On the concept of delusions: Global trends and psychopathology in Japan.

The present article spotlights challenging conceptual and epistemological issues regarding delusions. A research history of various approaches to delusions in Europe, the United States, and Japan reveals the difficulty of defining delusions. Facing these difficulties, the standard concept of delusions has become thinner than the traditional ones, making its boundary with minority opinions vaguer. Nevertheless, clinical typology and epistemological approaches are contributing to the continuous conceptual refinement of delusions. Both standpoints validate and promote each other in elaborating the characteristics of delusions and their boundaries with non-delusions. In addition, epistemological inquiries into delusions shed new light on the extraordinarily difficult problems in the relationship among belief, knowledge, certainty, and delusions, contributing to epistemology in general. These approaches to delusions promote the evolution of the concept of delusions and related epistemological inquiries.

Self-disorder explained: Yasunaga's "Phantom Space Theory" on schizophrenia.

The present article revisits the theoretical model of schizophrenia by Hiroshi YASUNAGA (1929-2011). Yasunaga restated ego disturbance in schizophrenia as the "Pattern Reversal" between selfhood and otherness, based on British philosopher Wauchope's concept of "pattern." This concept is meant as asymmetrical relatedness (A/B) within a pair of concepts, such as life and death, quality and quantity, and self and other, prioritizing the former (A side) over the latter (B side). When applied to the pair of self and other, the pattern is vital for human experiences, and its disruption fundamentally alters every lived experience. Subsequently, Yasunaga extended the theory of pattern and invented his original "Phantom Space Theory," in which he postulated "Phantom Space," an experiential space that constitutes system a (A-side-led and consciously determined distance) and system a' (B-side-dominated and extra-consciously given distance). He then constructed a kind of neural system model composed of systems a and a', and thereby schematically presented a novel viewpoint on experiences of self and the outside world. The theory further illustrated how the hypothesized imbalance (Phantom Space shrinkage or diminished elasticity of system a') causes symptoms of schizophrenia, such as ego disturbances, auditory hallucinations, and other unspecific symptoms. This article then examines the clinical and theoretical implications of Yasunaga's psychiatric works. Phantom Space Theory is a non-stigmatizing account of schizophrenia because it does not presuppose personal or existential causes of psychosis. The relationship between Phantom Space Theory and dual-process theory is also explored.

Modeling the sake brewing characteristics of rice from brown rice metabolites.

Sake, soy sauce, miso (Japanese bean paste), and beer are made from grains. The characteristics of the grain significantly affect the quality of the final product. Many studies have been performed to evaluate the sake-brewing characteristics of rice. However, current rice analysis methods are time and labor intensive and require large samples. We developed a novel method for predicting the brewing characteristics of sake rice using <1 g of sample. Brown rice extracts were analyzed by ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry, and mass chromatogram data were used as explanatory variables. The objective variables were the physical and chemical properties of the rice, the enzymatic activity of the rice-koji, the fermentation properties of the sake mash, the standard analytical values of the sake, and the flavor component concentrations in the sake. Prediction models were developed using the orthogonal projections to latent structures method. The prediction performances of the models were verified, and 32 out of the 54 objective variables were used in well-performing models. In conclusion, we developed a method for predicting the rice properties and brewing characteristics from results acquired by analyzing <1 g of brown rice. The method is a powerful tool for breeding new sake rice cultivars for good brewing characteristics in early generations and will improve our understanding of fluctuations in the brewing characteristics of sake rice before each sake brewing season starts.

Theory of mind and Verstehen (understanding) methodology.

Theory of mind is a prominent, but highly controversial, field in psychology, psychiatry, and philosophy of mind. Simulation theory, theory-theory and other views have been presented in recent decades, none of which are monolithic. In this article, various views on theory of mind are reviewed, and methodological problems within each view are investigated. The relationship between simulation theory and Verstehen (understanding) methodology in traditional human sciences is an intriguing issue, although the latter is not a direct ancestor of the former. From that perspective, lessons for current clinical psychiatry are drawn.

Tumorigenic risk of human induced pluripotent stem cell explants cultured on mouse SNL76/7 feeder cells.

