Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion.

We examined the role of innate cells in acquired resistance to the natural murine parasitic nematode, Nippostrongylus brasiliensis. Macrophages obtained from lungs as late as 45 d after N. brasiliensis inoculation were able to transfer accelerated parasite clearance to naive recipients. Primed macrophages adhered to larvae in vitro and triggered increased mortality of parasites. Neutrophil depletion in primed mice abrogated the protective effects of transferred macrophages and inhibited their in vitro binding to larvae. Neutrophils in parasite-infected mice showed a distinct transcriptional profile and promoted alternatively activated M2 macrophage polarization through secretory factors including IL-13. Differentially activated neutrophils in the context of a type 2 immune response therefore prime a long-lived effector macrophage phenotype that directly mediates rapid nematode damage and clearance.

Nasal and pharyngeal mucosal immunity to poliovirus in children following routine immunization with inactivated polio vaccine (IPV) in the United States of America.

BACKGROUND: Although polioviruses (PVs) replicate in lymphoid tissue of both the pharynx and ileum, research on polio vaccine-induced mucosal immunity has predominantly focused on intestinal neutralizing and binding antibody levels measured in stool. METHODS: To investigate the extent to which routine immunization with intramuscularly injected inactivated polio vaccine (IPV) may induce nasal and pharyngeal mucosal immunity, we measured PV type-specific neutralization and immunoglobulin (Ig) G, IgA, and IgM levels in nasal secretions, adenoid cell supernatants, and sera collected from 12 children, aged 2 to 5 years, undergoing planned adenoidectomies. All participants were routinely immunized with IPV and had no known contact with live PVs. RESULTS: PV-specific mucosal neutralization was detected in nasal and adenoid samples, mostly from children who had previously received four IPV doses. Across the three PV serotypes, both nasal (Spearman's rho ≥ 0.87, p≤0.0003 for all) and adenoid (Spearman's rho ≥0.57, p≤0.05 for all) neutralization titers correlated with serum neutralization titers. In this small study sample, there was insufficient evidence to determine which Ig isotype(s) was correlated with neutralization. CONCLUSIONS: Our findings provide policy-relevant evidence that routine immunization with IPV may induce nasal and pharyngeal mucosal immunity. The observed correlations of nasal and pharyngeal mucosal neutralization with serum neutralization contrast with previous observations of distinct intestinal and serum responses to PV vaccines. Further research is warranted to determine which antibody isotype(s) correlate with polio vaccine-induced nasal and pharyngeal mucosal neutralizing activity and to understand the differences from intestinal mucosal immunity.

A deep learning algorithm to detect cutaneous squamous cell carcinoma on frozen sections in Mohs micrographic surgery: A retrospective assessment.

Intraoperative margin analysis is crucial for the successful removal of cutaneous squamous cell carcinomas (cSCC). Artificial intelligence technologies (AI) have previously demonstrated potential for facilitating rapid and complete tumour removal using intraoperative margin assessment for basal cell carcinoma. However, the varied morphologies of cSCC present challenges for AI margin assessment. The aim of this study was to develop and evaluate the accuracy of an AI algorithm for real-time histologic margin analysis of cSCC. To do this, a retrospective cohort study was conducted using frozen cSCC section slides. These slides were scanned and annotated, delineating benign tissue structures, inflammation and tumour to develop an AI algorithm for real-time margin analysis. A convolutional neural network workflow was used to extract histomorphological features predictive of cSCC. This algorithm demonstrated proof of concept for identifying cSCC with high accuracy, highlighting the potential for integration of AI into the surgical workflow. Incorporation of AI algorithms may improve efficiency and completeness of real-time margin assessment for cSCC removal, particularly in cases of moderately and poorly differentiated tumours/neoplasms. Further algorithmic improvement incorporating surrounding tissue context is necessary to remain sensitive to the unique epidermal landscape of well-differentiated tumours, and to map tumours to their original anatomical position/orientation.

Evaluation of a Refined Implantable Resonator for Deep-Tissue EPR Oximetry in the Clinic.

