Varieties of living things: Life at the intersection of lineage and metabolism

publication-status: Publishedtypes: Articl

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Factors that contribute to faecal cyclooxygenase-2 mRNA expression in subjects with colorectal cancer

浜松医科大学学位論文　医博第600号（平成23年3月16日

Fecal Tests: From Blood to Molecular Markers

Detection of molecular markers for colorectal neoplasia in feces has the potential to improve performance of simple noninvasive screening tests for colorectal cancer. Most research has explored the value of DNA-based, RNA-based, and protein-based markers. In all cases there has been a trend to move from a single marker to a panel of markers to improve sensitivity. Unfortunately, no type of molecular marker has proved specific for neoplasia. DNA tests have been improved by combining mutation detection with assessment of DNA integrity plus epigenetic markers of neoplasia. RNA-based approaches are just beginning to explore the full power of transcriptomics. So far, no protein-based fecal test has proved better than fecal immunochemical tests for hemoglobin. Finally, no marker or panel of markers has yet been developed to the point where it has been evaluated in large unbiased population studies to assess performance across all stages of neoplasia and in all practical environments

Detection of methylated septin 9 in tissue and plasma of colorectal patients with neoplasia and the relationship to the amount of circulating cell-free DNA

BACKGROUND: Determination of methylated Septin 9 (mSEPT9) in plasma has been shown to be a sensitive and specific biomarker for colorectal cancer (CRC). However, the relationship between methylated DNA in plasma and colon tissue of the same subjects has not been reported. METHODS: Plasma and matching biopsy samples were collected from 24 patients with no evidence of disease (NED), 26 patients with adenoma and 34 patients with CRC. Following bisulfite conversion of DNA a commercial RT-PCR assay was used to determine the total amount of DNA in each sample and the fraction of mSEPT9 DNA. The Septin-9 protein was assessed using immunohistochemistry. RESULTS: The percent of methylated reference (PMR) values for SEPT9 above a PMR threshold of 1% were detected in 4.2% (1/24) of NED, 100% (26/26) of adenoma and 97.1% (33/34) of CRC tissues. PMR differences between NED vs. adenoma and NED vs. CRC comparisons were significant (p<0.001). In matching plasma samples using a PMR cut-off level of 0.01%, SEPT9 methylation was 8.3% (2/24) of NED, 30.8% (8/26) of adenoma and 88.2% (30/34) of CRC. Significant PMR differences were observed between NED vs. CRC (p<0.01) and adenoma vs. CRC (p<0.01). Significant differences (p<0.01) were found in the amount of cfDNA (circulating cell-free DNA) between NED and CRC, and a modest correlation was observed between mSEPT9 concentration and cfDNA of cancer (R2 = 0.48). The level of Septin-9 protein in tissues was inversely correlated to mSEPT9 levels with abundant expression in normals, and diminished expression in adenomas and tumors. CONCLUSIONS: Methylated SEPT9 was detected in all tissue samples. In plasma samples, elevated mSEPT9 values were detected in CRC, but not in adenomas. Tissue levels of mSEPT9 alone are not sufficient to predict mSEPT9 levels in plasma. Additional parameters including the amount of cfDNA in plasma appear to also play a role

Improving Fecal Occult Blood Testing Compliance Using a Mailed Educational Reminder

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the United States. Randomized controlled trials have shown that annual screening fecal occult blood testing (FOBT) reduces CRC mortality and incidence. However, patient compliance with FOBT is low. To determine whether a mailed educational reminder increases FOBT card return rates and to examine predictors of FOBT compliance. Blinded, randomized, controlled trial at the Veteran Affairs Medical Center, San Diego, California. Seven hundred and seventy-five consecutive patients ≥50 years of age referred by their primary care physicians for FOBT. Patients were randomly assigned to the usual care group or the intervention group. Ten days after picking up the FOBT cards, a 1-page reminder with information related to CRC screening was mailed to the intervention group only. The primary outcome was proportion of returned FOBT cards after 6 months. Patient demographic, clinical characteristics and prior FOBT completed were collected for multivariate regression analysis. At 6 months after card distribution, 64.6% of patients in the intervention group returned cards compared with 48.4% in the control group (P &lt; 0.001). Patients who received a mailed reminder (OR 2.02; 95% CI: 1.48–2.74) or have a prior history of returning the FOBT cards (OR 1.87; 95% CI: 1.29–2.70) were more likely to return the FOBT cards. Patients with current or recent illicit drug use were less likely to return the FOBT cards (OR 0.26; 95% CI: 0.13–0.50). A simple mailed educational reminder significantly increases compliance with FOBT for CRC screening

The effect of watchful waiting compared to immediate test ordering instructions on general practitioners' blood test ordering behaviour for patients with unexplained complaints; a randomized clinical trial (ISRCTN55755886)

<p>Abstract</p> <p>Background</p> <p>Immediate blood testing for patients presenting with unexplained complaints in family practice is superfluous from a diagnostic point of view. However, many general pracitioners (GPs) order tests immediately. Watchful waiting reduces the number of patients to be tested and the number of false-positive results. The objectives of this study are: to determine the feasibility of watchful waiting compared to immediate test ordering; to determine if a special quality improvement strategy can improve this feasibility; and to determine if watchful waiting leads to testing at a later time.</p> <p>Methods</p> <p>The study is a cluster-randomized clinical trial with three groups, on blood test ordering strategies in patients with unexplained complaints. GPs in group one were instructed to order tests immediately and GPs in group two to apply a watchful waiting approach. GPs in group three received the same instruction as group two, but they were supported by a systematically designed quality improvement strategy. A total of 498 patients with unexplained complaints from 63 practices of Dutch GPs participated. We measured: the percentage of patients for whom tests were ordered and number of tests ordered at the first consultation; performance on the strategy's performance objectives (i.e., ordering fewer tests and specific communication skills); the number of tests ordered after four weeks; and GP and patient characteristics.</p> <p>Results</p> <p>Immediate test ordering proved feasible in 92% of the patients; watchful waiting in 86% and 84%, respectively, for groups two and three. The two watchful waiting groups did not differ significantly in the achievement of any of the performance objectives. Of the patients who returned after four weeks, none from group one and six from the two watchful waiting groups had tests ordered for them.</p> <p>Conclusions</p> <p>Watchful waiting is a feasible approach. It does not lead to testing immediately afterwards. Furthermore, watchful waiting was not improved by the quality improvement strategy.</p> <p>Trial registration</p> <p>Clinical trial registration: <a href="http://www.controlled-trials.com/ISRCTN55755886">ISRCTN55755886</a></p

Improved blood tests for cancer screening: general or specific?

Diagnosis of cancer at an early stage leads to improved survival. However, most current blood tests detect single biomarkers that are of limited suitability for screening, and existing screening programmes look only for cancers of one particular type. A new approach is needed. Recent developments suggest the possibility of blood-based screening for multiple tumour types. It may be feasible to develop a high-sensitivity general screen for cancer using multiple proteins and nucleic acids present in the blood of cancer patients, based on the biological characteristics of cancer. Positive samples in the general screen would be submitted automatically for secondary screening using tests to help define the likelihood of cancer and provide some indication of its type. Only those at high risk would be referred for further clinical assessment to permit early treatment and mitigate potential overdiagnosis. While the assays required for each step exist, they have not been used in this way. Recent experience of screening for breast, cervical and ovarian cancers suggest that there is likely to be widespread acceptance of such a strategy