Search

Hedgehog (Hh) signaling regulates cell fate and self-renewal in development and cancer. Canonical Hh signaling is mediated by Hh ligand binding to the receptor Patched (Ptch), which in turn activates Gli-mediated transcription through Smoothened (Smo), the molecular target of the Hh pathway inhibitors used as cancer therapeutics. Small cell lung cancer (SCLC) is a common, aggressive malignancy with universally poor prognosis. Although preclinical studies have shown that Hh inhibitors block the self-renewal capacity of SCLC cells, the lack of activating pathway mutations have cast doubt over the significance of these observations. In particular, the existence of autocrine, ligand-dependent Hh signaling in SCLC has been disputed. In a conditional Tp53;Rb1 mutant mouse model of SCLC, we now demonstrate a requirement for the Hh ligand Sonic Hedgehog (Shh) for the progression of SCLC. Conversely, we show that conditional Shh overexpression activates canonical Hh signaling in SCLC cells, and markedly accelerates tumor progression. When compared to mouse SCLC tumors expressing an activating, ligand-independent Smo mutant, tumors overexpressing Shh exhibited marked chromosomal instability and Smoothened-independent upregulation of Cyclin B1, a putative non-canonical arm of the Hh pathway. In turn, we show that overexpression of Cyclin B1 induces chromosomal instability in mouse embryonic fibroblasts lacking both Tp53 and Rb1. These results provide strong support for an autocrine, ligand-dependent model of Hh signaling in SCLC pathogenesis, and reveal a novel role for non-canonical Hh signaling through the induction of chromosomal instability.

2,4-Dihydro-4-(β-d-ribofuranosyl)-1,2,4(3H)-triazol-3-one (2) was identified as the principal phytotoxic component of a fermentation broth derived from an Actinomadura. The compound is a new natural product, but known by synthesis. Broad-spectrum herbicidal activity was demonstrated in greenhouse tests. Metabolite reversal studies suggested the target site was adenylosuccinate synthetase, which was confirmed by direct measurement of the activity of the 5‘-phosphorylated derivative on the isolated enzyme.

Benign pleural disease is the commonest manifestation of asbestos exposure encountered by radiologists. Benign pleural thickening can appear as circumscribed parietal pleural plaques or as more diffuse thickening of the visceral pleura. Benign-asbestos induced pleural effusions are a significant and under-recognized manifestation of asbestos exposure with important sequelae, such as diffuse pleural thickening which may be associated with functional impairment and for which compensation may be sought. This review concentrates on the strengths and weaknesses of chest radiography and computed tomography for the detection and characterization of benign asbestos-related pleural disease and the relevance of imaging abnormalities to compensation and functional impairment.Peacock, C. (2000). Clinical Radiology55, 422–432.

Joint contractures which do not respond to conventional physiotherapy can be difficult to treat. Serial plastering has been used effectively but is expensive, inconvenient to the patient and does not permit daily hygiene or clinical inspection. A mechanical device has been developed consisting a hinged orthosis which spans the affected joint to which is attached a gas strut to provide a corrective moment about the anatomical joint. Such an arrangement enables prescribed corrective moments to be applied accurately following clinical assessment using routine physiotherapy techniques. The inherently low spring rate of a gas strut ensures that the specified corrective torque is maintained as correction occurs.Initial treatment experience under the control of the developers had generated wider interest in the system. A geographically distant independent orthotic supply centre was trained in the techniques of application. They treated nine elbow and three knee joints in patients who had not responded to physiotherapy treatment. All of the patients experienced improvement. The average for elbow joints was a reduction in the contracture of 25.6° with a corrective moment of 6.8Nm over a period of 3.9 weeks. For the knee joints the averages were a reduction in contracture of 10.7° with a corrective moment of 12.7Nm over a period of 4 weeks.The results confirmed the practicality of transferring the system to independent clinical centres and provide evidence to support funding for a formal prospective clinical trial of the treatment approach.