OBJECTIVES: (1) Summarize revisions made to the implantable resonator (IR) design and results of testing to characterize biocompatibility;(2) Demonstrate safety of implantation and feasibility of deep tissue oxygenation measurement using electron paramagnetic resonance (EPR) oximetry. STUDY DESIGN: In vitro testing of the revised IR and in vivo implantation in rabbit brain and leg tissues. METHODS: Revised IRs were fabricated with 1-4 OxyChips with a thin wire encapsulated with two biocompatible coatings. Biocompatibility and chemical characterization tests were performed. Rabbits were implanted with either an IR with 2 oxygen sensors or a biocompatible-control sample in both the brain and hind leg. The rabbits were implanted with IRs using a catheter-based, minimally invasive surgical procedure. EPR oximetry was performed for rabbits with IRs. Cohorts of rabbits were euthanized and tissues were obtained at 1 week, 3 months, and 9 months after implantation and examined for tissue reaction. RESULTS: Biocompatibility and toxicity testing of the revised IRs demonstrated no abnormal reactions. EPR oximetry from brain and leg tissues were successfully executed. Blood work and histopathological evaluations showed no significant difference between the IR and control groups. CONCLUSIONS: IRs were functional for up to 9 months after implantation and provided deep tissue oxygen measurements using EPR oximetry. Tissues surrounding the IRs showed no more tissue reaction than tissues surrounding the control samples. This pre-clinical study demonstrates that the IRs can be safely implanted in brain and leg tissues and that repeated, non-invasive, deep-tissue oxygen measurements can be obtained using in vivo EPR oximetry.

Hunger and BMI modulate neural responses to sweet stimuli: fMRI meta-analysis.

OBJECTIVE: Consuming sweet foods, even when sated, can lead to unwanted weight gain. Contextual factors, such as longer time fasting, subjective hunger, and body mass index (BMI), may increase the likelihood of overeating. Nevertheless, the neural mechanisms underlying these moderating influences on energy intake are poorly understood. METHODS: We conducted both categorical meta-analysis and meta-regression of factors modulating neural responses to sweet stimuli, using data from 30 functional magnetic resonance imaging (fMRI) articles incorporating 39 experiments (N = 995) carried out between 2006 and 2019. RESULTS: Responses to sweet stimuli were associated with increased activity in regions associated with taste, sensory integration, and reward processing. These taste-evoked responses were modulated by context. Longer fasts were associated with higher posterior cerebellar, thalamic, and striatal activity. Greater self-reported hunger was associated with higher medial orbitofrontal cortex (OFC), dorsal striatum, and amygdala activity and lower posterior cerebellar activity. Higher BMI was associated with higher posterior cerebellar and insular activity. CONCLUSIONS: Variations in fasting time, self-reported hunger, and BMI are contexts associated with differential sweet stimulus responses in regions associated with reward processing and homeostatic regulation. These results are broadly consistent with a hierarchical model of taste processing. Hunger, but not fasting or BMI, was associated with sweet stimulus-related OFC activity. Our findings extend existing models of taste processing to include posterior cerebellar regions that are associated with moderating effects of both state (fast length and self-reported hunger) and trait (BMI) variables.

Multi-method assessment of palatable food exposure in women with and without eating disorders.

OBJECTIVE: Eating disorders (EDs) are characterized by dysregulated responses to palatable food. Using a multi-method approach, this study examined responses to palatable food exposure and subsequent ad libitum eating in women with binge-eating disorder (BED: n = 64), anorexia nervosa (AN: n = 16), and bulimia nervosa (BN: n = 35) and 26 healthy controls (HCs). METHOD: Participants were exposed to palatable food followed by an ad libitum eating opportunity. Affective and psychophysiological responses were measured before and during the task. RESULTS: Participants with EDs reported greater negative affect, particularly fear, following the food cue exposure, whereas HCs reported no change. BN and BED groups reported greater urge to binge after the food cue exposure, whereas AN and HC groups reported no change. Respiratory sinus arrhythmia levels, skin conductance and tonic skin conductance levels increased during food exposure for all groups. Across baseline and during the food exposure, the BED group had lower respiratory sinus arrhythmia levels relative to the BN and HC groups. The BED group consumed significantly more palatable food than the AN group. CONCLUSIONS: 'Palatable' food stimuli elicited more negative affect, particularly fear, in individuals with EDs; and this, rather than psychophysiological responses, distinguishes individuals with EDs from those without.

