The therapeutic potential of inhibiting PPARγ phosphorylation to treat type 2 diabetes.

A promising approach for treating type 2 diabetes mellitus (T2DM) is to target the Peroxisome Proliferator-Activated Receptor γ (PPARγ) transcription factor, which regulates the expression of proteins critical for T2DM. Mechanisms involved in PPARγ signaling are poorly understood, yet globally increasing T2DM prevalence demands improvements in drug design. Synthetic, nonactivating PPARγ ligands can abolish the phosphorylation of PPARγ at Ser273, a posttranslational modification correlated with obesity and insulin resistance. It is not understood how these ligands prevent phosphorylation, and the lack of experimental mechanistic information can be attributed to previous ambiguity in the field as well as to limitations in experimental approaches; in silico modeling currently provides the only insight into how ligands block Ser273 phosphorylation. The future availability of experimental evidence is critical for clarifying the mechanism by which ligands prevent phosphorylation and should be the priority of future T2DM-focused research. Following this, the properties of ligands that enable them to block phosphorylation can be improved upon to generate ligands tailored for blocking phosphorylation and therefore restoring insulin sensitivity. This would represent a significant step forward for treating T2DM. This review summarizes current knowledge of the roles of PPARγ in T2DM as well as the effects of synthetic ligands on the modulation of these roles. We hypothesize potential factors that contribute to the reduction in recent developments and summarize what has currently been done to shed light on this critical field of research.

Glyoxal as an alternative fixative to formaldehyde in immunostaining and super-resolution microscopy.

Paraformaldehyde (PFA) is the most commonly used fixative for immunostaining of cells, but has been associated with various problems, ranging from loss of antigenicity to changes in morphology during fixation. We show here that the small dialdehyde glyoxal can successfully replace PFA Despite being less toxic than PFA, and, as most aldehydes, likely usable as a fixative, glyoxal has not yet been systematically tried in modern fluorescence microscopy. Here, we tested and optimized glyoxal fixation and surprisingly found it to be more efficient than PFA-based protocols. Glyoxal acted faster than PFA, cross-linked proteins more effectively, and improved the preservation of cellular morphology. We validated glyoxal fixation in multiple laboratories against different PFA-based protocols and confirmed that it enabled better immunostainings for a majority of the targets. Our data therefore support that glyoxal can be a valuable alternative to PFA for immunostaining.

Efficacy of parent-infant psychotherapy compared to care as usual in children with regulatory disorders in clinical and outpatient settings: study protocol of a randomised controlled trial as part of the SKKIPPI project.

BACKGROUND: The first years of life are a significant period for child development, when children are particularly sensitive and prone to crises. This early phase lays the foundation for healthy growth. Clinical assessment of psychological symptoms in early infancy and adequate treatment are both important in improving the diagnostic outcome and preventing later long-term developmental consequences. The most common psychological problems in the first 3 years of life are regulatory disorders. The aim of this trial is to investigate the efficacy of Parent-Infant Psychotherapy (PIP) for infants and young children (aged 0-36 months, diagnosed with at least one regulatory disorder) and their mothers, compared to care as usual (CAU). METHODS: In this open multicentre randomised controlled trial, 160 mother-infant dyads are randomised to receive PIP or CAU for 6 weeks of intervention in clinical or outpatient (including home treatment) settings. The primary outcome is the maternal sensitivity (sensitivity scale of the Emotional Availability Scales (EAS)) after 6 weeks. Secondary outcomes include assessment of interaction, mental health problems, attachment, development, psychological factors, treatment adherence, health care system utilisation, and costs, after 6 weeks and 12 months. DISCUSSION: This study will evaluate whether a manualised focus-based short-term psychodynamic psychotherapeutic intervention in mother-child dyads improves the care situation for families of children diagnosed with regulatory disorders, and helps prevent long-term psychopathologies. Assessment of the intervention in different settings will support the development of more tailored interventions for affected infants and their mothers. TRIAL REGISTRATION: German Clinical Trial Register, ID: DRKS00017008 . Registered 03/20/2019.

[Postpartum mental health problems: healthcare service situation and effectiveness of parent-infant psychotherapy. Presentation of the SKKIPPI project funded by the German Innovationsfonds]. / Postpartale psychische Erkrankungen: Versorgungslage und Wirksamkeit der Eltern-Säugling-Kleinkind-Psychotherapie. Vorstellung des Innovationsfondprojektes SKKIPPI.

