Acute toxicity study of antibacterial organophilic bentonite incorporated with geranyl acetate in mice and geranyl acetate liberation in simulated gastric fluid.

In the present study, the antibacterial property of the organophilic bentonite (Bent-ODA) and organophilic bentonite incorporated with geranyl acetate ester (Bent-ODA-GA) was evaluated against bacteria Staphylococcus aureus, Escherichia coli and Salmonella typhimurium. Oral acute toxicity of Bent-ODA-GA was evaluated in mice, by a single oral dose of 300 and 2000 mg kg-1. Animals were observed for any toxicity clinical signs or mortality for 15 days according to OECD 423 guidelines. The release assay of GA presents in Bent-ODA in simulated gastric fluid, pH 3.5 and pH 6.5 was also performed. Bent-ODA-GA composite presented antibacterial activity against S. aureus and S. typhimurium bacteria with 10.7 ± 0.6 mm and 2.2 ± 0.1 mm inhibition halo, respectively, which make it possible to associate the composite antimicrobial feature due to the ester presence. The composite did not reveal any toxicity signs or mortality in any animal for acute toxicity treatment during the 15 days observation period. The LD50 of Bent-ODA-DA was estimated to be greater than 2000 mg kg-1. It was also observed that geranyl acetate is released from Bent-ODA in concentrations lower than 0.03 mg kg-1 for pH 3.5 and 0.004 mg kg-1 for pH 6.5, which are lower than those that could cause some toxic effects in animals.

Palmitic acid coating of allogeneic cancellous bone for local antibiotic treatment: A porcine impaction bone grafting model.

Introduction: The worldwide rising number of joint replacements results in increasing revision surgery including a relevant portion of septic loosening accompanied by bone deficiencies. Loading of allogeneic bone with antibiotics provides high local antibiotic concentrations and might eradicate bacteria which appear resistant to systemic antibiotic application. Hydrophobic palmitic acid was shown to be a suitable carrier for antibiotics and prevents biofilm. Methods: Cancellous bone derived from 6 to 7 months old piglets was used for a standardized in vitro impaction bone grafting model according to previous studies. The specimens were either thermodisinfected or remained native and palmitic acid with one third and two third partial weight were added and compared with control. Shear force at the interface prosthesis to cement and between cement and bone was measured. The relative micromovements were measured with 6 inductive sensors with a resolution of 0.1 µm at three different measuring heights up to a maximum movement of 150 µm between cement and bone. Taking into account the corresponding applied torque the measured values were normalized in µm/Nm. Statistical analysis was done with SPSS Statistics® Version 26.0 IBM. Results: Smallest movement was measured for thermodisinfected cancellous bone and a not significant decrease of shear force resistance with addition of palmitic acid was found since supplementing native cancellous bone reduced shear force resistance significantly depending on the weight percentage of palmitic acid. Conclusion: Supplementation of porcine cancellous bone with palmitic acid did not significantly reduce shear force resistance of thermodisinfected bone since adding palmitic acid to native bone decreased it significantly depending on the volume added. Palmitic acid seems to be a suitable coating for allogeneic cancellous bone to deliver high local antibiotic concentrations and thermodisinfected cancellous bone might be able to store larger volumes of palmitic acid than native bone without relevant influence on shear force resistance.

Of the necessary interplay of therapy and pedagogy in psychiatric hospitals for children with intellectual disability.

BACKGROUND: Mentally ill children with intellectual disabilities do not always receive the services they need for effective change at psychiatric hospitals, as their verbal limitations render standard procedures in diagnostics and therapy difficult or impossible, as their ability to transfer insights acquired in one setting to another is impaired and as their families and caretakers are often overwhelmed by their needs. This is why an integral vision for children with intellectual disabilities is presented. Drawing on three case reports, it is highlighted how an interdisciplinary approach, a changed hospital set-up and constant interplay between therapy and pedagogy, between services to the child and to its caregivers can help overcome these difficulties. METHOD: Case reports. CONCLUSIONS: Some children risk being mistakenly treated as intellectually disabled. If testing reveals, for example, autism with a mild learning disability, psychoeducation and the pedagogical training for (special school) personnel can help prevent underachievement and bring about a setting that can help the child flourish. Both sensitive care and pedagogical intervention that fit the developmental age of severely intellectually disabled children can prevent their receiving sedatives to treat aggressive behaviour. Substantial and lasting shifts in mood, even happiness can result if parents and caregivers get the pedagogical training and the assistance they need to take care of their children. Reliable and well-structured pedagogical training and environments can enhance and often substitute for unavailable therapeutic interventions for this specific group. With some profound intellectually and multiply disabled children, beginning medical treatment at home may not be safe. The (in)effectiveness of specific psychiatric medications needs to be monitored by observations however. For reliable results with intellectually disabled children, a clinical setting that resembles their everyday life is needed.

