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Supplementary Data from Pharmacokinetic Analysis and Phase 1 Study of MRX-1024 in Patients Treated with Radiation Therapy with or without Cisplatinum for Head and Neck Cancer

Purpose: A previous study reported radiation protection from mucosal injury with D-methionine (D-met) in preclinical evaluation; therefore, the pharmacokinetics, safety, and utility of D-met were evaluated clinically.Experimental Design: The pharmacokinetics of D-met following oral administration of a bioavailable formulation (MRX-1024) was evaluated in normal volunteers. Subsequently, 25 patients were enrolled on a phase 1 study of MRX-1024 concurrent with radiation therapy (RT) with or without weekly cisplatinum. Toxicity and mucosal events were evaluated weekly.Results: Oral MRX-1024 resulted in rapid and dose-dependent increases in plasma D-met concentrations with a half-life of 3 hours. When administered concurrent with RT without chemotherapy, it was associated with a modest increase in grade 2 (two of six patients) and grade 3 (one of six patients) emesis. In those treated with MRX-1024 along with RT and weekly cisplatinum, there was no appreciable increase in emesis. Overall, five patients withdrew from the study due to emesis (four grade 2 and one grade 3). Only one incidence of dose-limiting toxicity (grade 3 emesis) was identified in 25 patients (4%). Finally, in 18 evaluable patients treated with MRX-1024 at 100 mg/kg twice daily (BID), the incidence of severe (grade 3) oral mucositis was 6% (1 of 18) with no grade 4 mucositis.Conclusions: There is a dose-dependent increase in D-met exposure following MRX-1024 administration at 50 and 100 mg/kg, and MRX-1024 is safe for use concurrent with combined radiation and chemotherapy. The observed rate of mucositis seems less than that for similar treatment regimens within the published literature. Clin Cancer Res; 16(9); 2666–76. ©2010 AACR.

Purpose: Oral mucositis is a common acute morbidity associated with radiation and/or chemotherapy treatment for cancer. d-Methionine (d-Met), the dextro-isomer of the common amino acid l-methionine, has been documented to protect normal tissues from a diverse array of oxidative insults.Experimental Design: We evaluated if d-Met could selectively prevent radiation-induced oral mucositis using in vitro cell culture models as well as an in vivo model of radiation injury to the oral mucosa in C3H mice.Results: Unlike free-radical scavengers, which protected both normal and transformed tumor cells in vitro from radiation-induced cell death, treatment with d-Met in culture protected nontransformed primary human cells from radiation-induced cell death (protective factor between 1.2 and 1.6; P < 0.05) whereas it did not confer a similar protection on transformed tumor cells. d-Met treatment also provided significant protection to normal human fibroblasts, but not to tumor cell lines, from radiation-induced loss of clonogenicity (protection factor, 1.6 ± 0.15). d-Met treatment did not alter DNA damage (as measured by histone phosphorylation) following irradiation but seemed to selectively mitigate the loss of mitochondrial membrane potential in nontransformed cells, whereas it did not provide a similar protection to tumor cells. Tumor control of implanted xenografts treated with radiation or concurrent cisplatin and radiation was not altered by d-Met treatment. Pharmacokinetics following administration of a liquid suspension of d-Met in rats showed 68% bioavailability relative to i.v. administration. Finally, in a murine model of mucositis, a dose-dependent increase in protection was observed with the protective factor increasing from 1.6 to 2.6 over a range of oral d-Met doses between 200 and 500 mg/kg (P < 0.0003).Conclusions:d-Met protected normal tissues, but not tumor cells, in culture from radiation-induced cell death; it also protected normal cells from radiation-induced mucosal injury in a murine model but did not alter tumor response to therapy. Further studies on the use of d-Met to protect from oral mucositis are warranted.

Supplementary Data from Evaluation of d-Methionine as a Novel Oral Radiation Protector for Prevention of Mucositis

Premise The sooty molds are a globally distributed ecological group of ascomycetes with epiphyllous, saprotrophic habit, comprising several phylogenetically distant taxa (i.e., members of the classes Dothideomycetes and Eurotiomycetes). Their fossil record extends almost continuously back to the early Cretaceous; however, they are hypothesized to have originated in the early Mesozoic. Here, we describe new specimens of sooty molds associated with conifer leaves from Jurassic hot spring deposits of Patagonia, Argentina. Methods Thin sections of chert samples from the La Matilde Formation, Deseado Massif (Santa Cruz, Argentina) were observed using light microscopy. Results The fungi occur on the surface and axils of leafy twigs with podocarpaceous affinities, forming dense subicula comprised by opaque moniliform hyphae. Additionally, several asexual and sexual reproductive structures are observed. On the basis of vegetative (i.e., dense subicula composed of moniliform hyphae; hyphae composed of opaque cells deeply constricted at the septa) and reproductive characters (i.e., poroconidial and sympodioconidial asexual stages and diverse spores), two morphotypes were identified with affinities within lineages of the subphylum Pezizomycotina that encompass the ecological group of sooty molds, and a third morphotype was within the phylum Ascomycota. Conclusions This finding extends the fossil record of sooty molds to the Jurassic and their geographic fossil range to the South American continent. In particular, their association with podocarpaceous conifers is shown to be ancient, dating back to the Jurassic. This new record provides an additional reference point on the diversity of interactions that characterized Jurassic forests in Patagonia.

Meiofaunal assemblages are often overlooked, yet they are important ecological components of estuarine ecosystems. To evaluate variations in meiofaunal communities in estuarine habitats, we conduct...

