Neuropathy after burn injury

The purpose of this study was to evaluate the incidence of neuropathy in a consecutive cohort of patients with major burn injuries and investigate the clinical correlates for both mononeuropathy and generalized peripheral polyneuropathy. Of 572 patients examined, 64 (11%) patients had clinical evidence of mononeuropathy or peripheral neuropathy or both. Associations of mononeuropathy and peripheral neuropathy with potential risk factors were identified using logistic regression analyses. Electrical cause (odds ratio [OR] = 4.1022, P < .01), history of alcohol abuse (OR = 2.2893, P <.05), and number of days in intensive care (OR = 1.0457, P < .001) were significantly associated with mononeuropathy. The number of days in intensive care (OR = 1.0740, P < .001) and patient age (OR = 1.0543, P < .01) were significantly associated with peripheral neuropathy. This study demonstrates that neuropathy is a common complication of severe burn injury in patients who are older, critically ill, have an electrical cause, or history of alcohol abuse.     

Sensibility after burn injury

Summary. Thresholds for touch, temperature, pain and two-point discrimination were examined in 27 healthy subjects and in 36 burn patients. Three groups of injuries were examined; superficial dermal burns, which were allowed to heal spontaneously, deep dermal and subdermal burns treated by either early or late excision and skin grafting. Uninjured areas on the contralateral side served as control. In spontaneously healed superficial burns, the sensibility recovered to normal, except for touch. In deep dermal or subdermal burns all thresholds were significantly higher than in the corresponding control areas. There was no recovery beyond one month after the injury. The sensibility was better on the upper than on the lower extremities and also in deep dermal than in subdermal burns. There was no significant difference in sensibility between burns excised and grafted early or late, respectively. The results indicate that current treatment of deep dermal and subdermal burns is not followed by complete recovery of cutaneous sensation. Furthermore, even superficial burns results in incomplete recovery of touch sensibility.     

Inhibition of protein tyrosine phosphatases prevents mesenteric lymph node T-cell suppression following alcohol intoxication and burn injury.

Previously, we have shown that acute alcohol (EtOH) intoxication before burn injury potentiates the suppression of mesenteric lymph node T-cell effector responses. Moreover, the suppression in T-cell was accompanied with a decrease in p-38 and extracellular-signal-regulated kinase (ERK) activation. This study examined the role of protein tyrosine phosphatases (PTP) in suppressed T-cell p-38, ERK, and cytokine production after EtOH intoxication and burn injury. A blood EtOH level of approximately 100 mg/dl in male rats (approximately 250 g) was achieved by gavaging animals with 5 ml of 20% EtOH suspension 4 hours before burn or sham injury (approximately 12.5% or 25% total body surface area [TBSA]). One day after injury, rats were killed and mesenteric lymph node T-cell cytokine (IL-2/IFN-gamma) production, p-38, and ERK activation were measured. As compared with shams, there was a significant decrease in T-cell cytokine production after 25% and not 12.5% TBSA burn injury. However, T-cell IL-2/IFN-gamma levels were significantly decreased in rats receiving a combined insult of EtOH and burn injury regardless of the percentage of burn area. Furthermore, we found a significant decrease in p-38 and ERK-1/2 phosphorylation in T-cells of rats receiving a combined insult of EtOH and 12.5% TBSA burn compared with shams. Treatment of cells with PTP inhibitor pervanadate (10 muM) prevented T-cell p-38/ERK suppression. The suppression in IL-2/IFN-gamma production was also attenuated in T-cells cultured in the presence of pervanadate. These findings suggest that an increase in PTP activity may contribute to T-cell suppression after EtOH intoxication and burn injury.     

History injury in the presence of alcohol intoxication

The difficulty of distinguishing between serious head injury and intoxication is presented in the case of an injured patient whose signs and symptoms were attributed to alcohol withdrawal. This report emphasizes the need for a high level of suspicion for all trauma patients, for all health care providers to be familiar with common forms of life-threatening trauma, and how to distinguish between altered levels of consciousness resulting from alcohol intoxication versus intracranial disorders. This case may also demonstrate that a person's wealth and social influence and an Institution's orientation to a medical specialty can affect care givers' decisions.     

