Osteogenic and angiogenic potential of molybdenum-containing mesoporous bioactive glass nanoparticles: An ionic approach to bone tissue engineering.

Biomaterials intended for application in bone tissue engineering (BTE) ideally stimulate osteogenesis and angiogenesis simultaneously, as both mechanisms are of critical importance for successful bone regeneration. Mesoporous bioactive glass nanoparticles (MBGNs) can be tailored towards specific biological needs, for example by addition of ions like Molybdenum (Mo). While Mo has been shown to enhance osteogenic differentiation of human bone marrow-derived mesenchymal stromal cells (BMSCs) as well as their ability to form and mature a primitive osseous extracellular matrix (ECM), there are contradictory findings regarding its impact on angiogenesis. In this study, the effects of Mo-MBGNs (mol%: 70 SiO2, 25 CaO, 5 MoO3) on viability, proliferation, osteogenic differentiation, ECM formation and angiogenic response of BMSCs were compared to undoped MBGNs (in mol%: 70 SiO2, 30 CaO) and a control group of BMSCs. Furthermore, a human umbilical vein endothelial cells tube formation assay and a chorioallantoic membrane-assay using fertilized chicken eggs were used to analyze angiogenic properties. Mo-MBGNs were cytocompatible and promoted the proliferation of BMSCs. Furthermore, Mo-MBGNs showed promising osteogenic properties as they enhanced osteogenic differentiation, ECM formation and maturation as well as the gene expression and protein production of relevant osteogenic factors in BMSCs. However, despite the promising outcome on osteogenic properties, the addition of Mo to MBGNs resulted in anti-angiogenic effects. Due to the high relevance of vascularization in-vivo, the anti-angiogenic properties of Mo-MBGNs might hamper their osteogenic properties and therefore might restrict their performance in BTE applications. These limitations can be overcome by the addition of ions with distinct pro-angiogenic properties to the Mo-MBGNs-composition. Due to their promising osteogenic properties, Mo-MBGNs constitute a suitable basis for further research in the field of ionic (growth factor free) BTE.

The role of artificial intelligence in informed patient consent for radiotherapy treatments-a case report.

Recent advancements in large language models (LMM; e.g., ChatGPT (OpenAI, San Francisco, California, USA)) have seen widespread use in various fields, including healthcare. This case study reports on the first use of LMM in a pretreatment discussion and in obtaining informed consent for a radiation oncology treatment. Further, the reproducibility of the replies by ChatGPT 3.5 was analyzed. A breast cancer patient, following legal consultation, engaged in a conversation with ChatGPT 3.5 regarding her radiotherapy treatment. The patient posed questions about side effects, prevention, activities, medications, and late effects. While some answers contained inaccuracies, responses closely resembled doctors' replies. In a final evaluation discussion, the patient, however, stated that she preferred the presence of a physician and expressed concerns about the source of the provided information. The reproducibility was tested in ten iterations. Future guidelines for using such models in radiation oncology should be driven by medical professionals. While artificial intelligence (AI) supports essential tasks, human interaction remains crucial.

Microplastics in stomach contents of juvenile Patagonian blennies (Eleginops maclovinus).

Microplastics are one of the major environmental issues that need to be addressed because they are starting to impact food chains and are also affecting human populations. The size, colour, form, and abundance of microplastics in young blennies of the species Eleginops maclovinus were examined in the current study. While the stomach contents of 70 % of the studied individuals contained microplastics, 95 % of them included fibres. Individual size and the largest particle size that can be eaten, which ranges between 0.09 and 1.5 mm present no statistical correlation. The quantity of particles taken in by each individual does not change with size. The most present microfibers colours were blue and red. Sampled fibres were analysed with FT-IR and no natural fibres were detected, proving the synthetic origin of the detected particles. These findings suggest that protected coastlines create conditions that favour the encounter of microplastics increasing local wildlife exposure to microplastics, raising the danger of their ingestion with potential physiological, ecological, economical and human health consequences.

Effectiveness of the sesquiterpene (-)-α-bisabolol in dogs with naturally acquired canine leishmaniosis: an exploratory clinical trial.

