A Review of the EUSO-Balloon Pathfinder for the JEM-EUSO Program.

EUSO-Balloon is a pathfinder for JEM-EUSO, the mission concept of a spaceborne observatory which is designed to observe Ultra-High Energy Cosmic Ray (UHECR)-induced Extensive Air Showers (EAS) by detecting their UltraViolet (UV) light tracks "from above." On August 25, 2014, EUSO-Balloon was launched from Timmins Stratospheric Balloon Base (Ontario, Canada) by the balloon division of the French Space Agency CNES. After reaching a floating altitude of 38 km, EUSO-Balloon imaged the UV light in the wavelength range ∼290-500 nm for more than 5 hours using the key technologies of JEM-EUSO. The flight allowed a good understanding of the performance of the detector to be developed, giving insights into possible improvements to be applied to future missions. A detailed measurement of the photoelectron counts in different atmospheric and ground conditions was achieved. By means of the simulation of the instrument response and by assuming atmospheric models, the absolute intensity of diffuse light was estimated. The instrument detected hundreds of laser tracks with similar characteristics to EASs shot by a helicopter flying underneath. These are the first recorded laser tracks measured from a fluorescence detector looking down on the atmosphere. The reconstruction of the direction of the laser tracks was performed. In this work, a review of the main results obtained by EUSO-Balloon is presented as well as implications for future space-based observations of UHECRs.

Pathological and Therapeutic Approach to Endotoxin-Secreting Bacteria Involved in Periodontal Disease.

It is widely recognized that periodontal disease is an inflammatory entity of infectious origin, in which the immune activation of the host leads to the destruction of the supporting tissues of the tooth. Periodontal pathogenic bacteria like Porphyromonas gingivalis, that belongs to the complex net of oral microflora, exhibits a toxicogenic potential by releasing endotoxins, which are the lipopolysaccharide component (LPS) available in the outer cell wall of Gram-negative bacteria. Endotoxins are released into the tissues causing damage after the cell is lysed. There are three well-defined regions in the LPS: one of them, the lipid A, has a lipidic nature, and the other two, the Core and the O-antigen, have a glycosidic nature, all of them with independent and synergistic functions. Lipid A is the "bioactive center" of LPS, responsible for its toxicity, and shows great variability along bacteria. In general, endotoxins have specific receptors at the cells, causing a wide immunoinflammatory response by inducing the release of pro-inflammatory cytokines and the production of matrix metalloproteinases. This response is not coordinated, favoring the dissemination of LPS through blood vessels, as well as binding mainly to Toll-like receptor 4 (TLR4) expressed in the host cells, leading to the destruction of the tissues and the detrimental effect in some systemic pathologies. Lipid A can also act as a TLRs antagonist eliciting immune deregulation. Although bacterial endotoxins have been extensively studied clinically and in a laboratory, their effects on the oral cavity and particularly on periodontium deserve special attention since they affect the connective tissue that supports the tooth, and can be linked to advanced medical conditions. This review addresses the distribution of endotoxins associated with periodontal pathogenic bacteria and its relationship with systemic diseases, as well as the effect of some therapeutic alternatives.

Differences in Antioxidants, Polyphenols, Protein Digestibility and Nutritional Profile between Ganoderma lingzhi from Industrial Crops in Asia and Ganoderma lucidum from Cultivation and Iberian Origin.

Carpophores of Ganoderma lingzhi (GZ) from industrial crops in China were analysed and compared with carpophores of three Iberian strains of cultivated Ganoderma lucidum (GL) (Aveiro, Madrid, Palencia) previously genetically characterized. The genetic determination of all the fungi in the study coincided with the identification provided by the companies and entities that supplied the samples. Cultivation time ranged between 107 and 141 days. The analysis of total phenol content showed to be 56.8% higher for GL from Palencia than for GZ. Intraspecific variation was a maximum of 56% from GL. The content of antioxidants, both intraspecific and interspecific, was found to be strain-dependent with a maximum variation of 78.5%. The nutritional analysis shows that there are differences in dietary fiber, protein, ash and sodium content between GL and GZ. In fatty acids analysis, only trans fatty acids showed significant differences, being higher in GL. Protein profile and digestibility of GZ and GL-Madrid mushroom proteins were evaluated by digestion with simulated gastric fluid and were different. The two species were perfectly differentiated according to their protein profile. These results should be considered for nutritional and industrial applications.

