Characteristics of shifting ability in children with mild intellectual disabilities: an experimental study with a task-switching paradigm.

BACKGROUND: Shifting enables flexible switch between tasks or mental sets. It is a component of the executive function that plays critical roles in human behaviour control. However, shifting ability in individuals with intellectual disability (ID) has not been well clarified because of the use of intellectually demanding tasks in previous studies. The present study invented a novel shifting task with minimal intellectual demands and aimed to clarify the characteristics of shifting in adolescents with ID. METHODS: Adolescents with ID (n = 21) and chronological-age-matched (n = 10) and mental-age-matched controls (n = 33) performed a novel shifting task with simple rule switching (i.e. change in direction). Analyses focused on the switch cost or the increase in the reaction time associated with rule switching. RESULTS: Two subtypes of adolescents with ID were found with respect to the switch cost: one that lacks it and another with an increased switch cost. The lack of a switch cost was unique to the subgroup adolescents with ID and was not indicated in the control group. CONCLUSIONS: The present study indicated that shifting in adolescents with ID does not depend solely on their intellectual function and is highly heterogeneous. This finding further implies that executive functions, including shifting, must be evaluated separately from their intellectual functions.

Evaluation of microbial diversity in the pilot-scale beer brewing process by culture-dependent and culture-independent method.

AIMS: In the brewing industry, microbial management is very important for stabilizing the quality of the product. We investigated the detailed microbial community of beer during fermentation and maturation, to manage beer microbiology in more detail. METHODS AND RESULTS: We brewed a beer (all-malt) and two beerlike beverages (half- and low-malt) in pilot-scale fermentation and investigated the microbial community of them using a next-generation sequencer (454 GS FLX titanium), quantitative PCR, flow cytometry and a culture-dependent method. From 28 to 88 genera of bacteria and from 9 to 38 genera of eukaryotic micro-organisms were detected in each sample. Almost all micro-organisms died out during the boiling process. However, bacteria belonging to the genera Acidovorax, Bacillus, Brevundimonas, Caulobacter, Chryseobacterium, Methylobacterium, Paenibacillus, Polaromonas, Pseudomonas, Ralstonia, Sphingomonas, Stenotrophomonas, Tepidimonas and Tissierella were detected at the early and middle stage of fermentation, even though their cell densities were low (below approx. 10(3) cells ml(-1) ) and they were not almost detected at the end of fermentation. CONCLUSIONS: We revealed that the microbial community of beer during fermentation and maturation is very diverse and several bacteria possibly survive during fermentation. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, we revealed the detailed microbial communities of beer using next-generation sequencing. Some of the micro-organisms detected in this study were found in beer brewing process for the first time. Additionally, the possibility of growth of several bacteria at the early and middle stage of fermentation was suggested.

Cardiac involvements in myasthenia gravis associated with anti-Kv1.4 antibodies.

BACKGROUND AND PURPOSE: There is no general consensus as to whether autoimmune myasthenia gravis (MG) is associated with heart diseases, despite the fact that myocarditis, a serious cardiac involvement treatable by immunotherapy, is a complication of MG. It has been observed previously that MG patients with clinically suspected myocarditis had anti-Kv1.4 antibodies. The purpose of this study was to disclose the association between anti-Kv1.4 antibodies and cardiac involvements in MG patients. METHODS: Anti-Kv1.4 antibody was detected by an immunoprecipitation assay using (35) S-labeled rhabdomyosarcome cellular extract as the antigen source. Cardiac findings including electrocardiography (ECG) and clinical features of clinically suspected myocarditis in MG patients with anti-Kv1.4 antibodies were investigated. Ultrasound echocardiography (UCG) of ex vivo chick embryos was performed to determine the suppressive effects of sera with or without anti-Kv1.4 antibodies on heart muscle functions. RESULTS: Seventy (10.8%) of 650 MG patients had anti-Kv1.4 antibodies and 60% of them had abnormal ECG findings with high frequencies of T-wave abnormality and QT prolongation. Clinically suspected myocarditis was found in eight MG patients with anti-Kv1.4 antibodies but in none of the MG patients without anti-Kv1.4 antibodies. Most patients showed rapid deterioration with lethal arrhythmias such as ventricular tachycardia, sick sinus syndrome, or complete atrial ventricular block and severe heart failure. It was concluded using UCG of ex vivo chick embryos that MG serum with anti-Kv1.4 antibodies suppressed heart muscle functions. CONCLUSION: It has been demonstrated that anti-Kv1.4 antibodies are possible markers for cardiac involvements in MG patients.

