A novel animal model for understanding secondary traumatic stress and visceral pain in male rats.

Empathetic relationships and the social transference of behaviours have been shown to occur in humans, and more recently through the development of rodent models, where both fear and pain phenotypes develop in observer animals. Clinically, observing traumatic events can induce 'trauma and stressor-related disorders' as defined in the DSM 5. These disorders are often comorbid with pain and gastrointestinal disturbances; however, our understanding of how gastrointestinal - or visceral - pain can be vicariously transmitted is lacking. Visceral pain originates from the internal organs, and despite its widespread prevalence, remains poorly understood. We established an observation paradigm to assess the impact of witnessing visceral pain. We utilised colorectal distension (CRD) to induce visceral pain behaviours in a stimulus rodent while the observer rodent observed. Twenty four hours post-observation, the observer rodent's visceral sensitivity was assessed using CRD. The observer rodents were found to have significant hyperalgesia as determined by lower visceral pain threshold and higher number of total pain behaviours compared with controls. The behaviours of the observer animals during the observation were found to be correlated with the behaviours of the stimulus animal employed. We found that observer animals had hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis, highlighted by reduced corticosterone at 90 minutes post-CRD. Using c-Fos immunohistochemistry we showed that observer animals also had increased activation of the anterior cingulate cortex, and decreased activation of the paraventricular nucleus, compared with controls. These results suggest that witnessing another animal in pain produces a behavioural phenotype and impacts the brain-gut axis.

The gut microbiota in persistent post-operative pain following breast cancer surgery.

Persistent post-surgical pain (PPSP) is defined as pain which continues after a surgical operation in a significant form for at least three months (and is not related to pre-existing painful conditions). PPSP is a common, under-recognised, and important clinical problem which affects millions of patients worldwide. Preventative measures which are currently available include the selection of a minimally invasive surgical technique and an aggressive multimodal perioperative analgesic regimen. More recently, a role for the gut microbiota in pain modulation has become increasingly apparent. This study aims to investigate any relationship between the gut microbiota and PPSP. A prospective observational study of 68 female adult patients undergoing surgery for management of breast cancer was carried out. Stool samples from 45 of these patients were obtained to analyse the composition of the gut microbiota. Measures of pain and state-trait anxiety were also taken to investigate further dimensions in any relationship between the gut microbiota and PPSP. At 12 weeks postoperatively, 21 patients (51.2%) did not have any pain and 20 patients (48.8%) reported feeling pain that persisted at that time. Analysis of the gut microbiota revealed significantly lower alpha diversity (using three measures) in those patients reporting severe pain at the 60 min post-operative and the 12 weeks post-operative timepoints. A cluster of taxa represented by Bifidobacterium longum, and Faecalibacterium prausnitzii was closely associated with those individuals reporting no pain at 12 weeks postoperatively, while Megamonas hypermegale, Bacteroides pectinophilus, Ruminococcus bromii, and Roseburia hominis clustered relatively closely in the group of patients fulfilling the criteria for persistent post-operative pain. We report for the first time specific associations between the gut microbiota composition and the presence or absence of PPSP. This may provide further insights into mechanisms behind the role of the gut microbiota in the development of PPSP and could inform future treatment strategies.

Beta 3-adrenoceptor agonism ameliorates early-life stress-induced visceral hypersensitivity in male rats.

Visceral hypersensitivity, a hallmark of disorders of the gut-brain axis, is associated with exposure to early-life stress (ELS). Activation of neuronal ß3-adrenoceptors (AR) has been shown to alter central and peripheral levels of tryptophan and reduce visceral hypersensitivity. In this study, we aimed to determine the potential of a ß3-AR agonist in reducing ELS-induced visceral hypersensitivity and possible underlying mechanisms. Here, ELS was induced using the maternal separation (MS) model, where Sprague Dawley rat pups were separated from their mother in early life (postnatal day 2-12). Visceral hypersensitivity was confirmed in adult offspring using colorectal distension (CRD). CL-316243, a ß3-AR agonist, was administered to determine anti-nociceptive effects against CRD. Distension-induced enteric neuronal activation as well as colonic secretomotor function were assessed. Tryptophan metabolism was determined both centrally and peripherally. For the first time, we showed that CL-316243 significantly ameliorated MS-induced visceral hypersensitivity. Furthermore, MS altered plasma tryptophan metabolism and colonic adrenergic tone, while CL-316243 reduced both central and peripheral levels of tryptophan and affected secretomotor activity in the presence of tetrodotoxin. This study supports the beneficial role of CL-316243 in reducing ELS-induced visceral hypersensitivity, and suggests that targeting the ß3-AR can significantly influence gut-brain axis activity through modulation of enteric neuronal activation, tryptophan metabolism, and colonic secretomotor activity which may synergistically contribute to offsetting the effects of ELS.

