The Effects of Chronic Ethanol Consumption on Carcinogen Metabolism and on O6-Methylguanine Transferase-Mediated Repair of Alkylated DNA

This article presents a review and update of recent experiments conducted in collaboration with Dr. C. S. Lieber on mechanisms underlying the increased cancer risk associated with alcohol abuse. Ethanol has been found to be a potent inducer of microsomal enzymes involved in carcinogen metabolism in a variety of rat tissues including liver, esophagus, lungs, and intestines. In some of these tissues, ethanol's inductive effect on microsomal cytochrome P-450 enzyme activity may result in enhanced levels of electrophilic metabolites of procarcinogens which are not readily detoxified. In addition, chronic ethanol feeding has been found to depress the activity of O⁶-methylguanine transferase, an enzyme involved in the repair of carcinogen-induced DNA alkylation. The effects of ethanol on carcinogen metabolism and on DNA repair would be expected to enhance the initiation phase of chemically induced cancers.     

Isometric handgrip training improves local flow-mediated dilation in medicated hypertensives

Increased HSP expression in response to acute exercise is well documented in animal studies, and there is growing evidence that similar responses occur in man. In general, many human exercise studies have investigated the HSP response to low force continuous activity, while the knowledge about the HSP response to high force intermittent type of activity, like weight training, is so far sparse. In addition, most studies have used untrained subjects, and a common observation is that acute low force continuous activity in untrained individuals increases the HSP expression in these individuals. The main scope of this study was to investigate the HSP response in very well trained males subjected to longitudinal high intensity exercise, and if this response was dependent on exercise modality [i.e. eccentric (ECC) or concentric (CON) contractions]. Very well trained males performed progressive strength training consisting of either high force ECC or high force CON elbow flexions 2–3 times a week for 12 weeks. Compared with pre-exercise levels, HSP72 expression decreased by 46.1% (P<0.05) after CON contractions. GRP75 expression was unchanged after ECC or CON contractions, while ubiquitin expression decreased by 19.9% (P<0.02) after ECC contractions. These findings imply that chronic, intensive exercise may attenuate the HSP response in well-trained males.     

An Efficient Method of Identifying Major Depression and Panic Disorder in Primary Care

The research literature is replete with evidence of and concerns about the prevalence and undertreatment of mental disorders in primary care. Although screening, on its own, may not directly affect clinical outcomes, it is still the most efficient and effective way to identify psychologically distressed patients for either research purposes or to provide patients with or refer patients to appropriate care. The current study sought to establish the utility of the MHI-5 for the detection of patients suffering from major depression or panic disorder, two of the most common psychiatric conditions seen in primary care settings. This study was conducted in a family medicine clinic and 246 adult outpatients participated. Patients completed the Mental Health Index-5 (MHI-5) as the screening measure and the PRIME-MD Patient Health Questionnaire (PHQ) as the diagnostic instrument. ROC analyses indicated that a cut-off score of 23 on the MHI-5 yielded a sensitivity of 91% and a specificity of 58% for predicting provisional diagnoses of major depression or panic disorder from the PHQ. Using a single item to screen for a PHQ diagnosis of major depression yielded a sensitivity of 88% and a specificity of 62% and a second question had a sensitivity of 100% and specificity of 63% for PHQ diagnosis of panic disorder. These results indicate that it is possible to use a small number of items to efficiently and effectively screen for mental disorders affecting a significant portion of primary care patients.     

Knowledge, attitudes and beliefs of women about the importance of prostate cancer screening

OBJECTIVES: To understand women's knowledge, attitudes and beliefs about prostate cancer. METHODS: A survey was self-administered to 324 women age >18 years. It contained 42 questions that assessed women's knowledge about prostate cancer, possible risk factors, and opinions regarding screening and early detection. Women were grouped as married or unmarried for convenient comparisons. Chi-squared and F statistics were performed. RESULTS: Ninety-seven percent of married women reported having some influence over the healthcare decisions of their spouse. Married women's worst fear about their spouse or family member's diagnosis of prostate cancer was death. The most important benefit of prostate cancer screening was the possibility of cure, while the main hindrance was fear of the digital rectal exam. Marital status, age, educational level and income were all significantly associated with women's knowledge about prostate cancer (p<0.001). CONCLUSIONS: Women play an important role in health-related matters in the home. Educating women on prostate cancer may improve early detection efforts and reduce the devastating impact of this disease on their family.     

In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS/RAF/MEK/ERK/MAP-kinase pathway. Activating mutations in BRAF have recently been identified in melanomas, colorectal cancers, and thyroid and ovarian tumours. In the present study, an extensive characterization of BRAF and KRAS mutations has been performed in 264 epithelial and non-epithelial ovarian neoplasms. The epithelial tumours ranged from adenomas and borderline neoplasms to invasive carcinomas including serous, mucinous, clear cell, and endometrioid lesions. It is shown that BRAF mutations in ovarian tumours occur exclusively in low-grade serous neoplasms (33 of 91, 36%); these included serous borderline tumours (typical and micropapillary variants), an invasive micropapillary carcinoma and a psammocarcinoma. KRAS mutations were identified in 26 of 91 (29.5%) low-grade serous tumours, 7 of 49 (12%) high-grade serous carcinomas, 2 of 6 mucinous adenomas, 22 of 28 mucinous borderline tumours, and 10 of 18 mucinous carcinomas. Of note, two serous borderline tumours were found to harbour both BRAF and KRAS mutations. The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK-MAP-kinase pathway (BRAF 36%, KRAS 30%) compared with 12% of high-grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serous borderline tumours do not progress to serous carcinomas. Furthermore, no BRAF mutations were detected in the other 173 ovarian tumours in this study.     

