Comparative bronchodilatory activity of cetiedil citrate monohydrate, theophylline, orciprenaline and placebo in adult asthmatics.

In 40 patients, a seven day observation period in which oral bronchodilators and corticosteroids were eliminated, cetiedil (100 mg, t.i.d.), theophylline (200 mg, t.i.d.) or orciprenaline (20 mg, t.i.d.) and placebo (100 mg Lactose, t.i.d.) were given for one week each, according to a double blind, crossover randomized code. Wheezing scores were improved by all three active drugs. Twenty five of these patients undertook a moderate degree of exercise. Cetiedil was the most effective drug in blocking exercise-induced bronchospasm of the drugs studied. At rest, FEV1/VC was improved by theophylline, while PEFR improved after orciprenaline. Cetiedil improved both parameters, significantly. In another 21 patients, cetiedil (100 mg, t.i.d.) was given, according to the 'patient blinded' method for two weeks. PEFR and Asthma Disability Scores steadily improved. Clinical effectiveness was observed as early as the 3rd or 4th day of cetiedil therapy, with maximum improvement detected on the 14th day. No major side effects or abnormalities in clinical laboratory tests were noted. Cetiedil also had a 'liquidifying effect' on bronchial mucous in these asthmatics.     

The discovery and mechanism of action of novel tumor-selective and apoptosis-inducing 3,5-diaryl-1,2,4-oxadiazole series using a chemical genetics approach

A novel series of 3,5-diaryl-oxadiazoles was identified as apoptosis-inducing agents through our cell and chemical genetics-based screening assay for compounds that induce apoptosis using a chemical genetics approach. Several analogues from this series including MX-74420 and MX-126374 were further characterized. MX-126374, a lead compound from this series, was shown to induce apoptosis and inhibit cell growth selectively in tumor cells. To elucidate the mechanism(s) by which this class of compounds alters the signal transduction pathway that ultimately leads to apoptosis, expression profiling using the Affymetrix Gene Chip array technology was done along with other molecular and biochemical analyses. Interestingly, we have identified several key genes (cyclin D1, transforming growth factor-beta1, p21, and insulin-like growth factor-BP3) that are altered in the presence of this compound, leading to characterization of the pathway for activation of apoptosis. MX-126374 also showed significant inhibition of tumor growth as a single agent and in combination with paclitaxel in murine tumor models. Using photoaffinity labeling, tail-interacting protein 47, an insulin-like growth factor-II receptor binding protein, was identified as the molecular target. Further studies indicated that down-regulation of tail-interacting protein 47 in cancer cells by small interfering RNA shows a similar pathway profile as compound treatment. These data suggest that 3,5-diaryl-oxadiazoles may be a new class of anticancer drugs that are tumor-selective and further support the discovery of novel drugs and drug targets using chemical genetic approaches.     

High dose vitamin A supplementation in the course of pneumonia in Vietnamese children

We carried out a randomized, placebo-controlled, double-blinded trial to evaluate the effect on morbidity of high dose oral vitamin A, given on hospital admission to 592 children aged 1–59 months with moderate and severe pneumonia. Severely underweight children were not included, but 45% were moderately underweight. The vitamin A and placebo groups were comparable in baseline characteristics. Four patients died. Among all of the surviving children, no differences were found regarding mean time for normalization of fever, respiratory rate and time of hospitalization. Stratification for moderate malnutrition, degree of pneumonia, age and sex revealed moderately malnourished vitamin A-supplemented children to have a shorter time of hospitalization ( p = 0. 04), due to an effect in females aged > 12 months ( p = 0. 02) and females with very severe pneumonia ( p = 0. 048). This study indicates that, in developing countries like Vietnam, supplementation with vitamin A in children with pneumonia could shorten the recovery rate in the ones that are undernourished, especially females > 1 y old.     

