Brine residues and organics in the Urvara basin on Ceres.

Ceres is a partially differentiated dwarf planet, as confirmed by NASA's Dawn mission. The Urvara basin (diameter ~170 km) is its third-largest impact feature, enabling insights into the cerean crust. Urvara's geology and mineralogy suggest a potential brine layer at the crust-mantle transition. Here we report new findings that help in understanding the structure and composition of the cerean crust. These results were derived by using the highest-resolution Framing Camera images acquired by Dawn at Ceres. Unexpectedly, we found meter-scale concentrated exposures of bright material (salts) along the crater's upper central ridge, which originate from an enormous depth, possibly from a deep-seated brine or salt reservoir. An extended resurfacing modified the southern floor ~100 Myr after crater formation (~250 Myr), long after the dissipation of the impact-generated heat. In this resurfaced area, one floor scarp shows a granular flow pattern of bright material, showing spectra consistent with the presence of organic material, the first such finding on Ceres beyond the vast Ernutet area. Our results strengthen the hypothesis that Ceres is and has been a geologically active world even in recent epochs, with salts and organic-rich material playing a major role in its evolution.

Prospective study of the natural history of chronic acid sphingomyelinase deficiency in children and adults: eleven years of observation.

BACKGROUND: Acid sphingomyelinase deficiency (ASMD) (also known as Niemann-Pick disease types A and B) is a rare and debilitating lysosomal storage disorder. This prospective, multi-center, multinational longitudinal study aimed to characterize the clinical features of chronic forms of ASMD and disease burden over time in children and adults. RESULTS: Fifty-nine patients (31 males/28 females) ranging in age from 7 to 64 years with chronic ASMD types A/B and B and at least two disease symptoms participated from 5 countries. Disease characteristics were assessed at baseline, after 1 year, and at the final visit (ranging from 4.5 to 11 years). Thirty patients (51%) were < 18 years at baseline (median age 12 years), and 29 were adults (median age 32 years). Overall, 32/59 patients completed the final visit, 9 died, 9 discontinued, and 9 were lost to follow up. Common clinical characteristics that tended to worsen gradually with time were splenomegaly, hepatomegaly, interstitial lung disease, lung diffusion capacity (DLCO), and dyslipidemia. Spleen volumes ranged from 4 to 29 multiples of normal at baseline, and splenomegaly was moderate or severe in 86%, 83%, and 90% of individuals at baseline, year 1, and final visits, respectively. The proportion of all individuals with interstitial lung disease was 66% (39/59) at baseline and 78% (25/32) at the final visit, while median % predicted DLCO decreased by > 10% from baseline to the final visit. Nine patients died (15%), eight of causes related to ASMD (most commonly pneumonia); of these eight patients, five (63%) had symptom onset at or before age 2. Overall, six of the nine deaths occurred before age 50 with three occurring before age 20. Individuals with either severe splenomegaly or prior splenectomy were ten times more likely to have died during the follow-up period than those with smaller or intact spleens (odds ratio 10.29, 95% CI 1.7, 62.7). Most children had growth deficits that persisted into adulthood. CONCLUSIONS: This study provides important information about the natural history of chronic ASMD and provides a longitudinal view of the spectrum of disease manifestations and major morbidities in children and adults and supports the selection of clinically meaningful endpoints in therapeutic trials.

Clinical outcomes in a subpopulation of adults with Morquio A syndrome: results from a long-term extension study of elosulfase alfa.