Supplementation with milk fat globule membrane from early life reduces maternal separation-induced visceral pain independent of enteric nervous system or intestinal permeability changes in the rat.

Nutritional approaches have emerged over the past number of years as suitable interventions to ameliorate the enduring effects of early life stress. Maternal separation (MS) is a rodent model of early life stress which induces widespread changes across the microbiota-gut-brain axis. Milk fat globule membrane (MFGM) is a neuroactive membrane structure that surrounds milk fat globules in breast milk and has been shown to have positive health effects in infants, yet mechanisms behind this are not fully known. Here, we investigated the effects of MFGM supplementation from birth on a variety of gut-brain signalling pathways in MS and non-separated control animals across the lifespan. Specifically, visceral sensitivity as well as spatial and recognition memory were assessed in adulthood, while gut barrier permeability, enteric nervous system (ENS) and glial network structure were evaluated in both early life and adulthood. MS resulted in visceral hypersensitivity, which was ameliorated to a greater extent by supplementation with MFGM from birth. Modest effects of both MS and dietary supplementation were noted on spatial memory. No effects of MS were observed on enteric neuronal or glial networks in early life or adulthood, however an increase in the immunoreactivity of ßIII-tubulin in adult colonic myenteric ganglia was noted in the MFGM intervention non-separated group. In conclusion, dietary supplementation with MFGM from birth is sufficient to block MS-induced visceral hypersensitivity, highlighting its potential value in visceral pain-associated disorders, but future studies are required to fully elucidate the mechanistic role of this supplementation on MS-induced visceral pain.

Estrous cycle and ovariectomy-induced changes in visceral pain are microbiota-dependent.

Visceral hypersensitivity (VH) is a hallmark of many functional gastrointestinal disorders including irritable bowel syndrome and is categorized by a dull, diffuse sensation of abdominal pain. Recently, the gut microbiota has been implicated in VH in male mice, but the effects in females have yet to be explored fully. To this end, we now show that somewhat surprisingly, female germ-free mice have similar visceral pain responses to colorectal distension (CRD) as their conventional controls. However, we show that although sensitivity to CRD is estrous cycle stage-dependent in conventional mice, it is not in germ-free mice. Further, ovariectomy (OVX) induced VH in conventional but not germ-free mice, and induced weight gain regardless of microbiota status. Finally, we show that estrogen-replacement ameliorated OVX-induced VH. Taken together, this study provides evidence for a major role of female sex hormones and the gut microbiota in sensation of visceral pain in females.

Of bowels, brain and behavior: A role for the gut microbiota in psychiatric comorbidities in irritable bowel syndrome.

BACKGROUND: The gastrointestinal microbiota has emerged as a key regulator of gut-brain axis signalling with important implications for neurogastroenterology. There is continuous bidirectional communication between the gut and the brain facilitated by neuronal, endocrine, metabolic, and immune pathways. The microbiota influences these signalling pathways via several mechanisms. Studies have shown compositional and functional alterations in the gut microbiota in stress-related psychiatric disorders. Gut microbiota reconfigurations are also a feature of irritable bowel syndrome (IBS), a gut-brain axis disorder sharing high levels of psychiatric comorbidity including both anxiety and depression. It remains unclear how the gut microbiota alterations in IBS align with both core symptoms and these psychiatric comorbidities. METHODS: In this review, we highlight common and disparate features of these microbial signatures as well as the associated gut-brain axis signalling pathways. Studies suggest that patients with either IBS, depression or anxiety, alone or comorbid, present with alterations in gut microbiota composition and harbor immune, endocrine, and serotonergic system alterations relevant to the common pathophysiology of these comorbid conditions. KEY RESULTS: Research has illustrated the utility of fecal microbiota transplantation in animal models, expanding the evidence base for a potential causal role of disorder-specific gut microbiota compositions in symptom set expression. Moreover, an exciting study by Constante and colleagues in this issue highlights the possibility of counteracting this microbiota-associated aberrant behavioral phenotype with a probiotic yeast, Saccharomyces boulardii CNCM I-745. CONCLUSIONS AND INFERENCES: Such data highlights the potential for therapeutic targeting of the gut microbiota as a valuable strategy for the management of comorbid psychiatric symptoms in IBS.

