[Diet therapy in hyperlipidemia].
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Alcoholic Beverages↗
Biomedical subjects
H Kondoh
Publications and source records attributed to H Kondoh.
[A case of small cell carcinoma of the pancreas].
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Antineoplastic Combined Chemotherapy Protocols↗
PACS linked to EPR.
We developed a new PACS linked to Electronic Patient Record system (EPR). It was a hospital-wide PACS storing all the radiological examinations. The images and reports were linked on EPR. The concept of navigation servers and segment servers was introduced for prefetchig and quick displaying. After the start of operation, increasing retrieval indicated its effectiveness on practical work in spite of remaining delivery of radiographs.
Computer Communication Networks↗
Pairing SOX off: with partners in the regulation of embryonic development.
The SOX family of high-mobility group (HMG) domain proteins has recently been recognized as a key player in the regulation of embryonic development and in the determination of the cell fate. In the case of certain SOX proteins, they regulate the target genes by being paired off with specific partner factors. This partnering might allow SOX proteins to act in a cell-specific manner, which is key to their role in cell differentiation. The focus of this article is the mechanism of action of SOX proteins, in particular, how SOX proteins specifically pair off with respective partner factors and, as a consequence, select distinct sets of genes as their regulatory targets.
Animals↗
Zebrafish mutations in Gli-mediated hedgehog signaling lead to lens transdifferentiation from the adenohypophysis anlage.
It is known that the earliest lens marker delta-crystallin is expressed abundantly in Rathke's pouch of the chicken, suggesting a close relationship between the cell states of the adenohypophysis (pituitary) anlage and the early lens. We show here that the zebrafish midline mutants you-too (yot) and iguana (igu) develop lenses from the adenohypophysis anlage. The early adenohypophysis anlage of normal zebrafish expresses lim3 and six3 but in yot(ty119) mutants the anterior part of the anlage lacks lim3 expression, and instead produces a crystallin-expressing cell population which develops into a large lens structure expressing beta and gamma-crystallins, but is not associated with retina tissues. Among the zebrafish mutants with midline defects, midline lenses were observed in two mutant alleles of yot and an allele of igu, but not in other mutants (syu, con, smh, dtr, uml, spi and lok). Two yot mutant alleles with midline lenses likely encode dominant negative forms of the Gli2 protein which will interfere with transcriptional activation by other Gli proteins. The observation argues that overall inhibition of Shh-Gli signaling leads the adenohypophysis anlage to transdifferentiate into lens.
Alleles↗
Dual control of melanogenesis and melanoma growth: overview molecular to clinical level and the reverse.
Utilizing increased melanin pigmentation and accentuated melanogenesis seen in malignant melanoma, we newly developed melanoma-selective boron neutron capture therapy (BNCT) after designing and synthesizing the 10B-DOPA analogue, 10B-p-boronophenylalanine (10B-BPA). After multi-disciplined and extensive basic and pre-clinical investigations, we successfully treated 18 cases of human melanoma. Recently, we found that accentuated synthesis of melanin monomers, richest within coated vesicles (CV) in melanoma cells, plays a critical role in attracting 10B-BPA through chemical complex formation of monomers and 10B-BPA. CV are indeed BPA-localizing organelles. This led us to the new clinical endeavor that BPA may possess the potential ability to suppress melanin polymer formation through 'melanin monomer trapping' out of the melanogenic pathway which is highly regulated by the function of CV in pigment cells. It was soon found that melanin polymer formation can be suppressed by BPA at the chemical and cellular levels, then at the clinical level. Our discovery, that single molecule 10B-BPA possesses the dual nature of eradication of melanoma with BNCT and suppression of melanin hyperpigmentation, resulted from pursuing bilateral feedback at each stage from pure science to clinical application and vice versa. A further example of bilateral feedback is the development of gene-transfer applied BNCT (gBNCT). This also has its roots in clinical hurdles faced in treating amelanotic melanomas by 10B-BPA BNCT. The transfer of tyrosinase and melanin monomer synthesis-related genes into target cancer cells has produced more effective BNCT and may lead to gBNCT for non-melanoma cancers.
Animals↗
A novel approach to gene therapy of albino hair in histoculture with a retroviral streptomyces tyrosinase gene.