Is there any circadian variation consequence on acute case fatality of stroke? Takashima Stroke Registry, Japan (1990-2003).

BACKGROUND: Circadian periodicity in the onset of stroke has been reported. However, it is unclear whether this variation affects the acute stroke case fatality. Time of the day variation in stroke case fatality was examined using population-based stroke registration data. METHODS: Stroke event data were acquired from the Takashima Stroke Registry, which covers a stable population of approximately 55,000 in Takashima County in central Japan. During the period of 1990-2003, there were 1080 (549 men and 531 women) cases with classifiable stroke onset time. Stroke incidence was categorized as occurring at night (midnight-6 a.m.), morning (6 a.m.-noon), afternoon (noon-6 p.m.), and evening (6 p.m.-midnight). The 28-day case fatality rates and 95% confidence intervals (95% CI) were calculated by gender, age, and stroke subtype across the time blocks. After adjusting for gender, age at onset, and stroke severity at onset, the hazard ratios for fatal strokes in evening, night, and morning were calculated, with afternoon serving as the reference. RESULTS: For all strokes, the 28-day case fatality rate was 23.3% (95% CI:19.4-27.6) for morning onset, 16.9% (95% CI:13.1-21.6) for afternoon onset, 18.3% (95% CI:13.6-24.1) for evening onset, and 21.0% (95% CI:15.0-28.5) for the night onset stroke. The case fatality for strokes during the morning was higher than the case fatality for strokes during afternoon. This fatality risk excess for morning strokes persisted even after adjusting for age, gender, and stroke severity on onset in multivariate analysis. CONCLUSION: In the examination of circadian variation of stroke case fatality, 28-day case fatality rate tended to be higher for the morning strokes.

Relation of dietary and lifestyle traits to difference in serum leptin of Japanese in Japan and Hawaii: the INTERLIPID study.

BACKGROUND AND AIMS: Previously, we found significantly higher serum leptin in Japanese-Americans in Hawaii than Japanese in Japan. We investigated whether differences in dietary and other lifestyle factors explain higher serum leptin concentrations in Japanese living a Western lifestyle in Hawaii compared with Japanese in Japan. METHODS AND RESULTS: Serum leptin and nutrient intakes were examined by standardized methods in men and women ages 40-59 years from two population samples, one Japanese-American in Hawaii (88 men, 94 women), the other Japanese in central Japan (123 men, 111 women). Multiple linear regression models were used to assess role of dietary and other lifestyle traits in accounting for serum leptin difference between Hawaii and Japan. Mean leptin was significantly higher in Hawaii than Japan (7.2 ± 6.8 vs 3.7 ± 2.3 ng/ml in men, P < 0.0001; 12.8 ± 6.6 vs 8.5 ± 5.0 in women <0.0001). In men, higher BMI in Hawaii explained over 90% of the difference in serum leptin; in women, only 47%. In multiple linear regression analyses in women, further adjustment for physical activity and dietary factors--alcohol, dietary fiber, iron--produced a further reduction in the coefficient for the difference, total reduction 70.7%; P-value for the Hawaii-Japan difference became 0.126. CONCLUSION: The significantly higher mean leptin concentration in Hawaii than Japan may be attributable largely to differences in BMI. Differences in nutrient intake in the two samples were associated with only modest relationship to the leptin difference.

Expression of BMP-7 in human gastric cancer and its clinical significance.

