Childhood maltreatment moderates the effect of combat exposure on cingulum structural integrity.

Limbic white matter pathways link emotion, cognition, and behavior and are potentially malleable to the influences of traumatic events throughout development. However, the impact of interactions between childhood and later life trauma on limbic white matter pathways has yet to be examined. Here, we examined whether childhood maltreatment moderated the effect of combat exposure on diffusion tensor imaging measures within a sample of military veterans (N = 28). We examined five limbic tracts of interest: two components of the cingulum (cingulum, cingulate gyrus, and cingulum hippocampus [CGH]), the uncinate fasciculus, the fornix/stria terminalis, and the anterior limb of the internal capsule. Using effect sizes, clinically meaningful moderator effects were found only within the CGH. Greater combat exposure was associated with decreased CGH fractional anisotropy (overall structural integrity) and increased CGH radial diffusivity (perpendicular water diffusivity) among individuals with more severe childhood maltreatment. Our findings provide preliminary evidence of the moderating effect of childhood maltreatment on the relationship between combat exposure and CGH structural integrity. These differences in CGH structural integrity could have maladaptive implications for emotion and memory, as well as provide a potential mechanism by which childhood maltreatment induces vulnerability to later life trauma exposure.

Technology, Affordances and Occupational Identity Amongst Older Telecommunications Engineers: From Living Machines to Black-Boxes.

This article explores the relationship between technology and occupational identity based on working-life biographical interviews with older telecommunications engineers. In the construction of their own working-life biographical narratives, participants attached great importance to the technology with which they worked. The article contends that workers' relationship with technology can be more nuanced than either the sociology of technology literature or the sociology of work literature accommodates. Adopting the concept of affordances, it is argued that the physical nature of earlier electromechanical technology afforded engineers the opportunity to 'fix' things through the skilled application of tools and act as autonomous custodians of 'living' machines: factors that were inherent to their occupational identity. However, the change to digital technology denied the affordances to apply hands-on skill and undermined key elements of the engineering occupational identity. Rather than simply reflecting the nostalgic romanticizing of the past, the biographies captured deterioration in the material realities of work.

Analysis and correction of crosstalk effects in pathway analysis.

Identifying the pathways that are significantly impacted in a given condition is a crucial step in understanding the underlying biological phenomena. All approaches currently available for this purpose calculate a P-value that aims to quantify the significance of the involvement of each pathway in the given phenotype. These P-values were previously thought to be independent. Here we show that this is not the case, and that many pathways can considerably affect each other's P-values through a "crosstalk" phenomenon. Although it is intuitive that various pathways could influence each other, the presence and extent of this phenomenon have not been rigorously studied and, most importantly, there is no currently available technique able to quantify the amount of such crosstalk. Here, we show that all three major categories of pathway analysis methods (enrichment analysis, functional class scoring, and topology-based methods) are severely influenced by crosstalk phenomena. Using real pathways and data, we show that in some cases pathways with significant P-values are not biologically meaningful, and that some biologically meaningful pathways with nonsignificant P-values become statistically significant when the crosstalk effects of other pathways are removed. We describe a technique able to detect, quantify, and correct crosstalk effects, as well as identify independent functional modules. We assessed this novel approach on data from four experiments involving three phenotypes and two species. This method is expected to allow a better understanding of individual experiment results, as well as a more refined definition of the existing signaling pathways for specific phenotypes.

Understanding Local Alcohol Control in Wisconsin: Building a Database of Local Municipal Alcohol Policies.

In Wisconsin, many alcohol policies are regulated at the local level. To examine the relationship between local policies, alcohol use and health outcomes, our team developed a database to collect local alcohol policies. Initial results highlight differences in how policies are defined, enforced, and made available to the public.

Long-term results of hypofractionated radiation therapy for breast cancer.

