Psychophysical Investigations into the Role of Low-Threshold C Fibres in Non-Painful Affective Processing and Pain Modulation

We recently showed that C low-threshold mechanoreceptors (CLTMRs) contribute to touch-evoked pain (allodynia) during experimental muscle pain. Conversely, in absence of ongoing pain, the activation of CLTMRs has been shown to correlate with a diffuse sensation of pleasant touch. In this study, we evaluated (1) the primary afferent fibre types contributing to positive (pleasant) and negative (unpleasant) affective touch and (2) the effects of tactile stimuli on tonic muscle pain by varying affective attributes and frequency parameters. Psychophysical observations were made in 10 healthy participants. Two types of test stimuli were applied: stroking stimulus using velvet or sandpaper at speeds of 0.1, 1.0 and 10.0 cm/s; focal vibrotactile stimulus at low (20 Hz) or high (200 Hz) frequency. These stimuli were applied in the normal condition (i.e. no experimental pain) and following the induction of muscle pain by infusing hypertonic saline (5%) into the tibialis anterior muscle. These observations were repeated following the conduction block of myelinated fibres by compression of sciatic nerve. In absence of muscle pain, all participants reliably linked velvet-stroking to pleasantness and sandpaper-stroking to unpleasantness (no pain). Likewise, low-frequency vibration was linked to pleasantness and high-frequency vibration to unpleasantness. During muscle pain, the application of previously pleasant stimuli resulted in overall pain relief, whereas the application of previously unpleasant stimuli resulted in overall pain intensification. These effects were significant, reproducible and persisted following the blockade of myelinated fibres. Taken together, these findings suggest the role of low-threshold C fibres in affective and pain processing. Furthermore, these observations suggest that temporal coding need not be limited to discriminative aspects of tactile processing, but may contribute to affective attributes, which in turn predispose individual responses towards excitatory or inhibitory modulation of pain

Sarcopenia Exacerbates Obesity-Associated Insulin Resistance and Dysglycemia: Findings from the National Health and Nutrition Examination Survey III

Sarcopenia often co-exists with obesity, and may have additive effects on insulin resistance. Sarcopenic obese individuals could be at increased risk for type 2 diabetes. We performed a study to determine whether sarcopenia is associated with impairment in insulin sensitivity and glucose homeostasis in obese and non-obese individuals.We performed a cross-sectional analysis of National Health and Nutrition Examination Survey III data utilizing subjects of 20 years or older, non-pregnant (N = 14,528). Sarcopenia was identified from bioelectrical impedance measurement of muscle mass. Obesity was identified from body mass index. Outcomes were homeostasis model assessment of insulin resistance (HOMA IR), glycosylated hemoglobin level (HbA1C), and prevalence of pre-diabetes (6.0≤ HbA1C<6.5 and not on medication) and type 2 diabetes. Covariates in multiple regression were age, educational level, ethnicity and sex.Sarcopenia was associated with insulin resistance in non-obese (HOMA IR ratio 1.39, 95% confidence interval (CI) 1.26 to 1.52) and obese individuals (HOMA-IR ratio 1.16, 95% CI 1.12 to 1.18). Sarcopenia was associated with dysglycemia in obese individuals (HbA1C ratio 1.021, 95% CI 1.011 to 1.043) but not in non-obese individuals. Associations were stronger in those under 60 years of age. We acknowledge that the cross-sectional study design limits our ability to draw causal inferences.Sarcopenia, independent of obesity, is associated with adverse glucose metabolism, and the association is strongest in individuals under 60 years of age, which suggests that low muscle mass may be an early predictor of diabetes susceptibility. Given the increasing prevalence of obesity, further research is urgently needed to develop interventions to prevent sarcopenic obesity and its metabolic consequences

Interrogating and Predicting Tolerated Sequence Diversity in Protein Folds: Application to E. elaterium Trypsin Inhibitor-II Cystine-Knot Miniprotein

Cystine-knot miniproteins (knottins) are promising molecular scaffolds for protein engineering applications. Members of the knottin family have multiple loops capable of displaying conformationally constrained polypeptides for molecular recognition. While previous studies have illustrated the potential of engineering knottins with modified loop sequences, a thorough exploration into the tolerated loop lengths and sequence space of a knottin scaffold has not been performed. In this work, we used the Ecballium elaterium trypsin inhibitor II (EETI) as a model member of the knottin family and constructed libraries of EETI loop-substituted variants with diversity in both amino acid sequence and loop length. Using yeast surface display, we isolated properly folded EETI loop-substituted clones and applied sequence analysis tools to assess the tolerated diversity of both amino acid sequence and loop length. In addition, we used covariance analysis to study the relationships between individual positions in the substituted loops, based on the expectation that correlated amino acid substitutions will occur between interacting residue pairs. We then used the results of our sequence and covariance analyses to successfully predict loop sequences that facilitated proper folding of the knottin when substituted into EETI loop 3. The sequence trends we observed in properly folded EETI loop-substituted clones will be useful for guiding future protein engineering efforts with this knottin scaffold. Furthermore, our findings demonstrate that the combination of directed evolution with sequence and covariance analyses can be a powerful tool for rational protein engineering