Assessment of magnetic flux density properties of electromagnetic noninvasive phrenic nerve stimulations for environmental safety in an ICU environment.

Diaphragm weakness affects up to 60% of ventilated patients leading to muscle atrophy, reduction of muscle fiber force via muscle fiber injuries and prolonged weaning from mechanical ventilation. Electromagnetic stimulation of the phrenic nerve can induce contractions of the diaphragm and potentially prevent and treat loss of muscular function. Recommended safety distance of electromagnetic coils is 1 m. The aim of this study was to investigate the magnetic flux density in a typical intensive care unit (ICU) setting. Simulation of magnetic flux density generated by a butterfly coil was performed in a Berlin ICU training center with testing of potential disturbance and heating of medical equipment. Approximate safety distances to surrounding medical ICU equipment were additionally measured in an ICU training center in Bern. Magnetic flux density declined exponentially with advancing distance from the stimulation coil. Above a coil distance of 300 mm with stimulation of 100% power the signal could not be distinguished from the surrounding magnetic background noise. Electromagnetic stimulation of the phrenic nerve for diaphragm contraction in an intensive care unit setting seems to be safe and feasible from a technical point of view with a distance above 300 mm to ICU equipment from the stimulation coil.

Material modifications enhancing the antibacterial properties of two biodegradable poly(3-hydroxybutyrate) implants.

The aim of this study was to evaluate the antimicrobial efficacy of adding a gentamicin palmitate (GP) coating and zirconium dioxide (ZrO2) to biodegradable poly(3-hydroxybutyrate) (PHB) to reduce biofilm formation. Cylindrical pins with and without a coating were incubated in Müller-Hinton broth inoculated with 2 × 105 colony-forming units (CFU) ml-1 of Staphylococcus aureus for 2 d or 7 d, then sonicated to disrupt biofilms. Pure PHB (PHB + GP) and PHB pins with ZrO2 added (PHBzr + GP) were coated with GP and compared with PHB pins lacking a coating (PHB). Cells (CFU) were counted to quantify the number of bacteria in the biofilm and a cell proliferation assay was employed to evaluate metabolic activity, and scanning electron microscopy (SEM) was performed to visualize the structure of the biofilm. After 2 d of incubation there were significantly more cells in biofilms on PHB pins than PHB + GP and PHBzr + GP pins (p < 0.0001), and cells in the sonication fluid obtained from GP-coated pins exhibited significantly lower metabolic activity than cells from uncoated PHB pins (p < 0.0001). After 7 d of incubation metabolic activity was lowest for PHBzr + GP, with significant differences between PHB and PHBzr + GP (p = 0.001). SEM revealed more cells attached to the surface, and more structured biofilms, on pins without a coating. Coating pins with GP significantly reduced early biofilm formation on PHB implants. This could lower the potential risk of surgical site infections when using PHB implants. Addition of ZrO2 might further enhance the antibacterial properties. Such modification of the implant material should therefore be considered when developing new biodegradable PHB implants.

Comment on Early versus delayed mobilization for in-hospital mortality and health-related quality of life among critically ill patients: a systematic review and meta-analysis (Okada et al., Journal of Intensive Care 2019).

Critical comment on the review by Okada et al. on the effect of early versus delayed mobilization because of their definition of early mobilization as mobilization within a week of ICU admission in contrast to current evidence.

Molecular dissection of TNFR-TNFα bidirectional signaling reveals both cooperative and antagonistic interactions with p75 neurotrophic factor receptor in axon patterning.