BACKGROUND: The optimal fractionation schedule for whole-breast irradiation after breast-conserving surgery is unknown. METHODS: We conducted a study to determine whether a hypofractionated 3-week schedule of whole-breast irradiation is as effective as a 5-week schedule. Women with invasive breast cancer who had undergone breast-conserving surgery and in whom resection margins were clear and axillary lymph nodes were negative were randomly assigned to receive whole-breast irradiation either at a standard dose of 50.0 Gy in 25 fractions over a period of 35 days (the control group) or at a dose of 42.5 Gy in 16 fractions over a period of 22 days (the hypofractionated-radiation group). RESULTS: The risk of local recurrence at 10 years was 6.7% among the 612 women assigned to standard irradiation as compared with 6.2% among the 622 women assigned to the hypofractionated regimen (absolute difference, 0.5 percentage points; 95% confidence interval [CI], -2.5 to 3.5). At 10 years, 71.3% of women in the control group as compared with 69.8% of the women in the hypofractionated-radiation group had a good or excellent cosmetic outcome (absolute difference, 1.5 percentage points; 95% CI, -6.9 to 9.8). CONCLUSIONS: Ten years after treatment, accelerated, hypofractionated whole-breast irradiation was not inferior to standard radiation treatment in women who had undergone breast-conserving surgery for invasive breast cancer with clear surgical margins and negative axillary nodes. (ClinicalTrials.gov number, NCT00156052.)

Novel heterocyclic DPP-4 inhibitors for the treatment of type 2 diabetes.

Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man.

Controlled in situ nanoscale enhancement of gold nanowire arrays with plasmonics.

The controlled in situ growth of ordered gold nanoparticles and nanowire arrays has been studied by optically tracking changes in the local surface plasmon resonance (LSPR) spectrum. A spectrometer and custom-programmed analysis software track changes in the LSPR spectrum. The peak position, peak height (i.e. extinction intensity) and peak width (e.g. radius of curvature) were tracked over time to quantify the dynamic growth of gold as soon as the system was exposed to a commercial gold enhancement solution. This enables the controlled dynamic growth of nano-objects without the necessity of characterizing the growth and aggregation kinetics of the gold enhancement solution. The result was the successful enhancement of their electrically conductive and plasmonic properties, as well as the controlled growth and transformation of line-patterned nanoparticles into conductive particle-based nanowires.

A review of the outcomes of children with designated additional needs receiving cochlear implantation for severe to profound hearing loss.

OBJECTIVE: To evaluate one year outcomes of children with additional needs receiving cochlear implantation at the Yorkshire Auditory Implant Service (YAIS) over a ten-year period. METHODS: Retrospective chart review yielded 270 children who received cochlear implants (CIs) at YAIS between 2007 and 2017; 49 children were classified as having additional needs. Audiological performance scales (Meaningful Auditory Information Scale (MAIS), Meaningful Use of Speech Scale (MUSS), Listening in Progress (LIP), Categories of Auditory Performance (CAP), and Speech Intelligibility Rating Scale (SIR)) were analysed pre- and 12 months post-implantation. Comparison was made with children without additional needs. RESULTS: Children with additional needs demonstrated significantly lower pre-implantation audiological performance in MAIS, LIP, and MUSS (P <0.05). Despite showing improvement, children with additional needs consistently achieved lower scores in all metrics at one year (P < 0.05). Similarly, the rate of change was statistically significantly lower in children with additional needs. CONCLUSION: All children were able to gain access to sound following CI. Improvements were seen in all outcome measures especially in the MAIS, CAP and LIP whereas limited improvement was seen in measures assessing speech production and improvement. The rate of improvement was statistically significantly lower in children with additional needs.

Optical sensing with simultaneous electrochemical control in metal nanowire arrays.