BACKGROUND: Bone morphogenetic protein-7 (BMP-7) is a signalling molecule belonging to the transforming growth factor--superfamily. Recent studies have demonstrated the clinical impact of BMP-7 expression in various human cancers. However, there have been few reports detailing this in gastric cancer. METHODS: We immunohistochemically investigated the expression of BMP-7 in 233 gastric cancer patients to disclose the clinicopathological features of BMP-7-positive gastric cancer. RESULTS: Immunohistochemically, in human gastric cancer, BMP-7 expression was identified in cellular membranes but also in the cytoplasm of cancer cells. Bone morphogenetic protein-7-positive expression was found in 129 of 233 patients (55%). Bone morphogenetic protein-7 expression was correlated with tumour size, nodal involvement, lymphatic invasion, venous invasion and histology (P<0.05). Bone morphogenetic protein-7 expression was significantly correlated with patient postoperative outcome, especially in the undifferentiated group. Multivariate analysis revealed BMP-7 expression as one of the independent prognostic factors next to the depth of invasion and nodal involvement (P<0.01). CONCLUSIONS: From the data collected, it would be appropriate to conclude on the possible regulation of gastric cancer progression by autocrine or paracrine BMP-7 loops. We can use BMP-7 expression as one of the strong predictors of risk of tumour recurrence in gastric cancer.

Critical role of cytosolic phospholipase A2{alpha} in bronchial mucus hypersecretion in CFTR-deficient mice.

Cystic fibrosis (CF) is due to mutations in the CF transmembrane conductance regulator gene CFTR. CF is characterised by mucus dehydration, chronic bacterial infection and inflammation, and increased levels of cytosolic phospholipase A2α (cPLA2α) products in airways. We aimed to examine the role of cPLA2α in the modulation of mucus production and inflammation in CFTR-deficient mice and epithelial cells. Mucus production was assessed using histological analyses, immuno-histochemistry and MUC5AC ELISA. cPLA2α activation was measured using an enzymatic assay and lung inflammation determined by histological analyses and polymorphonuclear neutrophil counts in bronchoalveolar lavages. In lungs from Cftr(-/-) mice, lipopolysaccharide induced mucus overproduction and MUC5AC expression associated with an increased cPLA2α activity. Mucus overproduction was mimicked by instillation of the cPLA2α product arachidonic acid, and abolished by either a cPLA2α null mutation or pharmacological inhibition. An increased cPLA2α activity was observed in bronchial explants from CF patients. CFTR silencing induced cPLA2α activation and MUC5AC expression in bronchial human epithelial cells. This expression was enhanced by arachidonic acid and reduced by cPLA2α inhibition. However, inhibition of CFTR chloride transport function had no effect on MUC5AC expression. Reduction of CFTR expression increased cPLA2α activity. This led to an enhanced mucus production in airway epithelia independent of CFTR chloride transport function. cPLA2α represents a suitable new target for therapeutic intervention in CF.

Expression of uPAR mRNA in peripheral blood is a favourite marker for metastasis in gastric cancer cases.

Urokinase-type plasminogen activator receptor (uPAR) plays a central role in the plasminogen activation cascade and participates in extracellular matrix degradation, cell migration and invasion. We evaluated the expression level of uPAR mRNA and the presence of isolated tumour cells (ITCs) in bone marrow (BM) and peripheral blood (PB) in gastric cancer patients and clarified its clinical significance. We assessed specific uPAR mRNA expression by quantitative real-time reverse transcriptase- polymerase chain reaction (RT-PCR) in BM and PB in 846 gastric cancer patients as well as three epithelial cell markers, carcinoembryonic antigen (CEA), cytokeratin (CK)-19 and CK-7. The uPAR mRNA expression in bone marrow and peripheral blood expressed significantly higher than normal controls (P<0.0001). The uPAR mRNA in BM showed concordant expression with the depth of tumour invasion, distant metastasis, and the postoperative recurrence (P=0.015, 0.044 and 0.010, respectively); whereas in PB, we observed more intimate significant association between uPAR expression and clinicopathologic variables, such as depth of tumour invasion, the distant metastasis, the venous invasion and the clinical stage (P=0.009, 0.002, 0.039 and 0.008, respectively). In addition, the uPAR mRNA expression in PB was an independent prognostic factor for distant metastasis by multivariate analysis. We disclosed that it was possible to identify high-risk patients for distant metastasis by measuring uPAR mRNA especially in peripheral blood at the timing of operation in gastric cancer patients.

