bluuebunny/crossref_metadata_2025 huggingface dataset:
Transient Receptor Potential Cation Channels in Disease
Authors: Nilius Bernd , Owsianik Grzegorz , Voets Thomas , Peters John A.
Published: January 2007

The transient receptor potential (TRP) superfamily consists of a large number of cation channels that are mostly permeable to both monovalent and divalent cations. The 28 mammalian TRP channels can be subdivided into six main subfamilies: the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and the TRPA (ankyrin) groups. TRP channels are expressed in almost every tissue and cell type and play an important role in the regulation of various cell functions. Currently, significant scientific effort is being devoted to understanding the physiology of TRP channels and their relationship to human diseases. At this point, only a few channelopathies in which defects in TRP genes are the direct cause of cellular dysfunction have been identified. In addition, mapping of TRP genes to susceptible chromosome regions (e.g., translocations, breakpoint intervals, increased frequency of polymorphisms) has been considered suggestive of the involvement of these channels in hereditary diseases. Moreover, strong indications of the involvement of TRP channels in several diseases come from correlations between levels of channel expression and disease symptoms. Finally, TRP channels are involved in some systemic diseases due to their role as targets for irritants, inflammation products, and xenobiotic toxins. The analysis of transgenic models allows further extrapolations of TRP channel deficiency to human physiology and disease. In this review, we provide an overview of the impact of TRP channels on the pathogenesis of several diseases and identify several TRPs for which a causal pathogenic role might be anticipated.
HU-331, a novel cannabinoid-based anticancer topoisomerase II inhibitor
Authors: Kogan Natalya M. , Schlesinger Michael , Priel Esther , Rabinowitz Ruth , Berenshtein Eduard , Chevion Mordechai , Mechoulam Raphael
Published: January 2007

Anthracyclines, a large group of quinonoid compounds, are used to treat some forms of cancer. Although highly effective in cancer therapy, the mechanism of action of these compounds is not specific; they act on cancer and other cells by numerous mechanisms. A new anticancer quinone (HU-331) was synthesized from cannabidiol. It shows significant high efficacy against human cancer cell lines in vitro and against in vivo tumor grafts in nude mice. In this study, we investigated its mode of action and present evidence on its unique mechanism. HU-331 does not cause cancer cell cycle arrest, cell apoptosis, or caspase activation. HU-331–caused cell death of human cancer cell lines is not mediated by reactive oxygen intermediates/species, as exposure to HU-331 failed to elicit the generation of reactive oxygen species. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations but has only a slight nonsignificant effect on DNA topoisomerase I action. The cannabinoid quinone HU-331 is a highly specific inhibitor of topoisomerase II, compared with most known anticancer quinones. It might represent a new potent anticancer drug. [Mol Cancer Ther 2007;6(1):173–83]
Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma
Authors: Kato Yukihiko , Salumbides Brenda C. , Wang Xiao-Fei , Qian David Z. , Williams Simon , Wei Yongfeng , Sanni Tolib B. , Atadja Peter , Pili Roberto
Published: January 2007

Resistance to chemotherapy is a major hurdle in the treatment of malignant melanoma. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor types, including melanoma, and to reverse epigenetic repression of tumor suppressor genes, such as retinoic acid receptor β (RARβ). In this study, we tested the antitumor effect of the HDAC inhibitor LAQ824 in combination with 13-cis-retinoic acid (CRA) on two human melanoma cell lines both in vitro and in vivo. Treatment of LAQ824 showed a dose-dependent inhibitory effect on A2058 and HMV-I cell lines in a clonogenic assay. These cell lines were relatively resistance to CRA. On treatment with combination of LAQ824 and CRA, a greater inhibitory effect (up to 98%) was achieved compared with single agents. Lack of RARβ2 gene expression was associated with histone acetylation and gene methylation at the promoter level. Treatment with LAQ824 restored retinoid sensitivity by reverting RARβ2 epigenetic silencing. The biological effect of LAQ824 was associated with p21 induction in both cell lines but G2 cell cycle arrest in A2058 and apoptosis in HMV-I cell line. The induction of apoptosis by LAQ824 was associated with increased reactive oxygen species and induction of SM22 gene expression in HMV-I but not in A2058 cell line. Administration of the free radical scavenger l-N-acetylcysteine blocked LAQ824 + CRA–mediated apoptosis in HMV-I cells, suggesting a primary role for reactive oxygen species generation in LAQ824 + CRA–associated lethality. Combination treatment showed 61% and 82% growth inhibition in A2058 and HMV-I tumors, respectively. Greater induction of in vivo apoptosis was observed in the HMV-I but not in the A2058 tumors treated with combination therapy compared with single agents. These results suggest that the HDAC inhibitor LAQ824 has a greater antitumor activity in combination with CRA in melanoma tumors but the degree of induced apoptosis may vary. Combination of HDAC inhibitors and retinoids represents a novel therapeutic approach for malignant melanoma that warrants clinical testing. [Mol Cancer Ther 2007;6(1):70–81]
Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib
Authors: An Jiabin , Rettig Matthew B.
Published: January 2007

