Expert proposal to analyze the combination of aortic and mitral regurgitation in multiple valvular heart disease by comprehensive echocardiography.

The assessment of valvular pathologies in multiple valvular heart disease by echocardiography remains challenging. Data on echocardiographic assessment-especially in patients with combined aortic and mitral regurgitation-are rare in the literature. The proposed integrative approach using semi-quantitative parameters to grade the severity of regurgitation often yields inconsistent findings and results in misinterpretation. Therefore, this proposal aims to focus on a practical systematic echocardiographic analysis to understand the pathophysiology and hemodynamics in patients with combined aortic and mitral regurgitation. The quantitative approach of grading the regurgitant severity of each compound might be helpful in elucidating the scenario in combined aortic and mitral regurgitation. To this end, both the individual regurgitant fraction of each valve and the total regurgitant fraction of both valves must be determined. This work also outlines the methodological issues and limitations of the quantitative approach by echocardiography. Finally, we present a proposal that enables verifiable assessment of regurgitant fractions. The overall interpretation of echocardiographic results includes the symptomatology of patients with combined aortic and mitral regurgitation and the individual treatment options with respect to their individual risk. In summary, a reproducible, verifiable, and transparent in-depth echocardiographic investigation might ensure consistent hemodynamic plausibility of the quantitative results in patients with combined aortic and mitral regurgitation.

Biocellulose patch technique for fetoscopic repair of open spina bifida in twin pregnancy.

OBJECTIVES: Twin pregnancy is currently an exclusion criterion for prenatal repair of open spina bifida (OSB). The main objective of this study was to report on our experience of treating twin pregnancies with OSB using the skin-over-biocellulose for antenatal fetoscopic repair (SAFER) technique. We also discuss reconsideration of the current exclusion criteria for fetal OSB repair. METHODS: Eight fetuses with OSB from seven twin pregnancies underwent successful prenatal repair. Six pregnancies were dichorionic diamniotic with only one twin affected, and one was monochorionic diamniotic with both twins affected. Percutaneous fetoscopy was performed under CO2 insufflation of the sac of the affected twin. Neurosurgical repair was performed using a biocellulose patch to protect the placode, with the skin sutured to hold the patch in place, with or without a myofascial flap. Neurodevelopment was assessed using the pediatric evaluation of disability inventory scale in babies older than 6 months of adjusted age, whereas the Alberta scale was used for babies younger than 6 months of adjusted age. RESULTS: All 14 fetuses were liveborn and none required additional repair. Gestational age at surgery ranged from 27.3 to 31.1 weeks, and gestational age at birth ranged from 31.6 to 36.0 weeks. Four out of eight affected twins developed sepsis, but had a good recovery. No sequela of prematurity was found in any of the unaffected twins. Short-term neurodevelopment was normal in all evaluated unaffected twins (5/5) and in all but one affected twins (7/8). In the affected group, only one baby required ventriculoperitoneal shunt placement. CONCLUSIONS: Prematurity is frequent after fetal surgery, and the risk is increased in twin pregnancy. Nevertheless, prenatal surgery using the SAFER technique is feasible, with low risk to both twins and their mother when performed by a highly experienced team. Long-term cognitive assessment of the unaffected twin is needed. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Women's experiences of age-related discontinuation from mammography screening: A qualitative interview study.

INTRODUCTION: In Denmark, women are discontinued from mammography screening at age 69 due to decreased likelihood of benefits and increased likelihood of harm. The risk of harm increases with age and includes false positives, overdiagnosis and overtreatment. In a questionnaire survey, 24 women expressed unsolicited concerns about being discontinued from mammography screening due to age. This calls for further investigation of experiences related to discontinuation from screening. METHODS: We invited the women, who had left comments on the questionnaire, to participate in in-depth interviews with the purpose to explore their reactions, preferences, and conceptions about mammography screening and discontinuation. The interviews lasted 1-4 h and were followed up with a telephone interview 2 weeks after the initial interview. RESULTS: The women had high expectations of the benefits of mammography screening and felt that participation was a moral obligation. Following that, they perceived the screening discontinuation as a result of societal age discrimination and consequently felt devalued. Further, the women perceived the discontinuation as a health threat, felt more susceptible to late diagnosis and death, and therefore sought out new ways to control their risk of breast cancer. CONCLUSION: Our findings indicate that the age-related discontinuation from mammography screening might be of more importance than previously assumed. This study raises important questions about screening ethics, and we encourage research to explore this in other settings. PATIENT AND PUBLIC CONTRIBUTION: This study was conducted as a result of the women's unsolicited concerns about being discontinued from screening. This particular group contributed to the study with their own statements, interpretations and perspectives on the discontinuation of screening, and the initial analysis of data was discussed with the women during follow-up interviews.

