Working Memory-Related Neural Activity Predicts Future Smoking Relapse

Brief abstinence from smoking impairs cognition, particularly executive function, and this has a role in relapse to smoking. This study examined whether working memory-related brain activity predicts subsequent smoking relapse above and beyond standard clinical and behavioral measures. Eighty treatment-seeking smokers completed two functional magnetic resonance imaging sessions (smoking satiety vs 24 h abstinence challenge) during performance of a visual N-back task. Brief counseling and a short-term quit attempt followed. Relapse during the first 7 days was biochemically confirmed by the presence of the nicotine metabolite cotinine. Mean percent blood oxygen level-dependent (BOLD) signal change was extracted from a priori regions of interest: bilateral dorsolateral prefrontal cortex (DLPFC), medial frontal/cingulate gyrus, posterior cingulate cortex (PCC), and ventromedial prefrontal cortex. Signal from these brain regions and additional clinical measures were used to model outcome status, which was then validated with resampling techniques. Relapse to smoking was predicted by increased withdrawal symptoms, decreased left DLPFC and increased PCC BOLD percent signal change (abstinence vs smoking satiety). Receiver operating characteristic analysis demonstrated 81% area under the curve using these predictors, a significant improvement over the model with clinical variables only. The combination of abstinence-induced decreases in left DLPFC activation and reduced suppression of PCC may be a prognostic marker for poor outcome, specifically early smoking relapse.     

Role of endogenous TRPV1 agonists in a postburn pain model of partial-thickness injury

Oxidized linoleic acid metabolites (OLAMs) are a class of endogenous transient receptor potential vanilloid 1 (TRPV1) channel agonists released on exposure of tissue to transient noxious temperatures. These lipid compounds also contribute to inflammatory and heat allodynia. Because persistent pain after a burn injury represents a significant clinical challenge for treatment, we developed an in vivo rat model of partial-thickness cutaneous thermal injury and examined whether TRPV1 and specific OLAM metabolites play a role in mediating postburn pain injury. This peripheral model of burn injury had marked thermal allodynia peaking at 24 h after thermal injury, with allodynia being maintained for up to 7 d. Immunohistochemical characterization of tissue taken from injury sites revealed an increase in leukocyte/macrophage infiltration that was colocalized with TRPV1-positive fibers. Using this peripheral thermal injury model, we found that pharmacological blockade of peripheral TRPV1 receptors reduced thermal allodynia by about 98%. Moreover, there was a significant increase in OLAM levels compared to naive controls in hind paw skin biopsies. Additional studies of the metabolism of [C¹⁴]-linoleic acid in skin biopsies revealed the role of the cytochrome P450 (CYP) system in mediating the metabolism of linoleic acid after thermal injury. Finally, we demonstrated that direct inhibition of OLAMs using OLAM antibodies and indirect inhibition using the CYP inhibitor ketoconazole significantly reduced postburn thermal allodynia. Collectively, these findings point to a novel role of the OLAMs and CYP-related enzymes in generating postburn allodynia via activation of peripheral TRPV1.     