In renal cell carcinoma (RCC) models, maximal cytotoxicity of the proteasome inhibitor bortezomib is dependent on efficient blockade of constitutive nuclear factor κB (NF-κB) activity. Signaling through the epidermal growth factor receptor (EGFR) has been shown to result in NF-κB activation. Thus, we sought to investigate whether inhibition of the EGFR sensitizes RCC cells to the cytotoxic effects of bortezomib. We first established that constitutive NF-κB activity is dependent on signaling through the EGFR in RCC cells. Indeed, blockade of EGFR signaling with an EGFR tyrosine kinase inhibitor (TKI) resulted in inhibition of NF-κB activity. Using pharmacologic and genetic approaches, we also showed that EGFR-mediated NF-κB activation occurs through the phosphotidylinositol-3-OH kinase/AKT pathway. Combinations of the EGFR-TKI and bortezomib resulted in synergistic cytotoxic effects when RCC cells were pretreated with the EGFR-TKI, but an antagonistic interaction was observed with bortezomib pretreatment. Evaluation of the effects of drug sequencing on inhibition of NF-κB activity revealed that EGFR-TKI pretreatment markedly augmented the NF-κB inhibitory effect of bortezomib, whereas bortezomib preexposure resulted in suboptimal NF-κB blockade and thus provides a biochemical explanation for the drug interaction results. We conclude that the constitutive NF-κB activity observed in RCC cells is mediated, at least in part, through an EGFR/phosphotidylinositol-3-OH kinase/AKT signaling cascade. Pretreatment with an EGFR-TKI sensitizes to bortezomib-mediated cytotoxicity by inhibiting constitutive NF-κB activity. The combination of bortezomib and a currently approved EGFR inhibitor warrants clinical investigation. [Mol Cancer Ther 2007;6(1):61–9]
Pharmacologic inhibition of CDC25 phosphatases impairs interphase microtubule dynamics and mitotic spindle assembly
Authors: Cazales Martine , Boutros Rose , Brezak Marie-Christine , Chaumeron Sophie , Prevost Grégoire , Ducommun Bernard
Published: January 2007

The CDC25 cell cycle regulators are promising targets for new pharmacologic approaches in cancer therapy. Inhibitory compounds such as BN82685 have proven to be effective in specifically targeting CDC25 in cultured cells and in inhibiting tumor cell growth. Here, we report that BN82685 impairs microtubule dynamic instability and alters microtubule organization and assembly at the centrosome in interphase cells. Treatment of mitotic cells with BN82685 delays mitotic spindle assembly, chromosome capture, and metaphase plate formation. Furthermore, we show that combining low concentrations of both BN82685 and paclitaxel inhibits the proliferation of HT29 human colon cancer cells. Our results show a role for CDC25 phosphatases in regulating microtubule dynamics throughout the cell cycle and suggest that combinations of CDC25 inhibitors with microtubule-targeting agents may be of therapeutic value. [Mol Cancer Ther 2007;6(1):318–25]
Novel cell death pathways induced by N-(4-hydroxyphenyl)retinamide: therapeutic implications
Authors: Venè Roberta , Arena Giuseppe , Poggi Alessandro , D'Arrigo Cristina , Mormino Michele , Noonan Douglas M. , Albini Adriana , Tosetti Francesca
Published: January 2007

We previously reported that N-(4-hydroxyphenyl)retinamide (4HPR) inhibits retinoblastoma tumor growth in a murine model in vivo and kills Y79 retinoblastoma cells in vitro. In this work, we assayed different cell death–related parameters, including mitochondrial damage and caspase activation, in Y79 cells exposed to 4HPR. 4HPR induced cytochrome c release from mitochondria, caspase-3 activation, and oligonucleosomal DNA fragmentation. However, pharmacologic inactivation of caspases by the pan-caspase inhibitor BOC-D-fmk, or specific caspase-3 inhibition by Z-DEVD-fmk, was not sufficient to prevent cell death, as assessed by loss of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction, lactate dehydrogenase release, disruption of mitochondrial transmembrane potential (Δψm), and ATP depletion. We found that 4HPR causes lysosomal membrane permeabilization and cytosolic relocation of cathepsin D. Pepstatin A partially rescued cell viability and reduced DNA fragmentation and cytosolic cytochrome c. The antioxidant N-acetylcysteine attenuated cathepsin D relocation into the cytosol, suggesting that lysosomal destabilization is dependent on elevation of reactive oxygen species and precedes mitochondrial dysfunction. Activation of AKT, which regulates energy level in the cell, by the retinal survival facto]r insulin-like growth factor I was impaired and insulin-like growth factor I was ineffective against ATP and Δψm loss in the presence of 4HPR. Lysosomal destabilization, associated with mitochondrial dysfunction, was induced by 4HPR also in other cancer cell lines, including PC3 prostate adenocarcinoma and the vascular tumor Kaposi sarcoma KS-Imm cells. The novel finding of a lysosome-mediated cell death pathway activated by 4HPR could have implications at clinical level for the development of combination chemoprevention and therapy of cancer. [Mol Cancer Ther 2007;6(1):286–98]
Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells
Authors: Chaudhuri Devyani , Orsulic Sandra , Ashok Badithe T.
Published: January 2007