Assessment of executive functioning in binge-eating disorder independent of weight status.

OBJECTIVE: Executive functioning (EF) problems may serve as vulnerability or maintenance factors for Binge-Eating Disorder (BED). However, it is unclear if EF problems observed in BED are related to overweight status or BED status. The current study extends this literature by examining EF in overweight and normal-weight BED compared to weight-matched controls. METHOD: Participants were normal-weight women with BED (n = 23), overweight BED (n = 32), overweight healthy controls (n = 48), and normal-weight healthy controls (n = 29). The EF battery utilized tests from the National Institutes of Health (NIH) Toolbox and Delis-Kaplan Executive Function System (D-KEFS). RESULTS: After controlling for years of education and minority status, overweight individuals performed more poorly than normal-weight individuals on a task of cognitive flexibility requiring generativity (p < .01), and speed on psychomotor performance tasks (p = .01). Normal-weight and overweight BED performed worse on working memory tasks compared to controls (p = .04). Unexpectedly, normal-weight BED individuals out-performed all other groups on an inhibitory control task (p < .01). No significant differences were found between the four groups on tasks of planning. DISCUSSION: Regardless of weight status, BED is associated with working memory problems. Replication of the finding that normal-weight BED is associated with enhanced inhibitory control is needed.

Taste assessment in normal weight and overweight individuals with co-occurring Binge Eating Disorder.

BACKGROUND: Taste perception influences food choice, and may contribute to both weight status and disordered eating. Relatively little work has attempted to disentangle contributions of weight status and Binge Eating Disorder (BED) to human taste perception. We predicted weight status and BED would interact, showing difference in taste perception from non-eating disorder matched groups. METHODS: The four study groups included: normal weight BED (NW BED), normal weight healthy controls (NW HC), overweight BED (OW BED), and overweight healthy controls (OW HC) (N = 60). Groups were matched for age (±5 years), ethnicity, and weight status. Participants were assessed using the Structured Clinical Interview for DSM-IV Axis I Disorders, the Eating Disorder Examination Version 16.0, and the NIH Toolbox Gustatory Assessment with additional taste solutions and taste stimulus delivered with edible taste strips. RESULTS: Interactions were found between weight status and diagnosis on measures of regional taste intensity for quinine hydrochloride (CI 95% [44.61, 56.31], p = 0.018), sucrose (CI 95% [46.79, 56.45], p = 0.003), and 6-n-propylthiouracil (CI 95% [25.557, 39.269], p = 0.015). OW BED participants perceived these taste stimuli significantly less intensely than OW HC and NW BED. Whole mouth taste intensity tests at suprathreshold amounts did not reveal group differences. All four groups reported similar hedonic response to taste stimuli. Edible taste strips had medium to large significant correlations with NIH Gustatory Assessment taste stimuli. CONCLUSIONS: There were significant differences in the taste perception of OW BED relative to the other three groups. These findings may provide partial explanation as to why previous studies correlating taste and weight status have mixed results. Replication in larger samples assessed longitudinally is needed to extend this work.

Behavioral evidence of emotion dysregulation in binge eaters.

Binge eating is the most common disordered eating symptom and can lead to the development of obesity. Previous self-report research has supported the hypothesis that individuals who binge eat report greater levels of general emotion dysregulation, which may facilitate binge-eating behavior. However, to date, no study has experimentally tested the relation between binge eating history and in-vivo emotion dysregulation. To do this, a sample of female college students who either endorsed binge eating (n = 40) or denied the presence of any eating pathology (n = 47) completed the Difficulties with Emotion Regulation Scale (DERS) and a behavioral distress tolerance task (the Paced Auditory Serial Addition Task-Computer: PASAT-C) known to induce negative affect and distress. The binge eating group was 2.96 times more likely to quit the PASAT-C early (χ2 = 5.04, p = 0.025) and reported greater irritability (F(1,84) = 7.09 p = 0.009) and frustration (F(1,84) = 5.00, p = 0.028) after completing the PASAT-C than controls, controlling for initial levels of these emotions. Furthermore, across the entire sample, quitting early was associated with greater emotion dysregulation on the DERS (rpb = 0.342, p < 0.01). This study is the first to demonstrate that individuals who binge eat show in-vivo emotional dysregulation on a laboratory task. Future studies should examine the PASAT-C to determine its potential clinical utility for individuals with or at risk of developing binge eating.

