Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.

TALDICE-1 age scale of the Talos Dome deep ice core, East Antarctica

A new deep ice core drilling program, TALDICE, has been successfully handled by a European team at Talos Dome, in the Ross Sea sector of East Antarctica, down to 1620 m depth. Using stratigraphic markers and a new inverse method, we produce the first official chronology of the ice core, called TALDICE-1. We show that it notably improves an a priori chronology resulting from a one-dimensional ice flow model. It is in agreement with a posteriori controls of the resulting accumulation rate and thinning function along the core. An absolute uncertainty of only 300 yr is obtained over the course of the last deglaciation. This uncertainty remains lower than 600 yr over Marine Isotope Stage 3, back to 50 kyr BP. The phasing of the TALDICE ice core climate record with respect to the central East Antarctic plateau and Greenland records can thus be determined with a precision allowing for a discussion of the mechanisms at work at sub-millennial time scales.

Water isotopic ratios from a continuously melted ice core sample

A new technique for on-line high resolution isotopic analysis of liquid water, tailored for ice core studies is presented. We built an interface between a Wavelength Scanned Cavity Ring Down Spectrometer (WS-CRDS) purchased from Picarro Inc. and a Continuous Flow Analysis (CFA) system. The system offers the possibility to perform simultaneuous water isotopic analysis of δ18O and δD on a continuous stream of liquid water as generated from a continuously melted ice rod. Injection of sub μl amounts of liquid water is achieved by pumping sample through a fused silica capillary and instantaneously vaporizing it with 100% efficiency in a~home made oven at a temperature of 170 °C. A calibration procedure allows for proper reporting of the data on the VSMOW–SLAP scale. We apply the necessary corrections based on the assessed performance of the system regarding instrumental drifts and dependance on the water concentration in the optical cavity. The melt rates are monitored in order to assign a depth scale to the measured isotopic profiles. Application of spectral methods yields the combined uncertainty of the system at below 0.1‰ and 0.5‰ for δ18O and δD, respectively. This performance is comparable to that achieved with mass spectrometry. Dispersion of the sample in the transfer lines limits the temporal resolution of the technique. In this work we investigate and assess these dispersion effects. By using an optimal filtering method we show how the measured profiles can be corrected for the smoothing effects resulting from the sample dispersion. Considering the significant advantages the technique offers, i.e. simultaneuous measurement of δ18O and δD, potentially in combination with chemical components that are traditionally measured on CFA systems, notable reduction on analysis time and power consumption, we consider it as an alternative to traditional isotope ratio mass spectrometry with the possibility to be deployed for field ice core studies. We present data acquired in the field during the 2010 season as part of the NEEM deep ice core drilling project in North Greenland.

Deep ocean ventilation, carbon isotopes, marine sedimentation and the deglacial CO2 rise

The link between the atmospheric CO2 level and the ventilation state of the deep ocean is an important building block of the key hypotheses put forth to explain glacial-interglacial CO2 fluctuations. In this study, we systematically examine the sensitivity of atmospheric CO2 and its carbon isotope composition to changes in deep ocean ventilation, the ocean carbon pumps, and sediment formation in a global 3-D ocean-sediment carbon cycle model. Our results provide support for the hypothesis that a break up of Southern Ocean stratification and invigorated deep ocean ventilation were the dominant drivers for the early deglacial CO2 rise of ~35 ppm between the Last Glacial Maximum and 14.6 ka BP. Another rise of 10 ppm until the end of the Holocene is attributed to carbonate compensation responding to the early deglacial change in ocean circulation. Our reasoning is based on a multi-proxy analysis which indicates that an acceleration of deep ocean ventilation during early deglaciation is not only consistent with recorded atmospheric CO2 but also with the reconstructed opal sedimentation peak in the Southern Ocean at around 16 ka BP, the record of atmospheric δ13CCO2, and the reconstructed changes in the Pacific CaCO3 saturation horizon.

Outcome and patterns of failure after postoperative intensity modulated radiotherapy for locally advanced or high-risk oral cavity squamous cell carcinoma

Background To determine the outcome and patterns of failure in oral cavity cancer (OCC) patients after postoperative intensity modulated radiotherapy (IMRT) with concomitant systemic therapy. Methods All patients with locally advanced (AJCC stage III/IV) or high-risk OCC (AJCC stage II) who underwent postoperative IMRT at our institution between December 2006 and July 2010 were retrospectively analyzed. The primary endpoint was locoregional recurrence-free survival (LRRFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), acute and late toxicities. Results Overall 53 patients were analyzed. Twenty-three patients (43%) underwent concomitant chemotherapy with cisplatin, two patients with carboplatin (4%) and four patients were treated with the monoclonal antibody cetuximab (8%). At a median follow-up of 2.3 (range, 1.1–4.6) years the 3-year LRRFS, DMFS and OS estimates were 79%, 90%, and 73% respectively. Twelve patients experienced a locoregional recurrence. Eight patients, 5 of which had both a flap reconstruction and extracapsular extension (ECE), showed an unusual multifocal pattern of recurrence. Ten locoregional recurrences occurred marginally or outside of the high-risk target volumes. Acute toxicity grades of 2 (27%) and 3 (66%) and late toxicity grades of 2 (34%) and 3 (11%) were observed. Conclusion LRRFS after postoperative IMRT is satisfying and toxicity is acceptable. The majority of locoregional recurrences occurred marginally or outside of the high-risk target volumes. Improvement of high-risk target volume definition especially in patients with flap reconstruction and ECE might transfer into better locoregional control.

Deep brain stimulation of the globus pallidus internal improves symptoms of chorea-acanthocytosis

Chorea-acanthocytosis is a rare autosomal recessive disorder. To date, treatment is only symptomatic and supportive. Results from the few reports of chorea-acanthocytosis patients treated with deep brain stimulation (DBS) have been inconsistent. We present case reports for two patients with chorea-acanthocytosis who received DBS treatment and compare the outcomes with results from the literature. Both patients showed the typical clinical features of chorea-acanthocytosis with motor symptoms resistant to medical treatment. Chorea was significantly improved following low-frequency DBS treatment in both patients. However, dystonia was only mildly improved. Four chorea-acanthocytosis patients treated with DBS treatment have been reported in the literature. One patient had improvement with low-frequency DBS stimulation, while another two had improvement with higher-frequency DBS. One patient, however, did not improve with either low-frequency or high-frequency DBS. Bilateral DBS to the GPi can improve chorea and dystonia in some patients with intractable chorea-acanthocytosis. However, selection criteria for the most promising candidates must be defined, and the long-term benefits evaluated in clinical studies.