Epidemiologic studies show a correlation between increased consumption of fruits and vegetables with reduced risk of ovarian cancer. One major bioactive compound found in cruciferous vegetables, particularly broccoli, is sulforaphane, derived from the breakdown of glucoraphanin. We observed potent antiproliferative effects of sulforaphane on human ovarian cancer cell line SKOV3 (IC50 40 μmol/L) and mouse ovarian cancer cell lines C3 and T3 (IC50 25 μmol/L each) by cell viability assays. The loss of viability is reflected by a down-regulation of cell cycle transition regulators cyclin D1, cyclin-dependent kinase 4 (cdk4), and cdk6. The upstream mediators of sulforaphane effects on the cell cycle in ovarian cancer are still unknown. However, because the Akt signal transduction pathway is overactivated in ovarian cancer, we investigated the effects of sulforaphane on this prosurvival pathway. Both total Akt protein and active phosphorylated levels of Akt (Ser473) and phosphoinositide 3-kinase were significantly decreased in sulforaphane-treated SKOV3, C3, and T3 cells with a concomitant inhibition of Akt kinase activity by sulforaphane in SKOV3 and C3 cells. This inhibitory effect of sulforaphane leads to a potent induction of apoptosis in all three cell lines, along with the cleavage of poly(ADP)ribose polymerase. Our study is the first to report the antiproliferative effects of sulforaphane in ovarian cancer and identifying the Akt pathway as a target of sulforaphane, with implications for the inhibition of carcinogenesis by diet-based chemoprevention. [Mol Cancer Ther 2007;6(1):334–45]
Pulmonary adenocarcinoma–targeted gene therapy by a cancer- and tissue-specific promoter system
Authors: Fukazawa Takuya , Maeda Yutaka , Durbin Mary L. , Nakai Toru , Matsuoka Junji , Tanaka Hirotoshi , Naomoto Yoshio , Tanaka Noriaki
Published: January 2007

Gene therapy is one of the approaches used to treat lung cancer. The benefit of cancer gene therapy is that different types of tumors can be selectively targeted by tumor-specific expression of therapeutic genes that include an apoptosis gene to destroy the tumor. Previously, we described a promoter (TTS promoter) that we designed that is specifically targeted to lung cancer cells but not to other types of cancer or normal cells including stem cells. In this pursuit, we further characterize the specificity of the TTS promoter in four types of lung cancer cells (squamous cell lung carcinoma, pulmonary adenocarcinoma, small-cell lung carcinoma, large-cell lung carcinoma). The TTS promoter is highly active only in pulmonary adenocarcinoma cells but not in the other three types of lung cancer cells. The specificity seems to be derived from transcription factor thyroid transcription factor 1–associating cofactors that affect human surfactant protein A1 promoter activity in pulmonary adenocarcinoma. We inserted the proapoptotic gene Bcl-2–associated X protein (Bax) into the TTS promoter (TTS/Bax). The TTS/Bax selectively causes BAX expression and cell death in pulmonary adenocarcinoma but not in other cells. Cell death caused by the BAX expression was also observed in pulmonary adenocarcinoma that is resistant to the anticancer drug gefitinib (epidermal growth factor receptor tyrosine kinase inhibitor). BAX expression and cell death can be suppressed by dexamethasone (a glucocorticoid) treatment through negative glucocorticoid elements in the TTS promoter. Here we report a drug-controllable TTS/Bax system targeting pulmonary adenocarcinoma. [Mol Cancer Ther 2007;6(1):244–52]
Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma
Authors: Huynh Hung , Soo Khee Chee , Chow Pierce K.H. , Tran Evelyn
Published: January 2007

Hepatocellular carcinoma (HCC) is a common malignancy in Asia and Africa. We previously reported that overexpression of extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2) and ERK1/2 was detected in HCC, and that their activation was required for liver cancer cell proliferation and survival. In the present study, we determined the efficacy of a specific MEK1/2 inhibitor AZD6244 (ARRAY-142886) in treatment of HCC. Treatment of primary HCC cells with AZD6244 led to growth inhibition, elevation of the cleavage of caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase, but inhibition of ERK1/2 and p90RSK phosphorylation. Studying the protein expression profile of seven HCC xenografts revealed that their growth rate was positively correlated with the levels of phosphorylated MEK. AZD6244, when given p.o. to mice bearing these xenografts, resulted in a dose-dependent inhibition of tumor growth. AZD6244-induced growth suppression was associated with inactivation of ERK1/2 and p90RSK, and up-regulation of activated caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase. Our data suggest that the MEK-ERK pathway plays an important role in the growth and survival of liver cancer cells and that the HCC xenograft models are excellent tools for screening preclinical drugs. Targeted inhibition of the MEK-ERK pathway with AZD6244 may represent an alternative approach for the treatment of this disease. [Mol Cancer Ther 2007;6(1):138–45]
Livin/melanoma inhibitor of apoptosis protein as a potential therapeutic target for the treatment of malignancy
Authors: Chang Hong , Schimmer Aaron D.
Published: January 2007

Livin, also called melanoma inhibitor of apoptosis protein (IAP) or kidney IAP, is a member of the IAP family of caspase inhibitors that selectively binds the endogenous IAP antagonist SMAC and caspase-3, caspase-7, and caspase-9. As such, Livin inhibits apoptosis, and its overexpression renders malignant cells resistant to chemotherapy. Therefore, inhibitors of Livin could be useful adjuncts to chemotherapy in the treatment of malignancies. This review will discuss Livin as a potential therapeutic target and strategies for its inhibition, including antisense oligonucleotides, small-molecule inhibitors, and immune-mediated approaches. [Mol Cancer Ther 2007;6(1):24–30]
Chemotherapeutic selectivity conferred by selenium: a role for p53-dependent DNA repair
Authors: Fischer Joshua L. , Mihelc Elaine M. , Pollok Karen E. , Smith Martin L.
Published: January 2007