BACKGROUND: This post hoc subanalysis examined outcomes in adult patients with Morquio A (mucopolysaccharidosis IVA) who received enzyme replacement therapy (ERT) with elosulfase alfa over a 120-weeks period. Patients ≥18 years of age evaluated in an open-label, long-term extension study of elosulfase alfa (modified per protocol [MPP], n = 32; intent-to-treat [ITT], n = 37; MOR-005; NCT01415427) were compared with the ≥18-year-old untreated population with 2-years follow-up from a Morquio A natural history study (n = 10; MorCAP; NCT00787995). The MOR-005 MPP population excluded patients who underwent orthopedic surgical procedures or were noncompliant with study protocol (defined as missing ≥20% of ERT infusions). No MorCAP patients underwent orthopedic surgical procedures during the relevant time period. Endurance was assessed by the 6-min walk test (6MWT) and 3-min stair climb test (3MSCT). Activities of daily living (ADLs) were assessed by the MPS Health Assessment Questionnaire (MPS HAQ). RESULTS: Least squares (LS) mean (SE) 6MWT distances increased by 34.9 (11.7) m (MPP) and 30.5 (10.8) m (ITT) by week 120; LS mean (SE) change in 3MSCT at week 120 was 6.7 (1.8) stairs/min (MPP) and 5.9 (1.7) stairs/min (ITT). MorCAP patients showed no improvement in 6MWT distance or 3MSCT over a similar period of time. Pulmonary function measures remained unchanged in both MOR-005 and MorCAP adults. All MPS HAQ domain scores improved in MOR-005 adults, whereas MorCAP adults had unchanged caregiver assistance and mobility outcomes and worsened self-care outcomes. CONCLUSIONS: Long-term ERT in adult patients with Morquio A was associated with increased endurance and improvement in performance of ADLs. TRIAL REGISTRATION: Trial Registration NCT01415427 . Name of registry: Long-Term Efficacy and Safety Extension Study of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome). Registered 8 August 2011, retrospectively registered.

Sublimation in bright spots on (1) Ceres.

The dwarf planet (1) Ceres, the largest object in the main asteroid belt with a mean diameter of about 950 kilometres, is located at a mean distance from the Sun of about 2.8 astronomical units (one astronomical unit is the Earth-Sun distance). Thermal evolution models suggest that it is a differentiated body with potential geological activity. Unlike on the icy satellites of Jupiter and Saturn, where tidal forces are responsible for spewing briny water into space, no tidal forces are acting on Ceres. In the absence of such forces, most objects in the main asteroid belt are expected to be geologically inert. The recent discovery of water vapour absorption near Ceres and previous detection of bound water and OH near and on Ceres (refs 5-7) have raised interest in the possible presence of surface ice. Here we report the presence of localized bright areas on Ceres from an orbiting imager. These unusual areas are consistent with hydrated magnesium sulfates mixed with dark background material, although other compositions are possible. Of particular interest is a bright pit on the floor of crater Occator that exhibits probable sublimation of water ice, producing haze clouds inside the crater that appear and disappear with a diurnal rhythm. Slow-moving condensed-ice or dust particles may explain this haze. We conclude that Ceres must have accreted material from beyond the 'snow line', which is the distance from the Sun at which water molecules condense.

Evaluation of Bone Marrow Infiltration in Non-Neuropathic Gaucher Disease Patients with Use of Whole-Body MRI--A Retrospective Data Analysis.

PURPOSE: To evaluate whole-body magnetic resonance imaging (WB-MRI) for the assessment of bone marrow infiltration in patients with confirmed Gaucher disease type 1 under long-term enzyme replacement therapy (ERT). MATERIALS AND METHODS: This retrospective data analysis included 38 patients in two subgroups. Group A: 10 females, 9 males, 15-29 years, mean age 22 years and Group B: 11 females, 8 males, 29-77 years, mean age 49 years, all treated with alglucerase or imiglucerase for at least 12.5 years. Whole-body MRI was carried out in all patients using a standard MRI protocol. Two radiologists assessed all MR images retrospectively with the use of three different MRI score systems: The bone marrow burden (BMB) score, the Düsseldorf-Gaucher score (DGS) and the vertebra disc ratio (VDR). As a clinical component, severity score index type 1 (GD-DS3) was determined. RESULTS: In both groups the MR scores showed low to moderate pathologic levels but no statistically significant difference was found between both groups. The median scores in group A/group B were 7.00/9.00 for the BMB score (p=0.07), 4.00/3.00 for the DGS score (p=0.062) and 1.54/1.62 for the VDR score (p=0.267). The GD-DS3 score was statistically significantly different between both groups (1.6/3.9, p=0.000) and osseous Gaucher disease complications were only found in group B. CONCLUSION: Bone marrow involvement and typical clinical manifestations are reduced to a minimum, when ERT starts immediately after the confirmed diagnosis of Gaucher disease type 1. The applied MR scores are useful markers to control bone marrow infiltration under enzyme replacement therapy in older patients. Pathologic MR scores in young patients may reflect postponed fat conversion of the juvenile bone marrow. This issue has to be examined in further studies. KEY POINTS: Whole-body MRI is valuable for the staging of Gaucher disease type 1. Osseous complications are reduced to a minimum in early treated patients. MR score systems have to be adjusted in young Gaucher patients.

