Secondary Trigger Research Articles

Secondary Trigger Point Deactivation Surgery for Nerve Compression Headaches: A Scoping Review.

Primary trigger point deactivation surgery has been successful in reducing or eliminating nerve compression headaches between 79% and 90% of the time. The aim of this review article was to discuss the factors that contribute to index trigger point deactivation surgery failure, the importance of reevaluating trigger points following failure, and the options for secondary surgery. A literature search was performed using a combination of keywords involving "chronic headache" and "nerve deactivation surgery," in databases until February 2023. Data of 1071 patients were evaluated and included (11 articles). The failure rate after index trigger point deactivation surgery occurs is approximately 12%, primarily due to incomplete primary trigger point deactivation. Secondary trigger points may not appear until the primary trigger is eliminated, which occurs in 17.8% of patients. Reevaluation of previously diagnosed trigger points as well as uncovered trigger points and additional preoperative testing is indicated to help determine candidacy for further surgical deactivation. To address scarring that could contribute to failure, corticosteroid injection, acellular dermal matrix, adipofascial fat, or expanded polytetrafluoroethylene sleeves have been described with beneficial effects. For neuroma management, regenerative peripheral nerve interface, targeted muscle reinnervation, a combination of both, relocation nerve grafting, or nerve capping have also been described. Neurectomy can be performed when patients prefer anesthesia and/or paresthesia over current pain symptoms. Secondary trigger point deactivation surgery is indicated when there is suspicion of incomplete deactivation, internal scarring, neuroma, or newly-diagnosed trigger points.

Outcome of atypical hemolytic uremic syndrome: role of triggers and complement abnormalities in the response to C5 inhibition.

Atypical-hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy often due to uncontrolled complement activation, characterized by high risk of end-stage kidney disease (ESKD). Eculizumab has improved the outcome, however, its efficacy varies among patients and its discontinuation is debated. To identify characteristics associated with treatment response, we analyzed 244 aHUS patients referred to our center. Patients were classified according to the presence/absence of complement abnormalities and/or triggers at onset in 4 categories: (1) primary (complement abnormality without trigger), (2) secondary (trigger without complement abnormality), (3) combined (trigger and complement abnormality), (4) idiopathic (no trigger, no complement abnormality). Response to treatment was evaluated by comparing the response to eculizumab with that of conventional therapy. Short- and long-term outcomes were evaluated with the relapse rate after discontinuation of C5-inhibition. Patients had a better outcome with eculizumab compared to conventional treatment, with a response rate of 81.9% vs 56.9%, p < 0.001 and a long-term cumulative incidence of ESKD of 5.8% vs 22.5% (hazard ratio 0.25, 95% confidence interval: 0.10-0.80). The excellent global response was driven by the primary and combined groups (89.8% vs 54.0% and 89.3% vs 54.2%, respectively). The relapse rate following discontinuation of the C5-inhibitor was as high as 66.7% in the primary group, 18.7% in the combined, and 0% in the secondary and idiopathic groups. Our data show a better outcome in aHUS patients treated with C5-inhibition, particularly in the primary and combined forms, which have a high risk of relapse after discontinuation that is not observed in the secondary and idiopathic forms.

Geospatial conditions of landslide formation on the territory of Sakhalin Island

The paper considers the conditions for the formation of landslide-prone areas of Sakhalin Island, the intensity of development and the main characteristics of landslides of various types common on the territory of Sakhalin Island. Sakhalin Island, determined by the geospatial location of the territory. It is due to the geospatial location of the territory as a result of the tectonic and geological history of its development that the present relief, in addition to extensive sedimentation basins, is represented by steeply sloping erosion-denudation and abrasion forms of macro and mesorelief with high potential energy, overlain by layered significantly dislocated and structurally disturbed terrigenous strata represented by relatively weak rocks, the accumulation of which occurred as a result of cyclic sedimentation. The tectonic and accompanying seismic activity, as well as the geologic history of the terrane formation, have led to the formation of complex engineering, geological, and hydrogeological conditions of the territory. Furthermore, the marginal position of the region determines its monsoon climate with high cyclonic activity, leading to a general high moisture content of the territory and activation of exogenous processes. Thus, due to the geospatial position of Sakhalin in the transition zone, a whole complex of natural factors of landslide formation was formed in the territory, including global factors (tectonic, climatic) and their subordinate determinants, as well as secondary (trigger) factors (geomorphologic, geological, hydrogeological, seismic), contributing to the widespread development of modern active landslides of different scales, characteristics, as well as types of landslide process and mechanism of mountain displacement.