Morning surge in circadian periodicity of ischaemic stroke is independent of conventional risk factor status: findings from the Takashima Stroke Registry 1990-2003.

BACKGROUND: We examined the circadian periodicity of ischaemic stroke (IS) onset and its relationship with conventional risk factors using 14-year stroke registration data. METHODS: Ischaemic stroke event data were acquired from the Takashima Stroke Registry, which covers a stable population of approximately 55,000 in Takashima County in central Japan. During 1990-2003 there were 637 (353 men and 284 women) cases with classifiable onset time. IS incidence was categorized as occurring at night (midnight to 6 am), morning (6 am to noon), afternoon (noon to 6 pm), and evening (6 pm to midnight). The OR (with 95% CI) of having an IS in the morning, afternoon, and evening were calculated, with night serving as reference. RESULTS: There was significant diurnal variation in IS incidence (P < 0.001). The proportion of events was highest in the morning (40.7; 95% CI: 36.9-44.5), and lowest in the night (14.0; 95% CI: 11.5-16.9). In the morning an excess incidence of IS was observed in both genders, in subjects <65 years and > or =65 years, and in all IS subtypes. The morning excess of IS incidence was similar across seasons and days of the week. For all IS, morning excess was higher (odds ratio: 2.91; 95% CI: 2.29-3.70) compared to the night period. Similar trends persisted after adjusting for age, gender, and risk factors. CONCLUSION: In the examination of circadian variation of IS onset, a predominant morning peak independent of conventional risk factors was observed in a Japanese population with similar pattern across seasons of the year and days of the week.

EML4-ALK fusion transcript is not found in gastrointestinal and breast cancers.

Fusion genes have been identified as chromosomal rearrangements in certain cancers, such as leukaemia, lymphoma, and sarcoma. The EML4-ALK (EML4: echinoderm microtubule-associated-protein-like 4; ALK: anaplastic lymphoma kinase) fusion gene has been identified as an oncogene in non-small-cell lung cancer (NSCLC). This study examined the presence of this fusion transcript in gastrointestinal and breast cancers. We evaluated the expression of the EML4-ALK transcript in 104 lung cancer cases and in 645 gastrointestinal and breast cancer samples. Only one of the lung cancer samples tested positive for the EML4-ALK fusion transcript, whereas none were detected in 555 gastrointestinal and 90 breast cancer cases. Our data suggest that the EML4-ALK fusion transcript is not present in gastrointestinal or breast cancers and is specific to NSCLC.

A rescue factor for Alzheimer's diseases: discovery, activity, structure, and mechanism.

Alzheimer's disease (AD) is a complex disease, involving multiple factors such as the production of aggregation-prone amyloid beta (Abeta) peptides, the formation of fibrillarly tangles of microtubule-associating proteins, Tau, and the polymorphism of cholesterol binding protein, APOE4. While understanding the mechanism of AD and the involvement of key players should lead to rational drug discovery against this disease, a traditional screening approach should also work for identifying drugs using AD models. We have used a cellular AD model, in which a cell death was induced by AD-causing neurotoxicities, and then screened the genes, which rescued the cells from the cell death. This resulted in isolation of a gene encoding a novel 24-amino acid long peptide, termed Humanin (HN), which protected neuronal cells at approximately microM level. Surprisingly, these gene products and the synthetic peptides not only protected neurons from cell death induced by Abeta-related neurotoxicities, but also Abeta-unrelated neurotoxicities. While a broad range of activities of HN against AD-related insults is discovered, the detailed mechanism of its action is still obscure. Structure analysis of HN showed that it is largely disordered and flexible at low peptide concentrations and heavily aggregates at high concentrations. Interestingly, one of the HN analogs, which is 10000-times more active than the parent HN molecule (i.e. active below nM range), was found to be monomeric. Based on findings of structural analyses, we propose here that membrane environment may enable HN to achieve high affinity for target protein(s) with multiple-transmembrane domains, such as G-protein coupled receptors.