Limitations and Challenges in the Stability of Cysteamine Eye Drop Compounded Formulations.

Accumulation of cystine crystals in the cornea of patients suffering from cystinosis is considered pathognomonic and can lead to severe ocular complications. Cysteamine eye drop compounded formulations, commonly prepared by hospital pharmacy services, are meant to diminish the build-up of corneal cystine crystals. The objective of this work was to analyze whether the shelf life proposed for six formulations prepared following different protocols used in hospital pharmacies is adequate to guarantee the quality and efficacy of cysteamine eye drops. The long-term and in-use stabilities of these preparations were studied using different parameters: content of cysteamine and its main degradation product cystamine; appearance, color and odor; pH and viscosity; and microbiological analysis. The results obtained show that degradation of cysteamine was between 20% and 50% after one month of storage in the long-term stability study and between 35% and 60% in the in-use study. These data confirm that cysteamine is a very unstable molecule in aqueous solution, the presence of oxygen being the main degradation factor. Saturation with nitrogen gas of the solutions offers a means of reducing cysteamine degradation. Overall, all the formulae studied presented high instability at the end of their shelf life, suggesting that their clinical efficacy might be dramatically compromised.

Current situation of carboplatin desensitisation protocols in the hospitals of Spain.

Desensitisation protocols allow the continuation of treatment in patients who have presented hypersensitivity reactions. Carboplatin desensitisation solutions are usually prepared in the chemotherapy centralised units of hospital pharmacies and they are diluted under the established concentration limit to guarantee the stability of the preparation. An online survey was sent to hospital pharmacies, inquiring about local desensitisation protocols: reasons for use of desensitisation protocols, the protocols used and the stability given to carboplatin solutions. An important variability among the hospitals in carboplatin desensitisation practice was detected. Six different carboplatin desensitisation protocols were described and discordance with the storage period of the carboplatin solutions was observed. The lack of consensus on which protocol must be followed and data supporting the stability of the diluted product, contribute to distrust of carboplatin desensitisation protocols. Although the efficacy and safety of carboplatin desensitisation protocols has been widely demonstrated, many professionals still have concerns.

Development of a Solid Formulation Containing a Microemulsion of a Novel Artemisia Extract with Nematocidal Activity for Oral Administration.

BACKGROUND: Intestinal nematode infections are usually treated with benzimidazole drugs, but the emergence of resistance to these drugs has led to an increasing demand of new anthelmintic strategies. A new microemulsion formulation (ME) consisting of an Artemisia absinthium extract with proven nematocidal efficacy was previously developed. The aim of our study is to implement a D-optimal mixture design methodology to increase the amount of a silica material (loaded with this ME) in a tablet formulation, considering its tensile strength and disintegration time. METHODS: 16 experiments or combinations of the 6 tablet components (loaded silica, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose, Syloid® 244 FP and magnesium stearate) were assessed. Tensile strength and disintegration time models were developed, and an optimization process was carried out. RESULTS: Tensile strength was improved by increasing the polyvinylpyrrolidone content, while croscarmellose decreased the disintegration time. The optimized powder mixture contains 49.7% w/w of the loaded silica material. A compression force of 12 kN was applied to the powder mixture to form tablets with a tensile strength of 2.0 MPa and a disintegration time of 3.8 min. CONCLUSIONS: Our results show that D-optimal mixture designs provide a promising approach to formulate liquid-loaded silica materials.

Unexpected Toxicity of Green Tea Polyphenols in Combination with the Sambucus RIL Ebulin.

The safety of concentrated food complements intake is a major health concern. It has been well established that green tea polyphenols (GTPs) consumption promotes healthy effects. However, the ingestion of large amounts of GTPs is a matter of controversy due to reported adverse effects. We underwent a preliminary exploration of the effects of the oral administration of a standardized concentrated GTPs preparation on mice which suffered from reversible intestinal derangement promoted by sublethal amounts of the antiribosomal lectin ebulin f from dwarf elder (Sambucus ebulus L.). Neither independent oral administration of 30 mg/kg body weight Polyphenon 60 nor intraperitoneal administration of 2.5 mg/kg body weight ebulin f triggered lethal toxicity. In contrast, the simultaneous administration of these same doses of both Polyphenon 60 and ebulin f triggered an important and unexpected synergistic toxic action featured by the biphasic reduction of weight, which continued after eight days, reaching a reduction of 40%. Lethality appeared 2 days after the onset of the combined treatment and reached more than 50% after 10 days.