Relationship Between Psychological Trauma and Irritable Bowel Syndrome and Functional Dyspepsia in a Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Patient Population.

There is frequent overlap between and the connective tissue diseases Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome (JHS/EDS) and disorders of the gut-brain interaction (DGBIs). Because not all JHS/EDS patients develop DGBIs, we sought to determine whether secondary environmental triggers may lead to development of irritable bowel syndrome (IBS) and functional dyspepsia (FD) in patients with JHS/EDS. We sent electronic surveys to 253 patients from a JHS/EDS support group, with responses collected over one year. IBS and FD were diagnosed by the Rome IV criteria, with additional validated assessments of adverse childhood experiences (ACEs) and traumatic stressors according to DSM-V criteria. We compared clinical and psychological characteristics of JHS/EDS patients with and without DGBIs using univariable and multivariable analyses. We enrolled 193 JHS/EDS patients, of whom 67.9% met Rome IV criteria for IBS. The IBS and JHS/EDS overlap group reported significantly more traumatic exposures (P < 0.001) and were more likely to have experienced greater than 3 ACEs (P < 0.001) than JHS/EDS patients without IBS. FD was found in 35.2% of patients and was associated with significantly more traumatic exposures (P < 0.001) and were more likely to have experienced greater than 3 ACEs (P < 0.001) than JHS/EDS patients without FD. We found that JHS/EDS patients with IBS and FD overlap reported significantly more traumatic exposures and ACEs compared to JHS/EDS patients without overlapping IBS or FD. JHS/EDS patients may have increased susceptibility to DGBIs, with traumatic life experiences and/or ACEs acting a secondary environmental trigger driving the subsequent development of DGBIs.

Mobilization Of Political Protest In The Russian Segment Of Social Media (2021): Triggers, Audience, Communication Channels

The article presents the results of applied political research, the purpose of which is to determine the scale, mobilization potential, social base, and digital communication technologies of protest-oriented information flow in the Russian segment of social media on the eve of the Single Voting Day of 2021. The cognitive mapping implemented in the study made it possible to identify the meaningful characteristics of the information flow. The social media analysis made it possible to determine the dynamic and structural characteristics of the information flow, the gender and age specifics of the users involved in it, as well as quantitative characteristics of the activity of key communities forming protest information flows. The method of social graphs revealed the structure of interaction between the opposition and protest communities of Telegram in 2021. The event analysis carried out during the study made it possible to fix the key peaks of growth in the dynamics of user activity around protest events and discourses. On this basis, it was possible to identify the triggers used to involve users in protest information flows (elections, law enforcement agencies, vaccination, socio-economic problems), typologize the communities forming the protest information flow (protest aggregator communities, news aggregator communities, local analytics communities), and model of mass protest mobilization (primary trigger — secondary trigger — offline protest).

Measurement of the muon lifetime and the Michel spectrum in the LAGO water Cherenkov detectors as a tool to enhance the signal-to-noise ratio

The Latin American Giant Observatory (LAGO) consists of a network of water Cherenkov detectors (WCDs) installed in the Latin American region at various latitudes, from Sierra Negra in Mexico, 18°59′ N 97°18′ W to the Antarctic Peninsula, 64°14′ S 56°38′ W and altitudes from Lima, Peru at 20m a.s.l. to Chacaltaya, Bolivia at 5500m a.s.l.The detectors of the network are built from commercial water tanks, so they have several geometries (cylindrical in general) and different water purification methods. All these features generate different profiles in the response to air shower particles measured by our detectors and produce pulse-shaped electronic signals. Common sources of noise in a WCD come from light leakage, electronic noise, and noise associated with the operation of photomultiplier tubes (PMTs) such as thermionic emission and after-pulses; they all could produce detectable pulses recorded by the LAGO data acquisition (DAQ) system. In LAGO WCDs, these noise signals are expected to present a short pulse width (of a few nanoseconds), while secondary radiation typically produces pulses of several tens of nanoseconds.We used data from the LAGO DAQ system, which digitises pulses at 40MHz sampling rate on windows of 300ns (12 temporal bins) and with a 10-bit resolution. The LAGO DAQ configuration uses a single threshold-based trigger in the third temporal bin. We proposed a secondary trigger threshold at the fourth bin to improve the noise rejection. In this work, we show how the optimal values for these triggers are now obtained from the measurement of the muon lifetime within the water volume and the resulting Michel spectrum. Our results were also simulated using the LAGO ARTI simulation framework to estimate the expected flux of secondary particles at the detector site; and the Meiga framework, a Geant4-based simulator used to estimate the WCDs response to the atmospheric radiation flux.

