FP Levels Research Articles

Modulations of bioactive lipids and their receptors in postmortem Alzheimer's disease brains.

Analyses of brain samples from Alzheimer's disease (AD) patients may be expected to help us improve our understanding of the pathogenesis of AD. Bioactive lipids, including sphingolipids, glycerophospholipids, and eicosanoids/related mediators have been demonstrated to exert potent physiological actions and to be involved in the pathogenesis of various human diseases. In this cross-sectional study, we attempted to elucidate the associations of these bioactive lipids with the pathogenesis/pathology of AD through postmortem studies of human brains. We measured the levels of glycerophospholipids, sphingolipids, and eicosanoids/related mediators in the brains of patients with AD (AD brains), patients with Cerad score B (Cerad-b brains), and control subjects (control brains), using a liquid chromatography-mass spectrometry method; we also measured the mRNA levels of specific receptors for these bioactive lipids in the same brain specimens. The levels of several species of sphingomyelins and ceramides were higher in the Cerad-b and AD brains. Levels of several species of lysophosphatidic acids (LPAs), lysophosphatidylcholine, lysophosphatidylserine, lysophosphatidylethanolamine (LPE), lysophosphatidylinositol, phosphatidylcholine, phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol, and phosphatidylglycerol were especially high in the Cerad-b brains, while those of lysophosphatidylglycerol (LPG) were especially high in the AD brains. Several eicosanoids, including metabolites of prostaglandin E2, oxylipins, metabolites of epoxide, and metabolites of DHA and EPA, such as resolvins, were also modulated in the AD brains. Among the lipid mediators, the levels of S1P2, S1P5, LPA1, LPA2, LPA6, P2Y10, GPR174, EP1, DP1, DP2, IP, FP, and TXA2r were lower in the AD and/or Cerad-b brains. The brain levels of ceramides, LPC, LPI, PE, and PS showed strong positive correlations with the Aβ contents, while those of LPG showed rather strong positive correlations with the presence of senile plaques and neurofibrillary tangles. A discriminant analysis revealed that LPG is especially important for AD and the LPE/PE axis is important for Cerad-b. Comprehensive lipidomics, together with the measurement of lipid receptor expression levels provided novel evidence for the associations of bioactive lipids with AD, which is expected to facilitate future translational research and reverse translational research.

Structural studies offer a framework for understanding the role of properdin in the alternative pathway and beyond.

Structures of alternative pathway proteins have offered a comprehensive structural basis for understanding the molecular mechanisms governing activation and regulation of the amplification pathway of the complement cascade. Although properdin (FP) is required in vivo to sustain a functional alternative pathway, structural studies have been lagging behind due to the extended structure and polydisperse nature of FP. We review recent progress with respect to structure determination of FP and its proconvertase/convertase complexes. These structures identify in detail regions in C3b, factor B and FP involved in their mutual interactions. Structures of FP oligomers obtained by integrative studies have shed light on how FP activity depends on its oligomerization state. The accumulated structural knowledge allows us to rationalize the effect of point mutations causing FP deficiency. The structural basis for FP inhibition by the tick CirpA proteins is reviewed and the potential of alphafold2 predictions for understanding the interaction of FP with other tick proteins and the NKp46 receptor on host immune cells is discussed. The accumulated structural knowledge forms a comprehensive basis for understanding molecular interactions involving FP, pathological conditions arising from low levels of FP, and the molecular strategies used by ticks to suppress the alternative pathway.

Optical Redox Imaging of Ex Vivo Hippocampal Tissue Reveals Age-Dependent Alterations in the 5XFAD Mouse Model of Alzheimer's Disease.