During neural development, complex organisms rely on progressive and regressive events whereby axons, synapses, and neurons are overproduced followed by selective elimination of a portion of these components. Tumor necrosis factor α (TNFα) together with its cognate receptor (Tumor necrosis factor receptor 1; TNFR1) have been shown to play both regressive (i.e. forward signaling from the receptor) and progressive (i.e. reverse signaling from the ligand) roles in sympathetic neuron development. In contrast, a paralog of TNFR1, p75 neurotrophic factor receptor (p75NTR) promotes mainly regressive developmental events in sympathetic neurons. Here we examine the interplay between these paralogous receptors in the regulation of axon branch elimination and arborization. We confirm previous reports that these TNFR1 family members are individually capable of promoting ligand-dependent suppression of axon growth and branching. Remarkably, p75NTR and TNFR1 physically interact and p75NTR requires TNFR1 for ligand-dependent axon suppression of axon branching but not vice versa. We also find that p75NTR forward signaling and TNFα reverse signaling are functionally antagonistic. Finally, we find that TNFα reverse signaling is necessary for nerve growth factor (NGF) dependent axon growth. Taken together these findings demonstrate several levels of synergistic and antagonistic interactions using very few signaling pathways and that the balance of these synergizing and opposing signals act to ensure proper axon growth and patterning.

Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity.

Interactions between the microbiota and distal gut are important for the maintenance of a healthy intestinal barrier; dysbiosis of intestinal microbial communities has emerged as a likely contributor to diseases that arise at the level of the mucosa. Intraepithelial lymphocytes (IELs) are positioned within the epithelial barrier, and in the small intestine they function to maintain epithelial homeostasis. We hypothesized that colon IELs promote epithelial barrier function through the expression of cytokines in response to interactions with commensal bacteria. Profiling of bacterial 16S ribosomal RNA revealed that candidate bacteria in the order Bacteroidales are sufficient to promote IEL presence in the colon that in turn produce interleukin-6 (IL-6) in a MyD88 (myeloid differentiation primary response 88)-dependent manner. IEL-derived IL-6 is functionally important in the maintenance of the epithelial barrier as IL-6-/- mice were noted to have increased paracellular permeability, decreased claudin-1 expression, and a thinner mucus gel layer, all of which were reversed by transfer of IL-6+/+ IELs, leading to protection of mice in response to Citrobacter rodentium infection. Therefore, we conclude that microbiota provide a homeostatic role for epithelial barrier function through regulation of IEL-derived IL-6.

Whole-genome sequencing of Campylobacter jejuni isolated from Danish routine human stool samples reveals surprising degree of clustering.

OBJECTIVES: Outbreaks of Campylobacter are traditionally considered to be rare; however, rather than being the true nature of the disease, this may reflect our present inability to detect them. The aim of this study was to determine the genetic and epidemiological degree of clustering among Campylobacter jejuni isolates from Danish patients. METHODS: Whole-genome sequencing (WGS) was applied to 245 C. jejuni isolates from patients with domestically acquired infection over a 9-month period in 2015 and 2016. RESULTS: WGS demonstrated that 62 of the 245 isolates (25%) clustered genetically. In total, 21 genetic clusters were identified of which four (18%) consisted of five isolates or more. Seventeen (81%) of the 21 genetic clusters were clustered in space and/or time. Of the 245 isolates, 49 (20%) were part of a temporal and/or geographical cluster. The identified clusters included two outbreaks; one which had not been identified through the existing surveillance system. CONCLUSIONS: Using WGS, we show that Campylobacter case clustering and even outbreaks appear to occur more often than previously assumed, providing important new insight into the relatively poorly understood epidemiology of the most important cause of bacterial gastroenteritis in the industrialized world.

[Bone substitute materials as local drug carriers : Current status of substitutes of various origins]. / Knochenersatzwerkstoffe als lokale Wirkstoffträger : Aktueller Stand bei Ersatzstoffen verschiedenen Ursprungs.

