Association between Alcohol Consumption and Pancreatic Cancer Risk: A Case-Control Study

Purpose

Evidence is inconsistent regarding alcohol and pancreatic cancer risk, although heavy drinking may increase risk.

Methods

A population-based case-control study was conducted using 345 pancreas cancer cases diagnosed 2011–2012 and 1,285 frequency-matched controls from Ontario, Canada. Logistic regression was used to evaluate alcohol consumption and pancreatic cancer risk; data was also stratified by sex and smoking status to assess interaction.

Results

Alcohol consumption was not associated with pancreatic cancer risk (age-adjusted odds ratio=0.78, 95% CI: 0.58, 1.05 for 1 - 3 drinks/week; age-adjusted odds ratio=0.86, 95% CI: 0.63, 1.17 for 4 - 20 drinks/week), however there was a non-significant increased risk for heavy drinkers consuming ≥21 drinks/week (age-adjusted odds ratio=1.35, 95% CI: 0.81, 2.27). Cigarette smoking modified the alcohol-cancer relationship; among current smokers, heavy alcohol consumption was associated with a significantly increased pancreatic cancer risk (age-adjusted odds ratio=4.04, 95% CI: 1.58, 10.37), whereas this significant association with heavy drinking was not observed among non-smokers (age-adjusted odds ratio=2.01, 95% CI: 0.50, 8.18). Furthermore, light – moderate alcohol intake was associated with increased pancreas cancer risk among current smokers.

Conclusions

While alcohol was not significantly associated with pancreatic cancer risk, smoking status modified this relationship such that among current smokers, alcohol intake was associated with a greater than two-fold increased risk of pancreatic cancer. The results should be interpreted with caution due to small sample sizes within subgroups and correction for multiple comparisons should be considered. These findings should be replicated in larger studies where more precise estimates of risk can be obtained.     

Quality Control Measures over 30 Years in a Multicenter Clinical Study: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.     

Sensitive isotope dilution liquid chromatography/tandem mass spectrometry method for quantitative analysis of bumetanide in serum and brain tissue

We have developed and validated a simple and sensitive stable isotope dilution liquid chromatography/tandem mass spectrometric (LC-MS/MS) method for the quantification of bumetanide in human serum. Samples were prepared with a simple acetonitrile based protein precipitation. The supernatant was then analyzed directly using LC-MS/MS. Chromatographic separation was achieved on a C18 reversed phase column using a methanol and water gradient. The detection was performed in selected reaction monitoring (SRM) mode via a positive electrospray ionization (ESI) interface. The method had a lower limit of quantification (LLOQ) of 1 ng/mL, linearity up to 1250 ng/mL, intra- and inter-day precision less than 10%, and accuracy within ±10%. This method was also demonstrated to be suitable for the analysis of bumetanide in rat serum and brain tissue. Bumetanide concentrations in rat serum and brain were determined for samples collected at several intervals following intraperitoneal (i.p.) injection of bumetanide, and were used to calculate bumetanide permeability through the blood-brain barrier.     

Exertional rhabdomyolysis in an adolescent athlete during preseason conditioning: a perfect storm

Cleary, MA, Sadowski, KA, Lee, SY-C, Miller, GL, and Nichols, AW. Exertional rhabdomyolysis in an adolescent athlete during preseason conditioning: a perfect storm. J Strength Cond Res 25(12): 3506-3513, 2011-The purpose of this brief review is to present a case of a healthy, male adolescent athlete (age = 16 years, body mass = 67.9 kg, height = 165.5 cm) who participated in a 3-day preseason wrestling camp which resulted in hospitalization for exertional rhabdomyolysis. As part of the preseason conditioning program directed by the coaches, the athlete completed 60 minutes of short, intense intervals of wall-sits, squats, sit-ups, push-ups, lunges, and plyometric jumps. The following day, the athlete continued his vigorous training consisting of running drills. That night he noticed voiding dark brown urine the color of cola. The day after the camp ended, the athlete reported to his Athletic Trainers with the chief complaint of severe bilateral leg pain in his quadriceps. Two days after the initial assessment, he was admitted to the hospital where he was diagnosed with exertional rhabdomyolysis based on creatine kinase (CK) levels that peaked at 146,000 IU·L, elevated far beyond normal (normal range = 58-280 IU·L). The athlete was hospitalized for 6 days where he received intravenous normal saline for rehydration, and his CK levels were assessed daily. Athletic Trainers, personal trainers, physical education teachers, and coaches should be aware that exertional rhabdomyolysis is the most common form of rhabdomyolysis and affects individuals who participate in novel and intense exercise to which they are unaccustomed. Stressful ambient conditions may lead to dehydration and exacerbation of the condition, particularly when the individual is not accustomed to the exercise intensity.     

Replication fork dynamics and dynamic mutations: the fork-shift model of repeat instability

Gene-specific repeat instability is responsible for >36 human diseases. Active instability varies in a tissue-, developmental stage- and locus-specific manner and occurs in both proliferative and non-proliferative cells. In proliferative cells, DNA replication can contribute to repeat instability either by switching the direction of replication, which changes the repeat sequence that serves as the lagging-strand template (origin switching), or by shifting the location of the origin of replication without altering the replication direction (origin shifting). We propose that changes in the dynamics of replication-fork progression, or architecture, will alter the location of the repeat within the single-stranded lagging-strand template, thereby influencing instability (fork shifting). The fork-shift model, which does not require origin relocation, is influenced by cis-elements and trans-factors associated with driving and maintaining replication forks. The fork-shift model can explain some of the complex behaviours of repeat instability because it is dynamic and responsive to variations in epigenomic and locus activity.     

