Search

Sonic Hedgehog (SHH) signaling at primary cilia drives the proliferation and progression of a subset of medulloblastomas, the most common malignant paediatric brain tumor. Severe side effects associated with conventional treatments and resistance to targeted therapies has led to the need for new strategies. SHH signaling is dependent on primary cilia for signal transduction suggesting the potential for cilia destabilizing mechanisms as a therapeutic target. INPP5E is an inositol polyphosphate 5-phosphatase that hydrolyses PtdIns(4,5)P2and more potently, the phosphoinositide (PI) 3-kinase product PtdIns(3,4,5)P3. INPP5E promotes SHH signaling during embryonic development via PtdIns(4,5)P2hydrolysis at cilia, that in turn regulates the cilia recruitment of the SHH suppressor GPR161. However, the role INPP5E plays in cancer is unknown and the contribution of PI3-kinase signaling to cilia function is little characterized. Here, we reveal INPP5E promotes SHH signaling in SHH medulloblastoma by negatively regulating a cilia-compartmentalized PI3-kinase signaling axis that maintains primary cilia on tumor cells. Conditional deletion of Inpp5ein a murine model of constitutively active Smoothened-driven medulloblastoma slowed tumor progression, suppressed cell proliferation, reduced SHH signaling and promoted tumor cell cilia loss. PtdIns(3,4,5)P3, its effector pAKT and the target pGSK3β, which when non-phosphorylated promotes cilia assembly/stability, localized to tumor cell cilia. The number of PtdIns(3,4,5)P3/pAKT/pGSK3β-positive cilia was increased in cultured Inpp5e-null tumor cells relative to controls. PI3-kinase inhibition or expression of wild-type, but not catalytically inactive HA-INPP5E partially rescued cilia loss in Inpp5e-null tumor cells in vitro. INPP5EmRNA and copy number were reduced in human SHH medulloblastoma compared to other molecular subtypes and consistent with the murine model, reduced INPP5Ewas associated with improved overall survival. Therefore our study identifies a compartmentalized PtdIns(3,4,5)P3/AKT/GSK3β signaling axis at cilia in SHH-dependent medulloblastoma that is regulated by INPP5E to maintain tumor cell cilia, promote SHH signaling and thereby medulloblastoma progression.

Congestive heart failure and subclinical left ventricular systolic dysfunction (LVSD) affect long-term survivors of hematopoietic stem cell transplant (HSCT). Echocardiographic measurements of global longitudinal and circumferential strain have shown promise in identifying subclinical LVSD in cancer survivors. We analyzed echocardiograms in 95 children and young adults with malignancies or bone marrow failure syndromes performed before HSCT and 1–6 years after HSCT. We additionally measured the biomarkers soluble suppression of tumorigenicity-2 (sST-2) and cardiac troponin-I (cTn-I) in the same children through 49 days post HSCT. Ejection fraction (EF) after HSCT was unchanged from baseline (baseline: z-score −0.73 vs long-term follow up: −0.44, P=0.11). Global longitudinal strain was unchanged from baseline (−20.66 vs −20.74%, P=0.90) as was global circumferential strain (−24.3 vs −23.5%, P=0.32). Levels of sST-2 were elevated at all time points compared with baseline samples and cTn-I was elevated at days 14 and 28. Cardiac biomarkers at any time point did not correlate with long-term follow-up EF. In children and young adult survivors of HSCT, EF was unchanged in the first years after HSCT. Elevation in cardiac biomarkers occurring after HSCT suggest subclinical cardiac injury occurs in many patients and long-term monitoring for LVSD should continue.