BACKGROUND: Autologous bone grafts (autografts) are used in surgery for defect filling and impaction grafting during hip socket and femur reconstruction. Because of their superior osteoinductive capacity, autografts are considered the "gold standard" for these treatments. However, because of a better cost-benefit ratio, allografts are also often used. In the case of limited donor availability for autologous or allogenic bone grafts, bone substitute materials (BSMs) are a reasonable alternative or supplement. BSM are based on or combine different substances. Growth factors of the bone morphogenetic protein family BMP are recombinant proteins that specifically induce the growth of bone and cartilage tissue. CHARACTERISTICS: One advantage of BSM is the option to combine them with several anti-infective agents. The choice of the anti-infective substance should not only be based on the antimicrobial efficacy, but should also take into account possible dose-dependent cellular and pharmacological side effects at the implantation site. Thus, microbiologists, pharmacists and surgeons should decide together which combination is the most appropriate. COMBINATION PRODUCTS: BSM with active agent additives are considered combination products that are characterized by a main effect (bone replacement function) and a secondary effect (prophylaxis of bacterial recolonization of BSM). Both functions must be thoroughly (clinically) evidenced in the course of the registration process as a class III medical device. Drug authorities evaluate the active agents, their function and corresponding indication. Currently, only a few combination products are available on the market. As a consequence of the only limited availability of such commercial combination products, surgeons in clinical practice often manually add the active agent to BSM in the theatre prior to implantation. However, such a customized addition of antibiotics places the surgeon in a situation of a manufacturer where he assumes liability for the product.

[Potential of allogeneic bone grafts as antibiotic carriers : Effect of different preparation processes on efficacy]. / Allogene spongiöse Knochenpräparate als Antibiotikaträger : Einfluss verschiedener Aufbereitungsverfahren auf die Wirksamkeit.

BACKGROUND: The rising number of primary joint replacements worldwide is causing an increase of endoprosthetic revision surgery due bacterial infection. Revision surgery using non-cemented implants seems beneficial for the long-term outcome, and the use of antibiotic-impregnated bone grafts might control the infection and provide a good support for the implant. In this study, we evaluated the release of antibiotics from fresh-frozen and lyophilized allogeneic bone grafts. METHODS: Heat-treated, lyophilized and fresh frozen cryopreserved bone chips were impregnated with gentamicin sulphate, gentamicin palmitate and vancomycin, and calcium carbonate/calcium sulphate treated with antibiotics. The efficacy of each preparation was measured by drug release tests and bacterial susceptibility using B. subtilis, S. aureus and methicillin-resistant Staphylococcus aureus. RESULTS: The release of gentamicin from lyophilized bone was similar to the release rate from fresh frozen bone during the entire experiment. This might be related to the similar porosity and microstructure of the bone chips. The release of gentamicin from lyophilized and fresh frozen bone was high on the first and second days, then decreased and stayed at a low rate until the end of the second week. CONCLUSION: Depending on the surgical strategy, either polymethylmethacrylate or allogeneic bone are able to deliver sufficient concentrations of gentamicin to achieve bacterial inhibition within 2 weeks after surgery. In the case of uncemented revision of joint replacements, allogeneic bone can deliver therapeutic doses of gentamicin and peak levels immediately and a fortnight after implantation.

Epidemiology of campylobacteriosis in Denmark 2000-2015.

Campylobacter is the most frequently occurring cause of bacterial gastroenteritis in Europe. Unlike other zoonotic diseases, European-wide incidences of Campylobacter infections have increased during the past decade, resulting in a significant disease burden. In Denmark, campylobacteriosis is notifiable by laboratory and a unique registration system of electronic transfer and storage of notified Campylobacter cases linked to the national person register of age, gender and geographical location allows collection of comprehensive case data. Using national surveillance data, we describe Campylobacter infections in Denmark from 2000 to 2015, focusing on age-specific incidences, geography, seasonality and outbreaks. During the observed period, a total of 60,725 Campylobacter infections were registered with a mean annual incidence of 69.3 cases/100,000 population. From 2000 to 2014, the incidence of campylobacteriosis decreased by 20%, followed by an apparent increase of 20% from 2014 to 2015. Approximately one-third of cases were travel-related. Incidences were highest in males, young adults aged 20-29 years and children under 5 years of age. Generally, children under 10 years of age living in rural areas were at higher risk of infection. Infection patterns were seasonal with an increase from May to October, peaking in August. Outbreaks were identified each year, including four large waterborne outbreaks which all occurred following heavy rainfall events. For the most part, patterns of Campylobacter infection in Denmark during 2000 to 2015 remained remarkably constant and followed what is known about the disease with respect to demographic, temporal and spatial characteristics. To establish better targeted prevention and control measures, the current knowledge gaps regarding both Campylobacter microbiology (degree of clonal diversity and clustering) and the importance of different risk factors (food versus environment/climate) need to be filled.