Impact of puberty on the evolution of cerebral perfusion during adolescence

Puberty is the defining biological process of adolescent development, yet its effects on fundamental properties of brain physiology such as cerebral blood flow (CBF) have never been investigated. Capitalizing on a sample of 922 youths ages 8–22 y imaged using arterial spin labeled MRI as part of the Philadelphia Neurodevelopmental Cohort, we studied normative developmental differences in cerebral perfusion in males and females, as well as specific associations between puberty and CBF. Males and females had conspicuously divergent nonlinear trajectories in CBF evolution with development as modeled by penalized splines. Seventeen brain regions, including hubs of the executive and default mode networks, showed a robust nonlinear age-by-sex interaction that surpassed Bonferroni correction. Notably, within these regions the decline in CBF was similar between males and females in early puberty and only diverged in midpuberty, with CBF actually increasing in females. Taken together, these results delineate sex-specific growth curves for CBF during youth and for the first time to our knowledge link such differential patterns of development to the effects of puberty.Blood perfusion is one of the fundamental physiologic properties of any organ and is of particular relevance for the human brain, which receives 15% of cardiac output despite only representing 2% of body mass (1). Prior work has shown that cerebral blood flow (CBF) declines markedly throughout childhood and adolescence (2–4). Along with gray matter loss and white matter expansion (5), CBF thus represents one of the most important properties of brain physiology that changes during youth and may be critical for establishing normative growth charts of brain development. CBF is coupled to regional metabolism (6, 7), changes under cognitive demands (8), responds specifically to psychoactive drugs (9), and is abnormal in a variety of psychiatric conditions including schizophrenia (10) and addiction (11). Thus, characterization of normative trajectories of CBF during adolescent development is highly relevant for understanding both normal brain function and its aberrations in psychopathology.Growth curves of height, weight, and head circumference used in typical pediatric practice are separated by sex, because the timing and tempo of growth are different among males and females. One reason for this is the influence of puberty, which is the defining biological process of adolescence. Puberty results in divergent, sex-specific maturation that is driven by the influence of steroid and other metabolic hormones including estrogen and testosterone. Prior work has demonstrated sex differences in patterns of structural brain development (5, 12), and a growing body of literature has begun to establish the influence of puberty on this process (13, 14).In contrast to research on structural brain development, work on cerebral perfusion during development has thus far been relatively sparse. Early research by Kennedy and Sokoloff (15), using a modified Kety–Schmidt nitrous oxide method (16), established that whole-brain CBF was 106 mL⋅100 g⁻¹⋅min⁻¹ in children, compared with 60 mL⋅100 g⁻¹⋅min⁻¹ in adults. Later, CBF was measured on a regional basis using techniques such as ¹³³Xe clearance or ¹⁵O PET. However, sample sizes of these studies were limited by the need for ionizing radiation exposure, which is particularly problematic in pediatric populations. Nonetheless, these studies reliably demonstrated that CBF is elevated during childhood then declines throughout adolescence (3, 17, 18). In adulthood, females have higher CBF than males (8, 19). However, prior nuclear imaging studies in youth were too small (typically n = 20–40) to characterize sex differences during development.Arterial spin labeling (ASL) using MRI permits noninvasive quantification of cerebral perfusion without the use of ionizing radiation (20, 21) but gives comparable gray matter CBF measurements when validated versus PET (22, 23). This feature provides a critical advantage for applications in pediatric populations (4), allowing for a substantial increase in sample size. Using ASL, Taki et al. (24, 25) replicated prior findings of declining perfusion in adolescence and also reported that females had higher perfusion in the posterior cingulate cortex (pCC), owing to a steeper rate of CBF decline in males. However, it is not known whether such effects are limited only to the pCC or whether developmental trajectories of perfusion differ between males and females in other regions, potentially in a complex nonlinear fashion. Divergent trajectories in multiple regions are to be expected, because adult females have higher CBF than males across brain regions beyond the pCC (8, 19, 26, 27). However, it is not yet known when such differences emerge in development.Importantly, no study has investigated whether emerging sex differences in cerebral perfusion seen in adolescence are due to the differential impact of puberty. Studies from both animals and humans provide good reason to suspect that puberty may play a key role in CBF sex differences: Estrogens increase CBF in both animals and humans and also may promote neurogenesis and axonal sprouting (28–31). However, because the progression of age and puberty are correlated, large samples are required to systematically parse the relative influence of each. Here, we investigated developmental patterns of cerebral perfusion in males and females using ASL data from the Philadelphia Neurodevelopmental Cohort (PNC) (32), which constitutes the largest sample of cerebral perfusion yet reported. We hypothesized that differences in cerebral perfusion between males and females would relate to the impact of puberty. As described below, we found pronounced evidence for differential patterns of developmental perfusion in males and females, driven in part by the effects of puberty.     

Investigation on the reduction of electron contamination with a 6-MV x-ray beam

Experimental investigations have been carried out on the reduction of electron contamination of a 6-MV x-ray beam of Clinac model 1800 for square field sizes 5 X 5 to 30 X 30 cm2 in steps of 5 cm and for rectangular field sizes 19 X 7 and 7 X 19 cm2. The electron contamination of both the open beam and the beam with the tray can be effectively reduced by placing a lead foil filter immediately below the blocking tray. Measurements at 100-cm source-skin distance with filter in place showed a reduction in dose in the buildup region and also a displacement of the location of Dmax to greater depths, even for small field sizes such as 10 X 10 cm2.     

TEP and Lichtenstein anatomy: does simulation accelerate acquisition among interns?

Purpose

The anatomy of the inguinal region is notoriously challenging to master. We sought to teach open inguinal hernia (OIH) and totally extraperitoneal (TEP) anatomy with simulation models among general surgery (GS) interns.

Methods

Low-fidelity OIH and TEP models were constructed out of cardboard, plastic bins, fabric, and yarn. GS interns (n = 30) participated in a 3-h hernia session including a pretest, anatomy lecture, simulated OIH and TEP hernia repair, and posttest. Pre- and posttest scores were based on a difficult 30-point exam which included didactic questions (10 points), drawing relevant TEP (10 points), and OIH (10 points) anatomy. Participants were surveyed following the session.

Results

Median pretest scores were 13 % (range 0–60 %). Median posttest scores improved to 47 % (range 20–93 %, p < 0.001). Median number of structures drawn in the TEP image improved from 2 (range 0–14) to 11 (range 1–21, p < 0.001). Median number of structures drawn in the OIH image improved from 3 (range 0–15) to 7 (range 1–19, p < 0.001). 67 % (12/18) demonstrated improvement in knowledge of abdominal wall layers. 23 % (7/30) knew the triangles of pain/doom on the pretest vs. 77 % (23/30) on the posttest. Mean Likert scores favored session enjoyability (4.5), not a waste of training time (4.4), and improved understanding of OIH and TEP anatomy (4.4, 4.2).

Conclusions

Low-fidelity simulators can be used to teach and assess knowledge of TEP and OIH anatomy. While enjoyable and useful, one 3-h session does not create master hernia surgeons or expert anatomists out of novice trainees.

