Stereotactic body radiotherapy with helical TomoTherapy for medically inoperable early stage primary and second-primary non-small-cell lung neoplasm: 1-year outcome and toxicity analysis.

OBJECTIVE: This study investigated the effectiveness of stereotactic body radiotherapy with helical TomoTherapy (T-SBRT) for treating medically inoperable primary and second-primary early stage non-small-cell lung neoplasm (SPLN) and evaluated whether the movement of organizing pneumonia (OP) within the irradiation field (IF) can be detected via analysis of radiological changes. METHODS: Patients (n = 16) treated for 1 year (2011-12) at our hospital by T-SBRT at a total dose of 60 Gy in five fractions were examined retrospectively. Outcome and toxicity were recorded and were separately described for SPLN. CT scans were reviewed by a single radiologist. RESULTS: Of the 16 patients, 5 (31.3%) had primary lung malignancies, 10 (62.5%) had SPLN, and 1 case (6.3%) had isolated mediastinal metastasis of lung neoplasm. Pathological evidence was obtained for 72.2% of all lesions. The median radiological follow-up was 11 months (10.5 months for SPLN). For all cases, the 6- and 12-month survival rates were 100% and 77.7% (100% and 71.4%, respectively, for SPLN), and the 6- and 12-month locoregional control rates were 100% in all cases. 2 (12.5%) of 16 patients developed grade 3 late transient radiation pneumonitis following steroid therapy and 1 (6.3%) presented asymptomatic infiltrates comparable to OP opacities. CONCLUSION: T-SBRT seems to be safe and effective. ADVANCES IN KNOWLEDGE: Mild OP is likely associated with radiation-induced anomalies in the IF, identification of migrating opacities can help discern relapse of radiation-induced opacities.

The border of reproductive control: undocumented immigration as a risk factor for unintended pregnancy in Switzerland.

Unintended pregnancies reflect an unmet need for family planning, and are part of health disparities. Using the only database to inquire about pregnancy intention among women in Switzerland, this study examined the relationship between immigrant documentation and unintended pregnancy (UP). Among pregnant women presenting to a Swiss hospital, we compared pregnancy intention between documented and undocumented women. We used logistic regression to examine whether undocumented status was associated with UP after adjusting for other significant predictors. Undocumented women had more unintended pregnancies (75.2 vs. 20.6 %, p = 0.00). Undocumented status was associated with UP after adjustment (OR 6.23, 95 % CI 1.83-21.2), as was a history of psychological problems (OR 4.09, 95 % CI 1.32-12.7). Contraception non-use was notably associated with lower odds of UP (OR 0.01, 95 % CI 0.004-0.04). Undocumented status was significantly associated with UP, even after adjusting for well-recognized risk factors. This highlights the tremendous risk of undocumented status on UP among women in Switzerland.

The anticancer drug metabolites endoxifen and 4-hydroxy-tamoxifen induce toxic effects on Daphnia pulex in a two-generation study.

Although pharmaceutical metabolites are found in the aquatic environment, their toxicity on living organisms is poorly studied in general. Endoxifen and 4-hydroxy-tamoxifen (4OHTam) are two metabolites of the widely used anticancer drug tamoxifen for the prevention and treatment of breast cancers. Both metabolites have a high pharmacological potency in vertebrates, attributing prodrug characteristics to tamoxifen. Tamoxifen and its metabolites are body-excreted by patients, and the parent compound is found in sewage treatment plan effluents and natural waters. The toxicity of these potent metabolites on non-target aquatic species is unknown, which forces environmental risk assessors to predict their toxicity on aquatic species using knowledge on the parent compounds. Therefore, the aim of this study was to assess the sensitivity of two generations of the freshwater microcrustacean Daphnia pulex towards 4OHTam and endoxifen. Two chronic tests of 4OHTam and endoxifen were run in parallel and several endpoints were assessed. The results show that the metabolites 4OHTam and endoxifen induced reproductive and survival effects. For both metabolites, the sensitivity of D. pulex increased in the second generation. The intrinsic rate of natural increase (r) decreased with increasing 4OHTam and endoxifen concentrations. The No-Observed Effect Concentrations (NOECs) calculated for the reproduction of the second generation exposed to 4OHTam and endoxifen were <1.8 and 4.3μg/L, respectively, whereas the NOECs that were calculated for the intrinsic rate of natural increase were <1.8 and 0.4μg/L, respectively. Our study raises questions about prodrug and active metabolites in environmental toxicology assessments of pharmaceuticals. Our findings also emphasize the importance of performing long-term experiments and considering multi-endpoints instead of the standard reproduction outcome.