In order to induce melanin production in mammalian cells with pigment disorders such as albino hair, a recombinant retrovirus containing the mel locus of Streptomyces antibioticus was constructed. The S. antibioticus mel locus, which consists of the open reading frame (ORF)-438 and the tyrosinase gene, was specifically derived by polymerase chain reaction (PCR) from Streptomyces plasmid pIJ702. The ORF-438 is required for the transfer of copper to apotyrosinase, which is essential for tyrosinase enzymatic activity. The tyrosinase gene was inserted into the XhoI/BamHI cloning site of the pLXSN retroviral vector to obtain pLtyrSN. An internal ribosome entry site (IRES) suitable for mammalian cell expression was obtained from the pLXIN retroviral vector by PCR. The ORF-438 and IRES DNA fragments were inserted into the pLtyrSN vector to obtain the tyrosinase-expression retroviral vector pLmelSN. The expression vector was amplified in murine PT67 packaging cells, where the ORF-438 and tyrosinase genes were also co-expressed as determined by reverse transcription-PCR. In order to evaluate the vector's ability to restore pigment production in cells with a pigment disorder, albino-mouse skins were histocultured and then infected with the pLmelSN retrovirus. Six days after infection, melanin granules were observed in approximately 60% of albino-mouse hair follicles in the histocultured skin. These results demonstrated that the S. antibioticus mel operon could express an active tyrosinase and produce melanin in the albino-mouse hair follicles. This novel gene therapy approach, using a small and simple tyrosinase operon in a high-expression vector, has a potentially wide application for therapy of pigment disorders in hair follicles.
Albinism↗
Mis3 with a conserved RNA binding motif is essential for ribosome biogenesis and implicated in the start of cell growth and S phase checkpoint.
BACKGROUND: In normal somatic cell cycle, growth and cell cycle are properly coupled. Although CDK (cyclin-dependent kinase) activity is known to be essential for cell cycle control, the mechanism to ensure the coupling has been little understood. RESULTS: We here show that fission yeast Mis3, a novel evolutionarily highly conserved protein with the RNA-interacting KH motif, is essential for ribosome RNA processing, and implicated in initiating the cell growth. Growth arrest of mis3-224, a temperature sensitive mutant at the restrictive temperature, coincides with the early G2 block in the complete medium or the G1/S block in the release from nitrogen starvation, reflecting coupling of cell growth and division. Genetic interactions indicated that Mis3 shares functions with cell cycle regulators and RNA processing proteins, and is under the control of Dsk1 kinase and PP1 phosphatase. Mis3 is needed for the formation of 18S ribosome RNA, and may hence direct the level of proteins required for the coupling. One such candidate is Mik1 kinase. mis3-224 is sensitive to hydroxyurea, and the level of Mik1 protein increases during replication checkpoint in a manner dependent upon the presence of Mis3 and Cds1. CONCLUSIONS: Mis3 is essential for ribosome biogenesis, supports S phase checkpoint, and is needed for the coupling between growth and cell cycle. Whether Mis3 interacts solely with ribosomal precursor RNA remains to be determined.
Amino Acid Motifs↗
Suppression of polydactyly of the Gli3 mutant (extra toes) by deltaEF1 homozygous mutation.
Digit patterning is established through multiple genetic interactions. Delta-crystallin enhancer/E2-box factor (deltaEF1) is a zinc finger and homeodomain containing repressor protein, and is expressed in the posterior half of the forelimb bud and in the entire hindlimb bud during the early stage of limb development. The 6EF1-deficient mutant mice display various skeletal abnormalities, among which inferior ossification and abnormal patterning of autopodial bones are similar to those observed in Hox and Gli gene mutants. Gli3 mutant mice, extra toes (Xt), exhibit pre-axial polydactyly losing the identity of digit I. It is demonstrated here that deltaEF1null(lacZ) homozygosity suppressed formation of the extra digit, uniquely of the hindlimb, in both Gli3XtJ heterozygous and homozygous mutants, but with no restoration of digit I identity. In Gli3XtJ mutants, the Hoxd13 expression domain was expanded more dramatically in homozygotes. In Gli3XtJ;deltaEF1null(lacZ) double homozygous mutants, Hoxd13 expression once expanded in Gli3XtJ homozygous mutant was reduced, more conspicuously in the hindlimbs, which may account for hindlimb-restricted suppression of formation of the extra digit. The data suggest the possibility that the extent of Hoxd13 expression along the distal margin of the limb bud is determinative in defining the digit number.
Animals↗
Biodistribution of boron concentration on melanoma-bearing hamsters after administration of p-, m-, o-boronophenylalanine.
