IL-1/MyD88-Dependent G-CSF and IL-6 Secretion Mediates Postburn Anemia.

The anemia of critical illness (ACI) is a nearly universal pathophysiological consequence of burn injury and a primary reason burn patients require massive quantities of transfused blood. Inflammatory processes are expected to drive postburn ACI and prevent meaningful erythropoietic stimulation through iron or erythropoietin supplementation, but to this day no specific inflammatory pathways have been identified as a critical mechanism. In this study, we examined whether secretion of G-CSF and IL-6 mediates distinct features of postburn ACI and interrogated inflammatory mechanisms that could be responsible for their secretion. Our analysis of mouse and human skin samples identified the burn wound as a primary source of G-CSF and IL-6 secretion. We show that G-CSF and IL-6 are secreted independently through an IL-1/MyD88-dependent mechanism, and we ruled out TLR2 and TLR4 as critical receptors. Our results indicate that IL-1/MyD88-dependent G-CSF secretion plays a key role in impairing medullary erythropoiesis and IL-6 secretion plays a key role in limiting the access of erythroid cells to iron. Importantly, we found that IL-1α/ß neutralizing Abs broadly attenuated features of postburn ACI that could be attributed to G-CSF or IL-6 secretion and rescued deficits of circulating RBC counts, hemoglobin, and hematocrit caused by burn injury. We conclude that wound-based IL-1/MyD88 signaling mediates postburn ACI through induction of G-CSF and IL-6 secretion.

Integrating mental health and disaster preparedness in intervention: a randomized controlled trial with earthquake and flood-affected communities in Haiti.

BACKGROUND: Given the frequency of natural hazards in Haiti, disaster risk reduction is crucial. However, evidence suggests that many people exposed to prior disasters do not engage in disaster preparedness, even when they receive training and have adequate resources. This may be partially explained by a link between mental health symptoms and preparedness; however, these components are typically not integrated in intervention. METHODS: The current study assesses effectiveness of an integrated mental health and disaster preparedness intervention. This group-based model was tested in three earthquake-exposed and flood-prone communities (N = 480), across three time points, using a randomized controlled trial design. The 3-day community-based intervention was culturally-adapted, facilitated by trained Haitian lay mental health workers, and focused on enhancing disaster preparedness, reducing mental health symptoms, and fostering community cohesion. RESULTS: Consistent with hypotheses, the intervention increased disaster preparedness, reduced symptoms associated with depression, post-traumatic stress disorder, anxiety, and functional impairment, and increased peer-based help-giving and help-seeking. Mediation models indicated support for the underlying theoretical model, such that the effect of the intervention on preparedness was mediated by mental health, and that effects on mental health were likewise mediated by preparedness. CONCLUSIONS: The community-based mental health-integrated disaster preparedness intervention is effective in improving mental health and preparedness among community members in Haiti vulnerable to natural hazards. This brief intervention has the potential to be scaled up for use with other communities vulnerable to earthquakes, seasonal flooding, and other natural hazards.

Mitogenic stimulation accelerates influenza-induced mortality by increasing susceptibility of alveolar type II cells to infection.

Development of pneumonia is the most lethal consequence of influenza, increasing mortality more than 50-fold compared with uncomplicated infection. The spread of viral infection from conducting airways to the alveolar epithelium is therefore a pivotal event in influenza pathogenesis. We found that mitogenic stimulation with keratinocyte growth factor (KGF) markedly accelerated mortality after infectious challenge with influenza A virus (IAV). Coadministration of KGF with IAV markedly accelerated the spread of viral infection from the airways to alveoli compared with challenge with IAV alone, based on spatial and temporal analyses of viral nucleoprotein staining of lung tissue sections and dissociated lung cells. To better define the temporal relationship between KGF administration and susceptibility to IAV infection in vivo, we administered KGF 120, 48, 24, and 0 h before intrapulmonary IAV challenge and assessed the percentages of proliferating and IAV-infected, alveolar type II (AECII) cells in dispersed lung cell populations. Peak AECII infectivity coincided with the timing of KGF administration that also induced peak AECII proliferation. AECII from mice that were given intrapulmonary KGF before isolation and then infected with IAV ex vivo exhibited the same temporal pattern of proliferation and infectious susceptibility. KGF-induced increases in mortality, AECII proliferation, and enhanced IAV susceptibility were all reversed by pretreatment of the animals with the mTOR inhibitor rapamycin before mitogenic stimulation. Taken together, these data suggest mTOR signaling-dependent, mitogenic conditioning of AECII is a determinant of host susceptibility to infection with IAV.