Selenium in various chemical forms has been the subject of cancer chemoprevention trials, but, more recently, selenium has been used in combination with DNA-damaging chemotherapeutics. Specifically, selenium protected tissues from dose-limiting toxicity and, in fact, allowed delivery of higher chemotherapeutic doses. At the same time, selenium did not protect cancer cells. Therefore, we seek to define the genetic basis for the observed selectivity of selenium in combination chemotherapeutics. The tumor suppressor p53 is mutated in the vast majority of cancers, but is by definition wild-type in nontarget tissues such as bone marrow and gut epithelium, tissues that are often dose-limiting due to DNA damage. We used primary, low-passage mouse embryonic fibroblasts that are wild-type or null for p53 genes to test differential effects of selenium. Seleno-l-methionine, nontoxic by itself, was used to pretreat cell cultures before exposure to UV radiation or UV-mimetic cancer chemotherapy drugs. Seleno-l-methionine pretreatment caused a DNA repair response, which protected from subsequent challenge with DNA-damaging agents. The observed DNA repair response and subsequent DNA damage protection were p53 dependent as neither was observed in p53-null cells. The data suggest that (a) p53 may be an important genetic determinant that distinguishes normal cells from cancer cells, and (b) combinatorial chemotherapeutics that act by p53-dependent mechanisms may enhance chemotherapeutic efficacy by increasing the chemotherapeutic window distinguishing cancer cells from normal cells. [Mol Cancer Ther 2007;6(1):355–61]
Modulation of topoisomerase IIα expression by a DNA sequence-specific polyamide
Authors: Hochhauser Daniel , Kotecha Minal , O'Hare Caroline , Morris Peter J. , Hartley Janet M. , Taherbhai Zarmeen , Harris Dorothy , Forni Claudia , Mantovani Roberto , Lee Moses , Hartley John A.
Published: January 2007

Topoisomerase IIα (topo IIα) is an important target for several chemotherapeutic agents, including etoposide and doxorubicin. Confluent cells express low levels of topo IIα and are resistant to etoposide treatment. Repression of transcription in confluent cells is mediated by binding of the transcription factor NF-Y to inverted CCAAT motifs within the topo IIα promoter. To block the repressive binding of NF-Y, a polyamide (JH-37) was designed to bind to the flanking regions of selected CCAAT sites within the topo IIα promoter. Electrophoretic mobility shift assays and DNase I footprinting assays showed occupancy of the inverted CCAAT sites by JH-37. Chromatin immunoprecipitation assays confirmed in vivo inhibition of NF-Y binding to the topo IIα promoter. Following incubation of confluent NIH3T3 cells with JH-37, increased expression of topo IIα mRNA and protein was detectable. This correlated both with increased DNA double-strand breaks as shown by comet assay and decreased cell viability following exposure to etoposide. Polyamides can modulate gene expression and chemosensitivity of cancer cells. [Mol Cancer Ther 2007;6(1):346–54]
Chrysin inhibits expression of hypoxia-inducible factor-1α through reducing hypoxia-inducible factor-1α stability and inhibiting its protein synthesis
Authors: Fu Beibei , Xue Jing , Li Zhaodong , Shi Xianglin , Jiang Bing-Hua , Fang Jing
Published: January 2007

Chrysin is a natural flavonoid and has been shown recently to have anticancer effects. However, the mechanisms that chrysin inhibits cancers are not well known. In this study, we investigated the effects of chrysin on expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor in human prostate cancer DU145 cells. Chrysin inhibited insulin-induced expression of HIF-1α by reducing its stability. Chrysin increases ubiquitination and degradation of HIF-1α by increasing its prolyl hydroxylation. In addition, chrysin interfered with interaction between HIF-1α and heat shock protein 90. Chrysin was also found to inhibit HIF-1α expression through AKT signaling. Inhibition of HIF-1α by chrysin resulted in abrogation of vascular endothelial growth factor expression. Finally, we showed that chrysin inhibited DU145 xenograft-induced angiogenesis in nude mice. Taken together, these results suggest that chrysin is a potent inhibitor of HIF-1α and provide a new sight into the mechanisms of chrysin against cancers. [Mol Cancer Ther 2007;6(1):220–6]
Effect of population and gender on chemotherapeutic agent–induced cytotoxicity
Authors: Huang Rong Stephanie , Kistner Emily O. , Bleibel Wasim K. , Shukla Sunita J. , Dolan M. Eileen
Published: January 2007

Large interindividual variance is observed in both response and toxicity associated with chemotherapy. Our goal is to identify factors that contribute to chemotherapy-induced toxicity. To this end, we used EBV-transformed B-lymphoblastoid HapMap cell lines derived from 30 Yoruban trios (African descent) and 30 Centre d' Etude du Polymorphisme Humain (CEPH) trios (European descent) to evaluate population- and gender-specific differences in cytotoxicity of carboplatin, cisplatin, daunorubicin, and etoposide using a high-throughput, short-term cytotoxicity assay. The IC50 was compared for population- and gender-specific differences for the four drugs. We observed large interindividual variance in IC50 values for carboplatin, cisplatin, daunorubicin, and etoposide for both Yoruban and CEPH populations (range from 8- to 433-fold). Statistically significant differences in carboplatin and daunorubicin IC50 were shown when comparing Yoruban cell lines (n = 89) to CEPH cell lines (n = 87; P = 0.002 and P = 0.029, respectively). This population difference in treatment induced cytotoxicity was not seen for either cisplatin or etoposide. In the Yoruban population, cell lines derived from females were less sensitive to platinating agents than males [median carboplatin IC50, 29.1 versus 24.6 μmol/L (P = 0.012); median cisplatin IC50, 7.0 versus 6.0 μmol/L (P = 0.020) in female and male, respectively]. This difference was not observed in the CEPH population. These results show that population and gender may affect risk for toxicities associated with certain chemotherapeutic agents. [Mol Cancer Ther 2007;6(1):31–6]
Diversity of Brain Morphology in Teleosts: Brain and Ecological Niche
Authors: Ito Hironobu , Ishikawa Yuji , Yoshimoto Masami , Yamamoto Naoyuki
Published: January 2007