We hypothesized that subclinical cardiac injury in the peri-transplant period is more frequent than currently appreciated in children and young adults. We performed echocardiographic screening on 227 consecutive patients prior to hematopoietic stem cell transplantation (HSCT), and 7, 30 and 100 days after transplant. We measured cardiac biomarkers cardiac troponin-I (cTn-I), and soluble suppressor of tumorigenicity 2 (sST2) prior to transplant, during conditioning, and days +7, +14, +28 and +49 in 26 patients. We subsequently analyzed levels of cTn-I every 48–72 h in 15 consecutive children during conditioning. Thirty-two percent (73/227) of patients had a new abnormality on echocardiogram. New left ventricular systolic dysfunction (LVSD) occurred in 6.2% of subjects and new pericardial effusion in 27.3%. Eight of 227 (3.5%) patients underwent pericardial drain placement, and 5 (2.2%) received medical therapy for clinically occult LVSD. cTn-I was elevated in 53.0% of all samples and sST2 in 38.2%. At least one sample had a detectable cTn-I in 84.6% of patients and an elevated sST2 in 76.9%. Thirteen of fifteen patients monitored frequently during condition had elevation of cTn-I. Echocardiographic and biochemical abnormalities are frequent in the peri-HSCT period. Echocardiogram does not detect all subclinical cardiac injuries that may become clinically relevant over longer periods.

High-level amplification of the protein phosphatase PPM1D(WIP1) is present in a subset of medulloblastomas (MBs) that have an expression profile consistent with active Sonic Hedgehog (SHH) signaling. We found that WIP1overexpression increased expression of Shhtarget genes and cell proliferation in response to Shh stimulation in NIH3T3 and cerebellar granule neuron precursor cells in a p53-independent manner. Thus, we developed a mouse in which WIP1is expressed in the developing brain under control of the Neurod2promoter (ND2:WIP1). The external granule layer (EGL) in early postnatal ND2:WIP1mice exhibited increased proliferation and expression of Shhdownstream targets. MB incidence increased and survival decreased when ND2:WIP1mice were crossed with an Shh-activated MB mouse model. Conversely, Wip1knockout significantly suppressed MB formation in two independent mouse models of Shh-activated MB. Furthermore, Wip1knockdown or treatment with a WIP1 inhibitor suppressed the effects of Shh stimulation and potentiated the growth inhibitory effects of SHHpathway-inhibiting drugs in Shh-activated MB cells in vitro. This suggests an important cross-talk between SHHand WIP1pathways that accelerates tumorigenesis and supports WIP1 inhibition as a potential treatment strategy for MB.

Postnatal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells of origin for the SHH-associated subgroup of medulloblastoma, is driven by Sonic hedgehog (Shh) and insulin-like growth factor (IGF) in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3. We observed that YB-1 is upregulated across human medulloblastoma subclasses as well as in other varieties of pediatric brain tumors. Utilizing the cerebellar progenitor model for the Shh subgroup of medulloblastoma in mice, we show for the first time that YB-1 is induced by Shh in CGNPs. Its expression is YAP-dependent and it is required for IGF2 expression in CGNPs. Finally, both gain-of function and loss-of-function experiments reveal that YB-1 activity is required for sustaining CGNP and medulloblastoma cell (MBC) proliferation. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and MBCs and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas.

This paper assesses a potentially interesting soil process, dealumination, as the mechanism for the increase observed in strong acid recoverable Al and associated elements in farmed soils compared with background soils in the Waikato Region of New Zealand. Waikato Regional Council has been measuring an established set of 7 soil quality chemical and physical parameters and concentrations of 33 elements as part of a Regional Soil Quality Monitoring program since 2003. Statistical comparison of farmed to background soils, relative surface enrichments, and inter-element correlations enable us to infer likely and potential sources of those elements which show some form of enrichment. Acid-recoverable Al is 1.5 times higher (P<0.0001) in the Waikato region's farmed soils than its background soils. This increase is not readily explained as an external source of recoverable Al (due to lack of enrichment at the soil surface). However, it could be explained as an increase in the concentration of acid-recoverable Al as a result of accelerated weathering or chemical attack of primary crystalline and short-range order aluminosilicates. In keeping with this interpretation, acid recoverable concentrations of several trace elements that are normally retained inside aluminosilicates (in residual phases) are also significantly higher in farmed than background soils but are not selectively enriched at the soil surface. These include (with enrichment-to-background factors) Li (2.5), La (2.1), Mn (1.5), and Ag, Bi, Mo, Sn, and Tl (1.4). Also, this process may contribute one-quarter of the observed increase in acid-recoverable U. If it is occurring, accelerated Al weathering may be a normal part of an increase in soil productivity, or may be facilitated by an external agent capable of attacking crystalline aluminosilicates. A candidate in the latter category is the F (and/or possibly free HF) in phosphate fertilisers, because this substantially increases Al species in soil porewater. Two specific mechanisms that could favour Al mobilisation from clay surfaces include partial dissolution by local areas of high acidity associated with fertiliser granules, and surface complexation and extraction by the fluoride and residual hydrofluoric acid present in phosphate fertilisers. Based on the high reactivity between F and both Al and Si, potential exists for significant production of SiF4(g)as another side-effect of phosphate fertiliser use.