Keratinocyte growth factor supports pulmonary innate immune defense through maintenance of alveolar antimicrobial protein levels and macrophage function.

Keratinocyte growth factor (KGF) is an epithelial mitogen that has been reported to protect the lungs from a variety of toxic and infectious insults. In prior studies we found that recombinant human KGF accelerates clearance of bacteria from the murine lung by augmenting the function of alveolar macrophages (AM). In this study we tested the hypothesis that endogenous KGF plays a role in the maintenance of innate pulmonary defense against gram-negative bacterial infections. KGF-deficient mice exhibited delayed clearance of Escherichia coli from the lungs, attenuated phagocytosis by AM, and decreased antimicrobial activity in bronchoalveolar lavage (BAL) fluid, due in part to reductions in levels of surfactant protein A, surfactant protein D, and lysozyme. These immune deficits were accompanied by lower alveolar type II epithelial cell counts and reduced alveolar type II epithelial cell expression of collectin and lysozyme genes on a per cell basis. No significant between-group differences were detected in selected inflammatory cytokines or BAL inflammatory cell populations at baseline or after bacterial challenge in the wild-type and KGF-deficient mice. A single intranasal dose of recombinant human KGF reversed defects in bacterial clearance, AM function, and BAL fluid antimicrobial activity. We conclude that KGF supports alveolar innate immune defense through maintenance of alveolar antimicrobial protein levels and functions of AM. Together these data demonstrate a role for endogenous KGF in maintenance of normal pulmonary innate immune function.

G-CSF drives a posttraumatic immune program that protects the host from infection.

Traumatic injury is generally considered to have a suppressive effect on the immune system, resulting in increased susceptibility to infection. Paradoxically, we found that thermal injury to the skin induced a robust time-dependent protection of mice from a lethal Klebsiella pneumoniae pulmonary challenge. The protective response was neutrophil dependent and temporally associated with a systemic increase in neutrophils resulting from a reprioritization of hematopoiesis toward myeloid lineages. A prominent and specific activation of STAT3 in the bone marrow preceded the myeloid shift in that compartment, in association with durable increases in STAT3 activating serum cytokines G-CSF and IL-6. Neutralization of the postburn increase in serum G-CSF largely blocked STAT3 activation in marrow cells, reversing the hematopoietic changes and systemic neutrophilia. Daily administration of rG-CSF was sufficient to recapitulate the changes induced by injury including hematopoietic reprioritization and protection from pulmonary challenge with K. pneumoniae. Analysis of posttraumatic gene expression patterns in humans reveals that they are also consistent with a role for G-CSF as a switch that activates innate immune responses and suppresses adaptive immune responses. Our findings suggest that the G-CSF STAT3 axis constitutes a key protective mechanism induced by injury to reduce the risk for posttraumatic infection.

Recent advances in phase change materials for thermal energy storage.

Efficient storage of thermal energy can be greatly enhanced by the use of phase change materials (PCMs). The selection or development of a useful PCM requires careful consideration of many physical and chemical properties. In this review of our recent studies of PCMs, we show that linking the molecular structures of organic molecules to their physical properties can be used to focus attention on the most useful PCMs, including eutectic mixtures. Two of the major limitations concerning broader use of phase change materials are low thermal conductivity, especially for organic phase change materials, and suitable containment. We have addressed both issues in our recent investigations of novel form-stable composite PCMs with a freeze-cast matrix. The use of thorough experimental investigations, including cycling of materials hundreds or thousands of times through the melt-freeze processes, promotes our goals of advancing the use of PCMs for increased energy efficiency and sustainability.

PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium.

We showed that stop of flow triggers a mechanosignaling cascade that leads to the generation of reactive oxygen species (ROS); however, a mechanosensor coupled to the cytoskeleton that could potentially transduce flow stimulus has not been identified. We showed a role for KATP channel, caveolae (caveolin-1), and NADPH oxidase 2 (NOX2) in ROS production with stop of flow. Based on reports of a mechanosensory complex that includes platelet endothelial cell adhesion molecule-1 (PECAM-1) and initiates signaling with mechanical force, we hypothesized that PECAM-1 could serve as a mechanosensor in sensing disruption of flow. Using lungs in situ, we observed that ROS production with stop of flow was significantly reduced in PECAM-1(-/-) lungs compared with lungs from wild-type (WT) mice. Lack of PECAM-1 did not affect NOX2 activation machinery or the caveolin-1 expression or caveolae number in the pulmonary endothelium. Stop of flow in vitro triggered an increase in angiogenic potential of WT pulmonary microvascular endothelial cells (PMVEC) but not of PECAM-1(-/-) PMVEC. Obstruction of flow in lungs in vivo showed that the neutrophil infiltration as observed in WT mice was significantly lowered in PECAM-1(-/-) mice. With stop of flow, WT lungs showed higher expression of the angiogenic marker VEGF compared with untreated (sham) and PECAM-1(-/-) lungs. Thus PECAM-1 (and caveolae) are parts of the mechanosensing machinery that generates superoxide with loss of shear; the resultant ROS potentially drives neutrophil influx and acts as an angiogenic signal.

Lay mental health in the aftermath of disaster: preliminary evaluation of an intervention for Haiti earthquake survivors.

In the year following the 2010 Haiti earthquake, local earthquake survivors trained as lay mental health workers implemented a culturally-adapted, psychosocial and trauma-focused group intervention for residents of camps for internally displaced peoples (IDPs). Analysis of evaluation data collected at three Port-au-Prince IDP camps revealed decreased self-reported posttraumatic distress (measured using the Harvard Trauma Questionnaire) associated with participation in this intervention. Improvement occurred across all three PTSD symptom clusters (re-experiencing, avoidance, and hyperarousal). Female participants reported higher baseline distress, were more likely to participate in the intervention, and benefitted more than did men. Results provide initial support for the effectiveness of train-the-trainer interventions utilizing local lay disaster survivors.

Insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis.

Pulmonary alveolar microlithiasis is an autosomal recessive lung disease caused by a deficiency in the pulmonary epithelial Npt2b sodium-phosphate co-transporter that results in accumulation of phosphate and formation of hydroxyapatite microliths in the alveolar space. The single cell transcriptomic analysis of a pulmonary alveolar microlithiasis lung explant showing a robust osteoclast gene signature in alveolar monocytes and the finding that calcium phosphate microliths contain a rich protein and lipid matrix that includes bone resorbing osteoclast enzymes and other proteins suggested a role for osteoclast-like cells in the host response to microliths. While investigating the mechanisms of microlith clearance, we found that Npt2b modulates pulmonary phosphate homeostasis through effects on alternative phosphate transporter activity and alveolar osteoprotegerin, and that microliths induce osteoclast formation and activation in a receptor activator of nuclear factor-κB ligand and dietary phosphate dependent manner. This work reveals that Npt2b and pulmonary osteoclast-like cells play key roles in pulmonary homeostasis and suggest potential new therapeutic targets for the treatment of lung disease.

Persistent Eosinophilia and Fever in Pancreatitis: A Clinical Conundrum.