Expert proposal to characterize cardiac diseases with normal or preserved left ventricular ejection fraction and symptoms of heart failure by comprehensive echocardiography.

Currently, the term "heart failure with preserved left ventricular ejection fraction (HFpEF)" is based on echocardiographic parameters and clinical symptoms combined with elevated or normal levels of natriuretic peptides. Thus, "HFpEF" as a diagnosis subsumes multiple pathophysiological entities making a uniform management plan for "HFpEF" impossible. Therefore, a more specific characterization of the underlying cardiac pathologies in patients with preserved ejection fraction and symptoms of heart failure is mandatory. The present proposal seeks to offer practical support by a standardized echocardiographic workflow to characterize specific diagnostic entities associated with "HFpEF". It focuses on morphological and functional cardiac phenotypes characterized by echocardiography in patients with normal or preserved left ventricular ejection fraction (LVEF). The proposal discusses methodological issues to clarify why and when echocardiography is helpful to improve the diagnosis. Thus, the proposal addresses a systematic echocardiographic approach using a feasible algorithm with weighting criteria for interpretation of echocardiographic parameters related to patients with preserved ejection fraction and symptoms of heart failure. The authors consciously do not use the diagnosis "HFpEF" to avoid misunderstandings. Central illustration: Scheme illustrating the characteristic echocardiographic phenotypes and their combinations in patients with "HFpEF" symptoms with respect to the respective cardiac pathology and pathophysiology as well as the underlying typical disease.

Chemical and electronic structure of the heavily intermixed (Cd,Zn)S:Ga/CuSbS2 interface.

The interface formation and chemical and electronic structure of the (Cd,Zn)S:Ga/CuSbS2 thin-film solar cell heterojunction were studied using hard X-ray photoelectron spectroscopy (HAXPES) of the bare absorber and a buffer/absorber sample set for which the buffer thickness was varied between 1 and 50 nm. We find a heavily intermixed interface, involving Cu, Zn, and Cd as well as significant Ga and Cu profiles in the buffer. The valence band (VB) offset at the buffer/absorber interface was derived as (-1.3 ± 0.1) eV, which must be considered an upper bound as the Cu diffused into the buffer might form a Cu-derived VB maximum located closer to the Fermi level. The estimated conduction band minimum was 'cliff'-like; a situation made more severe considering the Cu-deficiency found for the CuSbS2 surface. The complex interface structure's effect on the performance of (Cd,Zn)S:Ga/CuSbS2-based solar cells and its limitation is discussed together with possible mitigation strategies.

The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma.

