A Comparison between SARS-CoV-2 and Gram-Negative Bacteria-Induced Hyperinflammation and Sepsis.

Sepsis is a life-threatening condition caused by the body's overwhelming response to an infection, such as pneumonia or urinary tract infection. It occurs when the immune system releases cytokines into the bloodstream, triggering widespread inflammation. If not treated, it can lead to organ failure and death. Unfortunately, sepsis has a high mortality rate, with studies reporting rates ranging from 20% to over 50%, depending on the severity and promptness of treatment. According to the World Health Organization (WHO), the annual death toll in the world is about 11 million. One of the main toxins responsible for inflammation induction are lipopolysaccharides (LPS, endotoxin) from Gram-negative bacteria, which rank among the most potent immunostimulants found in nature. Antibiotics are consistently prescribed as a part of anti-sepsis-therapy. However, antibiotic therapy (i) is increasingly ineffective due to resistance development and (ii) most antibiotics are unable to bind and neutralize LPS, a prerequisite to inhibit the interaction of endotoxin with its cellular receptor complex, namely Toll-like receptor 4 (TLR4)/MD-2, responsible for the intracellular cascade leading to pro-inflammatory cytokine secretion. The pandemic virus SARS-CoV-2 has infected hundreds of millions of humans worldwide since its emergence in 2019. The COVID-19 (Coronavirus disease-19) caused by this virus is associated with high lethality, particularly for elderly and immunocompromised people. As of August 2023, nearly 7 million deaths were reported worldwide due to this disease. According to some reported studies, upregulation of TLR4 and the subsequent inflammatory signaling detected in COVID-19 patients "mimics bacterial sepsis". Furthermore, the immune response to SARS-CoV-2 was described by others as "mirror image of sepsis". Similarly, the cytokine profile in sera from severe COVID-19 patients was very similar to those suffering from the acute respiratory distress syndrome (ARDS) and sepsis. Finally, the severe COVID-19 infection is frequently accompanied by bacterial co-infections, as well as by the presence of significant LPS concentrations. In the present review, we will analyze similarities and differences between COVID-19 and sepsis at the pathophysiological, epidemiological, and molecular levels.

Anti-Infective and Anti-Inflammatory Mode of Action of Peptide 19-2.5.

The polypeptide Pep19-2.5 (Aspidasept®) has been described to act efficiently against infection-inducing bacteria by binding and neutralizing their most potent toxins, i.e., lipopolysaccharides (LPS) and lipoproteins/peptides (LP), independent of the resistance status of the bacteria. The mode of action was described to consist of a primary Coulomb/polar interaction of the N-terminal region of Pep19-2.5 with the polar region of the toxins followed by a hydrophobic interaction of the C-terminal region of the peptide with the apolar moiety of the toxins. However, clinical development of Aspidasept as an anti-sepsis drug requires an in-depth characterization of the interaction of the peptide with the constituents of the human immune system and with other therapeutically relevant compounds such as antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs). In this contribution, relevant details of primary and secondary pharmacodynamics, off-site targets, and immunogenicity are presented, proving that Pep19-2.5 may be readily applied therapeutically against the deleterious effects of a severe bacterial infection.

Synthetic Anti-lipopolysaccharide Peptides (SALPs) as Effective Inhibitors of Pathogen-Associated Molecular Patterns (PAMPs).

Antimicrobial peptides (AMPs) are in the focus of scientific research since the 1990s. In most cases, the main aim was laid on the design of AMP to kill bacteria effectively, with particular emphasis on broadband action and independency on antibiotic resistance. However, so far no approved drug on the basis of AMP has entered the market.Our approach of constructing AMP, called synthetic anti-lipopolysaccharide peptides (SALPs), on the basis of inhibiting the inflammatory action of lipopolysaccharide (LPS, endotoxin) from Gram-negative bacteria was focused on the neutralization of the decisive toxins. These are, beside LPS from Gram-negative bacteria, the lipoproteins (LP) from Gram-positive origin. Although some of the SALPs have an antibacterial action, the most important property is the high-affinity binding to LPS and LP, whether as constituent of the bacteria or in free form which prevents the damaging inflammation, that could otherwise lead to life-threatening septic shock. Most importantly, the SALP may inhibit inflammation independently of the resistance status of the bacteria, and so far the repeated use of the peptides apparently does not cause resistance of the attacking pathogens.In this chapter, an overview is given over the variety of possible applications in the field of fighting against severe bacterial infections, from the use in systemic infection/inflammation up to various topical applications such as anti-biofilm action and severe skin and soft tissue infections.