Modern teleosts have more copies of developmental regulatory genes than other vertebrates, probably due to a whole genome duplication that occurred specifically at the base of the lineage of ray-finned fishes. The genome duplication generates duplicated genes (including their regulatory regions), and one of the duplicates might become redundant and free from selective pressures. These redundant genes might be more easily mutated during evolution. Brain morphogenesis is a process that is dependent on a large genetic program in which a subprogram for the regionalization of the brain is coupled with that for cell-proliferation control. If beneficial mutations took place in key genes within the genetic program for brain morphogenesis, it might result in the enhancement of region-specific cell proliferation and cell survival in the corresponding brain subdivisions. This mechanism might account for the appearance of various forms of teleost brains, which have been preserved under selection pressure in diverse environments. It is conceivable that variously modified brains might evolve under the conditions of natural selection so that the brains help fit the teleost species for diverse ecological niches.
A New Interpretation on the Homology of the Teleostean Telencephalon Based on Hodology and a New Eversion Model
Authors: Yamamoto Naoyuki , Ishikawa Yuji , Yoshimoto Masami , Xue Hao-Gang , Bahaxar Nurmamat , Sawai Nobuhiko , Yang Chun-Ying , Ozawa Hitoshi , Ito Hironobu
Published: January 2007

Various hypotheses regarding the homology of the teleostean telencephalon with that of other vertebrates have been proposed to date. However, a firm conclusion on this issue has yet to be drawn. We propose here a new hypothesis with a new eversion model. Our hodological data and the analysis of dorsal telencephalic organization in adult cyprinids suggest that: (1) the area dorsalis pars posterior corresponds to the lateral pallium; (2) ventral region of area dorsalis pars lateralis to the medial pallium; (3) pars medialis, dorsal region of pars lateralis, pars dorsalis, and pars centralis of the area dorsalis to the dorsal pallium, and (4) nucleus taenia to the ventral pallium. We propose in a three dimensional model that the eversion process occurs not only dorsolaterally but also caudolaterally. We consider that the caudally directed component dominates for ventral zones of the pallium, or the lateral and ventral pallia; and the periventricular surface of these zones shift caudally, laterally, and then rostrally in teleosts with pronounced telencephalic eversion. This new model fits well with the putative homology based on hodology and the organization of telencephalic divisions in the adult brain.
Ion Channels and Their Neural Functions: Contribution to General Problems from Studies of Brains in Non-Mammalian Species
Authors: Tsutsui Hidekazu , Oka Yoshitaka
Published: January 2007

Ion channels and their neural functions have often been studied in the brains of mammals. However, the brains of some teleost fish species have special features that, at first glance, appear to be atypical and peculiar to that species alone. These teleost fish will contribute considerably to the understanding of general features of the ion channels and their neural functions. We have been interested in the neural mechanisms underlying the adaptive and flexible response of animals to changing environments and have been studying gonadotropin-releasing hormone (GnRH) peptidergic neuron systems, which we think are central for controlling such biologically adaptive responses. We have also been interested in a pretectal nucleus, corpus glomerulosum, which is tentatively regarded to play important roles in the organization of visually-guided feeding behaviors. In both systems, we found that certain types of apparently ‘non-typical’ Na+ channels play important roles in neurobiological functions. Here we discuss how the study of functions of these apparently non-typical ion channels might contribute to our understanding of neural functions of vertebrate brains in general.
Innervation of Sonic Muscles in Teleosts: Occipital vs. Spinal Nerves
Authors: Onuki Atsushi , Somiya Hiroaki
Published: January 2007

The innervation of sonic muscles in teleosts has been categorized into three types: occipital nerve, spinal nerve, and a combination of occipital and spinal nerves. The innervation patterns of sonic muscles were examined (or re-examined) in seven sonic fish species (rockfish, pinecone fish, sweeper, tigerfish, piranha, dory, and pollack) that use the sonic muscles to vibrate the swimbladder. The peripheral nerves (occipital or spinal) were identified based on skeletal preparations. The sonic muscle innervation was of the occipital type in four species (rockfish, pinecone fish, sweeper, and tigerfish) and of the spinal type in three species (piranha, dory, and pollack); none of the seven species examined showed the combination type. Therefore, we hypothesized that innervation patterns could be divided simply into occipital and spinal types. Moreover, the present results revealed that previously reported innervation patterns are inaccurate for three species (tigerfish, piranha, and dory) re-examined in this study. Therefore, it is important to define the peripheral nerves precisely, by using skeletal preparations, in future investigations of sonic muscle innervation.
Central Mechanisms Underlying Fish Swimming
Authors: Uematsu Kazumasa , Baba Yoshihiko , Kake Yasuyuki , Ikenaga Takanori , Moon Soon-Ju , Miyai Yuuki , Yoshida Masayuki
Published: January 2007