Human Health Effects of Lactose Consumption as a Food and Drug Ingredient.

Lactose is a reducing sugar consisting of galactose and glucose, linked by a ß (1→4) glycosidic bond, considered as an antioxidant due to its α-hydroxycarbonyl group. Lactose is widely ingested through the milk and other unfermented dairy products and is considered to be one of the primary foods. On the other hand, lactose is also considered as one of the most widely used excipients for the development of pharmaceutical formulations. In this sense, lactose has been related to numerous drug-excipient or drug-food pharmacokinetic interactions. Intolerance, maldigestion and malabsorption of carbohydrates are common disorders in clinical practice, with lactose-intolerance being the most frequently diagnosed, afflicting 10% of the world's population. Four clinical subtypes of lactose intolerance may be distinguished, namely lactase deficiency in premature infants, congenital lactase deficiency, adult-type hypolactasia and secondary lactase intolerance. An overview of the main uses of lactose in human nutrition and in the pharmaceutical industry and the problems derived from this circumstance are described in this review.

Transungual Delivery of Ciclopirox Is Increased 3⁻4-Fold by Mechanical Fenestration of Human Nail Plate in an In Vitro Model.

Onychomycosis is a fungal infection of nails that is widespread and difficult to treat because of the impermeable nature of human nails. Topically applied anti-fungal agents cannot penetrate this structure, and treatment regimens often resort to systemic antifungals with concomitant side effects. One recent clinical study suggested that mechanical fenestration of the nail using an intelligent nail drill might be a possible solution to this problem. In this work, an in vitro model of the transungual delivery of antifungal agents is presented, which utilizes real nail tissue and an inline flow system. This system was deployed to measure transungual delivery of ciclopirox and determined that nail fenestration improved drug delivery by 3⁻4-fold after 42 days. This study bolsters the argument that nail fenestration should be accepted as a pretreatment for onychomycosis and offers a way of evaluating new drugs or formulations designed to combat this condition.

Endotoxins from a Pharmacopoeial Point of View.

A pyrogen is a substance that causes fever after intravenous administration or inhalation. Gram negative endotoxins are the most important pyrogens to pharmaceutical laboratories. In the International, United States, Japanese and European Pharmacopoeias, there are two official methods to evaluate pyrogenicitythat is, the bacterial endotoxin test, and the pyrogen test. The main objective of this review is to compare the monographs of each test among the different Pharmacopeias, to detect similarities and differences. The former can be considered fully harmonized, and only non-significant differences were detected. The latter, which is the only available assay for some products and formulations to demonstrate apyrogenicity, shows large differences, which should be considered.

In vivo toxicity of the ribosome-inactivating lectin ebulin f in elderly mice.

Ebulin f is a ribosome-inactivating protein (RIP) present in green fruits of the dwarf elder (Sambucus ebulus L). Since dwarf elder fruits are used for food and as a medicine, we assessed the study of toxicological effects and safety of ebulin f in elderly mice, comparing these results with those reported in young animals and with other RIPs. Female Swiss mice aged 6 and 12 months of age were intraperitoneally injected with a single dose from 1.4 to 4.5 mg/kg ebulin f. Heart, stomach, intestines, lung, kidney, liver, spleen, pancreas, adrenal gland, uterus, ovary and brain were studied. Histology analysis was carried out by staining with hematoxylin and eosin and Masson's trichrome observed with a light microscope, or apoptosis detection by TUNEL method observed with a confocal laser microscope. Treated animals injected with the lower dose could recover their weights, but after 14 days half of them died. The higher dose caused a progressive loss of body weight leading to death. In the animals of the experimental groups it was found atrophy of Lieberkühn's crypts, pneumonia, nephronal degeneration, myocardial atrophy, centrolobular hepatic necrosis, splenic white pulp necrosis foci and increased rate of apoptosis in the intestines and liver, in which apoptoses were mainly located in the vicinity of the lobular central vein. We conclude that ebulin f affects vital organs in elderly mice.