After the birth of a child, parents may experience episodes of stress and psychological strain. Some infants show psychological or somatic stress in the form of early regulatory disorders. While the close connection between parental psychological stress, early regulatory disorders, and the development of the parent-child relationship is well documented, current data on effective treatment options are lacking. Previous care services mostly operate on a preventive basis; evidence-based psychotherapeutic services with a special focus on the parent-child relationship are rare.SKKIPPI is a multicenter research project (Berlin, Flensburg, Hamburg, Leipzig) and consists of several study parts with a mixed methods approach: an epidemiological cohort study, two randomized controlled intervention studies (RCTs), and a qualitative study. A population-based cohort study records the occurrence and determinants of psychosocial stress and mental health disorders, as well as the use of health and social services by parents and their children within the first two years of life, using online questionnaires and telephone interviews. The aim of the two RCTs is to evaluate the efficacy of a focused, dyadic parent-infant psychotherapy (Eltern-Säugling-Kleinkind-Psychotherapie, ESKP) compared to routine treatment in inpatient and outpatient settings. The focus of these RCTs is on the improvement of maternal sensitivity and on mother-child attachment, as well as child development and the reduction of mother-child psychopathological symptoms. The qualitative study intends to reconstruct the perspectives of parents on the assistance system and to explore reasons for underuse. The results are expected to help develop preventive as well as therapeutic strategies in the German health system.

Viability and biocompatibility of an adhesive system for intrarenal embedding and endoscopic removal of small residual fragments in minimally-invasive stone treatment in an in vivo pig model.

PURPOSE: To evaluate the viability and biocompatibility of a novel, patented bioadhesive system for intrarenal embedding and retrieval of residual fragments after endoscopic lithotripsy. Complete stone clearance via active removal of residual fragments (RF) after intracorporeal laser lithotripsy may be time-consuming and fail in many cases. Therefore, the novel adhesive has been developed and evaluated for the first time in an in vivo pig model in the present work. METHODS: Four female domestic pigs underwent flexible ureteroscopy (RIRS) or percutaneous nephrolithotomy (PNL) under general anesthesia (8 kidneys, 4 × RIRS, 4 × PNL) evaluating the bioadhesive system. INTERVENTIONS: RIRS without adhesive system (sham procedure, kidney I); 3 × RIRS using the bioadhesive system (kidneys II-IV); and 4 × PNL using the bioadhesive system (V-VIII). We endoscopically inserted standardized human stone probes followed by comminution using Ho:YAG lithotripsy. The bioadhesive (kidney II-VIII) was then applied and the adhesive-stone fragment complex extracted. After nephrectomy, all kidneys were evaluated by two independent, blinded pathologists. Endpoints were the procedure's safety and adhesive system's biocompatibility. RESULTS: We observed no substantial toxic effects. We were able to embed and remove 80-90% of fragments. However, because of the pig's hampering pyelocaliceal anatomy, a quantified, proportional assessment of the embedded fragments was compromised. CONCLUSIONS: For the first time, we demonstrated the proven feasibility and safety of this novel bioadhesive system for embedding and endoscopically removing small RF in conjunction with a lack of organ toxicity in vivo.

A Topical Hydrogel with Deferiprone and Gallium-Protoporphyrin Targets Bacterial Iron Metabolism and Has Antibiofilm Activity.

Many infectious diseases are associated with multidrug-resistant (MDR) bacteria residing in biofilms that require high antibiotic concentrations. While oral drug delivery is frequently ineffective, topical treatments have the potential to deliver higher drug concentrations to the infection site while reducing systemic side effects. This study determined the antibiofilm activity of a surgical wound gel loaded with the iron chelator deferiprone (Def) and the heme analogue gallium-protoporphyrin (GaPP), alone and in combination with ciprofloxacin. Activity against MDR Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Acinetobacter johnsonii biofilms was assessed in the colony biofilm and artificial wound model by enumeration of CFU and correlative light/electron microscopy. While Staphylococcus biofilms were equally susceptible to GaPP and Def-GaPP gels (log10 reduction of 3.8 and 3.7, respectively), the Def-GaPP combination was crucial for significant activity against P. aeruginosa biofilms (log10 reduction of 1.3 for GaPP and 3.3 for Def-GaPP). When Def-GaPP gel was combined with ciprofloxacin, the efficacy exceeded the activity of the individual compounds. Def-GaPP delivered in a surgical wound gel showed significant antibiofilm activity against different MDR strains and could enhance the gel's wound-healing properties. Moreover, Def-GaPP indicated a potentiation of ciprofloxacin. This antibiofilm strategy has potential for clinical utilization as a therapy for topical biofilm-related infections.