Trained immunity in the pathogenesis of vitiligo.

Vitiligo is caused by an autoimmune reaction against melanocytes leading to melanocyte loss. The cause of vitiligo is an interaction between genetic susceptibility and environmental factors. Both the adaptive immune system-through cytotoxic CD8+ T cells and melanocyte specific antibodies-and the innate immune system are involved in these immune processes in vitiligo. While recent data stressed the importance of innate immunity in vitiligo, the question remains why vitiligo patients' immune response becomes overly activated. Could a long-term increase in innate memory function, described as trained immunity after vaccination and in other inflammatory diseases, play a role as an enhancer and continuous trigger in the pathogenesis of vitiligo? After exposure to certain stimuli, innate immune system is able to show an enhanced immunological response to a secondary trigger, indicating a memory function of the innate immune system, a concept termed trained immunity. Trained immunity is regulated by epigenetic reprogramming, including histone chemical modifications and changes in chromatin accessibility that cause sustained changes in the transcription of specific genes. In responses to an infection, trained immunity is beneficial. However, there are indications of a pathogenic role of trained immunity in inflammatory and autoimmune diseases, with monocytes presenting features of a trained phenotype, resulting in increased cytokine production, altered cell metabolism through mTOR signaling, and epigenetic modifications. This hypothesis paper focusses on vitiligo studies that have shown these indications, suggesting the involvement of trained immunity in vitiligo. Future studies focusing on metabolic and epigenetic changes in innate immune cell populations in vitiligo could help in elucidating the potential role of trained immunity in vitiligo pathogenesis.

Relationship between Chemotherapy-Induced Diarrhea and Intestinal Microbiome Composition

Background and Aim: Fluoropyrimidines (FPs) are key drugs in many chemotherapy regimens; however, recipients are often prone to diarrhea due to gastrointestinal toxicity. Disruption of the intestinal epithelial barrier function by FPs leads to dysbiosis, which may exacerbate intestinal epithelial cell damage as a secondary effect and trigger diarrhea. However, despite studies on chemotherapy-induced changes in the intestinal microbiome of humans, the relationship between dysbiosis and diarrhea is unclear. In this study, we aimed to investigate the relationship between chemotherapy-induced diarrhea and the intestinal microbiome. Methods: We conducted a single-center prospective observational study. Twenty-three patients who received chemotherapy, including FPs as first-line chemotherapy for colorectal cancer, were included. Stool samples were collected before the start of chemotherapy and after one cycle of treatment to analyze intestinal microbiome composition and perform PICRUSt predictive metagenomic analysis. Results: Gastrointestinal toxicity was observed in 7 of 23 patients (30.4%), diarrhea was observed in 4 (17.4%), and nausea and anorexia were observed in 3 (13.0%). In 19 patients treated with oral FPs, the α diversity of the microbial community decreased significantly following chemotherapy only in the diarrheal group. At the phylum level, the diarrheal group showed a significant decrease in the abundance of Firmicutes and a significant increase in the abundance of Bacteroidetes with chemotherapy (p = 0.013 and 0.011, respectively). In the same groups, at the genus level, Bifidobacterium abundance was significantly decreased (p = 0.019). In contrast, in the non-diarrheal group, Actinobacteria abundance increased significantly with chemotherapy at the phylum level (p = 0.011). Further, Bifidobacterium, Fusicatenibacter, and Dorea abundance significantly increased at the genus level (p = 0.006, 0.019, and 0.011, respectively). The PICRUSt predictive metagenomic analysis revealed that chemotherapy caused significant differences in membrane transport in KEGG pathway level 2 and in 8 KEGG pathway level 3, including transporters and oxidative phosphorylation in the diarrhea group. Conclusion: Organic-acid-producing bacteria seem to be involved in diarrhea associated with chemotherapy, including FPs.