Our understanding of habitable early Earth environments is limited by the preservation potential of Archean rock deposits. Sedimentary intervals within the relatively homogeneous volcanic sequences of the Barberton Greenstone Belt (BGB), South Africa and Swaziland, and the eastern Pilbara Craton (PC) in Western Australia provide the best windows into interpreting variability in early Earth environments due to their low strain and low metamorphic grade. These deposits host Earth's oldest, most convincing, evidence of life (~3.3-3.5 Ga), and contribute to a better understanding of both the setting and the origin of life (OoL) and the search for life on other planets, such as Mars.The 3481 ± 2 Ma Dresser Formation, PC contains one of these preservation windows. Previous outcrop studies indicate changes in dominant volcanism composition (mafic to felsic), transitions from subaqueous to subaerial sedimentary facies, and large regional tectonic events that promoted circulation of hydrothermal fluids and secondary alteration. Here we present detailed lithologic and mineralogic details of this early Earth surface deposit, obtained from a recent drilling campaign.Three fresh drillcores obtained through the lower chert member of the Dresser Formation (~15 m thickness) were drilled at ~75 m below the weathered surface via HQ diamond drilling. Core sites were selected to provide a 3D perspective of geologic variability. Results show a high degree of complex lithology consisting of repeating bedded black carbonaceous cherts (TOC of up to 0.16 wt %), jaspilitic cherts, bedded carbonates, volcanogenic sandstones, beds of sulfidized stromatolites, edgewise conglomerates, laminated siliceous deposits that are texturally similar to hot spring sinter and directly overlie putative feeder veins, and thin spherulitic beds with petrographic similarities (spherical shapes, quenched features, radial crystal splays, and off-centered vesicles) to younger impact spherule beds. In addition, veins of carbonate, chert, barite and sulfides were identified throughout much of the lower chert member. Lithologic variability occurs on scales of millimetres-decimetres vertically, and from metres to decametres laterally, while mapping of regional scale (kms) stratigraphic sections indicate repetition of specific lithologic successions identified in the cores.The marked heterogeneity and variability both across stratigraphy and along strike contrasts sharply with marine settings, which are relatively homogeneous and consistent over 10’s-100’s of kilometres laterally, and across tens of metres vertically. Younger geologic systems that show similar depositional associations and sharp lateral facies changes include geothermal environments. The presence of sulfidized stromatolites, bedded black cherts, and hot spring deposit indicate that there were a diverse range of habitats (both marine and terrestrial) that hosted life. If spherulitic beds are impactor in origin, they would represent the oldest evidence of a bolide impact in the geologic record. The Dresser Formation provides insights into complex, dynamic, early Earth environments that host apparently already diverse microbial communities adapted to a range of habitats.

The etiology of portal hypertension (pHTN) in children differs from that of adults and may require different management strategies. We set out to review the etiology, management, and natural history of pHTN at a pediatric liver center. From 2008 to 2018, 151 children and adolescents with pHTN were identified at a free‐standing children’s hospital. Patients were stratified by etiology of pHTN (intrahepatic disease [IH], defined as cholestatic disease and fibrotic or hepatocellular disease; extrahepatic disease [EH], defined as hepatic vein obstruction and prehepatic pHTN). Patients with EH were more likely to undergo an esophagoduodenscopy for a suspected gastrointestinal bleed (77% vs. 41%; P

Hot spring environments are commonly dominated by silica sinters that precipitate by the rapid cooling of silica-saturated fluids and the activity of microbial communities. However, the potential for preservation of organic traces of life in silica sinters back through time is not well understood. This is important for the exploration of early life on Earth and possibly Mars. Most previous studies have focused on physical preservation in samples

The origin and age of opaline silica deposits discovered by the Spirit rover adjacent to the Home Plate feature in the Columbia Hills of Gusev crater remains debated, in part because of their proximity to sulfur-rich soils. Processes related to fumarolic activity and to hot springs and/or geysers are the leading candidates. Both processes are known to produce opaline silica on Earth, but with differences in composition, morphology, texture, and stratigraphy. Here, we incorporate new and existing observations of the Home Plate region with observations from field and laboratory work to address the competing hypotheses. The results, which include new evidence for a hot spring vent mound, demonstrate that a volcanic hydrothermal system manifesting both hot spring/geyser and fumarolic activity best explains the opaline silica rocks and proximal S-rich materials, respectively. The opaline silica rocks most likely are sinter deposits derived from hot spring activity. Stratigraphic evidence indicates that their deposition occurred before the emplacement of the volcaniclastic deposits comprising Home Plate and nearby ridges. Because sinter deposits throughout geologic history on Earth preserve evidence for microbial life, they are a key target in the search for ancient life on Mars.

Premise of research. Despite the ecological significance of arbuscular mycorrhizae in modern terrestrial ecosystems, knowledge about their evolution based on the fossil record is still scarce, especially concerning the case of root nodules harboring arbuscular mycorrhizal fungi, as in some extant gymnosperms and angiosperms. Exceptionally preserved conifer nodular roots were found in the Jurassic fossil-bearing chert deposits of the Deseado Massif (Santa Cruz, Argentina), raising the possibility of studying them in association with arbuscular mycorrhizal fungi. The aim of this study is to describe the plant organs and their fungal partners and to discuss the ecological significance of the interactions observed, particularly with respect to their occurrence in the hot spring settings. Methodology. Thin sections of chert samples from the Cañadón Nahuel locality of the La Matilde Formation, Deseado Massif (Santa Cruz, Argentina) were observed using light microscopy. Pivotal results. The cortex of the nodules is occupied by several glomeromycotan fungal structures. The structures occur in a specific zone of the cortex—toward its center—and include intracellular hyphal coils and arbuscules. Glomoid spores and coenocytic hyphae possibly penetrating the epidermal cells are also described and analyzed. Conclusions. The root nodules have affinities with the Araucariales, representing the oldest record of such structures for this conifer clade. This is also the first record of nodules harboring arbuscular mycorrhizal fungi for the Jurassic; it extends our knowledge of the fossil record for this particular type of fungal association. Fil: Nunes, Cristina Isabel. Museo Paleontológico Egidio Feruglio; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: García Massini, Juan Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja. - Universidad Nacional de La Rioja. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja. - Universidad Nacional de Catamarca. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja. - Secretaría de Industria y Minería. Servicio Geológico Minero Argentino. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja. - Provincia de La Rioja. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja; Argentina Fil: Escapa, Ignacio Hernán. Museo Paleontológico Egidio Feruglio; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Guido, Diego Martin. Instituto de Recursos Minerales; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Campbell, Kathleen. University of Auckland; Nueva Zelanda

