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.     

Psychosocial correlates of alcohol intake among women aged 45 to 64 years: The Framingham Study

This study of 749 women, aged 45 to 64 years, investigates the psychological, behavioral, and social correlates of alcohol intake. These data from the Framingham Study are uniquely based on a community sample of women, which results in a normative study of drinking behavior in women. Two measures of alcohol intake were utilized in these analyses: (1) the frequency of alcohol intake over 1 week and (2) drinking vs abstaining from alcohol. Among this sample of women, increased socioeconomic status, worrying about aging, and being easily upset were positively associated with frequency of alcohol intake. The rigid attitude scale was the strongest discriminating variable for drinkers vs nondrinkers. Older women were more likely to be nondrinkers compared to younger women, however, among older women, being a homemaker was significantly associated with increased alcohol intake. Contrarily, younger women who were homemakers were more likely to be abstainers than women employed outside the home. As would be expected, cigarette smoking was associated with drinking alcohol.This research is dedicated in fond remembrance to our friend and colleague Joseph Stokes III, M.D.     

Brain regions and their dynamics in prospective memory retrieval: a MEG study.

We measured brain activity using magnetoencephalography in five participants during ongoing tasks that included prospective memory, retrospective memory, and oddball trials. Sources were identified in the hippocampal formation and posterior parietal and frontal lobes. Posterior parietal cortex activation had an earlier onset in the prospective memory condition than retrospective memory or oddball conditions, a higher level of theta activity in the retrospective condition, and higher levels of upper alpha in the prospective and oddball conditions. Activation of the hippocampal formation had a longer duration in the retrospective memory and prospective memory conditions than the oddball condition, but prominent alpha and theta band activity was present in all three conditions. We interpret the early (87 ms) onset of activity in parietal cortex as evidence for an initial noticing of appropriate conditions for a PM response. Hippocampal activity may reflect a subsequent memory search for the intended action.     

The distribution of mucosal lymphoid nodules in the equine respiratory tract

Mucosal lymphoid nodules were identified within the equine respiratory tract by an acetic acid fixation technique. Nodules were identified in foetuses from nine months gestational age, and estimates of total and regional nodule populations were made in foetal, neonatal and adult horses. Nodules occurred at specific sites within the tract, which probably relate to areas where inhaled antigens accumulate. The largest populations of nodules occurred in the nasopharynx and larynx, with smaller numbers in the nasal cavity, trachea and bronchi. There was an age-related change in the size of these nodule populations, with an increase in number from late gestation to the neonatal period to early adulthood (up to 5 years of age), followed by a decrease in older adults.     

Genes encoded in the major histocompatibility complex affecting the generation of peptides for TAP transport

The B cell line 721.174 has lost the ability to present intracellular antigens to major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTL). This phenotype results from a homozygous deletion in the MHC that includes the peptide transporter genes TAP1 and TAP2, and the proteasome subunits LMP2 and LMP7. Recent work has shown that such cells transfected with TAP genes load their class I molecules with endogenous peptides, and present several viral epitopes to class I-restricted CTL. These data implied that the LMP2 and LMP7 genes were not required for the presentation of most epitopes through class I molecules. By contrast, while confirming the previous reports, we have identified several epitopes that appear to require genes in the MHC in addition to the TAP for their presentation. Further analysis localizes the defect to proteolysis in the cytosol. In one case, presentation could be partially restored by re-expression of full-length LMP7. Control experiments with LMP7, from which the putative pro-region had been removed, failed to restore presentation, and this lack of effect correlated with failure of the shortened LMP7 to incorporate into the proteasome. These results suggest a role for LMP7 in the generation of a viral epitope, but leave open the possibility that additional genes within the .174 deletion are required for full restoration of antigen presentation.     