This work explores the alternative use of noble metal nanowire systems in large-scale array configurations to exploit both the nanowires' conductive nature and localized surface plasmon resonance (LSPR). The first known nanowire-based system has been constructed, with which optical signals are influenced by the simultaneous application of electrochemical potentials. Optical characterization of nanowire arrays was performed by measuring the bulk refractive index sensitivity and the limit of detection. The formation of an electrical double layer was controlled in NaCl solutions to study the effect of local refractive index changes on the spectral response. Resonance peak shifts of over 4 nm, a bulk refractive index sensitivity up to 115 nm/RIU and a limit of detection as low as 4.5 × 10(-4) RIU were obtained for gold nanowire arrays. Simulations with the Multiple Multipole Program (MMP) confirm such bulk refractive index sensitivities. Initial experiments demonstrated successful optical biosensing using a novel form of particle-based nanowire arrays. In addition, the formation of an ionic layer (Stern-layer) upon applying an electrochemical potential was also monitored by the shift of the plasmon resonance.

Physical and Physiological Determinants of Rock Climbing.

PURPOSE: Rock climbing performance relies on many characteristics. Herein, the authors identified the physical and physiological determinants of peak performance in rock climbing across the range from lower grade to elite. METHODS: Forty four male and 33 female climbers with onsight maximal climbing grades 5a-8a and 5a-7b+, respectively, were tested for physical, physiological, and psychological characteristics (independent variables) that were correlated and modeled by multiple regression and principal component analysis to identify the determinants of rock climbing ability. RESULTS: In males, 23 of 47 variables correlated with climbing ability (P < .05, Pearson correlation coefficients .773-.340), including shoulder endurance, hand and finger strength, shoulder power endurance, hip flexibility, lower-arm grip strength, shoulder power, upper-arm strength, core-body endurance, upper-body aerobic endurance, hamstrings and lower-back flexibility, aerobic endurance, and open-hand finger strength. In females, 10 of 47 variables correlated with climbing ability (P < .05, Pearson correlation coefficients .742-.482): shoulder endurance and power, lower-arm grip strength, balance, aerobic endurance, and arm span. Principal component analysis and univariate multiple regression identified the main explanatory variables. In both sexes, shoulder power and endurance measured as maximum pull-ups, average arm crank power, and bent-arm hang, emerged as the main determinants (P < .01; adjusted R2 = .77 in males and .62 in females). In males, finger pincer (P = .07) and grip strength also had trends (P = .09) toward significant effects. Finally, in test-of-principle training studies, they trained to increase main determinants 42% to 67%; this improved climbing ability 2 to 3 grades. CONCLUSIONS: Shoulder power and endurance majorly determines maximal climbing. Finger, hand, and arm strength, core-body endurance, aerobic endurance, flexibility, and balance are important secondary determinants.

The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects.

Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis. A common variant in MTHFD1, p.Arg653Gln (c.1958G>A), may increase the risk for neural tube defects (NTD). To examine the biological impact of this variant on MTHFD1 function, we measured enzyme activity and stability in vitro and assessed substrate flux in transfected mammalian cells. The purified Arg653Gln enzyme has normal substrate affinity but a 36% reduction in half)life at 42 degrees C. Thermolability is reduced by magnesium adenosine triphosphate and eliminated by the substrate analog folate pentaglutamate, suggesting that folate status may modulate impact of the variant. The mutation reduces the metabolic activity of MTHFD1 within cells: formate incorporation into DNA in murine Mthfd1 knockout cells transfected with Arg653Gln is reduced by 26%+/-7.7% (P<0.05), compared to cells transfected with wild)type protein, indicating a disruption of de novo purine synthesis. We assessed the impact of the variant on risk for congenital heart defects (CHD) in a cohort of Quebec children (158 cases, 110 controls) and mothers of children with heart defects (199 cases, 105 controls). The 653QQ genotype in children is associated with increased risk for heart defects (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.01-4.42), particularly Tetralogy of Fallot (OR, 3.60; 95% CI, 1.38-9.42) and aortic stenosis (OR, 3.13; 95% CI, 1.13-8.66). There was no effect of maternal genotype. Our results indicate that the Arg653Gln polymorphism decreases enzyme stability and increases risk for CHD. Further evaluation of this polymorphism in folate)related disorders and its potential interaction with folate status is warranted.

Signal transducer and activator of transcription-3 is required in hypothalamic agouti-related protein/neuropeptide Y neurons for normal energy homeostasis.