Background Terrestrial hot spring settings span a broad spectrum of physicochemistries. Physicochemical parameters, such as pH and temperature, are key factors influencing differences in microbial composition across diverse geothermal areas. Nonetheless, analysis of hot spring pools from the Taupo Volcanic Zone (TVZ), New Zealand, revealed that some members of the bacterial genus, Acidithiobacillus, are prevalent across wide ranges of hot spring pHs and temperatures. To determine the genomic attributes of Acidithiobacillus that inhabit such diverse conditions, we assembled the genomes of 19 uncultivated hot spring Acidithiobacillus strains from six geothermal areas and compared these to 37 publicly available Acidithiobacillus genomes from various habitats. Results Analysis of 16S rRNA gene amplicons from 138 samples revealed that Acidithiobacillus comprised on average 11.4 ± 16.8% of hot spring prokaryotic communities, with three Acidithiobacillus amplicon sequence variants (ASVs) (TVZ_G1, TVZ_G2, TVZ_G3) accounting for > 90% of Acidithiobacillus in terms of relative abundance, and occurring in 126 out of 138 samples across wide ranges of temperature (17.5–92.9 °C) and pH (1.0–7.5). We recovered 19 environmental genomes belonging to each of these three ASVs, as well as a fourth related group (TVZ_G4). Based on genome average nucleotide identities, the four groups (TVZ_G1-TVZ_G4) constitute distinct species (ANI Acidithiobacillus species (TVZ_G2-TVZ_G4) and one belongs to Acidithiobacillus caldus (TVZ_G1). All four TVZ Acidithiobacillus groups were found in hot springs with temperatures above the previously known limit for the genus (up to 40 °C higher), likely due to significantly higher proline and GC contents than other Acidithiobacillus species, which are known to increase thermostability. Results also indicate hot spring-associated Acidithiobacillus have undergone genome streamlining, likely due to thermal adaptation. Moreover, our data suggest that Acidithiobacillus prevalence across varied hot spring pHs is supported by distinct strategies, whereby TVZ_G2-TVZ_G4 regulate pH homeostasis mostly through Na+/H+ antiporters and proton-efflux ATPases, whereas TVZ_G1 mainly relies on amino acid decarboxylases. Conclusions This study provides insights into the distribution of Acidithiobacillus species across diverse hot spring physichochemistries and determines genomic features and adaptations that potentially enable Acidithiobacillus species to colonize a broad range of temperatures and pHs in geothermal environments.

Los estudios tafonómicos se realizaron en la localidad Laguna Flecha Negra (Complejo Bahía Laura, Jurásico Medio-Tardío), Provincia de Santa Cruz, Argentina. Se definieron facies sedimentarias y estilos de conservación para reconocer tafofacies de plantas en la secuencia estudiada. Se identificaron once tafofacies y se proponen fuentes vegetales dentro de un sistema volcánico y geotérmico. Los restos vegetales son de origen autóctono a para-autóctono y la mejor conservación se encontró en facies distales de sistemas silíceos de aguas termales (sinter). Se encontraron diferencias tafonómicas laterales y verticales en la secuencia estudiada. Estos se deben a cambios en la entrada sedimentaria y la distancia a los fluidos geotérmicos. Los resultados permiten reconstruir la historia deposicional de esta región de la provincia geológica del Macizo del Deseado. Inferimos la formación de un sistema de aguas termales (sinterizado) que posteriormente fue destruido por un proceso de erupción freática en el margen de una cúpula efusiva andesítica en subfacies piroclásticas de otoño parcialmente reelaboradas. Después de la destrucción del sistema geotérmico, se desarrolló una subfacies epiclástica fluvial y lacustre preservando una comunidad vegetal típica del Jurásico Medio-Tardío de Gondwana. Posteriormente, la actividad volcánica produjo subfacies piroclásticas, con espesos depósitos de ceniza y flujo de diferentes fuentes y separados por un intervalo de tiempo que promovió la fosilización de un bosque in situ. Los estudios tafonómicos de estas comunidades vegetales permitieron reconstruir una cadena de eventos geológicos y cómo estos procesos han influido en la preservación de una flora jurásica de la Patagonia, contribuyendo así al conocimiento de la paleoecología de la provincia geológica del Macizo del Deseado. Taphonomic studies were carried out at Laguna Flecha Negra locality (Bahía Laura Complex, Middle–Late Jurassic), Santa Cruz Province, Argentina. Sedimentary facies and preservational styles were defined to recognize plant taphofacies in the studied sequence. Eleven taphofacies were identified and plant sources within a volcanic and geothermal system are proposed. Plant remains are of autochthonous to para-autochthonous origin and best preservation was found in distal facies of siliceous hot spring (sinter) systems. Lateral and vertical taphonomic differences were found in the studied sequence. These are due to changes in the sedimentary input and distance to the geothermal fluids. Results enable the reconstruction of the depositional history of this region of the Deseado Massif geological Province. We infer formation of a hot-spring (sinter) system that was subsequently destroyed by a phreatic eruption process at the margin of an andesitic effusive dome in partially reworked fall pyroclastic subfacies. After the destruction of the geothermal system, a fluvial and lacustrine epiclastic subfacies developed preserving a plant community typical of the Middle-Late Jurassic of Gondwana. Later, volcanic activity produced pyroclastic subfacies, with thick ash-fall and flow deposits from different sources and separated by a time gap that promoted fossilization of an in situ forest. Taphonomic studies of these plant communities allowed reconstruction of a chain of geological events and how these processes have influenced the preservation of a Jurassic flora from Patagonia, thus contributing to an understanding of the paleoecology of the Deseado Massif geological province. Fil: Sagasti, Ana Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; Argentina Fil: Guido, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; Argentina Fil: García Massini, Juan Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja. - Universidad Nacional de La Rioja. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja. - Universidad Nacional de Catamarca. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja. - Secretaría de Industria y Minería. Servicio Geológico Minero Argentino. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja. - Provincia de La Rioja. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica de La Rioja; Argentina Fil: Campbell, Kathleen. University of Auckland; Nueva Zelanda

