Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome

A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ~10-15% of cases of suspected Lynch syndrome, no disease-causing mechanism can be detected

A Single-Lumen Central Venous Catheter for Continuous and Direct Intra-abdominal Pressure Measurement

Background: Abdominal compartment syndrome (ACS) is associated with high morbidity and mortality rates. Therefore, the need for a good diagnostic tool to predict intra-abdominal hypertension (IAH) and progression to ACS is paramount. Bladder pressure (BP) has been used for several years for intra-abdominal pressure (IAP) measurement but has the disadvantage that it is not a continuous measurement. In this study, a single-lumen central venous catheter (CVC) is placed through the abdominal wall into the abdominal cavity to continuously and directly monitor the intra-abdominal pressure (CDIAP). The aim of this study was to evaluate the use of CDIAP to measure BP as a representative of the true IAP. Methods: Both BP and CDIAP were prospectively recorded on a variety of surgical patients admitted to the intensive care unit (ICU) from March 2003 up to December 2004. At the end of the surgical procedure, the CVC was placed through the abdominal wall and connected to a pressure transducer. In addition, the BP was measured through the urine drainage port after clamping the catheter and filling the bladder with 50 ml of 0.9% saline. At least three paired measurements (BP and CDIAP) were performed for at least one day on the ICU in a standardized manner at preset time intervals on each patient. The paired measurements were compared using the Bland-Altman (B-A) method. Data are presented as mean ± standard deviation. Results: Over a period of 22 months (March 2003 until December 2004), 125 paired measurements of both BP and CDIAP were recorded on 25 patients. The mean age was 72.4 ± 6.6 years. Eighteen patients underwent central vascular surgery, and seven patients with peritonitis received laparotomy. The mean CDIAP was 11.4 ± 4.8 (range 2-30) mmHg, and the BP was 12.9 ± 5.3 (range 3-37) mmHg. The mean difference between CDIAP and BP was 1.6 ± 2.7 mmHg. There was an acceptable level of agreement (intraclass correlation 0.82) between IAP measured by BP and IAP measured via CDIAP. Conclusion: Continuous direct intra-abdominal pressure measurement proved that the BP measurement approach of Kron is representative of the IAP. CDIAP measurement is accurate and makes it easier for the nursing staff to be informed of the IAP

Polymorphisms of genes coding for ghrelin and its receptor in relation to colorectal cancer risk: a two-step gene-wide case-control study

<p>Abstract</p> <p>Background</p> <p>Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also indicates a role of ghrelin in cancer development.</p> <p>Methods</p> <p>We conducted a case-control study to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with colorectal cancer risk. Pairwise tagging was used to select the 11 polymorphisms included in the study. The selected polymorphisms were genotyped in 680 cases and 593 controls from the Czech Republic.</p> <p>Results</p> <p>We found two SNPs associated with lower risk of colorectal cancer, namely SNPs rs27647 and rs35683. We replicated the two hits, in additional 569 cases and 726 controls from Germany.</p> <p>Conclusion</p> <p>A joint analysis of the two populations indicated that the T allele of rs27647 SNP exerted a protective borderline effect (P_trend= 0.004).</p

Tendencies, variability and persistence of sea surface temperature anomalies

Quantifying global trends and variability in sea surface temperature (SST) is of fundamental importance to understanding changes in the Earth’s climate. One approach to observing SST is via remote sensing. Here we use a 37-year gap-filled, daily-mean analysis of satellite SSTs to quantify SST trends, variability and persistence between 1981-2018. The global mean warming trend is 0.08 K per decade globally, with 95 % of local trends being between -0.1 K and +0.35 K. Excluding perennial sea-ice regions, the mean warming trend is 0.11 K per decade. After removing the long-term trend we calculate the SST power spectra over different time periods. The maximum variance in the SST power spectra in the equatorial Pacific is 1.9 K2 on 1-5 year timescales, dominated by ENSO processes. In western boundary currents characterised by an intense mesoscale activity, SST power on sub-annual timescales dominates, with a maximum variance of 4.9 K2. Persistence timescales tend to be shorter in the summer hemisphere due to the shallower mixed layer. The median short-term persistence length is 11-14 days, found over 71-79 % of the global ocean area, with seasonal variations. The mean global correlation between monthly SST anomalies with a three-month time-lag is 0.35, with statistically significant correlations over 54.0 % of the global oceans, and notably in the northern and equatorial Pacific, and the sub-polar gyre south of Greenland. At six months, the mean global SST anomaly correlation falls to 0.18. The satellite data record enables the detailed characterisation of temporal changes in SST over almost four decades

