Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases

Introduction

Seven SNPs in five genomic loci were recently found to confer a mildly increased risk of breast cancer.

Methods

We have investigated the correlations between disease characteristics and the patient genotypes of these SNPs in an unselected prospective cohort of 1,267 consecutive patients with primary breast cancer.

Results

Heterozygote carriers and minor allele homozygote carriers for SNP rs889312 in the MAP3K1 gene were less likely to be lymph node positive at breast cancer diagnosis (P = 0.044) relative to major allele homozygote carriers. Heterozygote carriers and minor allele homozygote carriers for SNP rs3803662 near the TNCR9 gene were more likely to be diagnosed before the age of 60 years (P = 0.025) relative to major allele homozygote carriers. We also noted a correlation between the number of minor alleles of rs2981582 in FGFR2 and the average number of first-degree and second-degree relatives with breast cancer and/or ovarian cancer (P = 0.05). All other disease characteristics, including tumour size and grade, and oestrogen or progesterone receptor status, were not significantly associated with any of these variants.

Conclusion

Some recently discovered genomic variants associated with a mildly increased risk of breast cancer are also associated with breast cancer characteristics or family history of breast cancer and ovarian cancer. These findings provide interesting new clues for further research on these low-risk susceptibility alleles.     

Urinary albumin excretion and transcapillary escape rate of albumin in malignancies

Transcapillary escape rate of albumin was determined in 22 patients with different malignancies. In addition, urinary albumin excretion rate was measured in 24-h urine samples using a sensitive immunoassay. Increased urinary albumin excretion was defined as ≥20 μg/min according to conventional standards. Renal glomerular filtration and tubular function was estimated by⁵¹Cr-EDTA plasma clearance and urinary beta 2-microglobulin, respectively. Median urinary albumin excretion rate was 15.0 μg/min (range 6–510 μg/min) and the frequency of increased urinary albumin excretion was 41%. This agrees with other studies showing increased albuminuria in several types of malignant diseases. Patients with advanced disease (tumour, node, metastasis (TNM) stage II–IV) had a significantly higher urinary albumin excretion rate than patients with localized disease (TNM stage I). Serum creatinine, glomerular filtration rate and urinary beta 2-microglobulin were all within normal limits. Median transcapillary escape rate of albumin was 5.5%/h (range 2–8%/h) and this level is comparable with values in healthy subjects. There was no significant difference in transcapillary escape rate between patients with elevated urinary albumin excretion and the normoalbuminuric group. Median value of the absolut outflux of albumin was 10.6 g/h with similar levels in patients with increased urinary albumin excretion and patients with normoalbuminuria. Our results indicate a high prevalence of minor glomerular dysfunction with a slightly elevated urinary albumin excretion in patients with malignancies. The normal endothelial function, as estimated by the transcapillary escape rate of albumin, suggests an overal unaffected capillary permeability and increased urinary albumin loss appears to be an isolated renal phenomenon in cancer patients.     

Poverty and health promotion in primary health care: professionals' perspectives

This paper examines the effectiveness of current strategies for health promotion in the UK in the light of knowledge about the links between health, illness and poverty. The implications of recent policies which target health promotion within primary health care (PHC) settings are examined. The results of an exploratory study undertaken during 1993/94 in a city in South West England are discussed. This qualitative study used semi-structured interviews to investigate the perceptions of a range of PHC professionals. Fifty-four interviews were carried out amongst staff in 16 PHC practices. This paper reports on professionals' views and practice in relation to promoting health in areas of poverty and with low-income clients. These findings are discussed in relation to the literature and the constraints on effective health promotion in PHC are explored particularly in relation to issues of poverty and deprivation.     

Gamma-knife radiosurgery for trigeminal neuralgia

Gamma knife was installed at the PD Hinduja National Hospital and Medical Research Centre, Mumbai, India, in January 1997. In the first year of gamma-knife radiosurgery to January 1998, we treated 110 patients, of whom six had medically refractory trigeminal neuralgia. Seven treatments were administered to this group of six patients (one had bilateral neuralgia). This report evaluates the effectiveness of radiosurgery treatment in these patients. The median age of the patients was 56 years and there were five males and one female. Following Leksell stereotactic frame fixation, a magnetic resonance imaging scan was done in all. The Leksell gamma plan was used for planning. A radiosurgery dose of 70–80 Gy was delivered to the trigeminal root entry zone, 2–4 mm anterior to the junction of the pons and trigeminal nerve with a single 4 mm collimator helmet. Complete pain relief was achieved in four patients. Two had partial relief. No patient developed any radiosurgery related morbidity during the follow-up period of 5–16 months. Radiosurgery seems to be an effective approach for medically or surgically refractory trigeminal neuralgia.     