A substantial decline in nicotinamide adenine dinucleotide (NAD) has been reported in brain tissue homogenates or neurons isolated from Alzheimer’s disease (AD) models. NAD, together with flavin adenine dinucleotide (FAD), critically supports energy metabolism and maintains mitochondrial redox homeostasis. Optical redox imaging (ORI) of the intrinsic fluorescence of reduced NAD (NADH) and oxidized FAD yields cellular redox and metabolic information and provides biomarkers for a variety of pathological conditions. However, its utility in AD has not been characterized at the tissue level. We performed ex vivo ORI of freshly dissected hippocampi from a well-characterized AD mouse model with five familial Alzheimer’s disease mutations (5XFAD) and wild type (WT) control littermates at various ages. We found (1) a significant increase in the redox ratio with age in the hippocampi of both the WT control and the 5XFAD model, with a more prominent redox shift in the AD hippocampi; (2) a higher NADH in the 5XFAD versus WT hippocampi at the pre-symptomatic age of 2 months; and (3) a negative correlation between NADH and Aβ42 level, a positive correlation between Fp and Aβ42 level, and a positive correlation between redox ratio and Aβ42 level in the AD hippocampi. These findings suggest that the ORI can be further optimized to conveniently study the metabolism of freshly dissected brain tissues in animal models and identify early AD biomarkers.

Assessing filtered permeability around the globe: The unknown beloved principle of cycling cities

Cycling cities have one point in common: they are characterized by high levels of “filtered permeability” (FP), a principle that still isn’t widely known or studied. In these cities, a cyclist’s freedom of movement is considerably greater than a motorist’s. The objective of this article is to highlight and operationalize this principle for the first time. For this purpose, a FP index has been developed and calculated in 60 cities throughout the world. The results demonstrate that the freedom of movement of a cyclist in a European city is on average 44% greater than a motorist’s, which is a FP level about three times greater than what was measured in the other geographic areas studied (South and Central America, North America, Asia and Oceania). As other well-known factors (e.g. safety, accessibility, traffic calming measures), FP could be an effective dimension to create a conducive urban environment for cycling and thus, promote more sustainable mobility behaviours.

Association between thrombotic microangiopathy and activated alternative complement pathway in malignant nephrosclerosis.

Malignant nephrosclerosis, defined as renal microangiopathy in the setting of severe hypertension, remains a critical renal emergency leading to end-stage renal disease despite aggressive anti-hypertensive treatment. Recently, activation of the complement alternative pathway (AP) has been reported to play a prominent role in the pathogenesis of malignant nephrosclerosis. However, subsequent study failed to recapitulate the findings of genetic complement abnormalities in the disease. This study aimed to determine the presence of AP activation and genetic complement defects and establish their correlations to renal microangiopathy lesions, clinical features and prognosis in patients with malignant nephrosclerosis. Fifty patients with malignant hypertension and concomitant thrombotic microangiopathy (TMA) proven by renal biopsy were investigated; 25 cases of kidney donors who received zero-hour allograft biopsies were used as normal controls. Various renal TMA lesions in patients with malignant nephrosclerosis were reviewed and evaluated using a semi-quantitative scoring system. Deposition of C5b-9, C3a, C5a, C4d and mannose-binding lectin was assessed by immunohistochemistry. Co-localization of C5b-9 and CD34 was detected by confocal microscopy. Complement factor B (FB), factor P (FP; properdin), factor D (FD), factor H (FH), C3a and C5a levels were quantified by enzyme-linked immonosorbent assay in plasma and urine samples of patients with malignant nephrosclerosis and controls. Genetic abnormalities of complement components were analysed by whole-exome sequencing. Renal biopsies of malignant nephrosclerosis showed identical histopathological and ultrastructural features to atypical haemolytic uraemic syndrome. C5b-9, C3a and C5a deposits were found along the walls of arteries/arterioles and glomerular capillaries and localized in the endothelial cells. Elevated plasma and urinary levels of FB, FP, FD, C3a and C5a as well as decreased FH levels were observed in patients with malignant nephrosclerosis compared with normal controls. The urinary levels of complement AP components, but not the plasma levels, were correlated with renal functions, prognosis and active TMA lesions except for arteriolar thrombi. Finally, mutations of the MCP, CFB, CFH and CFHR5 genes were identified in 8 of 20 patients with malignant nephrosclerosis. Aberrant complement AP dysregulation was demonstrated and associated with the activity, severity and renal outcomes of malignant nephrosclerosis. This observation warrants screening for complement defects in patients with malignant nephrosclerosis for the potential use of complement regulators and also highlights the need for further investigation of the precise role of AP in the pathogenesis of the disease.