A call for new approaches to quantifying biases in observations of sea-surface temperature

Global surface-temperature changes are a fundamental expression of climate change. Recent, much-debated, variations in the observed rate of surface-temperature change have highlighted the importance of uncertainty in adjustments applied to sea-surface temperature (SST) measurements. These adjustments are applied to compensate for systematic biases and changes in observing protocol. Better quantification of the adjustments and their uncertainties would increase confidence in estimated surface-temperature change and provide higher- quality gridded SST fields for use in many applications. Bias adjustments have been based either on physical models of the observing processes or on the assumption of an unchanging relationship between SST and a reference data set such as night marine air temperature. These approaches produce similar estimates of SST bias on the largest space and timescales, but regional differences can exceed the estimated uncertainty. We describe challenges to improving our understanding of SST biases. Overcoming these will require clarification of past observational methods, improved modeling of biases associated with each observing method, and the development of statistical bias estimates that are less sensitive to the absence of metadata regarding the observing method. New approaches are required that embed bias models, specific to each type of observation, within a robust statistical framework. Mobile platforms and rapid changes in observation type require biases to be assessed for individual historic and present-day platforms (i.e., ships or buoys) or groups of platforms. Lack of observational metadata and of high-quality observations for validation and bias model development are likely to remain major challenges

Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition?

<p>Abstract</p> <p>Background</p> <p>To investigate the etiology of <it>MLH1 </it>promoter methylation in mismatch repair (MMR) mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high ages, young patients bearing this type of malignancy are rare and could provide additional insight into the etiology of sporadic MSI-H colon cancer.</p> <p>Methods</p> <p>We studied a set of 46 MSI-H colon tumors cases with <it>MLH1 </it>promoter methylation which was enriched for patients with an age of onset below 50 years (n = 13). Tumors were tested for CIMP marker methylation and mutations linked to methylation: <it>BRAF, KRAS</it>, <it>GADD45A </it>and the <it>MLH1 </it>-93G>A polymorphism. When available, normal colon and leukocyte DNA was tested for <it>GADD45A </it>mutations and germline <it>MLH1 </it>methylation. SNP array analysis was performed on a subset of tumors.</p> <p>Results</p> <p>We identified two cases (33 and 60 years) with <it>MLH1 </it>germline promoter methylation. <it>BRAF </it>mutations were less frequent in colon cancer patients below 50 years relative to patients above 50 years (p-value: 0.044). CIMP-high was infrequent and related to <it>BRAF </it>mutations in patients below 50 years. In comparison with published controls the G>A polymorphism was associated with our cohort. Although similar distribution of the pathogenic A allele was observed in the patients with an age of onset above and below 50 years, the significance for the association was lost for the group under 50 years. <it>GADD45A </it>sequencing yielded an unclassified variant. Tumors from both age groups showed infrequent copy number changes and loss-of-heterozygosity.</p> <p>Conclusion</p> <p>Somatic or germline <it>GADD45A </it>mutations did not explain sporadic MSI-H colon cancer. Although germline <it>MLH1 </it>methylation was found in two individuals, locus-specific somatic <it>MLH1 </it>hypermethylation explained the majority of sporadic early onset MSI-H colon cancer cases. Our data do not suggest an intrinsic tendency for CpG island hypermethylation in these early onset MSI-H tumors other than through somatic mutation of <it>BRAF</it>.</p