Identifying a biological signature of prenatal maternal stress.

Psychological stress affects maternal gastrointestinal (GI) permeability, leading to low-grade inflammation, which can negatively affect fetal development. We investigated a panel of circulating markers as a biological signature of this stress exposure in pregnant women with and without the stress-related GI disorder irritable bowel syndrome (IBS). Markers of GI permeability and inflammation were measured in plasma from healthy and IBS cohorts of women at 15 and 20 weeks' gestation. Biomarkers were evaluated with respect to their degree of association to levels of stress, anxiety, and depression as indicated by responses from the Perceived Stress Scale, State-Trait Anxiety Inventory, and Edinburgh Postnatal Depression Scale. High levels of stress were associated with elevations of soluble CD14, lipopolysaccharide binding protein (LBP), and tumor necrosis factor-α, while anxiety was associated with elevated concentrations of C-reactive protein (CRP) in otherwise healthy pregnancies. Prenatal depression was associated with higher levels of soluble CD14, LBP, and CRP in the healthy cohort. High levels of prenatal anxiety and depression were also associated with lower concentrations of tryptophan and kynurenine, respectively, in the IBS cohort. These markers may represent a core maternal biological signature of active prenatal stress, which can be used to inform intervention strategies via stress reduction techniques or other lifestyle approaches. Such interventions may need to be tailored to reflect underlying GI conditions, such as IBS.

Evaluation of Syndromic Surveillance Systems in 6 US State and Local Health Departments.

OBJECTIVE: Evaluating public health surveillance systems is critical to ensuring that conditions of public health importance are appropriately monitored. Our objectives were to qualitatively evaluate 6 state and local health departments that were early adopters of syndromic surveillance in order to (1) understand the characteristics and current uses, (2) identify the most and least useful syndromes to monitor, (3) gauge the utility for early warning and outbreak detection, and (4) assess how syndromic surveillance impacted their daily decision making. DESIGN: We adapted evaluation guidelines from the Centers for Disease Control and Prevention and gathered input from the Centers for Disease Control and Prevention subject matter experts in public health surveillance to develop a questionnaire. PARTICIPANTS: We interviewed staff members from a convenience sample of 6 local and state health departments with syndromic surveillance programs that had been in operation for more than 10 years. RESULTS: Three of the 6 interviewees provided an example of using syndromic surveillance to identify an outbreak (ie, cluster of foodborne illness in 1 jurisdiction) or detect a surge in cases for seasonal conditions (eg, influenza in 2 jurisdictions) prior to traditional, disease-specific systems. Although all interviewees noted that syndromic surveillance has not been routinely useful or efficient for early outbreak detection or case finding in their jurisdictions, all agreed that the information can be used to improve their understanding of dynamic disease control environments and conditions (eg, situational awareness) in their communities. CONCLUSION: In the jurisdictions studied, syndromic surveillance may be useful for monitoring the spread and intensity of large outbreaks of disease, especially influenza; enhancing public health awareness of mass gatherings and natural disasters; and assessing new, otherwise unmonitored conditions when real-time alternatives are unavailable. Future studies should explore opportunities to strengthen syndromic surveillance by including broader access to and enhanced analysis of text-related data from electronic health records. Health departments may accelerate the development and use of syndromic surveillance systems, including the improvement of the predictive value and strengthening the early outbreak detection capability of these systems. These efforts support getting the right information to the right people at the right time, which is the overarching goal of CDC's Surveillance Strategy.