Although the basic swimming rhythm is created by central pattern generators (CPGs) located in each spinal segment, command signals from the brain should be indispensable for the activation of CPGs to initiate swimming. We hypothesized that the nucleus of medial longitudinal fascicles (Nflm) is the midbrain locomotor region driving swimming rhythms in teleosts. To test this hypothesis, we recorded neuronal activities from Nflm neurons in swimming carp and analyzed the cytoarchitecture of the nucleus. We identified two types of Nflm neurons exhibiting electric activities closely related to swimming rhythms. Remarkably, tonic neurons that continued firing during swimming were found. The Nflm and neighboring oculomotor nucleus contain about 600 neurons in total, and among them as many as 500 were labeled retrogradely by an intraspinal tracer implantation and 400 neurons showed glutamatergic immunoreactivity. They are the most likely candidates for the descending neurons as the origin of driving signals that initiate swimming. Double-labeling experiments demonstrated direct connections of Nflm neurons to spinal neurons consisting of the CPG. These data imply that most Nflm neurons possibly exert an excitatory drive to the spinal CPGs through the descending axons with excitatory transmitter(s), probably glutamate. Furthermore, we confirmed that the caudal part of Nflm and the rostral part of the oculomotor nucleus overlap rostrocaudally by approximately 200 µm. In connection with the control of swimming by the brain, we carried out experiments to clarify the efferent system of the cerebellum of the goldfish. Cerebellar efferent fibers terminated in most brain regions except for the telencephalon. Importantly, the cerebellum projected also to the Nflm, suggesting the involvement of this brain region in the control of swimming. We have also determined that in the carp so-called eurydendroid cells are cerebellar efferent neurons.
Nerve Ring of the Hypostome in Hydra: Is It an Origin of the Central Nervous System of Bilaterian Animals?
Authors: Koizumi Osamu
Published: January 2007

A hypothesis, ‘the nerve ring in hydra shares a common origin with the central nervous system in bilaterian animals’, is discussed in this review. The nerve ring of hydra is a ring of neurons whose neurites make a bundle running circumferentially around the hypostome just above the tentacle zone. This nervous structure has unique features in the hydra nervous system. It shows a tight association of neurons in contrast to the diffuse nerve net seen in other regions. It shows static developmental characters in contrast to the dynamic features of hydra nerve net present in other regions. Moreover, its structure and location are similar to the central nervous system (CNS) of other animals without a complex CNS such as nematodes and starfishes. Functions of the hydra nerve ring are also studied to test the hypothesis. The identified function is a crumpling of the tentacles, corresponding to the function of the inner nerve ring of hydrozoan jellyfish. The jellyfish nerve ring is considered to be a primitive central nervous system of radiates. Considering all the information available, the hypothesis is highly possible.
Grief and Post-Traumatic Growth in Parents 2–6 Years after the Death of Their Extremely Premature Baby
Authors: Büchi Stefan , Mörgeli Hanspeter , Schnyder Ulrich , Jenewein Josef , Hepp Urs , Jina Eveline , Neuhaus Rachel , Fauchère Jean-Claude , Bucher Hans Ulrich , Sensky Tom
Published: January 2007

Objective: To assess grief and post-traumatic growth in parents 2–6 years after the death of a premature baby (24–26 weeks’ gestation) and to evaluate Pictorial Representation of Illness and Self-Measure (PRISM) in the assessment of bereavement. Method: Fifty-four parents were assessed for their experiences during hospitalization and by questionnaires regarding grief (MTS), post-traumatic growth, affective symptoms and the visual representation of the baby and the self of the parents (PRISM). Results: Even 2–6 years after the loss of their extremely preterm infant the parents still suffer a lot from their bereavement, mothers more so than fathers (Mann-Whitney U test, U = 230.5, p < 0.05). Having another child reduced the level of grief (U = 119.0, p < 0.05). Mothers showed more post-traumatic growth than fathers (U = 140.5, p < 0.001). For all parents a shorter distance between the baby and the self (PRISM) correlated with greater grief (ρ = –0.62, p < 0.001); in multiple regression analysis MTS explained 38% of the SBS-variance. Conclusions: Clinicians should be aware that the death of an extremely premature infant triggers not only a painful long-term process of mourning but also of individual personal growth. Adaptation processes after the death differ depending on gender, with mothers experiencing more intense grief but also more growth than fathers. The modified PRISM test is recommended as a visual, non-verbal and easy-to-use instrument to assess bereavement.
An Overview of Neurological Disorders in Wales
Authors: Jader Layla
Published: January 2007

This pragmatic work was undertaken to assist commissioners of health services in Wales in their planning for future provision of services for neurological and neurosurgical patients. A literature search, which was carried out to ascertain the epidemiology of neurological and neurosurgical disorders in Wales, revealed limited epidemiological surveys of patients in Wales, while other literatures although outdated were still relevant. More recent national reports, published by professional bodies and patients’ organisations, were also identified. These disorders were also grouped according to their aetiology and symptoms into 13 groups. Using all the available literature, total estimates of annual incidence and point prevalence of these disorders were arrived at. We can conclude that approximately 5.8% of the population in Wales are affected by neurological and neurosurgical disorders that include headaches, traumatic and infectious diseases of the nervous system.
Human Skin Penetration of Sunscreen Nanoparticles: In-vitro Assessment of a Novel Micronized Zinc Oxide Formulation
Authors: Cross Sheree E. , Innes Brian , Roberts Michael S. , Tsuzuki Takuya , Robertson Terry A. , McCormick Paul
Published: January 2007