Stability of daptomycin reconstituted vials and infusion solutions.

OBJECTIVES: Daptomycin is a cyclic lipopeptide with selective action against drug-resistant Gram-positive bacteria. The stability of daptomycin solutions in different containers while stored at different temperatures was assessed. METHODS: Daptomycin vials were reconstituted with NaCl (50 mg/mL). Daptomycin infusion solutions (5.6 and 14.0 mg/mL) were prepared in polypropylene infusion bags. All test solutions were stored either under refrigeration or at room temperature over 7 days. Samples were withdrawn on days 0, 2, 4 and 7 and assayed in triplicate using a stability-indicating high-performance liquid chromatography (HPLC) method. RESULTS: The HPLC analysis revealed no significant loss in daptomycin concentration in vials or bags when stored at 2-8°C. All samples remained clear and colourless and there were no significant changes in pH throughout the study period. CONCLUSIONS: Reconstituted daptomycin vials (50 mg/mL) and infusion bags (5.6 and 14 mg/mL) were found to be physicochemically stable over a period of 1 week when stored at 2-8°C.

NegAIT: A new parser for medical text simplification using morphological, sentential and double negation.

Many different text features influence text readability and content comprehension. Negation is commonly suggested as one such feature, but few general-purpose tools exist to discover negation and studies of the impact of negation on text readability are rare. In this paper, we introduce a new negation parser (NegAIT) for detecting morphological, sentential, and double negation. We evaluated the parser using a human annotated gold standard containing 500 Wikipedia sentences and achieved 95%, 89% and 67% precision with 100%, 80%, and 67% recall, respectively. We also investigate two applications of this new negation parser. First, we performed a corpus statistics study to demonstrate different negation usage in easy and difficult text. Negation usage was compared in six corpora: patient blogs (4K sentences), Cochrane reviews (91K sentences), PubMed abstracts (20K sentences), clinical trial texts (48K sentences), and English and Simple English Wikipedia articles for different medical topics (60K and 6K sentences). The most difficult text contained the least negation. However, when comparing negation types, difficult texts (i.e., Cochrane, PubMed, English Wikipedia and clinical trials) contained significantly (p<0.01) more morphological negations. Second, we conducted a predictive analytics study to show the importance of negation in distinguishing between easy and difficulty text. Five binary classifiers (Naïve Bayes, SVM, decision tree, logistic regression and linear regression) were trained using only negation information. All classifiers achieved better performance than the majority baseline. The Naïve Bayes' classifier achieved the highest accuracy at 77% (9% higher than the majority baseline).

Lectin Digestibility and Stability of Elderberry Antioxidants to Heat Treatment In Vitro.

Elderberry contains healthy low molecular weight nutraceuticals and lectins which are sequence-related to the elderberry allergen Sam n1. Some of these lectins are type II ribosome-inactivating proteins. The sensitivity of native lectins present in elderberry fruits and bark to the proteolysis triggered by in vitro simulated gastric and duodenal fluids has been investigated. It was found that these lectins are refractory to proteolysis. Nonetheless, incubation for 5-10 min in a boiling water bath completely sensitized them to the hydrolytic enzymes in vitro. Under these conditions neither total Folin-Ciocalteau's reagent reactive compounds, total anthocyanins and the mixture of cyanidin-3-glucoside plus cyanidin-3-sambubioside, nor antioxidant and free-radical scavenging activities were affected by more than 10% for incubations of up to 20 min. Therefore, short-time heat treatment reduces potential allergy-related risks deriving from elderberry consumption without seriously affecting its properties as an antioxidant and free-radical scavenging food.

The Role of Surface, Semantic and Grammatical Features on Simplification of Spanish Medical Texts: A User Study.