FK506-protective effects against trimethyltin neurotoxicity in rats: hippocampal expression analyses reveal the involvement of periarterial osteopontin.

There is little information on the molecular mechanisms in FK506-mediated neuroprotection. In the present study, we investigated the protective effect of FK506, an immunosuppressant and neuroprotectant, on trimethyltin (TMT)-induced neurotoxicity in the rat hippocampus. Histologically, TMT-induced neuronal damage was partially prevented by FK506 in the hippocampal CA1 region, but not in CA3. FK506 treatment significantly reduced the number of apoptotic cells in CA1, but not in CA3, and also prevented induction of cognitive deficits by TMT. Microarray analysis of the rat hippocampus detected 14 genes with TMT-induced alteration of mRNA expression that was rescued by FK506 treatment. Subsequent quantitative RT-PCR analysis confirmed elevated mRNA levels for four inflammatory genes, glutathione S-transferase, lysozyme, matrix Gla protein, and osteopontin after TMT treatment. Upregulation of these genes was reversed by FK506 treatment at 5 days postgavage. Immunohistochemistry revealed that FK506 reduced osteopontin (OPN) induction by TMT in the periarterial area at 5 days postgavage. Our data suggest that inflammatory gene expression is involved in TMT-induced damage to the hippocampal CA1 region, resulting in apoptosis, and that this process is initiated by periarterial OPN activation, and can be alleviated by FK506.

Paired stimulation study of the median nerve sensory action potential in diabetic patients.

OBJECTIVES: Conventional nerve conduction studies (NCS) are not sensitive to detect mild diabetic neuropathy. In order to detect subtle changes, we compared the conventional NCS with the relative refractory period (RRP) measurement of the median sensory nerve action potential by a paired stimulation method. METHODS: Subjects were 29 diabetic patients whose conventional NCS were all normal. They were divided into two groups: neurologically symptomatic and asymptomatic groups. Twenty-eight age-matched control subjects were also studied. RESULTS: The RRP of the symptomatic diabetic patients (5.9 +/- 0.5 ms) and that of the asymptomatic patients (5.6 +/- 0.5 ms) was significantly longer than that of the control subjects (4.9 +/- 0.6 ms). There was no significant difference in RRP between the symptomatic and asymptomatic patients. This may be due to the fact that NCS reflects mainly large myelinated fiber function and early symptoms represent mainly thin myelinated or unmyelinated fiber function. CONCLUSIONS: The RRP measurement could reveal some mild involvement of peripheral nerves undetectable by conventional NCS, even though they caused no clinical symptoms.

Common T cell receptor clonotype in lacrimal glands and labial salivary glands from patients with Sjögren's syndrome.

Sjogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration into lacrimal and salivary glands leading to symptomatic dry eyes and mouth. Immunohistological studies have clarified that the majority of infiltrating lymphocytes around the lacrimal glands and labial salivary glands are CD4 positive alphabeta T cells. To analyze the pathogenesis of T cells infiltrating into lacrimal and labial salivary glands, we examined T cell clonotype of these cells in both glands from four SS patients using PCR-single-strand conformation polymorphism (SSCP) and a sequencing method. SSCP analysis showed that some infiltrating T cells in both glands expand clonally, suggesting that the cells proliferate by antigen-driven stimulation. Intriguingly, six to sixteen identical T cell receptor (TCR) Vbeta genes were commonly found in lacrimal glands and labial salivary glands from individual patients. This indicates that some T cells infiltrating into both glands recognize the shared epitopes on autoantigens. Moreover, highly conserved amino acid sequence motifs were found in the TCR CDR3 region bearing the same TCR Vbeta family gene from four SS patients, supporting the notion that the shared epitopes on antigens are limited. In conclusion, these findings suggest that some autoreactive T cells infiltrating into the lips and eyes recognized restricted epitopes of a common autoantigen in patients with SS.