Photoproduction of eta-mesic 3He.

The photoproduction of eta-mesic 3He has been investigated using the TAPS calorimeter at the Mainz Microtron accelerator facility MAMI. The total inclusive cross section for the reaction gamma3He-->etaX has been measured for photon energies from threshold to 820 MeV. The total and angular differential coherent eta cross sections have been extracted up to energies of 745 MeV. A resonancelike structure just above the eta production threshold with an isotropic angular distribution suggests the existence of a resonant quasibound state. This is supported by studies of a competing decay channel of such a quasibound eta-mesic nucleus into pi(0)pX. A binding energy of (-4.4+/-4.2) MeV and a width of (25.6+/-6.1) MeV is deduced for the quasibound eta-mesic state in 3He.

In-medium modifications of the pipi interaction in photon-induced reactions.

Differential cross sections of the reactions (gamma,pi(0)pi(0)) and (gamma,pi(0)pi(+/-)) have been measured for several nuclei (1H,12C, and (nat)Pb) at an incident-photon energy of E(gamma)=400-460 MeV at the tagged-photon facility at MAMI-B using the TAPS spectrometer. A significant nuclear-mass dependence of the pipi invariant-mass distribution is found in the pi(0)pi(0) channel. This dependence is not observed in the pi(0)pi(+/-) channel and is consistent with an in-medium modification of the pipi interaction in the I=J=0 channel. The data are compared to pi-induced measurements and to calculations within a chiral-unitary approach.

The reaction gammap-->pi0gamma'p and the magnetic dipole moment of the Delta+ 1232 resonance.

The reaction gammap-->pi(0)gamma'p has been measured with the TAPS calorimeter at the Mainz Microtron accelerator facility MAMI for energies between sqrt[s]=1221-1331 MeV. The cross section's differential in angle and energy have been determined for the photon gamma' in three bins of the excitation energy. This reaction channel provides access to the magnetic dipole moment of the Delta(+)(1232) resonance and, for the first time, a value of mu(Delta(+))=[2.7(+1.0)(-1.3)(stat)+/-1.5(syst)+/-3(theor)]mu(N) has been extracted.

Apoplastic pH and Fe(3+) reduction in intact sunflower leaves

It has been hypothesized that under NO(3)(-) nutrition a high apoplastic pH in leaves depresses Fe(3+) reductase activity and thus the subsequent Fe(2+) transport across the plasmalemma, inducing Fe chlorosis. The apoplastic pH in young green leaves of sunflower (Helianthus annuus L.) was measured by fluorescence ratio after xylem sap infiltration. It was shown that NO(3)(-) nutrition significantly increased apoplastic pH at distinct interveinal sites (pH >/= 6.3) and was confined to about 10% of the whole interveinal leaf apoplast. These apoplastic pH increases presumably derive from NO(3)(-)/proton cotransport and are supposed to be related to growing cells of a young leaf; they were not found in the case of sole NH(4)(+) or NH(4)NO(3) nutrition. Complementary to pH measurements, the formation of Fe(2+)-ferrozine from Fe(3+)-citrate was monitored in the xylem apoplast of intact leaves in the presence of buffers at different xylem apoplastic pH by means of image analysis. This analysis revealed that Fe(3+) reduction increased with decreasing apoplastic pH, with the highest rates at around pH 5. 0. In analogy to the monitoring of Fe(3+) reduction in the leaf xylem, we suggest that under alkaline nutritional conditions at interveinal microsites of increased apoplastic pH, Fe(3+) reduction is depressed, inducing leaf chlorosis. The apoplastic pH in the xylem vessels remained low in the still-green veins of leaves with intercostal chlorosis.