The extent to which topically applied solid nanoparticles can penetrate the stratum corneum and access the underlying viable epidermis and the rest of the body is a great potential safety concern. Therefore, human epidermal penetration of a novel, transparent, nanoparticulate zinc oxide sunscreen formulation was determined using Franz-type diffusion cells, 24-hour exposure and an electron microscopy to verify the location of nanoparticles in exposed membranes. Less than 0.03% of the applied zinc content penetrated the epidermis (not significantly more than the zinc detected in receptor phase following application of a placebo formulation). No particles could be detected in the lower stratum corneum or viable epidermis by electron microscopy, suggesting that minimal nanoparticle penetration occurs through the human epidermis.
Propylthiouracil-Associated Eosinophilic Pleural Effusion: A Case Report
Authors: Sen Nazan , Ermis Hilal , Karatasli Meltem , Habesoglu Mehmet Ali , Eyuboglu Fusun Oner
Published: January 2007

We describe an unusual case of a patient with eosinophilic pleural effusion (EPE) associated with long-term propylthiouracil (PTU) administration. A 43-year-old woman was admitted to our hospital after complaining of chest pain. She had had Graves’ disease, which had been treated with PTU for 11 years. Right-sided pleural effusion was detected and the result of thoracentesis confirmed an EPE. The patient’s detailed medical evaluation failed to reveal any other cause of EPE. PTU was terminated since it was thought to be the cause. Despite withdrawal of the medication, however, the pleural effusion persisted for 6 weeks, and steroid therapy was planned for 15 days in decreasing dosages. During the control visit 10 days after the initiation of steroid therapy, no pleural effusion was observed, and the steroid was discontinued. Rechallenge with PTU produced recurrent pleural effusion. Therapy with PTU was again terminated, and treatment with methimazole and a brief course of low-dose corticosteroids were begun. Chest radiography revealed disappearance of the effusion within 10 days and it did not recur during a 1-year follow-up. To our knowledge, there is only 1 other case in the English-language literature describing EPE caused by PTU. Our report is of particular importance because it describes the development of that disorder in the 11th year of PTU treatment. It also shows that steroid therapy can be effective in treating drug-induced EPE.
Angiotensin II Induces Endothelial Xanthine Oxidase Activation
Authors: Landmesser Ulf , Spiekermann Stephan , Preuss Christoph , Sorrentino Sajoscha , Fischer Dieter , Manes Costantina , Mueller Maja , Drexler Helmut
Published: January 2007

Objective—

Xanthine oxidase (XO), a major source of superoxide, has been implicated in endothelial dysfunction in atherosclerosis. Mechanisms, however, leading to endothelial XO activation remain poorly defined. We tested the effect of angiotensin II (Ang II) on endothelial XO and its relevance for endothelial dysfunction in patients with coronary disease.

Methods and Results—

XO protein levels and XO-dependent superoxide production were determined in cultured endothelial cells in response to Ang II. In patients with coronary disease, endothelium-bound XO activity as determined by ESR spectroscopy and endothelium-dependent vasodilation were analyzed before and after 4 weeks of treatment with the AT
1
-receptor blocker losartan, the XO inhibitor allopurinol, or placebo. Ang II substantially increased endothelial XO protein levels and XO-dependent superoxide production in cultured endothelial cells, which was prevented by NAD(P)H-oxidase inhibition. In vivo, endothelium-bound XO activity was reduced by losartan and allopurinol, but not placebo therapy in patients with coronary disease. XO inhibition with oxypurinol improved endothelium-dependent vasodilation before, but not after losartan or allopurinol therapy.

Conclusions—

These findings suggest a novel mechanism whereby Ang II promotes endothelial oxidant stress, ie, by redox-sensitive XO activation. In patients with coronary disease, losartan therapy reduces endothelium-bound XO activity likely contributing to improved endothelial function.
Triglyceride-Rich Lipoproteins Prime Aortic Endothelium for an Enhanced Inflammatory Response to Tumor Necrosis Factor-α
Authors: Ting Harold J. , Stice James P. , Schaff Ulrich Y. , Hui David Y. , Rutledge John C. , Knowlton Anne A. , Passerini Anthony G. , Simon Scott I.
Published: January 2007

High levels of triglyceride-rich lipoproteins (TGRLs) in blood are linked to development of atherosclerosis, yet the mechanisms by which these particles initiate inflammation of endothelium are unknown. TGRL isolated from human plasma during the postprandial state was examined for its capacity to bind to cultured human aortic endothelial cells (HAECs) and alter the acute inflammatory response to tumor necrosis factor-α. HAECs were repetitively incubated with dietary levels of freshly isolated TGRL for 2 hours per day for 1 to 3 days to mimic postprandial lipidemia. TGRL induced membrane upregulation of the low-density lipoprotein family receptors LRP and LR11, which was inhibited by the low-density lipoprotein receptor-associated protein-1. TGRLs alone did not elicit inflammation in HAECs but enhanced the inflammatory response via a 10-fold increase in sensitivity to cytokine stimulation. This was reflected by increased mitogen-activated protein kinase activation, nuclear translocation of NF-κB, amplified expression of endothelial selectin and VCAM-1, and a subsequent increase in monocyte-specific recruitment under shear flow as quantified in a microfabricated vascular mimetic device.
Notch Ligand Delta-Like 1 Is Essential for Postnatal Arteriogenesis
Authors: Limbourg Anne , Ploom Merlin , Elligsen Diana , Sörensen Inga , Ziegelhoeffer Tibor , Gossler Achim , Drexler Helmut , Limbourg Florian P.
Published: January 2007

