Comparative genomic hybridization profiles in human BRCA1 and BRCA2 breast tumors highlight differential sets of genomic aberrations

BRCA1 or BRCA2 germline mutations cause approximately 30% of breast cancers within high-risk families. This represents 5% of total breast cancer incidence. Although BRCA1 and BRCA2 are both implicated in DNA repair and genome stability, it is unknown whether BRCA1 and BRCA2 are associated with similar or distinct diseases. In a previous study we reported that BRCA1-related breast carcinomas show a distinct genomic profile as determined by comparative genomic hybridization (CGH). We now hypothesize that, if functionally equivalent, mutations in BRCA1 and BRCA2 would result in similar genomic profiles in tumors. Here we report the chromosomal gains and losses as measured by CGH in 25 BRCA2-associated breast tumors and compared them with our existing 36 BRCA1 and 30 control profiles. We compared all chromosomal regions and determined the regions of differential gain or loss between tumor classes and controls. BRCA2 and control tumors have very similar genomic profiles. As a consequence, and in contrast to BRCA1-associated tumors, CGH profiles from BRCA2-associated tumors could not be distinguished from control tumors using the classification methodology as we have developed before. The largest number of significant differences existed between BRCA1 and controls, followed by BRCA1 compared with BRCA2, suggesting different tumor development pathways for BRCA1 and BRCA2.     

Measuring serum oestradiol in women with Alzheimer's disease: the importance of the sensitivity of the assay method

OBJECTIVE: Oestrogens could be protective against the development of Alzheimer's disease (AD) but reports on oestrogen levels in AD have been conflicting. DESIGN AND METHODS: A meta-analysis using robust regression was carried out to assess whether the sensitivity of the assays of past studies had affected the reported level of total oestradiol. We had also measured total oestradiol in women with AD (n=66) and controls (n=62) not using hormone replacement therapy. We used two assays for total oestradiol to assess the difference between sensitive (radioimmunoassay with a specific rabbit antibody: 3 pmol/l) and relatively insensitive (immunoassay: 37 pmol/l) assays. RESULTS: Meta-analysis using robust regression indicated that insensitive assays gave higher levels of total oestradiol when many samples fall below the level of sensitivity of the method. Earlier reports of low levels of total oestradiol in AD might be explained by this phenomenon, since total oestradiol levels (using the sensitive assay) in our controls were one third of those reported in the earlier studies. Using the sensitive assay we found that women with AD had significantly (P<0.01) higher levels (26+/-13 pmol/l) of total oestradiol than controls (21+/-13 pmol/l). Using the insensitive assay, there was no significant difference in the levels of total oestradiol. CONCLUSIONS: The sensitivity of the assay determines the reported value of the oestradiol levels. Studies using a sensitive assay do not report significantly lower levels of total oestradiol in women with AD. This weighs against the hypothesis that low levels of total oestradiol are a risk factor for AD.     

The menopause and HRT. HRT and cognitive decline

It is biologically plausible that hormone replacement therapy (HRT) would be protective against cognitive decline and Alzheimer's disease (AD). We review observational and randomized trials to determine whether HRT might protect against cognitive decline in cognitively unimpaired and demented women. We also address issues of clinical relevance, including duration and type of treatment and patient characteristics, including type of menopause (surgical versus natural), age, education and menopausal symptoms. Differences in participant characteristics and testing methods limit the ability to draw conclusions across randomized studies of HRT in non-demented women. The available evidence suggests no detrimental effect of HRT on cognitive function and inconsistent benefits on verbal memory and reasoning, frontal functions and speeded attention. Meta-analyses of observational trials suggest that HRT protects against the development of AD, but randomized trials indicate no long-lasting benefit in patients with AD. Evidence is insufficient to recommend HRT to maintain cognitive function.     

