No abstract

This study compares the susceptibility of winter wheat (Triticum aestivum L.) cultivars to Fusarium head blight (FHB) and accumulation of mycotoxins in kernels and chaff under different climatic conditions in two locations-Cerekwica near Poznan (Central West Poland) and Sitaniec, near Zamosc, Lublin region (South East Poland). Very high variations were found in the concentrations of mycotoxins (zearalenone, ZEA; nivalenol, NIV; deoxynivalenol, DON; moniliformin, MON) in examined fractions: Fusarium-damaged kernels (FDK) and healthy looking kernels (HLK) and in chaff for individual cultivars in both locations. In most cases, significantly higher concentrations of investigated toxins were recorded in wheat from the area of Lublin than from Poznan (p < 0.05). The highest Fusarium infection rates and mycotoxin biosynthesis levels were observed in the Lublin location, with the percentage of the FDK fraction ranging 8.1-81.6. In this region, ZEA concentration (microg g(-1)) after inoculation with F. culmorum and F. graminearum ranged from 0.02-0.48 and 0.32-1.04, respectively. In the Poznan area, the toxin concentrations were considerably lower, ranging 0.01-0.10 and 0.03-0.13 microg g(-1) for both isolates, respectively. The concentration of DON was significantly higher than ZEA or NIV levels. The levels of MON accumulation (microg g(-1)) in the FDK fraction were between 0.14 and 1.73 (Poznan area) and ND (not detected) to 2.51 (Lublin area). F. avenaceum infection rate ranged 7-35% in samples where the toxin was detected.

Objective To determine if the selective vasopressin type 1a receptor (V1aR) agonist selepressin (FE 202158) is as effective as the mixed V1a/V2 receptor (V1aR/V2R) agonist vasopressor hormone arginine vasopressin (AVP) when used as a titrated first-line vasopressor therapy in an ovine model of Pseudomonas aeruginosa pneumonia-induced severe sepsis. Design Prospective, randomized, controlled laboratory experiment. Setting University animal research facility. Subjects Forty-five chronically instrumented sheep. Interventions Sheep were anesthetized, insufflated with cooled cotton smoke via tracheostomy, and P. aeruginosa were instilled into their airways. They were then placed on assisted ventilation, awakened, and resuscitated with lactated Ringer's solution titrated to maintain hematocrit ± 3% from baseline levels. If, despite fluid management, mean arterial pressure (MAP) fell by > 10 mm Hg from baseline levels, a continuous i.v. infusion of AVP or selepressin was titrated to raise and maintain MAP within 10 mm Hg of baseline. Effects of combination treatment of selepressin with the selective V2R agonist desmopressin were similarly investigated. Measurements and Main Results In septic sheep, MAP fell by ~30 mm Hg, systemic vascular resistance index (SVRI) decreased by ~50%, and ~7 L of fluid were retained over 24 h; this fluid accumulation was partially reduced by AVP and almost completely blocked by selepressin; combined infusion of selepressin and desmopressin increased fluid accumulation to levels similar to AVP treatment. Conclusions Resuscitation with the selective V1aR agonist selepressin blocked vascular leak more effectively than the mixed V1aR/V2R agonist AVP because of its lack of agonist activity at the V2R.

Toxigenic Fusarium species are common pathogens of wheat and other cereals worldwide. In total, 449 wheat heads from six localities in Poland, heavily infected with Fusarium during 2009 season, were examined for Fusarium species identification. F. culmorum was the most common species (72.1% on average) with F. graminearum and F. avenaceum the next most commonly observed, but much less frequent (13.4 and 12.5% respectively). F. cerealis was found in 1.8% of all samples, and F. tricinctum was found only in one sample (0.2%). Subsequent quantification of the three major mycotoxins (deoxynivalenol, zearalenone and moniliformin) in grain and chaff fractions with respect to associated prevailing pathogen species uncovered the following patterns. Moniliformin (MON) was found in low amounts in all samples with F. avenaceum present. In contrast, deoxynivalenol (DON) and zearalenone (ZEA) were the contaminants of F. culmorum- and F. graminearum-infected heads. The highest concentration of DON was recorded in grain sample collected in Radzików (77 µg g−1). High temperatures in Central Poland during July and August accompanied with high rainfall in July were responsible for this high DON accumulation. Trichothecene, zearalenone, enniatin and beauvericin chemotypes were identified among 21 purified isolates using gene-specific PCR markers.