Metabolic and hepatic effects of liraglutide,obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis

AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis(NASH) in obese mouse models of biopsy-confirmedNASH.METHODS Male wild-type C57 BL/6 J mice(DIO-NASH) and Lep~(ob/ob)(ob/ob-NASH) mice were fed a diet high in trans-fat(40%), fructose(20%) and cholesterol(2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score(NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide(0.2 mg/kg, SC, BID), obeticholic acid(OCA, 30 mg/kg PO, QD), or elafibranor(30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1 a1.RESULTS Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1 a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression(RNA sequencing) and liver lipid biochemistry.CONCLUSION DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH.     

From the Cover: Agricultural expansion and the ecological marginalization of forest-dependent people

Agricultural expansion into subtropical and tropical forests causes major environmental damage, but its wider social impacts often remain hidden. Forest-dependent smallholders are particularly strongly impacted, as they crucially rely on forest resources, are typically poor, and often lack institutional support. Our goal was to assess forest-smallholder dynamics in relation to expanding commodity agriculture. Using high-resolution satellite images across the entire South American Gran Chaco, a global deforestation hotspot, we digitize individual forest-smallholder homesteads (n = 23,954) and track their dynamics between 1985 and 2015. Using a Bayesian model, we estimate 28,125 homesteads in 1985 and show that forest smallholders occupy much larger forest areas (>45% of all Chaco forests) than commonly appreciated and increasingly come into conflict with expanding commodity agriculture (18% of homesteads disappeared; n = 5,053). Importantly, we demonstrate an increasing ecological marginalization of forest smallholders, including a substantial forest resource base loss in all Chaco countries and an increasing confinement to drier regions (Argentina and Bolivia) and less accessible regions (Bolivia). Our transferable and scalable methodology puts forest smallholders on the map and can help to uncover the land-use conflicts at play in many deforestation frontiers across the globe. Such knowledge is essential to inform policies aimed at sustainable land use and supply chains.