The potential for tumor formation from transplanted human induced pluripotent stem cell (hiPSC) derivatives represents a high risk in their application to regenerative medicine. We examined the genetic origin and characteristics of tumors, that were formed when 13 hiPSC lines, established by ourselves, and 201B7 hiPSC from Kyoto University were transplanted into severe combined immune-deficient (SCID) mice. Though teratomas formed in 58% of mice, five angiosarcomas, one malignant solitary fibrous tumor and one undifferentiated pleomorphic sarcoma formed in the remaining mice. Three malignant cell lines were established from the tumors, which were derived from mitomycin C (MMC)-treated SNL76/7 (MMC-SNL) feeder cells, as tumor development from fusion cells between MMC-SNL and hiPSCs was negative by genetic analysis. While parent SNL76/7 cells produced malignant tumors, neither MMC-SNL nor MMC-treated mouse embryo fibroblast (MEF) produced malignant tumors. When MMC-SNL feeder cells were co-cultured with hiPSCs, growing cell lines were generated, that expressed genes similar to the parent SNL76/7 cells. Thus, hiPSCs grown on MMC-SNL feeder cells have a high risk of generating feeder-derived malignant tumors. The possible mechanism(s) of growth restoration and the formation of multiple tumor types are discussed with respect of the interactions between MMC-SNL and hiPSC.

The theoretical root of Karl Jaspers' General Psychopathology. Part 1: Reconsidering the influence of phenomenology and hermeneutics.

The present paper investigates the methodology involved in Jaspers' psychopathology and compares it with Husserl's phenomenology and with Dilthey's cultural science. Allgemeine Psychopathologie and other methodological works by Jaspers, the works of Husserl and Dilthey that Jaspers cited, and previous research papers on Jaspers are reviewed. Jaspers had conflicting views on understanding, which were comprised of both empathic understanding and rational, ideal-typical understanding. Such a standpoint on understanding is considerably different from Dilthey's. Additionally, the present paper reconfirms that Jaspers' 'phenomenology' as a form of descriptive psychology for the understanding of empirical psychic states is different from Husserl's phenomenology. Thus, this paper casts doubt on the common opinion that Jaspers was under the profound influence of Husserl or Dilthey.

The theoretical root of Karl Jaspers' General Psychopathology. Part 2: The influence of Max Weber.

The present study explores and compares Jaspers' methodology of psychopathology with Weber's methodology of sociology. In his works, Weber incorporated the arguments of many other researchers into his own methodology. Jaspers respected Weber as a mentor and presented arguments that were very similar to Weber's. Both Weber and Jaspers began from empathic understanding, but at the same time aimed for a rational and ideal-typical conceptualization. In addition, their methodologies were similar with respect to their detailed terminology. Such similarities cannot be seen with any other scholars. This suggests that Weber may have played an integral role as a mediator between his contemporary scholars and Jaspers. Thus, Weber may have had the most significant influence on Jaspers.

LIN54 harboring a mutation in CHC domain is localized to the cytoplasm and inhibits cell cycle progression.

The mammalian LIN complex (LINC) plays important roles in regulation of cell cycle genes. LIN54 is an essential core subunit of the LINC and has a DNA binding region (CHC domain), which consists of two cysteine-rich (CXC) domains separated by a short spacer. We generated various LIN54 mutants, such as CHC deletion mutant, and investigated their subcellular localizations and effects on cell cycle. Wild-type LIN54 was predominantly localized in the nucleus. We identified two nuclear localization signals (NLSs), both of which were required for nuclear localization of LIN54. Interestingly, deletion of one CXC domain resulted in an increased cytoplasmic localization. The cytoplasmic LIN54 mutant accumulated in the nucleus after leptomycin B treatment, suggesting CRM1-mediated nuclear export of LIN54. Point mutations (C525Y and C611Y) in conserved cysteine residues of CXC domain that abolish DNA binding activity also increased cytoplasmic localization. These data suggest that DNA binding activity of LIN54 is required for its nuclear retention. We also found that LIN54 (C525Y) and LIN54 (C611Y) inhibited cell cycle progression and led to abnormal nuclear morphology. Other CXC mutants also induced similar abnormalities in cell cycle progression. LIN54 (C525Y) led to a decreased expression of some G2/M genes, whose expressions are regulated by LINC. This cell cycle inhibition was partially restored by overexpression of wild-type LIN54. These results suggest that abnormal cellular localization of LIN54 may have effects on LINC activity.

Establishment of ultra long-lived cell lines by transfection of TERT into normal human fibroblast TIG-1 and their characterization.