Relationship between Optical Redox Status and Reactive Oxygen Species in Cancer Cells

Shifted NAD(H) redox status and enhanced reactive oxygen species (ROS) scavenging systems have been observed in cancers. However, how such redox shift is related to the ROS level in cancer cells is less clear. Based on collecting the intrinsic fluorescence of oxidized flavoproteins (Fp containing flavin adenine dinucleotide) and reduced nicotinamide adenine dinucleotide (NADH), optical redox imaging (ORI) provides a quantitative measure of the mitochondrial redox state by the optical redox ratio, Fp/(NADH+Fp), a surrogate marker of the NAD+-coupled redox state NAD+/NADH. Our study aims to explore the relationship between NAD(H) redox status and ROS by imaging NADH, Fp, and ROS levels using cultured breast cancer cell models. By manipulating either ROS levels via application of exogenous H2O2 or redox status via metabolic perturbation compounds, we found that: (1) oxidation of NAD(H) redox status correlates with ROS levels at lower H2O2 concentrations (up to ~700 μM), but not necessarily at higher concentrations; (2) an elevated ROS level diminishes NADH and reduces redox ratio plasticity; (3) either more oxidized or more reduced status can correlate to an increased ROS level; and (4) sometimes, a more oxidized status can correlate to a decreased ROS level depending on cell lines. These observations indicated that cellular NAD(H) redox state and ROS are intricately related but can also change separately. This study can benefit cancer research as both NAD(H) redox status and ROS have been implicated in cancer transformation and progression.

Analysis of Tightening Sequence Effects on Preload Behaviour of Offshore Wind Turbine M72 Bolted Connections

Offshore wind turbines in shallow waters are predominantly installed using a monopile foundation, onto which a transition piece and wind turbine are attached. Previously, the monopile to transition piece (MP-TP) connection was made using a grouted connection, however, cases of grout failure causing turbine slippage, among other issues, were reported. One solution is to use bolted ring flange connections, which involve using a large number of M72 bolts to provide a firm fixing between the MP-TP. It is in the interest of offshore wind operators to reduce the number of maintenance visits to these wind turbines by maintaining a preload (Fp) level above the minimum requirement for bolted MP-TP connections. The present study focuses on the effect of the tightening sequence on the Fp behaviour of M72 bolted connections. A detailed finite element (FE) model of a seven-bolt, representative segment of a monopile flange was developed with material properties obtained from the available literature. Three analyses were made to examine the effect on Fp after tightening, including the initial Fp level applied to the bolts, the tightening sequence and the effect of an additional tightening pass.

Effects of Acute Tryptophan Depletion on Repetitive Behavior in Laying Hens.

Repetitive pecking at the feather cover of other birds (FP) is one of the most important welfare problems in domestic birds. It is not only characterized by motor symptoms, but also by an innate vulnerability of the serotonergic system. Moreover, the serotonergic system influences cognitive function. Acute tryptophan depletion (ATD) is a widely used method for studying serotonergic function in mammals and has been recently validated in birds. However, a tryptophan-deficient amino acid mixture has never been tested on groups of birds to impact their social behavior, including repetitive feather pecking, nor has it been given to potentially impact their cognition and motor performance. One hundred and sixty White Leghorn laying hens consisting of two genetic lines divergently selected to perform high (H) or low (L) levels of FP, and an unselected control line (UC), were kept in 10 groups consisting of 4 H, 3 L, and 9 UC genotypes. In a counterbalanced order, half of the groups were first subjected to an ATD treatment, while the other half were first given a balanced control (BC) treatment, and vice versa, after which their feather pecking behavior was observed. The effect of ATD/BC on repetitive pecking, motor performance, and cognition was investigated in a 5-s delayed reward task in an operant chamber with 10 phenotypic feather peckers, 10 recipients of feather pecking, and 10 bystanders (who neither performed nor received feather pecks). ATD given to groups of birds induced gentle, repetitive feather pecking in all genotypes. Following ATD, phenotypic feather peckers performed more poorly during the delayed reward task, as seen by their higher number of repetitive, non-rewarded key, and non-key pecks in the operant chamber. In conclusion, ATD impacted the hens' social behavior by increasing the number of repetitive gentle feather pecks at conspecifics. Furthermore, feather peckers were more likely to peck while waiting for a reward after ATD, suggesting a role for the serotonergic system on cognition in these birds.

