Cutaneous C-fibres in the rat and the rabbit - How efferent actions and axonal properties vary with functional class

The aim of this study was to investigate further some efferent actions and axonal properties of the unmyelinated fibres innervating rabbit and rat skin. This investigation can be separated into two parts. Firstly, single unit studies were carried out to determine which functional class(es) or sub-class(es) of C-fibre are responsible for antidromic vasodilatation in both rabbit and rat skin. The findings of these single unit studies were compared with the flare responses of the skin to noxious mechanical and heat stimuli. Secondly, activity-dependent slowing of conduction velocity and axonal spike shape were examined in identified cutaneous C-fibres in the rat in order to determine whether such axonal properties could be used to identify the different functional classes of C-fibre. For the antidromic vasodilatation study, fine filaments were dissected from the cut proximal end of the saphenous nerve in anaesthetized rabbits and rats. Individual C-fibres (conduction velocity <2m/s) were classified into functional groups according to their responses to mechanical and thermal stimulation. The threshold for electrical stimulation of individual C-fibres was determined using the collision technique. Filaments were antidromically electrically stimulated at intensities sufficient to excite the conducting C-fibres, and skin blood flow was monitored before, during and after filament stimulation using laser Doppler perfusion imaging or laser Doppler flowmetry. In both species, the only C-fibres capable of producing a detectable vasodilator response following antidromic stimulation were nociceptive in nature, and in all cases the area of vasodilatation coincided well with the afferent receptive field. However, not all nociceptors produced a detectable vasodilatation, and it seems that a sub-group of polymodal and heat nociceptors are responsible for the efferent action of antidromic vasodilatation in rabbit and rat skin. Flare responses in rabbit and rat skin were only detected following mechanical and heat stimuli within noxious ranges. The spread of the flare responses, together with the sizes of the afferent and efferent receptive fields of individual C-units, provide support for the axon reflex mechanism for the production of flare and antidromic vasodilatation. The percentage slowing of conduction velocity was calculated following a standard electrical tetanus in identified C-fibres dissected from the saphenous nerve in anaesthetized rats. Nociceptive C-fibres showed a greater slowing of conduction velocity than non-nociceptive fibres, and moreover, one could separate the two classes of non-nociceptive afferent C-fibres found in the rat saphenous nerve (the mechanoreceptors and cold thermoreceptors) on the basis of their conduction velocity slowing. In addition, activity-dependent slowing of conduction velocity could be used to differentiate between the afferent and non-afferent populations of inexcitable C-fibres. Spike shapes of functionally classified C-fibres were recorded extracellularly using standardized filter settings, and some variations in spike shape in relation to receptor type were found. Polymodal nociceptors displayed wider spikes than mechanoreceptors, and cold thermoreceptor units tended to have monophasic spikes. Also, the spontaneously active sympathetic efferent C-fibres tended to have spikes of relatively long duration. The use of axonal properties such as activity-dependent slowing of conduction velocity and spike shape to differentiate nociceptors from non-nociceptors has great potential in experiments where axons are isolated from their terminals

Dimethylsulfoxide exposure modulates HL-60 cell rolling interaction

Human leukaemic HL-60 cells are widely used for studying interactions involving adhesion molecules [e.g. P-selectin and PSGL-1 (P-selectin glycoprotein ligand-1)] since their rolling behaviour has been shown to mimic the dynamics of leucocyte rolling in vitro. HL-60 cells are neutrophilic promyelocytes that can undergo granulocytic differentiation upon exposure to compounds such as DMSO (dimethylsulfoxide). Using a parallel plate flow chamber functionalized with recombinant P-selectin–Fc chimaera, undifferentiated and DMSO-induced (48, 72 and 96 h) HL-60 cells were assayed for rolling behaviour. We found that depending on P-selectin incubation concentration, undifferentiated cells incurred up to a 6-fold increase in rolling velocity while subjected to an approximately 10-fold increase in biologically relevant shear stress. HL-60 cells exposed to DMSO for up to 72 h incurred up to a 3-fold increase in rolling velocity over the same shear stress range. Significantly, cells exposed for up to 96 h incurred up to a 9-fold decrease in rolling velocity, compared with undifferentiated HL-60 cells. Although cell surface and nuclear morphological changes were evident upon exposure to DMSO, flow cytometric analysis revealed that PSGL-1 expression was unchanged, irrespective of treatment duration. The results suggest that DMSO-treated HL-60 cells may be problematic as a substitute for neutrophils for trafficking studies during advanced stages of the LAC (leucocyte adhesion cascade). We suggest that remodelling of the cell surface during differentiation may affect rolling behaviour and that DMSO-treated HL-60 cells would behave differently from the normal leucocytes during inflammatory response in vivo