BACKGROUND: Targeted therapies have improved survival and quality of life for patients with non-small-cell lung cancer with actionable driver mutations. However, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 gene (HER2, also known as ERBB2) exon 20 insertions (Ex20mut) are characterized by a poor response to currently approved tyrosine kinase inhibitors and immunotherapies. The underlying immune biology is not well understood. MATERIALS AND METHODS: We carried out messenger RNA expression profiling of lung adenocarcinomas (ADCs) with ERBB2 (n = 19) and EGFR exon 20-insertion mutations (n = 13) and compared these to tumors with classical EGFR mutations (n = 40, affecting EGFR exons 18, 19 or 21) and EGFR/ERBB2 mutation-negative lung ADC (EGFR/ERBB2wt, n = 26) focusing on immunologically relevant transcripts. Tumor-infiltrating immune cells were estimated from gene expression profiles. RESULTS: Cytotoxic cells were significantly lower in EGFR-mutated tumors regardless of the affected exon, while Th1 cells were significantly lower in EGFR-Ex20mut compared to EGFR/ERBB2wt tumors. We assessed the differentially expressed genes of ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. Of these, the genes GUSB, HDAC11, IFNGR2, PUM1, RASGRF1 and RBL2 were up-regulated, while a lower expression of CBLC, GBP1, GBP2, GBP4 and MYC was observed in all three comparison groups. The omnibus test revealed 185 significantly (FDR = 5%) differentially expressed genes and we found these four most significant gene expression changes in the study cohort: VHL and JAK1 were overexpressed in ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to both EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. RIPK1 and STK11IP showed the highest expression in ERBB2-Ex20mut tumors. CONCLUSIONS: Targeted gene expression profiling is a promising tool to read out the characteristics of the tumor microenvironment from routine diagnostic lung cancer biopsies. Significant immune reactivity and specific immunosuppressive characteristics in ERBB2-Ex20mut and EGFR-Ex20mut lung ADC with at least some degree of immune infiltration support further clinical evaluation of immune-modulators as partners of immune checkpoint inhibitors in such tumors.

[Cluster headache and other trigeminal autonomic cephalalgias]. / Clusterhoofdpijn en andere trigeminale autonome cefalalgieën.

Trigeminal autonomic cephalalgias (TACs) are a group of 4 different primary headache syndromes that have a lot of pathophysiological and clinical features in common. The 4 different TACs are: cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks and hemicrania continua. TACs are characterized by frequent, strictly unilateral, (very) intense headache attacks with ipsilateral cranial autonomic symptoms or intrinsic restlessness or both. A distinction can be made between the 4 TACs on the basis of the duration and frequency of the headache attacks. The treatment of cluster headache consists of an acute treatment and a maintenance treatment. Headache attacks in the context of paroxysmal hemicrania and hemicrania continua (almost) always respond to treatment with indomethacin. More and more neuromodulation therapies are becoming available, such as vagus nerve stimulation, stimulation and blocking of the sphenopalatine ganglion, stimulation and blocking of the occipital nerve and deep brain stimulation.

Percutaneous fetoscopic closure of large open spina bifida using a bilaminar skin substitute.

OBJECTIVE: We have described previously our percutaneous fetoscopic technique for the treatment of open spina bifida (OSB). However, approximately 20-30% of OSB defects are too large to allow primary skin closure. Here we describe a modification of our standard technique using a bilaminar skin substitute to allow closure of large spinal defects. The aim of this study was to report our clinical experience with the use of a bilaminar skin substitute and a percutaneous fetoscopic technique for the prenatal closure of large OSB defects. METHODS: Surgery was performed between 24.0 and 28.9 gestational weeks with the woman under general anesthesia, using an entirely percutaneous fetoscopic approach with partial carbon dioxide insufflation of the uterine cavity, as described previously. If there was enough skin to be sutured in the midline, only a biocellulose patch was placed over the placode (single-patch group). In cases in which skin approximation was not possible, a bilaminar skin substitute (two layers: one silicone and one dermal matrix) was placed over the biocellulose patch and sutured to the skin edges (two-patch group). The surgical site was assessed at birth, and long-term follow-up was carried out. RESULTS: Percutaneous fetoscopic OSB repair was attempted in 47 consecutive fetuses, but surgery could not be completed in two. Preterm prelabor rupture of membranes (PPROM) occurred in 36 of the 45 (80%) cases which formed the study group, and the mean gestational age at delivery was 32.8 ± 2.5 weeks. A bilaminar skin substitute was required in 13/45 (29%) cases; in the remaining 32 cases, direct skin-to-skin suture was feasible. There were 12 cases of myeloschisis, of which 10 were in the two-patch group. In all cases, the skin substitute was located at the surgical site at birth. In five of the 13 (38.5%) cases in the two-patch group, additional postnatal repair was needed. In the remaining cases, the silicone layer detached spontaneously from the dermal matrix (on average, 25 days after birth), and the lesion healed by secondary intention. The mean operating time was 193 (range, 83-450) min; it was significantly longer in cases requiring the bilaminar skin substitute (additional 42 min on average), although the two-patch group had similar PPROM rate and gestational age at delivery compared with the single-patch group. Complete reversal of hindbrain herniation occurred in 68% of the 28 single-patch cases and 33% of the 12 two-patch cases with this information available (P < 0.05). In four cases there was no reversal; half of these occurred in myeloschisis cases. CONCLUSIONS: Large OSB defects may be treated successfully in utero using a bilaminar skin substitute over a biocellulose patch through an entirely percutaneous approach. Although the operating time is longer, surgical outcome is similar to that in cases closed primarily. Cases with myeloschisis seem to have a worse prognosis than do those with myelomeningocele. PPROM and preterm birth continue to be a challenge. Further experience is needed to assess the risks and benefits of this technique for the management of large OSB defects. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Evolution of morphology and locomotor performance in anurans: relationships with microhabitat diversification.

