Long Term Amperometric Recordings in the Brain Extracellular Fluid of Freely Moving Immunocompromised NOD SCID Mice.

We describe the in vivo characterization of microamperometric sensors for the real-time monitoring of nitric oxide (NO) and oxygen (O2) in the striatum of immunocompromised NOD SCID mice. The latter strain has been utilized routinely in the establishment of humanized models of disease e.g., Parkinson's disease. NOD SCID mice were implanted with highly sensitive and selective NO and O2 sensors that have been previously characterized both in vitro and in freely moving rats. Animals were systemically administered compounds that perturbed the amperometric current and confirmed sensor performance. Furthermore, the stability of the amperometric current was investigated and 24 h recordings examined. Saline injections caused transient changes in both currents that were not significant from baseline. l-NAME caused significant decreases in NO (p < 0.05) and O2 (p < 0.001) currents compared to saline. l-Arginine produced a significant increase (p < 0.001) in NO current, and chloral hydrate and Diamox (acetazolamide) caused significant increases in O2 signal (p < 0.01) compared against saline. The stability of both currents were confirmed over an eight-day period and analysis of 24-h recordings identified diurnal variations in both signals. These findings confirm the efficacy of the amperometric sensors to perform continuous and reliable recordings in immunocompromised mice.

Real-Time Amperometric Recording of Extracellular H2O2 in the Brain of Immunocompromised Mice: An In Vitro, Ex Vivo and In Vivo Characterisation Study.

We detail an extensive characterisation study on a previously described dual amperometric H2O2 biosensor consisting of H2O2 detection (blank) and degradation (catalase) electrodes. In vitro investigations demonstrated excellent H2O2 sensitivity and selectivity against the interferent, ascorbic acid. Ex vivo studies were performed to mimic physiological conditions prior to in vivo deployment. Exposure to brain tissue homogenate identified reliable sensitivity and selectivity recordings up to seven days for both blank and catalase electrodes. Furthermore, there was no compromise in pre- and post-implanted catalase electrode sensitivity in ex vivo mouse brain. In vivo investigations performed in anaesthetised mice confirmed the ability of the H2O2 biosensor to detect increases in amperometric current following locally perfused/infused H2O2 and antioxidant inhibitors mercaptosuccinic acid and sodium azide. Subsequent recordings in freely moving mice identified negligible effects of control saline and sodium ascorbate interference injections on amperometric H2O2 current. Furthermore, the stability of the amperometric current was confirmed over a five-day period and analysis of 24-h signal recordings identified the absence of diurnal variations in amperometric current. Collectively, these findings confirm the biosensor current responds in vivo to increasing exogenous and endogenous H2O2 and tentatively supports measurement of H2O2 dynamics in freely moving NOD SCID mice.

New ways of seeing and being: Evaluating an acceptance and mindfulness group for parents of young people with intellectual disabilities who display challenging behaviour.

The current study presents findings from an acceptance and commitment therapy-based intervention for family carers of children who have an intellectual/developmental disability and display high levels of challenging behaviour. The parent well-being workshops consist of two workshops incorporating acceptance and mindfulness-based exercises and discussions. Semi-structured interviews were conducted with five family carers following attendance of the workshops. Participants found the workshops useful and reported that they were better able to cope with stress. They also described how they had incorporated mindfulness into their daily lives and how their practice had had positive effects on their own well-being and on those around them (e.g. their child). Implications of the findings are discussed with emphasis on how the workshops can be included within a positive behaviour support framework. Future directions include a more robust quantitative evaluation, inclusion of follow-up sessions and the application of the workshops with other client groups and in other delivery formats.

A phase 2b, Randomized, double blinded comparison of the safety and efficacy of the monoclonal antibody mixture SYN023 and human rabies immune globulin in patients exposed to rabies.