Novel Biocompatible Adhesive for Intrarenal Embedding and Endoscopic Removal of Small Residual Fragments after Minimally Invasive Stone Treatment in an Ex Vivo Porcine Kidney Model: Initial Evaluation of a Prototype.

PURPOSE: Residual fragments related to endoscopic intracorporeal lithotripsy are a challenging problem. The impact of residual fragments remains a subject of discussion and growing evidence highlights that they have a central role in recurrent stone formation. Therefore, we developed a novel bioadhesive system for intrarenal embedding and retrieval of residual fragments after endoscopic lithotripsy in an ex vivo porcine kidney model. MATERIALS AND METHODS: In a standardized setting 30 human stone fragments 1 mm or less were inserted in the lower pole of an ex vivo porcine kidney model. We assessed the extraction efficacy of flexible ureteroscopy using the bioadhesive system in 15 preparations and a conventional retrieval basket in 15. Outcomes were compared regarding the endoscopic and macroscopic stone-free rate, and overall time of retrieval. RESULTS: Embedding and retrieving the residual fragment-bioadhesive complex were feasible in all trial runs. We observed no adverse effects such as adhesions between the adhesive and the renal collecting system or the instruments used. The stone-free rate was 100% and 60% in the bioadhesive and conventional retrieval groups, respectively (p = 0.017). Mean retrieval time was significantly shorter at 10 minutes 33 seconds vs 36 minutes 56 seconds in the bioadhesive group vs the conventional group (p = 0.001). CONCLUSIONS: This novel method involving adhesive based complete removal of residual fragments from the collecting system has proved to be feasible. Our evaluation in a porcine kidney model revealed that this technology performed well. Further tests, including inpatient studies, are required to thoroughly evaluate the benefit and potential drawbacks of bioadhesive based extraction of residual fragments after intracorporeal lithotripsy.

Secretory cells in honeybee hypopharyngeal gland: polarized organization and age-dependent dynamics of plasma membrane.

The honeybee hypopharyngeal gland consists in numerous units, each comprising a secretory cell and a canal cell. The secretory cell discharges its products into a convoluted tubular membrane system, the canaliculus, which is surrounded at regular intervals by rings of actin filaments. Using probes for various membrane components, we analyze the organization of the secretory cells relative to the apicobasal configuration of epithelial cells. The canaliculus was defined by labeling with an antibody against phosphorylated ezrin/radixin/moesin (pERM), a marker protein for the apical membrane domain of epithelial cells. Anti-phosphotyrosine visualizes the canalicular system, possibly by staining the microvillar tips. The open end of the canaliculus leads to a region in which the secretory cell is attached to the canal cell by adherens and septate junctions. The remaining plasma membrane stains for Na,K-ATPase and spectrin and represents the basolateral domain. We also used fluorophore-tagged phalloidin, anti-phosphotyrosine and anti-pERM as probes for the canaliculus in order to describe fine-structural changes in the organization of the canalicular system during the adult life cycle. These probes in conjunction with fluorescence microscopy allow the fast and detailed three-dimensional analysis of the canalicular membrane system and its structural changes in a developmental mode or in response to environmental factors.

Pluronic-Functionalized Silica-Lipid Hybrid Microparticles: Improving the Oral Delivery of Poorly Water-Soluble Weak Bases.