One strain of Fusarium subglutinans (ITEM-1434) isolated from maize ear rot in Poland was tested for the ability to synthesize moniliformin (MON), beauvericin (BEA) and fusaproliferin (FP) on six cereal substrates (wheat, rye, barley, oat, maize and rice kernels) for 3 weeks at 25 degrees C and on rice at three different temperatures (20, 25 and 30 degrees C). Most MON (497 micrograms/g) was produced on rice; most BEA (704 micrograms/g) on wheat or rice, and most FP (422 micrograms/g) on rye. When cultured on rice, F. subglutinans produced the highest levels of BEA and FP at 20-25 degrees C, while MON production was best at 30 degrees C.

Glucagon-like peptide-2 receptor agonists have therapeutic potential for the treatment of intestinal diseases. The native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a suitable clinical candidate, due to its very short half-life in humans. In search of GLP-2 receptor agonists with better pharmacokinetic characteristics, a series of GLP-2 analogues containing Gly substitution at position 2, norleucine in position 10, and hydrophobic substitutions in positions 11 and/or 16 was designed and synthesized. In vitro receptor potency at the human GLP-2, selectivity vs the human GLP-1 and GCG receptors, and PK profile in rats were determined for the new analogues. A number of compounds more potent at the hGLP-2R than the native hormone, showing excellent receptor selectivity and very low systemic clearance (CL) were discovered. Analogues 69 ([Gly(2),Nle(10),D-Thi(11),Phe(16)]hGLP-2-(1-30)-NH2), 72 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-OH), 73 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NH2), 81 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NHEt), and 85 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NH-((CH2)2O)4-(CH2)2-CONH2) displayed the desired profiles (EC50 (hGLP-2R) < 100 pM, CL in rat <0.3 mL/min/kg, selective vs hGLP-1R and hGCGR). Compound 73 (FE 203799) was selected as a candidate for clinical development.

Mothers of preterm babies frequently have difficulty establishing or maintaining lactation, thought to be due to interference with the milk ejection reflex. Administration of exogenous oxytocin can produce alveolar contraction and adequate breast emptying resulting in establishment of successful lactation. The natural hormone oxytocin is not receptor-selective and may cause hyponatremia via V2 receptor mediated antidiuresis. We have designed a series of potent oxytocin analogues containing N-alkylglycines in position 7 with excellent selectivity versus the related V1a, V1b, and V2 vasopressin receptors and short half-life: agonists 31 ([2-ThiMeGly(7)]dOT), 47 (carba-6-[Phe(2),BuGly(7)]dOT), 55 (carba-6-[3-MeBzlGly(7)]dOT), and 57 (carba-1-[4-FBzlGly(7)]dOT) have EC50 values at hOTR < 0.1 nM, selectivity ratios versus related human vasopressin receptors of >2000, IC50 at hV1aR > 500 nM, and total clearance in rats in the range of 60-80 mL min(-1) kg(-1). Compound 57 (FE 202767) is currently in clinical development for the treatment of preterm mothers requiring lactation support.

[Arg(8)]vasopressin (AVP) produces vasoconstriction via V(1a) receptor (V(1a)R)-mediated vascular smooth muscle cell contraction and is being used to increase blood pressure in septic shock, a form of vasodilatory hypotension. However, AVP also induces V(2) receptor (V(2)R)-mediated antidiuresis, vasodilation, and coagulation factor release, all deleterious in septic shock. The V(1a)R agonist terlipressin (H-Gly(3)[Lys(8)]VP) also lacks selectivity vs the V(2)R and has sizably longer duration of action than AVP, preventing rapid titration of its vasopressor effect in the clinic. We designed and synthesized new short acting V(1a)R selective analogues of general structure [Xaa(2),Ile(3),Yaa(4),Zaa(8)]VP. The most potent and selective compounds in in vitro functional assays (e.g., [Phe(2),Ile(3),Asn(Me(2))(4),Orn(8)]VP (31), [Phe(2),Ile(3),Asn((CH(2))(3)OH)(4),Orn(8)]VP (34), [Phe(2),Ile(3),Hgn(4),Orn(iPr)(8)]VP (45), [Phe(2),Ile(3),Asn(Et)(4),Dab(8)]VP (49), [Thi(2),Ile(3),Orn(iPr)(8)]VP (59), [Cha(2),Ile(3),Asn(4),Orn(iPr)(8)]VP (68)) were tested by intravenous bolus in rats for duration of vasopressive action. Analogues 31, 34, 45, and 49 were as short-acting as AVP. Compound 45, FE 202158, is currently undergoing clinical trials in septic shock.