Surgical therapy of migraine: a 12-year single-center experience

BackgroundIn recent years, surgical therapy has taken on an increasingly decisive role in the therapeutic armamentarium of migraine. All surgical techniques are aimed at the complete neurolysis of some extra-cranial nerves, of which the most involved (in our experience) are the greater and lesser occipital, auriculotemporal, supraorbital, and supratrochlear nerves. This paper describes our surgical approaches for the treatment of occipital, temporal, and frontal trigger sites. MethodsA single-center, retrospective study was conducted on all patients who underwent surgical treatment of migraine between 2011 and 2022. Patients were asked to fill out a headache diary and complete a migraine questionnaire assessing parameters before surgery, after 3 months, and 1 year after surgery. Data regarding age, sex, age at onset, migraines per month (in days), associated symptoms, severity (on a scale from 1 to 10), inability to work per month (in days), health status, history of neck trauma, and family history were collected. The Migraine Disability Assessment Scale (MIDAS) score was also used to evaluate the degree of disability for each patient.ResultsWe have operated on 612 patients: n.266 occipital, n.248 temporal, n.98 frontal. The surgical procedure elicited a positive response in 90% of the patients (69% complete recovery). Complications were mild and temporary: mainly, hypoesthesia and numbness of the undermined areas, lasting from 3 weeks to 6 months. We observed the onset of secondary trigger sites in 257 (42%) patients.DiscussionThe described procedure is minimally invasive and highly reproducible and allows to obtain a high degree of success with a negligible rate of complications. Nevertheless, given the high percentage of occurrence of secondary trigger points, it is particularly important to warn the patient of this possibility in pre-operative visits.Level of evidence:Level III, Therapeutic

Microglial immune regulation by epigenetic reprogramming through histone H3K27 acetylation in neuroinflammation.

Epigenetic reprogramming is the ability of innate immune cells to form memories of environmental stimuli (priming), allowing for heightened responses to secondary stressors. Herein, we explored microglial epigenetic marks using the known inflammagen LPS as a memory priming trigger and Parkinsonian-linked environmental neurotoxic stressor manganese (Mn) as the secondary environmental trigger. To mimic physiological responses, the memory priming trigger LPS treatment was removed by triple-washing to allow the cells' acute inflammatory response to reset back before applying the secondary insult. Our results show that after the secondary Mn insult, levels of key proinflammatory markers, including nitrite release, iNOS mRNA and protein expression, Il-6, Il-α and cytokines were exaggerated in LPS-primed microglia. Our paradigm implies primed microglia retain immune memory that can be reprogrammed to augment inflammatory response by secondary environmental stress. To ascertain the molecular underpinning of this neuroimmune memory, we further hypothesize that epigenetic reprogramming contributes to the retention of a heightened immune response. Interestingly, Mn-exposed, LPS-primed microglia showed enhanced deposition of H3K27ac and H3K4me3 along with H3K4me1. We further confirmed the results using a PD mouse model (MitoPark) and postmortem human PD brains, thereby adding clinical relevance to our findings. Co-treatment with the p300/H3K27ac inhibitor GNE-049 reduced p300 expression and H3K27ac deposition, decreased iNOS, and increased ARG1 and IRF4 levels. Lastly, since mitochondrial stress is a driver of environmentally linked Parkinson's disease (PD) progression, we examined the effects of GNE-049 on primary trigger-induced mitochondrial stress. GNE-049 reduced mitochondrial superoxide, mitochondrial circularity and stress, and mitochondrial membrane depolarization, suggesting beneficial consequences of GNE-049 on mitochondrial function. Collectively, our findings demonstrate that proinflammatory primary triggers can shape microglial memory via the epigenetic mark H3K27ac and that inhibiting H3K27ac deposition can prevent primary trigger immune memory formation and attenuate subsequent secondary inflammatory responses.

