TCF7L2 gene polymorphisms do not predict susceptibility to diabetes in tropical calcific pancreatitis but may interact with SPINK1 and CTSB mutations in predicting diabetes

<p>Abstract</p> <p>Background</p> <p>Tropical calcific pancreatitis (TCP) is a type of chronic pancreatitis unique to developing countries in tropical regions and one of its important features is invariable progression to diabetes, a condition called fibro-calculous pancreatic diabetes (FCPD), but the nature of diabetes in TCP is controversial. We analysed the recently reported type 2 diabetes (T2D) associated polymorphisms in the <it>TCF7L2 </it>gene using a case-control approach, under the hypothesis that <it>TCF7L2 </it>variants should show similar association if diabetes in FCPD is similar to T2D. We also investigated the interaction between the <it>TCF7L2 </it>variants and N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations, since they are strong predictors of risk for TCP.</p> <p>Methods</p> <p>Two polymorphisms rs7903146 and rs12255372 in the <it>TCF7L2 </it>gene were analyzed by direct sequencing in 478 well-characterized TCP patients and 661 healthy controls of Dravidian and Indo-European ethnicities. Their association with TCP with diabetes (FCPD) and without diabetes was tested in both populations independently using chi-square test. Finally, a meta analysis was performed on all the cases and controls for assessing the overall significance irrespective of ethnicity. We dichotomized the whole cohort based on the presence or absence of N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations and further subdivided them into TCP and FCPD patients and compared the distribution of <it>TCF7L2 </it>variants between them.</p> <p>Results</p> <p>The allelic and genotypic frequencies for both <it>TCF7L2 </it>polymorphisms, did not differ significantly between TCP patients and controls belonging to either of the ethnic groups or taken together. No statistically significant association of the SNPs was observed with TCP or FCPD or between carriers and non-carriers of N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations. The minor allele frequency for rs7903146 was different between TCP and FCPD patients carrying the N34S <it>SPINK1 </it>variant but did not reach statistical significance (OR = 1.59, 95% CI = 0.93–2.70, P = 0.09), while, <it>TCF7L2</it><it/>variant showed a statistically significant association between TCP and FCPD patients carrying the 26V allele (OR = 1.69, 95% CI = 1.11–2.56, P = 0.013).</p> <p>Conclusion</p> <p>Type 2 diabetes associated <it>TCF7L2 </it>variants are not associated with diabetes in TCP. Since, <it>TCF7L2 </it>is a major susceptibility gene for T2D, it may be hypothesized that the diabetes in TCP patients may not be similar to T2D. Our data also suggests that co-existence of <it>TCF7L2 </it>variants and the <it>SPINK1 </it>and <it>CTSB </it>mutations, that predict susceptibility to exocrine damage, may interact to determine the onset of diabetes in TCP patients.</p

Antigenotoxic potential of rutin and quercetin in Swiss mice exposed to gamma radiation

Background: Ionizing radiation induces a variety of genetic damages through the formation free radicals such as reactive oxygen species (ROS). Appropriate antioxidant intervention may inhibit or reduce free radical toxicity and thus offer protection against radiation. Rutin (RUT) and quercetin (QRT) are flavonoids known to be potent dietary antioxidants. Methods: The present study tested the antigenotoxic effect of RUT and QRT in vivo against radiation- induced chromosomal damage. Swiss albino mice were administered orally with RUT and QRT (10 and 20 mg/kg b.wt.) once daily for five consecutive days. One hour after the last administration of RUT and QRT on the fifth day, the animals were whole body exposed to 3 Gy gamma radiation. The anti-genotoxic potential was assessed in terms of chromosomal aberrations, micronucleus test, and alkaline comet assay. Results: Significant decline in dicentric formation was observed in RUT and QRT treated group. Further, the antigenotoxic potential of RUT and QRT caused a significant (p < 0.001) reduction in micronucleated polychromatic, normochromatic erythrocytes; increased PCE/NCE ratio was observed in the RUT and QRT treated group. Administration of RUT and QRT before irradiation resulted in a significant (p < 0.01) decrease in the DNA damage at the post-irradiation time when compared with irradiation alone group. Conclusions: Present findings demonstrate the potential of RUT and QRT in mitigating radiation-induced mortality and cytogenetic damage, which may be attributed to scavenging of radiation-induced free radicals

Synthesis of Perdeuterated Linoleic Acid-d31 and Chain Deuterated 1-Palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine-d62