A Pluronic-functionalized silica-lipid hybrid (Plu-SLH) microparticle system for the oral delivery of poorly water-soluble, weak base drugs is reported for the first time. A highly effective Plu-SLH microparticle system was composed of Labrasol as the lipid phase, Pluronic F127 as the polymeric precipitation inhibitor (PPI), and silica nanoparticles as the solid carrier. For the model drug cinnarizine (CIN), the Plu-SLH delivery system was shown to offer significant biopharmaceutical advantages in comparison with unformulated drug and drug in the silica-lipid hybrid (SLH) system. In vitro two-phase dissolution studies illustrated significantly reduced pH provoked CIN precipitation and an 8- to 14-fold improvement in the extent of dissolution in intestinal conditions. In addition, under simulated intestinal digesting conditions, the Plu-SLH provided approximately three times more drug solubilization than the SLH. Oral administration in rats resulted in superior bioavailability for Plu-SLH microparticles, i.e., 1.6- and 2.1-fold greater than the SLH and the unformulated CIN, respectively. A physical mixture of Pluronic and SLH (Plu&SLH), having the same composition as Plu-SLH, was also evaluated, but showed no significant increase in CIN absorption when compared to unmodified CIN or SLH. This work represents the first study where different methods of incorporating PPI to formulate solid-state lipid-based formulations were compared for the impact on the biopharmaceutical performance. The data suggest that the novel physicochemical properties and structure of the fabricated Plu-SLH microparticle delivery system play an important role in facilitating the synergistic advantage of Labrasol and Pluronic F127 in preventing drug precipitation, and the Plu-SLH provides efficient oral delivery of poorly water-soluble weak bases.

Alternative nutrient sources for biotechnological use of Sporosarcina pasteurii.

The potential use of Sporosarcina pasteurii in possible biotechnological applications on a large scale (ground improvement, consolidation of building structures and ornamental stone, or in developing bio-materials for the building industry), is based on its ability to produce high amounts of carbonate in a short period of time via urea hydrolysis. Industrial biomass production would have a low environmental impact and would be most economical if the standard growth media could be replaced with alternative nutrient sources, such as byproducts or wastes from other industries, or other low cost ingredients. The use of cost effective ingredients must guarantee ureolytic activities and growth conditions that are comparable to those resulting from the standard nutrient medium. In this work, three types of alternative media were tested for growing the ureolytic active bacteria S. pasteurii: (1) alternative nutrient sources such as industrial wastes resulting from the dairy and brewery industries, (2) fertilizer urea as an alternative urea substitute, and (3) different types of poultry manure based fertilizers as nutrient and urea substitutes. The comparison between the standard media, the nutrient alternatives and urea substitutes was possible by taking the protein concentration and nitrogen content into account. Bacterial activity was evaluated in terms of biomass changes over time (CFU, optical density, ATP measurements) and indirect estimation of the enzyme production (Nessler assay, conductivity measurement). The results revealed that some of the dairy wastes tested, such as whey and buttermilk, are potential alternative nutrients for bacterial development, while the urea fertilizer is perfectly suitable as an economical substitute for pure laboratory grade urea.

Efficacy of Plasma-Treated Water against Salmonella Typhimurium: Antibacterial Activity, Inhibition of Invasion, and Biofilm Disruption.

Plasma-treated water (PTW) has emerged as a potential sanitizing agent. This study evaluated antibacterial activity, inhibition of invasion, and biofilm disruption effects of PTW against Salmonella Typhimurium. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined for different PTW types. Time-kill assays were conducted to assess bactericidal effects, while polarized Caco-2 cells were used to evaluate invasion inhibition. Biofilm formation and cell viability were examined following PTW treatment using Salmonella Typhimurium isolates, while biofilm disruption and regrowth prevention were investigated using the Bioflux system. PTW exhibited antibacterial activity against all Salmonella Typhimurium isolates, with MICs of 25% for PTW1 and PTW2, and 50% for PTW3, PTW4, and PTW5. MBCs of 50% in media were observed for all PTW types. Undiluted PTW1 and PTW2 showed the highest bactericidal capacity, significantly reduced Salmonella viability, and completely inhibited bacterial invasion, while PTW3 and PTW5 also showed significant invasion reduction. Bioflux experiments confirmed the eradication of biofilms by PTW1 and PTW2, with no regrowth observed 72 h after PTW was removed. PTW demonstrated significant antibacterial activity, inhibition of invasion, biofilm disruption, and reduction of bacterial viability against Salmonella Typhimurium. This highlights PTW's potential as an effective sanitizer for reducing Salmonella contaminations.

Saos-2 cells cultured under hypoxia rapidly differentiate to an osteocyte-like stage and support intracellular infection by Staphylococcus aureus.

