Uncovering the dynamics of cellular responses induced by iron-carbohydrate complexes in human macrophages using quantitative proteomics and phosphoproteomics.

Iron-carbohydrate complexes are widely used to treat iron deficiencies. Macrophages play a crucial role in the uptake and fate of these nanomedicines, however, how complexed iron carbohydrates are taken up and metabolized by macrophages is still not fully understood. Using a (phospho-)proteomics approach, we assessed differences in protein expression and phosphorylation in M2 macrophages triggered by iron sucrose (IS). Our results show that IS alters the expression of multiple receptors, indicative of a complex entry mechanism. Besides, IS induced an increase in intracellular ferritin, the loss of M2 polarization, protective mechanisms against ferroptosis, and an autophagic response. These data indicate that macrophages can use IS as a source of iron for its storage and later release, however, the excess of iron can cause oxidative stress, which can be successfully regulated by the cells. When comparing IS with ferric carboxymaltose (FCM) and iron isomaltoside-1000 (IIM), complexes with a higher carbohydrate ligand stability, we observed that FCM and IIM are metabolized at a slower rate, and trigger M2 polarization loss to a lower extent. These results indicate that the surface characteristics of the iron-carbohydrate complexes may influence the cell responses. Our data show that the application of (phospho-)proteomics can lead to a better understanding of metabolic processes, including the uptake, biodegradation and bioavailability of nanomedicines.

Targeting tight junctions to fight against viral neuroinvasion.

The clinical impact of viral neuroinvasion on the central nervous system (CNS) ranges from barely detectable to deadly, including acute and chronic outcomes. Developing innovative therapeutic strategies is important to mitigate virus-induced neurological and psychiatric disorders. A key gatekeeper to the CNS is the neurovascular unit (NVU), a major obstacle to viral neuroinvasion and antiviral therapies. The NVU isolates the brain from the blood through firm sealing operated by the tight junctions (TJs) of endothelial cells. Here, we make the thought-provoking assumption that TJs can be targets to prevent or treat viral neuroinvasion and resulting disorders. This review aims at defining the conceptual diverse mode of actions of such approaches, evaluates their feasibility, and discusses future challenges in the field.

Neutropthil-to-Lymphocyte Ratio as a Predictor of Postsurgical Intraabdominal Abscess in Children Operated for Acute Appendicitis.

Aim of the study: Postoperative intra-abdominal abscess (PIAA) is a frequent and severe complication of acute appendicitis (AA) with peritonitis. The neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker that has been related to the development of peritonitis; however, its diagnostic role in predicting PIAA has not been evaluated. This is the first study that analyzes the usefulness of NLR as a predictor of PIAA in children operated for AA. Material and Methods: Retrospective observational study in children operated for AA in our institution during 2017-2018. Patients aged under 5 years or with incomplete laboratory determinations at hospital admission (blood count, C-reactive protein, and fibrinogen) were excluded. Demographic and laboratory parameters and the development of PIAA were analyzed. NLR was calculated by dividing the absolute number of neutrophils by the absolute number of lymphocytes. By means of ROC curves, we determined the sensitivity and specificity of the different laboratory parameters to predict the development of PIAA. Results: A total of 388 patients aged 10.5 ± 2.9 year were included. Twenty (5.2%) developed PIAA. NLR presented an area under the curve (AUC) of 0.85, significantly higher than the determination of leukocytes (AUC 0.69, p < 0.001), neutrophils (AUC 0.74, p < 0.001), fibrinogen (AUC 0.68, p < 0.001) and C-reactive protein (AUC 0.73, p < 0.001). We estimated the optimal cut-off point of NLR > 10.5, with a sensitivity of 85% and a specificity of 75.2%. Conclusions: NLR is the laboratory parameter with the highest sensitivity and specificity for predicting the development of PIAA in children operated for AA. It can be useful as a predictor of worse postoperative course.

Pancreatic Kaposiform Hemangioendothelioma Not Responding to Sirolimus.