The repetitive use of non-thermal dielectric barrier discharge plasma boosts cutaneous microcirculatory effects.

BACKGROUND: Non-thermal atmospheric plasma has proven its benefits in sterilization, cauterization and even in cancer reduction. Furthermore, physical plasma generated by dielectric barrier discharge (DBD) promotes wound healing in vivo and angiogenesis in vitro. Moreover, cutaneous blood flow and oxygen saturation can be improved in human skin. These effects are mostly explained by reactive oxygen species (ROS), but electric fields, currents and ultraviolet radiation may also have an impact on cells in the treated area. Usually, single session application is used. The aim of this study was to evaluate the effects of the repetitive use of cold atmospheric plasma (rCAP) on cutaneous microcirculation. HYPOTHESIS: The repetitive use of non-thermal atmospheric plasma boosts cutaneous microcirculation effects. METHODS: Microcirculatory data was assessed at a defined skin area of the radial forearm of 20 healthy volunteers (17 males, 3 females; mean age 39.1±14.8years; BMI 26.4±4.6kg/m(2)). Microcirculatory measurements were performed under standardized conditions using a combined laser Doppler and photospectrometry system. After baseline measurement, CAP was applied by a DBD plasma device for 90s and cutaneous microcirculation was assessed for 10min. Afterwards, a second session of CAP application was performed and microcirculation was measured for another 10min. Then, the third application was made and another 20min of microcirculatory parameters were assessed. RESULTS: Tissue oxygen saturation and postcapillary venous filling pressure significantly increased after the first application and returned to baseline values within 10min after treatment. After the second and third applications, both parameters increased significantly vs. baseline until the end of the 40-minute measuring period. Cutaneous blood flow was significantly enhanced for 1min after the first application, with no significant differences found during the remainder of the observation period. The second application improved and prolonged the effect significantly until 7min and the third application until 13min. CONCLUSION: These data indicate that the repetitive use of non-thermal atmospheric plasma boosts and prolongs cutaneous microcirculation and might therefore be a potential tool to promote wound healing.

Management of pediatric hand burns.

PURPOSE: Hand burns are common in the pediatric population. Optimal hand function is a crucial component of a high-quality survival after burn injury. This can only be achieved with a coordinated approach to the injuries. The aim of this study was to review the management algorithm and outcomes of pediatric hand burns at our institution. METHODS: In total, 70 children fulfilling our study criteria were treated for a burn hand injury in our Burn Care Center between January 2008 and May 2013. RESULTS: 14 of the 70 pediatric patients underwent surgery because of the depth of the hand burns. The management algorithm depending on the depth of the burn is described. Two patients underwent correction surgery due to burn contractures later. CONCLUSION: For a successful outcome of the burned hand, the interdisciplinary involvement and cooperation of the plastic and pediatric surgeon, hand therapist, burn team, patient and their parents are crucial.

Removal of collagen nerve conduits (NeuraGen) after unsuccessful implantation: focus on histological findings.

Nerve conduits are nonneural, hollow tubular structures designed to bridge the gap of a sectioned nerve, to protect the nerve from scar formation, and to guide the regenerating fibers into the distal nerve stump. In the 8-year experience of our department, four patients aged 14 to 50 years had an unsuccessful implantation of a nerve conduit (NeuraGen, Integra, Plainsboro, NJ). In these four patients, the collagen tubes were replaced by an autogenous nerve graft. The histological specimens showed characteristic histological findings of a scar neuroma without any signs of foreign body reaction in three cases and with minimal foreign body reaction in one case. The collagen nerve tube was completely resorbed in all cases after a time period of 6 to 17 months and could not be detected marco- or microscopically.To our knowledge, this is the first report in the English and German literature describing the histological characteristics of explanted collagen nerve tubes in humans.