Distribution and management of Fallopia japonica in riparian biotopes in Slovakia and Austria

Globally, invasive species represent a serious threat to biodiversity and to the ecosystem. As an undesirable part of riparian ecosystems, invasive plants form continuous growths on the banks of watercourses. One of the biggest problems at river bank sites is Japanese knotweed, Fallopia japonica (Houtt.) Ronse Decr, which is an extremely invasive and aggressive weed. The topic of the interaction of flow and invasive plant species in shore stands is rich and presents a wide range of possibilities for research. The presented paper brings the results of our studies on the invasions of F. japonica in chosen riparian vegetation sites in Austria and Slovakia from 2011–2020 (36 stands). Our research was aimed at the survey on the changes in the distribution (spread) of F. japonica at the selected river sites; assessment of the impact of the watercourse regime on the spread of F. japonica; monitoring of the population growth dynamics of F. japonica and assessment of possibilities for effective eradication of F. japonica in context of the riparian vegetation management. We used standard techniques of field survey, mapping, flow modeling/simulation, and laboratory experiments. Our research results showed that water streams are not primary invasion starters until there is a flood. As long as flooding does not exceed the critical speed of the water stream, there is no direct damage to the invasive plant. The water body can be a secondary trigger for plant invasion at normal speeds. In addition, F. japonica reproduction ability directly conditions its population dynamic growth. We can report that selective invasion removal adapted to local conditions can be most suitable and beneficial for municipalities.

Palmitate Inhibits Mouse Macrophage Efferocytosis by Activating an mTORC1-Regulated Rho Kinase 1 Pathway: Therapeutic Implications for the Treatment of Obesity.

Every day, billions of our cells die and get cleared without inducing inflammation. When, clearance is improper, uncleared cells undergo secondary necrosis and trigger inflammation. In addition, proper efferocytosis would be required for inducing resolution of inflammation, thus clearance deficiencies in the long term lead to development of various chronic inflammatory diseases. Increasing evidence indicates that obesity, itself being a low-grade inflammatory disease, predisposes to a variety of other chronic inflammatory diseases. Previous studies indicated that this later might be partially related to an impaired efferocytosis induced by increased uptake of circulating saturated fatty acids by macrophages in obese people. Here, we show that palmitate inhibits efferocytosis by bone marrow-derived macrophages in a dose-dependent manner. Palmitate triggers autophagy but also activates an energy-sensing mTORC1/ROCK1 signaling pathway, which interferes with the autophagosome-lysosome fusion, resulting in accumulation of the cellular membranes in autophagosomes. We propose that lack of sufficient plasma membrane supply attenuates efferocytosis of palmitate-exposed macrophages. AMP-activated protein kinase activators lead to mTORC1 inhibition and, consequently, released the palmitate-induced efferocytosis block in macrophages. Thus, they might be useful in the treatment of obesity not only by affecting metabolism thought so far. ROCK1 inhibitors could also be considered.

The Scratch Collapse Test for Diagnosis and Treatment of Trigger Sites for Migraine Surgery.

Summary:Diagnosis of trigger sites for migraine surgery relies on history to detect a constellation of symptoms and secondarily, nerve blocks, imaging studies, and Doppler probe examination. The scratch collapse test (SCT) has been described for localization of compressive neuropathies in the upper and lower extremities. In this study, we hypothesized that the SCT could also be used to diagnose trigger sites for surgical planning in migraine surgery. Eleven consecutive patients presenting for migraine surgery, and four patients presenting with recurrent headaches and secondary trigger sites after initial successful migraine surgery were examined with the SCT using a standard protocol to assess involvement of bilateral sites I, II, IV, V, and VI, with the carpal tunnel as a negative control. The SCT was positive bilaterally at sites I, II, IV, V, and VI for all patients presenting primarily for migraine surgery, regardless of trigger sites localized by history and other secondary modalities. The SCT, however, correlated with secondary trigger sites localized through history and examination for patients presenting with recurrent migraine headaches after previous primary surgery. The SCT is not reliable for localization of trigger sites in patients presenting primarily for migraine surgery. This likely relates to central sensitization of migraine headaches, leading to global cutaneous allodynia in the head and neck. In patients with recurrent migraine headaches, abrogation of central sensitization following the initial surgery allows diagnosis of secondary trigger sites through the SCT.

A Review of Hemophagocytic Lymphohistiocytosis in Patients With HIV.