Signal transducer and activator of transcription (Stat)-3 signals mediate many of the metabolic effects of the fat cell-derived hormone, leptin. In mice, brain-specific depletion of either the long form of the leptin receptor (Lepr) or Stat3 results in comparable obese phenotypes as does replacement of Lepr with an altered leptin receptor locus that codes for a Lepr unable to interact with Stat3. Among the multiple brain regions containing leptin-sensitive Stat3 sites, cells expressing feeding-related neuropeptides in the arcuate nucleus of the hypothalamus have received much of the focus. To determine the contribution to energy homeostasis of Stat3 expressed in agouti-related protein (Agrp)/neuropeptide Y (Npy) arcuate neurons, Stat3 was deleted specifically from these cells, and several metabolic indices were measured. It was found that deletion of Stat3 from Agrp/Npy neurons resulted in modest weight gain that was accounted for by increased adiposity. Agrp/Stat3-deficient mice also showed hyperleptinemia, and high-fat diet-induced hyperinsulinemia. Stat3 deletion in Agrp/Npy neurons also resulted in altered hypothalamic gene expression indicated by increased Npy mRNA and decreased induction of suppressor of cytokine signaling-3 in response to leptin. Agrp mRNA levels in the fed or fasted state were unaffected. Behaviorally, mice without Stat3 in Agrp/Npy neurons were mildly hyperphagic and hyporesponsive to leptin. We conclude that Stat3 in Agrp/Npy neurons is required for normal energy homeostasis, but Stat3 signaling in other brain areas also contributes to the regulation of energy homeostasis.

Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion.

Two known types of leptin-responsive neurons reside within the arcuate nucleus: the agouti gene-related peptide (AgRP)/neuropeptide Y (NPY) neuron and the proopiomelanocortin (POMC) neuron. By deleting the leptin receptor gene (Lepr) specifically in AgRP/NPY and/or POMC neurons of mice, we examined the several and combined contributions of these neurons to leptin action. Body weight and adiposity were increased by Lepr deletion from AgRP and POMC neurons individually, and simultaneous deletion in both neurons (A+P LEPR-KO mice) further increased these measures. Young (periweaning) A+P LEPR-KO mice exhibit hyperphagia and decreased energy expenditure, with increased weight gain, oxidative sparing of triglycerides, and increased fat accumulation. Interestingly, however, many of these abnormalities were attenuated in adult animals, and high doses of leptin partially suppress food intake in the A+P LEPR-KO mice. Although mildly hyperinsulinemic, the A+P LEPR-KO mice displayed normal glucose tolerance and fertility. Thus, AgRP/NPY and POMC neurons each play mandatory roles in aspects of leptin-regulated energy homeostasis, high leptin levels in adult mice mitigate the importance of leptin-responsiveness in these neurons for components of energy balance, suggesting the presence of other leptin-regulated pathways that partially compensate for the lack of leptin action on the POMC and AgRP/NPY neurons.

Electrochemical Biosensors - Sensor Principles and Architectures.

Quantification of biological or biochemical processes are of utmost importance for medical, biological and biotechnological applications. However, converting the biological information to an easily processed electronic signal is challenging due to the complexity of connecting an electronic device directly to a biological environment. Electrochemical biosensors provide an attractive means to analyze the content of a biological sample due to the direct conversion of a biological event to an electronic signal. Over the past decades several sensing concepts and related devices have been developed. In this review, the most common traditional techniques, such as cyclic voltammetry, chronoamperometry, chronopotentiometry, impedance spectroscopy, and various field-effect transistor based methods are presented along with selected promising novel approaches, such as nanowire or magnetic nanoparticle-based biosensing. Additional measurement techniques, which have been shown useful in combination with electrochemical detection, are also summarized, such as the electrochemical versions of surface plasmon resonance, optical waveguide lightmode spectroscopy, ellipsometry, quartz crystal microbalance, and scanning probe microscopy. The signal transduction and the general performance of electrochemical sensors are often determined by the surface architectures that connect the sensing element to the biological sample at the nanometer scale. The most common surface modification techniques, the various electrochemical transduction mechanisms, and the choice of the recognition receptor molecules all influence the ultimate sensitivity of the sensor. New nanotechnology-based approaches, such as the use of engineered ion-channels in lipid bilayers, the encapsulation of enzymes into vesicles, polymersomes, or polyelectrolyte capsules provide additional possibilities for signal amplification. In particular, this review highlights the importance of the precise control over the delicate interplay between surface nano-architectures, surface functionalization and the chosen sensor transducer principle, as well as the usefulness of complementary characterization tools to interpret and to optimize the sensor response.