Land application has become a widely applied method for treating wastewater. However, it is not always clear which soil–plant systems should be used, or why. The objectives of our study were to determine if four contrasting soils, from which the pasture is regularly cut and removed, varied in their ability to assimilate nutrients from secondary‐treated domestic effluent under high hydraulic loadings, in comparison with unirrigated, fertilized pasture. Grassed intact soil cores (500 mm in diameter by 700 mm in depth) were irrigated (50 mm wk−1) with secondary‐treated domestic effluent for two years. Soils included a well‐drained Allophanic Soil (Typic Hapludand), a poorly drained Gley Soil (Typic Endoaquept), a well‐drained Pumice Soil formed from rhyolitic tephra (Typic Udivitrand), and a well‐drained Recent Soil formed in a sand dune (Typic Udipsamment). Effluent‐irrigated soils received between 746 and 815 kg N ha−1and 283 and 331 kg P ha−1over two years of irrigation, and unirrigated treatments received 200 kg N ha−1and 100 kg P ha−1of dissolved inorganic fertilizer over the same period. Applying effluent significantly increased plant uptake of N and P from all soil types. For the effluent‐irrigated soils plant N uptake ranged from 186 to 437 kg N ha−1yr−1, while plant P uptake ranged from 40 to 88 kg P ha−1yr−1for the effluent‐irrigated soils. Applying effluent significantly increased N leaching losses from Gley and Recent Soils, and after two years ranged from 17 to 184 kg N ha−1depending on soil type. Effluent irrigation only increased P leaching from the Gley Soil. All P leaching losses were less than 49 kg P ha−1after two years. The N and P leached from effluent treatments were mainly in organic form (69–87% organic N and 35–65% unreactive P). Greater N and P leaching losses from the irrigated Gley Soil were attributed to preferential flow that reduced contact between the effluent and the soil matrix. Increased N leaching from the Recent Soil was the result of increased leaching of native soil organic N due to the higher hydraulic loading from the effluent irrigation.

Sewage sludge is increasingly been applied to land in New Zealand in an attempt to recycle the valuable plant nutrients such material contains. However, there are concerns regarding the environmental fate of heavy metals contained in the sludge. This study examines the soil profile distributions of metals (Cd, Cr, Cu, Ni, Pb, Zn) in large undisturbed soil lysimeters treated with metal-spiked sewage sludge, following 3 years of drainage leachate monitoring. For 3 forest soils that had all received surface applications of sludge, analytical results demonstrated considerable transport of metals from the sludge into the underlying litter and mineral soil layers. Determination of individual metal/Cr ratios revealed considerable differential mobility between metals, with Cd, Ni, and Zn being most mobile, and Cu and Pb being only slightly more mobile than Cr. Total metal analysis was relatively insensitive in detecting metal movement down the soil profile compared with determination of extractable metals (EDTA or Ca(NO3)2 extraction). Maximum depths of metal penetration varied between metals, but were similar for all 3 forest soils, averaging 0.15, 0.20, 0.25, 0.35, and 0.45 m for Pb, Cu, Cd, Ni, and Zn, respectively. In contrast to the forest soils, when sludge was incorporated into the top 0.10 m of 2 pasture soils, little movement of metals could be detected below the layer of incorporation. However, even in these soils, the determination of metal/Cr ratios indicated that some differential movement of metals had taken place. For the forest soils, the results indicate considerable potential for the long-term and sustained leaching of metals by normal convective and diffusive transport processes. This would appear to be of less concern where sludge has been incorporated into the pasture soils. These results clearly have implications for selection of the most appropriate soils and conditions for sludge application to the land.