BACKGROUND: Congenital portosystemic shunt (CPSS) is a rare malformation in which splanchnic venous flow bypasses the liver. CPSS is associated with other congenital anomalies and syndromes and can be associated with life-threatening complications. CPSS and their management remain underreported in the literature. Here, we review the clinical characteristics, management, and outcomes of a cohort of children and young adults with CPSS from two pediatric centers. METHODS: Cases of CPSS from Cincinnati Children’s Hospital Medical Center and C.S. Mott Children’s Hospital were reviewed to define CPSS anatomy, associated anomalies, complications, interventions, and outcomes. The imaging features and histopathology of liver lesions were characterized in detail. RESULTS: A total of 11 cases were identified. Median age was 10 years (range 0–26); 8 (73%) cases were female. Associated anomalies included six patients with heterotaxy (55%), five patients with congenital heart disease (45%), three patients with Turner syndrome (27%), and two patients with omphalocele, exstrophy, imperforate anus, spinal defects (OEIS) complex (18%). Eight (73%) cases had hyperammonemia ± encephalopathy. A 4-month-old presented with hepatopulmonary syndrome, and 12-year-old presented with pulmonary hypertension. Eight patients (73%) had liver lesions including five with premalignant adenomas and three with well-differentiated hepatocellular carcinoma (HCC). Four children underwent successful CPSS occlusion/ligation. Three children underwent liver transplant (2) or resection (1) for HCC without recurrence at extended follow-up. CONCLUSIONS: CPSS is associated with multiple anomalies (heterotaxy, congenital heart disease) and syndromes (Turner syndrome). CPSS liver lesions should be very carefully evaluated due to risk of premalignant adenomas and HCC. Serious complications of CPSS can occur at a young age but can be managed endovascularly or with open surgery.

The Late Miocene Whitianga Volcanic Centre of the Coromandel Volcanic Zone, North Island, New Zealand, is host to 18 known, siliceous and intensely silicified deposits including: silicified volcanics; sediments of inferred lacustrine, fluvial and mud pool origin; siliceous hot spring deposits, or sinters; and silicic veins. Collectively these siliceous and silicified deposits indicate past geothermal activity that occurred at the Earth's surface and in the shallow subsurface. Sinters, in particular, are of interest because they are derived from deep geothermal reservoirs and precipitate from discharged thermal fluids at the intersection of the water table with the land surface. However, some siliceous and silicified features in hydrothermal paleoenvironments have been misidentified as sinters. By studying textural types, distributions, structural setting, mineral paragenesis and trace elemental composition of the siliceous and silicified deposits in the Whitianga Volcanic Centre, it is possible to differentiate sinters and identify their spring-vent source areas (100–70 °C) from more distal thermal spring discharge locations ( Ag mineralisation may have occurred at depth. This has important implications for the exploration of mineralised epithermal ore deposits at local to regional scales, in particular for the Hauraki Goldfield of the Coromandel Volcanic Zone.

Methane-derived authigenic carbonates (MDACs) in Miocene bathyal mudstones in North Island, New Zealand are typically expressed as either sub-seafloor conduit concretions or as seafloor seep limestones, but rarely are both types exposed in outcrop at one locality. Consequently, any potential genetic link between them is usually inferred. This also appears to be the case for global occurrences of MDAC. At the Rocky Knob seep complex near Gisborne both seep limestones and conduit concretions co-occur. The petrography and stable carbon (δ13C) and oxygen (δ18O) isotope compositions of their various authigenic carbonate components (automicrite, fibrous aragonite crystals, and granular, blocky and bladed calcite crystals) show that distinctive isotope and petrographic groupings for precipitates within the conduit concretions match or “correlate” with several of those in the seep limestones. This corroborates their genetic tie and derivation from the same fluids, albeit in different parts (i.e. sub-seafloor vs. seafloor) of the seep complex.