Regulation of phosphatidylinositol 3-kinase by polyisoprenyl phosphates in neutrophil-mediated tissue injury

Neutrophils play a central role in host defense, inflammation, and tissue injury. Recent findings indicate a novel role for polyisoprenyl phosphates (PIPPs) as natural down-regulatory signals in neutrophils. The relationship between PIPPs and neutrophil early activating signals, such as phosphoinositides, has not been previously determined. Here, we establish presqualene diphosphate (PSDP) as an endogenous PIPP regulator of phosphatidylinositol 3-kinase (PI3K). In human neutrophils, leukotriene B4 (LTB4) triggered rapid decreases in PSDP and reciprocal increases in PI3K activity. In addition, PSDP was identified by gas chromatography/mass spectrometry in p110gamma-PI3K immunoprecipitates obtained 30 s after LTB4, indicating a physical interaction between PSDP and PI3K in activated neutrophils. Moreover, PSDP (0.4-800 pmol) directly inhibited recombinant human p110gamma-PI3K activity. During an experimental model of lung injury and inflammation, a reciprocal relationship was also present in vivo for lung PSDP and PI3K activity. To investigate its therapeutic potential, we developed a new PSDP structural mimetic that blocked human neutrophil activation and mouse lung PI3K activity and inflammation. Together, our findings indicate that PSDP is an endogenous PI3K inhibitor, and suggest that in inflammatory diseases characterized by excessive neutrophil activation, PIPPs can serve as structural templates in a novel antineutrophil therapeutic strategy to limit tissue injury.     

Acute pancreatitis after carbamate insecticide intoxication

A 29-year-old woman was admitted to the Rouen University Hospital for attempted suicide by ingestion of a carbamate insecticide (Temik G^®, containing 10% aldicarb). Cardio-respiratory arrest occurred at the second hour and acute necrotic hemorrhagic pancreatitis on the second day. Further evolution was uneventful, and the patient was discharged after 43 days. Carbamate intoxication was confirmed by high urinary aldicarb metabolite concentrations. Pseudocholinesterase levels took 77 days to return to normal. Carbamate pesticides share the same pancreatic risk as organophosphorus pesticides, and should be monitored similarly.     

Urine proteins after burn injury

Two-dimensional immunoelectrophoresis was used to examine the proteins present in urine during the first week following burn injury. Of the "serum" proteins present in the urine some glycoproteins were found to be in different relative proportions from those observed in serum. In patients sustaining severe burns the amount of protein excreted was increased compared to patients with mild burns and to controls. alpha 1-Antichymotrypsin detected in the urine of patients with severe burns was at times seen as a twin peak. This altered peak was of slower electrophoretic mobility and may represent a polymer of the protein or a complex of the protein with some other, possibly tissue-derived, protein.     

Community integration outcome after burn injury

It is important to focus on community integration, including return to work and school, early during treatment after burn injuries. A careful analysis of the potential barriers to return to activities can help focus a treatment team and provide appropriate support for a return to work or school plan. Psychological intervention is often an important component of a return to work or school plan. Vocational rehabilitation counselors and school reentry coordinators are valuable assets to coordinating with a treatment team and communicating with a workplace or school. A successful return to work or school is often achieved with a coordinated and supportive approach.     

Acute ammonia intoxication 37 years after ureterosigmoidostomy

Ureterosigmoidostomy causes hyperammonemia, which can, especially in the presence of hepatic disease, lead to metabolic encephalopathy and coma. In the case reported here, acute hyperammonemic encephalopathy developed 37 years after the operation, and responded promptly to oral neomycin therapy, with clinical and electroencephalographic resolution. Magnetic resonance imaging of the brain, not previously reported in this disorder, showed symmetric lesions of the white matter.     

Sleep disturbance after burn injury.

This study describes sleep disturbance and related factors in a group of 74 patients at 1 week after discharge using a sleep problems questionnaire developed by the authors. Results indicated that a significant proportion of patients reported a problem with their sleep (73%). Several items were identified as highly prevalent, including frequent nighttime awakenings (87%), napping during the daytime (65%), sleeping alone (64%), experiencing pain during the night (62%), and difficulties with sleep onset (62%). Results suggest numerous possible interventions to improve patients' sleep quality. The usefulness of a more extensive questionnaire was also indicated.     