[Retrospective Evaluation of the Use of a Dermal Substitute in Septorhinoplasty]. / Retrospektive Auswertung der Anwendung eines dermalen Ersatzmaterials bei der Indikation zur Septorhinoplastik.

BACKGROUND: At the present time, various methods exist for camouflaging the dorsum of the nose in septorhinoplasty. The subject of this paper is a retrospective descriptive evaluation of the surgical use of the bovine collagen/glycosaminoglycan matrix Integra Dermal Regeneration Template Single Layer Thin (IDRT-SL Thin) developed by Integra LifeSciences in septorhinoplasty procedures. METHODOLOGY: The focus of this work is to evaluate the postoperative tolerability, the safety, and the course of wound healing when IDRT-SL Thin is applied as a collagen sheet in septorhinoplasty. The evaluation was performed using an evaluation form that was developed for this paper. Patients included in the study were followed up for one year postoperatively; however, the postoperative observation period considered in the evaluation was 14 weeks. RESULTS: The analysis of the surgical results shows relatively homogeneous results for the criteria and time period we examined. No notable complications were observed within the patient cohort up to the 14th postoperative week. DISCUSSION: Despite the limiting factors within the study due to the lack of a control group undergoing other surgical treatment procedures and the small number of patient cases, the observation period of six and 14 weeks applied in this study is suitable to determine the suitability and tolerability in principle. The results presented in this study can therefore be understood as a possible starting point for further investigations on the use of IDRT-SL Thin in septorhinoplasty.

Toxicological and Safety Pharmacological Profiling of the Anti-Infective and Anti-Inflammatory Peptide Pep19-2.5.

Aspidasept (Pep19-2.5) and its derivative Pep19-4LF ("Aspidasept II") are anti-infective and anti-inflammatory synthetic polypeptides currently in development for application against a variety of moderate to severe bacterial infections that could lead to systemic inflammation, as in the case of severe sepsis and septic shock, as well as application to non-systemic diseases in the case of skin and soft tissue infections (SSTI). In the present study, Aspidasept and Aspidasept II and their part structures were analysed with respect to their toxic behavior in different established models against a variety of relevant cells, and in electrophysiological experiments targeting the hERG channel according to ICH S7B. Furthermore, the effects in mouse models of neurobiological behavior and the local lymph node according to OECD test guideline 429 were investigated, as well as a rat model of repeated dose toxicology according to ICH M3. The data provide conclusive information about potential toxic effects, thus specifying a therapeutic window for the application of the peptides. Therefore, these data allow us to define Aspidasept concentrations for their use in clinical studies as parenteral application.

An update on endotoxin neutralization strategies in Gram-negative bacterial infections.

INTRODUCTION: Gram-negative bacterial infections represent still a severe problem of human health care, regarding the increase in multi-resistance against classical antibiotics and the lack of newly developed antimicrobials. For the fight against these germs, anti-infective agents must overcome and/or bind to the Gram-negative outer membrane consisting of a lipopolysaccharide (LPS, endotoxin) outer leaflet and an inner leaflet from phospholipids, with additional peripheral or integral membrane proteins (OMP's). AREAS COVERED: The current article reviews data of existing therapeutic options and summarizes newer approaches for targeting and neutralizing endotoxins, ranging from in vitro over in vivo animal data to clinical applications by using databases such as Medline. EXPERT OPINION: Conventional antibiotic treatment of the bacteria leads to their killing, but not necessary LPS neutralization, which may be a severe problem in particular for the systemic pathway. This is the reason why there is an increasing number of therapeutic approaches, which - besides combating whole bacteria - at the same time try to neutralize endotoxin within or outside the bacterial cells mainly responsible for the high inflammation induction in Gram-negative species.

Antibacterial action of synthetic antilipopolysaccharide peptides (SALP) involves neutralization of both membrane-bound and free toxins.