A substantial volume (c. 5000 m 3 ) of siliceous hot spring deposits (sinter) has been deposited down to 1 m depth in and around the Tokaanu Domain, a 0.2 km 2 , thermally active central area of the Hipaua-Waihi-Tokaanu geothermal field. Associated thermal manifestations in the Domain included geysers, fumaroles, and hot pools with spring outflows depositing sinter from deeply derived NaCl-type waters as already described over 150 years ago. Later observations showed that flat flooded marshes hosting minor sinter deposits decreased in surface areal extent from at least 15,000 m 2 in 1870 to less than 800 m 2 in 2007. Decline in the area of flooded marshland reflects a decline in flow rate of feeding source pools. Depth and thickness (up to 0.5 m) of concealed (i.e. vegetative overgrown or covered in soil) sinter aprons in the Domain were mapped by students of the 1983–1987 Geothermal Diploma (UoA) field classes. The information was used recently to locate sites for coring of two buried sinter aprons. Radiometric dating of the lower Matewai apron yielded a 0.44 kyr age for sinter at 0.2 m depth. Sinter cores from three sites along a c. 60 m long N–S profile, following the apron axis of the Takarea pool source, yielded radiometric ages between 1.2 kyr at 0.25 m depth to 6.2 kyr at 0.35 m depth. Sinter deposition was found to be highly irregular. Sub-rounded sinter clasts at >2 m depth at two drill sites show no genetic relation to sinter found at the top of the cored section. The topmost sinter cap exhibits only minor diagenetic changes; some acidic hydrothermal alteration, however, is visible in the bottom section at >2.5 m depth of the cored sites pointing to a separate geothermal discharge phase. The irregular deposition of sinter in the Domain points to: 1. tortuous fluid flow paths in the shallow subsurface, and/or 2. shifting discharge channel flow directions on top of the developing sinter apron. The present and last sinter depositing episode appears to have come to an end; it probably lasted, with major interruptions, over 6 kyr.

Hypothesis Moringa extract, a naturally occurring anti-oxidant, protects against aminoglycoside-induced hair cell death and hearing loss within the organ of Corti. Background Reactive oxygen species (ROS) arise primarily in the mitochondria and have been implicated in aminoglycoside-induced ototoxicity. Mitochondrial dysfunction results in loss of membrane potential, release of caspases, and cell apoptosis. Moringa extract has not previously been examined as a protective agent for aminoglycoside-induced ototoxicity. Methods Putative otoprotective effects of moringa extract were investigated in an organotypic model using murine organ of Corti explants subjected to gentamicin-induced ototoxicity. Assays evaluated hair cell loss, cytochrome oxidase expression, mitochondrial membrane potential integrity, and caspase activity. Results In vitro application of moringa conferred significant protection from gentamicin-induced hair cell loss at dosages from 25 to 300 μg/mL, with dosages above 100 μg/mL conferring near complete protection. Assays demonstrated moringa extract suppression of ROS, preservation of cytochrome oxidase activity, and reduction in caspase production. Conclusion Moringa extract demonstrated potent antioxidant properties with significant protection against gentamicin ototoxicity in cochlear explants.

Summary The search for life on Mars has been guided in part by the search for biosignatures in Martian analogues on Earth. Siliceous hot springs are key astrobiological targets as they provide ideal conditions for biogenesis. This work documents biomarker analyses carried out on siliceous hot spring sinters from El Tatio, Chile, and from the Taupo Volcanic Zone, New Zealand, with an age range from actively forming to fossil deposits (∼1–21 ka). In addition, older samples (Pliocene–Miocene) were analysed from the Coromandel Volcanic Zone, New Zealand. Some of the data have already been published. The key hydrocarbons detected in some (or all) of the samples include n-alkanes, isoprenoids, monomethylalkanes, tricyclic and tetracyclic terpanes, hopanes, 2α-methylhopanes, steranes, and some aromatic hydrocarbons. A series of biomarker and aromatic hydrocarbon maturity parameters suggest that most samples have entered the oil generation window, and that maturity is strongly variable between samples and by parameter. These signals are indicative of organic matter sourced from subsurface hydrothermal fluids migrating from deeper immature source rocks that have been hydrothermally altered, rather than from the in situ material preserved within the samples in the hot spring environment.

Recent discoveries of geyserite and siliceous sinter with textural biosignatures in the ∼3.5 Ga Dresser Formation of the Pilbara Craton, Western Australia, extended the record of inhabited subaerial hot springs on Earth by ∼3 billion years, back to the time when siliceous sinter deposits are known to have formed on Mars (

Objective Non-adherence to pediatric regimens is a common concern. Low health literacy is correlated with poor outcomes in adults but is understudied in pediatrics. The current project aimed to determine the relationship between health literacy, adherence, and outcomes in pediatric liver transplant recipients. Hypotheses included a) parent and patient health literacy would be positively correlated; and b) low patient and/or parent health literacy would be negatively correlated with adherence and health outcomes. Patients and methods Eligible participants were recruited during routine follow-up visits in a pediatric liver transplant clinic. Parents and patients (>13 years old) completed 2 measures of health literacy. Patients ≥18 years completed health literacy measures without corresponding parent surveys. Adherence variables and health outcomes were obtained from medical records. Results Seventy-nine patients across two sites completed the study. Variance in classification of health literacy between measures was observed; however, most parents (82%-100%) scored within an "adequate literacy" range. More adolescents scored in lower health literacy ranges relative to the parents. Markers of SES were positively correlated with health literacy. Parent health literacy was negatively associated with biopsy-proven rejection episodes and the number of hospitalizations; however, it was not associated with measures of tacrolimus adherence. There were no relationships observed between parent and adolescent health literacy. Conclusions Health literacy is an important consideration in managing patient care; however, available measures demonstrate variability in capturing the skills of patients. Effective communication strategies may ameliorate admittedly small, but negative, impacts of limited health literacy on outcomes.