Toxicity of allyl esters in insect cell lines and in Spodoptera littoralis larvae

We investigated the effects of five allyl esters, two aromatic (allyl cinnamate and allyl 2-furoate) and three aliphatic (allyl hexanoate, allyl heptanoate, and allyl octanoate) in established insect cell lines derived from different species and tissues. We studied embryonic cells of the fruit fly Drosophila melanogaster (S2) (Diptera) and the beet armyworm Spodoptera exigua (Se4) (Lepidoptera), fat body cells of the Colorado potato beetle Leptinotarsa decemlineata (CPB) (Coleoptera), ovarian cells of the silkmoth Bombyx mori (Bm5), and midgut cells of the spruce budworm Choristoneura fumiferana (CF203) (Lepidoptera). Cytotoxicity was determined with use of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and trypan blue. In addition, we tested the entomotoxic action of allyl cinnamate against the cotton leafworm Spodoptera littoralis .The median (50%) cytotoxic concentrations (EC50s) of the five allyl esters in the MTT bioassays ranged between 0.25 and 27 mM with significant differences among allyl esters (P = 0.0012), cell lines (P < 0.0001), and the allyl estercell line interaction (P < 0.0001). Allyl cinnamate was the most active product, and CF203 the most sensitive cell line. In the trypan blue bioassays, cytotoxicity was produced rapidly and followed the same trend observed in the MTT bioassay. In first instars of S. littoralis, allyl cinnamate killed all larvae at 0.25% in the diet after 1 day, while this happened in third instars after 5 days. The LC50 in first instars was 0.08%. In addition, larval weight gain was reduced (P < 0.05) after 1 day of feeding on diet with 0.05%. In conclusion, the data provide evidence of the significant but differential cytotoxicity among allyl esters in insect cells of different species and tissues. Midgut cells show high sensitivity, indicating the insect midgut as a primary target tissue. Allyl cinnamate caused rapid toxic effects in S. littoralis larvae at low concentrations, suggesting further potential for use in pest control.

Toxicity assessment of refill liquids for electronic cigarettes.

We analyzed 42 models from 14 brands of refill liquids for e-cigarettes for the presence of micro-organisms, diethylene glycol, ethylene glycol, hydrocarbons, ethanol, aldehydes, tobacco-specific nitrosamines, and solvents. All the liquids under scrutiny complied with norms for the absence of yeast, mold, aerobic microbes, Staphylococcus aureus, and Pseudomonas aeruginosa. Diethylene glycol, ethylene glycol and ethanol were detected, but remained within limits authorized for food and pharmaceutical products. Terpenic compounds and aldehydes were found in the products, in particular formaldehyde and acrolein. No sample contained nitrosamines at levels above the limit of detection (1 μg/g). Residual solvents such as 1,3-butadiene, cyclohexane and acetone, to name a few, were found in some products. None of the products under scrutiny were totally exempt of potentially toxic compounds. However, for products other than nicotine, the oral acute toxicity of the e-liquids tested seems to be of minor concern. However, a minority of liquids, especially those with flavorings, showed particularly high ranges of chemicals, causing concerns about their potential toxicity in case of chronic oral exposure.

Toxicity screenings of nanomaterials: challenges due to interference with assay processes and components of classic in vitro tests.

Given the multiplicity of nanoparticles (NPs), there is a requirement to develop screening strategies to evaluate their toxicity. Within the EU-funded FP7 NanoTEST project, a panel of medically relevant NPs has been used to develop alternative testing strategies of NPs used in medical diagnostics. As conventional toxicity tests cannot necessarily be directly applied to NPs in the same manner as for soluble chemicals and drugs, we determined the extent of interference of NPs with each assay process and components. In this study, we fully characterized the panel of NP suspensions used in this project (poly(lactic-co-glycolic acid)-polyethylene oxide [PLGA-PEO], TiO2, SiO2, and uncoated and oleic-acid coated Fe3O4) and showed that many NP characteristics (composition, size, coatings, and agglomeration) interfere with a range of in vitro cytotoxicity assays (WST-1, MTT, lactate dehydrogenase, neutral red, propidium iodide, (3)H-thymidine incorporation, and cell counting), pro-inflammatory response evaluation (ELISA for GM-CSF, IL-6, and IL-8), and oxidative stress detection (monoBromoBimane, dichlorofluorescein, and NO assays). Interferences were assay specific as well as NP specific. We propose how to integrate and avoid interference with testing systems as a first step of a screening strategy for biomedical NPs.

Right ventricular dysfunction in children and adolescents conceived by assisted reproductive technologies.