BACKGROUND: SYN023 is an anti-rabies monoclonal antibody mixture administered as part of post-exposure prophylaxis regimens. The rabies virus neutralizing antibody (RVNA) concentration generally accepted as an adequate immune response to vaccination is ≥ 0.5 IU/mL. METHODS: Within 54 h of potential rabies exposure, 448 patients in two risk substrata of WHO Category III exposure were randomized to receive either 0.3 mg/kg SYN023 or 0.133 mL/kg human rabies immunoglobulin (HRIG) injected in and around the wound site(s) plus a course of rabies vaccination. Patients were followed for safety and absence of rabies for ≥ 365 days. RESULTS: GMT RVNA was higher with SYN023 throughout the 2-week post-treatment period. In the primary analysis group (n = 368), 99.4 % of SYN023 recipients versus 4.5 % of HRIG recipients had protective RVNA levels on Day 4. On Day 8, 98.1 % SYN023 versus 12.2 % HRIG recipients were protected. The SYN023:HRIG ratio of geometric mean titer of RVNA (RVNA GMTs) on Day 8 (19.42) exceeded the 10 % superiority margin (P < 0.0001) indicating higher Day 8 RVNA with SYN023. On Day 99, the SYN023:HRIG RVNA GMT ratio (0.66) was below the non-inferiority margin of 20 % (P = 0.9485) suggesting some moderation of vaccine immune response by SYN023 relative to HRIG. The ratio of percent SYN023:HRIG recipients achieving RVNA ≥ 0.5 IU/mL on Day 99 (0.98) met the non-inferiority margin of 20 % (P = 0.013) indicating anti-rabies immune response with SYN023 was non-inferior to HRIG despite this effect. There were no probable/confirmed rabies cases in any patient. Study regimens were well tolerated. CONCLUSIONS: SYN023 provided higher RVNA than HRIG soon after rabies exposure. By Day 99 post-treatment, GM RVNA with SYN023 was lower than HRIG, however, the percent of SYN023 recipients with a protective response was not inferior at this time point. No rabies cases were reported in the study. The SYN023 safety profile was acceptable. CLINICALTRIALS: gov ID: NCT03961555.

The continuing evolution of a cancer prevention, screening, and survivorship ECHO: A second year of implementation.

INTRODUCTION: An estimated 39,010 Indiana residents were diagnosed with cancer in 2021. To address the cancer burden, Project ECHO (Extension Community Healthcare Outcomes) was launched in 2019 in Indiana to build specialty healthcare capacity among non-specialists. Due to positive outcomes from the pilot year, the Cancer Prevention, Screening, and Survivorship ECHO was implemented for a second year. The purpose of this study was to measure the participation and regional impact of this ECHO. METHODS: ECHO sessions occurred twice monthly from October 2020 to October 2021. Changes were implemented in response to feedback from the pilot year, including making the curriculum more practical for learners and adding accreditation opportunities. Participant information and feedback was extracted from electronic surveys for review. RESULTS: There were 24 ECHO sessions with 213 unique participants, increased from 140 unique participants in the pilot year. An average of 23.5 individuals attended each session, increased from 15.5 individuals per session. Enrolled participants served in a diverse set of roles and represented 247 zip codes, 30 Indiana counties, and 32 states across the United States, each of which increased from the pilot year. DISCUSSION: In this second year, this ECHO expanded to reach more participants with increased attendance and a more diverse distribution of roles within healthcare, which may be attributed to feedback-driven curriculum design. Cancer care is multi-disciplinary, with health educators, nurses, and administrators, each acting within the cancer care continuum. As a result, this ECHO has been adapted to serve an increasingly broad distribution of professionals. CONCLUSION: The second year of the Cancer Prevention, Screening, and Survivorship ECHO displayed increased overall enrollment and participation, greater diversity among participant roles, and a wider reach across Indiana and the United States.

Rabies virus neutralizing activity, pharmacokinetics, and safety of the monoclonal antibody mixture SYN023 in combination with rabies vaccination: Results of a phase 2, randomized, blinded, controlled trial.

BACKGROUND: SYN023-002 is a randomized, blinded, controlled study comparing rabies virus neutralizing activity (RVNA) and safety of SYN023, a monoclonal anti-rabies antibody mixture, to human-serum derived anti-rabies immunoglobulin (RIG) when administered with commercially available vaccines to healthy adult volunteers. METHODS: Participants were randomized among 4 treatment groups (SYN023 + Imovax, SYN023 + RabAvert, HyperRab + Imovax, HyperRab + RabAvert). On Day 0, subjects received 1 dose of RIG (0.3 mg/kg SYN023 or 20 IU/mL HyperRab) and their first of 5 vaccine doses. The primary objective was to compare cumulative RVNA between SYN023 and HyperRab recipients. Secondary objectives were to compare safety and to assess SYN023 pharmacokinetics and immunogenicity. RESULTS: All 164 randomized subjects initiated treatment and were included in safety analyses. At least 34 subjects/treatment group received all treatment and had complete RVNA results, thus were included in the primary endpoint analysis. Mean RVNAs were approximately ten-fold higher in SYN023 recipients compared to HyperRab recipients until Day 14. From Day 14 onwards, mean RVNA was lower in SYN023 recipients, but remained above the RVNA level widely considered adequate (≥0.5 IU/mL) through Day 112 (study end). The point estimate of the cumulative RVNA (83.22% SYN023/HyperRab), but not the lower CI bound (90% CI: 66.06%, 104.83%), fell within the protocol-defined similarity margin. Each RIG + vaccine regimen appeared safe with mostly mild AEs and no serious or severe related events observed. Except injection site pain (22% HyperRab recipients vs. 6% SYN023 recipients), treatment-related AEs incidences were similar between RIGs. Anti-SYN023 antibodies were observed but had no apparent effects on PK or safety. CONCLUSIONS: SYN023 administered with commercially available vaccines provides adequate antibody coverage beginning earlier than other commercially available RIGs with an acceptable safety profile. Some suppression of vaccine response occurred, but RVNA levels ≥ 0.5 IU/mL were maintained throughout the relevant period. REGISTRATION: ClinicalTrials.gov #NCT02956746. FUNDING: Synermore biologics.