Fluid shifts after burn injury.

Following significant burn injury, severe translocations occur in the distribution of water and solute. These result in major deficits in functional extracellular fluid and circulating water volume which may result in shock. The weight of evidence suggests that resuscitational regimens must contain large quantities of water which should be at least isotonic with respect at sodium; and some evidence suggests that current resuscitational regimens may not provide sufficient potassium to maintain the normal relationship between intracellular and extracellular solute and to prevent sodium sequestration. It is clear, however, that most of the currently used resuscitational "formulas" are effective in restoring and maintaining water balance, renal function, cardiac output, and in preventing or correcting shock.     

Restoring nitrogen balance after burn injury

The metabolic response to burn injury is characterized by weight loss and marked protein wasting. This phenomenon is mediated hormonally, resulting in hypermetabolism. Energy expenditure increases linearly with the extent of burn injury, reaching a plateau of twice resting energy expenditure when 50% of the total body surface area is involved. It is therefore essential to minimize other factors that may further augment postburn catabolism. Occlusive dressings, a warm ambient environment, analgesics, and timely closure of the burn wound are all important therapeutic measures in this regard. Furthermore, it is imperative to institute early nutritional support in order to offset the negative metabolic effects of severe burn injury.     

Respiratory changes after major burn injury

In 32 major burn patients, routine respiratory measurements and blood gases analysis were performed. Striking differences were found between survivors and nonsurvivors in these variables. Marked increased in minute volume and respiratory rate were observed in nonsurvivors starting from the 6th day postburn, while PaCO2 increased with larger tidal and minute volumes. At the same time, PaO2 was lower than in survivors. In survivors, the closing volume, maximum mid-expiratory flow rate, and peak rate were lower than the predicted normal values. This may indicate that after major burn injury, ventilatory power decreased and some pathological changes occurred in small airways and alveoli without apparent pulmonary complications. Marked differences in the changes of respiratory rate and min volume between survivors and nonsurvivors may indicate the value of simple respiratory measurements for prediction of outcome in burn patients.     

Role of non-muscle Myosin light chain kinase in neutrophil-mediated intestinal barrier dysfunction during thermal injury

ABSTRACT: Neutrophils and non-muscle myosin light chain kinase (nmMLCK) have been implicated in intestinal microvascular leakage and mucosal hyperpermeability in inflammation and trauma. The aim of this study was to characterize the role of nmMLCK in neutrophil-dependent gut barrier dysfunction following thermal injury, a common form of trauma that typically induces inflammation in multiple organs. Histopathological examination of the small intestine in mice after a full-thickness burn revealed morphological evidence of mucosa inflammation characterized by neutrophil infiltration into the lamina propria, epithelial contraction, and narrow villi with blunt brush borders and loss of goblet cells. Compared with their wild-type counterparts, nmMLCK mice displayed diminished morphological abnormalities. Likewise, intravital microscopic studies showed significant leukocyte adhesion in intestinal microvessels after burn, a response that was blunted in the absence of nmMLCK. Functionally, thermal injury significantly increased the gut lumen-to-blood transport of fluorescein isothiocyanate-dextran (4 kd), and this hyperpermeability was attenuated by either neutrophil depletion or nmMLCK deficiency. Consistent with the in vivo observations, in vitro assays with Caco-2 epithelial cell monolayers revealed a decrease in transcellular electric resistance coupled with myosin light chain phosphorylation, actomyosin ring condensation, and claudin-1 internalization upon stimulation with fMLP (N-formyl-methionyl-leucyl-phenylalanine)-activated neutrophils. Pretreatment of the cells with the MLCK inhibitor ML-7 prevented the tight junction responses. Taken together, the results suggest that nmMLCK plays an important role in neutrophil-dependent intestinal barrier dysfunction during inflammatory injury.     

Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage

Disruption of the intestinal epithelial barrier allows bacterial translocation and predisposes to destructive inflammation. To ensure proper barrier composition, crypt-residing stem cells continuously proliferate and replenish all intestinal epithelial cells within days. As a consequence of this high mitotic activity, mucosal surfaces are frequently targeted by anticancer therapies, leading to dose-limiting side effects. The cellular mechanisms that control tissue protection and mucosal healing in response to intestinal damage remain poorly understood. Type 3 innate lymphoid cells (ILC3s) are regulators of homeostasis and tissue responses to infection at mucosal surfaces. We now demonstrate that ILC3s are required for epithelial activation and proliferation in response to small intestinal tissue damage induced by the chemotherapeutic agent methotrexate. Multiple subsets of ILC3s are activated after intestinal tissue damage, and in the absence of ILC3s, epithelial activation is lost, correlating with increased pathology and severe damage to the intestinal crypts. Using ILC3-deficient Lgr5 reporter mice, we show that maintenance of intestinal stem cells after damage is severely impaired in the absence of ILC3s or the ILC3 signature cytokine IL-22. These data unveil a novel function of ILC3s in limiting tissue damage by preserving tissue-specific stem cells.The intestinal epithelium combines efficient uptake of nutrients and water while providing a physical barrier between the intestinal microbiota and the body (Peterson and Artis, 2014). Damage sustained by intestinal epithelial cells (IECs) needs to be swiftly and efficiently repaired to prevent inappropriate immune responses to commensal bacteria. Intestinal damage is an early event in the development of both graft-versus-host disease (Reddy and Ferrara, 2003) and alimentary mucositis (Sonis, 2004) and a driver of bacterial translocation and T cell activation in inflammatory bowel disease (Salim and Söderholm, 2011).A major pathway involved in the intestinal epithelial response to damage is the activation of Stat3, which is expressed along the crypt–villus axis of the intestinal epithelium (Grivennikov et al., 2009; Heneghan et al., 2013). Phosphorylated Stat3 translocates to the nucleus and activates genes involved in proliferation, survival, and mucosal defense (Bollrath et al., 2009; Pickert et al., 2009; Ernst et al., 2014). Mutations in STAT3 have been identified as susceptibility factors for inflammatory bowel disease (Bollrath et al., 2009; Anderson et al., 2011; Demaria et al., 2012), and in mice, upon DSS-induced colitis, epithelial Stat3 is required for mucosal wound healing (Pickert et al., 2009).Intestinal regeneration depends on the continuous differentiation of epithelial cells from crypt-residing intestinal stem cells (ISCs; Potten et al., 1978; Günther et al., 2013; Ritsma et al., 2014). Even though multiple intestinal progenitor cells have been described, the best-characterized populations are the Lgr5-expressing cells that reside at the crypt bottom, interspersed with Paneth cells. These stem cells have the ability to give rise to all IECs ex vivo (Sato et al., 2009). Similar to its role in differentiated epithelial cells, Stat3 activation is also an important pathway for survival of intestinal epithelial stem cells (Matthews et al., 2011).Type 3 innate lymphoid cells (ILC3s) are innate immune cells that reside in the lamina propria of both the small and large intestines and are involved in tissue homeostasis, early defense against enteric pathogens, and containment of microbiota (Spits and Cupedo, 2012; Artis and Spits, 2015). In the intestines, multiple ILC3 subsets exist, two of which can be distinguished by mutual exclusive expression of the natural cytotoxicity receptor NKp46 and the chemokine receptor CCR6 (Sawa et al., 2010; Reynders et al., 2011). Most Nkp46⁺ ILC3s are found dispersed throughout the lamina propria, a localization that depends on the expression of CXCR6 (Satoh-Takayama et al., 2014). In contrast, the majority of CCR6⁺ ILC3s are located in close proximity to the intestinal crypts in anatomically defined sites known as cryptopatches (Kanamori et al., 1996). Recent findings indicated that under inflammatory conditions, such as experimental graft-versus-host disease, ILC3s can interact with the epithelial stem cells in the crypts, protecting them from T cell–mediated killing (Hanash et al., 2012).The well-known ability of ILC3s to condition the local microenvironment, the close proximity of ILC3s to intestinal crypts, and the ability of ILC3s to communicate with epithelial stem cells led us to hypothesize that ILC3s are involved in directing intestinal epithelial responses to tissue damage. Using the methotrexate (MTX) model of small intestinal damage, we now show that ILC3s are activated immediately after MTX administration, leading to a rapid activation of epithelial Stat3 and maintenance of ISCs. Our data reveal a novel function for ILC3s as organizers of the intestinal epithelial response to tissue damage through activation of epithelial cells and maintenance of ISCs and suggest that ILC3s might in future be therapeutically harnessed to prevent stem cell loss during chemotherapy.     