Effects of NH(4)(+), NO(3)(-) and HCO(3)(-) on apoplast pH in the outer cortex of root zones of maize, as measured by the fluorescence ratio of fluorescein boronic acid

A fluorimetric ratio technique was elaborated to measure apoplastic pH in the outer root cortex of maize (Zea mays L.) grown hydroponically. A newly synthesized fluorescent probe, fluorescein boronic acid (pK(a) = 5.48), which covalently binds to the cell wall of the outer cell layers, was used. Under conditions of saturating ion concentrations the apoplastic pH was determined along the root axis ranging from 1 to 30 mm behind the root tip. Apoplastic pH was recorded for root segment areas (1 mm(2)), and pH values of high statistical significance were obtained. With an external solution of pH 5, the apoplastic pH was about pH 5.1 in the division zone, between pH 4.8 and 4.9 in the elongation region and about pH 4.9 in the root hair zone. At an external pH of 8.6, the difference between the external pH and the apoplastic pH was considerably more, with a pH of 5.2-5.3 in all root zones. Addition of 1 mM NH(4)(+) caused a small apoplastic pH decrease (0.05 of a pH unit) in all root zones. Apoplastic alkalization upon application of 6 mM NO(3)(-) was highest (0.3 of a pH unit) in the zone where root hairs emerge; in the division and early elongation zones, apoplastic pH increased only transiently. In the presence of 10 mM HCO(3)(-), NO(3)(-) elicited a higher and persistent alkalization (0.06-0.25 of a pH unit) in all root zones. Application of fusicoccin reduced apoplastic pH from 4.85 to 4.75 in the elongation zone, while inhibition of the H(+)-ATPase with vanadate alkalized the apoplast in the root hair zone from pH 5.4 to 5.6. The observed pH differences along the root axis upon differential N supply and application of HCO(3)(-) provide evidence that this new pH technique is a useful tool with which to measure apoplastic pH, and in future may permit measurements at microsites at the cell level by use of microscope imaging.

The effects of patellar taping on stride characteristics and joint motion in subjects with patellofemoral pain.

Although patellar taping has been reported to be effective in reducing pain, the effects of this procedure on functional outcomes, such as ambulation, have not been documented. The purpose of this study was to compare stride characteristics and joint motion in subjects with patellofemoral pain, with and without the application of patellar taping using the McConnell technique. Fifteen female subjects between the ages of 14 and 41 years with diagnosis of patellofemoral pain participated in this study. Stride characteristics (Stride Analyzer) and sagittal plane joint motion (VICON) were recorded simultaneously during taped and untaped trials of free walking, fast walking, and ascending and descending a ramp and stairs. A repeated measures analysis of variance was used to determine differences between taped and untaped trials. Although subjects reported an average pain reduction of 78% using a visual analogue scale, the only significant change in stride characteristics was an increase in stride length during ramp ascent. Patellar taping did, however, result in a small but significant increase in loading response knee flexion across all conditions tested. We believe this finding demonstrates more willingness by the patellofemoral pain subjects to load the knee joint, thus permitting increased shock absorption, increased quadriceps activity, and tolerance of increased patellofemoral joint reaction force.

In vivo effects of fluconazole on lymphocyte subpopulations of the thymus and spleen in mice: flow cytometry analysis.