Scattering of the Halo Nucleus

Angular distributions of the elastic, inelastic, and breakup cross sections of the halo nucleus ^{11}Be on ^{197}Au were measured at energies below (E_{lab}=31.9 MeV) and around (39.6 MeV) the Coulomb barrier. These three channels were unambiguously separated for the first time for reactions of ^{11}Be on a high-Z target at low energies. The experiment was performed at TRIUMF (Vancouver, Canada). The differential cross sections were compared with three different calculations: semiclassical, inert-core continuum-coupled-channels and continuum-coupled-channels ones with including core deformation. These results show conclusively that the elastic and inelastic differential cross sections can only be accounted for if core-excited admixtures are taken into account. The cross sections for these channels strongly depend on the B(E1) distribution in ^{11}Be, and the reaction mechanism is sensitive to the entanglement of core and halo degrees of freedom in ^{11}Be.

Epidemiological and serological investigation of a waterborne Campylobacter jejuni outbreak in a Danish town.

Following an unusually heavy rainfall in June 2009, a community-wide outbreak of Campylobacter gastroenteritis occurred in a small Danish town. The outbreak investigation consisted of (1) a cohort study using an e-questionnaire of disease determinants, (2) microbiological study of stool samples, (3) serological study of blood samples from cases and asymptomatic members of case households, and (4) environmental analyses of the water distribution system. The questionnaire study identified 163 cases (respondent attack rate 16%). Results showed a significant dose-response relationship between consumption of tap water and risk of gastroenteritis. Campylobacter jejuni belonging to two related flaA types were isolated from stool samples. Serum antibody levels against Campylobacter were significantly higher in cases than in asymptomatic persons. Water samples were positive for coliform bacteria, and the likely mode of contamination was found to be surface water leaking into the drinking-water system. This geographically constrained outbreak presented an ideal opportunity to study the serological response in persons involved in a Campylobacter outbreak. The serology indicated that asymptomatic persons from the same household may have been exposed, during the outbreak period, to Campylobacter at doses that did not elicit symptoms or alternatively had been exposed to Campylobacter at a time prior to the outbreak, resulting in residual immunity and thus absence of clinical signs.

A Diabetes-specific Oral Nutritional Supplement Improves Glycaemic Control in Type 2 Diabetes Patients.

AIMS: Reducing the intake of low molecular weight carbohydrates with artificial nutrition may lower glycaemic response in patients with diabetes. We evaluated effects of a diabetes-specific carbohydrate modified oral nutritional supplement (ONS) during 12 weeks administration in 40 elderly type 2 normal weight patients with diabetes with previous involuntary weight loss. METHODS: Prospective, randomised, double-blind, controlled trial. Patients ingested 2×200 ml/day diabetes-specific or isocaloric standard ONS (control) in addition to their regular diet. Parameters of glucose and lipid metabolism, functional and nutritional status were assessed at baseline, weeks 6 and 12. RESULTS: Postprandial glucose incremental area under the curve (iAUC0-240 min) was comparable between treatment groups on day 1 (467.9±268.4 vs. 505.1±206.1 mmol/l*min, n.s. - arithmetic means±standard deviation) and was significantly lower with the diabetes-specific ONS vs. controls in weeks 6 and 12 (355.2±115.8 vs. 634.9±205.9 and 364.9±153.1 vs. 743.4±202.7; both P<0.0001). Postprandial peak glucose was significantly lower with the diabetes-specific ONS vs. controls in weeks 6 and 12 (P<0.0001) and the decrease in HbA1c, (baseline to week 12) was markedly pronounced (P=0.028). There were no differences between groups in insulin, HOMA-IR, lipid parameters, nutritional and performance status. Body weight and body mass index (BMI) increased significantly over time in both groups. CONCLUSIONS: Administration of a diabetes-specific ONS for 12 weeks reduced postprandial glycaemia after ingestion of the study treatment and improved long-term glycaemic control in elderly patients with type 2 diabetes and involuntary weight loss, thereby reducing their risk for diabetes-associated long-term complications.

Parenteral trace element provision: recent clinical research and practical conclusions.