To establish useful human normal cell lines, TERT (telomerase reverse transcriptase) cDNA was transfected into normal female lung fibroblast, TIG-1. After long-term-sub-cultivation of 74 individual clones selected for resistance to G418, we obtained 55 cultures with normal range of life span [75 PDL (population doubling level)], 16 cultures with extended life span (75-140 PDL). In addition, 3 immortal cell strains and unexpectedly, one ultra long-lived cell line (ULT-1) with life span of 166 PDL were established. IMT-1, one of the immortal cell strains was confirmed to maintain long telomere length, high telomerase activity and an extremely low level of p16INK4A. They also showed moderate p53 and p21CIP1 expression, keeping vigorous growth rate even at 450 PDL. High level of fibronectin and collagen 1α expression confirmed IMT-1 as normal fibroblasts, although one X chromosome had been lost. ULT-1, however, kept a near normal karyotypes and had shortening of telomere length, high expression of p16INK4A, moderate levels of senescence associated-ß-galactosidase positive cells and decreased growth rate only after 150 PDs (population doublings), and finally reached senescence at 166 PDL with morphology of normal senescent fibroblasts. As resources of standard normal human cell, abundant vials of early and middle passages of ULT-1 have been stocked. The use of the cell line is discussed, focusing on isograft of artificial skin and screening of anti-aging or safe chemical agents.

What is a'mood-congruent' delusion? History and conceptual problems.

This article investigates the history of the concept of mood-congruent delusions and the problems accompanying this concept. In the late nineteenth century, there were conflicting views regarding the relationship between the contents of an individual's delusional thought and his/her affective state. The differentiation between delusion-like ideas secondary to affective state and incomprehensible primary delusions was introduced in the early twentieth century; this differentiation is the origin of the present-day distinction between mood-congruent and -incongruent delusions. Although the themes of delusions are clearly described in the operational diagnostic criteria for mood-congruent psychotic symptoms, the concept of mood congruence inevitably involves ambiguity. This article argues that a dilemma between reliability and validity emerges when diagnosing mood-congruent (and -incongruent) psychotic symptoms.

Establishment of human induced pluripotent stem cell lines from normal fibroblast TIG-1.

Normal human cells have a replicative life span and therefore senesce. Usually, normal human cell strains are differentiated cells and reach a terminally differentiated state after a number of cell divisions. At present, definitive differences are not known between replicative senescence and terminal differentiation. TIG-1 is a human fibroblast strain established from fetal lung and has been used extensively in studies of cellular senescence, and numerous data were accumulated at the molecular level. Recently, a method for generating induced pluripotent stem cells (iPSCs) was developed. Using the method, we introduced four reprogramming genes to TIG-1 fibroblasts and succeeded in isolating colonies that had embryonic stem cell (ESC)-like morphologies. They showed alkaline phosphatase activity and expressed ESC markers, as shown by immunostaining of OCT4, SOX2, SSEA4, and TRA-1-81 as well as reverse-transcription polymerase chain reaction (RT-PCR) for OCT4 and NANOG transcripts. Thus, we succeeded in establishing iPSC clones from TIG-1. The iPSC clones could differentiate to cells originated from all three germ-cell layers, as shown by RT-PCR, for messenger RNA (mRNA) expression of α-fetoprotein (endoderm), MSX1 (mesoderm) and microtubule-associated protein 2 (ectoderm), and by immunostaining for α-fetoprotein (endoderm), α-smooth muscle actin (mesoderm), and ß-III-tubulin (ectoderm). The iPSCs formed teratoma containing the structures developed from all three germ-cell layers in severe combined immune-deficiency mice. Thus, by comparing the aging process of parental TIG-1 cells and the differentiation process of iPSC-derived fibrocytes to fibroblasts, we can reveal the exact differences in processes between senescence and terminal differentiation.

Differentially expressed genes throughout the cellular immortalization processes are quite different between normal human fibroblasts and endothelial cells.

It is widely accepted that activation of telomerase and maintenance of telomeres play central roles in cellular immortalization for most cancer cells. However, they seem to be insufficient for normal human cells. To elucidate critically responsible genes for telomerase mediated cellular immortalization in non-cancerous cells, we explored the genes that are differentially expressed throughout the immortalization process of normal human cells using cDNA microarrays with novel normalization procedures. We found that the number of genes, differentially expressed during cellular immortalization after ectopic expression of telomerase, dramatically increased in a later phase, especially in fibroblasts. We identified 18 and 20 genes/ESTs dysregulated throughout the cellular immortalization processes in fibroblasts and endothelial cells, respectively, but none of them overlapped. Only BGN and COL5A2 were commonly downregulated, except for at early phase in fibroblasts, and a few genes showed controversial expression changes, with regard to previous reports in cancer cells. These findings indicate that normal somatic cells would require cell-type specific events in addition to telomerase activation, and a rare population that eventually experience such events would acquire immortality. The key molecules that distinguish the immortalization mechanisms in cancerous and non-cancerous cells may become crucial targets for anticancer therapy and regenerative therapy.

Differential gene expressions during immortalization of normal human fibroblasts and endothelial cells transfected with human telomerase reverse transcriptase gene.