Assisted reproductive technologies (ART) predispose the offspring to vascular dysfunction, arterial hypertension, and hypoxic pulmonary hypertension. Recently, cardiac remodeling and dysfunction during fetal and early postnatal life have been reported in offspring of ART, but it is not known whether these cardiac alterations persist later in life and whether confounding factors contribute to this problem. We, therefore, assessed cardiac function and pulmonary artery pressure by echocardiography in 54 healthy children conceived by ART (mean age 11.5 ± 2.4 yr) and 54 age-matched (12.2 ± 2.3 yr) and sex-matched control children. Because ART is often associated with low birth weight and prematurity, two potential confounders associated with cardiac dysfunction, only singletons born with normal birth weight at term were studied. Moreover, because cardiac remodeling in infants conceived by ART was observed in utero, a situation associated with increased right heart load, we also assessed cardiac function during high-altitude exposure, a condition associated with hypoxic pulmonary hypertension-induced right ventricular overload. We found that, while at low altitude cardiac morphometry and function was not different between children conceived by ART and control children, under the stressful conditions of high-altitude-induced pressure overload and hypoxia, larger right ventricular end-diastolic area and diastolic dysfunction (evidenced by lower E-wave tissue Doppler velocity and A-wave tissue Doppler velocity of the lateral tricuspid annulus) were detectable in children and adolescents conceived by ART. In conclusion, right ventricular dysfunction persists in children and adolescents conceived by ART. These cardiac alterations appear to be related to ART per se rather than to low birth weight or prematurity.

Reproductive morphology in Mediterranean Seirospora giraudyi (Ceramiales, Rhodophyta)

This paper presents a detailed description of the reproductive characters of Mediterranean Seirospora giraudyi based on fresh material collected in the northwestern coast of Spain. Vegetative cells are uninucleate. The plant is monoecious. Spermantangial parent’s cells are clustered on modified dwarf determinate filaments, usually situated on adaxial surfaces of branches. One to four spermatia are formed by elongation and proximal divisions of the spermatangial parent cells. Spermatium with a nucleus situated ina mec. The thallus is procarpic. The four-celled carpogonial branch is initially L-shaped, and it is situated on a periaxial supporting fertile axial cell. The mature carpogonial branch is U-shaped and the supporting cell and second periaxial cell enlarge and divide transversely to reproduce a pair uninicleate auxiliary cell. The nucleus in the ferlilized carpogonium divides twice and the carpogonium cleaves vertically into two cells that, turn, cut off a pair of uninucleate connecting cells that fuse with the auxiliary cells on opposite sides; the diploid nuclei in the connecting cells divide at the site of fusion and one of the nuclei enters the auxiliary cell white the other is extruded. Each auxiliary cell gives to a terminal primary gonimolobe initials. Gonimolobes form lax chains of carposporangia. As the gonimoblasts mature, both lobes of the foot cell which is situated on the supporting cell elongate the upper one secondary connecting with the supporting cell, and the lower one with the fertile axial cell. The gonimoblasts are subtended at maturity by one to several clusters of involucral flaments. Seirospora is currently placed in the tribe Euptiloteae; however the reproductive character of S.giraudyi is dentical to those described for the Cañllithamnieae. Molecular studies are needed to confirm the taxonomic position of S.giraudyi as well as that of the other species placed Seirospora

The reproductive cycle of the sea urchin Arbacia lixula in northwest mediterranean: potential influence of temperature and photoperiod

We studied the reproductive cycle of the sea urchin Arbacia lixula in a subtidal population from northeast Spain over four years using a gonadosomatic index (GSI) and gonad histology. Our results show that the GSI of A. lixula follows a seasonal cycle which peaks in May-July and attains its lowest values in October-November every year. The time course of the GSI matched closely the photoperiod cycle. We also found a remarkable inter-annual variability in the maximum value of GSI, which correlated with mean water temperature during the gonad growth period (winter and spring). Gonad histology was also in agreement with a single gametogenic cycle per year in this species. We explored the application of circular statistics to present and analyse gonadal development data, which allowed us to adequately handle the high intra-individual variability detected, with several developmental stages commonly found within the same gonad. The picture that emerged is one of a gametogenic timing driven by photoperiod, while the amount of reproductive output is determined by temperature. This is coherent with the tropical origin of the species and lends support to recent warnings about an increase in the abundance of this species in the Mediterranean as a result of global warming, with associated increased impact potential in sublittoral communities.