Primary signet ring cell carcinoma of the eccrine sweat gland in the eyelid. Immunohistochemical and ultrastructural study of a case

We report a case of a 45-year-old woman who exhibited a primitive eccrine sweat gland carcinoma of the eyelid. Histological study showed cellular proliferation with an Indian file pattern and some signet ring cells with sialomucin secretion. Immunohistochemical study demonstrated these cells to be positive with the anticytokeratin, anti-EMA, anti-HMFG, antiestrogen receptor and antiprogesterone receptor antibodies. Ultrastructural study showed intracytoplasmic vacuoles with numerous microvilli at the apical side. Differential diagnosis with a metastasis from a mammary adenocarcinoma is difficult and a complete staging is necessary to confirm the primitive origin of the tumor. The behavior of this tumor is marked by locoregional recurrence.     

Diagnosing dementia: interrater reliability assessment and accuracy of the NINCDS/ADRDA criteria versus CERAD histopathological criteria for Alzheimer's disease

We investigated the interrater reliability and accuracy of two independent medical doctors in using NINCDS/ADRDA criteria to classify 82 elderly subjects enrolled in OPTIMA, a longitudinal study investigating dementia. Kappa statistics revealed moderate agreement (0.5) in overall classification of dementia type, and almost perfect agreement (0.9) on the absence or presence of dementia. Combining NINCDS/ADRDA 'possible' and 'probable' Alzheimer's disease (AD) categories produced substantial agreement (0.7). Comparison with CERAD histopathological criteria for AD showed that combining 'possible' and 'probable' AD resulted in a high sensitivity and accuracy, but a low specificity. To increase specificity, the NINCDS/ADRDA 'probable AD' category should be used alone. An important finding was that the accuracy of diagnoses of AD made from the case notes alone was not different from the diagnoses obtained following active involvement with participants.     

T cell reactivity to an epitope of the mycobacterial 65-kDa heat-shock protein (hsp 65) corresponds with arthritis susceptibility in rats and is regulated by hsp 65-specific cellular responses.

Adjuvant arthritis (AA) can be induced in genetically susceptible rats by immunization with heat-killed mycobacteria suspended in mineral oil. From our analysis of arthritogenic T cell clone A2b, obtained from an arthritic Lewis rat and specific for the 180-188 epitope of mycobacterial 65-kDa heat-shock protein (hsp 65), the possible origin of AA was explained by the existence of a molecular mimicry of the 180-188 epitope with a cartilage-associated self antigen. We now have shown that Lewis rats respond to the 180-188 epitope after Mycobacterium tuberculosis immunization and that arthritis-resistant Fisher and (Lewis x Fisher)F1 rats, although major histocompatibility complex class II identical with Lewis, do not respond to this epitope. However, in rare cases of arthritis in Fisher rats, responses to the epitope were seen. We obtained no evidence for a defect at the level of antigen processing and presentation or for suppression in Fisher rats. Thus, non-responsiveness in Fisher rats was likely due to a difference at the level of the T cell repertoire. Previously, we have reported that pretreatment with hsp 65 in experimental arthritis, and not only in AA, caused resistance to arthritis induction. We now present evidence that immunization with hsp 65 or in vitro stimulation with hsp 65 may lead to inhibition of responses specific for epitope 180-188. Thus the hsp 65-induced resistance to arthritis is probably caused by the induction of regulatory control specifically targeted at the 180-188 epitope. Especially in rats that tend to focus their responses on the critical 180-188 sequence, such as Lewis, regulation seems to develop following immunization with hsp 65. Since recent evidence suggests that hsp 65 and also the 180-188 epitope have a role in human arthritic conditions, the present findings are expected to contribute to further experimentation directed at exploiting hsp 65 or its epitopes for the development of new therapeutical approaches in humans.     