Immediate pleasures and future consequences. A neuropsychological study of binge eating and obesity.

Longitudinal data indicate that our capacity for adaptive self-regulation is a relatively stable predisposition that appears in childhood and predicts future life successes. In 2004, we published the first study demonstrating decision-making deficits in overweight/obese adult women. The present study is an extension of these findings. We assessed obese women with (n=65) and without (n=73) binge-eating disorder (BED), and a group (n=71) of normal-weight women, on two neuropsychological tests: the Iowa Gambling Task and a Delay Discounting measure. The BED and obese groups had worse performance scores on both tasks compared to normal controls, but did not differ from each other. These findings suggest that adaptive decision-making and the ability to delay gratification may influence our eating behaviours, particularly in a food environment where effortful control of energy intake is essential for the maintenance of a healthy body weight. There were also group differences in education level with fewer BED and obese individuals having a post-secondary degree, in accord with established links between socioeconomic status and body weight. Interestingly, when education level was added to the models, those with a higher education performed better on both tasks, and the group differences were not significant.

An electrochemical investigation into the effects of local and systemic administrations of sodium nitroprusside in brain extracellular fluid of mice.

Sodium nitroprusside (SNP) is a nitric oxide (NO)-donor drug used clinically to treat severe hypertension, however, there are limitations associated with its mechanism of action that prevent widespread adoption. In particular, its impact on cerebral hemodynamics is controversial and direct evidence on its effects are lacking. Electrochemical methods provide an attractive option to undertake real time neurochemical measurements in situ using selective microsensors. Herein, we report the novel application of an existing platinum (Pt)-Nafion® sensor to measure the release of NO from SNP under in vitro and in vivo conditions. Initially, the temporal release of NO was measured and the effect of the reducing agent, ascorbic acid (AA), was elucidated in vitro. A combined microdialysis/NO sensor construct was implanted into the striatum of anaesthetised mice and the local perfusion of 10 mM SNP with/without AA resulted in increased NO concentration detected using the Pt-Nafion® sensor. Subsequently, the NO sensor, coupled with carbon paste electrodes (CPEs) for the electrochemical measurement of O2, were applied to investigate SNP effects in freely moving mice. A complex mechanism of action was identified that infers NO inhibition and biphasic O2 dynamics. The preliminary findings within support a strong cerebrovascular effect of systemic SNP administration that warrants careful consideration for clinical use.

False positives in functional near-infrared topography.

Functional cranial near-infrared spectroscopy (NIRS) has been widely used to investigate the haemodynamic changes which occur in response to functional activation. The technique exploits the different absorption spectra of oxy- and deoxy-haemoglobin ([HbO2] [HHb]) in the near-infrared region to measure the changes in oxygenation and haemodynamics in the cortical tissue. The aim of this study was to use an optical topography system to produce topographic maps of the haemodynamic response of both frontal cortex (FC) and motor cortex (MC) during anagram solving while simultaneously monitoring the systemic physiology (mean blood pressure, heart rate, scalp flux). A total of 22 young healthy adults were studied. The activation paradigm comprised of 4-, 6- and 8- letter anagrams. 12 channels of the optical topography system were positioned over the FC and 12 channels over the MC. During the task 12 subjects demonstrated a significant change in at least one systemic variable (p < or = 0.05). Statistical analysis of task-related changes in [HbO2] and [HHb], based on a Student's t-test was insufficient to distinguish between cortical haemodynamic activation and systemic interference. This lead to false positive haemodynamic maps of activation. It is therefore necessary to use statistical testing that incorporates the systemic changes that occur during brain activation.

Reward sensitivity and the D2 dopamine receptor gene: A case-control study of binge eating disorder.