Joint contractures which do not respond to conventional physiotherapy can be difficult to treat. Serial plastering has been used effectively but is expensive, inconvenient to the patient and does not permit daily hygiene or clinical inspection. A mechanical device has been developed consisting a hinged orthosis which spans the affected joint to which is attached a gas strut to provide a corrective moment about the anatomical joint. Such an arrangement enables prescribed corrective moments to be applied accurately following clinical assessment using routine physiotherapy techniques. The inherently low spring rate of a gas strut ensures that the specified corrective torque is maintained as correction occurs.Initial treatment experience under the control of the developers had generated wider interest in the system. A geographically distant independent orthotic supply centre was trained in the techniques of application. They treated nine elbow and three knee joints in patients who had not responded to physiotherapy treatment. All of the patients experienced improvement. The average for elbow joints was a reduction in the contracture of 25.6° with a corrective moment of 6.8Nm over a period of 3.9 weeks. For the knee joints the averages were a reduction in contracture of 10.7° with a corrective moment of 12.7Nm over a period of 4 weeks.The results confirmed the practicality of transferring the system to independent clinical centres and provide evidence to support funding for a formal prospective clinical trial of the treatment approach.

Increased need for salt tolerant grasses continues due to increased restrictions on limited water resources and to salt water intrusion into groundwater. Seashore paspalum (Paspalum vaginatumSwartz.) is used in Australia as a salt tolerant turfgrass, and cultivars are commercially available in the USA. The purpose of this investigation was to document the glasshouse response of four Seashore paspalum turfgrasses to solution cultures differentially salinized with synthetic sea water. A sea salt mixture was added to half‐strength Hoagland's number 2 nutrient solution to provide six salinity treatments ranging from 0.9 to 39.7 dS m−1. A split‐plot design with five replications was utilized to study salinity as the main plot effect and grass as the sub‐plot effect. Turfgrasses differed markedly in salt tolerance. Based on inverse regression analyses, the most salt tolerant experimental selection was FSP‐1 with 50% of its top growth reduced at 28.6 dS m−1; FSP‐2 and ‘Futurf’ were intermediate in salt tolerance with 50% top growth reductions at 21.9 dS m−1; whereas ‘Adalayd’ (‘Excaliber’) was the most sensitive cultivar with 50% top growth reduction at 18.4 dS m−1. The FSP‐1 selection was 3.1 times more salt tolerant than the other grasses when top growth was reduced only 5% at low salt concentrations. Salinity differentially affected tissue content of Ca, C1, K, Mg, and Na between grasses but had no affect on N which averaged 37.3 g kg−1. Maximum tissue content of 22.3 g kg−1of CI and 16.4 g kg−1of Na were at a salt concentration of 31 dS m−1in FSP‐1. However, concentrations of Cl and Na in the other grasses increased linearly 0.4 and 0.5 g kg−1, respectively, with each increase in salinity concentration. Maximum accumulation in this group was at the highest salt treatment of 39.7 dS m−1where Cl varied between grasses from 24 to 31 g kg−1and Na varied from 20 to 24 g kg1. Tissue content of Ca, K, and Mg decreased with increased salinity and differed between grasses. No mortality was observed although top growth of all grasses was severely reduced at the highest salt level.

Soil variability and its relation to family taxa used to classify the soils in a consociation used as a mapping unit in a second‐order soil survey are evaluated statistically. Most of the variability is within delineations and results from short‐range variability within and longrange variability among pedons. The ranges for the clayeyparticle size and thermictemperature classes correspond to those in this mapping unit. Ranges in soil mineralogy cannot be delineated by soil mapping since differences cannot be quantified. The use of mixedvs. oxidicmineralogy classes, as differentiating criteria at the family level for classifying soil series in this consociation, is questionable with the present definition of these mineralogical classes, since in some instances, both classes occur with 7 m. Confidence intervals on the means, estimations of the means, and prediction intervals for future observations indicate that the number of samples needed to establish statistical validity in soil classification and correlation is much larger than presently collected. The amount of variability in soils within 7 m and in sampling and analytical procedures is indicated by the percentages of the total variance contributed by the error terms in analysis of variance. These percentages are low for all the soil components used to classify the soils except hydroxy‐interlayered vermiculite.

Eleven families with X-linked dominant hypophosphataemic rickets (HPDR) have been typed for a series of X chromosome markers. Linkage with probe 99.6 (DXS41) was demonstrated with a peak lod score of 4.82 at 10% recombination. Multilocus linkage analysis showed that HPDR maps distal to 99.6; this probe has previously been located at Xp22.31-p21.3 by in situ hybridisation. In the mouse hypophosphataemia (Hyp) maps to the distal part of the X chromosome; our location in man is consistent with a scheme which relates the mouse and human X chromosomes by two rearrangements. No marker has yet been found which shows no recombination with HPDR.