Evolutionary steps in the reproductive biology of Annonaceae

Flowers of Annonaceae are characterized by fleshy petals, many stamens with hard connective shields and numerous carpels with sessile stigmas often covered by sticky secretions. The petals of many representatives during anthesis form a closed pollination chamber. Protogynous dichogamy with strong scent emissions especially during the pistillate stage is a character of nearly all species. Scent emissions can be enhanced by thermogenesis. The prevailing reproductive system in the family seems to be self-compatibility. The basal genus Anaxagorea besides exhibiting several ancestral morphological characters has also many characters which reappear in other genera. Strong fruit-like scents consisting of fruit-esters and alcohols mainly attract small fruit-beetles (genus Colopterus, Nitidulidae) as pollinators, as well as several other beetles (Curculionidae, Chrysomelidae) and fruit-flies (Drosophilidae), which themselves gnaw on the thick petals or their larvae are petal or ovule predators. The flowers and the thick petals are thus a floral brood substrate for the visitors and the thick petals of Anaxagorea have to be interpreted as an antipredator structure. Another function of the closed thick petals is the production of heat by accumulated starch, which enhances scent emission and provides a warm shelter for the attracted beetles. Insight into floral characters and floral ecology of Anaxagorea, the sister group of the rest of the Annonaceae, is particularly important for understanding functional evolution and diversification of the family as a whole. As beetle pollination (cantharophily) is plesiomorphic in Anaxagorea and in Annonaceae, characters associated with beetle pollination appear imprinted in members of the whole family. Pollination by beetles (cantharophily) is the predominant mode of the majority of species worldwide. Examples are given of diurnal representatives (e.g., Guatteria, Duguetia, Annona) which function on the basis of fruit-imitating flowers attracting mainly fruit-inhabiting nitidulid beetles, as well as nocturnal species (e.g., large-flowered Annona and Duguetia species), which additionally to most of the diurnal species exhibit strong flower warming and provide very thick petal tissues for the voracious dynastid scarab beetles (Dynastinae, Scarabaeidae). Further examples will show that a few Annonaceae have adapted in their pollination also to thrips, flies, cockroaches and even bees. Although this non-beetle pollinated species have adapted in flower structure and scent compounds to their respective insects, they still retain some of the specialized cantharophilous characters of their ancestors.

Spectrum of digoxin-induced ocular toxicity: a case report and literature review.

BACKGROUND: Digoxin intoxication results in predominantly digestive, cardiac and neurological symptoms. This case is outstanding in that the intoxication occurred in a nonagenarian and induced severe, extensively documented visual symptoms as well as dysphagia and proprioceptive illusions. Moreover, it went undiagnosed for a whole month despite close medical follow-up, illustrating the difficulty in recognizing drug-induced effects in a polymorbid patient. CASE PRESENTATION: Digoxin 0.25 mg qd for atrial fibrillation was prescribed to a 91-year-old woman with an estimated creatinine clearance of 18 ml/min. Over the following 2-3 weeks she developed nausea, vomiting and dysphagia, snowy and blurry vision, photopsia, dyschromatopsia, aggravated pre-existing formed visual hallucinations and proprioceptive illusions. She saw her family doctor twice and visited the eye clinic once until, 1 month after starting digoxin, she was admitted to the emergency room. Intoxication was confirmed by a serum digoxin level of 5.7 ng/ml (reference range 0.8-2 ng/ml). After stopping digoxin, general symptoms resolved in a few days, but visual complaints persisted. Examination by the ophthalmologist revealed decreased visual acuity in both eyes, 4/10 in the right eye (OD) and 5/10 in the left eye (OS), decreased color vision as demonstrated by a score of 1/13 in both eyes (OU) on Ishihara pseudoisochromatic plates, OS cataract, and dry age-related macular degeneration (ARMD). Computerized static perimetry showed non-specific diffuse alterations suggestive of either bilateral retinopathy or optic neuropathy. Full-field electroretinography (ERG) disclosed moderate diffuse rod and cone dysfunction and multifocal ERG revealed central loss of function OU. Visual symptoms progressively improved over the next 2 months, but multifocal ERG did not. The patient was finally discharged home after a 5 week hospital stay. CONCLUSION: This case is a reminder of a complication of digoxin treatment to be considered by any treating physician. If digoxin is prescribed in a vulnerable patient, close monitoring is mandatory. In general, when facing a new health problem in a polymorbid patient, it is crucial to elicit a complete history, with all recent drug changes and detailed complaints, and to include a drug adverse reaction in the differential diagnosis.

Relationship between diet and reproductive success in the Israeli barn owl

The effect of diet on barn owl (Tyto alba) breeding biology has been well studied in the temperate regions but not in the more arid Middle East. In temperate regions, barn owls are darker colored and mainly prey upon Cricetidae rodents, whereas in arid regions, they are lighter colored and prey to a larger degree upon Muridae rodents. In this study we analyzed the diet and breeding success of 261 barn owl pairs nesting in Israel. The reproductive success of barn owls declined from March to August, and fledged more young when they consumed a larger proportion of social voles (Microtus socialis guentheri). Although the diet of the lighter colored barn owls in Israel comprises more Muridae than that of the darker morphs in temperate regions, in both regions the number of barn owl young increases with an increased proportion of voles in the diet.