Growth of functional arteries is essential for the restoration of blood flow to ischemic organs. Notch signaling regulates arterial differentiation upstream of ephrin-B2 during embryonic development, but its role during postnatal arteriogenesis is unknown. Here, we identify the Notch ligand Delta-like 1 (
Dll1
) as an essential regulator of postnatal arteriogenesis.
Dll1
expression was specifically detected in arterial endothelial cells, but not in venous endothelial cells or capillaries. During ischemia-induced arteriogenesis endothelial
Dll1
expression was strongly induced, Notch signaling activated and ephrin-B2 upregulated, whereas perivascular cells expressed proangiogenic vascular endothelial growth factor, and the ephrin-B2 activator EphB4. In heterozygous
Dll1
mutant mice endothelial Notch activation and ephrin-B2 induction after hindlimb ischemia were absent, arterial collateral growth was abrogated and recovery of blood flow was severely impaired, but perivascular vascular endothelial growth factor and EphB4 expression was unaltered. In vitro, angiogenic growth factors synergistically activated Notch signaling by induction of
Dll1
, which was necessary and sufficient to regulate ephrin-B2 expression and to induce ephrin-B2 and EphB4-dependent branching morphogenesis in human arterial EC. Thus,
Dll1
-mediated Notch activation regulates ephrin-B2 expression and postnatal arteriogenesis.
Low-Frequency Variability in the Midlatitude Baroclinic Atmosphere Induced by an Oceanic Thermal Front
Authors: Feliks Yizhak , Ghil Michael , Simonnet Eric
Published: January 2007

This study examines the flow induced by an east–west-oriented oceanic thermal front in a highly idealized baroclinic model. Previous work showed that thermal fronts could produce energetic midlatitude jets in an equivalent-barotropic atmosphere and that barotropic instabilities of this jet had dominant periods of 25–30 and 65–75 days.

The present study extends this work to a two-mode baroclinic free atmosphere. The baroclinic jet produced in this case is subject to both barotropic and baroclinic instabilities. A barotropic symmetric instability propagates westward with periods of roughly 30 days and is similar to those found in the equivalent-barotropic model. A baroclinic instability results in standing-dipole anomalies and oscillates with a period of 6–8 months. A mixed barotropic–baroclinic instability results in anomalies that propagate northward, perpendicular to the jet, with a period of 2–3 months. The later anomalies are reminiscent of the 70-day oscillation found over the North Atlantic in observed fields.

The atmospheric flow has two distinct states: the flow in the high-energy state exhibits two large gyres and a strong eastward jet; its antisymmetric component is dominant. The low-energy flow is characterized by small gyres and a weak jet.

The model’s dynamics depends on the layer-depth ratio. When the model is nearly equivalent-barotropic, symmetric oscillatory modes dominate. As the two layers become nearly equal, antisymmetric oscillatory modes become significant and the mean energy of the flow increases.

When the oceanic thermal front’s strength T* is weak (T* ≤ 1.5°C), the flow is steady. For intermediate values of the strength (1.5°C < T* < 3°C), several oscillatory instabilities set in. As the frontal strength increases further (T* ≥ 3°C), the flow becomes more turbulent. These results all depend on the atmospheric model’s horizontal resolution being sufficiently high.
Dynamics of Eddy-Driven Low-Frequency Dipole Modes. Part II: Free Mode Characteristics of NAO and Diagnostic Study
Authors: Luo Dehai , Gong Tingting , Lupo Anthony R.
Published: January 2007

Through calculating the scatter diagrams of the streamfunction (ψP or ψT) versus potential vorticity (PV) (qP or qT), where ψP and ψT are the planetary-scale streamfunction and total streamfunction, respectively, and using a weakly nonlinear NAO model proposed in Part I of this paper, it is suggested that negative- and positive-phase NAO events may approximately correspond to free modes even though driven by synoptic-scale eddies. In a planetary-scale field, the qP(ψP) scatter diagram of an NAO event exhibits a linear multivalued functional relationship in a narrow region for the negative phase, but exhibits a linear single-valued functional relationship during the positive phase. It was also found that there is no steepening of the slope of the main straight line in the qP(ψP) scatter diagrams for two phases of the NAO event. Instead, the slope of the straight line in the scatterplots is time independent throughout the life cycle of the NAO event.

However, when synoptic-scale eddies are included in the streamfunction field, the qT(ψT) scatter diagram of the negative-phase NAO event shows a trend toward steepening during the intensification phase, and this tendency reverses during the decay phase. During the positive NAO phase the slope of the qt(ψT) scatter diagram shoals during the intensification phase and then steepens during the decay phase. Thus, it appears that the steepening and shoaling of the scatter diagrams of the streamfunction versus PV for the negative- and positive-phase NAO events are attributed to the effect of synoptic-scale eddies that force NAO events to form. Diagnostic studies using both composite and unfiltered fields of observed NAO events are presented to confirm these conclusions.
Back toward a Comprehensive Liberalism?
Authors: Abbey Ruth
Published: January 2007

This article examines the attempts by John Rawls in the works published after Political Liberalism to engage with some of the feminist responses to his work. Rawls goes a long way toward addressing some of the major feministliberal concerns. Yet this has the unintended consequence of pushing justice as fairness in the direction of a more comprehensive, rather than a strictly political, form of liberalism. This does not seem to be a problem peculiar to Rawls: rather, any form of liberalism hospitable to feminist concerns must be, at the very least, a partly comprehensive, rather than a strictly political, doctrine.