The use of natural products is a promising approach for treating visceral leishmaniosis. (-)-α-Bisabolol is a sesquiterpene that have been proved active in vivo on Leishmania infantum-infected mice without showing toxicity. A single-centre, parallel-group, randomized, exploratory study was designed to assess its efficacy in a canine leishmaniosis model involving naturally infected dogs. In this clinical trial, 12 dogs were allocated into two groups and were treated with either meglumine antimoniate (100 mg/kg) through subcutaneous route or (-)-α-bisabolol (30 mg/kg) through oral route for two treatment series of 30 days, separated by a 30-day interval. A 4-month follow-up period was established as well. Parasite loads in bone marrow, lymph node and blood were estimated through quantitative PCR. Antibody titres were determined through immunofluorescence antibody test and cytokine expression values were estimated through real-time reverse transcription-PCR. Treatment safety was assessed through the evaluation of weight, gastrointestinal alterations and hematological and biochemical parameters in blood. Analyses were performed before and after treatment, and after a 4-months follow-up period. Treatment with the sesquiterpene was effective at decreasing parasite loads and increasing gamma-interferon expression level. Dogs treated with (-)-α-bisabolol did not show any toxicity sign. These results were better than those obtained using the reference drug, meglumine antimoniate. The natural compound seemed to induce a Th1 immune response that led to parasitological and clinical improvement without showing any safety issue, suggesting a high potential for the treatment of canine and human visceral leishmaniosis.

Extracellular matrix mimicking scaffold promotes osteogenic stem cell differentiation: A new approach in osteoporosis research.

BACKGROUND: Osteoporosis is a common metabolic disease, with mesenchymal stem cells discussed to play an important role in its pathomechanism. For in vitro osteoporosis studies, selection of adequate culture conditions is mandatory so as to preserve cell properties as far as possible. A suitable cell culture surface would ideally provide reproducible experimental conditions by resembling those in-vivo. OBJECTIVE: Generating an improved growth surface for osteogenic differentiation of human bone marrow derived mesenchymal stem cells (hBMSCs). METHODS: We modified electrospun gelatine meshes with hydroxyapatite nanopowder. The potential beneficial impact of the ensuing culture conditions were evaluated by cultivating and comparing the growth of cells from osteoporotic and non-osteoporotic donors on either hydroxyapatite-gelatine (HA) meshes, pure gelatine meshes, or 2D standard tissue culture surfaces. RESULTS: After 21 days of differentiation, cells grown on pure or HA-gelatine meshes showed significantly higher mineralization levels compared to cells cultured in standard conditions. The amount of mineralization varied considerably in hBMSC cultures of individual patients but showed no significant difference between stem cells obtained from osteoporotic or non-osteoporotic donors. CONCLUSIONS: Overall, these results indicate that the use of HA-gelatine meshes as growth surfaces may serve as a valuable tool for cultivation and differentiation of mesenchymal stem cells along the osteogenic lineage, facilitating future research on osteoporosis and related issues.

The sesquiterpene (-)-α-bisabolol is active against the causative agents of Old World cutaneous leishmaniasis through the induction of mitochondrial-dependent apoptosis.

Cutaneous leishmaniasis treatment remains challenging due to the absence of a satisfactory treatment. The screening of natural compounds is a valuable strategy in the search of new drugs against leishmaniasis. The sesquiterpene (-)-α-bisabolol is effective in vivo against visceral leishmaniasis due to Leishmania infantum, but its mechanism of action remains elusive. The aim of this study is to validate this promising compound against the causative species of Old World cutaneous leishmaniasis and to get an insight into its antileishmanial mode of action. The compound was evaluated on L. tropica promastigotes and intracellular amastigotes using bone marrow-derived macrophages and its cytotoxicity was evaluated on L929 fibroblasts. The reactive oxygen species generation was evaluated using a sensitive probe. Mitochondrial depolarization was assessed evaluating the fluorescence due to rhodamine 123 in a flow cytometer. Apoptosis was investigated by measuring the fluorescence due to annexin V and propidium iodide in a flow cytometer. The ultrastructure of treated promastigotes and intracellular amastigotes was analysed through transmission electron microscopy. (-)-α-Bisabolol was active against L. tropica intracellular amastigotes displaying an inhibitory concentration 50 % of 25.2 µM and showing low cytotoxicity. This compound induced time and dose-dependent oxidative stress, mitochondrial depolarization and phosphatidilserine externalization (a marker of apoptosis). These effects were noticed at a low concentration and short exposure time. In the ultrastructural analyses, the treated parasites showed mitochondrial disruption, presence of electron-dense structures and chromatin condensation. These results suggest that this natural compound induces oxidative stress and mitochondrial-dependent apoptosis on Leishmania without disturbing the plasma membrane.