The intracellular infection of osteocytes represents a clinically important aspect of osteomyelitis. However, few human osteocyte in vitro models exist and the differentiation of immature osteoblasts to an osteocyte stage typically takes at least 4-weeks of culture, making the study of this process challenging and time consuming. The osteosarcoma cell line Saos-2 has proved to be a useful model of human osteoblast to mature osteocyte differentiation. Culture under osteogenic conditions in a standard normoxic (21% O2 ) atmosphere results in reproducible mineralization and acquisition of mature osteocyte markers over the expected 28-35 day culture period. In order to expedite experimental assays, we tested whether reducing available oxygen to mimic concentrations experienced by osteocytes in vivo would increase the rate of differentiation. Cells cultured under 1% O2 exhibited maximal mineral deposition by 14 days. Early (COLA1, MEPE) and mature (PHEX, DMP1, GJA1, SOST) osteocyte markers were upregulated earlier under hypoxia compared to normoxia. Cells differentiated under 1% O2 for 14 days displayed a similar ability to internalize Staphylococcus aureus as day 28 cells grown under normoxic conditions. Thus, low oxygen accelerates Saos-2 osteocyte differentiation, resulting in a useful human osteocyte-like cell model within 14 days.

In vitro and in vivo evaluation of diethyldithiocarbamate with copper ions and its liposomal formulation for the treatment of Staphylococcus aureus and Staphylococcus epidermidis biofilms.

Surgical site infections (SSIs) are mainly caused by Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis) biofilms. Biofilms are aggregates of bacteria embedded in a self-produced matrix that offers protection against antibiotics and promotes the spread of antibiotic-resistance in bacteria. Consequently, antibiotic treatment frequently fails, resulting in the need for alternative therapies. The present study describes the in vitro efficacy of the Cu(DDC)2 complex (2:1 M ratio of diethyldithiocarbamate (DDC-) and Cu2+) with additional Cu2+ against S. aureus and S. epidermidis biofilms in models mimicking SSIs and in vitro antibacterial activity of a liposomal Cu(DDC)2 + Cu2+ formulation. The in vitro activity on S. aureus and S. epidermidis biofilms grown on two hernia mesh materials and in a wound model was determined by colony forming unit (CFU) counting. Cu2+-liposomes and Cu(DDC)2-liposomes were prepared, and their antibacterial activity was assessed in vitro using the alamarBlue assay and CFU counting and in vivo using a Galleria mellonella infection model. The combination of 35 µM DDC- and 128 µM Cu2+ inhibited S. aureus and S. epidermidis biofilms on meshes and in a wound infection model. Cu(DDC)2-liposomes + free Cu2+ displayed similar antibiofilm activity to free Cu(DDC)2 + Cu2+, and significantly increased the survival of S. epidermidis-infected larvae. Whilst Cu(DDC)2 + Cu2+ showed substantial antibiofilm activity in vitro against clinically relevant biofilms, its application in mammalian in vivo models is limited by solubility. The liposomal Cu(DDC)2 + Cu2+ formulation showed antibiofilm activity in vitro and antibacterial activity and low toxicity in G. mellonella, making it a suitable water-soluble formulation for future application on infected wounds in animal trials.

Can intracellular Staphylococcus aureus in osteomyelitis be treated using current antibiotics? A systematic review and narrative synthesis.

Approximately 40% of treatments of chronic and recurrent osteomyelitis fail in part due to bacterial persistence. Staphylococcus aureus, the predominant pathogen in human osteomyelitis, is known to persist by phenotypic adaptation as small-colony variants (SCVs) and by formation of intracellular reservoirs, including those in major bone cell types, reducing susceptibility to antibiotics. Intracellular infections with S. aureus are difficult to treat; however, there are no evidence-based clinical guidelines addressing these infections in osteomyelitis. We conducted a systematic review of the literature to determine the demonstrated efficacy of all antibiotics against intracellular S. aureus relevant to osteomyelitis, including protein biosynthesis inhibitors (lincosamides, streptogramins, macrolides, oxazolidines, tetracyclines, fusidic acid, and aminoglycosides), enzyme inhibitors (fluoroquinolones and ansamycines), and cell wall inhibitors (beta-lactam inhibitors, glycopeptides, fosfomycin, and lipopeptides). The PubMed and Embase databases were screened for articles related to intracellular S. aureus infections that compared the effectiveness of multiple antibiotics or a single antibiotic together with another treatment, which resulted in 34 full-text articles fitting the inclusion criteria. The combined findings of these studies were largely inconclusive, most likely due to the plethora of methodologies utilized. Therefore, the reported findings in the context of the models employed and possible solutions for improved understanding are explored here. While rifampicin, oritavancin, linezolid, moxifloxacin and oxacillin were identified as the most effective potential intracellular treatments, the scientific evidence for these is still relatively weak. We advocate for more standardized research on determining the intracellular effectiveness of antibiotics in S. aureus osteomyelitis to improve treatments and patient outcomes.