Biotechnology applications of amino acids in protein purification and formulations.

Amino acids are widely used in biotechnology applications. Since amino acids are natural compounds, they can be safely used in pharmaceutical applications, e.g., as a solvent additive for protein purification and as an excipient for protein formulations. At high concentrations, certain amino acids are found to raise intra-cellular osmotic pressure and adjust to the high salt concentrations of the surrounding medium. They are called "compatible solutes", since they do not affect macromolecular function. Not only are they needed to increase the osmotic pressure, they are known to increase the stability of the proteins. Sucrose, glycerol and certain amino acids were used to enhance the stability of unstable proteins after isolation from natural environments. The mechanism of the action of these protein-stabilizing amino acids is relatively well understood. On the contrary, arginine was accidentally discovered as a useful reagent for assisting in the refolding of recombinant proteins. This effect of arginine was ascribed to its ability to suppress aggregation of the proteins during refolding, thereby increasing refolding efficiency. By the same mechanism, arginine now finds much wider applications than previously anticipated in the research and development of proteins, in particular in pharmaceutical applications. For example, arginine solubilizes proteins from loose inclusion bodies, resulting in efficient production of active proteins. Arginine suppresses protein-protein interactions in solution and also non-specific adsorption to gel permeation chromatography columns. Arginine facilitates elution of bound proteins from various column resins, including Protein-A or dye affinity columns and hydrophobic interaction columns. This review covers various biotechnology applications of amino acids, in particular arginine.

Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin-mediated mitochondrial clearance.

High CD44 expression is associated with enhanced malignant potential in esophageal squamous cell carcinoma (ESCC), among the deadliest of all human carcinomas. Although alterations in autophagy and CD44 expression are associated with poor patient outcomes in various cancer types, the relationship between autophagy and cells with high CD44 expression remains incompletely understood. In transformed oesophageal keratinocytes, CD44Low-CD24High (CD44L) cells give rise to CD44High-CD24-/Low (CD44H) cells via epithelial-mesenchymal transition (EMT) in response to transforming growth factor (TGF)-ß. We couple patient samples and xenotransplantation studies with this tractable in vitro system of CD44L to CD44H cell conversion to investigate the functional role of autophagy in generation of cells with high CD44 expression. We report that high expression of the autophagy marker cleaved LC3 expression correlates with poor clinical outcome in ESCC. In ESCC xenograft tumours, pharmacological autophagy inhibition with chloroquine derivatives depletes cells with high CD44 expression while promoting oxidative stress. Autophagic flux impairment during EMT-mediated CD44L to CD44H cell conversion in vitro induces mitochondrial dysfunction, oxidative stress and cell death. During CD44H cell generation, transformed keratinocytes display evidence of mitophagy, including mitochondrial fragmentation, decreased mitochondrial content and mitochondrial translocation of Parkin, essential in mitophagy. RNA interference-mediated Parkin depletion attenuates CD44H cell generation. These data suggest that autophagy facilitates EMT-mediated CD44H generation via modulation of redox homeostasis and Parkin-dependent mitochondrial clearance. This is the first report to implicate mitophagy in regulation of tumour cells with high CD44 expression, representing a potential novel therapeutic avenue in cancers where EMT and CD44H cells have been implicated, including ESCC.

Are comprehensive environmental changes as effective as health education for smoking cessation?