Early mortality of lambs is a major constraint on total productivity. In 6 different environments the early death rate varied from 12 to 30% of all lambs born. Cause of death differed among systems but only a proportion could definitely be ascribed to infectious disease: nutrition, management and other environmental factors also contribute to the mortality rate. Mortality can be reduced by isolating solutions due to any of these factors but best results (lowest death rates) would be obtained by an integrated package containing elements of all these aspects.

OBJECTIVE--To document the range of disease in African children infected with HIV. DESIGN--Necropsy results in consecutive children aged 1 month or more who were HIV positive and in children who were HIV negative for comparison; IgA western blots on serum samples from children under 2 years of age who were positive for HIV-1 to test the validity of routine HIV serology. SETTING--Largest hospital in Abidjan, Cte d'Ivoire. SUBJECTS--78 children who were HIV positive and 77 children who were HIV negative on whom a necropsy was performed; their median ages at death were 18 and 21 months respectively. 36 HIV positive children and 29 HIV negative children were 1-14 months old; 42 HIV positive and 48 HIV negative children were > or = 15 months old. MAIN OUTCOME MEASURES--Cause of death and prevalence of diseases confirmed pathologically. RESULTS--Respiratory tract infections were more common in HIV positive than in HIV negative children (73 (94%) v 52 (68%); P < 0.05), and were aetiologically heterogeneous. Pneumocystis carinii pneumonia was found in 11 out of 36 (31%) HIV positive children aged < 15 months, but in no HIV negative children. Among older children measles was more common in HIV positive children (8/42 (19%) v 2/48 (4%); P < 0.06). Pyogenic meningitis was present in similar proportions of HIV positive and HIV negative children aged < 15 months (7/36 (19%) and 7/29 (24%)). In HIV positive children tuberculosis (1/78), lymphocytic interstitial pneumonitis (1/78), and HIV encephalitis (2/78) were rare. CONCLUSIONS--There is greater overlap between diseases associated with HIV infection and other common health problems in African children than there is in adults. Compared with adults, HIV positive children had a high prevalence of P carinii pneumonia and a low prevalence of tuberculosis. Measles, but not malaria, was associated with HIV infection.

Salt marshes, historically, were considered to be of minimal value. Current concepts consider these marshes to have a very high biomass. This study was conducted to characterize soils in seaside salt marshes on Virginia's eastern shore and to classify them according to criteria in Soil Taxonomyand proposed amendments. Results indicate that salt‐meadow marshes, dominantly vegetated by saltmeadow hay (Spartina patens), contain soils with halmyric and nonsulfidic properties and aquic moisture regimes. Classification of these soils as members of the proposed Halmyraqualfs will necessarily broaden the definition of halmyric materials to include an aquic moisture regime and the definition of the argillic horizon to include sodium adsorption ratios (SARs) considerably >13. We propose that soils in these marshes with subsoil illuvial clay accumulations and SARs >13 be classified as members of Typic Natraqualfs even though they lack structure currently defined for natric horizons. Saltmarsh cordgrass marshes, dominantly vegetated by S. alterniflora, contain soils with halmyric and sulfidic properties, silty textures, and peraquic moisture regimes. Tidal mudflats, not vegetated by vascular plants, contain sediments that have halmyric, but dominantly nonsulfidic properties. These results indicate that conditions necessary for the formation and accumulation of sulfide minerals exists in the salt‐marsh‐cordgrass marshes and to a limited extent in the tidal mudflats and in the salt‐meadow marshes. Considerably more information concerning properties of all the soils in the study area is conveyed by the proposed halmyric great groups and subgroups than by taxa currently defined by Soil Taxonomy. Moist incubation of samples provides a convenient and economical method for evaluating soils and sediments as sulfidic materials. Results of this study support the need for the proposed amendments to Soil Taxonomy.

Changes in SAR (sodium adsorption ratio), pH, and EC (electrical conductivity) of shallow groundwaters as a result of disposal of septic tank effluents into wet-tile-drained soils (Typic and Aeric Ochraquults) were studied during 1974, 1975, and 1976. Changes in these constituents in groundwaters were monitored at selected distances from the drainfield (by placement of sampling wells in the direction of groundwater flow), in waters intercepted by the agricultural tile, and control wells. Sodium adsorption ratio, pH, and EC generally decreased with increasing distance from the disposal area. The SAR decreased from 20 to 25 in samples adjacent to the drainfield to 2 in the control wells. The SAR in the drinking water supply was 40.