Dietary administration of ferula (Ferula asafoetida) powder as a feed additive in diet of koi carp, Cyprinus carpio koi: effects on hemato-immunological parameters, mucosal antibacterial activity, digestive enzymes, and growth performance.

This study investigated the impacts of various levels (0, 5, 10, 15, 20, and 25gkg-1) of dietary ferula (Ferula asafoetida) powder (FP) on the hemato-immunological indices, antibacterial properties of skin mucus, survival rate, and growth performance as well as digestive enzyme activity of Koi carp, Cyprinus carpio koi, fingerlings. Following 63days of feeding trail, WBCs, RBCs, Hb, hematocrit, MCV, MCH, MCHC, and lymphocyte levels increased coincident with an increasing FP level in experimental diets compared with control diet (P < 0.05). Dietary FP significantly increased total protein content and the activities of total immunoglobulins, lysozyme, and alternative hemolytic complement in a concentration-dependent manner in the serum of koi fish (P < 0.05). The elevation of the FP level in experimental diets resulted in an increase in SGR value and a reduction in FCR value (P < 0.05). The survival rate also increased significantly coincident with the increasing dietary FP level (P < 0.05). The results revealed that dietary ferula powder especially at levels of 20 and 25gkg-1 could be used as an effective herbal dietary supplement in the enhancement of humoral innate immune responses and growth of koi carp.

P880 Dysbiotic changes caused by polyethylene glycol in ulcerative colitis patients: "Lavage" or intrinsic effect?

Dysbiotic changes have been described in fecal microbiome composition in ulcerative colitis (UC) patients when compared with fecal microbiome of healthy individuals. It is not clear if these changes persist during remission periods. Some UC patients report a clinical relapse after a colonoscopy. We sought to evaluate the effect of polyethylene glycol (PEG) preparation on fecal microbiome of UC patients in clinical remission and healthy controls, through the application of 16S rRNA gene sequencing techniques. All subjects received identical standard colonoscopy preparation with PEG. Only the UC patients underwent surveillance colonoscopy required by their treating physician. Stool samples were collected at different time points: −30, -1 day (before bowel preparation), the first formed stool sample after bowel preparation, +15, +30 and +60 days. We performed 16S rRNA gene sequencing techniques by amplification of the variable region V4. We used Chao1 to estimate microbiome diversity. Eleven UC patients in clinical remission and 12 Healthy controls (HC) were recruited. One hundred and thirty-seven samples were analysed. We obtained 3892300 high-quality sequences, with a mean base pair number of 314 and 558 Operational taxonomic Units (OTUs). At baseline, diversity in terms of Chao1 was significantly lower in UC patients compared with HC (Median: 132.3 vs. 188.2, p < 0.01). PEG induced a decline in Chao1 in both UC and HC subjects. The magnitude of this decrease was not different between the groups. The microbiome diversity returned to baseline levels at the +60 day time point. Neither Faecalibacterium prausnitzii (Fp) nor Escherichia coli (E. coli) abundance differed at baseline between the groups, however, after PEG, an decrease in Fp abundance was observed in UC patients while in HC FP levels were increased (median Fp −0.004 vs. 0.0025, p < 0.01). PEG had the opposite effect on E. coli abundance, with an increase in UC patients and a decrease in HC (Median E coli 0.0015 vs. −4.85 × 10–5, p < 0.05). Akkermansia muciniphila (Akk) was not detected in any of the UC patients at any time point and in the HC group, Akk was measured in 7 out of 12 at baseline. After PEG preparation, it was just detected in 2 out of the 12 HC. PEG induces similar diversity changes in both UC and Healthy subjects, regardless of baseline diversity. In UC patients PEG has dysbiotic effects, mostly on Fp and E coli abundance. This may be due to a “lavage” effect of PEG, which could unmask an existing dysbiosis on the right colon of these patients, or secondary to a direct effect of PEG on the microbiome.