The combination of diethyldithiocarbamate and copper ions is active against Staphylococcus aureus and Staphylococcus epidermidis biofilms in vitro and in vivo.

Staphylococcus aureus and Staphylococcus epidermidis are associated with life-threatening infections. Despite the best medical care, these infections frequently occur due to antibiotic resistance and the formation of biofilms of these two bacteria (i.e., clusters of bacteria embedded in a matrix). As a consequence, there is an urgent need for effective anti-biofilm treatments. Here, we describe the antibacterial properties of a combination treatment of diethyldithiocarbamate (DDC) and copper ions (Cu2+) and their low toxicity in vitro and in vivo. The antibacterial activity of DDC and Cu2+ was assessed in vitro against both planktonic and biofilm cultures of S. aureus and S. epidermidis using viability assays, microscopy, and attachment assays. Cytotoxicity of DDC and Cu2+ (DDC-Cu2+) was determined using a human fibroblast cell line. In vivo antimicrobial activity and toxicity were monitored in Galleria mellonella larvae. DDC-Cu2+ concentrations of 8 µg/ml DDC and 32 µg/ml Cu2+ resulted in over 80% MRSA and S. epidermidis biofilm killing, showed synergistic and additive effects in both planktonic and biofilm cultures of S. aureus and S. epidermidis, and synergized multiple antibiotics. DDC-Cu2+ inhibited MRSA and S. epidermidis attachment and biofilm formation in the xCELLigence and Bioflux systems. In vitro and in vivo toxicity of DDC, Cu2+ and DDC-Cu2+ resulted in > 70% fibroblast viability and > 90% G. mellonella survival. Treatment with DDC-Cu2+ significantly increased the survival of infected larvae (87% survival of infected, treated larvae vs. 47% survival of infected, untreated larvae, p < 0.001). Therefore, DDC-Cu2+ is a promising new antimicrobial with activity against planktonic and biofilm cultures of S. epidermidis and S. aureus and low cytotoxicity in vitro. This gives us high confidence to progress to mammalian animal studies, testing the antimicrobial efficacy and safety of DDC-Cu2+.

A Thermosensitive, Chitosan-Based Hydrogel as Delivery System for Antibacterial Liposomes to Surgical Site Infections.

Prophylaxis and the treatment of surgical site infections (SSIs) with antibiotics frequently fail due to the antibiotic resistance of bacteria and the ability of bacteria to reside in biofilms (i.e., bacterial clusters in a protective matrix). Therefore, alternative antibacterial treatments are required to combat biofilm infections. The combination of diethyldithiocarbamate (DDC-) and copper ions (Cu2+) exhibited antibiofilm activity against the staphylococci species associated with SSIs; however, the formation of a water-insoluble Cu(DDC)2 complex limits its application to SSIs. Here, we describe the development and antibiofilm activity of an injectable gel containing a liposomal formulation of Cu(DDC)2 and Cu2+ (lipogel). Lyophilized liposomes were incorporated into a mixture of chitosan (CS) and beta-glycerophosphate (ßGP), and the thermosensitive gelling properties of CS-ßGP and the lipogel were determined. The liposomes remained stable after lyophilization over six months at 4-6 °C and -20 °C. The sol-gel transition of the gel and lipogel occurred between 33 and 39 °C, independently of sterilization or storage at -20 °C. CS-ßGP is biocompatible and the liposomes were released over time. The lipogel prevented biofilm formation over 2 days and killed 98.7% of the methicillin-resistant Staphylococcus aureus and 99.9% of the Staphylococcus epidermidis biofilms. Therefore, the lipogel is a promising new prophylaxis and treatment strategy for local application to SSIs.

The revival of dithiocarbamates: from pesticides to innovative medical treatments.

Dithiocarbamates (DTCs) have been used for various applications, including as hardening agents in rubber manufacturing, as fungicide in agriculture, and as medications to treat alcohol misuse disorder. The multi-faceted effects of DTCs rely mainly on metal binding abilities and a high reactivity with thiol groups. Therefore, the list of potential applications is still increasing, exemplified by the US Food and Drug Administration approval of disulfiram (Antabuse) and its metabolite diethyldithiocarbamate in clinical trials against cancer, human immunodeficiency virus, and Lyme disease, as well as new DTC-related compounds that have been synthesized to target diseases with unmet therapeutic needs. In this review, we will discuss the latest progress of DTCs as anti-cancer agents and provide a summary of the mechanisms of action. We will explain the expansion of DTCs' activity in the fields of microbiology, neurology, cardiology, and ophthalmology, thereby providing evidence for the important role and therapeutic potential of DTCs as innovative medical treatments.