Increasing failure of conventional antibiotics to combat bacterial infections requires the urgent development of new antibacterial drugs; a promising class of new drugs based on antimicrobial peptides. Here, we studied the molecular interaction of polycationic synthetic antilipopolysaccharide peptides (SALPs) with various gram-negative and gram-positive bacteria, including resistant strains. The analysis of antimicrobial activity by conventional techniques and atomic force microscopy showed a strict dependence on amino acid (aa) sequences, with the type of amino acid, its position within the primary structure, and the sequence length being critical parameters. By monitoring lipopolysaccharide (LPS)- or bacteria-induced cytokine production in human mononuclear cells and whole blood, we found a direct link between the binding of the lead compound Pep19-2.5 to Salmonella enterica and the anti-inflammatory activity of the peptide. Thermodynamic analysis of Pep19-2.5 binding to the bacterial cell envelope showed an exothermic reaction with saturation characteristics, whereas small-angle X-ray scattering data indicated a direct attachment of Pep19-2.5 to the bacterial cell envelope. This binding preferentially takes place to the LPS outer monolayer, as evidenced by the change in the LPS acyl chain and phosphate vibrational bands seen by Fourier-transform infrared spectroscopy. We report here that the anti-inflammatory activity of Pep19-2.5 is not only connected with neutralization of cell-free bacterial toxins but also with a direct binding of the peptide to the outer leaflet of the bacterial outer membrane.

Reduced Amputation Rate by Circular TNP Application on Split-Skin Grafts After Deep Dermal Foot Scalds in Insulin-Dependent Diabetic Patients.

The incidence of insulin-dependent diabetes mellitus (IDDM) is expected to increase significantly. Due to peripheral neuropathy and angiopathy in IDDM patients, feet scalding results in deep burn injuries. Regularly amputations are needed with tremendous consequences. In relatively healthy patients, split-skin graft (SSG) take is better when topical negative pressure (TNP) is applied. We compared the outcome of circular TNP dressing with that of antiseptic dressing on freshly laid SSG after tangential excision in IDDM patients with deep dermal foot scalds. Seventy patients admitted to a burn center with isolated foot burns were identified (2008-2013). Ten of them suffered from IDDM and presented with a deep dermal foot scald. After tangential excision and split-skin grafting, five of them were treated with TNP. The others received an antiseptic dressing regime. Differences were analyzed using either Chi-square or Student's t-test. Group comparison regarding age, gender, body mass index, HbA1c on arrival, glucose in serum, IDDM disease duration, and TBSA revealed no significant differences. But percentage of graft take was at a significantly higher rate in the TNP group (90.2 ± 4.017 vs 39 ± 15.362) and fewer operations had to be performed compared to the control group (2.0 ± 0.447 vs 4.6 ± 0.927). Due to reduced occurrence of necrosis, the number of amputations required was significantly lower in the TNP group. TNP application on freshly laid SSG following tangential excision in IDDM patients after deep dermal foot scalds minimized amputation rates and therefore is of great benefit for such patients.

Obese patients in a burn care unit: a major challenge.

OBJECTIVE: Obesity is an important predictor of mortality and morbidity during a hospital stay. There is very little data concerning the impact of the BMI on clinical outcomes in obese burn patients. The purpose of this study is to document the general epidemiological aspects of thermal injuries in an obese population and draw attention to topics relating to the management, rehabilitation and prognosis of burns in this emerging subpopulation of patients. METHODS: All patients >16 years of age admitted to the burn unit between January 2008 and December 2012 and fulfilling the burn center referral criteria were enrolled in the study. SPSS version 20 (SPSS GmbH Software, Illinois, USA) was employed for data analysis. RESULTS: Eleven extreme obese patients (men:women, 6:5) had a mean BMI of 38kg/m(2). Their incidence in our study was 5.5%. The mean length of stay was 41.5 days, almost twice that of the non-obese. The presence of co-morbidities such as diabetes, hypertension, cardiac disease, or pulmonary disease, the problematic wound healing and the burn wound infection were significantly higher in the obese patients than in the non-obese. The mortality of obese burned patients was 36.4%. CONCLUSIONS: These facts indicate admission of these patients to a burn care unit for the best possible treatment although they might not always fulfill criteria for admission to burn intensive care unit. Burn centers must be also prepared in terms of special nursing equipment for obese patients.

The effect of a bacterial contamination on the formation of capsular contracture with polyurethane breast implants in comparison with textured silicone implants: an animal study.