Although p-boronophenylalanine (p-BPA), a boronate analogue of tyrosine, has proven to be one of the most successful compounds for boron neutron capture therapy (BNCT) of malignant melanoma, the selective uptake mechanism of this compound into melanoma cells is not well understood. Therefore, the relationship between the structure of BPA and its specific affinity to melanoma cells appears worthy of investigation. In the present study, m- and o-boronophenylalanine (m- and o-BPA) were administered to melanoma-bearing hamsters and their uptake was measured. The time courses (0.5, 2.0, 4.0 and 48.0 h) of boron concentrations in melanoma, normal skin, and blood were determined in male Syrian (golden) hamsters bearing Greene's melanomas following a single intraperitoneal injection of either p-, m- or o-BPA (100 mg/kg of BPA fructose in 1.0 ml of saline). The boron concentrations in these tissues were measured by inductively coupled plasma-atomic emission spectrometry (ICP-AES). In melanoma, the order of boron uptake was p- > m- > o-BPA at all time points, and the boron concentrations obtained with p-BPA and m-BPA resembled each other in that they had a peak at 2 h after administration and decreased with time. The melanoma/skin boron concentration ratio of p-BPA had a peak at 4 h after administration and the ratio ranged between 7/1 and 8/1. On the other hand, m-BPA and o-BPA had a peak at 2 h and their ratios ranged between 4/1 and 5/1. The difference in the accumulations of p-BPA and m-BPA could be due to a difference in the property of p-BPA as a tyrosine analogue for melanin synthesis. The accumulation of m-BPA into melanoma might indicate the baseline level of metabolism-related amino acid transport. Our experimental findings indicate that this melanin synthesis, or the structural analogy between the boron compound and tyrosine as a precursor of melanin, is an important factor in the increased accumulation of p-BPA in melanoma cells.
Animals↗
Hyperintense basal ganglia on T1-weighted magnetic resonance images following postoperative parenteral nutrition in a pancreatoduodenectomized patient.
The authors reported the magnetic resonance imaging (MRI) detection of manganese (Mn) deposition in the basal ganglia of a pancreatoduodenectomized patient following 30-day parenteral nutrition. A multi-trace element supplement solution including 20 micromol Mn/day was parenterally administered for 30 days postoperatively. The serum level of total bilirubin normalized on the 3rd postoperative day, while the level of alkaline phosphatase continued to exceed the higher limit of normal controls even 2 months after operation. T1-weighted MRI on the 49th postoperative day demonstrated bilateral and symmetrical hyperintense lesions in the globus pallidus. The whole-blood Mn level on the 67th postoperative day was 3.1 (normal range 0.8-2.5) microg/l. T1-weighted MRI on the 103rd postoperative day revealed improvement in the hyperintense lesions, and MRI on the 225th postoperative day revealed no abnormality. The blood Mn level normalized on the 194th postoperative day. Even short-term postoperative parenteral nutrition may result in Mn deposition in the brain, especially in patients with cholestasis following pancreatoduodenectomy.
Aged↗
Combination therapy using prednisolone and cyclophosphamide slows the progression of moderately advanced IgA nephropathy.
AIM: We retrospectively examined the effect of combination therapy using prednisolone (PSL) and cyclophosphamide (CPA) on the progression of IgA nephropathy (IgAN) in 45 patients with moderate to severe histological changes. PATIENTS AND METHODS: Patients were recruited from 129 consecutive patients with IgAN seen over 10 years based on semiquantitative histological grading. They were divided into two groups: PSL+CPA group (n = 26, male/female = 11/15, age 40+/-3 years (SEM)) or control group undergone conventional therapy with or without antiplatelet agents (n = 19, male/female = 10/9, age 41+/-3). In PSL+CPA group, PSL and CPA treatment commenced using a dose of 30 and 50 mg/day, respectively. PSL was reduced by 5 mg every month. RESULTS: The clinical parameters at the start of treatment such as age, gender, histological score, blood pressure, urinary protein excretion and serum creatinine concentration (SCr) were not different between the groups. The mean observation period in PSL+CPA group (3.3+/-0.3 years) was not different from the control group (4.0+/-0.7 years). In PSL+CPA group, urinary protein excretion, defined as the ratio of urinary protein to creatinine concentration (UP/UCr), significantly decreased from 3.9+/-0.4 to 1.3 +/-0.2 (p<0.01), whereas it remained high in the control group (3.8+/-0.7 to 2.7+/-0.8). The progression rate (PR), which was determined by the slope of the correlation between time after renal biopsy and reciprocal SCr, was significantly lower in PSL+CPA (0.054+/-0.014) than in the control group (0.172+/-0.032 dl/mg/year, p<0.001). Our results indicated that PSL+CPA combination therapy was effective in slowing the progression of moderately advanced IgAN. CONCLUSION: We suggest that the immunosuppressive treatment with CPA is sometimes necessary to preserve renal function in patients with histologically advanced IgAN.