A healthy 11-year-old girl presents with epigastric abdominal pain, fever, weight loss, and decreased appetite for 1 month. On physical examination, she appears ill, dehydrated, and cachectic. Her abdominal examination is significant for large ascites with a fluid wave and is nontender to palpation. Her labs show leukocytosis with an eosinophilic-predominant granulocytosis and an absolute eosinophil count of 6800/mm3. She has elevated serum inflammatory markers, hypoalbuminemia, and lipase is 5000 U/L. Magnetic resonance cholangiopancreatography (MRCP) shows an irregular and dilated pancreatic duct, so she had an endoscopic retrograde cholangiopancreatography with pancreatic stent placement, paracentesis, and colonoscopy. Her peritoneal fluid was significant for an eosinophilic-predominant granulocytosis with no evidence of malignancy on flow cytometry. All other studies and cultures did not reveal an etiology. She initially showed improvement, 18 days later she developed a fever, night sweats, tachycardia, and abdominal distention. Empiric antibiotics were initiated due to concern for infected pancreatic necrosis versus spontaneous bacterial peritonitis. Repeat MRCP showed interval development of 2 peripancreatic fluid collections and re-accumulation of ascites. She continued to have daily fever ranging from 39°C to 40°C. Repeat paracentesis and evaluation of her peritoneal fluid showed resolution of eosinophilia with an elevated neutrophil count, negative Gram stain, and no growth on culture. She completed a 10-day course of antibiotics, however, remained febrile with elevated inflammatory markers and leukocytosis throughout her hospitalization. A genetic panel to evaluate for a hereditary cause of chronic pancreatitis was sent and returned positive for a mutation of the serine protease inhibitor Kazal type 1.

M-CSF supports medullary erythropoiesis and erythroid iron demand following burn injury through its activity on homeostatic iron recycling.

M-CSF receptor signaling supports the development and survival of mononuclear phagocytes and is thought to play a role in post burn anemia by promoting myeloid lineage bias. We found M-CSF secretion was increased in burn patients and a murine model of post burn ACI, so we neutralized M-CSF in ACI mice to determine if erythropoiesis was improved. Instead, M-CSF blockade further impaired erythropoiesis and erythroid cells access to iron. M-CSF blockade enhanced inflammatory cytokine secretion, further increased systemic neutrophil counts, and led to tissue iron sequestration that was dependent, in part, on augmented IL-6 secretion which induced hepcidin. Deleterious effects of post burn M-CSF blockade were associated with arrest of an iron recycling gene expression signature in the liver and spleen that included Spi-C transcription factor and heme oxygenase-1, which promote heme metabolism and confer a non-inflammatory tone in macrophages. Hepatic induction of these factors in ACI mice was consistent with a recovery of ferroportin gene expression and reflected an M-CSF dependent expansion and differentiation of Spi-C+ monocytes into Kupffer cells. Together, this data indicates M-CSF secretion supports a homeostatic iron recycling program that plays a key role in the maintenance of erythroid cells access to iron following burn injury.

Interaction and spectral gaps of surface plasmon modes in gold nano-structures.

The transmission of ultrashort (7 fs) broadband laser pulses through periodic gold nano-structures is studied. The distribution of the transmitted light intensity over wavelength and angle shows an efficient coupling of the incident p-polarized light to two counter-propagating surface plasmon (SP) modes. As a result of the mode interaction, the avoided crossing patterns exhibit energy and momentum gaps, which depend on the configuration of the nano-structure and the wavelength. Variations of the widths of the SP resonances and an abrupt change of the mode interaction in the vicinity of the avoided crossing region are observed. These features are explained by the model of two coupled modes and a coupling change due to switching from the higher frequency dark mode to the lower frequency bright mode for increasing wavelength of the excitation light.

Neonatal seizures: diagnosis and management.