Synthetic shRNAs as potent RNAi triggers

Designing potent silencing triggers is key to the successful application of RNA interference (RNAi) in mammals. Recent studies suggest that the assembly of RNAi effector complexes is coupled to Dicer cleavage. Here we examine whether transfection of optimized Dicer substrates results in an improved RNAi response. Dicer cleavage of chemically synthesized short hairpin RNAs (shRNAs) with 29-base-pair stems and 2-nucleotide 3' overhangs produced predictable homogeneous small RNAs comprising the 22 bases at the 3' end of the stem. Consequently, direct comparisons of synthetic small interfering RNAs and shRNAs that yield the same small RNA became possible. We found synthetic 29-mer shRNAs to be more potent inducers of RNAi than small interfering RNAs. Maximal inhibition of target genes was achieved at lower concentrations and silencing at 24 h was often greater. These studies provide the basis for an improved approach to triggering experimental silencing via the RNAi pathway.     

Abnormalities of caudal pharyngeal pouch development in Pbx1 knockout mice mimic loss of Hox3 paralogs

Pbx1 is a TALE-class homeodomain protein that functions in part as a cofactor for Hox class homeodomain proteins. Previous analysis of the in vivo functions of Pbx1 by targeted mutagenesis in mice has revealed roles for this gene in skeletal patterning and development and in the organogenesis of multiple systems. Both RNA expression and protein localization studies have suggested a possible role for Pbx1 in pharyngeal region development. As several Hox mutants have distinct phenotypes in this region, we investigated the potential requirement for Pbx1 in the development of the pharyngeal arches and pouches and their organ derivatives. Pbx1 homozygous mutants exhibited delayed or absent formation of the caudal pharyngeal pouches, and disorganized patterning of the third pharyngeal pouch. Formation of the third pouch-derived thymus/parathyroid primordia was also affected, with absent or hypoplastic primordia, delayed expression of organ-specific differentiation markers, and reduced proliferation of thymic epithelium. The fourth pouch and the fourth pouch-derived ultimobranchial bodies were usually absent. These phenotypes are similar to those previously reported in Hoxa3(-/-) single mutants and Hoxa1(-/-);Hoxb1(-/-) or Hoxa3(+/-);Hoxb3(-/-);Hoxd3(-/-) compound mutants, suggesting that Pbx1 acts together with multiple Hox proteins in the development of the caudal pharyngeal region. However, some aspects of the Pbx1 mutant phenotype included specific defects that were less severe than those found in known Hox mutant mice, suggesting that some functions of Hox proteins in this region are Pbx1-independent.     

The genome sequence of Mycoplasma hyopneumoniae strain 232, the agent of swine mycoplasmosis

We present the complete genome sequence of Mycoplasma hyopneumoniae, an important member of the porcine respiratory disease complex. The genome is composed of 892,758 bp and has an average G+C content of 28.6 mol%. There are 692 predicted protein coding sequences, the average protein size is 388 amino acids, and the mean coding density is 91%. Functions have been assigned to 304 (44%) of the predicted protein coding sequences, while 261 (38%) of the proteins are conserved hypothetical proteins and 127 (18%) are unique hypothetical proteins. There is a single 16S-23S rRNA operon, and there are 30 tRNA coding sequences. The cilium adhesin gene has six paralogs in the genome, only one of which contains the cilium binding site. The companion gene, P102, also has six paralogs. Gene families constitute 26.3% of the total coding sequences, and the largest family is the 34-member ABC transporter family. Protein secretion occurs through a truncated pathway consisting of SecA, SecY, SecD, PrsA, DnaK, Tig, and LepA. Some highly conserved eubacterial proteins, such as GroEL and GroES, are notably absent. The DnaK-DnaJ-GrpR complex is intact, providing the only control over protein folding. There are several proteases that might serve as virulence factors, and there are 53 coding sequences with prokaryotic lipoprotein lipid attachment sites. Unlike other mycoplasmas, M. hyopneumoniae contains few genes with tandem repeat sequences that could be involved in phase switching or antigenic variation. Thus, it is not clear how M. hyopneumoniae evades the immune response and establishes a chronic infection.     

Assessing the use of butterflies as indicators of logging in Borneo at three taxonomic levels

Logging is an issue of major conservation concern. Less than 5% of tropical forests are currently protected, and many of these are in so-called "paper parks." Many species may therefore depend on exploited forests, and management decisions concerning these forests will be a major determinant of their survival. An important aspect of forest management will entail the use of reliable, practical, and inexpensive indicator taxa to monitor exploitation. Here, butterflies are proposed as such indicators. Species, generic, and subfamily richness was significantly higher in logged than unlogged forest and community composition differed significantly at all three taxonomic levels (species, genus, and subfamily). Richness estimators were, furthermore, highly correlated among all three taxonomic levels. Significant individual indicator taxa were found at all three taxonomic levels, but the best overall taxa (highest indicator values) were found at the generic level and included the butterfly genera Ragadia and Paralaxita as indicators of unlogged forest and the genera Ypthima, Allotinus, and Athyma as indicators of logged forest. The use of genera instead of species presents a number of practical advantages. Identification is faster, easier, and more reliable. Genera can, furthermore, usually be identified "on the wing," thereby preventing accidental mortality due to capture.     

Sepsis progression and outcome: a dynamical model

Background  

Sepsis (bloodstream infection) is the leading cause of death in non-surgical intensive care units. It is diagnosed in 750,000 US patients per annum, and has high mortality. Current understanding of sepsis is predominately observational and correlational, with only a partial and incomplete understanding of the physiological dynamics underlying the syndrome. There exists a need for dynamical models of sepsis progression, based upon basic physiologic principles, which could eventually guide hourly treatment decisions.