A cluster randomized,controlled trial of breast and cervix cancer screening in Mumbai,India: methodology and interim results after three rounds of screening

Cervix and Breast cancers are the most common cancers among women worldwide and extract a large toll in developing countries. In May 1998, supported by a grant from the NCI (US), the Tata Memorial Hospital, Mumbai, India, started a cluster‐randomized, controlled, screening‐trial for cervix and breast cancer using trained primary health workers to provide health‐education, visual‐inspection of cervix (with 4% acetic acid‐VIA) and clinical breast examination (CBE) in the screening arm, and only health education in the control arm. Four rounds of screening at 2‐year intervals will be followed by 8 years of monitoring for incidence and mortality from cervix and breast cancers. The methodology and interim results after three rounds of screening are presented here. Good randomization was achieved between the screening (n = 75360) and control arms (n = 76178). In the screening arm we see: High screening participation rates; Low attrition; Good compliance to diagnostic confirmation; Significant downstaging; Excellent treatment completion rate; Improving case fatality ratios. The ever‐screened and never‐screened participants in the screening arm show significant differences with reference to the variables religion, language, age, education, occupation, income and health‐seeking behavior for gynecological and breast‐related complaints. During the same period, in the control arm we see excellent participation rate for health education; Low attrition and a good number of symptomatic referrals for both cervix and breast.     

The impact of cytokines on the expression of drug transporters,cytochrome P450 enzymes and chemokine receptors in human PBMC

Background and purpose:

The function of transporters in peripheral blood mononuclear cells (PBMC) has been characterized, but less is known about cytochrome P450 (CYP) enzyme function in these cells. Given that cytokines are dysregulated in many diseases, the purpose of this work was to assess the impact of cytokines on the expression of CYPs, transporters and chemokine receptors in PBMC.

Experimental approach:

Human PBMC were incubated with cytokines for 48 h. ATP-binding cassette (ABC)B1, ABCC1, ABCC2, CYP2B6, CYP3A4, CXCR4 and CCR5 expression were measured by quantitative polymerase chain reaction and flow cytometry at 0, 4, 8, 24 and 48 h. Enzyme activity was assessed using fluorescent probes.

Key results:

We show here functional activity of CYP3A4 and CYP2B6 in PBMC. Furthermore, cytokines had a significant impact on the mRNA and protein expression of all proteins. For example, interleukin-2 (IL-2) had a marked impact on ABCB1 mRNA (% control 4745 ± 11961) and protein (% control 200 ± 57). Increases in drug efflux transporter expression, in response to cytokines, resulted in reduced cellular accumulation of digoxin [decrease of 17% and 26% for IL-2 and interferon-γ (IFNγ) respectively] and saquinavir (decrease of 28% and 30% for IL-2 and IFNγ respectively). The degree to which drug transporter and chemokine receptor expression changed in response to cytokines was positively correlated (e.g. ABCB1 and CXCR4, r² = 0.545).

Conclusions and implications:

These data have important implications for diseases in which cytokines are dysregulated and for which pharmacological intervention targets immune cells.     

中药升麻的化学成分

从中药兴安升麻[Cimicifuga dahurica(Turcz.)Maxim.]的干燥根茎中分得五个化合物,其中四个为三萜木糖甙:升麻醇-3-O-β-D-吡喃木糖甙(23R,24S)(Ⅰ),25-O-乙酰升麻醇-3-O-β-D-吡喃木糖甙(23R,24S)(Ⅱ),12-羟基升麻醇-3-O-β-D-吡喃木糖甙(23R,24S)(Ⅲ),升麻醇-3-O-β-D-吡喃木糖基(3→1)-β-D-吡喃木糖甙(23R,24S)(Ⅳ),另一个为异阿魏酸(Ⅴ)。Ⅲ和Ⅳ为新化合物,通过光谱(IR,MS,¹H及¹³C NMR)解析确定了它们的结构,分别命名为升麻甙A(cimiside A)和升麻甙B(cimiside B)。     

Expert system-controlled image display

Conventional computer-based medical expert systems deliver advice to physicians as written text. While such advice is useful, it has distinct limitations in a visually oriented discipline such as diagnostic radiology, in which decisions often depend on pattern recognition and appreciation of subtle morphologic features. The authors developed a prototype expert computer system, IMAGE/ICON, which displays groups of images sorted into a series of axes based on different ways in which they may be similar. They may share a common feature, group of features, causes, or clinical setting. IMAGE/ICON may display examples of morphologic variations of a dominant finding or a spectrum of abnormalities seen in an specific disease or group of diseases. The system also assembles a written analysis of key features of a case. Such a tool may be useful as a diagnostic aid or for continuing medical education. It is likely to have particular impact in the form of an intelligent radiologic workstation, as picture archiving and communication systems become available.     

Effect of methemoglobin formation on the MR appearance of subarachnoid hemorrhage

Subarachnoid hemorrhage has a much higher intensity in magnetic resonance (MR) images with the passage of time. Acute subarachnoid hemorrhage is difficult to see; within 1 week its appearance has become intensified on T1-weighted images. Different concentrations of blood and lysed red blood cells in cerebrospinal fluid (CSF) were examined spectroscopically but did not significantly alter T1 and T2 relaxation of CSF acutely. Ultraviolet visible spectroscopy of bloody CSF stored hypoxically for 3 days showed the presence of methemoglobin. The iron in methemoglobin is paramagnetic; in combination with water this facilitates T1 relaxation. It is concluded that methemoglobin formation with T1 shortening at least partially accounts for the increasing intensity of the MR appearance of subarachnoid hemorrhage over time in the central nervous system and may also explain the intense appearance of subacute hemorrhage in MR images elsewhere in the body.