The recognition of epileptic seizures in newborns is challenging as neonates exhibit a variety of paroxysmal motor phenomena, some epileptic but others not. The distinction, frequently requiring video-EEG monitoring, is crucial for management. Causes are often multi-factorial, specific to country/region, and change over time. Hypoxia-ischemia and infection are still common in both developed and developing countries. Venous and arterial strokes are being increasingly recognized. Treatable conditions, including inborn errors of metabolism, must be anticipated and considered early in the course. Etiology is the principal determinant of outcome. Management is based on uncontrolled studies and expert opinions. Information on neonatal seizures is reviewed, and suggestions for management provided. Phenobarbital remains the first anti-epileptic drug of choice, worldwide. Pharmacogenetic information and hepatic or renal dysfunction will influence doses of all drugs. The toxicity of excipients present in intravenous medicines should be kept in mind, especially when infusions are given to critically ill neonates. Therapeutic trials with pyridoxine or ideally pyridoxal phosphate, folinic acid and biotin should be considered early, if seizures are intractable. The management of electrographic seizures without clinical seizures needs critical study. When anti-epileptic drug treatment is required, maintenance should be for a short duration if seizures are of an acute symptomatic nature.

Gammadelta T cells mitigate the organ injury and mortality of sepsis.

Sepsis is a difficult condition to treat and is associated with a high mortality rate. Sepsis is known to cause a marked depletion of lymphocytes, although the function of different lymphocyte subsets in the response to sepsis is unclear. gammadelta T cells are found largely in epithelial-rich tissues, and previous studies of gammadelta T cells in models of sepsis have yielded divergent results. In the present study, we examined the function of gammadelta T cells during sepsis in mice using cecal ligation and puncture (CLP). Mice deficient in gammadelta T cells had decreased survival times and increased tissue damage after CLP compared with wild-type mice. Furthermore, bacterial load was increased in gammadelta T cell-deficient mice, yet antibiotic treatment did not change mortality. Additionally, we found that recruitment of neutrophils and myeloid suppressor cells to the site of infection was diminished in gammadelta T cell-deficient mice. Finally, we found that circulating levels of IFN-gamma were increased, and systemic levels of IL-10 were decreased in gammadelta T cell-deficient mice after CLP compared with wild-type mice. gammadelta T cell-deficient mice also had increased intestinal permeability after CLP compared with wild-type mice. Neutralization of IFN-gamma abrogated the increase in intestinal permeability in gammadelta T cell-deficient mice. The intestines taken from gammadelta T cell-deficient mice had decreased myeloperoxidase yet had increased tissue damage as compared with wild-type mice. Collectively, our data suggest that gammadelta T cells modulate the response to sepsis and may be a potential therapeutic target.

Propagation length of surface plasmons in a metal film with roughness.

The propagation of laser-excited surface plasmons along a gold film with surface roughness is directly observed via scattered light. The attenuation length of surface plasmons in a broad wavelength interval is calculated for smooth gold and silver films. The surface roughness, which was characterized with an AFM, introduces corrections to the attenuation length, angular dependence of the surface plasmon resonance, and the effective dielectric constant of the metal film. These corrections are also taken into account and discussed.

Clusters in Liquid Fatty Acids: Structure and Role in Nucleation.

Saturated fatty acids are used in many consumer products and have considerable promise as phase change materials for thermal energy storage, in part because they crystallize with minimal supercooling. The latter property correlates with the existence of molecular clusters in the liquid; when heated above a threshold temperature, clusters do not immediately re-form on cooling, and supercooling results. Raman spectroscopy, density functional theory calculations, and small-angle X-ray scattering were used to reveal the size, structure, and temperature dependence of the clusters. We found that the liquid phases of fatty acids contain some ordering at all temperatures, with the molecules showing, on average, short-range alignment along their long axes. At temperatures below the threshold temperature for increased susceptibility to supercooling, clusters of more highly ordered fatty acid dimers, several hundred molecules in size, exist in the liquid. Within these clusters, the alkyl chains of the fatty acid dimers are essentially completely inserted between the alkyl chains of their longitudinal neighbors. Above the threshold temperature, fatty acid clusters are smaller in size and number. We explored how the fatty acid clusters promote bulk crystallization and show quantitatively that their presence reduces the energy barrier to crystal growth, likely by a particle-attachment-type mechanism.

Nonepileptic motor phenomena in the neonate.