Family-Based Therapy for Young Adults with Anorexia Nervosa Restores Weight.

OBJECTIVE: We examined the preliminary acceptability and efficacy of family-based therapy (FBT) for weight restoration in young adults (FBTY) with Anorexia Nervosa (AN). METHOD: Twenty-two primarily female participants ranging from age 18 to 26, with AN or atypical AN (ICD-10) and their support adults were enrolled in a 6-month open trial of FBTY. Participants were assessed at baseline, after treatment, and at six and 12 month follow-up visits. The primary outcome was BMI and secondary outcomes included eating disorder psychopathology, current eating disorder obsessions, and compulsions, number of other Axis I disorders and global assessment of functioning. RESULTS: Although FBTY was rated as suitable by participants and their support adults, during FBTY, 9/22 participants dropped out and 3/22 dropped out at follow-up assessments. Despite being offered 18-20 sessions over six months, a mean of 12 FBTY sessions (SD = 6) were attended. After FBTY, 15 of the intent-to-treat sample of 22 were no longer underweight (BMIs ≥ 19 kg/m(2) ) and 12 months after treatment, 13/22 were no longer underweight. The magnitude of the BMI increase during FBTY (Hedges g = 1.20, 95th percentile CI = 0.55-1.85) was comparable to findings for adolescent FBT for AN. Secondary outcomes also improved. DISCUSSION: FBTY for young adults with AN and atypical AN, which involves support adults participants have chosen, results in weight restoration that is sustained up to a year after treatment. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:701-707).

Direct and Repeated Clinical Measurements of pO2 for Enhancing Cancer Therapy and Other Applications.

The first systematic multi-center study of the clinical use of EPR oximetry has begun, with funding as a PPG from the NCI. Using particulate oxygen sensitive EPR, materials in three complementary forms (India Ink, "OxyChips", and implantable resonators) the clinical value of the technique will be evaluated. The aims include using repeated measurement of tumor pO2 to monitor the effects of treatments on tumor pO2, to use the measurements to select suitable subjects for the type of treatment including the use of hyperoxic techniques, and to provide data that will enable existing clinical techniques which provide data relevant to tumor pO2 but which cannot directly measure it to be enhanced by determining circumstances where they can give dependable information about tumor pO2.

Addiction Vulnerability and Binge Eating in Women: Exploring Reward Sensitivity, Affect Regulation, Impulsivity & Weight/Shape Concerns.

Almost 40% of individuals with eating disorders have a comorbid addiction. The current study examined weight/shape concerns as a potential moderator of the relation between the hypothesized latent factor "addiction vulnerability" (i.e., impairments in reward sensitivity, affect regulation and impulsivity) and binge eating. Undergraduate women (n=272) with either high or low weight/shape concerns completed self-report measures examining reward sensitivity, emotion regulation, impulsivity and disordered (binge) eating. Results showed that (1) reward sensitivity, affect regulation and impulsivity all loaded onto a latent "addiction vulnerability" factor for both women with high and with low weight/shape concerns, (2) women with higher weight/shape concerns reported more impairment in these areas, and (3) weight/shape concerns moderated the relation between addiction vulnerability and binge eating. These findings suggest that underlying processes identified in addiction are present in individuals who binge eat, though weight/shape concerns may be a unique characteristic of disordered eating.

Insights revealed by rodent models of sugar binge eating.