The role of prolactin and testosterone in mediating seasonal differences in the self-grooming behavior of male meadow voles, Microtus pennsylvanicus

Self-grooming in response to the odors of conspecifics is a form of olfactory communication among meadow voles. The amount of time meadow voles spend self-grooming when they encounter the odors of conspecifics varies seasonally, with males targeting the odors of reproductively active females only during the breeding season. Other odor related behaviors in male voles such as odor preferences for conspecifics and the attractiveness of their odors to conspecifics vary seasonally as well. For male meadow voles, these behaviors are mediated by seasonal variations in testosterone (T) and prolactin (PRL) titers. The objective of this study was to determine whether seasonal differences in the amount of time male meadow voles self-groom in response to odors of conspecifics are mediated by seasonal rhythms in their circulating T and PRL titers. We tested the hypothesis that high titers of both T and PRL are necessary for reproductively active (long-photoperiod; LP) males and sufficient for reproductively quiescent (short-photoperiod; SP) male voles to spend more time self-grooming in response to odors of LP females than to those of other conspecifics. Results of this study demonstrate that high titers of PRL and T are necessary for LP male meadow vole to self-groom more in response to odors of LP females as compared to those of other conspecifics, but were not sufficient to induce SP males to preferentially self-groom to odors of LP females. The endocrine control of self-grooming by LP males appears to depend upon high titers of both PRL and T, which matches the endocrine mediation of other odor related behaviors in male voles. In contrast, the endocrine tissues that underlie self-grooming in SP male meadow voles appear to be refractory to the effects of LP-equivalent titers of PRL and T.     

Identifying undiagnosed diabetes: cross-sectional survey of 3.6 million patients' electronic records.

BACKGROUND: Around 1% of the UK population has diabetes that is either undiagnosed or unrecorded on practice disease registers. AIM: To estimate the number of people in UK primary care databases with biochemical evidence of undiagnosed diabetes. To develop simple practice-based search techniques to support early recognition of diabetes. DESIGN OF STUDY: Cross-sectional survey of 3 630 296 electronic records. SETTING: Four hundred and eighty UK practices contributing to the QRESEARCH database. METHOD: Electronic searches to identify people with no diabetes diagnosis in one of two categories (A and B), using the most recently recorded blood glucose measurement: random blood glucose level >or=11.1 mmol/l or fasting blood glucose level >or=7.0 mmol/l (A); either a random or a fasting blood glucose level >or=7.0 mmol/l (B). An additional outcome measure was the proportion of the population with at least one blood glucose measurement in the record. RESULTS: The number (percentage) identified in category A was 3758 (0.10% of the total population); the number in category B was 32 785 (0.90%). Projected to a practice of 7000 patients, around eight patients have biochemical evidence of undiagnosed diabetes, and 68 have results suggesting the need for further follow-up. One-third of people aged over 40 years without diabetes have a blood glucose measurement in the past 2 years in their record. CONCLUSION: People with possible undiagnosed diabetes are readily identifiable in UK primary care databases through electronic searches using blood glucose data. People with borderline levels, who may benefit from interventions to reduce their risk of progression to diabetes, can also be identified using practice-based software.     

"Doctors' Dilemmas

Three British physicians briefly review the final programs in a BBC series, "Doctors' Dilemmas," each consisting of a case history followed by a discussion involving health professionals, administrators, and lawyers. Taylor, an occupational physician, comments on the episode in which a company doctor is asked by management to disclose confidential information about an employee. Psychiatrist Jerram discusses his reactions to the program presenting the dilemmas of treating a patient with anorexia nervosa against her will. Forsythe, a community physician, reviews the final episode, which dealt with resource allocation, the role of health professionals within the National Health Service, and the potential conflict between the NHS and private practice.     

Hyperuricemia as a risk factor of coronary heart disease: The Framingham Study

Uric acid values were obtained on subjects of the original Framingham cohort at their fourth and 13th biennial examinations. The mean uric acid value for men was 5.0 mg/dl at the fourth examination and 5.7 mg/dl at examination 13 and was 3.9 mg/dl and 4.7 mg/dl, respectively, for women. This secular trend was due to both "laboratory drift" and increasing use of diuretics. Serum uric acid values were consistently higher in subjects of both sexes who were taking antihypertensive drugs at both examinations. Serum uric acid values correlated with systolic and diastolic blood pressure in both sexes; the relationship was stronger in women than in men and for systolic than for diastolic pressure. Correlations were stronger at examination 4 than at examination 13 when more antihypertensive treatment was used. Examination 4 serum uric acid predicted the subsequent development of coronary heart disease, in general, and myocardial infarction, in particular, but not angina pectoris. The uric acid relationship with myocardial infarction was equally strong in both sexes, even correcting for antihypertensive treatment. However, in multivariate analysis, including age, systolic blood pressure, relative weight, cigarette smoking, and serum cholesterol, serum uric acid did not add independently to the prediction of coronary heart disease.