Activation of the lectin pathway of complement by cardiopulmonary bypass contributes to the development of systemic inflammatory response syndrome after paediatric cardiac surgery.

The systemic inflammatory response is a challenge in the management of paediatric patients undergoing cardiac surgery. Although multi-factorial, a contribution by the lectin pathway of complement activation has been postulated. We therefore investigated the changes in serum levels of mannose binding lectin (MBL) and activities of MBL-MBL-associated serine protease (MASP)-1 and MBL-MASP-2 complexes immediately before and during surgery, throughout the first postoperative day and at discharge from the hospital. These changes were analysed in relation to postoperative complications. Blood samples were obtained from 185 children with congenital heart disease undergoing surgical correction with the use of cardiopulmonary bypass: preoperatively (MBL-1), 15 min after initiation of cardiopulmonary bypass (CPB) (MBL-E), 30 min (MBL-2), 4 h (MBL-3), 12 h (MBL-4) and 24 h (MBL-5) post-CPB and at discharge from hospital (MBL-K). Alterations in serum MBL levels were calculated as a ratio of its serum level at subsequent time-points (MBL-2, -3, -4, -5) to the preoperative (MBL-1) value. Decreases in MBL and MBL-MASP complexes were observed in all samples, correlating with a decrease in C4 and increase in C4a, confirming activation of the lectin pathway. Changes in MBL levels between children with an uncomplicated postoperative course and those suffering from infection or low cardiac output syndrome did not differ significantly, but significant differences were observed between the SIRS and non-SIRS groups. Paediatric cardiac surgery with the use of cardiopulmonary bypass activates the complement system via the lectin pathway and the latter contributes to the development of the post-bypass systemic inflammatory response.

(-)-α-Bisabolol, a Promising Oral Compound for the Treatment of Visceral Leishmaniasis.

The aim of the present study was to assess the in vitro and in vivo activity of (-)-α-bisabolol (1) against the etiological agents of visceral leishmaniasis. Bone-marrow-derived macrophages were infected with Leishmania infantum or L. donovani promastigotes and incubated with (-)-α-bisabolol at different concentrations. Pentamidine isethionate and meglumine antimoniate were used as reference drugs. Inhibitory concentration 50% (IC50) and cytotoxic concentration 50% (CC50) were calculated. Balb/c mice were infected intraperitoneally with stationary-phase promastigotes. They were treated with (-)-α-bisabolol at different doses orally, meglumine antimoniate at 104 mg Sb(V)/kg, or a combination of both. (-)-α-Bisabolol proved to be innocuous to mammal cells and active against L. infantum and L. donovani intracellular amastigotes (IC50 55 and 39 µM, respectively). Compound 1 also proved to be active in an in vivo model of visceral leishmaniasis due to L. infantum, as it reduced parasite load in the spleen and liver by 71.60% and 89.22%, respectively, at 200 mg/kg without showing toxicity. (-)-α-Bisabolol (1) is a nontoxic compound that was proven to be active against visceral leishmaniasis in an in vivo murine model orally. It was more effective than meglumine antimoniate at reducing spleen parasite load and as effective as this antimonial drug in the liver.

Human exposure to rabid free-ranging cats: a continuing public health concern in Pennsylvania.

Rabid free-ranging cats have been a public health concern in Pennsylvania since raccoon variant rabies first was recognized in the state in the early 1980s. Over the last decade, between 1.5 and 2.5% of cats submitted to Pennsylvania's state laboratories for rabies testing have been positive. In this report, we describe the extent of rabies in free-ranging cats in Pennsylvania. We also present two examples of human exposure to rabid free-ranging cats that occurred in Pennsylvania during 2010-2011 and the public health actions taken to address rabies exposure in the humans and animals. We then describe the concerns surrounding the unvaccinated and free-ranging cat population in Pennsylvania and possible options in managing this public and animal health problem.

Yersinia enterocolitica infections associated with improperly pasteurized milk products: southwest Pennsylvania, March-August, 2011.