The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis

We reviewed epidemiological and experimental studies of female gonadal hormone replacement therapy (HRT) on cognitive function in post-menopausal women and carried out meta-analyses. In healthy ageing women, HRT has small and inconsistent effects that include enhancement of verbal memory, abstract reasoning and information processing. Epidemiological studies show larger effects than experimental studies, which is not related to sample size. Important confounds may be that women who start using HRT are healthier than women who do not. Also, controlling for socio-economic status diminishes the effect of HRT. The effects of HRT may depend on the age and type of menopause and the therapeutic intervention used, with the most widely used drug, Premarin, having least effect. However, the effects are independent of mood and climacteric symptom alleviation. There is a paucity of experimental studies that include healthy elderly women. The evidence for an estrogen deficiency in women with dementia and cognitive dysfunction is inconsistent. Nevertheless, epidemiological studies suggest that HRT protects against the development of clinically diagnosed Alzheimer's disease. However, poor recall of HRT use by patients and altered physician behaviour may have confounded the effects. Surprisingly, both healthy and demented women with low education seem to benefit most from HRT. Three recent controlled experimental studies using Premarin showed no effects of HRT in preventing further cognitive decline in women who already have Alzheimer's disease. Duration of treatment seems to play an important role, with beneficial effects declining-and even reversing-with longer treatment in women with Alzheimer's disease.Future research should further investigate the cognitive effect of different HRT preparations, serum estrogen levels, and the interactions of HRT with age, menopausal status and existing protective (e.g. education) and risk factors (e.g. smoking and apolipoprotein E genotype) for cognitive decline and Alzheimer's disease.     

Effect on breast cancer screening response in The Netherlands of inviting women for an additional scientific investigation.

STUDY OBJECTIVE--The study aimed to determine whether asking women to undertake an additional scientific study would deter them from attending screening for breast cancer. DESIGN--A randomised study was conducted in all women aged 50-70 years who were eligible for breast cancer screening and living in the city of Utrecht. A total of 1863 women were invited for mammography only and 1863 women were invited to participate in the European Prospective Investigation into Cancer and Nutrition (EPIC) in addition to the mammography. SUBJECTS--The study population comprised a random sample of 3726, 15% of the female population of Utrecht aged 50-70 years. MAIN RESULTS--The attendance rate for breast cancer screening was 53%, irrespective of the invitation to participate in the additional scientific study. CONCLUSIONS--Asking women to attend for an investigation in addition to the routine screening procedure for breast cancer did not affect the overall response to screening.     

The mycobacterial 65 kD heat-shock protein and autoimmune arthritis

Summary Arthritis — induced experimentally in rats by immunization with mycobacteria has been shown to depend on specific T cell recognition of an epitope present on the mycobacterial 65-kD heat-shock protein. This particular epitope has been observed to have a structural mimicry with a cartilage-associated molecule present in the joints. Since the bacterial heat-shock proteins and the cartilage-associated molecules are of a conserved nature, one might infer from the experimental model that in humans similar mimicry could play a role in the initiation of autoimmune arthritis. Recent findings from the analysis of immunological reactivity to the 65-kD in rheumatoid arthritis patients seem to support such a role for the mycobacterial 65-kD heat-shock protein in human disease.     

Serum levels of estradiol and testosterone and performance in different cognitive domains in healthy elderly men and women

Sex hormones could protect against age-related cognitive decline in elderly men and women. We investigated the relationships between serum total testosterone (TT), total estradiol (TE2) levels and cognitive function in 145 non-demented elderly volunteers (aged 61-91 years) who were not using hormone replacement therapy (HRT).Women (n=66) were better at verbal recall than men (n=79) and men were slightly better at naming. There was a positive relationship between serum levels of TE2 and verbal list recall but not with other verbal memory tests (e.g. Verbal Paired Associates) in women. There was a negative relationship of serum TT levels with verbal recall. Surprisingly, women who were in the upper age tertile (> 77 years of age) were better at verbal recall than men and than women younger than 72; this effect was independent of hormone levels. Men between 61 and 72 years of age showed a positive relationship between high TE2 levels and Spatial Span performance and between high TT levels and speed of information processing, while for women of this age-group, a negative relationship was found. These preliminary results were unchanged when controlling for education, sex hormone binding globulin levels, body mass index, depression, daily alcohol use and smoking.In sum, not all cognitive functions were better with higher levels of sex steroids and effects seemed to be modified by sex; the sex-sensitive tests showing the clearest effects. More research is required to investigate whether there is a window of time in which hormone therapy could be beneficial for middle-aged men.