The relationships between morphology, performance, behavior and ecology provide evidence for multiple and complex phenotypic adaptations. The anuran body plan, for example, is evolutionarily conserved and shows clear specializations to jumping performance back at least to the early Jurassic. However, there are instances of more recent adaptation to habit diversity in the post-cranial skeleton, including relative limb length. The present study tested adaptive models of morphological evolution in anurans associated with the diversity of microhabitat use (semi-aquatic arboreal, fossorial, torrent, and terrestrial) in species of anuran amphibians from Brazil and Australia. We use phylogenetic comparative methods to determine which evolutionary models, including Brownian motion (BM) and Ornstein-Uhlenbeck (OU) are consistent with morphological variation observed across anuran species. Furthermore, this study investigated the relationship of maximum distance jumped as a function of components of morphological variables and microhabitat use. We found there are multiple optima of limb lengths associated to different microhabitats with a trend of increasing hindlimbs in torrent, arboreal, semi-aquatic whereas fossorial and terrestrial species evolve toward optima with shorter hindlimbs. Moreover, arboreal, semi-aquatic and torrent anurans have higher jumping performance and longer hindlimbs, when compared to terrestrial and fossorial species. We corroborate the hypothesis that evolutionary modifications of overall limb morphology have been important in the diversification of locomotor performance along the anuran phylogeny. Such evolutionary changes converged in different phylogenetic groups adapted to similar microhabitat use in two different zoogeographical regions.

Vitamin E Supplementation Reduces Cellular Loss in the Brain of a Premature Aging Mouse Model.

BACKGROUND: Aging is a highly complex biological process driven by multiple factors. Its progression can partially be influenced by nutritional interventions. Vitamin E is a lipid-soluble anti-oxidant that is investigated as nutritional supplement for its ability to prevent or delay the onset of specific aging pathologies, including neurodegenerative disorders. PURPOSE: We aimed here to investigate the effect of vitamin E during aging progression in a well characterized mouse model for premature aging. METHOD: Xpg-/- animals received diets with low (~2.5 mg/kg feed), medium (75 mg/kg feed) or high (375 mg/kg feed) vitamin E concentration and their phenotype was monitored during aging progression. Vitamin E content was analyzed in the feed, for stability reasons, and in mouse plasma, brain, and liver, for effectiveness of the treatment. Subsequent age-related changes were monitored for improvement by increased vitamin E or worsening by depletion in both liver and nervous system, organs sensitive to oxidative stress. RESULTS: Mice supplemented with high levels of vitamin E showed a delayed onset of age-related body weight decline and appearance of tremors when compared to mice with a low dietary vitamin E intake. DNA damage resulting in liver abnormalities such as changes in polyploidy, was considerably prevented by elevated amounts of vitamin E. Additionally, immunohistochemical analyses revealed that high intake of vitamin E, when compared with low and medium levels of vitamin E in the diet, reduces the number of p53-positive cells throughout the brain, indicative of a lower number of cells dying due to DNA damage accumulated over time. CONCLUSIONS: Our data underline a neuroprotective role of vitamin E in the premature aging animal model used in this study, likely via a reduction of oxidative stress, and implies the importance of improved nutrition to sustain health.

Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice.

Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1∆/-) show numerous accelerated ageing features that limit their lifespan to 4-6 months. They also exhibit a 'survival response', which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction). Here we report that a dietary restriction of 30% tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated ageing. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Other DNA-repair-deficient, progeroid Xpg-/- (also known as Ercc5-/-) mice, a model of Cockayne syndrome, responded similarly. The dietary restriction response in Ercc1∆/- mice closely resembled the effects of dietary restriction in wild-type animals. Notably, liver tissue from Ercc1∆/- mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon we also observed in several tissues ageing normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of γH2AX DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Our findings establish the Ercc1∆/- mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general.

Genome Sequences of Streptomyces Phages Amela and Verse.

Amela and Verse are two Streptomyces phages isolated by enrichment on Streptomyces venezuelae (ATCC 10712) from two different soil samples. Amela has a genome length of 49,452, with 75 genes. Verse has a genome length of 49,483, with 75 genes. Both belong to the BD3 subcluster of Actinobacteriophage.

Effects of forage-to-concentrate ratio and dietary fiber manipulation on gas emissions and olfactometry from manure of Holstein heifers.

The objective of this experiment was to determine the effects of differing ratios of forage to concentrate (F:C) and fiber levels on odor and gas emissions from manure. Eight Holstein dairy heifers (362.45±4.53 d of age and 335.6±7.41 kg of body weight) were randomly assigned to a split-plot, 4×4 Latin square design (21-d periods) with F:C as the whole plot (20 or 80% forage) and fiber level as sub-plot (0, 20, 40, or 60% inclusion of corn stover). Gas concentration was determined using an infrared photoacoustic analyzer over a 24-h period using a steady-state flux chamber setup. Odorous air samples were collected from chamber headspace and evaluated by 6 human assessors using a forced-choice dynamic olfactometry technique. Emissions of CO2 were greater for the low than high concentrate diets, and no differences were observed for NH3 and CH4 emissions between F:C. Although F:C had no effect on NH3 emissions, as dietary fiber increased, a linear interaction with opposite effects was found for high and low concentrate diets. Nitrous oxide emissions were below minimum detectable levels. Neither F:C nor neutral detergent fiber level affected odor intensity. Odor emissions were successfully assessed, and manipulation of dietary fiber has the potential to influence CH4 and NH3 emissions.

Application of alpha/theta neurofeedback and heart rate variability training to young contemporary dancers: state anxiety and creativity.

As one in a series on the impact of EEG-neurofeedback in the performing arts, we set out to replicate a previous dance study in which alpha/theta (A/T) neurofeedback and heart rate variability (HRV) biofeedback enhanced performance in competitive ballroom dancers compared with controls. First year contemporary dance conservatoire students were randomised to the same two psychophysiological interventions or a choreology instruction comparison group or a no-training control group. While there was demonstrable neurofeedback learning, there was no impact of the three interventions on dance performance as assessed by four experts. However, HRV training reduced anxiety and the reduction correlated with improved technique and artistry in performance; the anxiety scale items focussed on autonomic functions, especially cardiovascular activity. In line with the putative impact of hypnogogic training on creativity A/T training increased cognitive creativity with the test of unusual uses, but not insight problems. Methodological and theoretical implications are considered.

NMDA receptor subunit composition determines beta-amyloid-induced neurodegeneration and synaptic loss.

Aggregates of amyloid-beta (Aß) and tau are hallmarks of Alzheimer's disease (AD) leading to neurodegeneration and synaptic loss. While increasing evidence suggests that inhibition of N-methyl-D-aspartate receptors (NMDARs) may mitigate certain aspects of AD neuropathology, the precise role of different NMDAR subtypes for Aß- and tau-mediated toxicity remains to be elucidated. Using mouse organotypic hippocampal slice cultures from arcAß transgenic mice combined with Sindbis virus-mediated expression of human wild-type tau protein (hTau), we show that Aß caused dendritic spine loss independently of tau. However, the presence of hTau was required for Aß-induced cell death accompanied by increased hTau phosphorylation. Inhibition of NR2B-containing NMDARs abolished Aß-induced hTau phosphorylation and toxicity by preventing GSK-3ß activation but did not affect dendritic spine loss. Inversely, NR2A-containing NMDAR inhibition as well as NR2A-subunit knockout diminished dendritic spine loss but not the Aß effect on hTau. Activation of extrasynaptic NMDARs in primary neurons caused degeneration of hTau-expressing neurons, which could be prevented by NR2B-NMDAR inhibition but not by NR2A knockout. Furthermore, caspase-3 activity was increased in arcAß transgenic cultures. Activity was reduced by NR2A knockout but not by NR2B inhibition. Accordingly, caspase-3 inhibition abolished spine loss but not hTau-dependent toxicity in arcAß transgenic slice cultures. Our data show that Aß induces dendritic spine loss via a pathway involving NR2A-containing NMDARs and active caspase-3 whereas activation of eSyn NR2B-containing NMDARs is required for hTau-dependent neurodegeneration, independent of caspase-3.

