Mutation analysis of components of the Mediator kinase module in MED12 mutation-negative uterine leiomyomas.

BACKGROUND: Kinase module of Mediator complex ('CDK8 submodule') consists of four subunits: CDK8, Cyclin C, MED12, and MED13. Recently, we reported recurrent MED12 mutations in 70% of uterine leiomyomas. The aim of this study was to analyse whether mutations in other components of the module contribute to the development of these lesions. METHODS: Mutation screening of altogether 70 MED12 mutation-negative uterine leiomyomas was carried out by direct sequencing. RESULTS: None of the tumours displayed somatic mutations in the coding regions of CDK8/CDK19, CCNC, or MED13. CONCLUSIONS: Mutations in CDK8/CDK19, CCNC, and MED13 do not frequently contribute to genesis of uterine leiomyomas.

Somatic MED12 mutations in uterine leiomyosarcoma and colorectal cancer.

BACKGROUND: Mediator complex participates in transcriptional regulation by connecting regulatory DNA sequences to the RNA polymerase II initiation complex. Recently, we discovered through exome sequencing that as many as 70% of uterine leiomyomas harbour specific mutations in exon 2 of mediator complex subunit 12 (MED12). In this work, we examined the role of MED12 exon 2 mutations in other tumour types. METHODS: The frequency of MED12 exon 2 mutations was analysed in altogether 1158 tumours by direct sequencing. The tumour spectrum included mesenchymal tumours (extrauterine leiomyomas, endometrial polyps, lipomas, uterine leiomyosarcomas, other sarcomas, gastro-intestinal stromal tumours), hormone-dependent tumours (breast and ovarian cancers), haematological malignancies (acute myeloid leukaemias, acute lymphoid leukaemias, myeloproliferative neoplasms), and tumours associated with abnormal Wnt-signalling (colorectal cancers (CRC)). RESULTS: Five somatic alterations were observed: three in uterine leiomyosarcomas (3/41, 7%; Gly44Ser, Ala38_Leu39ins7, Glu35_Leu36delinsVal), and two in CRC (2/392, 0.5%; Gly44Cys, Ala67Val). CONCLUSION: Somatic MED12 exon 2 mutations were observed in uterine leiomyosarcomas, suggesting that a subgroup of these malignant tumours may develop from a leiomyoma precursor. Mutations in CRC samples indicate that MED12 may, albeit rarely, contribute to CRC tumorigenesis.

Is the evaluation of the global quality of life determined by emotional status?

The present study investigated relationships between global QOL perceptions and well-being dimensions. Especially our goal was to evaluate the impact of generally recognised four broad dimensions of QOL (physical, functional, social and emotional well-being) on global QOL perceptions, additionally person's satisfaction with life achievements and economical situation were measured as well as social demographic variables. The subjects were a representative sample of Finns (n = 4613, from 25 to 65 years) of the FINRISK-97 study. Correlation coefficients and models of hierarchical regression indicated that physical, functional and social well-being as well as sociodemographic factors and satisfaction with life achievements are important factors of global QOL perceptions both among males and females. However percentages of variances explained with these measures were only moderately high, ranging from 1 to 10%. After measures of emotional well-being were entered into the models of hierarchical analyses of regression, variances explained grew dramatically over 20%. The results of the study indicated that global QOL judgements are likely to be based on current emotional state.

Usefulness of repeated presentation of Mini-Mental State Examination as a diagnostic procedure--a population-based study.

MATERIAL AND METHODS: The 280 subjects who achieved 24 points or less in the Mini-Mental State Examination (MMSE) in the first survey of 1449 subjects were invited for a comprehensive diagnostic examination for dementia including medical history, thorough neurological and cardiovascular examinations and detailed neuropsychological evaluation, magnetic resonance imaging (MRI)-study, cerebrospinal fluid (CSF)-analysis, electrocardiogram (ECG), chest radiograph and blood tests after the first assessment. The MMSE was presented again. RESULTS: Out of 240 persons, 57 subjects were diagnosed as having dementia. When the cut-off point of 24 or less in the second MMSE was used, the sensitivity of the second MMSE was 82% and the specificity was 64%. The positive predictive value of the second MMSE was 42% and negative predictive value 92%. The non-demented subjects improved their MMSE score at the second examination. In contrast, the demented subjects maintained their low MMSE score at the second examination.

Midlife income, occupation, APOE status, and dementia: a population-based study.

OBJECTIVE: To examine the relationship between socioeconomic factors and APOE carrier status on the development of dementia. METHODS: Subjects were derived from random, population-based samples previously studied in surveys carried out in 1972, 1977, 1982, and 1987. After an average follow-up of 21 years, 1449 (73%) subjects aged 65 to 79 years were re-examined in 1998. The diagnosis of dementia among the nonparticipants was derived from patient records of the local hospitals and primary health care clinics. RESULTS: Low income level at old age was related to dementia, but low income level at midlife was not a risk factor for dementia. Dementia was also associated with decreasing income level, from midlife to old age 21 years later, when dementia was diagnosed. A sedentary occupation (office, service, or intellectual work) was associated with a decreased risk for dementia among participants; however, when the nonparticipants were included in the analysis, the associations were no longer significant. Low educational level and the APOE epsilon4 allele independently increased the risk for dementia. CONCLUSIONS: Reduction in income level during follow-up and low income level at old age might be the consequence of a dementing process rather than being associated with risk evolution of dementia.

Gender-associated differences in the quality of life after allogeneic BMT.