Background Kaposiform hemangioendothelioma (KHE) is a vascular tumor frequently associated with Kasabach-Merritt phenomenon (KMP), characterized by severe thrombocytopenia and consumptive coagulopathy. Visceral involvement in KHE is rare. In our recent experience, sirolimus has shown to be an effective treatment in cutaneous KHE, becoming indeed the treatment of choice in KMP. We report a case of pancreatic KHE associated with KMP and refractory to sirolimus. Case Report A 4-month-old infant is referred for obstructive jaundice (10 mg/dL conjugated bilirubin) secondary to vascular pancreatic tumor. Magnetic resonance (MR) and immunohistochemistry were compatible with KHE, but the tumor was considered unresectable. We initiated sirolimus (0.8 mg/m 2 /12 h) to treat KMP, and interventional radiology was performed for percutaneous biliary diversion. This procedure prompted KMP (platelets: 51,000/µL). Sirolimus treatment for 7 days showed no effect; therefore, we started our VAT protocol (vincristine/aspirine/ticlopidin) with great response after 10 days (platelets: 3,70,000/µL). Three months later, percutaneous biliary diversion was replaced by a biliary stent. The tumor disappeared leaving fibrosis and dilatation of biliary tract needing hepaticojejunostomy 6 months later. Discussion It is difficult to establish protocols for an unusual presentation of a tumor with different targets. This is a reason collaborative multicenter studies should be performed. Management of obstructive jaundice secondary to a tumor that usually regresses in 10 years is an added challenge; therefore, the management should be led by a multidisciplinary team. Sirolimus treatment in cutaneous KHE has been described as successful in the literature, as well as in our own experience; however, it failed in our first patient with visceral KHE. We need to investigate the different response to pharmacological agents in tumors with similar histopathology, but with visceral involvement.

Characterisation of hydration and nanophase separation during the temperature response in hydrophobic/hydrophilic elastin-like polypeptide (ELP) diblock copolymers.

To understand the complex nanoscale dehydration process during the lower critical solution temperature (LCST) based inverse phase transition of a class of thermoresponsive biopolymers, diblock elastin-like polypeptides (ELPs) were investigated by spin probing continuous wave electron paramagnetic resonance (CW EPR) spectroscopy. The diblock copolymers composed of a hydrophobic block and a hydrophilic block showed different mechanisms of a temperature-driven phase transition. While the phase transition temperature is a function of the hydrophobic mass fraction of the diblock ELPs, the hydrophilic block length determines the molecular structure of the polymer aggregates formed above the transition temperature. When the weight ratio of hydrophilic block length to hydrophobic block length is greater than or equal to 0.3, the polymer aggregates consist of a hydrophobic core and a hydrophilic corona. The interface of these two regions become permeable at temperatures above the transition temperature. In case of smaller ratios, the aggregating hydrophobic parts of the polymer enclose the hydrated hydrophilic blocks, that are too small to form a hydrophilic corona, leading to bigger and less dense aggregates of higher polarity.

Rupatadine: global safety evaluation in allergic rhinitis and urticaria.

INTRODUCTION: Rupatadine is a second-generation H1-antihistamine with dual affinity for histamine H1 and PAF receptors. Rupatadine is indicated for the treatment of allergic rhinitis and urticaria. AREAS COVERED: A Medline search was conducted to identify preclinical and clinical studies of rupatadine. This was supplemented with additional articles obtained from online sources. The focus of this review is on the safety profile of rupatadine. EXPERT OPINION: The review of these data indicates that rupatadine is highly selective for histamine H1-receptors, exhibits additional PAF antagonism in in vitro and in vivo studies, does not cross the blood-brain barrier, and has similar adverse events comparable with other second-generation antihistamines. Rupatadine is a safe and well tolerated drug in patients over 2 years old, with no central nervous system or cardiovascular effects and it can be taken with or without foods.

Safety evaluation of desloratadine in allergic rhinitis.

INTRODUCTION: Desloratadine is a biologically active metabolite of second-generation antihistamine loratadine. It is also indicated for the treatment of allergic diseases, including allergic rhinitis. AREAS COVERED: A Medline search was conducted to identify preclinical and clinical studies of desloratadine. This was supplemented with additional articles obtained from online sources. The focus of this review is on the safety profile of desloratadine. EXPERT OPINION: The review of these data indicates that the safety profile of desloratadine is similar to other second-generation antihistamines. Desloratadine is highly selective for histamine H1-receptors, does not cross the blood-brain barrier (BBB), and has minimal adverse events (very low sedation rate), with a better safety and tolerability than first-generation antihistamines. Desloratadine is safe and well tolerated without having central nervous system (CNS) or cardiovascular effects and with low drug interaction.

Impact of sleep as a specific marker of quality of life in allergic rhinitis.