The aim of this systematic review (PubMed, www.ncbi.nlm.nih.gov/pubmed and Cochrane, www.cochrane.org; last entry 31 December 2014) was to present data from recent clinical studies investigating parenteral trace element provision in adult patients and to draw conclusions for clinical practice. Important physiological functions in human metabolism are known for nine trace elements: selenium, zinc, copper, manganese, chromium, iron, molybdenum, iodine and fluoride. Lack of, or an insufficient supply of, these trace elements in nutrition therapy over a prolonged period is associated with trace element deprivation, which may lead to a deterioration of existing clinical symptoms and/or the development of characteristic malnutrition syndromes. Therefore, all parenteral nutrition prescriptions should include a daily dose of trace elements. To avoid trace element deprivation or imbalances, physiological doses are recommended.

[Peppermint oil in the acute treatment of tension-type headache]. / Oleum menthae piperitae (Pfefferminzöl) in der Akuttherapie des Kopfschmerzes vom Spannungstyp.

Tension-type headache is the most frequent form of headache. The local topical treatment with peppermint oil (oleum menthae piperitae) has proven to be significantly more effective than placebo in controlled studies. Peppermint oil targets headache pathophysiology in multiple ways. The efficacy is comparable to that of acetylsalicylic acid or paracetamol. Solutions of 10 % peppermint oil in ethanol are licensed for the treatment of tension-type headache in adults and children above 6 years. It is included in treatment recommendations and guidelines by the respective professional societies and is regarded as a standard treatment for the acute therapy of tension-type headaches.

Discussion of "Combining Health Data Uses to Ignite Health System Learning".

This article is part of a For-Discussion-Section of Methods of Information in Medicine about the paper "Combining Health Data Uses to Ignite Health System Learning" written by John D. Ainsworth and Iain E. Buchan [1]. It is introduced by an editorial. This article contains the combined commentaries invited to independently comment on the paper of Ainsworth and Buchan. In subsequent issues the discussion can continue through letters to the editor. With these comments on the paper "Combining Health Data Uses to Ignite Health System Learning", written by John D. Ainsworth and Iain E. Buchan [1], the journal seeks to stimulate a broad discussion on new ways for combining data sources for the reuse of health data in order to identify new opportunities for health system learning. An international group of experts has been invited by the editor of Methods to comment on this paper. Each of the invited commentaries forms one section of this paper.

In vitro evaluation of novel antimicrobial coatings for surgical sutures using octenidine.

BACKGROUND: Sutures colonized by bacteria represent a challenge in surgery due to their potential to cause surgical site infections. In order to reduce these type of infections antimicrobially coated surgical sutures are currently under development. In this study, we investigated the antimicrobial drug octenidine as a coating agent for surgical sutures. To achieve high antimicrobial efficacy and required biocompatibility for medical devices, we focused on optimizing octenidine coatings based on fatty acids. For this purpose, antimicrobial sutures were prepared with either octenidine-laurate or octenidine-palmitate at 11, 22, and 33 µg/cm drug concentration normalized per length of sutures. Octenidine containing sutures were compared to the commercial triclosan-coated suture Vicryl® Plus. The release of octenidine into aqueous solution was analyzed and long-term antimicrobial efficacy was assessed via agar diffusion tests using Staphylococcus aureus. For determining biocompatibility, cytotoxicity assays (WST-1) were performed using L-929 mouse fibroblasts. RESULTS: In a 7 days elution experiment, octenidine-palmitate coated sutures demonstrated much slower drug release (11 µg/cm: 7%; 22 µg/cm: 5%; 33 µg/cm: 33%) than octenidine-laurate sutures (11 µg/cm: 82%; 22 µg/cm: 88%; 33 µg/cm: 87%). Furthermore sutures at 11 µg/cm drug content were associated with acceptable cytotoxicity according to ISO 10993-5 standard and showed, similar to Vicryl® Plus, relevant efficacy to inhibit surrounding bacterial growth for up to 9 days. CONCLUSIONS: Octenidine coated sutures with a concentration of 11 µg/cm revealed high antimicrobial efficacy and biocompatibility. Due to their delayed release, palmitate carriers should be preferred. Such coatings are candidates for clinical testing in regard to their safety and efficacy.