OBJECTIVE: The sensitivity of dopamine reward pathways has been implicated in the risk for various psychiatric disorders including compulsive overeating. The evidence is divided, however, about the direction of causal association. One argument is that a Reward Deficiency Syndrome is the risk factor, while others contend that hyper-sensitivity to reward enhances the motivation for pleasurable activities like eating. Unfortunately, little human research has bridged the gap between psychological and neurobiological approaches to brain reward functioning and disorder. The present study addressed this issue by implementing psychological and biological markers of reward sensitivity in the assessment protocol. METHODS: Adults with binge eating disorder (BED) were compared to samples of normal-weight and obese controls on two personality measures of reward sensitivity and were genotyped for six markers of the DRD2 dopamine receptor gene. RESULTS: Genotype x Group ANOVAs revealed significant main effects and an interaction on the personality measures for Taq1A. BED and obese subjects reported greater reward sensitivity than normal-weight controls, but only among those carrying the A1 allele. We also found that normal-weight controls with at least one copy of the T allele of the C957T marker had significantly lower reward sensitivity scores than any of the other groups who did not differ from each other. CONCLUSIONS: Given evidence linking the A1 allele with reduced receptor density, an inverse relationship was expected between psychological measures of reward sensitivity and presence of the A1 allele. One explanation for our findings could be that the BED and obese participants possess another genetic variant that interacts with the A1 allele to produce higher dopamine activity. These findings have implications for future studies of the molecular genetics of BED and obesity, and for behavioural and pharmacologic therapies targeting these conditions.

Education level moderates learning on two versions of the Iowa Gambling Task.

The Iowa Gambling Task (IGT) is the major plank of behavioral support for the Somatic Marker Hypothesis--a prominent theory of emotionally-based decision making. Despite its widespread use, some have questioned the ecological and discriminative validity of the IGT because a substantial proportion of neurologically-normal adults display a response pattern indistinguishable from those with ventromedial prefrontal cortical brain lesions. In a large sample of healthy adults, we examined the statistical influence of several demographic variables on two versions of the IGT, with the specific prediction that educational attainment would moderate learning across trials. Results confirmed a highly significant effect of education. On the commonly used original version of the IGT, performance tended to improve more rapidly, and reach a higher eventual positive score, as the level of education increased. Age and gender were nonsignificant effects in the model, and Caucasians had slightly better IGT performance than their non-Caucasian counterparts. Conclusions are that education level, among neurologically-normal adults, should be treated as a stratification or matching variable in case-control research using this task.

Synthesis of novel benzamidine- and guanidine-derived polyazamacrocycles: Selective anti-protozoal activity for human African trypanosomiasis.

Efficient synthetic routes have been developed for the preparation of two new polyazamacrocycles tagged with structural motifs recognised by the Trypanosoma brucei P2 aminopurine transporter. Biological testing of these compounds showed highly selective anti-protozoal activity against trypanosomes.

Synthesis and anti-protozoal activity of C2-substituted polyazamacrocycles.

A focused library of C2-substituted-1,4,7,10-tetraazacyclododecanes was synthesised and the compounds were tested for their ability to kill trypanosome and malaria parasites. Several compounds showed significant in vitro activity and were selectively active against the parasites over human embryonic kidney cells used as a counter screen.

Personality and eating behaviors: a case-control study of binge eating disorder.

OBJECTIVE: Questions have been raised about the validity of binge eating disorder (BED) as psycho-pathologically distinct from other forms of overeating. Our purpose was to ascertain whether BED individuals differed in important ways from nonbinging obese adults. METHOD: BED adults were recruited from the community as were weight-matched (obese) and normal-weight control (NWC) groups. All groups were equivalent for age and gender distribution, and were assessed on several personality traits and eating behaviors. RESULTS: BED individuals and obese controls did not differ on the personality traits. Both were more reward sensitive, and had greater anxiousness, impulsivity, and addictive personality traits than NWC. However, BED individuals reported significantly greater hedonic eating compared with the obese, who had higher levels than NWC. CONCLUSION: Our findings provided no evidence of a psychological identity unique to obese adults with BED although their eating behaviors are markedly hedonically driven-i.e., more responsive to factors external to physiological needs.

Symptoms of attention-deficit/hyperactivity disorder, overeating, and body mass index in men.