We provide an elaborate review of cases published between January 2005 and April 2021 on hemophagocytic lymphohistiocytosis (HLH) in HIV patients. Seventy articles describing 81 adult patients (age ≥19 years) were included. The median age was 40 years, and 78% were males. Only 65% were known to have HIV before presentation. CD4 count was ≥200 cells/mm3 in 23%, and HIV viral load was <200 copies/mL in 41%. The lack of meticulous reporting of ≥5 of 8 criteria for HLH diagnosis was evident in a third of cases. At least 1 infectious agent—other than HIV—was believed to trigger HLH in 78% of patients. The most common were Epstein-Barr virus (26%), human herpesvirus 8 (21%), and Histoplasma capsulatum (17%). Sixty percent survived. Among those, 93% received treatment for identified secondary trigger(s), while 51% received HLH-directed therapy. There was significant heterogeneity in the treatment regimens used for HLH.

Assessing the Association of Mitochondrial Function and Inflammasome Activation in Murine Macrophages Exposed to Select Mitotoxic Tri-Organotin Compounds.

Background:Mitochondrial function is implicated as a target of environmental toxicants and found in disease or injury models, contributing to acute and chronic inflammation. One mechanism by which mitochondrial damage can propagate inflammation is via activation of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing receptor (NLRP)3 inflammasome, a protein complex that processes mature interleukin . plays an important role in the innate immune response and dysregulation is associated with autoinflammatory disorders.Objective:The objective was to evaluate whether mitochondrial toxicants recruit inflammasome activation and processing.Method:Murine macrophages (RAW 264.7) exposed to tri-organotins (triethyltin bromide (TETBr), trimethyltin hydroxide (TMTOH), triphenyltin hydroxide (TPTOH), bis(tributyltin)oxide) [Bis(TBT)Ox] were examined for pro-inflammatory cytokine induction. TMTOH and TETBr were examined in RAW 264.7 and bone marrow-derived macrophages for mitochondrial bioenergetics, reactive oxygen species (ROS) production, and inflammasome activation via visualization of aggregate formation, caspase-1 flow cytometry, enzyme-linked immunosorbent assay and Western blots, and microRNA (miRNA) and mRNA arrays.Results:TETBr and TMTOH induced inflammasome aggregate formation and release in lipopolysaccharide (LPS)-primed macrophages. Mitochondrial bioenergetics and mitochondrial ROS were suppressed. Il1a and Il1b induction with LPS or challenge was diminished. Differential miRNA and mRNA profiles were observed. Lower miR-151-3p targeted cyclic adenosine monophosphate (cAMP)-mediated and AMP-activated protein kinase signaling pathways; higher miR-6909-5p, miR-7044-5p, and miR-7686-5p targeted Wnt beta-catenin signaling, retinoic acid receptor activation, apoptosis, signal transducer and activator of transcription 3, IL-22, IL-12, and IL-10 signaling. Functional enrichment analysis identified apoptosis and cell survival canonical pathways.Conclusion:Select mitotoxic tri-organotins disrupted murine macrophage transcriptional response to LPS, yet triggered inflammasome activation. The differential response pattern suggested unique functional changes in the inflammatory response that may translate to suppressed host defense or prolong inflammation. We posit a framework to examine immune cell effects of environmental mitotoxic compounds for adverse health outcomes. https://doi.org/10.1289/EHP8314

Early local neutralization of CC16 in sepsis‑induced ALI following blunt chest trauma leads to delayed mortality without benefitting overall survival.