Relevance of Stress and Female Sex Hormones for Emotion and Cognition

There are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male animals. The strongest argument for not using female rodents is their estrous cycle and the fluctuating sex hormones per phase which multiplies the number of animals to be tested. Here, we will discuss studies focused on sex differences in emotionality and cognitive abilities in experimental conditions with and without stress. First, female sex hormones such as estrogens and progesterone affect emotions and cognition, contributing to sex differences in behavior. Second, females respond differently to stress than males which might be related to the phase of the estrous cycle. For example, female rats and mice express less anxiety than males in a novel environment. Proestrus females are less anxious than females in the other estrous phases. Third, males perform in spatial tasks superior to females. However, while stress impairs spatial memory in males, females improve their spatial abilities, depending on the task and kind of stressor. We conclude that the differences in emotion, cognition and responses to stress between males and females over the different phases of the estrous cycle should be used in animal models for stress-related psychiatric disorders

Spatial distribution and risk factors of Schistosoma haematobium and hookworm infections among schoolchildren in Kwale, Kenya

Background: Large-scale schistosomiasis control programs are implemented in regions with diverse social and economic environments. A key epidemiological feature of schistosomiasis is its small-scale heterogeneity. Locally profiling disease dynamics including risk factors associated with its transmission is essential for designing appropriate control programs. To determine spatial distribution of schistosomiasis and its drivers, we examined schoolchildren in Kwale, Kenya. Methodology/Principal findings: We conducted a cross-sectional study of 368 schoolchildren from six primary schools. Soil-transmitted helminths and Schistosoma mansoni eggs in stool were evaluated by the Kato-Katz method. We measured the intensity of Schistosoma haematobium infection by urine filtration. The geometrical mean intensity of S. haematobium was 3.1 eggs/10 ml urine (school range, 1.4?9.2). The hookworm geometric mean intensity was 3.2 eggs/g feces (school range, 0?17.4). Heterogeneity in the intensity of S. haematobium and hookworm infections was evident in the study area. To identify factors associated with the intensity of helminth infections, we utilized negative binomial generalized linear mixed models. The intensity of S. haematobium infection was associated with religion and socioeconomic status (SES), while that of hookworm infection was related to SES, sex, distance to river and history of anthelmintic treatment. Conclusions/Significance: Both S. haematobium and hookworm infections showed micro-geographical heterogeneities in this Kwale community. To confirm and explain our observation of high S. haematobium risk among Muslims, further extensive investigations are necessary. The observed small scale clustering of the S. haematobium and hookworm infections might imply less uniform strategies even at finer scale for efficient utilization of limited resources

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Application of thermal effusivity as a process analytical technology tool for monitoring and control of the roller compaction process

The aim of this study was to examine the relationship between physical characteristics of compacted ribbons and their thermal effusivity in an attempt to evaluate the feasibility of using effusivity for in-process monitoring of roller compaction. In this study, thermal effusivity, solid fraction, tensile strength, and Young's modulus of ribbons of microcrystal-line cellulose (MCC), anhydrous lactose, and placebo (PBO) formulations containing various ratios of MCC to anhydrous lactose (75∶20, 55∶40, 40∶55, and 20∶75) were determined at various compaction pressures (25–150 bars). The effusivity-square root of solid fraction relationship was linear for MCC and all the PBO formulations but was a second-order polynomial function for lactose. This could be due to the predominant deformation of lactose by brittle fracture, which might have significantly increased the number and size of contact points between particles, causing a change in thermal conductivity along with a density change. The effusivitytensile strength and effusivity-Young's modulus relationships were best described by logarithmic functions for MCC but were linear for lactose up to a compaction pressure of 65 bars. There were similar relationships for effusivity with tensile strength and Young's modulus for all PBO formulations except PBO IV, which might have been due to the deformation of lactose, the largest component in this formulation. Strong correlations between effusivity and physical properties of ribbons were established. Although these correlations were formulation-dependent, they demonstrate the possibility of using effusivity as a tool in monitoring roller compaction