In July 2011, a cluster of Yersinia enterocolitica infections was detected in southwestern Pennsylvania, USA. We investigated the outbreak's source and scope in order to prevent further transmission. Twenty-two persons were diagnosed with yersiniosis; 16 of whom reported consuming pasteurized dairy products from dairy A. Pasteurized milk and food samples were collected from this dairy. Y. enterocolitica was isolated from two products. Isolates from both food samples and available clinical isolates from nine dairy A consumers were indistinguishable by pulsed-field gel electrophoresis. Environmental and microbiological investigations were performed at dairy A and pasteurization deficiencies were noted. Because consumption of pasteurized milk is common and outbreaks have the potential to become large, public health interventions such as consumer advisories or closure of the dairy must be implemented quickly to prevent additional cases if epidemiological or laboratory evidence implicates pasteurized milk as the outbreak source.

Assessment for possible healthcare-associated transmission of a new variant influenza virus--Pennsylvania, August 2011.

In August 2011, one of the earliest cases of influenza A(H3N2) variant [A(H3N2)v] virus infection was hospitalized with severe illness. To investigate the potential for healthcare-associated transmission of influenza A(H3N2)v, we evaluated both healthcare providers and patient contacts of the case. We found that healthcare-associated transmission was unlikely.

Concurrent 2009 pandemic influenza A (H1N1) virus infection in ferrets and in a community in Pennsylvania.

We report a fall 2010 cluster of pandemic influenza A/H1N1 (pH1N1) infections in pet ferrets in Lehigh Valley region of Pennsylvania. The ferrets were associated with one pet shop. The influenza cluster occurred during a period when the existing human surveillance systems had identified little to no pH1N1 in humans in the Lehigh Valley, and there were no routine influenza surveillance systems for exotic pets. The index case was a 2.5-month-old neutered male ferret that was presented to a veterinary clinic with severe influenza-like illness (ILI). In response to laboratory notification of a positive influenza test result, and upon request from the Pennsylvania Department of Health (PADOH), the Pennsylvania Department of Agriculture (PDA) conducted an investigation to identify other ill ferrets and to identify the source and extent of infection. PDA notified the PADOH of the pH1N1 infection in the ferrets, leading to enhanced human surveillance and the detection of pH1N1 human infections in the surrounding community. Five additional ferrets with ILI linked to the pet shop were identified. This simultaneous outbreak of ferret and human pH1N1 demonstrates the important link between animal health and public health and highlights the potential use of veterinary clinics for sentinel surveillance of diseases shared between animals and humans.

Managing unforeseen events in anesthesia: collective trade-off between "understanding" and "doing".

This study aims to describe how anesthesia teams handle unforeseen events that may affect the patients' health. More precisely, it investigates the mechanisms of decisions made by anesthesia teams to manage unthought-of situations, i.e. situations that have not been foreseen as "possible" ones before their occurrence. An empirical study, based on the analysis of simulated situations, was conducted in a pediatric anesthesia service of a university hospital in France. The results highlighted three ways of managing unthought-of situations (determined management, cautious management and overwhelmed management). They support the hypothesis of a collective cognitive trade-off, whereby teams would behave as virtual operators, with their own collective trade-off between "understanding" and "doing". The discussion of the results questions the assessment criteria, the safety perspectives we adopt and the possible ways to improve the management of unforeseen situations.

Fatal pandemic (H1N1) 2009 influenza A virus infection in a Pennsylvania domestic cat.

We report the earliest recognized fatality associated with laboratory-confirmed pandemic H1N1 (pH1N1) influenza in a domestic cat in the United States. The 12-year old, indoor cat died on 6 November 2009 after exposure to multiple family members who had been ill with influenza-like illness during the peak period of the fall wave of pH1N1 in Pennsylvania during late October 2009. The clinical presentation, history, radiographic, laboratory and necropsy findings are presented to assist veterinary care providers in understanding the features of this disease in cats and the potential for transmission of infection to pets from infected humans.

[2-year follow-up examinations (Bayley II) in infants born at <32 weeks in a German perinatal center]. / 2-Jahres-Nachuntersuchung (Bayley) sehr kleiner Frühgeborener der Jahrgänge 2004-2007: Ergebnisse und Vollständigkeitsanalyse eines Perinatalzentrums.