Binge eating is seen across the spectrum of eating disorder diagnoses as well as among individuals who do not meet diagnostic criteria. Analyses of the specific types of foods that are frequently binged upon reveal that sugar-rich items feature prominently in binge-type meals, making the effects of binge consumption of sugar an important focus of study. One avenue to do this involves the use of animal models. Foundational and recent studies of animal models of sugar bingeing, both outlined here, lend insight into the various neurotransmitters and neuropeptides that may participate in or be altered by this behavior. Further, several preclinical studies incorporating sugar bingeing paradigms have explored the utility of pharmacological agents that target such neural systems for reducing sugar bingeing in an effort to enhance clinical treatment. Indeed, the translational implications of findings generated using animal models of sugar bingeing are considered here, along with potential avenues for further study.

Adapting dialectical behavior therapy for outpatient adult anorexia nervosa--a pilot study.

OBJECTIVE: Anorexia Nervosa (AN) is associated with excessive self-control. This iterative case series describes the augmentation of Dialectical Behavior Therapy (DBT) for outpatient adult AN with skills addressing emotional and behavioral overcontrol. An overly controlled style is theorized to develop from the transaction between an individual with heightened threat sensitivity and reduced reward sensitivity, interacting with an environment reinforcing overcontrol and punishing imperfection. METHOD: Case Series 1 utilized standard DBT, resulting in retention of 5/6 patients and a body mass index (BMI) effect size increase of d = -0.5 from pre- to post-treatment. Case series 2, using standard DBT augmented with skills addressing overcontrol, resulted in retention of 8/9 patients with an effect size increase in BMI at post-treatment that was maintained at 6- and 12-months follow-up (d = -1.12, d = -0.87, and d = -1.12). DISCUSSION: Findings suggest that skills training targeting rigidity and increasing openness and social connectedness warrant further study of this model and treatment for AN.

Advances in probes and methods for clinical EPR oximetry.

EPR oximetry, which enables reliable, accurate, and repeated measurements of the partial pressure of oxygen in tissues, provides a unique opportunity to investigate the role of oxygen in the pathogenesis and treatment of several diseases including cancer, stroke, and heart failure. Building on significant advances in the in vivo application of EPR oximetry for small animal models of disease, we are developing suitable probes and instrumentation required for use in human subjects. Our laboratory has established the feasibility of clinical EPR oximetry in cancer patients using India ink, the only material presently approved for clinical use. We now are developing the next generation of probes, which are both superior in terms of oxygen sensitivity and biocompatibility including an excellent safety profile for use in humans. Further advances include the development of implantable oxygen sensors linked to an external coupling loop for measurements of deep-tissue oxygenations at any depth, overcoming the current limitation of 10 mm. This paper presents an overview of recent developments in our ability to make meaningful measurements of oxygen partial pressures in human subjects under clinical settings.

Modulation of hypoxia by magnetic nanoparticle hyperthermia to augment therapeutic index.

A hypoxic microenvironment in solid tumors has been known to cause resistance to standard therapies and to increase the malignant potential of tumors. The utilization of magnetic nanoparticle hyperthermia (mNPH) has shown promise in improving therapeutic outcome by (1) killing of hypoxic tumor cells directly and (2) increasing tumor oxygenation and therefore susceptibility to therapies. In this study, the interaction of a hypoxic microenvironment with mNPH efficacy was investigated in a human breast cancer orthotopic xenograft model. Using electron paramagnetic resonance (EPR) to assess in vivo oxygen concentration in tumors repeatedly and non-invasively, we found that mNPH increased tumor pO2 from 3.5 to 68.8 mmHg on average for up to 10 days. Tumors treated once with mNPH showed growth delay. On Transmission Electron Microscopy, magnetic nanoparticles (mNPs) were localized intracellularly in multiple vesicles in the cytoplasm of cells within tumors 48 h after incubation of mNP. In conclusion, mNPH increased tumor oxygenation in vivo and resulted in decreased growth of hypoxic tumors. Future studies will establish tumor pO2-guided multimodal therapies, such as mNPH and radiation, to improve therapeutic efficacy.

Skeletal muscle and glioma oxygenation by carbogen inhalation in rats: a longitudinal study by EPR oximetry using single-probe implantable oxygen sensors.