Digitate siliceous hot spring deposits are a form of biomediated sinter that is relatively common in the Taupo Volcanic Zone (TVZ), New Zealand, and elsewhere on Earth. Such deposits have gained prominence recently because of their morphological similarity to opaline silica rocks of likely hot spring origin found by the Spirit rover on Mars and the consequent implications for potential biosignatures there. Here, we investigate the possible relationship between microbial community composition and morphological diversity among digitate structures from actively forming siliceous hot spring sinters depositing subaerially in shallow discharge channels and around pool rims at several physicochemically distinct geothermal fields in the TVZ. The TVZ digitate sinters range in morphologic subtype from knobby to spicular, and are shown to be microstromatolites that grow under varied pH ranges, temperatures, and water chemistries. Scanning electron microscopy and molecular analyses revealed that TVZ digitate sinters are intimately associated with a diverse array of bacterial, archaeal and eukaryotic micro-organisms, and for most digitate structures the diversity and quantity of prokaryotes was higher than that of eukaryotes. However, microbial community composition was not correlated with morphologic subtypes of digitate sinter, and observations provided limited evidence that pH (acidic versus alkali) affects morphology. Instead, results suggest hydrodynamics may be an important factor influencing variations in morphology, while water chemistry, pH, and temperature are strong drivers of microbial composition and diversity.

Biliary atresia is a newborn cholangiopathy that may lead to portopulmonary hypertension and cirrhosis-induced cardiomyopathy while awaiting liver transplantation. Extracorporeal life support and hepatic toxin filtration are life-saving interventions that provide cardiopulmonary support and hepatic dialysis to allow resolution of a child's illness. We utilized a combination of these extreme measures to bridge an infant with biliary atresia to transplantation. We reviewed cases of extracorporeal life support utilization in transplantation recipients in the Extracorporeal Life Support Organization database and determined that ours was the only use of pretransplant extracorporeal life support in biliary atresia.

The Hauraki Goldfield of the Coromandel Volcanic Zone, North Island, New Zealand, hosts up to 19 known siliceous hot spring deposits, or sinters, some directly associated with Au–Ag ore bodies, in a Miocene–Pliocene, sub-aerial, calc-alkaline volcanic arc overlying Jurassic meta-sedimentary basement. Sinters are surface expressions of predominately adularia-sericite epithermal systems, potentially linked to Au–Ag mineralised conduits at depth. They provide a paleosurface marker to determine the level of erosion, and help determine zones of thermal fluid upflow and/or lateral outflow. Mapped sinters of the Coromandel Volcanic Zone are mainly affiliated with rhyolite domes, occur along structural corridors of the volcanic arc, and contain characteristic textures, mineralogy and pathfinder elements typical of near-neutral pH alkali chloride fluid discharge derived from convectively circulating magmatic fluids diluted by meteoric waters. Textures and trace element compositions of the Coromandel sinters are similar to those of the Taupo Volcanic Zone, New Zealand, and the Jurassic Au–Ag mining districts of the Deseado Massif, Argentine Patagonia. Thus, detailed mapping, textural analysis and trace-element studies demonstrate the prospecting potential of siliceous hot spring deposits for locating ore deposits, and in particular to help define proximal to distal positions relative to vent zones at the paleo-surface. Fil: Hamilton, Ayrton. University of Auckland; Nueva Zelanda Fil: Campbell, Kathleen. University of Auckland; Nueva Zelanda Fil: Rowland, Julie V.. University of Auckland; Nueva Zelanda Fil: Barker, Shaun. University of Auckland; Nueva Zelanda Fil: Guido, Diego Martin. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina

From the 1950s, extraction of thermal fluids to generate electricity at Wairakei, Taupo Volcanic Zone, New Zealand, heralded a rapid transformation of surface manifestations at nearby Geyser Valley, 1 km NW of the power station. Active geysers and hot-springs fed by alkali-chloride waters ceased by 1968, replaced by acidic steam-dominated conditions. Field relationships indicate geothermal features are fault-controlled. Siliceous hot-spring (sinter) deposits represent spring-vent to distal marsh settings. The dominant mineralogy is opal-A, with some minor clay alteration. Some textures show silica dissolution and re-precipitation. Thus, only minor alteration and diagenesis has occurred, with vegetation overgrowing the extinct sinter. Fil: Watts Henwood, Nick. The University of Auckland; Nueva Zelanda Fil: Campbell, Kathleen. The University of Auckland; Nueva Zelanda Fil: Lynne, Bridget Y.. The University of Auckland; Nueva Zelanda Fil: Guido, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; Argentina Fil: Rowland, Julie V.. The University of Auckland; Nueva Zelanda Fil: Browne, Patrick R.L.. The University of Auckland; Nueva Zelanda

Noise induced hearing loss (NIHL) remains a severe health problem worldwide. Current noise metrics and models have assessment limitations on gradually developing NIHL (GDNIHL). In this study, we apply a complex velocity level (CVL) auditory fatigue model to quantitatively assess the impact of basilar membrane (BM) movement on GDNIHL. The transfer functions of chinchilla and human auditory systems, including the triple-path nonlinear (TRNL) filters to simulate the inner ear responses, are applied to obtain BM velocity distribution. Chinchilla and human experimental hearing loss data are used to validate the proposed CVL model’s effectiveness. The results reveal that the developed CVL model demonstrates high correlations with both chinchilla and human hearing loss data. The linear regression based correlation study indicates the proposed CVL model may accurately predict NIHL in both human and chinchilla.