Adolescent↗
Selective uptake of para-boronophenylalanine increases in amelanotic melanoma cells transfected by the tyrosinase gene.
To investigate the mechanism of uptake of para-boronophenylalanine (p-BPA), a capture agent for boron neutron capture therapy (BNCT) of melanoma and brain tumour, into melanoma cells, we studied the relationship between melanin synthesis and the concentration of boron using tyrosinase-deficient mouse amelanotic melanoma cells (A1059) and melanotic melanoma cells (TA1059). A1059 was established from mouse B16F10 cells, and TA1059 was constructed by transfecting human tyrosinase cDNA into A1059. The melanin content of TA1059 was 1.5-fold higher than that of B16F10, and was undetectable in A1059. The order of p-BPA uptake was TA1059 > B16F10 > A1059 at the time points examined, and the boron content of TA1059 was approximately 1.5-fold higher than that of B16F10. Our experimental findings indicated that melanin synthesis is a very important factor for characterizing the increase in accumulation of p-BPA in melanoma cells. A significant difference in boron uptake into TA1059 was observed between p-BPA and meta-BPA (m-BPA), but there were no apparent differences in the case of A1059. The difference in accumulation of p-BPA and m-BPA could be due to differences in the properties of p-BPA as a tyrosine analogue needed for melanin synthesis.
Animals↗
Identification of new genes ndr2 and ndr3 which are related to Ndr1/RTP/Drg1 but show distinct tissue specificity and response to N-myc.
Ndr1 was isolated as a gene upregulated in N-myc mutant mouse embryos and is repressed by N-myc and c-myc. Consistent with Myc regulation, the same gene was also isolated as one sensitive to transformation (Drg1), and in addition as one induced under a few stress conditions (RTP). Two new genes, Ndr2 and Ndr3, were identified which encode proteins highly related to Ndr1/RTP/Drg1 and constitute the Ndr gene family. Ndr2 and Ndr3 are under spatio-temporal regulations distinct from Ndr1, and are not activated in N-myc mutants. When whole embryo RNA was analyzed, Ndr3 expression was already high at 9.5 days postcoitus (dpc), while expression of Ndr2 and Ndr1 became significant after 12.5 dpc and 13. 5 dpc, respectively. At 14.5 dpc, expression of these genes partially overlaps, but many tissues are unique to one of them. For instance, Ndr1 is strongly expressed in the liver and gut epithelium, Ndr2 in the ventricular zone throughout the CNS, and Ndr3 in the spinal cord and the thymus rudiment. Genes of the Ndr family probably have tissue-dependent allotments of the possibly related functions.
Adaptor Proteins, Signal Transducing↗
Manganese deposition in the brain following parenteral manganese administration in association with radical operation for esophageal cancer: report of a case.
We report herein the case of a patient in whom manganese (Mn) deposition in the basal ganglia was detected by magnetic resonance imaging (MRI) subsequent to thoracic esophagectomy, performed following perioperative parenteral nutrition. A multi-trace-element supplement solution which included 20 micromol of Mn per day had been parenterally administered for 7 days preoperatively and 21 days postoperatively. The serum level of total bilirubin reached a maximum value of 5.1 mg/dl postoperatively. The T1-weighted MRI on the 32nd postoperative day demonstrated bilateral and symmetrical hyperintense lesions in the globus pallidus and the whole-blood Mn level on the 34th postoperative day was 4.9 microg/l, the normal range being 0.8-2.5 microg/l. This hyperintensity on T1-weighted MRI was gradually improved following normalization of the blood Mn level. This case report serves to demonstrate that even short-term perioperative parenteral nutrition may result in Mn deposition in the brain following radical surgery for esophageal cancer, especially in patients with hyperbilirubinemia.
Aged↗
Running closure of clean and contaminated abdominal wounds using a synthetic monofilament absorbable looped suture.