Irrigation is an integral part of a turfgrass management program and accounts for a large part of the energy inputs on a turf area. As potable water supplies decrease, use of limited water will impose stress on turfgrass areas which may result in reduced quality. Research on irrigation practices should help to minimize the effects of water stress resulting from reduced irrigation frequency. Response of St. Augustinegrass [Stenotaphrum secundatum(Walt.) Kuntze] to irrigation scheduling was studied during the summers of 1980 and 1981 on a loamy, siliceous, hyperthermic Grossarenic Palendult soil. An irrigation schedule of 2‐, 3‐, 4‐, and 6‐day intervals simulated conditions ranging from grass being under no water stress to severe water stress. Field plots were constructed to maintain an undisturbed soil profile that horizontally isolated adjacent plots to prevent lateral water movement. Irrigation treatments were implemented by irrigating with evapotranspiration estimates of 0.64 cm day−1in 1980 and 0.38 cm day−1in 1981 at either 2‐,3‐,4‐, or 6‐day intervals. Plots received equal volumes of water, only irrigation timing was varied. Turfgrass swards were evaluated on 12‐day cycles under water stress prior to irrigation and after 24 h of recovery following irrigation. Measured parameters included turfgrass quality, carbon exchange rates (CER), evapotranspiration rates (ET), plant water potential component changes, and leaf diffusive resistance, and transpiration. Irrigation scheduling affected many of the parameters studied. The 6‐day irrigation schedule caused a reduction in CER and ET and concurrent increase in stomatal resistance and a loss of turgor pressure prior to irrigation. Following irrigation, CER and ET increased, turgor pressure increased, and diffusive resistance decreased during each 12‐day cycle. When averaged over the entire study period preirrigation values of CER, ET, leaf water potential components, and transpiration were lowest and diffusive resistance highest for the 6‐day schedule, and these increased or decreased during recovery following irrigation. Even under the most severe conditions of 0.38 cm of water day−1applied every 6 days, the sward remained in positive carbon balance. Turfgrass quality and percent cover were not affected by irrigation treatments. Scheduling irrigation every 6 days with 2.3 cm of water will not affect St. Augustinegrass turf quality if adequate mowing height is maintained.

In the 1970s and 1980s, analysis of recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively ‘scan’ the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions of the genome were implicated in the control of infections caused by different Leishmaniaspecies which, because they show conserved synteny with regions of the human genome, immediately provides candidate gene regions for human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes (Nramp1) was identified for its role in controlling a range of intramacrophage pathogens including leishmania, salmonella and mycobacterium infections. In recent studies, multicase family data on visceral leishmaniasis and the mycobacterial diseases, tuberculosis and leprosy, have been collected from north–eastern Brazil and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family–based linkage analyses (combined segregation and linkage analysis; sib–pair analysis), which have the power to detect linkage between marker loci in candidate gene regions and the putative disease susceptibility genes over 10–;20 centimorgans, and transmission disequilibrium testing, which detects allelic associations over 1 centimorgan (ca.1 megabase), have been used to examine the role of four regions in determining disease susceptibility and/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H–2 in mouse, HLA in man: mouse chromosome 17/human 6p; candidates class II and class III including TNFalpha/beta genes) shows both linkage to, and allelic association with, leprosy per se, but is only weakly associated with visceral leishmaniasis and shows neither linkage to nor allelic association with tuberculosis; (ii) no evidence for linkage between NRAMP1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg(mouse chromosome 1/human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis could be demonstrated in this Brazilian population; (iii) the region of human chromosome 17q (candidates NOS2A, SCYA2–5) homologous with distal mouse chromosome 11, originally identified as carrying the Scl1gene controlling healing versus nonhealing responses to Leishmania major, is linked to tuberculosis susceptibility; and (iv) the ‘T helper 2’ cytokine gene cluster (proximal murine chromosome 11/human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. majorinfection, is not linked to human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. These studies demonstrate that the ‘mouse–to–man’ strategy, refined by our knowledge of the human immune response to infection, can lead to the identification of important candidate gene regions in man.

Electrotherapy has enjoyed little popularity with the medical profession. Its association with fraud and quackery, along with the strict limitations of the older type of apparatus, has done much to hinder its progress. Those who have been least disposed to credit any merit whatever to medical electricity must concede that, in diathermy, as employed with the newer type of apparatus, we have an agent whose potentialities for good have been but half developed. And in no branch of medicine is there a more fruitful field for its employment than in urology.Diathermy is the production of heat within the tissues of the body, not heat forced in. It is the formation of heat between two electrodes of a high frequency machine, due to the resistance encountered by the passing of an electric current through living cells of the body, from one electrode to the other. The current is of such

The data on the solvolysis of orthophosphoramidates are collected and rationalized into two groups: a mechanism involving a unimolecular decomposition of the compounds where nitrogen contains a positive charge, and a bimolecular one for molecules with uncharged nitrogen involving the entering and leaving groups at right angles to each other. The first mechanism is invoked for all acid catalyzed reactions and the decomposition of monoamidophosphoric acid, the second for all mononanions and acids except monoamidophosphoric and possibly the N-arylphosphoramidic.