The extent of metal (Cd, Cr, Cu, Ni, Pb, Zn) leaching from soils treated with metal-spiked sewage sludge was examined using large undisturbed soil lysimeters of 5 different New Zealand soils (2 pasture and 3 forest soils). Metal leaching from the soils was monitored continuously over a period of 3 years following a single application of sewage sludge. Metal speciation in leachates was estimated using GEOCHEM-PC. Application of the sludge resulted in decreased pH and increased concentrations and total amounts of Cd, Ni, and Zn in drainage leachates from some of the soils, but had little effect on, or decreased concentrations of, Cr, Cu, and Pb. In the case of Cu, and to a lesser extent Pb, the reduced leaching of these metals in the forest soils was considered related to the lack of plant cover and reduced pH and soluble organic C in leachates from the sludge-treated lysimeters. The peaking of Ni and Zn concentrations well before 1 pore volume of water had passed through the lysimeters indicated that macropore flow was an important process facilitating the leaching of these metals. The extent of metal leaching varied greatly between soils and was dependent on a number of soil properties and other factors, including plant cover (pasture v. forest soils). However, even under the extreme conditions of the study, very small proportions (~1% or less) of the applied metals were leached over the 3-year period. In some cases, Ni and Zn concentrations in drainage leachates exceeded drinking water and/or environmental standards. However, with further attenuation and dilution in the vadose zone, in the short-term at least, the leaching of these metals would seem unlikely to pose a major environmental threat.

Riparian wetlands are transition zones between terrestrial and aquatic environments that have the potential to serve as nutrient filters for surface and ground water due to their topographic location. We investigated a riparian wetland that had been receiving intermittent inputs of NO−3and PO3−4during storm runoff events to determine the mechanisms of nutrient attenuation in the wetland soils. Few studies have shown whether infrequent pulses of NO−3are sufficient to maintain substantial denitrifying communities. Denitrification rates were highest at the upstream side of the wetland where nutrient‐rich runoff first enters the wetland (17–58 μg N2O–N kg soil−1h−1) and decreased further into the wetland. Carbon limitation for denitrification was minor in the wetland soils. Samples not amended with dextrose had 75% of the denitrification rate of samples with excess dextrose C. Phosphate sorption isotherms suggested that the wetland soils had a high capacity for P retention. The calculated soil PO3−4concentration that would yield an equilibrium aqueous PO3−4concentration of 0.05 mg P L−1was found to be 100 times greater than the soil PO3−4concentration at the time of sampling. This indicated that the wetland could retain a large additional mass of PO3−4without increasing the dissolved PO3−4concentrations above USEPA recommended levels for lentic waters. These results demonstrated that denitrification can be substantial in systems receiving pulsed NO−3inputs and that sorption could account for extensive PO3−4attenuation observed at this site.

The study of human cellular immune responses to parasite infection under field conditions is very complex. Often, the only practical site from which to sample the cellular responses is the peripheral blood. Sampling peripheral blood lymphocytes (PBL) relies on the assumption that these peripheral responses accurately reflect the immune responses acting locally at the site of infection. This is a particularly important point for the human intestinal helminth Trichuris trichiura, which solely inhabits the cecum and large intestine and so will stimulate a localized immune response. Using the well-defined model of T. trichiura, T. muris in the mouse, we have demonstrated that the dominant cytokine responses of the mesenteric lymph nodes (MLN) can be detected by sampling PBL. Resistant mice which mount a type 2 cytokine response in their MLN had PBL producing interleukin-4 (IL-4), IL-5, and IL-9, with negligible levels of gamma interferon (IFN-gamma). Conversely, susceptible mice which mount a type 1 cytokine response in their MLN had PBL producing IFN-gamma and negligible levels of type 2 cytokines. We have also shown that the PBL are capable of mounting a functional immune response against T. muris. PBL from immune mice were capable of transferring immunity to T. muris-infected severe combined immunodeficient (C.B-17 scid/scid) mice. Sampling PBL responses is therefore a viable option for monitoring human intestinal immune responses during T. trichiura infection in the field.

To evaluate the visible and quantitative anatomic distribution of fluorine-18-labeled L-DOPA in the healthy human brain, to thereby expand the understanding of extrastriatal sites of levodopa function, and to provide a broader foundation for clinical and research studies of fluoroDOPA accumulation in patients.