Pretreatment of cultured preadipocytes with arachidonic acid during the differentiation phase without a cAMP-elevating agent enhances fat storage after the maturation phase

Arachidonic acid (AA) and the related prostanoids exert complex effects on the adipocyte differentiation depending on the culture conditions and life stages. Here, we investigated the effect of the pretreatment of cultured 3T3-L1 preadipocytes with exogenous AA during the differentiation phase without 3-isobutyl-1-methylxanthine (IBMX), a cAMP-elevating agent, on the storage of fats after the maturation phase. This pretreatment with AA stimulated appreciably adipogenesis after the maturation phase as evident with the up-regulated gene expression of adipogenic markers. The stimulatory effect of the pretreatment with AA was attenuated by the co-incubation with each of cyclooxygenase (COX) inhibitors. Among exogenous prostanoids and related compounds, the pretreatment with MRE-269, a selective agonist of the IP receptor for prostaglandin (PG) I2, strikingly stimulated the storage of fats in adipocytes. The gene expression analysis of arachidonate COX pathway revealed that the transcript levels of inducible COX-2, membrane-bound PGE synthase-1, and PGF synthase declined more greatly in cultured preadipocytes treated with AA. By contrast, the expression levels of COX-1, cytosolic PGE synthase, and PGI synthase remained constitutive. The treatment of cultured preadipocytes with AA resulted in the decreased synthesis of PGE2 and PGF2α serving as anti-adipogenic PGs although the biosynthesis of pro-adipogenic PGI2 was up-regulated during the differentiation phase. Moreover, the gene expression levels of EP4 and FP, the respective prostanoid receptors for PGE2 and PGF2α, were gradually suppressed by the supplementation with AA, whereas that of IP for PGI2 remained relatively constant. Collectively, these results suggest the predominant role of endogenous PGI2 in the stimulatory effect of the pretreatment of cultured preadipoccytes with AA during the differentiation phase without IBMX on adipogenesis after the maturation phase.

Biological activities of polyphenols-enriched propolis from Argentina arid regions

BackgroundPropolis is a bioactive natural product collected by honeybees (Apis mellifera) from plant sources. PurposeThis study was undertaken to determine the effect of propolis extracts from arid region of Argentina, on the activity/expression of pro-inflammatory enzymes, and as potential free radical scavenger, antifungal and anthelmintic agent as well as to get a first insight into the polyphenolic profile of the active fractions. Study design/methodsTwo propolis samples were collected in different time from hives located in Tucumán, Argentina. They are representative of the collection time of the raw material for phytotherapeutical purposes. Ethanolic extracts from both propolis were obtained. The PEEs were analyzed for total polyphenol (TP), non-flavonoid phenols (NFP) and flavonoid (FP) content followed by HPLC-DAD analysis and identification of components by HPLC-MS/MSn. The potentiality as anti-inflammatory (LOX, COX, iNOS enzymes), antioxidant, antifungal and nematicidal was determined. ResultsPEEs contain high levels of TP, NFP and FP, including cinnamic acid, caffeic acid prenyl ester, caffeoyl dihydrocaffeate and caffeic acid 3,4-dihydroxyphenethyl ester, liquiritigenin, 2′,4′-dihydroxychalcone and 2′,4′-dihydroxy-3′-methoxychalcone. The PEEs in vitro reduced the activity of LOX and COX-2. Pretreatment of RAW 264.7 cells with PEEs before the induction of inflammatory state, inhibited NO overproduction and the iNOS protein expression was significantly decreased. The PEEs exhibited antioxidant, antifungal (Candida sp.) and nematicidal effect (C. elegans). ConclusionThese findings show the potential use of characterized PEEs from arid regions of Argentina as phytomedicine.