It is widely accepted that telomerase, which compensates for telomere shortening, is finally activated in almost all kinds of human malignant neoplasms, and ectopic expression of telomerase may endow some kinds of human somatic cells with indefinite proliferation capacity, i.e., immortality. To clarify the intrinsic responses required in acquiring immortality, we investigated the chronological changes in the expression levels of the cell cycle and apoptosis-related genes by real-time RT-PCR in human normal fibroblasts and endothelial cells after hTERT transfection. We found that fibroblast MJ90 required intrinsic responses including reversible upregulation of cell-cycle promoting genes and down-regulation of apoptosis-inducing genes in early phase after transfection, whereas the endothelial cell HUE142-2 did not. In addition, the microarray analysis of the fibroblast strains revealed that the dysregulated genes during cellular immortalization were different from those reported in fibroblasts probably having acquired telomere maintenance mechanism concomitant with hTERT induction. These findings indicate that cell-type specific differential gene expression after telomerase activation may be important to acquire telomere-maintenance capacity and immortality in some non-cancerous human cells. Investigation of these molecules may elucidate the differences in the capacity of acquiring immortality in cancer and normal somatic cells in future.

Hypoxia-inducible factor-1alpha polymorphisms associated with enhanced transactivation capacity, implying clinical significance.

Hypoxia-inducible factor-1 (HIF-1) is a pivotal factor that regulates cellular responses to hypoxia and is presumably linked to regulation of angiogenesis and tumor growth. We assessed the difference in transcription activity of two HIF-1alpha polymorphic variants (P582S and A588T), along with molecular epidemiological study among head and neck squamous cell carcinoma (HNSCC) patients. Both HIF-1alpha variants revealed significantly higher transcription activity than wild-type (WT) did, under normoxic and hypoxic conditions (P < 0.02). Furthermore, tumors from HNSCC patients with heterozygous alleles having P582S or A588T had significantly increased numbers of microvessels compared with those with homozygous WT (P = 0.02). In addition, all patients with tumors of T1 (below 2 cm diameter) were WT, while 14 of 47 patients with tumors of > or =T2 were heterozygous. The elevated transactivation capacity of variant forms of HIF-1alpha implies a role of HIF-1alpha polymorphisms in generating individually different tumor progression.

Life span shortening of normal fibroblasts by overexpression of BCL-2: a result of potent increase in cell death.

It is well known that BCL-2 protects against cell death by both apoptosis and necrosis. The culture of bcl-2-transfected normal fibroblasts showed a shorter life span by about 12 population doubling levels compared to that of vector transfectants (64 vs 76 population doubling levels, respectively). An MTT assay revealed that BCL-2-overexpressing cells (HCA2/bcl-2) showed more severe growth suppression due to hydrogen peroxide or doxorubicin treatment than vector control cells (HCA2/vector). We observed a significant number of dead cells in the HCA2/bcl-2 culture, but not in the HCA2/vector culture. Other BCL-2 family proteins with both antiapoptotic and proapoptotic activity and other apoptosis-related factors were maintained at similar levels, indicating that overexpression of BCL-2 is the major reason that normal fibroblasts are sensitized to cell death. A broad caspase inhibitor (z-Val-Ala-Asp-fmk) and inhibitors of specific caspases (acetyl-Asp-Glu-Val-Asp-CHO, acetyl-Ile-Glu-Thr-Asp-CHO, and acetyl-Leu-Glu-His-Asp-CHO) suppressed cell death of HCA2/bcl-2 effectively, suggesting involvement of caspase 3-, 8-, and 9-dependent pathways in cell death and that the form of death is apoptosis. Unexpectedly, involvement of active MEK in cell death was shown by the use of its inhibitor, suggesting that crosstalk between BCL-2 and the MAP kinase cascade regulates death as well as life span.

Bcl-2 in cancer and normal tissue cells as a prediction marker of response to 5-fluorouracil.

Bcl-2 in cancer cells was shown to be a potent indicator of 5-FU efficacy, but the protein in normal tissue cells appeared not to be a marker of 5-FU toxicity probably due to the functional alteration of Bcl-2 associated with cell senescence. Transfection analysis of Bcl-2-S and Bcl-2-AS into A549 lung cancer cells revealed that Bcl-2 suppressed cell death induced by 5-FU, and the gene expression level of Bcl-2 was closely correlated with the IC50 for 5-FU in 21 fresh human gastric tumor specimens. Such correlation could not be observed in a neonatal human foreskin fibroblast strain, MJ90 (HCA2), and 21 human normal tissues adjacent to tumors. Transfection analysis of Bcl-2-S and Bcl-2-AS into MJ90 cells showed that Bcl-2 correlated with the resistance to 5-FU in the transfectants at PDL60 as in A549 cells, but increased Bcl-2 in the PDL72 senescent transfectant did not cause an increase of the resistance to 5-FU. Cell aging was observed in MJ90 cells and Bcl-2 in the cells was found to decrease with the cell senescence. The senescent cells, however, were more resistant to 5-FU than the younger PDL60 cells having proliferation activity.

