Zearalenones are estrogenic
Fusarium mycotoxins consisting of a resorcinol moiety fused to a 14-member macrocyclic lactone. Using an improved MCF7 human breast cell proliferation assay, we have ...compared the estrogenicity of 17 chromatographically-homogeneous zearalenones. Both similarities and substantial differences from published results in intact animal systems were observed. Substantial human estrogenicity was retained even in analogs lacking hydroxylation on the aromatic and macrocyclic rings.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Combination therapy with somatostatin receptor ligand (SRL) plus pegvisomant for patients with acromegaly is recommended after a maximizing dose on monotherapy. Lower-dose combination regimens are ...not well studied.
To compare cost-effectiveness and efficacy of 3 lower-dose combination regimens in controlled and uncontrolled acromegaly.
Prospective, randomized, open-label, parallel arm study at a tertiary referral pituitary center.
Adults with acromegaly regardless of response to prior SRL and biochemical control status at baseline, stratified by an SRL dose required for insulin-like growth factor (IGF)-I normalization during any 3-month period within 12 months preceding enrollment.
Combination therapy for 24 to 32 weeks on arm A, high-dose SRL (lanreotide 120 mg/octreotide long-acting release LAR 30 mg) plus weekly pegvisomant (40-160 mg/week); arm B, low-dose SRL (lanreotide 60 mg/octreotide LAR 10 mg) plus weekly pegvisomant; or arm C, low-dose SRL plus daily pegvisomant (15-60 mg/day).
Monthly treatment cost in each arm in participants completing ≥ 24 weeks of therapy.
Sixty patients were enrolled and 52 were evaluable. Fifty of 52 (96%) demonstrated IGF-I control regardless of prior SRL responsiveness (arm A, 14/15 93.3%; arm B, 22/23 95.7%; arm C, 14/14 100%). Arm B was least costly (mean, $9837 ± 1375 per month), arm C was most expensive (mean, $22543 ± 11158 per month), and arm A had an intermediate cost (mean, $14261 ± 1645 per month). Approximately 30% of patients required pegvisomant dose uptitration. Rates of adverse events were all < 10%.
Low-dose SRL plus weekly pegvisomant represents a novel dosing option for achieving cost-effective, optimal biochemical control in patients with uncontrolled acromegaly requiring combination therapy.
This paper describes a method for the analysis of DON and its derivatives in wheat and barley using combination gas chromatography/mass spectrometry (GC/MS). The method has been designed for the ...analysis of large batch (100 g) samples and single kernels. The sensitivity of the method is 50 ppb (ng/g), and the precision in terms of percent standard deviation lies between 0.0 and 11.1. The percent recovery for 1, 5, and 10 μg/g (ppm) recovered from wheat is 97.2, 88.4 and 87.9% respectively. A comparison of methods was made between two laboratories using GC/EC and our method. There was no significant difference between the results of the two methods. The method is also applicable to 15-acetyldeoxynivalenol (15-ADON) as well as nivalenol (NIV). Standard curves constructed for DON, 15-ADON, and NIV show a linear relationship between 0.025 ng (limit of sensitivity) and 8 ng. Keywords: Deoxynivalenol; nivalenol; analytical method
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Recent epidemics of Fusarium head blight (FHB) severely damaged the hard red spring wheat and barley crops in Minnesota. Samples of commercial grain were analyzed in 1993 and 1994 to determine the ...effects of FHB on several quality parameters. Wheat test weight (TW) averaged 832 kg m-(3) (55.4 lb/bu), thousand kernel weight (TKW) averaged 27.4 g, and the proportion of visually scabby kernels (VSK) averaged 11.0%. Deoxynivalenol (DON) was detected in 493 of 500 samples (98.6%). The mean concentration was 8.3 microgram/g (range = 0.0 to 44.7 microgram/g). Scab in wheat could rapidly be estimated using easy-to-prepare visual comparison standards. Scores of percent VSK were correlated with DON concentration at r = 0.897 and 0.908 in 1993 and 1994, respectively. TW and TKW were less effective estimators of DON (r = -0.622 and -0.550, respectively). DON was detected in 100 of 100 six-row barley samples collected during the survey and averaged 10.4 microgram/g (range = 0.5 to 39.7 microgram/g). DON concentration in barley could not be effectively estimated with grading parameters including TW, TKW, percent plump kernels, or a visual index of kernel discoloration. In 28 samples of oats, DON averaged 1.4 microgram/g (range = 0.0 to 6.4 microgram/g). Nivalenol was not detected in any of the 628 samples analyzed during the two-year study.