The effectiveness of using an absorbable suture material for continuous closure of abdominal wounds, especially contaminated wounds, has not yet been determined. Thus, the present study was conducted to investigate the wound complications that developed following continuous closure of clean and contaminated abdominal wounds using polydioxanone (PDS), compared with those that developed following interrupted closure using braided silk. Running closure using PDS was performed in 152 patients (PDS group), while 280 patients who underwent interrupted closure using braided silk served as controls (SILK group). The occurrence rates of wound dehiscence, early wound infection, and incisional hernia did not differ significantly between the two groups; however, the incidence of late suture sinus formation in the PDS group (1.3%) was significantly lower than that in the SILK group (7.1%). Moreover, late suture sinus formation following PDS suturing healed within 1 week after percutaneous drainage alone without removal of suture strings, whereas late suture sinus following braided silk suturing took an average of 16 days to heal and required removal of the infected suture strings in all 20 patients. These findings indicate the potential usefulness of PDS as a suture material to achieve running closure of clean or contaminated abdominal wounds.
Abdominal Injuries↗
N-myc-dependent repression of ndr1, a gene identified by direct subtraction of whole mouse embryo cDNAs between wild type and N-myc mutant.
To identify genes regulated by N-myc, subtraction of whole embryo cDNA was carried out between wild type and N-myc-deficient mutant mice. Six cDNA clones were isolated as representing genes expressed higher in the mutant embryos and two as those expressed lower. One of them, Ndr1, coding for 43 kDa cytoplasmic protein was studied in detail. The Ndr1 gene was augmented 20-fold in the mutant embryos at 10.5 days post coitus which is indicative of repression by N-myc. An inverse relationship actually existed between the expression of N-myc and Ndr1 in various developing tissues of the wild type embryos. In the early stage of differentiation of these tissues when N-myc expression was high Ndr1 expression was low or undetectable, and later when N-myc activity diminished Ndr1 expression was augmented concomitantly with the occurrence of terminal differentiation. To establish the direct link between N-myc activity and the Ndr1 regulation, the Ndr1 gene was cloned and analyzed. The Ndr1 promoter activity was down-regulated by N-myc, and more strongly by the combination of N-myc and Max in the cotransfection assay. This repressive effect was mediated by the promoter region within 52 base pairs from the transcription start site but direct binding of N-myc:Max to the promoter sequence was not demonstrated, which is analogous to the cases recently reported for transcriptional repression by c-myc. c-myc also repressed Ndr1 promoter activity similarly to N-myc. The effect of N-myc:Max was sensitive to Trichostatin A, indicating involvement of histone deacetylase activity in repression of the Ndr1 promoter. The strategy we adopted in identifying target genes of a transcription factor should prove widely applicable when mutant animals are available.
Amino Acid Sequence↗
Two distinct subgroups of Group B Sox genes for transcriptional activators and repressors: their expression during embryonic organogenesis of the chicken.
Group B Sox genes, Sox1, -2 and -3 are known to activate crystallin genes and to be involved in differentiation of lens and neural tissues. Screening of chicken genomic sequences for more Group B Sox genes identified two additional genes, Sox14 and Sox21. Proteins encoded by Sox14 and Sox21 genes are similar to each other but distinct from those coded by Sox1-3 (subgroup B1) except for the HMG domain and Group B homology immediately C-proximal of the HMG domain. C-terminal domains of SOX21 and SOX14 proteins function as strong and weak repression domains, respectively, when linked to the GAL4 DNA binding domain. These SOX proteins strongly (SOX21) or moderately (SOX14) inhibited activation of delta1-crystallin DC5 enhancer by SOX1 or SOX2, establishing that Sox14 and Sox21 are repressing subgroup (B2) of Group B Sox genes. This provides the first evidence for the occurrence of repressor SOX proteins. Activating (B1) and repressing (B2) subgroups of Group B Sox genes display interesting overlaps of expression domains in developing tissues (e.g. optic tectum, spinal cord, inner ear, alimentary tract, branchial arches). Within each subgroup, most expression domains of Sox1 and -3 are included in those of Sox2 (e.g. CNS, PNS, inner ear), while co-expression of Sox14 and Sox21 occurs in highly restricted sites of the CNS, with the likely temporal order of Sox21 preceding Sox14 (e.g. interneurons of the spinal cord). These expression patterns suggest that target genes of Group B SOX proteins are finely regulated by the counterbalance of activating and repressing SOX proteins.
Amino Acid Sequence↗