CanGEM: mining gene copy number changes in cancer

The use of genome-wide and high-throughput screening methods on large sample sizes is a well-grounded approach when studying a process as complex and heterogeneous as tumorigenesis. Gene copy number changes are one of the main mechanisms causing cancerous alterations in gene expression and can be detected using array comparative genomic hybridization (aCGH). Microarrays are well suited for the integrative systems biology approach, but none of the existing microarray databases is focusing on copy number changes. We present here CanGEM (Cancer GEnome Mine), which is a public, web-based database for storing quantitative microarray data and relevant metadata about the measurements and samples. CanGEM supports the MIAME standard and in addition, stores clinical information using standardized controlled vocabularies whenever possible. Microarray probes are re-annotated with their physical coordinates in the human genome and aCGH data is analyzed to yield gene-specific copy numbers. Users can build custom datasets by querying for specific clinical sample characteristics or copy number changes of individual genes. Aberration frequencies can be calculated for these datasets, and the data can be visualized on the human genome map with gene annotations. Furthermore, the original data files are available for more detailed analysis. The CanGEM database can be accessed at http://www.cangem.org/

Linear response of mutans streptococci to increasing frequency of xylitol chewing gum use: a randomized controlled trial [ISRCTN43479664]

BACKGROUND: Xylitol is a naturally occurring sugar substitute that has been shown to reduce the level of mutans streptococci in plaque and saliva and to reduce tooth decay. It has been suggested that the degree of reduction is dependent on both the amount and the frequency of xylitol consumption. For xylitol to be successfully and cost-effectively used in public health prevention strategies dosing and frequency guidelines should be established. This study determined the reduction in mutans streptococci levels in plaque and unstimulated saliva to increasing frequency of xylitol gum use at a fixed total daily dose of 10.32 g over five weeks. METHODS: Participants (n = 132) were randomized to either active groups (10.32 g xylitol/day) or a placebo control (9.828 g sorbitol and 0.7 g maltitol/day). All groups chewed 12 pieces of gum per day. The control group chewed 4 times/day and active groups chewed xylitol gum at a frequency of 2 times/day, 3 times/day, or 4 times/day. The 12 gum pieces were evenly divided into the frequency assigned to each group. Plaque and unstimulated saliva samples were taken at baseline and five-weeks and were cultured on modified Mitis Salivarius agar for mutans streptococci enumeration. RESULTS: There were no significant differences in mutans streptococci level among the groups at baseline. At five-weeks, mutans streptococci levels in plaque and unstimulated saliva showed a linear reduction with increasing frequency of xylitol chewing gum use at the constant daily dose. Although the difference observed for the group that chewed xylitol 2 times/day was consistent with the linear model, the difference was not significant. CONCLUSION: There was a linear reduction in mutans streptococci levels in plaque and saliva with increasing frequency of xylitol gum use at a constant daily dose. Reduction at a consumption frequency of 2 times per day was small and consistent with the linear-response line but was not statistically significant

Experimental evolution gone wild

Because of their large population sizes and rapid cell division rates, marine microbes have, or can generate, ample variation to fuel evolution over a few weeks or months, and subsequently have the potential to evolve in response to global change. Here we measure evolution in the marine diatom Skeletonema marinoi evolved in a natural plankton community in CO2-enriched mesocosms deployed in situ. Mesocosm enclosures are typically used to study how the species composition and biogeochemistry of marine communities respond to environmental shifts, but have not been used for experimental evolution to date. Using this approach, we detect a large evolutionary response to CO2 enrichment in a focal marine diatom, where population growth rate increased by 1.3-fold in high CO2-evolved lineages. This study opens an exciting new possibility of carrying out in situ evolution experiments to understand how marine microbial communities evolve in response to environmental change

Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

IMPORTANCE: Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE: To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS: Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES: The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS: Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892

Comparative effects of dexmedetomidine, propofol, sevoflurane, and S-ketamine on regional cerebral glucose metabolism in humans: a positron emission tomography study

Introduction: The highly selective alpha(2)-agonist dexmedetomidine has become a popular sedative for neurointensive care patients. However, earlier studies have raised concern that dexmedetomidine might reduce cerebral blood flow without a concomitant decrease in metabolism. Here, we compared the effects of dexmedetomidine on the regional cerebral metabolic rate of glucose (CMRglu) with three commonly used anaesthetic drugs at equi-sedative doses.Methods: One hundred and sixty healthy male subjects were randomised to EC50 for verbal command of dexmedetomidine (1.5 ng ml (1); n=40), propofol (1.7 mu g ml (1); n=40), sevoflurane (0.9% end-tidal; n=40) or S-ketamine (0.75 mu g ml (1); n=20) or placebo (n=20). Anaesthetics were administered using target-controlled infusion or vapouriser with end-tidal monitoring. F-18-labelled fluorodeoxyglucose was administered 20 min after commencement of anaesthetic administration, and high-resolution positron emission tomography with arterial blood activity samples was used to quantify absolute CMRglu for whole brain and 15 brain regions.Results: At the time of [F-18]fluorodeoxyglucose injection, 55% of dexmedetomidine, 45% of propofol, 85% of sevoflurane, 45% of S-ketamine, and 0% of placebo subjects were unresponsive. Whole brain CMRglu was 63%, 71%, 71%, and 96% of placebo in the dexmedetomidine, propofol, sevoflurane, and S-ketamine groups, respectively (PConclusions: At equi-sedative doses in humans, potency in reducing CMRglu was dexmedetomidine>propofol>ketamine=placebo. These findings alleviate concerns for dexmedetomidine-induced vasoconstriction and cerebral ischaemia.</p