A method for analyzing ergosterol in a single kernel and ground barley and wheat was developed using gas chromatography−mass spectrometry (GC-MS). Samples were saponified in methanolic KOH. ...Ergosterol was extracted by “one step” hexane extraction and subsequently silylated by N-trimethylsilylimidazole/trimethylchlorosilane (TMSI/TMCS) reagent at room temperature. The recoveries of ergosterol from ground barley were 96.6, 97.1, 97.1, 88.5, and 90.3% at the levels of 0.2, 1, 5, 10, and 20 μg/g (ppm), respectively. The recoveries from a single kernel were between 93.0 and 95.9%. The precision (coefficient of variance) of the method was in the range 0.8−12.3%. The method detection limit (MDL) and the method quantification limit (MQL) were 18.5 and 55.6 ng/g (ppb), respectively. The ergosterol analysis method developed can be used to handle 80 samples daily by one person, making it suitable for screening cereal cultivars for resistance to fungal infection. The ability for detecting low levels of ergosterol in a single kernel provides a tool to investigate early fungal invasion and to study mechanisms of resistance to fungal diseases. Keywords: Ergosterol; wheat; barley; single kernel; GC-MS
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Numerous cases of primary hypophysitis have been described over the past 25 years with, however, little insight into the cause(s) of this disease. In order to guide treatment, a better understanding ...of the pathogenesis is needed. We studied the pathogenesis of primary hypophysitis by analysing systematically the immune response at the pituitary tissue level of consecutive cases of 'lymphocytic' hypophysitis who underwent pituitary biopsy. In order to investigate further the pathogenesis of their diseases we characterized two cases at clinical, cellular and molecular levels. We show here, for the first time, that lymphocytic hypophysitis probably encompasses at least two separate entities. One entity, in agreement with the classical description of lymphocytic hypophysitis, demonstrates an autoimmune process with T helper 17 cell dominance and lack of T regulatory cells. The other entity represents a process in which T regulatory cells seem to control the immune response, which may not be self- but foreign-targeted. Our data suggest that it may be necessary to biopsy suspected primary hypophysitis and to analyse pituitary tissue with immune markers to guide treatment. Based on our results, hypophysitis driven by an immune homeostatic process should not be treated with immunosuppression, while autoimmune-defined hypophysitis may benefit from it. We show here for the first time two different pathogenic processes classified under one disease type and how to distinguish them. Because of our findings, changes in current diagnostic and therapeutic approaches may need to be considered.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Twenty-five strains of Fusarium sambucinum grown on wheat kernels were examined for trichothecene production and the synthesis of volatile sesquiterpenes. The volatiles were purged with air and ...collected on Tenax traps. Adsorbed compounds were eluted from the traps and injected into a gas chromatograph coupled with a mass spectrometer. Ten strains isolated from potato tubers produced high amounts of diacetoxyscirpenol and its derivatives. These strains were characterized by the production of high amounts of diverse sesquiterpenes. In 10 cultures, 19 compounds were detected, of which 6 were predominant and composed as much as 82% of the volatile sesquiterpene fraction (e.g., beta-farnesene, beta-chamigrene, beta-bisabolene, alpha-farnesene, trichodiene, and an unidentified compound). Fifteen strains isolated from various sources that did not produce trichothecenes produced much less volatile sesquiterpenes, with less chemical diversity. No more than six compounds were present in cultures. Two of these compounds were present in the toxigenic strains isolated from potatoes (beta-farnesene and acoradiene), but four were unique to the strains not producing trichothecenes (longifolene, isocaryophyllene, delta-elemene, and an unidentified one). The pattern of volatile sesquiterpenes was characteristic and distinctive for both toxic and nontoxic strains
Summary