Background: Previous studies have demonstrated greater efficacy for omeprazole compared with cimetidine in patients with endoscopically verified oesophagitis, but excluded the substantial group of gastro-oesophageal reflux disease (GERD) patients with reflux symptoms but without endoscopic abnormality. This prospective, randomized, double-blind study compared omeprazole and cimetidine in the treatment of GERD-associated heartburn both in patients with symptomatic non-ulcerative oesophagitis and in those with heartburn but without oesophagitis.

A synthesis of 6-amino-7-cyclohexyl-3,5-heptanediol 1 (CDH) and related amino 1,3-diols involving a nucleophilic ring opening of N-acyl activated lactams is described. Stereochemical proof of the 1,3-diol moiety is also presented.

Background: Previous studies have demonstrated greater efficacy for omeprazole compared with cimetidine in patients with endoscopically verified oesophagitis, but excluded the substantial group of gastro‐oesophageal reflux disease (GERD) patients with reflux symptoms but without endoscopic abnormality. This prospective, randomized, double‐blind study compared omeprazole and cimetidine in the treatment of GERD‐associated heartburn both in patients with symptomatic non‐ulcerative oesophagitis and in those with heartburn but without oesophagitis.

The cardiac and vascular activities of ethyl 5-cyano-1,4-dihydro-6-methyl-2-[(4-pyridinyl-sulfonyl)methyl]-4-[2- (trifluoromethyl)phenyl]-3-pyridine carboxylase (PD 122860), a novel dihydropyridine, were investigated in vitro using rat heart and rabbit aorta, and compared with reference inotropic and vasodilator agents. In the rat heart, PD 122860 increased left ventricular contractility, decreased coronary resistance and altered the shape of the electrocardiogram T-wave. All three effects were observed at comparable concentrations of PD 122860. The inotropic response to PD 122860 was reversed by the Na+ channel blocker tetrodotoxin and blunted by the Na+-Ca++ exchange inhibitor dichlorobenzamil. The effects of tetrodotoxin and dichlorobenzamil on the inotropic response to the reference Na+ channel stimulant veratridine were comparable to PD 122860, whereas tetrodotoxin and dichlorobenzamil had no inhibitory effect on the inotropic responses to the adenylate cyclase stimulator forskolin or the Ca++ channel stimulant BAY K 8644. PD 122860 selectively relaxed potassium-contracted aortic rings and inhibited [3H]nitrendipine binding to rat brain membranes, suggesting that the vasodilator activity of PD 122860 is due to Ca++ channel blockade. In contrast to BAY K 8644, PD 122860 did not contract partially depolarized aortic rings, suggesting an absence of Ca++ channel stimulant activity. PD 122860 is a racemic mixture and both the vasorelaxant and [3H]nitrendipine binding inhibitory activities selectively reside in the (+)-enantiomer [(+)-PD 122860]. In contrast, the inotropic response resides with both enantiomers of PD 122860. It is therefore concluded that PD 122860 represents a unique dihydropyridine derivative which possesses both Na+ channel stimulating and Ca++ channel blocking activities.

Seethoff and Shiflett [5] proved nice uniqueness theorems concerning doubly stochastic measures supported on the union of the graphs of two functions, but the existence theorems were more elusive. In this present paper, using a functional equations approach, not only uniqueness results but also existence theorems are obtained for doubly stochastic measures with support sets of the form g∪g-1where gis an increasing homeomorphism of [0,1] onto itself such that g(x) whenever 0