Fluconazole is a triazole compound developed for the therapy of fungal infections, especially for systemic fungal infections. In this study 2.5 and 5.0 mg oral doses of fluconazole per kg of body weight were administered to mice for 3-28 days, followed by lymphocyte phenotyping by flow cytometry analysis on a Becton-Dickinson FACScan. The results show that administration of fluconazole neither reduced body and organ weights nor thymocyte and spleen cell count. In the thymus and spleen the distribution of all the lymphocyte subpopulations studied was unchanged. These results suggest that fluconazole has no in vivo effects on the quantity of lymphocyte subpopulations in mice. The results tend to support the use of fluconazole in immunosuppressed patients.

Thermolabile hemoglobin formation by 2-cyanaziridine derivatives.

The erythrocyte toxicity of imexone, azimexone, ciamexone, and its derivatives was assessed by means of the thermolabile hemoglobin formation test. After administration of doses up to 500 mg/kg to mice, imexone had no effect, whereas in accordance with previous studies azimexone strongly and ciamexone moderately enhanced thermolabile hemoglobin formation. With regard to the derivatives (metabolites) of ciamexone, the alcohol was as active as ciamexone itself, whereas ciamexone aldehyde gave a weak reaction. Both ciamexone acid and ciamexone-cysteine had no influence. Demethyl ciamexone, however, was more toxic than ciamexone, further indicating that the metabolic oxidation of the methyl group represents a detoxifying step. In contrast to the in vivo results, after incubation with blood samples solely imexone (in the range of mg/ml blood) but none of the other 2-cyanaziridines enhanced thermolabile globin formation. Preincubation of imexone with cysteine inhibited this effect. The results are discussed in view of the hypothesis that binding of the nitrile group of the 2-cyanaziridines to mercapto groups of proteins precedes their biological effects.

No influence of cadmium on the production of specific antibodies in mice.

The in vivo effect of cadmium on specific antibody production of the immune system was investigated in mice. Female Balb/c mice were given 1, 10 or 100 ppm cadmium as cadmium chloride in the drinking water for 7, 14, 21, 28, 60 or 90 days. Immunization of the mice was carried out twice with a specific antigen (dinitrophenyl-bovine serum albumin) at an interval of 14 days. The antibodies (IgM and IgG) produced by this antigen were determined jointly with the aid of ELISA on days 0, 7, 14, and 21 after the first sensitization. The leucocyte count in the blood of the animals exposed to cadmium was unchanged. In spite of marked spleen and thymus atrophy in the 100-ppm group, the measurement of antibody concentrations in the blood, also, did not show any significant differences from controls. Our results show that orally administered cadmium at the doses selected does not have any effect on the specific antibody production and thus on the most important function of the humoral immune system. The marked loss of weight of the thymus, however, does suggest there were effects on the cellular immune system.

Effect of Low Root Medium pH on Net Proton Release, Root Respiration, and Root Growth of Corn (Zea mays L.) and Broad Bean (Vicia faba L.).

The effect of low pH on net H(+) release and root growth of corn (Zea mays L.) and broad bean (Vicia faba L.) seedlings was investigated in short-term experiments at constant pH. Broad bean was more sensitive to low pH than corn: the critical values (pH values below which net H(+) release and root growth ceased) were pH 4.00 (broad bean) and pH 3.50 (corn) at 1 millimolar Ca(2+). Both proton release and root growth were progressively inhibited as the medium pH declined. Additional Ca(2+) in the root medium helped to overcome the limitations of low pH for net H(+) release and root growth. Potassium (for corn) and abscisic acid (for broad bean) increased both net H(+) release and root growth rate at the critical pH value. It is concluded that poor root growth at low pH is caused by a lack of net H(+) release that may decrease cytoplasmic pH values. Inhibited net H(+) release at high external H(+) activity is not due to a shortage of energy supply to the H(+) ATPase. Instead, a displacement of Ca(2+) by H(+) at the external side of the plasmalemma may enhance reentry of H(+) into root cells.

