaling pathway and activator protein-1 (AP-1) activation. Alteration of ILK kinase activity controlled IL-1alpha-induced p38 MAPK phosphorylation and its downstream AP-1 activation with subsequent regulation of pancreatic cancer cell adhesion and invasion. Overexpressed ILK enhances the IL-1alpha-induced p38 MAPK phosphorylation more strongly through glycogen synthase kinase 3 (GSK-3) activation, and subsequently induces AP-1 activation, which promotes aggressive capabilities of pancreatic cancer cells. In contrast, knockdown of ILK kinase activity inhibits the IL-1alpha-induced activation of MAPK/AP-1 pathway via inhibition of GSK-3 phosphorylation. In immunohistochemical analysis, statistically significant association between strong expression of ILK and poor prognosis of pancreatic cancer patients were observed, and strong expression of ILK in cancerous tissues can be a significant prognostic indicator of pancreatic cancer patients. Our results suggest that ILK is involved with aggressive capability in pancreatic cancer and that these regulations can be helpful to understand biological processes for a better translational treatment for pancreatic cancer patients.