The newborn infant is prone to clinical motor phenomena that are not epileptic in nature. These include tremors, jitteriness, various forms of myoclonus and brainstem release phenomena. They are frequently misdiagnosed as seizures, resulting in unnecessary investigations and treatment with anticonvulsants, which have potentially harmful side effects. Unfortunately, there is a paucity of literature about many of these phenomena in the newborn, and some of the major textbooks refer to these events as nonepileptic seizures, leading to further confusion for the practitioner. The present paper aims to review these phenomena with special emphasis on differentiating them from epileptic seizures, and offers information on treatment and prognosis wherever possible.

Consideration of the Development of the Gastrointestinal Tract in the Choice of Species for Regulatory Juvenile Studies.

Although the rat is close to being the automatic choice for regulatory juvenile toxicity studies, there are several shortcomings in this model. Choosing a species should take into serious consideration the importance of gastrointestinal tract development in the period before weaning as this may have a major effect on exposure. A comparison of the anatomical changes in the stomach and small intestine of mini-pig and rat show that the mini-pig is a far closer model for man than is the rat, although there are a few unusual aspects of small intestinal development in the mini-pig. Considerations of the development of the gastrointestinal tract and choice of species have the potential to affect safety assessment and should be a prime consideration when planning an investigation. Birth Defects Research 110:56-62, 2018. © 2017 Wiley Periodicals, Inc.

Supercooling and Nucleation of Fatty Acids: Influence of Thermal History on the Behavior of the Liquid Phase.

Saturated fatty acids are an exceptionally important class of liquids, used in many consumer products and suggested as phase change materials (PCMs) for thermal energy storage, in part because they crystallize with minimal supercooling. Here we investigate fatty acid nucleation to understand why crystallization is so facile, as a step toward identifying potential mechanisms for the suppression of supercooling in other PCMs. We find that fatty acid supercooling can be induced only if the liquid is first heated above a material-dependent threshold temperature. NMR spin-lattice relaxation time studies show that the average mobility of the alkyl chains in the fatty acids increases more rapidly with temperature above the supercooling threshold temperature, and NMR T1 hysteresis also sets in at that temperature. Measurements of the real portion of the dielectric constant as a function of temperature show that a liquid fatty acid heated far above its melting point behaves with an apparent temperature upon cooling that is higher than the actual temperature, when compared to its behavior at the same temperature upon heating. Our results suggest that molecular clusters in the liquid fatty acids break apart when the liquids are heated above their threshold temperature and do not immediately re-form on cooling. The breakup of clusters leads to an increase in the mobility of the fatty acid molecules. Because the clusters do not re-form quickly on subsequent cooling, nucleation does not occur, and substantial supercooling results.

Thermal injury elevates the inflammatory monocyte subpopulation in multiple compartments.

Recent publications have demonstrated that human resident and inflammatory monocyte (IM) subpopulations have equivalents in rodents. The effect of thermal injury upon these subpopulations has not been studied. Mice were given a scald burn and killed on postburn days (PBDs) 2, 4, and 8. Bone marrow, blood, and spleen white cells were isolated, and the percentage of resident monocytes (CD11b LY6C), IMs (CD11b LY6C), and monocyte progenitors (macrophage-colony-forming unit [M-CFU]) were determined. The ability of each monocyte population to make TNF-alpha was determined by intracellular cytokine staining. Finally, the ability of sorted fractions from PBD 8 spleen to inhibit lymphocyte proliferation was performed. We noted that there was an increase in M-CFU in the blood and spleen at PBD 8, but the marrow only had a nonsignificant increase in M-CFU. All compartments showed a significant increase in the number of IMs by PBD 8, but no significant changes in resident monocytes were seen. In all compartments, IMs were a major source of TNF-alpha. The postburn increase in IMs and monocyte progenitors in the spleen was accompanied by an increase in the monocyte chemokine monocyte chemoattractant protein 1 and constitutively high levels of the progenitor chemokine stromal-derived factor 1alpha. After burn injury, mice deficient in the receptor for soluble TNF-alpha had equal levels of splenic M-CFU and monocytes, as did wild-type mice, suggesting that this cytokine is not essential for this effect. We conclude that in this model, IMs are a significant source of in vivo TNF-alpha.