Thiosulphate and hydroxocobalamin prophylaxis in progressive cyanide poisoning in guinea-pigs.

The duration of action of the cyanide antidotes sodium thiosulphate and hydroxocobalamin was investigated in guinea-pigs after prophylactic administration before a long-term infusion of NaCN. The parameter for the diminution of the antidote action was the point of time at which the concentration of HCN in the exhaled air of the animals exceeded 100 nmol/kg per min. The time taken to reach this threshold level in the control animals was 12 min. While the threshold level could be extended only to 35 min with hydroxocobalamin (300 mg/kg i.v.) the protective action of sodium thiosulphate (100, 500 and 1000 mg/kg i.v.) persisted dose dependently for about 1, 2 and 4 h, respectively. Additionally we found a plasma half-life of sodium thiosulphate in guinea-pigs of 26 min. This value corresponds approximately to the plasma half-life of sodium thiosulphate in humans given in the literature. Because of the large injection volume necessary, sodium thiosulphate is not suitable for prophylactic use in man.

Active extrusion of protons into deionized water by roots of intact maize plants.

The investigations were focussed on the question as to whether roots of intact maize plants (Zea mays L. cv Blizzard) release protons into deionized H(2)O. Plants in the six to seven leaf stage depressed the pH of deionized H(2)O from 6 to about 4.8 during an experimental period of 4 hours. Only one-third of the protons released could be ascribed to the solvation of CO(2) in H(2)O. The main counter anions released were Cl(-), NO(3) (-), and SO(4) (2-). At low temperature (2 degrees C), the H(+) release was virtually blocked while a relatively high amount of K(+) was released. The presence of K(+), Na(+), Ca(2+), and Mg(2+) in the external solution increased the H(+) secretion significantly. Addition of vanadate to the outer medium inhibited the H(+) release while fusicoccin had a stimulating effect. Substituting the nutrient solution of deionized H(2)O resulted in a substantial increase of the membrane potential difference from -120 to -190 millivolts. The experimental results support the conclusion that the H(+) release by roots of intact maize plants is an active process driven by a plasmalemmalocated ATPase. Since the net H(+) release was not associated with a net uptake of K(+), it is unlikely to originate from a K(+)/H(+) antiport.

The influence on the formation of unstable haemoglobin by the immunomodulating 2-cyanaziridines azimexone and BM 41.332 in mice.

Azimexone causes in mice the formation of unstable haemoglobins after a single dose of 20 mg/kg. BM 41.332, another immunomodulating drug of the 2-cyanaziridine class, induces these unstable haemoglobins only after a single oral administration of 500 mg/kg. Subsequently to the formation of unstable haemoglobins we observed a development of Heinz bodies. These effects of the 2-cyanaziridines were elicited neither by methaemoglobin formation nor by an impairment of the components protecting haemoglobin against oxidation (G6PD, catalase, glutathione). The elimination of the altered haemoglobin in the spleen could be followed by measurement of the rise in the iron content of the spleen.

Comparative investigations of various immunoregulatory substances in the delayed type hypersensitivity test of the mouse.

The substances D-penicillamine, auranofin, chloroquine, levamisole, BM 41.332, azimexone, bestatin, methisoprinol (inosiplex), thymosine (fraction 5), indomethacin and cyclophosphamide were examined comparatively in the delayed type hypersensitivity test after oxazolone sensitisation in mice. It was found, that only the basal antirheumatic drugs D-penicillamine, auranofin, chloroquine and levamisole and also BM 41.332 led to a potentiation of the DTH reactions. Methisoprinol, bestatin, azimexone, thymosine fraction 5 and indomethacin had no effect on the DTH, whilst the immunosuppressant cyclophosphamide led to an inhibition of the DTH reaction. It is concluded that this pharmacological model is suitable for screening of new basal drugs for rheumatoid arthritis.