Signal transducer and activator of transcription (stat) binding sites but not stat3 are required for fasting-induced transcription of agouti-related protein messenger ribonucleic acid.

Energy homeostasis depends on the regulation of hypothalamic neurons by leptin, an adipocyte hormone whose circulating levels communicate body energy stores. Leptin activates the transcription factor signal transducer and activator of transcription 3 (Stat3) in hypothalamic neurons, including neuronal subtypes producing Agouti-related protein (Agrp), a neuropeptide that stimulates feeding. Previous studies have suggested a model in which high levels of Agrp transcription during fasting represent a default state that is actively repressed by phospho-Stat3 induced by leptin signaling in the fed state. We identify putative Stat3 binding elements in the Agrp promoter that have been highly conserved during vertebrate evolution. Using a reporter assay in transgenic mice that faithfully recapitulates normal regulation of Agrp, we show that these sites are required, but in a way opposite to that predicted by the existing model: mutation of the sites leads to a default state characterized by a low level of Agrp transcription and insensitivity to fasting. We also find that removing activatable Stat3 from Agrp neurons has no detectable effect on steady-state levels of Agrp mRNA in the fed or fasted state. These results suggest a new model for transcriptional regulation of orexigenic neuropeptides in which the default level of expression is low in the fed state, and transcriptional activation in response to fasting is mediated by factors other than Stat3.

Radiotherapy With Curative Intent in Patients With Early-stage, Medically Inoperable, Non-Small-cell Lung Cancer: A Systematic Review.

Patients with early-stage non-small-cell lung cancer (NSCLC) who are unable to undergo surgery can be offered radiation therapy (RT). Previously, conventional RT was offered; however, newer techniques such as stereotactic body RT (SBRT) have become available. The objective of the present systematic review was to investigate the effectiveness of RT with curative intent in patients with early-stage medically inoperable NSCLC. MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing stereotactic RT with curative intent compared with observation or other types of RT for early-stage, medically inoperable, NSCLC. Comparisons of radiation dosing or fractionation schedules for SBRT were included. We include 4 systematic reviews and 52 observational studies. The evidence suggests that SBRT compared with observation or other forms of RT, such as accelerated hypofractionated RT, 3-dimensional conformal RT, conventional fractionated RT, external beam RT, proton beam therapy, and carbon ion therapy, could have similar or improved results in survival or local control, with similar or fewer adverse effects. Evidence also suggests that local tumor control and survival were associated with the biologically effective dose (BED) for SBRT. Several studies suggested a cutoff of approximately 100 BED correlated significantly with patient outcomes. The presented evidence suggests that SBRT compared with other forms of RT is a reasonable treatment option for patients with medically inoperable early-stage NSCLC.

Compromised local control due to treatment interruptions and late treatment breaks in early glottic cancer: Population-based outcomes study supporting need for intensified treatment schedules.

