Mutation cluster region,association between germline and somatic mutations and genotype-phenotype correlation in upper gastrointestinal familial adenomatous polyposis

Studies of adenomatous polyposis coli (APC) mutations in familial adenomatous polyposis (FAP) have focused on large bowel disease. It has been found that: 1) germline APC mutations around codon 1300 are associated with severe colorectal polyposis; 2) somatic APC mutations in colorectal tumors tend to cluster approximately between codons 1250 and 1450; and 3) patients with germline mutations close to codon 1300 tend to acquire somatic mutations (second hits) in their colorectal polyps by allelic loss, whereas the tumors of other FAP patients have truncating second hits. Using new and published data, we have investigated how germline and somatic APC mutations influence the pathogenesis of upper gastrointestinal polyps in FAP. We have compared the results with those from colorectal disease. We found that somatic mutations in upper gastrointestinal polyps cluster approximately between codons 1400 and 1580. Patients with germline APC mutations after codon 1400 tend to show allelic loss in their upper gastrointestinal polyps; the tumors of other patients have truncating somatic mutations after codon 1400. Finally, patients with germline mutations after codon 1400 tend to have more severe duodenal polyposis (odds ratio, 5.72; 95% confidence interval, 1.13 to 28.89; P = 0.035). Thus, in both upper gastrointestinal and colorectal tumors, a specific region of the APC gene is associated with severe disease, clustering of somatic mutations, and loss of the wild-type allele. However, the region concerned is different in upper gastrointestinal and colorectal disease. The data suggest that loss of all APC SAMP repeats is probably necessary for duodenal and gastric tumorigenesis in FAP, as it is in colonic tumors. Compared with colonic tumors, however, retention of a greater number of beta-catenin binding/degradation repeats is optimal for tumorigenesis in upper gastrointestinal FAP.     

The use of laparoscopic ovarian electrocautery in preventing cancellation of in-vitro fertilization treatment cycles due to risk of ovarian hyperstimulation syndrome in women with polycystic ovaries

Fifty women with polycystic ovaries took part in a prospective randomized study. All women required treatment by in-vitro fertilization (IVF) for reasons other than anovulation. They had all previously undergone ovarian stimulation with gonadotrophin therapy which had failed to result in pregnancy or had been abandoned due to high risk of developing ovarian hyperstimulation syndrome (OHSS). Twenty-five women were treated by long-term pituitary desensitization followed by gonadotrophin therapy, oocyte retrieval and embryo transfer (group 1). Twenty-five women underwent laparoscopic ovarian electrocautery after pituitary desensitization followed by gonadotrophin therapy, oocyte retrieval and embryo transfer (group 2). A significantly higher number of women in group 1 had to have the treatment cycle abandoned due to impending or actual OHSS, determined by endocrine and clinical findings. In addition, the development of moderate or severe OHSS in completed cycles was higher in group 1. The pregnancy rate and miscarriage rates in the two treatment groups were similar. The authors propose that laparoscopic ovarian electrocautery is a potentially useful treatment for women who have previously had an IVF treatment cycle cancelled due to risk of OHSS or who have suffered OHSS in a previous treatment cycle.      

Mean cerebral blood flow measurements using phase contrast MRI in the first year of life

Alterations in cerebral blood flow (CBF) are believed to be linked to many of the neurological pathologies that affect neonates and small infants. CBF measurements are nonetheless often difficult to perform in this population, as many techniques rely on radioactive tracers or other invasive methods. In this study, mean global CBF was measured in 21 infants under the age of one, using non-invasive MRI techniques adapted to the neonatal population. Mean CBF was computed as the ratio of blood flow delivered to the brain (measured using phase contrast MRI) and brain volume (computed by segmenting anatomical MR images). Tests in adult volunteers and repeated measurements showed the flow measurements using the proposed method to be both accurate and reproducible. It was also found that cardiac gating need not be employed in infants with no known cardiac pathology. The developed technique can easily be appended to a neonatal MRI examination to provide rapid, robust, and non-invasive estimates of mean CBF, thus providing a means to monitor developmental or pathology-related alterations in cerebral perfusion and the impact of different treatment courses. In the imaged cohort, mean CBF and flow to the brain were found to rapidly increase during the first year of life (from approx. 25 to 60 ml blood/100 ml tissue/min), in good agreement with literature from other modalities where available. Mean CBF also showed a significant correlation with arterial oxygen saturation level and heart rate, but no significant correlation was found between CBF and the hematocrit or body temperature.     