The feasibility of EPR oximetry using a single-probe implantable oxygen sensor (ImOS) was tested for repeated measurement of pO2 in skeletal muscle and ectopic 9L tumors in rats. The ImOS (50 mm length) were constructed using nickel-chromium alloy wires, with lithium phthalocyanine (LiPc, oximetry probe) crystals loaded in the sensor loop and coated with AF 2400(®) Teflon. These ImOS were implanted into the skeletal muscle in the thigh and subcutaneous 9L tumors. Dynamic changes in tissue pO2 were assessed by EPR oximetry at baseline, during tumor growth, and repeated hyperoxygenation with carbogen breathing. The mean skeletal muscle pO2 of normal rats was stable and significantly increased during carbogen inhalation in experiments repeated for 12 weeks. The 9L tumors were hypoxic with a tissue pO2 of 12.8 ± 6.4 mmHg on day 1; however, the response to carbogen inhalation varied among the animals. A significant increase in the glioma pO2 was observed during carbogen inhalation on day 9 and day 14 only. In summary, EPR oximetry with ImOS allowed direct and longitudinal oxygen measurements in deep muscle tissue and tumors. The heterogeneity of 9L tumors in response to carbogen highlights the need to repeatedly monitor pO2 to confirm tumor oxygenation so that such changes can be taken into account in planning therapies and interpreting results.

Recurrent low-dose chemotherapy to inhibit and oxygenate head and neck tumors.

A lack of strategy to counteract hypoxia (pO2 < 10-15 mmHg) and technique to repeatedly measure tumor pO2 has restricted therapeutic optimization. We report the results obtained with an innovative anti-angiogenic strategy of recurrent low-dose (metronomic) chemotherapy to modulate hypoxia and growth of the Head and Neck tumor xenografts.The FaDu tumors were established in the flank of immune deficient mice and EPR oximetry with lithium phthalocyanine crystals was used to follow the temporal changes in tumor pO2 on treatment with gemcitabine including controls for three weeks. The FaDu tumors were hypoxic with a baseline (pre-treatment) pO2 of 2-8 mmHg. A transient increase in the tumor pO2 was evident on day 3 on treatment with a conventional schedule of gemcitabine (150 mg/kg, d1, d8, d15). No significant change in the tumor pO2 on treatment with metronomic gemcitabine (25 mg/kg on d1, d3, d5 for 3 weeks) was observed. However, tumor pO2 increased significantly on d15-d18 during treatment with a metronomic schedule of 15 mg/kg gemcitabine (d1, d3, d5 for 3 weeks). A modest decrease in the tumor growth was evident on treatment with conventional gemcitabine. Notably, tumor growth was significantly inhibited by metronomic (25 and 15 mg/kg) gemcitabine treatment. The immunohistochemistry (IHC) analyses of the tumor samples indicate a decrease in HIF-1α and TSP-1 on treatment with metronomic gemcitabine.In conclusion, a significant inhibition of tumor growth on treatment with metronomic gemcitabine was observed; however, the increase in pO2 was dose dependent. EPR oximetry can be used to follow the temporal changes in tumor pO2 to identify a therapeutic window on treatment with metronomic chemotherapy for potential combination with radiotherapy.

Loneliness mediates the relationship between emotion dysregulation and bulimia nervosa/binge eating disorder psychopathology in a clinical sample.

Emotion dysregulation has been linked to binge eating disorder (BED) and bulimia nervosa (BN) although the mechanisms by which it affects BN/BED psychopathology are unclear. This study tested loneliness as a mediator between emotion dysregulation and BN/BED psychopathology. A treatment-seeking sample of 107 women with BN or BED was assessed for loneliness (UCLA Loneliness Scale), emotion dysregulation (Difficulties in Emotion Regulation Scale), and BN/BED psychopathology (Eating Disorder Examination) before treatment. Hierarchical linear regressions and bootstrapping mediation models were run. Greater overall emotion dysregulation was associated with greater BN/BED psychopathology, mediated by loneliness (95 % CI 0.03, 0.09). Emotion dysregulation, however, did not mediate between loneliness and BN/BED psychopathology (95 % CI −0.01, 0.01). Targeting loneliness may effectively treat emotional aspects of BN/BED in women.