BACKGROUND: Since 2008, follow-up examinations at 2 years of age with the standardized Bayley II test have become obligatory in Germany for all very low birth weight infants. AIM: We already performed such examinations before 2006. Here, we compared our data and the completeness of our examinations before and after the introduction of the obligatory 2-year follow-up. PATIENTS: From 2004-2007, 372 infants <1500 g or <32 weeks were discharged alive from our center, 19 infants died during their initial hospital stay, 2 after discharge. RESULTS: 271 patients participated in the follow-up examination at age 2 years, with the proportion of participating infants increasing from 64% to 84% after the introduction of obligatory tests. 75% of infants showed a normal development, while 4% had a severe impairment (defined as being blind (1), deaf (1) or having cerebral palsy (6), the CP rate thus being 2%). 49% of infants completed the Bayley test; the mean MDI was 100.3 (SD 10.6). There were no significant qualtitative differences in test results with the introduction of the obligatory test. CONCLUSIONS: The completeness of our follow-up increased over the years. In comparison with international data we found a low rate of severely impaired, deaf or blind VLBW infants.

NK cells and CD1d-restricted NKT cells respond in different ways with divergent kinetics to IL-2 treatment in primary HIV-1 infection.

Cytokine immunotherapy is being evaluated as adjunct treatment in infectious diseases. The effects on innate and adaptive immunity in vivo are insufficiently known. Here, we investigate whether combination treatment with antiretroviral therapy (ART) and Interleukin-2 (IL-2) of patients with primary HIV-1 infection induces sustained increases in circulating NKT cell and NK cell numbers and effector functions and investigate how changes are coordinated in the two compartments. Patients with primary HIV-1 infection starting ART were analyzed for numbers, phenotype and function of NKT cells, NK cells and dendritic cells (DC) in peripheral blood before, during and after IL-2 treatment. NKT cells expanded during IL-2 treatment as expected from previous studies. However, their response to α-galactosyl ceramide antigen were retained but not boosted. Myeloid DC did not change their numbers or CD1d-expression during treatment. In contrast, the NK cell compartment responded with rapid expansion of the CD56(dim) effector subset and enhanced IFNγ production. Expansions of NKT cells and NK cells retracted back towards baseline values at 12 months after IL-2 treatment ended. In summary, NKT cells and NK cells respond to IL-2 treatment with different kinetics. Effects on cellular function are distinct between the cell types and the effects appear not to be sustained after IL-2 treatment ends. These results improve our understanding of the effects of cytokine immunotherapy on innate cellular immunity in early HIV-1 infection.

Are recommended phototherapy thresholds safe enough for extremely low birth weight (ELBW) infants? A report on 2 ELBW infants with kernicterus despite only moderate hyperbilirubinemia.

Two extremely low birth weight (ELBW) infants developed characteristic signs of kernicterus at 4 and 8 months corrected age despite only moderate neonatal hyperbilirubinemia (peak serum bilirubin <10 g/dl) and phototherapy being applied according to current guidelines. Both girls were from twin pregnancies and had fetal complications (donor in a twin-twin transfusion syndrome and acardius-acranius malformation in the second twin, respectively), connatal anemia (initial hematocrit 30%), and mild acidosis after birth. They had been neurologically normal at discharge except for abnormal otoacustic emissions (OAE). At the time kernicterus was diagnosed, both infants were nearly deaf, showed severe psychomotor retardation with dystonic features and had marked bilateral hyperintensities in the globus pallidum on MRI. Based on these and similar cases from the literature, we question whether current phototherapy guidelines are appropriate for high-risk ELBW infants. Lower thresholds may be preferable, at least if additional risk factors, such as anemia, are present.

Activity of (-)alpha-bisabolol against Leishmania infantum promastigotes.

Many of the drugs used to treat leishmaniasis are associated with numerous adverse effects. Agents of natural origin have shown activity against different parasites. With this background, an in vitro study was conducted on the activity of (-)alpha-bisabolol, the principal component of Chamomilla recutita essential oil, against Leishmania infantum promastigotes, the main species responsible for human leishmaniasis in Spain. At the two highest concentrations tested (1000 and 500mug/ml), (-)alpha-bisabolol and pentamidine (control agent) achieved 100% inhibition of L. infantum promastigote. These in vitro data can be considered promising in support of the therapeutic use of (-)alpha-bisabolol preparations to treat leishmaniasis caused by L. infantum species.