Understanding Prediabetes Through Facebook: Pilot Study Protocol and Lessons Learned

Purpose/Background: Type 2 Diabetes is a serious contributor to mortality and morbidity. Rural populations (including those in Mountain West regions) exhibit greater health disparities than their urban counterparts for many conditions, including diabetes. It is therefore vital to address this important health issue, especially among rural populations. One way to address diabetes is with prevention, starting with enhanced detection of prediabetes. According to the CDC, more than 84 millions Americans (one in three adults) has prediabetes, but nine out of ten are not aware of their condition, which hampers prevention efforts. Infodemiology has been used successfully to track health information found on social media. Our project aims to find indicators of prediabetes through Facebook content, with a long-term goal of developing an effective social media screening tool for prediabetes. Materials & Methods: This study had an exploratory retrospective design (the study protocol has been published; Xu, Litchman, Geeet al., 2018 JMIR Research Protocols). Utilizing electronic medical records from a Mountain West region family medicine clinic, we recruited 17 patients diagnosed with prediabetes who were willing to share their Facebook posts. Participants completed a clinic session where they responded to a number of surveys (e.g., Facebook Intensity Scale, Prediabetes Online Community Engagement Scale, Computer-Mediated Social Support Scale) and provided us with their Facebook account information. We then accessed and coded all Facebook posts for the 6-month period surrounding their prediabetes diagnosis (3-months pre through 3-months post-diagnosis; see Figure 1). Coding included meta-data (e.g., time of post, post type), post text/visuals, social aspects of the post (e.g., comments, reactions, shares), and content of interest (e.g., health, physical symptoms, lifestyle factors, medical experiences, food etc.). Results: Descriptive information about participant demographics and their responses to surveys are provided (see Table 1). We are currently compiling the coded data and will use a mixed-method protocol for analyses. This includes both qualitative content analysis to identify themes as well as a quantitative approach to examine potential differences between the 3-months prediagnosis and the 3-months postdiagnosis for our participants. While we were able to code data for 17 patients, due to unanticipated barriers in recruitment and coding we did not meet our planned goal of 20 patients. To assist those planning on conducting this type of social media research, we will discuss some of these issues including the importance of having a large team of coders who can work simultaneously. Discussion/Conclusion: Data from this project should provide an initial taxonomy of prediabetes indicators indentifiable within a social media context. Future studies, with larger samples, can test the utility of the taxonomy on predicting prediabetes status from Facebook posts. We also hope that our lessons learned information will be helpful to other researchers working on social media health studies. The ultimate goal of our research is to develop an automated method to identify social media users who are likely to have prediabetes. This would be especially helpful for those who are unaware of their health condition, as identification can lead to efforts that can prevent the progression of prediabetes to diabetes

A Systems Engineering Approach to Modeling and Analysis of Chronic Obstructive Pulmonary Disease (COPD)

Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung disease characterized by airflow limitation. This study develops a systems engineering framework for representing important mechanistic details of COPD in a model of the cardio-respiratory system. In this model, we present the cardio-respiratory system as an integrated biological control system responsible for regulating breathing. Four engineering control system components are considered: sensor, controller, actuator, and the process itself. Knowledge of human anatomy and physiology is used to develop appropriate mechanistic mathematical models for each component. Following a systematic analysis of the computational model, we identify three physiological parameters associated with reproducing clinical manifestations of COPD - changes in the forced expiratory volume (FEV), lung volumes, and pulmonary hypertension. We quantify the changes in these parameters (airway resistance, lung elastance, and pulmonary resistance) as the ones that result in a systemic response that is diagnostic of COPD. A multivariate analysis reveals that the changes in airway resistance have a broad impact on the human cardio-respiratory system, and that the pulmonary circuit is stressed beyond normal under hypoxic environments in most COPD patients.Comment: 25 pages, 15 figure