Affective responses to climbing exercises in children and adolescents during in-patient treatment for mental health disorders a pilot study on acute effects of different exercise interventions.

The aim of the present study was to compare acute effects of a climbing intervention (CI) on affective responses with a different exercise intervention (swimming, SI) and an occupational therapy intervention (OTI) in children and adolescents during in-patient treatment for mental health disorders. The following study was designed as a cross-over study. Participants completed three single 60 min interventions of CI, SI and OTI. Affective responses were assessed pre and post intervention and at 20 and 40 min during intervention. The sample consisted of 33 children and adolescents in mental-health inpatient care (ᴓage: 13.3 ± 2.2 years, ♀=39.4%). A significant time effect was seen in all interventions in increasing positive and reducing negative affect, p<.028, eta²>0.144. Repeated measures ANOVAs revealed a significant time by intervention effect for affective valence (p=.011, eta²=0.09), but not for perceived activation, favouring CI over SI and OCT between pre-test and the first 20 or 40 min, respectively. All interventions showed similar effects on affective responses pre to post interventions. CI seems to increase affective valence more strongly during intervention compared to SI and OTI. The present results may have implications for therapy adherence and acute emotion regulation in children and adolescent in-patients with mental health disorders.

Prevention of peridural adhesions in spinal surgery: Assessing safety and efficacy of Chitogel with Deferiprone in a sheep model.

INTRODUCTION: Spinal laminectomy is a common procedure performed to relieve neural compression in patients suffering from myelopathy or radiculopathy. However, up to 40% of patients suffer from persistent post-operative pain and disability, a condition known as Failed Back Surgery Syndrome (FBSS). Excessive scarring in the surgical bed is implicated as a cause. Hydrogels have been proposed to prevent adhesion formation post-laminectomy; however, their efficacy has not been proven. This study uses Chitogel complexed with the iron chelator Deferiprone (Def) to prevent adhesion formation in a sheep laminectomy model. MATERIAL & METHODS: Fifteen Adult Merino sheep (Ovis Aries, 1-5 yrs old) underwent laminectomy at lumbar levels 1-5 and had hydrated aluminum silicate (kaolin) applied to promote adhesion formation. Subjects were randomised to receive at each laminectomy level no-treatment control, Chitogel, Chitogel with Def at 20 mM or 40 mM or Carboxy-methyl-cellulose and Polyethylene oxide (CMC/PEO) gel. The animals were recovered for 3 months post-surgery, followed by assessment with Magnetic Resonance Imaging (MRI) and histopathology of the spinal tissues for evaluating the presence and extent of adhesions. RESULTS: MRI and Histology assessment indicated that Kaolin induced severe inflammation with adhesion formation. Chitogel with and without 20 mM Def decreased inflammation (p < 0.01) and trended to reduce adhesions (p < 0.1). Chitogel with Def 40 mM was not significantly dis-similar to CMC/PEO and did not reduce inflammation or adhesions compared to no-treatment control. CONCLUSION: Chitogel in combination with Def 20 mM is safe and effective in decreasing the inflammatory process and may possibly reduce post-operative adhesions following laminectomy.

Antibody-driven capture of synaptic vesicle proteins on the plasma membrane enables the analysis of their interactions with other synaptic proteins.

Many organelles from the secretory pathway fuse to the plasma membrane, to exocytose different cargoes. Their proteins are then retrieved from the plasma membrane by endocytosis, and the organelles are re-formed. It is generally unclear whether the organelle proteins colocalize when they are on the plasma membrane, or whether they disperse. To address this, we generated here a new approach, which we tested on synaptic vesicles, organelles that are known to exo- and endocytose frequently. We tagged the synaptotagmin molecules of newly exocytosed vesicles using clusters of primary and secondary antibodies targeted against the luminal domains of these molecules. The antibody clusters are too large for endocytosis, and thus sequestered the synaptotagmin molecules on the plasma membrane. Immunostainings for other synaptic molecules then revealed whether they colocalized with the sequestered synaptotagmin molecules. We suggest that such assays may be in the future extended to other cell types and other organelles.