The organic carbon in New Zealand's vegetation and soils has been estimated for 1992 from updated national databases of vegetative cover and soil carbon. These databases were augmented by inclusion of vegetation and soils information for Stewart Island, and addition of carbon estimates for upland and high‐country soils of South Island. Plant biomass estimates from literature were combined with the Vegetative Cover Map of New Zealand to give an estimate of 2420 Mt carbon for vegetation carbon above and below ground, including litter and humus. More than 80% of this carbon occurs in indigenous forested ecosystems on less than 26% of the land area, with only about 5% in planted forests.Soil organic carbon estimates for two depth ranges (0–0.25 m, 0–1 m) were derived from the N.Z. Land Resource Inventory, the Soil Map of Stewart Island, and the National Soils Database. Totals were 2500 ± 77 Mt and 4260 ± 190 Mt C respectively. Yellow‐brown earths made the largest contribution, with 727 Mt C in North Island and 489 Mt C in South Island, to 1 m depth. Nationally this soil group also contributed most to the error variance for soil carbon.A I:1 relationship (R, 0.68) over a wide range of soil C contents for soils sampled recently and 30–50 years ago under pasture suggested that under the same land use, uncertainties introduced by the use of historical soil data would not be large.

Summary A measure µ on the unit squareI } I is doubly stochastic ifµ(A } I) = µ(I } A) = the Lebesgue measure ofA for every Lebesgue measurable subsetA ofI = [0, 1]. By the hairpinL ?L-1, we mean the union of the graphs of an increasing homeomorphismL onI and its inverseL-1. By the latticework hairpin generated by a sequence {xn:n ? Z} such thatxn-1 < xn (n ? Z), xn = 0 and xn = 1, we mean the hairpinL ?L-1, whereL is linear on [xn-1,xn] andL(n) =xn-1 forn ? Z. In this note, a characterization of latticework hairpins which support doubly stochastic measures is given. This allows one to construct a variety of concrete examples of such measures. In particular, examples are given, disproving J. H. B. Kemperman's conjecture concerning a certain condition for the existence of doubly stochastic measures supported in hairpins.

SummaryA double-blind, parallel-group, multi-centre study was carried out in 248 patients with symptomatic seasonal allergic rhinitis to assess the effectiveness and toler-ability of intranasal aqueous budesonide given as a single daily dose each morning of 400 μg compared with the conventional dosage regimen of 200 μg twice daily. After a 1-week run-in period during which only oral terfenadine was allowed for intolerable symptom relie J symptomatic patients were allocated at random to receive budesonide in one or other dosage regimen for 3 weeks. The results of assessments made by the phisician at clinic visits and by patients recording daily data on diary record cards showed that specific nasal symptom incidence and severity were significantly (p⁢0.001) reduced in both treatment groups. The proportions of patients symptom free at 3 weeks were 40% in the 400 μg once daily and 45% in the 200 μg twice daily group; in addition, mean nasal symptom scores from the daily diary cards were significantly (p⁢0.001) reduced in both groups, with a reduction in total symptom scores of 53% and 60%, respectively. The differences between the groups were not statistically significant. Total symptom scores were significantly (p⁢0.01) reduced in both dosage groups at all levels of pollen exposure. Patients rated treatment overall as being highly effective, mean scores being very similar in both groups, and tolerability was similar and good whether budesonide was given as a 400 μg once daily dose or as 200 μg twice daily. Assuming equal symptom control, 74% of patients stated they would prefer once daily to twice daily treatment.

The silver, lead and mercuric toluenedithiolates were synthesised and analysed by both conventional chemical methods and thermoanalytical methods. The thermal decomposition was studied by thermogravimetric analysis in air, nitrogen and vacuum. The formulae of the decomposition products were derived using the mole weights and i.r. absorption spectra. The activation energies for the first stage of decomposition were calculated. The volatile products contain mostly carbon and hydrogen while the residues contain the corresponding metals either free or combined with sulfur.

The theory of the effect of an intense radiation field on the interaction between two chiral molecules is presented. Two types of energy shifts are distinguished, one involving the molecular polarizabilities and fourth rank hyperpolarizabilities, and the other the third rank hyperpolarizabilities. The former is non-discriminatory whereas the latter is discriminatory with respect to the relative handedness of the optical isomers. In both cases the energy shifts are linearly dependent on the intensity of the incident field. In the near-zone they show an R-6 dependence similar to the conventional dispersion-type energies. Expressions for pair-polarizabilities are given.

We consider an alternative to the usual notion of the support of a measure which seems more suitable for the study of doubly stochastic measures.