General valence force field constants for NF3 have been calculated using very accurate frequency data, Coriolis coupling constants (ζ) and centrifugal distortion constants. The calculated constants are in excellent agreement with the experimental ones. Mean amplitudes of vibration were also calculated by some different methods, and thermodynamic functions are given for the temperature range 200 to 2000°k. Earlier investigations of these molecular constants are less accurate or incorrect.

A description of a number of methods of recording laser–Raman spectra of polymers is given. In particular, methods of obtaining adequate depolarization ratios in turbid species and avoidance of fluorescence are stressed. Consideration is also given to anisotropic scattering in oriented specimens and the interpretation of the effects observed.

Coccidioides immitis spherules cultured serially in a defined medium respond to certain stimuli by reverting to mycelium. A number of these stimuli have been identified and the response measured. Temperatures of incubation between 26°C and 40°C had only a minor effect on reversion. Reduction of the CO2 tension resulted in increased reversion. Human serum provided a powerful stimulus and most of the activity resided in the non-ultrafilterable fraction. No single fraction of the serum proteins was responsible for all the activity and the activity was not reversed by the addition of iron. Among saturated fatty acids maximal reversion occurred with myristic acid and maximal inhibition of growth with lauric acid. The unsaturated C18 acids were effective with reversion activity and toxicity increasing with unsaturation. Amphotericin B was both a growth inhibitor and a reversion stimulus.

A new member of the tartrolone series of macrodiolides, tartrolone C (1), was isolated from a Streptomyces species on the basis of its insecticidal activity. Metacycloprodigiosin (2) and undecylprodigiosin (3) were also isolated on the same basis. The structure of all compounds was established by spectroscopic data (NMR, MS, and UV).

Without Abstract:

Repair and improvement of sports turfs are difficult because of continuous use and damage to the turf ground cover. Sowing pregerminated rather the dormant seed is a possible means fo reducing establisment time. A series of experiments with seed of cool‐season turfgrasses were conducted under diferent temperature regimes to identify pregermination treatments that effect fast rates of germination. Italian ryegrass (Lolium multiflorumLam.), which has a relatively fast germination rate, was compared to ‘Kentucky 31’ tall fescue (Festuca arundinaceaSchreb.), which has a relatively slow germination rate. Seed was either treated by soaking for 24 or 48 h in aerated water, unaerated, in gibberellic acid (GA3) at 50 or 100 mg L−1, or by not soaking. Germination rates were compared 14 days after seed sown on blotters in petri dishes were incubated in controlled environments at optimum temperatures of 25 to 15°C or at suboptimum temperatures of 20 to 10°C and 15 to 5°C with an 8‐h photoperiod during the daily high temperature cycle. Fifty percent viable seed (Germ50)of Italian ryegrass germinated in 7 to 17 h depending on temperature, if pretreated with GA, at 100 mg L−1and kept moist for 48 h at 25°C. Untreated, dry seed had Germ50values of 4.2 to 7.1 days, respectively, depending on temperature. Germ50values for viable seed of Kentucky 31 tall fescue were 1.8 to 5.9 days depending on temperature, if seed was pretreated with GA3at 50 mg L−1and kept moist for 48 h at 25°C. Untreated, dry seed had Germ50values of 5.9 to 10.8 days, respectively, depending on temperature.

Presents tips and tricks on constructing model airplanes. Reduction of slop in an aileron torque rod; Use if hacksaw for cutting rounded openings through planking; Elimination of slop or end-play on giant-scale control surfaces; Process of strengthening control linkages.

Peacock, C. (2001). Clinical Radiology56, 85.

In an autopsy study in Abidjan, Côte d'lvoire, 14/155 brains of children <13 years had malaria parasites within cerebral blood vessels. This was associated with cerebral swelling (57% of brains), ventricular compression (86%) and mild basal grooving (43%), but not with coning of the medulla and cerebellum. The pathophysiology of cerebral malaria does not culminate in severe raised intracranial pressure and herniation, and over-concern over the safety of lumbar puncture in malaria may not be warranted.