Jurassic siliceous hot-spring (sinter) deposits from Argentine Patagonia were evaluated to determine the distribution and preservation quality of their entombed microbial fabrics. Detailed study showed that the Claudia palaeo-geothermal field hosts the best-preserved sinter apron in the Deseado Massif geological province, where we also found hot-spring silica?biotic interactions extending into hydrothermally influenced fluvial and lacustrine settings. Carbonaceous material was identified by petrography and Raman spectroscopy mapping; it is inter-laminated with silica across proximal vent to distal marsh facies. The ubiquitous presence of microbial biosignatures has application to studies of hydrothermal settings of early life on Earth and potentially Mars. Fil: Guido, Diego Martin. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina Fil: Campbell, Kathleen. University of Auckland; Nueva Zelanda Fil: Foucher, Frédéric. Centre National de la Recherche Scientifique; Francia Fil: Westall, Frances. Centre National de la Recherche Scientifique; Francia

A new and unusual type of fossil, siliceous hot-spring deposit (sinter) comprising monomictic, quartzose conglomerate encrusted with silicified microbial laminates has been recognized in distal portions of Jurassic and Miocene paleo-geothermal fields of South and North America, respectively. The siliceous clasts are inferred to have originated as conduit-delivered hydrothermal silica gel, owing to their general plastic morphologies,which were then locally reworked and redistributed in geothermally influenced stream paleoenvironments. Today, hot-spring-fed streams and creeks, in places with silica-armored pavements, host microbial mats coating streambeds and/or growing over, and silicifying at, stream air-water interfaces, for example, in Yellowstone National Park (USA) and Waimangu Volcanic Valley (New Zealand). However, the modern deposits do not contain the plastically deformed silica cobbles evident in Mesozoic and Cenozoic examples escribed herein. Moreover, the fossil microbial laminates of this study are relatively dense and strongly coat the silica cobbles, suggesting the mats stabilized the clasts under fully submerged and hot, high-energy conditions. Thus, this new sinter facies, typically found a few kilometers from main spring-vent areas, is a perhaps unexpected extreme environment in which life took hold in hydrothermal-fluvial settings of the past, and may serve as an additional target in the search for fossil biosignatures of early Earth and possibly Mars. Fil: Guido, Diego Martin. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina Fil: Campbell, Kathleen. University of Auckland; Nueva Zelanda

To prospectively assess the diagnostic performance of ultrasound shear wave elastography (SWE) and hepatobiliary laboratory biomarkers for discriminating biliary atresia from other causes of neonatal cholestasis.Forty-one patients3 months of age with neonatal cholestasis (direct bilirubin2 mg/dL) and possible biliary atresia were prospectively enrolled. Both 2-dimensional (2D) and point ultrasound SWE were performed prior to knowing the final diagnosis. Median 2D (8) and point (10) shear wave speed measurements were calculated for each subject and used for analyses. The Mann-Whitney U test was used to compare shear wave speed and laboratory measurements between patients with and without biliary atresia. Receiver operating characteristic curve analyses and multivariable logistic regression were used to evaluate diagnostic performance.Thirteen subjects (31.7%) were diagnosed with biliary atresia, and 28 subjects (68.3%) were diagnosed with other causes of neonatal cholestasis. Median age at the time of ultrasound SWE was 37 days. Median 2D (2.08 vs 1.49 m/s, P = .0001) and point (1.95 vs 1.21 m/s, P = .0014) ultrasound SWE measurements were significantly different between subjects with and without biliary atresia. Using a cut-off value of1.84 m/s, 2D ultrasound SWE had a sensitivity = 92.3%, specificity = 78.6%, and area under the receiver operating characteristic curve (AuROC) of 0.89 (P .0001). Using a cut-off value of320 (U/L), gamma-glutamyl transferase (GGT) had a sensitivity = 100.0%, specificity = 77.8%, and AuROC of 0.85 (P .0001). Multivariable logistic regression demonstrated an AuROC of 0.93 (P .0001), with 2 significant covariates (2D ultrasound SWE [OR = 23.06, P = .01]; GGT [OR = 1.003, P = .036]).Ultrasound SWE and GGT can help discriminate biliary atresia from other causes of neonatal cholestasis.

The Atastra Creek siliceous hot spring deposit, or sinter, occurs in the Paramount-Bald Peak alteration zone, due north of the Bodie precious metals mining district in the Miocene Bodie Hills volcanic field, California and Nevada, U.S.A. Distinctive features include its geomorphically intact geyser vent mounds, the presence of growth-fault-stepped sinter terraces that developed westward along a NNW trending fault, and atypical Hg, Sb and As concentrations. High-temperature (>75 °C), subaerial, proximal apron sinter occurs in two settings – (1) radiating botryoidal geyserite in vent mounds and (2) bedded geyserite (columnar, nodular, size-sorted geyser eggs) intercalated with mid- to low-temperature (

BackgroundFontan survivors have depressed cardiac index that worsens over time. Serum biomarker measurement is minimally invasive, rapid, widely available, and may be useful for serial monitoring. The purpose of this study was to identify biomarkers that correlate with lower cardiac index in Fontan patients.Methods and resultsThis study was a multi-centre case series assessing the correlations between biomarkers and cardiac magnetic resonance-derived cardiac index in Fontan patients ⩾6 years of age with biochemical and haematopoietic biomarkers obtained ±12 months from cardiac magnetic resonance. Medical history and biomarker values were obtained by chart review. Spearman’s Rank correlation assessed associations between biomarker z-scores and cardiac index. Biomarkers with significant correlations had receiver operating characteristic curves and area under the curve estimated. In total, 97 cardiac magnetic resonances in 87 patients met inclusion criteria: median age at cardiac magnetic resonance was 15 (6–33) years. Significant correlations were found between cardiac index and total alkaline phosphatase (−0.26, p=0.04), estimated creatinine clearance (0.26, p=0.02), and mean corpuscular volume (−0.32, p2versus lower-risk group=2.96 L/minute/m2, (pConclusionsHigher total alkaline phosphatase and mean corpuscular volume as well as lower estimated creatinine clearance identify Fontan patients with lower cardiac index. Using biomarkers to monitor haemodynamics and organ-specific effects warrants prospective investigation.

