Hypothesizing that brain reward circuitry genes are genetic antecedents of pain sensitivity and critical diagnostic and pharmacogenomic treatment targets for chronic pain conditions

While it is well established that the principal ascending pathways for pain originate in the dorsal horn of the spinal cord and in the medulla, the control and sensitivity to pain may reside in additional neurological loci, especially in the mesolimbic system of the brain (i.e., a reward center), and a number of genes and associated polymorphisms may indeed impact pain tolerance and or sensitivity. It is hypothesized that these polymorphisms associate with a predisposition to intolerance or tolerance to pain. It is further hypothesized that identification of certain gene polymorphisms provides a unique therapeutic target to assist in the treatment of pain. It is hereby proposed that pharmacogenetic testing of certain candidate genes (i.e., mu receptors, PENK etc.) will result in pharmacogenomic solutions personalized to the individual patient, with potential improvement in clinical outcomes.     

CD44-mediated phagocytosis induces inside-out activation of complement receptor-3 in murine macrophages

Diverse receptors, including Fcgamma receptors and beta(2) integrins (complement receptor-3 [CR3], CD11b/CD18), have been implicated in phagocytosis, but their distinct roles and interactions with other receptors in particle engulfment are not well defined. CD44, a transmembrane adhesion molecule involved in binding and metabolism of hyaluronan, may have additional functions in regulation of inflammation and phagocytosis. We have recently reported that CD44 is a fully competent phagocytic receptor that is able to trigger ingestion of large particles by macrophages. Here, we investigated the role of coreceptors and intracellular signaling pathways in modulation of CD44-mediated phagocytosis. Using biotinylated erythrocytes coated with specific antibodies (anti-CD44-coated erythrocytes [Ebabs]) as the phagocytic prey, we determined that CD44-mediated phagocytosis is reduced by 45% by a blocking CD11b antibody. Further, CD44-mediated phagocytosis was substantially (42%) reduced in CD18-null mice. Immunofluorescence microscopy revealed that CD11b is recruited to the phagocytic cup. The mechanism of integrin activation and mobilization involved activation of the GTPase Rap1. CD44-mediated phagocytosis was also sensitive to the extracellular concentration of the divalent cation Mg(2+) but not Ca(2+). In addition, buffering of intracellular Ca(2+) did not affect CD44-mediated phagocytosis. Taken together, these data suggest that CD44 stimulation induces inside-out activation of CR3 through the GTPase Rap1.     

Erratum to: Pulsed Dendritic Cells for the Therapy of Experimental Glioma

Bulletin of Experimental Biology and Medicine -     

An assessment of diagnostic performance of a filter-based antibody-independent peripheral blood circulating tumour cell capture paired with cytomorphologic criteria for the diagnosis of cancer

Objectives

Circulating tumour cells (CTCs) are reported to be predictive for prognosis and response to treatment in advanced lung cancer. However, the clinical utility of the CTCs detection remains unknown for early stage lung cancer as the number of CTCs is reported as low, providing challenges in identification. We have evaluated diagnostic performance of filtration-based technology using cytomorphologic criteria in patients undergoing surgery for lung cancer.

Material and methods

We processed blood from 76 patients undergoing surgery for known or suspected lung cancer using ScreenCell^® Cyto filter devices. Captured cells were stained using haematoxylin and eosin and independently assessed by two pathologists for the presence of atypical cells suspicious for cancer. Diagnostic performance was evaluated against pathologist reported diagnoses of cancer from surgically obtained specimens.

Results

Cancer was diagnosed in 57 patients (77.0%), including 32 with primary lung cancer (56.1%). The proportion of patients with early stage primary lung cancer in which CTCs were identified was 18 and 21 (56.3% and 65.6%, respectively) as reported by two pathologists. The agreement between the pathologists was 77.0% corresponding to a kappa-statistic of 53.7% indicating moderate agreement. No significant differences were found for the percentage of CTCs for primary and metastatic cancer as well as for cancer stages. On sensitivity weighted analysis, a sensitivity and specificity were 71.9% (95% CI 60.5–83.0) and 52.9% (95% CI 31.1–77.0), respectively. On specificity weighted analysis, a sensitivity and specificity were 50.9% (95% CI 39.3–64.4) and 82.4% (60.4–96.2), respectively.

Conclusion

The performance of the tested filter-based antibody-independent technology to capture CTCs using standard cytomorphologic criteria provides the potential of a diagnostic blood test for lung cancer.     