SummaryBeta2-agonist therapy effectively relieves asthmatic symptoms, but an improvement in patient lifestyle has not been demonstrated. This open study in which patients acted as their own controls, assessed the efficacy and acceptability of intermittent symptom-related use of terbutaline inhaled via ‘Turbohaler’, and its influence on the lifestyle of 1133 inhaler-naive, mild asthmatics treated in general practice. A 1-week run-in period was followed by 4-weeks' treatment with inhaled terbutaline (500 ng as required). Peak expiratory flow rate (PEFR) and ‘Turbohaler’ technique were assessed at clinic visits. Diary cards, completed daily, assessed: the number of terbutaline inhalations, the relief obtained after use, the severity of asthma symptoms (cough, morning wheeze, nocturnal wheeze and wheeze on activity), and lifestyle indices (sleep disturbance, work/school days lost, limitation of normal activity). After terbutaline treatment, PEFR increased by 54±2 1/min (p<0.001), the severity of asthma symptoms was almost halved (p<0.001), with over two-thirds (65% to 76%) of patients reporting improvements in each variable, and the adverse effect of asthma on lifestyle was at least halved (p<0.001). Improvements in lung function, asthma symptoms and lifestyle were comparable for all sub-groups: adults (>16 years), school-age children (6 to 16 years) and preschool children (≤5 years). This study not only confirmed the efficacy and acceptability of intermittent symptom-related use of terbutaline inhaled via ‘Turbohaler’, but also demonstrated that its use enhanced patients' lifestyles.

Immunogenic peptides are displayed in the context of class II histocompatibility proteins on the surface of antigen-presenting cells. Class II alpha and beta subunits bind the invariant chain (I-chain), a transmembrane glycoprotein which must dissociate prior to peptide presentation. Proteolytic release of I-chain in an acidic compartment is followed by class II alpha beta surface expression. Two distinct proteinases sequentially catalyze I-chain dissociation in B-lymphoblastoid cell lines. An aspartic proteinase initiates processing whereas a cysteine proteinase catalyzes the final stages of I-chain release. Inactivation of these enzymes prevents class II alpha beta maturation, demonstrating that acidic proteinases are essential for the generation of functional class II complexes. I-chain processing was localized to a dense endosomal compartment, suggesting this is the first site where class II alpha beta become accessible to peptides. I-chain fragments complexed with class II alpha beta accumulate in dense endosomes of B-lymphoblastoid cells treated with cysteine proteinase inhibitors. A signal for endosomal retention/targeting present in the cytoplasmic tail of these fragments may sequester class II alpha beta in this compartment until I-chain processing is complete.

SummaryA randomized, parallel group, double-blind multi-centre study was carried out in 342 patients with symptomatic seasonal allergic rhinitis to assess the efficacy and tolerability of intranasal budesonide administered either as a single morning dose of 400 μg or as a 200 μpg twice-daily dose, morning and evening, for 4 weeks. Both treatments improved the symptoms of seasonal allergic rhinitis; specific nasal symptom scores recorded daily by the patient being reduced. The proportions of patients symptom free after 4-weeks'treatment were 46% in the 400 μg once-daily group and 54% in the 200 μg twice-daily group, with total daily symptom scores recorded by diary cards reduced by 79% and 80%, respectively. The differences between the groups were not statistically significant. Subgroup analysis of patients allergic to grass pollen (n = 166) showed similar total symptom scores at each level of grass pollen exposure (no significant difference between treatment groups). Patients assessed both treatments to be effective (no significant dgference between groups), with 65% of patients questioned stating a preference for a once-daily treatment given equal symptom control. Both treatments were equally well tolerated and few side-effects were reported.

The modes of decomposition of a few rare earth metal formates and benzoates were studied by the use of DTA, DSC, TG and DTG techniques in air, nitrogen and vacuum. The volatile products and residues were identified. The activation energies of decompositions and the heat of reaction for transitions were calculated.

1,3‐Dipolar cycloaddition of the nitrile oxides (VI) with the 1,4‐dihydropyridines (V), obtained from o‐(trifluoromethyl)benzaldehyde (I) as shown in the reaction scheme, leads to the formation of the tetrahydroisoxazolo(5,4‐b)pyridines (VII).

Tetrahydropyridine derivatives such as (IV), (VI), and (IX) are prepared using the Hantzsch dihydropyridine synthesis.