The purpose of this study was to compare the quality of life (QOL) of male and female allogeneic BMT recipients. One hundred and nine BMT patients participated in this cross-sectional survey and completed the following instruments: Functional Assessment of Cancer Treatment (FACT-BMT version 3), shortened version of Profile of Mood States (POMS), MOS Survey of Social Support, and A Brief Measure of Social Support (SSQ6). Independent of the time post-BMT, perceived physical well-being, age at BMT, and education, females reported worse emotional well-being and more fatigue than males. Females also indicated more tiredness and less quality sleep. Males were found to experience less satisfaction with social support regardless of marital status. On the other hand, married males were more satisfied with their sexual life, more interested in sexual relationships, and more sexually active compared to married females. However, no significant differences between males and females were found in terms of overall physical, functional, and social well-being assessed by the FACT-BMT. The present results indicated that important gender differences exist among allogeneic BMT recipients which need to be addressed when designing post-treatment intervention programs for BMT recipients.

The N-methyl-D-aspartate antagonist memantine has no neuroprotective effect during hypothermic circulatory arrest: a study in the chronic porcine model.

BACKGROUND: Glutamate excitotoxicity has an important role in the development of brain injury after prolonged hypothermic circulatory arrest. The goal of the present study was to determine the potential efficacy of memantine, an N -methyl-D -aspartate receptor antagonist, to mitigate cerebral injury after hypothermic circulatory arrest. METHODS: Twenty pigs (23-33 kg) were randomly assigned to receive memantine (5 mg/kg) or placebo in a blinded fashion before a 75-minute period of hypothermic circulatory arrest at 20 degrees C. Hemodynamic, electroencephalographic, and metabolic monitoring were carried out. The intracerebral concentrations of glucose, lactate, glutamate, and glycerol were measured by means of enzymatic methods on a microdialysis analyzer. Daily behavioral assessment was performed until the animals died or were put to death on day 7. Histologic analysis of the brain was carried out in all animals. RESULTS: In the memantine group, 5 of 10 animals survived 7 days compared with 9 of 10 in the placebo group. The median behavioral score at day 7 was 3.5 in the memantine group and 7.5 in the placebo group (P >.2). Among the surviving animals, medians were 9.0 and 8.0 on day 7 (P >.2), respectively. The medians of recovered electroencephalographic bursts were equal in both groups. The median of total histopathologic score was 16 in the memantine group and 14 in the placebo group (P >.2). There was a negative correlation between glutamate levels and electroencephalographic burst recovery (tau = -0.377, P =.043). A positive correlation was found between the highest individual glutamate value and histopathologic score (tau = 0.336, P =.045). CONCLUSIONS: The present study demonstrates that memantine has no neuroprotective effect after hypothermic circulatory arrest in the pig. In addition, we have shown the accuracy of cerebral glutamate measurements to predict histopathologic injury after hypothermic ischemia.

Quality of life and factors related to perceived satisfaction with quality of life after allogeneic bone marrow transplantation.

The quality of life after bone marrow transplantation (BMT) was studied in 109 adult allogeneic BMT recipients transplanted on at the Helsinki University Central hospital for a haematological malignancy. Physical, functional, emotional and social well-being was measured on the Functional Assessment of Cancer Therapy Scale (FACT-BMT) and a shortened version of the Profile of Mood States Scale (POMS) and by the MOS social support survey and a Brief Measure of Social Support (SSQ6). The results of the present study replicate those of previous investigations by finding that physical well-being, educational level, age at BMT and social support have an impact on the perceived quality of life of BMT patients. Our results indicate that these factors have a varying impact at different time points during the post-BMT recovery process. During the first three years after BMT, physical well-being proved to be a highly significant (P < 0.001) factor for perceived life satisfaction. Moreover, physical well-being showed an average significant improvement after the first post-BMT year. The percentage of the recipients experiencing the highest levels of satisfaction with life increased from 51% during the first year after BMT to 81% for those patients five years post-BMT. One year after BMT, 75.6% of the BMT recipients were able to work, 67.8% of the patients were actively participating in work/school and 7.8% were unemployed.

Diamond coated total hip replacements.

Diamond has many superior, desired characteristics of implant materials such as low friction, high wear and corrosion resistance, and well bonding surface to bone. The potential of diamond for total hip replacement implants was studied in the form of amorphous diamond coatings on conventional metal implant materials. Amorphous diamond coatings (sp3 bonding fraction 80%, thickness 0.2 to 10 microns) were deposited on stainless steel AISI316L, Ti6A14V, and CoCrMo alloys using filtered pulsed plasma are discharge method. Superior attachment of coatings to the implant materials was achieved by using high energy plasma beams to deposit amorphous diamond and proper intermediate layers. Previously it was shown that these coatings are biocompatible causing no local tissue reactions. Tribologic studies using a pin on disk apparatus with coated or uncoated implant materials in 1 wt.% NaCl distilled water were performed. A simplified hip joint simulator was used for preliminary testing of metal on polyethylene and metal on metal artificial hip joints modified with amorphous diamond coating. The average coefficients of friction were typically in the range of 0.03 to 0.11 for amorphous diamond coated materials. In the case of metal on metal hip implants, the average friction during initial running in period was improved (coefficient of friction = 0.07) compared with the same metal on metal pair (coefficient of friction = 0.22) and sliding was significantly smoother. In pin on disk wear tests, the average wear factors obtained were 140.10(-6), 5.0.10(-6), and << 0.1.10(-6) mm3/Nm for the pairs of AISI316L, CoCrMo, and the same materials with amorphous diamond coating. The corrosion rates of these implant materials in 10 wt.% HCl solution were decreased by a factor of 10,000 to 15,000 and any damage of the coatings was not observed in 6 months. The results of the tests show that in all the combinations studied, amorphous diamond coating improved definitely the wear and corrosion resistance compared with the uncoated materials.