Hypermethylation of SOX2 Promoter in Endometrial Carcinogenesis

This paper aimed at investigating the expression and methylation profiles of SOX2, a gene coding for the stem cell-related transcription factor SOX2, in endometrial carcinomas. By methylation-specific polymerase chain reaction (MS-PCR), the methylation status of SOX2 promoter region in 72 endometrial carcinomas and 12 normal endometrial samples was examined. Methylated allele was found in 37.5% (27/72) of endometrial carcinomas but only in 8.3% (1/12) of normal endometrial, significantly more frequent in cancers (P = .0472). SOX2 mRNA level was significantly reduced in endometrial carcinoma compared with nonneoplastic endometrium (P = .045). A significant correlation between SOX2 mRNA expression and hypermethylation of SOX2 was found (P = .024). Hypermethylation of SOX2 tended to be more frequently found in type II serous or clear cell adenocarcinoma. SOX2 methylation was also significantly correlated with shorter survival of patients (P = .046). In conclusion, epigenetic mechanisms may play a crucial role on the transcriptional regulation of SOX2 and loss of SOX2 expression may be related to endometrial carcinogenesis

Modeling and Analysis of the Intrinsic Cardiac Nervous System in Closed-Loop Cardiovascular Control

The baroreceptor reflex is a multi-input, multi-output physiological control system that regulates short-term blood pressure by modulating nerve activity between the brainstem and the heart. The computational model by Park et al. (2020) is the most recent iteration in our exploration of the system. However, the contributions of”the little brain of the heart”, the intrinsic cardiac nervous system (ICN), to local control of the heart and to the integration of sensory information is unknown and has been overlooked in previous models. We have incorporated a high-fidelity representation of the ICN into a model of the baroreceptor reflex based on anatomical, molecular, and physiological evidence. The model consists of (1) differential equations to represent the cardiovascular system, and (2) transfer functions to represent neural control components, connected in a closed-loop control circuit. We use the model to evaluate the impact of alternative ICN network structures on overall cardiovascular control in response to mean arterial pressure and lung tidal volume perturbations. Our results show that the local circuit neurons that integrate sensory information into the ICN strengthen the response of ICN neuron activity, especially at low blood pressures, suggesting that the ICN amplifies the brainstem\u27s response to perturbations

Closed-Loop Modeling of Central and Intrinsic Cardiac Nervous System Circuits Underlying Cardiovascular Control

The baroreflex is a multi-input, multi-output physiological control system that regulates blood pressure by modulating nerve activity between the brainstem and the heart. Existing computational models of the baroreflex do not explicitly incorporate the intrinsic cardiac nervous system (ICN), which mediates central control of heart function. We developed a computational model of closed-loop cardiovascular control by integrating a network representation of the ICN within central control reflex circuits. We examined central and local contributions to the control of heart rate, ventricular functions, and respiratory sinus arrhythmia (RSA). Our simulations match the experimentally observed relationship between RSA and lung tidal volume. Our simulations predicted the relative contributions of the sensory and the motor neuron pathways to the experimentally observed changes in the heart rate. Our closed-loop cardiovascular control model is primed for evaluating bioelectronic interventions to treat heart failure and renormalize cardiovascular physiology

C5 Palsy After Cervical Spine Surgery: A Multicenter Retrospective Review of 59 Cases.

STUDY DESIGN: A multicenter, retrospective review of C5 palsy after cervical spine surgery. OBJECTIVE: Postoperative C5 palsy is a known complication of cervical decompressive spinal surgery. The goal of this study was to review the incidence, patient characteristics, and outcome of C5 palsy in patients undergoing cervical spine surgery. METHODS: We conducted a multicenter, retrospective review of 13 946 patients across 21 centers who received cervical spine surgery (levels C2 to C7) between January 1, 2005, and December 31, 2011, inclusive. P values were calculated using 2-sample t test for continuous variables and χ(2) tests or Fisher exact tests for categorical variables. RESULTS: Of the 13 946 cases reviewed, 59 patients experienced a postoperative C5 palsy. The incidence rate across the 21 sites ranged from 0% to 2.5%. At most recent follow-up, 32 patients reported complete resolution of symptoms (54.2%), 15 had symptoms resolve with residual effects (25.4%), 10 patients did not recover (17.0%), and 2 were lost to follow-up (3.4%). CONCLUSION: C5 palsy occurred in all surgical approaches and across a variety of diagnoses. The majority of patients had full recovery or recovery with residual effects. This study represents the largest series of North American patients reviewed to date