Effect of Origanum vulgare L. leaves on rumen fermentation, production, and milk fatty acid composition in lactating dairy cows.

This experiment investigated the effects of dietary supplementation of Origanum vulgare L. leaf material (OR) on rumen fermentation, production, and milk fatty acid composition in dairy cows. The experimental design was a replicated 4 × 4 Latin square with 8 rumen-cannulated Holstein cows and 20-d experimental periods. Treatments were control (no OR supplementation), 250 g/cow per day OR (LOR), 500 g/d OR (MOR), and 750 g/d OR (HOR). Oregano supplementation had no effect on rumen pH, volatile fatty acid concentrations, and estimated microbial protein synthesis, but decreased ammonia concentration and linearly decreased methane production per unit of dry matter intake (DMI) compared with the unsupplemented control: 18.2, 16.5, 11.7, and 13.6g of methane/kg of DMI, respectively. Proportions of rumen bacterial, methanogen, and fungal populations were not affected by treatment. Treatment had no effect on total-tract apparent digestibility of dietary nutrients, except neutral detergent fiber digestibility was slightly decreased by all OR treatments compared with the control. Urinary N losses and manure odor were not affected by OR, except the proportion of urinary urea N in the total excreted urine N tended to be decreased compared with the control. Oregano linearly decreased DMI (28.3, 28.3, 27.5, and 26.7 kg/d for control, LOR, MOR, and HOR, respectively). Milk yield was not affected by treatment: 43.4, 45.2, 44.1, and 43.4 kg/d, respectively. Feed efficiency was linearly increased with OR supplementation and was greater than the control (1.46, 1.59, 1.60, and 1.63 kg/kg, respectively). Milk composition was unaffected by OR, except milk urea-N concentration was decreased. Milk fatty acid composition was not affected by treatment. In this short-term study, OR fed at 250 to 750 g/d decreased rumen methane production in dairy cows within 8h after feeding, but the effect over a 24-h feeding cycle has not been determined. Supplementation of the diet with OR linearly decreased DMI and increased feed efficiency. Oregano had no effects on milk fatty acid composition.

Field olfactometry assessment of dairy manure land application methods.

Surface application of manure in reduced tillage systems generates nuisance odors, but their management is hindered by a lack of standardized field quantification methods. An investigation was undertaken to evaluate odor emissions associated with various technologies that incorporate manure with minimal soil disturbance. Dairy manure slurry was applied by five methods in a 3.5-m swath to grassland in 61-m-inside-diameter rings. Nasal Ranger Field Olfactometer (NRO) instruments were used to collect dilutions-to-threshold (D/T) observations from the center of each ring using a panel of four odor assessors taking four readings each over a 10-min period. The Best Estimate Threshold D/T (BET10) was calculated for each application method and an untreated control based on preapplication and <1 h, 2 to 4 h, and approximately 24 h after spreading. Whole-air samples were simultaneously collected for laboratory dynamic olfactometer evaluation using the triangular forced-choice (TFC) method. The BET10 of NRO data composited for all measurement times showed D/T decreased in the following order (a = 0.05): surface broadcast > aeration infiltration > surface + chisel incorporation > direct ground injection Sshallow disk injection > control, which closely followed laboratory TFC odor panel results (r = 0.83). At 24 h, odor reduction benefits relative to broadcasting persisted for all methods except aeration infiltration, and odors associated with direct ground injection were not different from the untreated control. Shallow disk injection provided substantial odor reduction with familiar toolbar equipment that is well adapted to regional soil conditions and conservation tillage operations.

PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models.

BACKGROUND: PG545 is a heparan sulfate (HS) mimetic that inhibits tumour angiogenesis by sequestering angiogenic growth factors in the extracellular matrix (ECM), thus limiting subsequent binding to receptors. Importantly, PG545 also inhibits heparanase, the only endoglycosidase which cleaves HS chains in the ECM. The aim of the study was to assess PG545 in various solid tumour and metastasis models. METHODS: The anti-angiogenic, anti-tumour and anti-metastatic properties of PG545 were assessed using in vivo angiogenesis, solid tumour and metastasis models. Pharmacokinetic (PK) data were also generated in tumour-bearing mice to gain an understanding of optimal dosing schedules and regimens. RESULTS: PG545 was shown to inhibit angiogenesis in vivo and induce anti-tumour or anti-metastatic effects in murine models of breast, prostate, liver, lung, colon, head and neck cancers and melanoma. Enhanced anti-tumour activity was also noted when used in combination with sorafenib in a liver cancer model. PK data revealed that the half-life of PG545 was relatively long, with pharmacologically relevant concentrations of radiolabeled PG545 observed in liver tumours. CONCLUSION: PG545 is a new anti-angiogenic clinical candidate for cancer therapy. The anti-metastatic property of PG545, likely due to the inhibition of heparanase, may prove to be a critical attribute as the compound enters phase I clinical trials.

Altered phosphorylation but no neurodegeneration in a mouse model of tau hyperphosphorylation.

The role of hyperphosphorylation of tau in Alzheimer's disease is still unsolved. Here we describe a novel transgenic mouse model, expressing a pseudohyperphosphorylated (PHP) variant of the longest human CNS tau isoform in forebrain neurons. We report that pseudohyperphosphorylation decreases phosphorylation at T205 while other sites (T212, S262) are less or not affected compared to mice expressing wildtype tau. Despite the differences in phosphorylation, the subcellular distribution of tau is not affected and mice do not develop highly aggregated states of tau. PHP tau expressing mice do not show any evidence for neurodegeneration as determined from morphometric measurements of neocortical regions, caspase activation, analysis of mitochondrial dysfunction, or determination of spine densities. In agreement, no differences in learning and memory are observed. The data indicates that moderate levels of modified tau alone are not sufficient to induce tau aggregation or neurodegeneration in transgenic mice. With our model it becomes possible to study the effects of hyperphosphorylation at conditions which may prevail in an early preaggregation state of the disease.

A widespread family of polymorphic contact-dependent toxin delivery systems in bacteria.

Bacteria have developed mechanisms to communicate and compete with one another in diverse environments. A new form of intercellular communication, contact-dependent growth inhibition (CDI), was discovered recently in Escherichia coli. CDI is mediated by the CdiB/CdiA two-partner secretion (TPS) system. CdiB facilitates secretion of the CdiA 'exoprotein' onto the cell surface. An additional small immunity protein (CdiI) protects CDI(+) cells from autoinhibition. The mechanisms by which CDI blocks cell growth and by which CdiI counteracts this growth arrest are unknown. Moreover, the existence of CDI activity in other bacteria has not been explored. Here we show that the CDI growth inhibitory activity resides within the carboxy-terminal region of CdiA (CdiA-CT), and that CdiI binds and inactivates cognate CdiA-CT, but not heterologous CdiA-CT. Bioinformatic and experimental analyses show that multiple bacterial species encode functional CDI systems with high sequence variability in the CdiA-CT and CdiI coding regions. CdiA-CT heterogeneity implies that a range of toxic activities are used during CDI. Indeed, CdiA-CTs from uropathogenic E. coli and the plant pathogen Dickeya dadantii have different nuclease activities, each providing a distinct mechanism of growth inhibition. Finally, we show that bacteria lacking the CdiA-CT and CdiI coding regions are unable to compete with isogenic wild-type CDI(+) cells both in laboratory media and on a eukaryotic host. Taken together, these results suggest that CDI systems constitute an intricate immunity network with an important function in bacterial competition.