INTRODUCTION: One of the most common complications following breast augmentation is capsular contracture. The subclinical infection of the implant is often considered to be one of the main risk factors. It is believed that polyurethane (PU) implants, because of their larger foam-like surface, have lower capsular contracture rates due to better tissue integration. It remains unclear if bacterial contamination and biofilm formation result in higher capsular contracture rates under the condition of the increased surface of PU implants compared to textured silicone-gel implants. The effect of this bacterial contamination was examined in an animal-based study. METHODS: A total of 80 mini implants (40 textured silicone-gel implants and 40 PU implants) were implanted in the dorsum of female Wistar rats. In each group, 20 implants were inoculated before implantation with a standard amount of Staphylococcus epidermidis. Capsules and implants were explanted after 60 days, followed by double-blind histological, immunohistochemical, and microbiological examinations. RESULTS: Macroscopic separation of the total capsule in the textured implant group was possible whereas the growth of surrounding tissue into the foam structure of PU implants made separation in that group difficult. After contamination, a thicker capsule could be observed in both groups without significant differences. Histologically, capsules around PU implants showed significantly lower expression of parallel myofibrils. We were able to describe a significant higher infiltration with inflammatory cells in capsules around PU implants both with and without contamination. Microbiological investigations revealed positive growth of S. epidermidis around one PU implant without related signs of capsular contracture. DISCUSSION: This study demonstrates that aside from the surface of silicone implants, bacterial contamination has major impact on the architecture of capsule formation. In our study, we were able to demonstrate that bacterial contamination leads to a thicker capsule and an increased tissue reaction with a higher amount of inflammatory cells. However, a resulting bacterial infection was only demonstrated in one case and had an insignificant influence on capsule architecture. The observed inflammatory reaction around PU implants was observed as a nonbacterial, granulomatose foreign body reaction. EBM RATING: Level I: Evidence obtained from at least one properly designed randomized controlled trial.

Effect of phrenic nerve palsy on early postoperative lung function after pneumonectomy: a prospective study.

BACKGROUND: The issue of phrenic nerve preservation during pneumonectomy is still an unanswered question. So far, its direct effect on immediate postoperative pulmonary lung function has never been evaluated in a prospective trial. METHODS: We conducted a prospective crossover study including 10 patients undergoing pneumonectomy for lung cancer between July 2011 and July 2012. After written informed consent, all consecutive patients who agreed to take part in the study and in whom preservation of the phrenic nerve during operation was possible, were included in the study. Upon completion of lung resection, a catheter was placed in the proximal paraphrenic tissue on the pericardial surface. After an initial phase of recovery of 5 days all patients underwent ultrasonographic assessment of diaphragmatic motion followed by lung function testing with and without induced phrenic nerve palsy. The controlled, temporary paralysis of the ipsilateral hemidiaphragm was achieved by local administration of lidocaine 1% at a rate of 3 mL/h (30 mg/h) via the above-mentioned catheter. RESULTS: Temporary phrenic nerve palsy was accomplished in all but 1 patient with suspected catheter dislocation. Spirometry showed a significant decrease in dynamic lung volumes (forced expiratory volume in 1 second and forced vital capacity; p < 0.05) with the paralyzed hemidiaphragm. Blood oxygen saturation levels did not change significantly. CONCLUSIONS: Our results show that phrenic nerve palsy causes a significant impairment of dynamic lung volumes during the early postoperative period after pneumonectomy. Therefore, in these already compromised patients, intraoperative phrenic nerve injury should be avoided whenever possible.

Accidental inclusions following blast injury in esthetical zones: ablation by a hydrosurgery system.

In case of blast injuries, traumatic tattoos can result from accidental inclusions of intradermal pigmented particles. To avoid these tattoos, especially in esthetical areas like the head and neck region and the hands, the primary goal in our treatment is to remove all particles and foreign bodies. Superficial foreign bodies can easily be removed by brushes or dermabrasion. Deeper lesions are a challenge for plastic surgeons, because they are not so easily removed. Ablation by a water jet surgical tool, the Versajet-system (Smith & Nephew Inc, Andover, MA), enables the removal of nearly all particles and foreign bodies, which sustained a blast injury of the face or the hands. Aim of this paper is to describe the method of using this hydrosurgery system in blast injuries in esthetical zones and its advantages by presenting cases of two patients of us.