     

Bone mineral density in breast cancer patients with positive estrogen receptor tumor status

AIM: The aim was to investigate bone mineral density (BMD) in breast cancer patients with positive estrogen receptor (ER) tumor status. METHODS: The participants were 110 postmenopausal breast cancer patients with positive estrogen receptor (ER+) tumor status. Two hundred and sixty-one age-matched, healthy postmenopausal women, all of whom were selected from our pooled data, served as controls. Age, age at menopause, years since menopause (YSM), height, weight, and body mass index (BMI, wt/ht(2)) were recorded. Lumbar spine (L2-4) BMD and Z-score were assessed by dual-energy X-ray absorptiometry. RESULTS: Bone mineral density in breast cancer patients was significantly higher than that in controls (0.89+/-0.12 g/cm(2) versus 0.84+/-0.16 g/cm(2), P<0.01). The Z-score in breast cancer patients was also higher than that in controls (110+/-13.6% versus 100+/-9.8%, P<0.001). Higher BMD and Z-score in breast cancer patients remained significant after adjusting for age, YSM, and BMI (P<0.05). CONCLUSIONS: Postmenopausal breast cancer patients with positive ER tumor status have higher BMD. Positive ER tumor status may be associated with higher cumulative exposure to estrogen.     

A quantitative model to predict pathogenicity of missense variants in the TP53 gene

Germline pathogenic variants in the TP53 gene cause Li‐Fraumeni syndrome, a condition that predisposes individuals to a wide range of cancer types. Identification of individuals carrying a TP53 pathogenic variant is linked to clinical management decisions, such as the avoidance of radiotherapy and use of high‐intensity screening programs. The aim of this study was to develop an evidence‐based quantitative model that integrates independent in silico data (Align‐GVGD and BayesDel) and somatic to germline ratio (SGR), to assign pathogenicity to every possible missense variant in the TP53 gene. To do this, a likelihood ratio for pathogenicity (LR) was derived from each component calibrated using reference sets of assumed pathogenic and benign missense variants. A posterior probability of pathogenicity was generated by combining LRs, and algorithm outputs were validated using different approaches. A total of 730 TP53 missense variants could be assigned to a clinically interpretable class. The outputs of the model correlated well with existing clinical information, functional data, and ClinVar classifications. In conclusion, these quantitative outputs provide the basis for individualized assessment of cancer risk useful for clinical interpretation. In addition, we propose the value of the novel SGR approach for use within the ACMG/AMP guidelines for variant classification.     

Resting quantitative cerebral blood flow in schizophrenia measured by pulsed arterial spin labeling perfusion MRI

Arterial spin labeling (ASL) perfusion MRI is a relatively novel technique that can allow for quantitative measurement of cerebral blood flow (CBF) by using magnetically labeled arterial blood water as an endogenous tracer. Available data on resting CBF in schizophrenia primarily come from invasive and expensive nuclear medicine techniques that are often limited to small samples and yield mixed results. The noninvasive nature of ASL offers promise for larger-scale studies. The utility of this approach was examined in 24 healthy controls and 30 patients with schizophrenia. Differences between groups in quantitative CBF were assessed, as were relationships between CBF and psychiatric symptoms. Group comparisons demonstrated greater CBF for controls in several regions including bilateral precuneus and middle frontal gyrus. Patients showed increased CBF in left putamen/superior corona radiata and right middle temporal gyrus. For patients, greater severity of negative symptoms was associated with reduced CBF in bilateral superior temporal gyrus, cingulate gyrus, and left middle frontal gyrus. Increased severity of positive symptoms was related to both higher CBF in cingulate gyrus and superior frontal gyrus and decreased CBF in precentral gyrus/middle frontal gyrus. These findings support the feasibility and utility of implementing ASL in schizophrenia research and expand upon previous results.     

Leptin production in pre- and postmenopausal women

OBJECTIVES: To investigate the differences in leptin production between pre- and postmenopausal women. METHODS: Subjects were 75 pre- and 75 postmenopausal women. Age, height, weight, and body mass index (BMI, wt/ht(2)) were recorded. Serum leptin levels were measured by RIA. Total body fat mass and percentage of body fat mass were measured by whole-body scanning with dual-energy X-ray absorptiometry. Serum leptin levels, the ratio of serum leptin levels to total body fat mass (leptin-fat mass ratio), baseline characteristics, and anthropometric variables were compared between the two groups. In all subjects (n=150), relationship of serum leptin levels with menopausal status (pre- and postmenopause) was investigated by univariate and multiple regression analysis. RESULTS: Serum leptin levels in premenopausal women 8.4+/-4.8 ng/ml, which did not differ from that in postmenopausal women (9.2+/-7.1 ng/ml). Total body fat mass, percentage of body fat mass, and BMI did not differ between the two groups. Leptin-fat mass ratio in premenopausal women was 0.43+/-0.17 ng/ml/kg, which did not differ from that in postmenopausal women (0.44+/-0.24 ng/ml/kg). On both univariate and multiple regression analysis, serum leptin levels were not correlated with menopausal status. CONCLUSIONS: Menopausal status does not have a significant impact on leptin production.