OBJECTIVES: To compare the effectiveness of health education on smoking cessation for all smokers regardless of their willingness to quit smoking and cumulative environmental changes including designation of smoking places, legislation, and price rise. DESIGN: Comparison of smoking cessation rates over two time periods: the period of health education on smoking cessation (1997-1999), and the period of cumulative environmental changes (2002-2004). SETTING: An occupational setting in a radiator manufacturing factory in Japan. SUBJECTS: All habitual male smokers who remained in the worksite through the pertinent time period (n = 202 in the period of health education and n = 170 in the period of environmental changes). MAIN OUTCOME MEASUREMENTS: Smoking cessation rates at the end of each time period. RESULTS: The smoking cessation rates over the periods of health education and environmental changes were 8.9% and 7.1%, respectively. There was no difference between these two proportions in a chi2 test (p = 0.513). The age adjustment did not significantly alter the cessation rate. CONCLUSIONS: Cumulative environmental changes are fairly effective in promoting smoking cessation, and may yield similar smoking cessation rates as a health education intervention reaching all smokers regardless of their willingness to quit smoking.

Alterations of repeated sequences in 5' upstream and coding regions in colorectal tumors from patients with hereditary nonpolyposis colorectal cancer and Turcot syndrome.

One of the characteristics of tumors from patients with germline mutations of DNA mismatch repair genes is instability at microsatellite regions (MSI). We analysed alterations at repeated sequences of coding regions, as well as those of 5' upstream regions, in 29 MSI-High colorectal tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) and Turcot syndrome. We found that repeated sequences in 5' upstream regions were altered in these tumors, at considerable frequencies. The (A)10 repeat in the promoter region (position -178 to approximately -169) of the GAPDH gene was altered in 17% of the tumors. The (A)10(TA)9 in the 5' upstream region (position -318 to approximately -291) of the mitochondrial isoleucyl tRNA synthetase gene (IleRS-A), coded in nuclear DNA, was altered in 59% of the tumors, whereas (A)9 in the 5' upstream region (position -859 to approximately -851) of cytoplasmic isoleucyl tRNA synthetase gene (IleRS-B) was not altered. Alteration at repeated sequences in the coding regions were 72% at TGFbetaRII(A)10, 24% at IGFIIR(G)8, 45% at BAX(G)8, 55% at E2F4(CAG)13, 66% at caspase-5 (A)10, 31% at MBD4(A)10, 55% at hMSH3(A)8 and 34% at hMSH6(C)8. The number of altered genes increased with the advancement of carcinoma according to Dukes categories: mean numbers of altered genes within these 10 genes were 2.6 for Dukes A, 4.7 for Dukes B and 7.8 for Dukes C. The mean number for adenomas was 2.0. These results suggest that the MSI phenotype also causes alteration of 5' upstream regions which may affect apoptosis and some mitochondrial functions in HNPCC and Turcot tumors, and that accumulation of altered genes with repeated sequences is associated with the progression of HNPCC and Turcot colorectal tumors.

Insulin-like growth factor I (IGF-I) protects cells from apoptosis by Alzheimer's V642I mutant amyloid precursor protein through IGF-I receptor in an IGF-binding protein-sensitive manner.

It has been found that insulin-like growth factor I (IGF-I) exerts cytoprotection against Abeta amyloid-induced neuronal cell death. Deposits of Abeta amyloid are one of the pathological hallmarks of Alzheimer's disease (AD). Here, we examined whether IGF-I exerts protective activity against cell death induced by a familial AD (FAD)-linked mutant of amyloid precursor protein (APP), and we found that IGF-I protected cells from toxicity of FAD-associated V642I mutant of APP in multiple cell systems. IGFBP-3 blocked this action of IGF-I, but not of des(1-3)IGF-I, which was as active as IGF-I in the presence of IGFBP-3. The data also demonstrated that the IGF-I receptor (IGF-IR) mediates the protective activity of IGF-I. The antagonizing function of the IGF-I/IGF-IR system against V642I-APP, which is further antagonized by IGFBP-3, provides a molecular clue to the understanding of AD pathophysiology and to the establishment of potential therapy for AD.