Hypervolemia induces and potentiates lung damage after recruitment maneuver in a model of sepsis-induced acute lung injury

Introduction

Recruitment maneuvers (RMs) seem to be more effective in extrapulmonary acute lung injury (ALI), caused mainly by sepsis, than in pulmonary ALI. Nevertheless, the maintenance of adequate volemic status is particularly challenging in sepsis. Since the interaction between volemic status and RMs is not well established, we investigated the effects of RMs on lung and distal organs in the presence of hypovolemia, normovolemia, and hypervolemia in a model of extrapulmonary lung injury induced by sepsis.

Methods

ALI was induced by cecal ligation and puncture surgery in 66 Wistar rats. After 48 h, animals were anesthetized, mechanically ventilated and randomly assigned to 3 volemic status (n = 22/group): 1) hypovolemia induced by blood drainage at mean arterial pressure (MAP)≈70 mmHg; 2) normovolemia (MAP≈100 mmHg), and 3) hypervolemia with colloid administration to achieve a MAP≈130 mmHg. In each group, animals were further randomized to be recruited (CPAP = 40 cm H₂O for 40 s) or not (NR) (n = 11/group), followed by 1 h of protective mechanical ventilation. Echocardiography, arterial blood gases, static lung elastance (Est,L), histology (light and electron microscopy), lung wet-to-dry (W/D) ratio, interleukin (IL)-6, IL-1β, caspase-3, type III procollagen (PCIII), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) mRNA expressions in lung tissue, as well as lung and distal organ epithelial cell apoptosis were analyzed.

Results

We observed that: 1) hypervolemia increased lung W/D ratio with impairment of oxygenation and Est,L, and was associated with alveolar and endothelial cell damage and increased IL-6, VCAM-1, and ICAM-1 mRNA expressions; and 2) RM reduced alveolar collapse independent of volemic status. In hypervolemic animals, RM improved oxygenation above the levels observed with the use of positive-end expiratory pressure (PEEP), but increased lung injury and led to higher inflammatory and fibrogenetic responses.

Conclusions

Volemic status should be taken into account during RMs, since in this sepsis-induced ALI model hypervolemia promoted and potentiated lung injury compared to hypo- and normovolemia.     

Hypnotizability and trauma symptoms after burn injury

This study investigated the association of trauma symptoms and hypnotizability in 43 hospitalized survivors of burn injury. Three to 17 days after the injury, participants rated the frequency of intrusive and avoidance symptoms and were interviewed with the posttraumatic stress disorder module of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-III-R. The Hypnotic Induction Profile was also administered at the postburn, hospital stage of recovery. Results indicated that when participants were divided into low, mid-range, and high hypnotizability categories, high hypnotizability was associated with more intrusive, avoidance, and arousal symptoms. Although causal relations cannot be assessed in this cross-sectional study, these results suggest that, as compared to the low and mid-range categories, high hypnotizables may experience a greater frequency of trauma symptoms after burn injury.     

Microcirculation in hypertrophic scars after burn injury

Hypertrophic scar formation is a common complication after burn injury. Early active scars show hyperemic appearances that change as the scar matures. This is a report on microcirculation in hypertrophic scars after burn injury among 50 Chinese patients with a laser Doppler flowmeter. The average period of follow-up for the patients was 20 months. The microcirculatory response in scars to vasodilation (heat) stimulus was studied. Significant differences (p less than 0.0001) were demonstrated between scars of different clinical grades of maturity when compared with normal skin. The qualitative and quantitative differences in microcirculatory blood flow were correlated with site variations and different physiologic demands from different grades of scars. The study showed that laser Doppler flowmetry was useful in the clinical grading assessment of or for scar maturity.