Herein, we report a gram-scale synthesis of perdeuterated linoleic acid-d31. The starting materials for the synthesis are two saturated fatty acids, azelaic acid-d14 and pentanoic acid-d9, which can be obtained by metal catalysed hydrothermal hydrogen-deuterium exchange. The synthesis utilises the fatty acids directly via decarboxylative coupling. Copper catalysed coupling of a terminal alkyne intermediate with a propargyl bromide derivative affords a skipped diyne, which can be reduced using P-2 nickel to obtain the desired cis,cis-diene geometry. The subsequent synthesis of the tail-deuterated phospholipid, 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine-d62 (PLPC-d62) is also described. Optimised reaction conditions were developed to access this phospholipid and its regioisomeric purity was characterised by two complementary mass spectrometry techniques.</p

Dependence of organic interlayer diffusion on glass-transition temperature in OLEDs

Organic light-emitting diodes (OLEDs) are subject to thermal stress from Joule heating and the external environment. In this work, neutron reflectometry (NR) was used to probe the effect of heat on the morphology of thin three-layer organic films comprising materials typically found in OLEDs. It was found that layers within the films began to mix when heated to approximately 20 °C above the glass-transition temperature (T) of the material with the lowest T. Diffusion occurred when the material with the lowest T formed a supercooled liquid, with the rates of interdiffusion of the materials depending on the relative T's. If the supercooled liquid formed at a temperature significantly lower than the T of the higher-T material in the adjacent layer, then pseudo-Fickian diffusion occurred. If the two T's were similar, then the two materials can interdiffuse at similar rates. The type and extent of diffusion observed can provide insight into and a partial explanation for the "burn in" often observed for OLEDs. Photoluminescence measurements performed simultaneously with the NR measurements showed that interdiffusion of the materials from the different layers had a strong effect on the emission of the film, with quenching generally observed. These results emphasize the importance of using thermally stable materials in OLED devices to avoid film morphology changes

Expert consensus on endoscopic papillectomy using a Delphi process

Background and Aims: Consensus regarding an optimal algorithm for endoscopic treatment of papillary adenomas has not been established. We aimed to assess the existing degree of consensus among international experts and develop further concordance by means of a Delphi process. Methods: Fifty-two international experts in the field of endoscopic papillectomy were invited to participate. Data were collected between August and December 2019 using an online survey platform. Three rounds were conducted. Consensus was defined as >= 70% agreement. Results: Sixteen experts (31%) completed the full process, and consensus was achieved on 47 of the final 79 statements (59%). Diagnostic workup should include at least an upper endoscopy using a duodenoscope (100%) and biopsy sampling (94%). There should be selected use of additional abdominal imaging (75%-81%). Patients with (suspected) papillary malignancy or over 1 cm intraductal extension should be referred for surgical resection (76%). To prevent pancreatitis, rectal nonsteroidal anti-inflammatory drugs should be administered before resection (82%) and a pancreatic stent should be placed (100%). A biliary stent is indicated in case of ongoing bleeding from the papillary region (76%) or concerns for a (micro)perforation after resection (88%). Follow-up should be started 3 to 6 months after initial papillectomy and repeated every 6 to 12 months for at least 5 years (75%). Conclusions: This is the first step in developing an international consensus-based algorithm for endoscopic management of papillary adenomas. Surprisingly, in many areas consensus could not be achieved. These aspects should be the focus of future studies.Peer reviewe

Primary ciliary dyskinesia ciliated airway cells show increased susceptibility to Haemophilus influenza biofilm formation

Nontypeable Haemophilus influenzae (NTHi) is the most common pathogen in primary ciliary dyskinesia (PCD) patients. We hypothesized that abnormal ciliary motility and low airway nitric oxide (NO) levels on airway epithelial cells from PCD patients might be permissive for NTHi colonization and biofilm evelopment. We used a primary epithelial cell co-culture model to investigate NTHi infection. Primary airway epithelial cells from PCD and non-PCD patients were differentiated to ciliation using air-liquid interface culture and then co-cultured with NTHi. NTHi adherence was greater on PCD epithelial cells compared to non-PCD cells (P&lt;0.05) and the distribution of NTHi on PCD epithelium showed more aggregated NTHi in biofilms (P&lt;0.001). Apart from defective ciliary motility, PCD cells did not significantly differ from non-PCD epithelial cells in the degree of ciliation and epithelial integrity or in cytokine, LL-37 and NO production. Treatment of PCD epithelia using exogenous NO and antibiotic significantly reduced NTHi viability in biofilms compared to antibiotic treatment alone. Impaired ciliary function was the primary defect in PCD airway epithelium underlying susceptibility to NTHi biofilm development compared with non-PCD epithelium. Although NO responses were similar, use of targeted NO with antibiotics enhanced killing of NTHi in biofilms, suggesting a novel therapeutic approach