PURPOSE: This population-based study describes the treatment of early glottic cancer in Ontario, Canada and assesses whether treatment variations were associated with treatment effectiveness. METHODS AND MATERIALS: We studied 491 T1N0 and 213 T2N0 patients. Data abstracted from charts included age, sex, stage, treatment details, disease control, and survival. RESULTS: The total dose ranged from 50 to 70 Gy, and the daily dose ranged from 1.9 to 2.8 Gy. In 90%, treatment duration was between 25 and 50 days. Field sizes, field reductions, beam arrangement, and beam energy varied. Late treatment breaks occurred in 13.6% of T1N0 and 27.1% of T2N0 cases. Local control was comparable to other reports for T1N0 (82% at 5 years), but was only 63.2% in T2N0. Variables associated with local failure in T1N0 were age less than 49 years (relative risk [RR], 3.21; 95% confidence interval [CI], 1.49-6.90) and >3 treatment interruption days (RR, 2.43; 95% CI, 1.00-5.91). In T2N0, these were field reduction (RR, 2.33; 95% CI, 1.23-4.42) and late treatment breaks (RR, 2.19; 95% CI, 1.09-4.41). CONCLUSION: Some aspects of treatment for early glottic cancer were associated with worse local control. Problems with protracted treatment are of particular concern, underscoring the need for randomized studies to intensify radiotherapy.

Obesity-associated mutations in the human melanocortin-4 receptor gene.

Mutations in the human melanocortin-4 receptor (MC4R) gene have been associated with severe obesity. Many of the mutations result in partial or complete loss-of-function based on the nature of the mutation or the function of mutated receptors when tested in heterologous expression systems. This review discusses the role of MC4R in the central regulation of body weight, the pathogenic mechanisms of the mutations, and the validity of MC4R as an anti-obesity drug target.

Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer.

BACKGROUND: Breast irradiation after lumpectomy is an integral component of breast-conserving therapy that reduces the local recurrence of breast cancer. Because an optimal fractionation schedule (radiation dose given in a specified number of fractions or treatment sessions over a defined time) for breast irradiation has not been uniformly accepted, we examined whether a 22-day fractionation schedule was as effective as the more traditional 35-day schedule in reducing recurrence. METHODS: Women with invasive breast cancer who were treated by lumpectomy and had pathologically clear resection margins and negative axillary lymph nodes were randomly assigned to receive whole breast irradiation of 42.5 Gy in 16 fractions over 22 days (short arm) or whole breast irradiation of 50 Gy in 25 fractions over 35 days (long arm). The primary outcome was local recurrence of invasive breast cancer in the treated breast. Secondary outcomes included cosmetic outcome, assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Cosmetic Rating System. All statistical tests were two-sided. RESULTS: From April 1993 through September 1996, 1234 women were randomly assigned to treatment, 622 to the short arm and 612 to the long arm. Median follow-up was 69 months. Five-year local recurrence-free survival was 97.2% in the short arm and 96.8% in the long arm (absolute difference = 0.4%, 95% confidence interval [CI] = -1.5% to 2.4%). No difference in disease-free or overall survival rates was detected between study arms. The percentage of patients with an excellent or good global cosmetic outcome at 3 years was 76.8% in the short arm and 77.0% in the long arm; the corresponding data at 5 years were 76.8% and 77.4%, respectively (absolute difference = -0.6%, 95% CI = -6.5% to 5.5%). CONCLUSION: The more convenient 22-day fractionation schedule appears to be an acceptable alternative to the 35-day schedule.

The expression of mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase supports a role in rapid cell growth.

Deletion of the gene encoding NAD-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase (NMDMC) in mice was demonstrated previously to result in failure to establish definitive erythropoiesis in the developing liver. We examined the expression pattern of nmdmc to look for evidence that would support a tissue specific role for this activity. However, whole mount in situ hybridization revealed ubiquitous expression of nmdmc in the tissues of E9.5 and E10.5 embryos suggesting a broader role. Analysis of chimeras demonstrated that nmdmc-/- cells can survive in liver and other tissues of chimeras establishing that the null defect can be rescued by metabolites supplied by surrounding normal cells. Both the expression pattern and metabolite rescue support the proposal that mitochondrial NMDMC provides one-carbon units for purine synthesis during embryogenesis. The elevated expression of NMDMC in tumour cells, but not in surrounding normal cells, is predicted to result in significant differences in folate-mediated support for purine synthesis in the two cell types.