Neurotrophin-3 administration alters neurotrophin, neurotrophin receptor and nestin mRNA expression in rat dorsal root ganglia following axotomy

In the months following transection of adult rat peripheral nerve some sensory neurons undergo apoptosis. Two weeks after sciatic nerve transection some neurons in the L4 and L5 dorsal root ganglia begin to show immunoreactivity for nestin, a filament protein expressed by neuronal precursors and immature neurons, which is stimulated by neurotrophin-3 (NT-3) administration. The aim of this study was to examine whether NT-3 administration could be compensating for decreased production of neurotrophins or their receptors after axotomy, and to determine the effect on nestin synthesis. The levels of mRNA in the ipsilateral and contralateral L4 and L5 dorsal root ganglia were analyzed using real-time polymerase chain reaction, 1 day, 1, 2 and 4 weeks after unilateral sciatic nerve transection and NT-3 or vehicle administration via s.c. micro-osmotic pumps. In situ hybridization was used to identify which cells and neurons expressed mRNAs of interest, and the expression of full-length trkC and p75NTR protein was investigated using immunohistochemistry. Systemic NT-3 treatment increased the expression of brain-derived neurotrophic factor, nestin, trkA, trkB and trkC mRNA in ipsilateral ganglia compared with vehicle-treated animals. Some satellite cells surrounding neurons expressed trkA and trkC mRNA and trkC immunoreactivity. NT-3 administration did not affect neurotrophin mRNA levels in the contralateral ganglia, but decreased the expression of trkA mRNA and increased the expression of trkB mRNA and p75NTR mRNA and protein. These data suggest that systemically administered NT-3 may counteract the decrease, or even increase, neurotrophin responsiveness in both ipsi- and contralateral ganglia after nerve injury.     

Coronary artery bypass graft imaging using ECG-gated multislice computed tomography: comparison with catheter angiography

AIM: To compare the value of multislice computerized tomography (MSCT) in imaging coronary artery bypass grafts (CABGs) by direct quantitative comparison with standard invasive angiography. METHODS: Using MSCT, 50 consecutive patients who had previously undergone CABG surgery and had recently undergone invasive angiography for recurrent angina pectoris, were studied further using MSCT after intravenous injection of non-ionic contrast agent; cardiac imaging was performed during a single breath-hold. Graft anatomy was quantified, using both quantitative coronary angiography (QCA) and MSCT, by different investigators blinded to each other. Reproducibility was quantified using the standard error of the measurement expressed as a percentage in log-transformed values (CV%) and intraclass correlation (ICC). RESULTS: All 150 grafts were imaged using MSCT; only 4 patent grafts were not imaged using selective angiography. Good agreement was achieved between MSCT and QCA on assessment of proximal anastomoses (CV% 25.2, ICC 0.84), mid-vessel luminal diameter (CV% 15.5, ICC 0.91) and aneurysmal dilations (CV% 14.3). Reasonable agreement was reached on assessment of distal anastomoses (CV% 26.7, ICC 0.66) and categorization of distal run-off (ICC 0.73). Good agreement was observed for stenoses of over 50% luminal loss (CV% 8.7, ICC 0.97) but agreement on assessment of less severe lesions was poor (CV% 208.7, ICC 0.51). CONCLUSION: This study demonstrates that CABGs can be quantitatively evaluated using MSCT, and that significant lesions present in all CABG segments can be reliably identified. Agreement between MSCT and QCA for lesions of less than 50% luminal loss was poor.     

Oral contrast medium in PET/CT: should you or shouldn’t you?

Purpose It has been suggested that the use of computed tomography (CT) positive contrast agents has led to attenuation-induced artefacts on ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET/CT) systems. Consequently, centres may withhold the use of such agents. Whilst there is theoretical evidence to support the aforementioned claim, the clinical relevance of the induced artefacts has not been widely established. Moreover, the potential benefits of bowel enhancement on PET/CT have yet to be formally evaluated. We therefore prospectively examined PET/CT studies to assess whether the use of oral contrast medium induces clinically relevant artefacts and whether the use of these agents is diagnostically helpful.Methods Over a 2-month period, ¹⁸F-FDG PET/CT images were prospectively reviewed from 200 patients following Gastrografin administration 2 h prior to examination. Both a radiologist and a nuclear medicine physician reviewed the images for contrast medium-mediated clinically relevant artefacts. Artefacts were sought on the CT attenuation-corrected images and were compared with the appearance on non-attenuated-corrected images. The number of examinations in which the oral contrast aided image interpretation was also noted.Results There were no oral contrast medium-induced clinically significant artefacts. In 38 of the 200 patients, oral contrast aided image interpretation (owing to differentiation of mass/node from bowel, discrimination of intestinal wall from lumen or definition of the anatomy of a relevant site). In 33 of these 38 patients, the anatomical site of interest was the abdomen/pelvis.Conclusion The use of oral contrast medium in ¹⁸F-FDG PET studies should not be withheld as it improves image interpretation and does not produce clinically significant artefacts.