Wheat ears were inoculated with conidia of Fusarium spp. at different growth stages between ear emergence and harvest and moist conditions were maintained for up to 7 days subsequently by ...mist irrigation. Of the fungi tested (Fusarium culmorum, F. avenaceum, F. tricinctum, F. sporotrichioides and Microdochium nivale), only F. culmorum produced ear blight symptoms and grain samples were found subsequently to contain deoxynivalenol. Most ear infection and deoxynivalenol formation occurred following inoculation at about mid‐anthesis. Small amounts of deoxynivalenol were formed and some F. culmorum was isolated even in the absence of ear blight symptoms. An overnight wet period was sufficient to initiate infection and deoxynivalenol formation but both were increased by extending the wet period up to at least 3 days. Recovery of Fusarium spp. from harvested grain was usually possible whether or not symptoms developed. F. culmorum usually persisted and often increased to moderately high levels after storage for 7 wk in a range of moisture conditions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This research examined the biosynthesis of deoxynivalenol (DON) and 15-acetyldeoxynivalenol (15-ADON) in barley spikelets inoculated with macroconidia of Fusarium graminearum (Group-II). ...Investigations were conducted to determine if these toxins were present in macroconidia of the pathogen prior to inoculating barley spikelets. Extracts of macroconidia cultured from mung bean agar were analyzed using gas chromatography-mass spectrometry. Neither DON or 15-ADON was detected in three isolates' macroconidia when compared with macroconidia-DON-matrix standards adjusted to 100, 200, 300, and 400 ng/g with a detection limit of 100 ng/g. Mean recovery of DON that was added to macroconidia was 89.5%. The same isolates were pathogenic on barley cultivars Robust (moderately susceptible) and Chevron (moderately resistant) and produced DON (0 to 3.69 ng/g) and 15-ADON (detected but not quantified) when grown in rice culture. Greenhouse experiments were performed to determine when DON and 15-ADON were detectable after inoculation and to quantify their amount in inoculated barley spikelets. The three isolates of F. graminearum were separately inoculated to a central spikelet on heads of barley cultivars Robust and Chevron. Both toxins were detected in spikelets 48 h postinoculation (PI). DON increased dramatically after 72 h and did not diminish thereafter. Accumulation of 15-ADON peaked at 72 to 120 h and decreased by 240 h PI. There were no statistical differences between cultivars or among fungal isolates for accumulation of either toxin when averaged over the time intervals. Differences of toxin accumulation at each sampling interval were significant (P < 0.0001) when averaged over isolates and cultivars. Spikelets of six cultivars and lines were sampled at inoculation and 18, 36, 54, 72, and 90 h PI. DON and 15-ADON were detected at 36 h PI, but differences among the cultivars and lines were not significant. Yield of DON in inoculated spikelets of 31 barley cultivars and lines at 72 h PI ranged from 0.14 to 1.26 μg per spikelet, and differences among the cultivars and lines were significant (P < 0.002). The data demonstrate a useful range of variability for toxin accumulation in inoculated spikelets among germ plasm in the Minnesota breeding program. Macroconidia with no detectable DON or 15-ADON could be used for in vitro studies of toxin biosynthesis. Establishing when DON and 15-ADON are synthesized facilitates studying the effects of promising fungicides, biocontrol organisms, and new or novel genetic resistance mechanisms and if or how they may prevent or delay the biosynthesis of toxins.
In view of the recent observations that gadolinium deposits in brain tissue after intravenous injection, our aim of this study was to compare signal changes in the globus pallidus and dentate nucleus ...on unenhanced T1-weighted MR images in patients receiving serial doses of gadobutrol, a macrocyclic gadolinium-based contrast agent, with those seen in patients receiving linear gadolinium-based contrast agents.
This was a retrospective analysis of on-site patients with brain tumors. Fifty-nine patients received only gadobutrol, and 60 patients received only linear gadolinium-based contrast agents. Linear gadolinium-based contrast agents included gadoversetamide, gadobenate dimeglumine, and gadodiamide. T1 signal intensity in the globus pallidus, dentate nucleus, and pons was measured on the precontrast portions of patients' first and seventh brain MRIs. Ratios of signal intensity comparing the globus pallidus with the pons (globus pallidus/pons) and dentate nucleus with the pons (dentate nucleus/pons) were calculated. Changes in the above signal intensity ratios were compared within the gadobutrol and linear agent groups, as well as between groups.
The dentate nucleus/pons signal ratio increased in the linear gadolinium-based contrast agent group (
= 4.215,
< .001), while no significant increase was seen in the gadobutrol group (
= -1.422,
= .08). The globus pallidus/pons ratios followed similarly, with an increase in the linear gadolinium-based contrast agent group (
= 2.931,
< .0001) and no significant change in those receiving gadobutrol (
= 0.684,
= .25).
Successive doses of gadobutrol do not result in T1 shortening compared with changes seen in linear gadolinium-based contrast agents.
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