Radiofrequency Thermal Ablation versus Microwave Ablation for Small Hepatocellular Carcinoma

Background and Study Aim : Hepato-cellular carcinoma (HCC) is the fifth most common form of cancer worldwide and the third most common cause of cancer-related deaths. This study was designed to investigate the therapeutic efficacy ofpercutaneous Radiofrequency ablation versus Microwave ablation for small HCC measuring ≤3 cm in diameter. Patients and methods : This study was carried out in Al-Mahalla Hepatology Teaching Hospital on 30 patients with cirrhosis and small HCC. All the patients were evaluated by thorough history, clinical examination, laboratory investigations, abdominal ultrasound and spiral triphasic CT. Results: The mean age was 56.2±5.8, 70% (21) were males and 30% (9) were females. There was highly statistical significant increase in liver function in MW ablation as regard AST, ALT and bilirubin, and decrease in a FP level of both groups after treatment. There was no significant difference between two groups in the response to treatment as regarding Triphasic CT and complications. Conclusion: Microwave (MW) and Radiofrequency (RF) ablation are similar in pathologic appearance and imaging characteristics, but RFA has many limitations and many complications. MW ablation offers many of the advantages of RF ablation while overcoming some of its limitations and the heat-sink effect.

Effect of dietary field pea (Pisum sativum L.) supplementation on growth performance, and carcass and meat quality of broiler chickens

In an experiment with 480 one-day-old male broiler chickens, the effect of partial replacement of soybean meal and corn with raw field peas (FP; Pisum sativum L.) on growth performance and carcass and meat quality was determined. In the 42-d experiment, broiler chickens were allocated to 5 dietary treatments: FP-none, FP-low, FP-medium, FP-high, and FP-very high with 4 pens per treatment and 24 broiler chickens per pen, and received a diet ad libitum. The experiment was divided into 3 periods: starter period (1–14d of age), grower period (15–28d of age), and finisher period (29–42d of age). In all 3 periods, the diets for treatment FP-none had no FP (control), while those for treatments FP-low, FP-medium, FP-high, and FP-very high included 40, 80, 120, and 160gFP/kg, respectively, during the starter period, 60, 120, 180, and 240gFP/kg, respectively, during the grower period, and 120, 240, 360, and 480gFP/kg, respectively, during the finisher period. Replacement of soybean meal and corn with up to 480gFP/kg of diet resulted in similar productive performance. Moreover, carcass yield traits, skin color, and chemical composition were not affected by feeding diets with increasing levels of FP. Some differences (P<0.05) were observed in fatty acid distribution in total lipids of breast- and leg muscles, but the ratio of saturated to unsaturated fatty acids remained unaffected. In conclusion, depending on the age, inclusion levels up to 480g raw FP/kg can be used as an alternative protein and energy source to replace soybean meal and corn in broiler chicken diets.

A new 2.5D representation for lymph node detection using random sets of deep convolutional neural network observations.

Automated Lymph Node (LN) detection is an important clinical diagnostic task but very challenging due to the low contrast of surrounding structures in Computed Tomography (CT) and to their varying sizes, poses, shapes and sparsely distributed locations. State-of-the-art studies show the performance range of 52.9% sensitivity at 3.1 false-positives per volume (FP/vol.), or 60.9% at 6.1 FP/vol. for mediastinal LN, by one-shot boosting on 3D HAAR features. In this paper, we first operate a preliminary candidate generation stage, towards -100% sensitivity at the cost of high FP levels (-40 per patient), to harvest volumes of interest (VOI). Our 2.5D approach consequently decomposes any 3D VOI by resampling 2D reformatted orthogonal views N times, via scale, random translations, and rotations with respect to the VOI centroid coordinates. These random views are then used to train a deep Convolutional Neural Network (CNN) classifier. In testing, the CNN is employed to assign LN probabilities for all N random views that can be simply averaged (as a set) to compute the final classification probability per VOI. We validate the approach on two datasets: 90 CT volumes with 388 mediastinal LNs and 86 patients with 595 abdominal LNs. We achieve sensitivities of 70%/83% at 3 FP/vol. and 84%/90% at 6 FP/vol. in mediastinum and abdomen respectively, which drastically improves over the previous state-of-the-art work.