Multi-modality imaging of transient osteoporosis of the hip.

Transient osteoporosis of the hip (TOH), also referred to as bone marrow edema syndrome (BMES) of the femoral head and neck, is an uncommon and therefore underdiagnosed benign skeletal disorder, affecting primarily women, particularly in their last trimester of pregnancy, and middle-aged men. The disease is characterized by self-limiting hip pain and radiographically evident osteopenia, but these radiographic findings can sometimes be delayed. In the early phase, the main diagnostic dilemma lies in differentiating TOH from osteonecrosis of the femoral head (ONFH). Conventional radiographs, Tc-99m bone scans (multiphase, SPECT or SPECT/CT) and MRI scans from 10 male patients with 12 TOH episodes were retrospectively and independently reviewed by two nuclear medicine physicians and a musculoskeletal radiologist. The purpose was to identify a typical imaging pattern, and secondly, to reliably distinguish TOH from ONFH. In the early phase of TOH, conventional radiography of the hip could not sufficiently detect focal osteopenia. But in all 10 patients (mean age 45 years, range, 34-62), bone scans and MRI scans demonstrated a similar pattern of diffuse hyperaemia, bony uptake, and bone marrow edema in the femoral head and neck, extending to and ending with a sharp demarcation at the intertrochanteric region. Additionally, neither SPECT nor SPECT/CT nor MRI revealed any cold area or crescent-shaped subchondral defect in the femoral head, indicating ONFH. In some cases there was a joint effusion in varying degree. In 9 patients, an uneventful recovery was eventually observed. Scintigraphically diffuse hyperaemic and/or homogeneous osseous uptake in femoral head and neck extending to the intertrochanteric region, as well as the recently introduced term transient bone marrow edema syndrome (BMES) of the hip on MRI, are probably both expressions of the same pathophysiological mechanism, and pathognomonic for TOH. Hopefully, recognizing this highly specific imaging pattern will exclude in the future more aggressive skeletal diseases like ONFH, severe arthritis, osteomyelitis or even malignancy.

US-guided injection of the upper and lower extremity joints.

There is a growing interest in the application of ultrasound (US) guidance for diagnostic and therapeutic joint injections. US provides direct visualization of soft tissues and the outer borders of bony structures. With real-time needle guidance the success rate of intra-articular injections improves and iatrogenic damage to anatomic structures can be avoided. An US machine is more readily available, transferrable and more affordable than a fluoroscopy machine or CT scanner and lacks the risk of radiation. These factors make US a valuable alternative to procedures performed either blind or under fluoroscopic or CT guidance. This article focuses on the rationale for injections in the upper and lower extremity joints and describes and illustrates the different US-guided injection techniques.

Unsuspected sonographic findings in patients with posttraumatic shoulder complaints.

PURPOSE: To prospectively assess the frequency of abnormal sonographic findings in patients with posttraumatic shoulder pain and/or disability in whom ultrasound (US) was not considered and to assess the effect of sonographic findings on working diagnosis and therapeutic strategy, to analyze the possible role of US in the diagnostic workup of these patients. METHODS: A survey was performed under general practitioners and orthopedic surgeons. They were requested to refer patients with persistent posttraumatic complaints for an US examination of the shoulder and to fill out a questionnaire concerning working diagnosis and therapy. In 50 patients examinations were performed separately by two radiologists. Findings were confirmed with additional radiographs and/or MRI and/or surgery. Four weeks after the US examination, the survey was repeated to inquire about changes in diagnosis and/or treatment that resulted from US. RESULTS: US showed relevant pathology in 45 (90%) of 50 patients, a proximal humerus fracture in 25 (50%) patients, and a rotator cuff tear in 43 (86%) patients. Twenty-three (92%) fractures were accompanied by a rotator cuff tear, and 23 (54%) rotator cuff tears were accompanied by a fracture. Ten fractures were initially missed radiographically. US findings changed the working diagnosis and therapeutic strategy in 37 (74%) and 26 (52%) patients, respectively. CONCLUSION: In patients with posttraumatic shoulder complaints, US showed a high rate (90%) of relevant pathology. This changed the initial working diagnosis in 74% of the patients and the therapeutic strategy in more than half of the patients. Active referral for US examination may identify these abnormalities in an earlier phase and improve clinical outcome.