Smallholders produce about one-third of all crops globally, manage one-quarter of the global agricultural area, and are key to food security in low-income countries around the world (1, 2). Despite their importance, however, smallholders remain widely overlooked in policy making (3). This is particularly so for forest-dependent people (hereafter: forest smallholders), who live inside the forest matrix and depend on forests as their resource base for fuelwood, timber, nonwood forests products, or livestock herding (4). Forest smallholders are widespread, particularly in the tropics and subtropics (5). Yet despite recent advances in estimating their number and spatial distribution (4), we lack reliable information on how deforestation and agricultural expansion affects them across the world’s major deforestation frontiers.Putting forest-dependent people on the map is furthermore urgently needed in order to guide sustainable development programs to support them (4). Forest smallholders are particularly vulnerable, as they are typically poor and often lack formal land titles as well as institutional support (6). Today, agricultural expansion into tropical forests is often driven by large-scale farmers, producing commodities for global markets (7, 8). Such expanding commodity frontiers can trigger substantial and sometimes violent conflicts between forest smallholders and large-scale farmers (9), causing outmigration of forest smallholders to urban areas (10). Where forest smallholders persist, their resource base often vanishes or they are displaced to environmentally more marginal lands (11, 12), two processes referred to as ecological marginalization (13). While ecological marginalization has often been hypothesized, it has rarely been assessed empirically, and no study has quantified the ecological marginalization of forest-dependent people across any tropical deforestation frontier.Despite the major challenges forest smallholders face where commodity agriculture expands (14), the geography of competition between forest smallholders and large-scale producers remains largely elusive. For instance, whereas major efforts have gone into mapping Indigenous communities (15), we lack similar datasets for forest smallholders more broadly. As a consequence, assessments of land available for further agricultural expansion often do not fully account for the fact that many areas highlighted as available might in fact be inhabited by forest smallholders (16). Furthermore, it remains largely unclear to what extent commodity frontiers affect forest smallholders not just directly by displacing them but also by reducing forest cover and thus their resource base around their communities. These knowledge gaps hinder targeted actions toward avoiding or mitigating negative livelihood outcomes for forest smallholders.Commodity frontiers have expanded particularly rapidly in South America in recent years, mostly driven by cattle and soy production (17). The expansion of commodity agriculture has been particularly rapid in the Gran Chaco (hereafter: Chaco), the world’s largest tropical dry forest extending across Argentina, Bolivia, and Paraguay. This region harbors major carbon stocks (18), unique biodiversity (19), and is home to many Indigenous and non-Indigenous smallholder communities (20). The Chaco has recently become a global deforestation hotspot, which brings with it serious environmental impacts such as globally significant carbon emissions (18) and major biodiversity loss (21). Although there is increasing evidence that conflicts over land have become widespread (11, 22), information about the social costs of this expansion is scarce (7, 20, 23).Our overarching goal was to assess forest-smallholder dynamics in relation to expanding commodity agriculture in the Chaco for the period 1985 to 2015, during which commodity frontiers expanded dramatically in the region. Specifically, we ask the following: 1) how did the expansion of commodity agriculture in the Chaco shape the numbers and geographic patterns of forest smallholders? and 2) did the expansion of commodity agriculture result in increasing ecological marginalization of forest smallholders? We addressed these questions by digitizing forest-smallholder homesteads using high-resolution satellite images across the entire 1.1 million-km² Chaco (Fig. 1). We then reconstructed dynamics of forest-smallholder homesteads back to 1985 and quantified trends in ecological marginalization by assessing resource base loss and environmental marginality (proxied by agroclimatic conditions and accessibility) around homesteads.Open in a separate windowFig. 1.Study region and key characteristics of forest-smallholder homesteads for digitization. Chaco region in South America and spatial patterns of agricultural expansion since 1985 (purple), agricultural expansion before 1985 (orange), and remaining forest (green, year 2015). “Other” represents natural grasslands, savannahs, wetlands, water bodies, and settlements (A). We used three key characteristics of forest-smallholder homesteads for digitization: 1) distinctive landscape patterns of Chacoan forest-smallholder homesteads (i.e., degradation of natural vegetation and soils, gradually decreasing with increasing distance from the center of the homestead) (B), (2) presence of at least one house (B and C), and (3) presence of a stable, corral, and/or water hole or well confirming livestock presence and thus a relatively permanent occupation (C and D). Photos: authors. Administrative units (provinces, departments, and states): APG, Alto Paraguay; BO, Boquerón; CA, Catamarca; CC, Concepción; CD, Cordillera; CE, Central; CH, Chaco; CO, Córdoba; CQ, Chuquisaca; CR, Corrientes; CZ, Caazapá; FO, Formosa; IT, Itapúa; JJ, Jujuy; LR, La Rioja; MI, Misiones; NE, Ñeembucú; PA, Paraguarí; PH, Presidente Hayes; SA, Salta; SC, Santa Cruz; SE, Santiago del Estero; SF, Santa Fe; SJ, San Juan; SL, San Luis; SP, San Pedro; TJ, Tarija; TU, Tucumán.     

Characterization of two solitary long terminal repeats of murine leukemia virus type that are conserved in the chromosome of laboratory inbred mouse strains

Twenty molecular clones containing sequences homologous to the long terminal repeats (LTRs) of the endogenous ecotropic murine leukemia virus (MuLV) of the RFM/Un mouse were isolated from a library of RFM/Un mouse spleen DNA in phage lambda. Three of these LTRs were not associated with any viral structural genes. Nucleotide sequence analysis demonstrated that they were solitary LTRs which were flanked by 4-bp directly repeated cellular sequences and which lacked primer binding sites. Two of the three subclones were found to be identical except for their orientations in the vector pBR322. Unique-sequence regions on either side of the two nonidentical elements were used to characterize their integration sites in genomic DNA. The solitary LTRs and their flanking regions were found to be conserved in a number of inbred mouse strains, including three strains known not to harbor endogenous ecotropic MuLV-type proviruses. Comparison of cleavage by the methylation-sensitive restriction enzyme SmaI and methylation-insensitive KpnI at the characteristic LTR SmaI/KpnI site suggested that at least one of these solitary LTRs is methylated to a lesser extent than are most endogenous proviral LTRs. These particular solitary LTRs, like endogenous proviral sequences, appear to be stably transmitted genetic elements.