Simplifying medical texts facilitates readability and comprehension. While most simplification work focuses on English, we investigate whether features important for simplifying English text are similarly helpful for simplifying Spanish text. We conducted a user study on 15 Spanish medical texts using Amazon Mechanical Turk and measured perceived and actual difficulty. Using the median of the difficulty scores, we split the texts into easy and difficult groups and extracted 10 surface, 2 semantic and 4 grammatical features. Using t-tests, we identified those features that significantly distinguish easy text from difficult text in Spanish and compare with prior work in English. We found that easy Spanish texts use more repeated words and adverbs, less negations and more familiar words, similar to English. Also like English, difficult Spanish texts use more nouns and adjectives. However in contrast to English, easier Spanish texts contained longer sentences and used grammatical structures that were more varied.

Effects of temperature, pH and sugar binding on the structures of lectins ebulin f and SELfd.

Ebulin f and SELfd are two lectins of Sambucus ebulus L. that show different stability and digestibility properties in gastric fluid due to their structural differences which may explain their different toxicological profiles. The main aim was to determine the effects of pH, temperature and sugar binding on the intrinsic structures of both proteins by fluorescence analyses. Quenching experiments were conducted, under different pH and temperature conditions, with acrylamide (uncharged) and iodide (charged), to study the possible changes of their intrinsic fluorescence. Results revealed that the native structure of SELfd is more folded than that of ebulin f. At pH 2.0, ebulin f displayed a more open structure than at neutral pH. It can be concluded that this is the main reason why ebulin f is accessible to pepsin action and more sensitive to degradation, in contrast to SELfd as we reported previously.

Anti-Human Endoglin (hCD105) Immunotoxin-Containing Recombinant Single Chain Ribosome-Inactivating Protein Musarmin 1.

Endoglin (CD105) is an accessory component of the TGF-ß receptor complex, which is expressed in a number of tissues and over-expressed in the endothelial cells of tumor neovasculature. Targeting endoglin with immunotoxins containing type 2 ribosome-inactivating proteins has proved an effective tool to reduce blood supply to B16 mice tumor xenografts. We prepared anti-endoglin immunotoxin (IT)-containing recombinant musarmin 1 (single chain ribosome-inactivating proteins) linked to the mouse anti-human CD105 44G4 mouse monoclonal antibody via N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP). The immunotoxin specifically killed L929 fibroblast mouse cells transfected with the short form of human endoglin with IC50 values in the range of 5 × 10(-10) to 10(-9) M.

Physical Stability Studies of Semi-Solid Formulations from Natural Compounds Loaded with Chitosan Microspheres.

A chitosan-based hydrophilic system containing an olive leaf extract was designed and its antioxidant capacity was evaluated. Encapsulation of olive leaf extract in chitosan microspheres was carried out by a spray-drying process. The particles obtained with this technique were found to be spherical and had a positive surface charge, which is an indicator of mucoadhesiveness. FTIR and X-ray diffraction results showed that there are not specific interactions of polyphenolic compounds in olive leaf extract with the chitosan matrix. Stability and release studies of chitosan microspheres loaded with olive leaf extract before and after the incorporation into a moisturizer base were performed. The resulting data showed that the developed formulations were stable up to three months. The encapsulation efficiency was around 44% and the release properties of polyphenols from the microspheres were found to be pH dependent. At pH 7.4, polyphenols release was complete after 6 h; whereas the amount of polyphenols released was 40% after the same time at pH 5.5.

Ebulin from dwarf elder (Sambucus ebulus L.): a mini-review.

Sambucus ebulus L. (dwarf elder) is a medicinal plant, the usefulness of which also as food is restricted due to its toxicity. In the last few years, both the chemistry and pharmacology of Sambucus ebulus L. have been investigated. Among the structural and functional proteins present in the plant, sugar-binding proteins (lectins) with or without anti-ribosomal activity and single chain ribosome-inactivating proteins (RIPs) have been isolated. RIPs are enzymes (E.C. 3.2.2.22) that display N-glycosidase activity on the 28S rRNA subunit, leading to the inhibition of protein synthesis by arresting the step of polypeptide chain elongation. The biological role of all these proteins is as yet unknown. The evidence suggests that they could be involved in the defense of the plant against predators and viruses or/and a nitrogen store, with an impact on the nutritional characteristics and food safety. In this mini-review we describe all the isoforms of ebulin that have to date been isolated from dwarf elder, as well as their functional characteristics and potential uses, whilst highlighting concern regarding ebulin toxicity.