Are sodium-dependent V1 receptors and sympathetic nerve activations involved in regulation of blood pressure in borderline-hypertensive Hiroshima rats?

Sympathetic nerve activity (SNA) was estimated by the magnitude of depressor response after ganglionic blockade with hexamethonium bromide (C6; 25 mg/kg weight). The depressor effects of C6 were significantly less in borderline-hypertensive Hiroshima rats (BHR) than in deoxycorticosterone acetate (DOCA)-salt hypertensive rats (DOCA rats) or in spontaneously hypertensive rats (SHR), but they were not different in BHR and normotensive control Wistar rats (NCR). After sympatho-inhibition, the depressor effects of a selective vasopressin V1 receptor antagonist (V1A; 10 microg/kg: [d(CH2)5(1), O-Me-Tyr2, Arg8]-vasopressin) were significantly greater in BHR than in DOCA rats, SHR or NCR. In a previous study, we reported that the depressor effects of C6 were significantly less in BHR than in SHR, but after sympatho-inhibition, the depressor effects of V1A were significantly greater in BHR than in SHR (Hypertens Res 2002; 25: 241-248). After high-salt diet loading in the present study (8% salt-containing diet for 10 weeks), the magnitudes of increase in mean arterial pressure in BHR and NCR were almost the same. There was almost no difference in the depressor effects of V1A after sympatho-inhibition between BHR with high-salt intake and BHR without high-salt intake. The depressor effects of an angiotensin-converting enzyme inhibitor, captopril (1 mg/kg), were almost the same between BHR and NCR both before and after sympatho-inhibition. However, these effects were completely inhibited after the high-salt diet. The results show that SNA was within the normal range in BHR and that no further accelerated responsiveness of endogenous vasopressin was observed in BHR after high-salt intake.

Effect of BCL-2 down-regulation on cellular life span.

Reactive oxygen species (ROS) are toxic for cells. BCL-2 is known as the anti-death protein and acts as an antioxidant. When the BCL-2 level of normal fibroblasts was suppressed by antisense bcl-2 oligodeoxynucleotide or antisense bcl-2 RNA expression, the life span of the culture was shortened by about 11 population doublings (approx. 15% of the total life span) in comparison to the control culture. Since about twice as many cell deaths were observed in the antisense culture than in the vector culture, the life span shortening was probably caused by ROS-induced death. Acceleration of telomere shortening was not evident in the antisense culture. Other BCL-2 family proteins showed no significant change in expression. Cell death was suppressed by N-acetyl-L-cysteine, an antioxidant, suggesting that ROS were the major cause of cell death. In conclusion, reduction of BCL-2 makes cells more sensitive to death induced by ROS and leads to shortening of the culture's life span.

Contribution of endogenous vasopressin to regional hemodynamics in borderline-hypertensive Hiroshima rats.

Inbred borderline-hypertensive Hiroshima rats (BHR) of the Wistar strain established in our laboratory are characterized by elevated plasma levels of vasopressin (Teranishi et al.: Jpn J Pharmacol 1999; 79: 251-255). To investigate the role of endogenous vasopressin in hypertension in BHR, we assessed the effect of a selective vasopressin V1 receptor antagonist (V1A) on regional hemodynamics using an electromagnetic flowmeter. The basal values of mean arterial pressure, heart rate, and regional resistances of renal and hindquarter vascular beds in conscious BHR were significantly higher than those in normotensive control rats (NCR). Injection of V1A (10 microg/kg) did not appreciably affect the hemodynamics in either animal. Successive administration of V1A after ganglionic blockade with hexamethonium bromide (C6; 25 mg/kg), however, significantly attenuated renal, mesenteric and hindquarter resistances in BHR but not in NCR. The hypotensive effect of V1A after sympathoinhibition was significantly greater in BHR than in both NCR and spontaneously hypertensive rats. However, the hypotensive effect induced by V1A was diminished only in BHR pretreated with a ganglionic blockade followed by injection of captopril (1 mg/kg). These findings indicate that BHR could be used as a new hypertensive model with an abnormality in endogenous vasopressin-mediated vasoconstriction appearing in the presence of angiotensin II after sympathoinhibition.