BACKGROUND: The high prevalence of obesity currently poses a global health crisis. Previous research has identified a novel link between obesity and Attention-Deficit/Hyperactivity Disorder (AD(H)D). Davis, Levitan, Smith, Tweed and Curtis [Davis, C., Levitan, R. D., Smith, M., Tweed, S., & Curtis, C. (2006). Associations among overeating, overweight, and attention deficit/hyperactivity disorder: A structural equation modeling approach. Eating Behaviors, 7, 266-274] recently tested a structural equation model predicting that AD(H)D symptoms foster overeating and subsequently contribute to the variation in Body Mass Index (BMI) in a sample of healthy adult females. The data were an excellent fit to the model. PURPOSE: In order to extend the generalizability of these findings, the present study tested the same model in 145 non-clinical adult males. RESULTS: Similar to the findings in females, AD(H)D symptoms positively predicted overeating in males, which in turn positively predicted BMI. CONCLUSIONS: Results highlight mechanisms whereby AD(H)D symptoms could influence body mass and stress the importance of addressing AD(H)D symptoms in both the prevention and treatment of overeating and obesity.

Dopamine transporter gene (DAT1) associated with appetite suppression to methylphenidate in a case-control study of binge eating disorder.

Response to psychomotor stimulants is highly variable across individuals. Such inconsistencies are influenced by many factors including drug dose and polymorphic differences in genes that encode proteins, such as the dopamine transporter (DAT1), which are relevant to the site of action of these substances. The current study used a double blind, crossover (methylphenidate vs placebo) design to assess DAT1 genotype differences on appetite ratings to a snack-food cue in subjects with binge eating disorder (BED) (n=32) and healthy age-matched controls (n=46). ANOVA results indicated a significant genotype x diagnostic group interaction whereby BED subjects with at least one copy of the 9-repeat allele showed a significant suppression of appetite in response to methylphenidate compared with controls with this allele, or to subjects with the 10/10 genotype (irrespective of diagnosis) whose drug response was indistinguishable from placebo. The most probable explanation for these findings is that some, currently unknown, genetic variant, which is overrepresented in those with BED, interacts with DAT1 to suppress appetite in response to stimulant administration. The current findings have implications for treatment response to drugs currently in use (or being developed) for the treatment of overeating and overweight.

Total syntheses of the marine pyrrole alkaloids polycitone A and B.

Polycitone B (2) was obtained in four steps from pyrrole dicarboxylic acid 3, including Friedel-Crafts reaction of the corresponding acid chloride with anisole. The conversion of 2 into polycitone A (1) was achieved in two steps via Mitsunobu alkylation of the pyrrolic NH group. The synthesis of polycitone A proceeds in 18% overall yield and offers the possibility of varying the substituents on the pyrrole ring.

Terahertz time-domain spectroscopy of human blood.

In the continuing development of terahertz technology to enable the determination of tissue pathologies in real-time during surgical procedures, it is important to distinguish the measured terahertz signal from biomaterials and fluids, such as blood, which may mask the signal from tissues of interest. In this paper, we present the frequency-dependent absorption coefficients, refractive indices, and Debye relaxation times of whole blood, red blood cells, plasma, and a thrombus.

Terahertz pulsed imaging of freshly excised human colonic tissues.

We present the results from a feasibility study which measures properties in the terahertz frequency range of excised cancerous, dysplastic and healthy colonic tissues from 30 patients. We compare their absorption and refractive index spectra to identify trends which may enable different tissue types to be distinguished. In addition, we present statistical models based on variations between up to 17 parameters calculated from the reflected time and frequency domain signals of all the measured tissues. These models produce a sensitivity of 82% and a specificity of 77% in distinguishing between healthy and all diseased tissues and a sensitivity of 89% and a specificity of 71% in distinguishing between dysplastic and healthy tissues. The contrast between the tissue types was supported by histological staining studies which showed an increased vascularity in regions of increased terahertz absorption.

Group schema therapy for eating disorders: a pilot study.

This paper describes the use of Group Schema Therapy for Eating Disorders (ST-E-g) in a case series of eight participants with chronic eating disorders and high levels of co-morbidity. Treatment was comprised of 20 sessions which included cognitive, experiential, and interpersonal strategies, with an emphasis on behavioral change. Specific schema-based strategies focused on bodily felt-sense and body-image, as well as emotional regulation skills. Six attended until end of treatment, two dropped-out at mid-treatment. Eating disorder severity, global schema severity, shame, and anxiety levels were reduced between pre- and post-therapy, with a large effect size at follow-up. Clinically significant improvement in eating severity was found in four out of six completers. Group completers showed a mean reduction in schema severity of 43% at post-treatment, and 59% at follow-up. By follow-up, all completers had achieved over 60% improvement in schema severity. Self-report feedback suggests that group factors may catalyze the change process in schema therapy by increasing perceptions of support and encouragement to take risks and try out new behaviors, whilst providing a de-stigmatizing and de-shaming therapeutic experience.