Blunt thoracic trauma (TxT) is a common injury pattern in polytraumatized patients. When combined with a secondary trigger, TxT often results in acute lung injury (ALI), which negatively affects outcomes. Recent findings suggest that ALI is caused by both local and systemic inflammatory reactions. Club cell protein (CC)16 is an anti-inflammatory peptide associated with lung injury following TxT. Recently, the anti-inflammatory properties of endogenous CC16 in a murine model of TxT with subsequent cecal-ligation and puncture (CLP) as the secondary hit were demonstrated by our group. The present study aimed to determine whether CC16 neutralization improves survival following 'double-hit'-induced ALI. For this purpose, a total of 120 C57BL/6N mice were subjected to TxT, followed by CLP after 24 h. Sham-operated animals underwent anesthesia without the induction of TxT + CLP. CC16 neutralization was performed by providing a CC16 antibody intratracheally following TxT (early) or following CLP (late). Survival was assessed in 48 animals for 6 days after CLP. Sacrifice was performed 6 or 24 h post-CLP to evaluate the anti-inflammatory effect of CC16. The results revealed that CC16 neutralization enhanced pro-inflammatory CXCL1 levels, thereby confirming the anti-inflammatory characteristics of CC16 in this model. Early CC16 neutralization immediately following TxT significantly prolonged survival within 60 h; however, the survival rate did not change until 6 days post-trauma. Late CC16 neutralization did not provide any survival benefits. On the whole, the present study demonstrated that neutralizing CC16 confirmed its anti-inflammatory potential in this double-hit ALI model. Early CC16 neutralization prolonged survival within 60 h; however, no survival benefits were observed after 6 days post-CLP in any group.

Mitochondrial-related effects of pentabromophenol, tetrabromobisphenol A, and triphenyl phosphate on murine BV-2 microglia cells

The predominant reliance on bromated flame retardants (BFRs) is diminishing with expanded use of alternative organophosphate flame retardants. However, exposure related issues for susceptible populations, the developing, infirmed, or aged, remain given environmental persistence and home-environment detection. In this regard, reports of flame retardant (FR)-related effects on the innate immune system suggest process by which a spectrum of adverse health effects could manifest across the life-span. As representative of the nervous system innate immune system, the current study examined changes in microglia following exposure to representative FRs, pentabromophenol (PBP), tetrabromobisphenol A (2,2′,6,6′,-tetrabromo-4,4′-isopropylidine diphenol; TBBPA) and triphenyl phosphate (TPP). Following 18hr exposure of murine BV-2 cells, at dose levels resulting in ≥80% viability (10 and 40 μM), limited alterations in pro-inflammatory responses were observed however, changes were observed in mitochondrial respiration. Basal respiration was altered by PBP; ATP-linked respiration by PBP and TBBPA, and maximum respiration by all three FRs. Basal glycolytic rate was altered by PBP and TBBPA and compensatory glycolysis by all three. Phagocytosis was decreased for PBP and TBBPA. NLRP3 inflammasome activation was assessed using BV-2-ASC (apoptosis-associated speck-like protein containing a CARD) reporter cells to visualize aggregate formation. PBP, showed a direct stimulation of aggregate formation and properties as a NLRP3 inflammasome secondary trigger. TBBPA showed indications of possible secondary triggering activity while no changes were seen with TPP. Thus, the data suggests an effect of all three FRs on mitochondria metabolism yet, different functional outcomes including, phagocytic capability and NLRP3 inflammasome activation.

Reduced Power Seat Heater System Using Thermal Wave Technology

&lt;div class="section abstract"&gt;&lt;div class="htmlview paragraph"&gt;This paper presents a method of controlling the seat heater using intentional oscillations between multiple, independently controlled temperatures (each with its own tolerance range). The amplitude and frequency of these oscillations can be changed based on secondary trigger events such as changes in the interior temperature. The benefits of using this technique to heat the seat surface are improved thermal sensation and reduced energy usage over the typical drive time.&lt;/div&gt;&lt;/div&gt;