Early monitoring of the viability of the buried intrathoracic omental flap: a feasibility study.

PURPOSE: The value of mobile, high-resolution gray-scale and color Doppler ultrasonography (US) in the immediate postoperative, intensive care setting for monitoring the buried flap and vascular pedicle of the laparoscopic or transdiaphragmatic harvested omentum for intrathoracic reconstruction was evaluated. In addition to flow, flap position, size, and findings of flap necrosis, other flap-related complications were investigated. DESCRIPTION: Two patients with deep sternal wound infection after coronary artery bypass grafting suspected with impending flap failure and reoperation in the immediate postreconstructive period were examined with a Philips HDI-5000 US scanner (Philips Medical Systems, Best, The Netherlands) equipped with an L12-5 MHz linear-array transducer at the bedside. The US findings were defined and the therapeutic decisions that were made based on the information gleaned, were compared with computed tomography controls and the eventual clinical outcomes. EVALUATION: Flow and flap viability could easily and repeatedly be demonstrated and recorded with the aid of high-resolution gray-scale and color-Doppler US. Despite the unusual, buried position of the pedicle and omental flap, the information gleaned was sufficient to reach a decision that prevented unnecessary surgery. CONCLUSIONS: Mobile high-resolution gray-scale US, combined with color Doppler US, was confirmed to be accurate and promises to be a valuable noninvasive tool for the immediate postoperative assessment of pedicle and intrathoracic omental flap perfusion and viability. It may also avert unnecessary and difficult surgical revision of an elegant but sensitive flap reconstruction.

Expanding role of 18F-fluoro-D-deoxyglucose PET and PET/CT in spinal infections.

(18)F-fluoro-D -deoxyglucose positron emission tomography ([(18)F]-FDG PET) is successfully employed as a molecular imaging technique in oncology, and has become a promising imaging modality in the field of infection. The non-invasive diagnosis of spinal infections (SI) has been a challenge for physicians for many years. Morphological imaging modalities such as conventional radiography, computed tomography (CT), and magnetic resonance imaging (MRI) are techniques frequently used in patients with SI. However, these methods are sometimes non-specific, and difficulties in differentiating infectious from degenerative end-plate abnormalities or postoperative changes can occur. Moreover, in contrast to CT and MRI, FDG uptake in PET is not hampered by metallic implant-associated artifacts. Conventional radionuclide imaging tests, such as bone scintigraphy, labeled leukocyte, and gallium scanning, suffer from relatively poor spatial resolution and lack sensitivity, specificity, or both. Initial data show that [(18)F]-FDG PET is an emerging imaging technique for diagnosing SI. [(18)F]-FDG PET appears to be especially helpful in those cases in which MRI cannot be performed or is non-diagnostic, and as an adjunct in patients in whom the diagnosis is inconclusive. The article reviews the currently available literature on [(18)F]-FDG PET and PET/CT in the diagnosis of SI.

Glenohumeral joint injection: a comparative study of ultrasound and fluoroscopically guided techniques before MR arthrography.

To assess the variability in accuracy of contrast media introduction, leakage, required time and patient discomfort in four different centres, each using a different image-guided glenohumeral injection technique. Each centre included 25 consecutive patients. The ultrasound-guided anterior (USa) and posterior approach (USp), fluoroscopic-guided anterior (FLa) and posterior (FLp) approach were used. Number of injection attempts, effect of contrast leakage on diagnostic quality, and total room, radiologist and procedure times were measured. Pain was documented with a visual analogue scale (VAS) pain score. Access to the joint was achieved in all patients. A successful first attempt significantly occurred more often with US (94%) than with fluoroscopic guidance (72%). Leakage of contrast medium did not cause interpretative difficulties. With US guidance mean room, procedure and radiologist times were significantly shorter (p < 0.001). The USa approach was rated with the lowest pre- and post-injection VAS scores. The four image-guided injection techniques are successful in injection of contrast material into the glenohumeral joint. US-guided injections and especially the anterior approach are significantly less time consuming, more successful on the first attempt, cause less patient discomfort and obviate the need for radiation and iodine contrast.