Effects of vatinoxan on cardiorespiratory function and gastrointestinal motility during constant-rate medetomidine infusion in standing horses

Background: Medetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral α2‐adrenoceptors. Vatinoxan, a peripheral α2‐antagonist, has been shown experimentally to alleviate the adverse effects of some α2‐agonists in horses. However, vatinoxan has not been investigated during constant‐rate infusion (CRI) of medetomidine in standing horses.Objectives: To evaluate effects of vatinoxan on cardiovascular function, gastrointestinal motility and on sedation level during CRI of medetomidine.Study design: Experimental, randomised, blinded, cross‐over study.Methods: Six healthy horses were given medetomidine hydrochloride, 7 μg/kg i.v., without (MED) and with (MED+V) vatinoxan hydrochloride, 140 μg/kg i.v., followed by CRI of medetomidine at 3.5 μg/kg/h for 60 min. Cardiorespiratory variables were recorded and borborygmi and sedation levels were scored for 120 min. Plasma drug concentrations were measured. The data were analysed using repeated measures ANCOVA and paired t‐tests as appropriate.Results: Initially heart rate (HR) was significantly lower and mean arterial blood pressure (MAP) significantly higher with MED compared with MED+V. For example at 10 min HR (mean ± s.d.) was 26 ± 2 and 31 ± 5 beats/minute (P = 0.04) and MAP 129 ± 15 and 103 ± 13 mmHg (PMain limitations: Experimental study with healthy, unstimulated animals.Conclusions: Vatinoxan administered i.v. with a loading dose of medetomidine improved cardiovascular function and gastrointestinal motility during medetomidine CRI in healthy horses. Sedation was slightly yet significantly reduced during the first 20 min.</p

The influence of maternal psychological distress on the mode of birth and duration of labor: findings from the FinnBrain Birth Cohort Study

Antepartum depression, general anxiety symptoms, and pregnancy-related anxiety have been recognized to affect pregnancy outcomes. Systematic reviews on these associations lack consistent findings, which is why further research is required. We examined the associations between psychological distress, mode of birth, epidural analgesia, and duration of labor. Data from 3619 women with singleton pregnancies, from the population-based FinnBrain Birth Cohort Study were analyzed. Maternal psychological distress was measured during pregnancy at 24 and 34 weeks, using the Pregnancy-Related Anxiety Questionnaire-Revised 2 (PRAQ-R2) and its subscale "Fear of Giving Birth" (FOC), the anxiety subscale of the Symptom Checklist-90 (SCL-90) and the Edinburgh Postnatal Depression Scale (EPDS). Mode of birth, epidural analgesia, and labor duration were obtained from the Finnish Medical Birth Register. Maternal psychological distress, when captured with PRAQ-R2, FOC, and SCL-90, increased the likelihood of women having an elective cesarean section (OR: 1.04, 95% CI 1.01-1.06, p = .003; OR: 1.13, 95% CI 1.07-1.20, p OR: 1.06, 95% CI 1.03-1.10, p = .001), but no association was detected for instrumental delivery or emergency cesarean section. A rise in both the PRAQ-R2, and FOC measurements increased the likelihood of an epidural analgesia (OR: 1.02, 95% CI 1.01-1.03, p = .003; OR: 1.09, 95% CI 1.05-1.12, p OR: 1.01, 95% CI 1.00-1.01, p = .023; OR: 1.03, 95% CI 1.02-1.05, p < .001). EPDS did not predict any of the analyzed outcomes. The results indicate that maternal anxiety symptoms (measured using PRAQ-R2, FOC, and SCL-90) are associated with elective cesarean section. Psychological distress increases the use of epidural analgesia, but is not associated with complicated vaginal birth.</p

Effects of intramuscular vatinoxan (MK-467), co-administered with medetomidine and butorphanol, on cardiopulmonary and anaesthetic effects of intravenous ketamine in dogs