Attachment, personality, and psychopathology among adult inpatients: self-reported romantic attachment style versus Adult Attachment Interview states of mind

The present study examined self-reported romantic attachment style and Adult Attachment Interview (AAI) states of mind regarding early attachment relationships, personality dimensions, and psychopathology in a psychiatric sample of trauma survivors. Inpatients (N = 80) admitted to a hospital trauma treatment program were administered the Experiences in Close Relationships Scale, AAI, Millon Clinical Multiaxial Inventory-III, Dissociative Experiences Scale, and Dissociative Disorder Interview Schedule. Self-report and AAI attachment classifications were not related, and different results emerged for the two measures. Self-reported romantic attachment style was significantly associated with personality dimensions, with fearful adults showing the most maladaptive personality profiles. Findings suggested that self-report dimensions of self and other independently contribute to different forms of psychological dysfunction. AAI unresolved trauma was uniquely associated with dissociation and posttraumatic stress disorder, whereas unresolved trauma and unresolved loss jointly contributed to schizotypal and borderline personality disorder scores. The differences in findings between the two measures are discussed with a view toward the developmental and clinical implications.     

Role of lipid rafts and flagellin in invasion of colonic epithelial cells by Shiga-toxigenic Escherichia coli O113:H21

Shiga-toxigenic Escherichia coli (STEC) O113:H21 strains that lack the locus of enterocyte effacement (LEE) efficiently invade eukaryotic cells in vitro, unlike LEE-positive O157:H7 strains. We used a fliC deletion mutant of the O113:H21 STEC strain 98NK2 (98NK2ΔfliC) to show that invasion of colonic epithelial (HCT-8) cells is heavily dependent on production of flagellin, even though adherence to the cells was actually enhanced in the mutant. Flagellin binds and signals through Toll-like receptor 5 (TLR5), but there was no evidence that either TLR5, the adaptor protein myeloid differentiation primary response gene 88 (MyD88), or the serine kinase interleukin-1 receptor-associated kinase (IRAK) were required for invasion of HCT-8 cells by strain 98NK2, as judged by transfection, RNA knockdown, or inhibitor studies. However, pretreatment of cells with anti-asialo-GM1 significantly decreased 98NK2 invasion (by 40.8%), while neuraminidase treatment (which cleaves terminal sialic acid residues, thus converting GM1 into asialo-GM1) significantly increased invasion (by 70.7%). Pretreatment of HCT-8 cells with either the cholesterol-depleting agent methyl-β-cyclodextrin (MβCD) or the tyrosine kinase inhibitor genistein significantly decreased invasion by 98NK2, indicating a potential role for lipid rafts in the invasion mechanism. Confocal microscopy also showed invading 98NK2 colocalized with lipid raft markers caveolin-1 and GM1. Interestingly, anti-asialo-GM1, neuraminidase, MβCD, and genistein have similar effects on the vestigial level of STEC invasion seen for STEC strain 98NK2ΔfliC, indicating that lipid rafts mediate a common step in flagellin-dependent and flagellin-independent cellular invasion.     

Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 (alpha 12 satellite sequences) signals in atypical lipomatous tumor

This study assessed whether analysis of MDM2 copy number by fluorescence in situ hybridization (FISH) would help distinguish lipomas from atypical lipomatous tumors, otherwise referred to as well-differentiated liposarcomas, using a commercially available MDM2 FISH kit. 227 lipomatous and 201 non-lipomatous tumors were analyzed to assess its sensitivity and specificity. Of 178 mature lipomatous tumors, 86 were classified histologically as lipoma and 92 as atypical lipomatous tumor. Two of the lipomas harboring MDM2 amplification were reclassified as atypical lipomatous tumors. Overall, 13 atypical lipomatous tumors did not reveal MDM2 or CDK4 amplification, although this was reduced to 12 following analysis of multiple slides. Three of these cases revealed very occasional tumor cells harboring high-level MDM2 amplification, two had a dedifferentiated component, and MDM2 amplification was detected when one tumor recurred. The remaining six cases exhibited reactive/inflammatory features and were reclassified as lipomas. The findings indicate that MDM2 amplification is 93.5% sensitive for diagnosing atypical lipomatous tumor. A total of 2 of the 20 dedifferentiated liposarcomas failed to reveal MDM2 amplification. All atypical lipomatous tumors measured >10?cm, two dedifferentiated liposarcoma presented de novo at <10?cm, and ～50% of lipomas measured >10?cm. Spindle cell lipomas, lipoblastomas, hibernomas and pleomorphic liposarcomas did not reveal MDM2 amplification. Of 201 non-lipomatous tumors, eight revealed MDM2 amplification or multiple faint alphoid 12 signals and were reclassified as dedifferentiated liposarcoma. Multiple faint alphoid 12 signals were observed in nine tumors from seven patients, an observation not previously reported on paraffin sections: these included four atypical lipomatous tumors, and three dedifferentiated liposarcomas, one previously diagnosed as a myxofibrosarcoma, all of which also revealed amplification of CDK4, although two lacked MDM2 amplification. MDM2 FISH test is a useful adjunct to histology for distinguishing lipoma from atypical lipomatous tumor. The limitations of molecular genetic tests must be known before introducing them into a clinical service.