Allergic rhinitis (AR) is a common disorder, which represents a considerable burden both on individual patients and society. It is associated with bothersome symptoms, which may impair usual daily activities, sleep quality, and productivity. Associated with impaired sleep, quality of life is significantly impaired in AR patients. AR significantly contributes to sleep-disordered breathing through multiple mechanisms, with the greatest impact mediated through nasal obstruction. Sleep impairment is very common in AR patients and has a significant impact on disease-specific measures of general health and quality of life. The degree of sleep disturbance is directly related to the severity of the disease. Nasal congestion also demonstrates circadian rhythm and positional variability, worsening during nighttime hours and in supine position. Increased sleep disordered events lead to poor sleep with fatigue and daytime somnolence, impaired performance, productivity and social functioning, and an increased risk of associated diseases.

Biological width following immediate implant placement in the dog: flap vs. flapless surgery.

OBJECTIVE: To assess the marginal soft tissue healing process after flap or flapless surgery in immediate implant placement in a dog model. MATERIAL AND METHODS: This study was carried out on five Beagle dogs. Four implants were placed in the lower jaw in each dog immediately after tooth extraction. Flap surgery was performed before the extraction on one side (control) and flapless on the other (test). After 3 months of healing, the dogs were sacrificed and prepared for histological analysis. RESULTS: Ten implants were placed in each group. Two failed (one of each group). The length of the junctional epithelium in the flapless group was 2.54 mm (buccal) and 2.11 mm (lingual). In the flap group, the results were very similar: 2.59 mm (buccal) and 2.07 mm (lingual), with no significant differences observed between the groups. The length of the connective tissue in the flapless group was 0.68 mm (buccal) and 0.54 mm (lingual), and 1.09 mm at the buccal and 0.91 mm at the lingual aspect in the flap group, with no significant differences between groups. The difference between the mean distance from the peri-implant mucosa margin to the first bone-implant contact at the buccal aspect was significant between both groups (3.02 mm-flapless and 3.69 mm flap group). However, this difference was mostly due to the Pm3 group (flapless: 2.95/flap: 3.76) because no difference could be detected in the Pm4 group. Both groups showed minimal recession, with no significant differences between groups (flapless group - 0.6 mm buccal and 0.42 mm lingual; flap group - 0.67 and 0.13 mm). CONCLUSION: The clinical evaluation of immediate implant placement after 3 months of healing indicated that buccal soft tissue retraction was lower in the flapless group than in the flap group, without significant differences. The mean values of the biological width longitudinal dimension at the buccal aspect were higher in the flap group than in the flapless group, this difference being mostly due to the Pm3, probably because of a thinner biotype in this region.

Ridge alterations following immediate implant placement in the dog: flap versus flapless surgery.

OBJECTIVE: To assess the healing process after flap or flapless surgery in immediate implant placement. MATERIAL AND METHODS: This study was carried out on five Beagle dogs. Four implants were placed in the lower jaw in each dog immediately after tooth extraction. Flap surgery was performed before the extraction on one side (control), and flapless on the contrary (test). After 3 months of healing, the dogs were sacrificed and prepared for histological analysis. RESULTS: Ten implants were placed in each group. Two failed (one of each group). The percentage of bone-implant contact was very similar in both groups: 64.8% and 65.1% for the flap and the flapless group, respectively. The difference between the mean distance from the peri-implant mucosa margin to the first bone-implant contact at the buccal aspect was statistically significant between both groups (3.02 mm. flapless and 3.69 mm. flap group). The mean first bone-implant contact at the buccal aspect was located in relation to the sand-blasted and acid-etched level at 0.82 mm for the flapless group and 1.33 mm for the flap group. This difference was not statistically significant. CONCLUSION: Flapless immediate implant surgery produces a significant reduction in the vestibular biologic width and a minor reduction in buccal bone plate resorption.

Sonic hedgehog is produced by follicular dendritic cells and protects germinal center B cells from apoptosis.

The Hedgehog (Hh) signaling pathway is involved in the development of many tissues during embryogenesis, but has also been described to function in adult self-renewing tissues. In the immune system, Sonic Hedgehog (Shh) regulates intrathymic T cell development and modulates the effector functions of peripheral CD4(+) T cells. In this study we investigate whether Shh signaling is involved in peripheral B cell differentiation in mice. Shh is produced by follicular dendritic cells, mainly in germinal centers (GCs), and GC B cells express both components of the Hh receptor, Patched and Smoothened. Blockade of the Hh signaling pathway reduces the survival, and consequently the proliferation and Ab secretion, of GC B cells. Furthermore, Shh rescues GC B cells from apoptosis induced by Fas ligation. Taken together, our data suggest that Shh is one of the survival signals provided by follicular dendritic cells to prevent apoptosis in GC B cells.