Behavioural eating disorders

Eating disorders are serious mental health disorders characterized by morbid preoccupation with weight and shape, manifest through distorted or chaotic eating. Planned changes to diagnostic criteria will broaden the definition of feeding and eating disorders to include presentations characterized by restricted food intake not associated with weight and shape concerns. Anorexia nervosa (AN), bulimia nervosa (BN) and partial syndromes are relatively common, and early intervention is advisable. Aetiology is multifactorial, with high heritability. Prognosis overall is good but treatment can be long and intensive, significantly impacting families. Essential aspects of management are an integrated multidisciplinary approach, working collaboratively with families and young people when possible. Psychological interventions focus on the eating disorder, supported by medical monitoring and dietetic guidance. Although working with families is the backbone of treatment for AN, young people also need opportunities for confidential discussion. The role of inpatient treatment is evolving. For BN, family or individual approaches may be equally effective. Paediatric expertise is of particular value in the assessment and management of acute malnutrition and complications secondary to disordered eating behaviours, in the early stages of re-feeding, and in the monitoring and management of long-term complications such as growth retardation, pubertal delay and osteopenia.     

Maternal blood pressures during pregnancy and the risk of delivering a small-for-gestational-age neonate

Objective: To determine the relationship between maternal blood pressures throughout pregnancy and the risk of delivering a small-for-gestational-age (SGA) neonate. Methods: Women were prospectively enrolled at 9–14 weeks and had serial blood pressure measurements throughout pregnancy. SGA prevalence was compared to maternal blood pressure at enrollment, average blood pressure during each trimester, and blood pressure trends throughout gestation. Blood pressure was categorized as normotension, prehypertension, or hypertension using Joint National Committee on Hypertension-7 (JNC-7) definitions. Information on preeclampsia prevalence was also obtained due to its frequent concurrence with SGA. Results: A total of 758 women had 8438 blood pressure measurements taken (average 11.1, range 3–14) and 65 (8.6%) delivered an SGA neonate. Forty-two of 514 (8.2%) normotensive women at enrollment and 23/244 (9.4%) women with enrollment prehypertension or hypertension delivered an SGA neonate. Women with persistent hypertensive range blood pressures had an SGA rate 2–3 times higher than other women (p = 0.272) as well as a significantly higher preeclampsia rate (p < 0.001). Women with elevated enrollment blood pressures did not have an increased SGA rate if their blood pressures improved throughout pregnancy. Logistic regression identified enrollment uterine artery Doppler, pregnancy-associated plasma protein-A levels, and ethnicity as primary contributors to SGA. Conclusion: Blood pressure improvement throughout pregnancy decreases the preeclampsia rate without increasing SGA frequency. Theoretical risks of fetal growth delay should not prevent investigations into improved maternal blood pressure control, possibly at thresholds lower than commonly used in obstetric practice, beginning in the first trimester of pregnancy.     

The Impact of COVID-19-Related Living Restrictions on Eating Behaviours in Children and Adolescents: A Systematic Review

The COVID-19 pandemic prompted the imposition of physical and social distancing measures worldwide. Emerging data suggest that younger age groups may be particularly vulnerable to the adverse mental health impacts of the pandemic. Since the start of the COVID-19 pandemic, there has been an unprecedented increase in demand for child and adolescent eating disorder services. The aim of this review was to systematically review and appraise the current literature on the impact of COVID-19-related living restrictions on the eating behaviours of children and adolescents. Searches of eight electronic databases were conducted in March 2021 and December 2021 for published and grey literature on eating behaviours of population samples of children and adolescents (aged 18 months to 18 years old) who were exposed to COVID-19-related living restrictions. Of 3165 retrieved references, sixteen studies were included in this review, comprising data from 125, 286 participants. There was a pattern towards healthier eating behaviours among children and adolescents during the COVID-19 lockdown. However, young people from lower socioeconomic groups showed a tendency towards more unhealthy eating behaviours, and there was an association between mood difficulties and greater changes in eating; this suggests that such groups may be more vulnerable to the adverse health consequences of lockdowns.     

Effects of an epidermal growth factor receptor‐based cancer vaccine on wound healing and inflammation processes in murine experimental models

Anti‐epidermal growth factor receptor (EGFR) therapies have been proven clinically effective for a variety of epithelial tumours. Vaccination of mice with the extracellular domain (ECD) of autologous EGFR overcomes the tolerance to self‐EGFR and has antimetastatic effect on EGFR+ tumour. Because EGF/EGFR‐signalling plays an important role in the inflammation stage of wound healing, the main objective of this study was to explore the possible role of murine (m) EGFR‐ECD vaccine in the croton‐oil‐induced ear oedema and wound healing process in mice as autologous experimental models, mimicking the possible post‐surgical wound complication in patients treated with human EGFR‐ECD/VSSP vaccine. Mice were intramuscularly immunised four times; biweekly with the mEGFR‐ECD/VSSP/Mont. Seven days later, an 8 mm diameter, full‐thickness skin wound was created on the back of each animal. Immunisation induced a strong specific humoral response against the mEGFR‐ECD protein and a DTH dose–response curve but interestingly, animals treated with mEGFR‐ECD/VSSP/Mont had similar inflammatory and healing speed responses compared to control ones. These data suggest that application of mEGFR‐ECD/VSSP vaccine as a therapeutic approach in cancer patients could not elicit a poor healing process after surgery.