The role of myeloid cells in lung injury‐induced muscle atrophy

RationaleIntensive care unit acquired weakness (ICUAW) occurs in nearly 50% of patients admitted to the ICU. Patients exhibiting ICUAW have increased in‐hospital and post‐ICU mortality. ICUAW, and the associated muscle atrophy specifically, cannot be completely explained by disuse and may involve a secondary trigger to enhance the breakdown of muscle fibers. Recent work has suggested that excessive systemic inflammation may contribute to this process. We hypothesized that muscle atrophy in ICUAW may, in part, be induced by myeloid cell recruitment to muscle.MethodsC57Bl6/J mice received intratracheal (IT) instillation of lipopolysaccharide (LPS, 3 μg/g) or saline and were euthanized 3, 6, 12, 24, 72 hours thereafter. For antibody‐mediated myeloid cell depletion, 200 μg of αGR‐1, αLy6G, or isotype control antibodies were administered IP 24 hours and 1 hour prior to injury and mice were examined 24 hours post‐injury. Whole gastrocnemius muscle was analyzed using RT‐qPCR. For in vitro studies, C2C12 myoblasts were differentiated for 7 days and stimulated with LPS (1 μg/ml) to elicit an inflammatory response. Bone marrow derived macrophages (BMDMs) were differentiated with 10 ng/ml of macrophage‐colony stimulation factor for 7 days and seeded at a density of 2600 cells/cm2 (4940 cells/well) onto C2C12 myotubes after 6 days of differentiation. On day 7 of C2C12 differentiation, cocultures were stimulated as previously described. Supernatants and cell lysates were analyzed by ELISA and RT‐qPCR. Myotube diameter was measured using ImageJ.ResultsIT LPS upregulates the atrogene muscle RING‐finger 1 (MuRF1) and induces atrophy in vivo. However, this effect of LPS is not seen in cultured C2C12 myotubes alone. Depletion of neutrophils and monocytes with αGR‐1 antibody reduced MuRF1 expression in vivo. Both C2C12 myotubes and whole muscle show rapid, transient expression of myeloid chemoattractants MCP‐1 and KC (CXCL1). Cocultures of BMDMs and C2C12 myotubes enhance the expression of IL‐6 and MCP‐1 synergistically and induce C2C12 myotubes to produce TNFα.ConclusionsOur data indicate that IT LPS induces MuRF1 in vivo and our in vitro data in myotubes suggests that this effect may require myeloid cells. Further supporting this conclusion, we found that antibody depletion of myeloid cells reduced IT LPS‐induced MuRF1 expression. Moreover, expression of key myeloid cell chemoattractants are induced in muscle both in vitro and in vivo in response to LPS and addition of BMDMs to C2C12 myotubes with LPS treatment reveals synergistic increases of IL‐6 and MCP‐1 and induces C2C12 myotubes to produce TNFα. The current study implicates macrophages and neutrophils as modulators of the muscle atrophy response to following lung injury.Support or Funding InformationNIH 5R01HL143452‐02NIH 2T32HL076122‐16

Isolated thrombotic microangiopathy of the small intestine in a patient with atypical hemolytic uremic syndrome \u2013 a case report

BackgroundAtypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by systemic thrombotic microangiopathy (TMA) reflected by hemolysis, anemia, thrombocytopenia and systemic organ injury. The optimal management of aHUS-patients when undergoing kidney transplantation to prevent recurrence in the allograft is eculizumab, an approved recombinant antibody targeting human complement component C5.Case presentationA 39 year-old woman presented with severe abdominal pain, diarrhea and emesis for 3 days. In her past medical history she had experienced an episode of aHUS leading to end stage renal disease (ESRD) in 2007 and a genetic workup revealed a heterozygous mutation in the membrane cofactor protein gene. In 2014 she underwent cadaveric kidney transplantation. Four years later she had to go back on hemodialysis due to allograft failure following a severe systemic cytomegalovirus infection resulting in transplant failure. At presentation she still received calcineurin-inhibitor therapy and reported subfebrile temperatures and pain projecting over the transplant prior to the current symptoms. A contrast enhanced CT-scan of the abdomen revealed inflammatory wall thickening of the small intestine. Diagnostic endoscopy discovered fresh blood in the small intestine without a clear source of bleeding. Histopathology of the small intestine biopsies showed severe thrombotic microangiopathy. Of note, the patient persistently had no signs of systemic hemolysis. Since the TMA of the small intestine was most likely due to aHUS, eculizumab treatment was initiated which abolished the symptoms.ConclusionHere we report a patient with thrombotic microangiopathy with predominant manifestation in a single organ, the small intestine, due to aHUS with absence of systemic signs and symptoms. aHUS patients usually require a secondary trigger for the disease to manifest. In this case, the trigger may be attributed to the dysfunctional renal transplant, which was subsequently explanted. Histology of the explanted kidney showed severe inflammation due to purulent nephritis and signs of cellular rejection. After nephrectomy, we continued eculizumab therapy until the patient completely recovered. No signs of TMA recurred after discontinuation of eculizumab, further supporting the concept of the renal transplant as the main trigger of TMA of the small intestine in our patient.