Objective To investigate the impact of intramuscular (IM)co-administration of the peripheral α2-adrenoceptor agonist vatinoxan (MK-467) with medetomidine and butorphanol prior to intravenous (IV) ketamine on the cardiopulmonaryand anaesthetic effects in dogs, followed by atipamezole reversal.Study design Randomized, masked crossover study.Animals A total of eight purpose-bred Beagle dogs aged 3 years.Methods Each dog was instrumented and administered two treatments 2 weeks apart: medetomidine (20 µg kg-1) and butorphanol (100 µg kg-1) premedication with vatinoxan (500 µg kg-1; treatment MVB) or without vatinoxan (treatment MB) IM 20 minutes before IV ketamine (4 mg kg-1). Atipamezole (100 µg kg-1) was administered IM 60 minutes after ketamine. Heart rate (HR), mean arterial (MAP) and central venous (CVP) pressures and cardiac output (CO) were measured; cardiac (CI) and systemic vascular resistance (SVRI) indices were calculated before and 10 minutes after MVB or MB, and 10, 25, 40, 55, 70 and 100 minutes after ketamine. Data were analysed with repeated measures analysis of covariance models. A p-value Results At most time points, HR and CI were significantly higher, and SVRI and CVP significantly lower with MVB than with MB. With both treatments, SVRI and MAP decreased after ketamine, whereas HR and CI increased. MAP was significantly lower with MVB than with MB; mild hypotension (57-59 mmHg) was recorded in two dogs with MVB prior to atipamezole administration. Sedation, induction, intubation and recovery scores were not different between treatments, but intolerance to the endotracheal tube was observed earlier with MVB. Conclusions and clinical relevance Haemodynamic performance was improved by vatinoxan co-administration with medetomidine-butorphanol, before and after ketamine administration. However, vatinoxan was associated with mild hypotension after ketamine with the dose used in this  study.  Vatinoxan  shortened  the  duration  of anaesthesia.</p

Effects of vatinoxan on cardiorespiratory function, fecal output and plasma drug concentrations in horses anesthetized with isoflurane and infusion of medetomidine

A constant rate infusion (CRI) of medetomidine is used to balance equine inhalation anesthesia, but its cardiovascular side effects are a concern. This experimental crossover study aimed to evaluate the effects of vatinoxan (a peripheral α2-adrenoceptor antagonist) on cardiorespiratory and gastrointestinal function in anesthetized healthy horses. Six horses received medetomidine hydrochloride 7 μg/kg IV alone (MED) or with vatinoxan hydrochloride 140 μg/kg IV (MED + V). Anesthesia was induced with midazolam and ketamine and maintained with isoflurane and medetomidine CRI for 60 min. Heart rate, carotid and pulmonary arterial pressures, central venous pressure, cardiac output and arterial and mixed venous blood gases were measured. Selected cardiopulmonary parameters were calculated. Plasma drug concentrations were determined. Fecal output was measured over 24 h. For statistical comparisons, repeated measures analysis of covariance and paired t-tests were applied.Heart rate decreased slightly from baseline in the MED group. Arterial blood pressures decreased with both treatments, but significantly more dobutamine was needed to maintain normotension with MED + V (P = 0.018). Cardiac index (CI) and oxygen delivery index (DO2I) decreased significantly more with MED, with the largest difference observed at 20 min: CI was 39 ± 2 and 73 ± 18 (P = 0.009) and DO2I 7.4 ± 1.2 and 15.3 ± 4.8 (P = 0.014) mL/min/kg with MED and MED + V, respectively. Fecal output or plasma concentrations of dexmedetomidine did not differ between the treatments. In conclusion, premedication with vatinoxan induced hypotension, thus its use in anesthetized horses warrants further studies. Even though heart rate and arterial blood pressures remained clinically acceptable with MED, cardiac performance and oxygen delivery were lower than with MED + V.</p

Prenatal Maternal Psychological Distress and Offspring Risk for Recurrent Respiratory Infections

ObjectiveTo assess the relation between maternal prenatal psychological distress, comprising depression and anxiety symptoms and relationship quality, and the risk of recurrent respiratory infections (RRIs) in children up to 2 years of age. Children with RRIs frequently use health care services and antibiotics. Prenatal maternal psychological distress can be one, previously unidentified risk factor for RRIs.Study designThe study population was drawn from a population-based pregnancy cohort in Finland (www.finnbrain.fi). Children with RRIs (n = 204) and a comparison group (n = 1014) were identified by maternal reports at the child age of 12 or 24 months. The Edinburgh Postnatal Depression Scale, Symptom Checklist-90 anxiety subscale, the Pregnancy-Related Anxiety Questionnaire–Revised 2, and the Revised Dyadic Adjustment Scale were used to assess maternal symptoms and parental relationship quality at 34 weeks of gestation. Adjustment for maternal postnatal depressive and anxiety symptoms was performed.ResultsMaternal prenatal Edinburgh Postnatal Depression Scale (OR, 1.24; 95% CI, 1.08-1.44), Symptom Checklist-90/Anxiety (OR, 1.40; 95% CI, 1.01-1.76), Pregnancy-Related Anxiety Questionnaire–Revised 2 (OR, 1.28; 95% CI, 1.11-1.47), and Revised Dyadic Adjustment Scale (OR, 1.32; 95% CI, 1.01-1.58) total sum scores were associated with child RRIs by the age of 24 months. Greater number of siblings, shorter duration of breastfeeding, and the level of maternal education were also identified as risk factors for child RRIs.ConclusionsMaternal prenatal psychological distress is linked with a higher risk for child RRIs.</p