This study examined potential prevention of music-induced temporary threshold shift (TTS) in normal-hearing participants. A dietary supplement composed of β-carotene, vitamins C and E, and magnesium was assessed using a randomized, placebo-controlled, double-blind study design. Dosing began 3 days prior to the music exposure with the final dose consumed approximately 30-min pre-exposure. Post-exposure TTS was measured, with no significant difference as a function of treatment. Distortion product otoacoustic emission amplitudes were suppressed after music exposure in both groups, with no significant difference as a function of treatment. Tinnitus was more likely to be reported by the treatment group, but there were no group differences in perceived loudness or bothersomeness. Taken together, this supplement had no effect on noise-induced changes in hearing. Recommendations for future clinical trials are discussed.

The Kohuamuri siliceous sinter is the largest known fossil hot-spring system in the Hauraki Goldfield, a 200 × 40 km volcanic terrain with at least 50 adularia-illite epithermal deposits formed 16.3–5.6 Ma within the Coromandel Volcanic Zone, New Zealand. The sinter is associated with rhyolite and ignimbrite of the Whitianga Caldera (Miocene–Pliocene) and consists of two deposits, the Kohuamuri deposit itself, a large in situ outcrop (47,000 m2) and its associated sinter boulder field (4500 m2), and the Kaitoke deposit 900 m to the southwest, comprising boulders in a landslide situated on a normal fault. The well-preserved macroscopic and microscopic textures at Kohuamuri are similar to actively forming and ancient hot-spring deposits elsewhere, derived from deep circulating, magmatically heated, near-neutral pH alkali chloride fluids oversaturated in amorphous silica and that discharge at the Earth’s surface at ≤100 °C. Lithofacies, petrography, mineralogy, as well as trace element concentrations of the Kohuamuri/Kaitoke deposits were used to locate likely palaeo-thermal conduits from the deep reservoir and to reconstruct the palaeoenvironmental setting of the siliceous sinter as an aid to assessing the economic potential of the ancient geothermal system. Both deposits contain the high-temperature (>75 °C) geyserite lithofacies, with the Kohuamuri deposit also exhibiting textures affiliated with cooler middle and distal sinter apron areas, as well as geothermally influenced marsh facies. Trace element analysis of sinter lithofacies revealed concentrations and zonations of Au, Ag, base metals (Pb, Cu, Zn) and pathfinder elements (As, Sb) associated with epithermal deposits, elevated in the proximal vent area, and providing evidence of possible Au and Ag ore mineralisation at depth. The methodology used in this study could be utilised globally to identify and assess as yet unidentified epithermal deposits.

In 1941, a 72-m-deep bore (Healy's Bore 2; HB2) at the Hipaua-Waihi-Tokaanu geothermal field, Taupo Volcanic Zone, New Zealand, tapped alkali chloride water of 145 °C at the bottom of the well. Since then, thermal fluid (

This review will summarise the current state of development of pharmaceutical interventions (prevention or treatment) for medication-induced ototoxicity.Currently published literature was reviewed using PubMed and ClinicalTrials.gov to summarise the current state of the science. Details on the stage of development in the market pipeline are provided, along with evidence for clinical safety and efficacy reported.This review includes reports from 44 articles and clinical trial reports regarding agents in clinical or preclinical trials, having reached approved Investigational New Drug status with the Federal Drug Administration.Vitamins and antioxidants are the most common agents currently evaluated for drug-induced ototoxicity intervention by targeting the oxidative stress pathway that leads to cochlear cell death and hearing loss. However, other strategies, including steroid treatment and reduction of ototoxic properties of the primary drugs, are discussed.Retention of hearing during and after a life threatening illness is a major quality-of-life issue for patients receiving ototoxic drugs and their families. The agents discussed herein, while not mature enough at this point, offer great promise towards that goal. This review will provide a knowledge base for hearing providers to inquiries about such options from patients and interdisciplinary care teams alike.

Intrahepatic bile duct development is a sophisticated process that begins with a simple, perivenular arrangement of hepatoblasts and ends with an intricate, arborizing, hierarchical network of ducts that navigate the liver parenchyma, contributing to liver health and disease not only via drainage of bile but via direct and indirect interactions with surrounding cells. Development of the intrahepatic bile ducts depends upon cell specification and subsequent morphogenesis, both involving intercellular signaling through the Notch pathway. Alteration of this pathway by mutations in critical Notch ligands and/or Notch receptors disrupts normal intrahepatic bile duct formation and leads to the hepatobiliary phenotype seen in Alagille syndrome. More complete insight into the complexities of intrahepatic bile duct development and the signaling pathways involved (Notch and others) is a requisite preamble to defining cellular and molecular therapies with the potential of attenuating, or reversing, biliary injury in Alagille syndrome and other cholangiopathies.

Three new fossil species of lucinids, Meganodontia haunuiensis, Elliptiolucina neozelandica, and Lucinoma saetheri, are described from lower to middle Miocene hydrocarbon seep carbonates from north and south of Hawke Bay, eastern North Island, New Zealand. Of these taxa Meganodontia haunuiensis is confined to seep sites south of Hawke Bay, while Elliptiolucina neozelandica comes only from the seep sites north of Hawke Bay. Using ecological information from modern bivalve species, we suggest the southern area seep sites formed in shallower waters than the northern sites. Among the lucinids, Meganodontia haunuiensis is one of the oldest records of the genus, and its distribution has shrunk from worldwide in the Miocene times to only around Taiwan today. Elliptiolucina neozelandica is the second oldest species in the genus. Since the Miocene the distribution of Elliptiolucina has narrowed but its habitat range has increased to both seeps and sandy environments, mainly around the Philippines.

New Zealand and Argentine (Late Jurassic-Recent) siliceous hot-spring deposits (sinter) reveal preservation pathways of environmentally controlled, microbe-dominated sedimentary facies over geological time scales. Texturally distinctive, laminated to thinly layered, dense and vertically oriented, microtubular "palisade" fabric is common in low-temperature (