Properdin is increased after allergen challenge of asthmatic patients and contributes to OVA-induced airway inflammation and AHR at the effector phase by enhancing C3a generation in mice (P1355)

Abstract The complement alternative pathway (AP) and anaphylatoxins have been implicated in allergic asthma, but the significance and mechanisms remain to be fully characterized. We hypothesized that factor properdin (fP), the only known positive regulator of AP contributes to allergen-induced airway inflammation. In human asthmatic patients, BALF collected after allergen challenge contained higher fP levels than before challenge. Mice were sensitized and challenged with OVA and examined for fP levels and airway inflammation. High levels of fP were detected in the BALF of OVA-sensitized and challenged but not naïve mice. Compared with WT mice, fP-deficient (fP-/-) mice had significantly reduced cell counts in BALF. fP-/- mice also had significantly attenuated AHR to methacholine stimulation. Antibody blocking of fP at both sensitization and challenge or at challenge phase alone, but not at sensitization phase alone, reduced airway inflammation. Conversely, intranasal reconstitution of fP to fP-/- mice at the challenge phase restored airway inflammation to WT levels. Notably, we found C3a levels in the BALF of OVA-challenged fP-/- mice to be significantly lower than in challenged WT mice, and intranasal co-administration of anti-C3a mAb with fP to fP-/- mice prevented restoration of airway inflammation. Collectively, our data suggest a detrimental role of fP in allergen-induced airway inflammation via C3a production and therapeutic targeting of fP may be beneficial in human asthma.

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Introduction: Fondaparinux (FP, Arixtra®) is a preferred drug for venous thromboembolism (VTE) prophylaxis in critically ill patients. However, it is contraindicated in renal failure due to concerns of drug accumulation and increased bleeding risk. We sought to prospectively study FP for VTE prophylaxis in critically ill patients with renal failure at an extended dosing interval of 2.5 mg every 48 hours (q48h), instead of the usual q24h. Hypothesis: FP, dosed at an extended interval regimen of 2.5 mg q48h in critically ill patients with renal failure, results in satisfactory peak (Pk) and trough (Tr) plasma FP levels. Methods: ICU patients with renal failure (acute or chronic, creatinine clearance < 30 ml/min, +/- dialytic therapy) were prospectively studied while receiving FP, dosed at 2.5 mg q48h. FP Pk and Tr plasma levels were obtained around doses 1-5. FP levels (µg/ml) are expressed as mean±SD for each dose and as % within 2 SD of reported levels in patients with normal renal function (Pk=0.47 ± 0.2 and Tr=0.18 ± 0.1). Clinical efficacy was assessed with lower extremity venous duplex scans at study entry and completion. Major and minor bleeding events were recorded. Results: Twenty one patients were studied to date, 13 on dialytic therapy. Patients received an average of 5 doses of FP. Mean of FP Pk and Tr levels for doses 1-5 were 0.34 ± 0.1 (n=60) and 0.15 ± 0.1 (n=47), respectively. For doses 1, 3, and 5, Pk levels were 0.23 ± 0.1 (n=20), 0.37 ± 0.1 (n=9), and 0.42 ± 0.1 (n=6), and Tr levels were 0.11 ± 0.1 (n=18), 0.20 ± 0.1 (n=10), and 0.18 ± 0.1 (n=4). There was a significant increase in Pk levels from dose 1 to dose 3 and 5, (p<0.005 by ANOVA and post-hoc). No significant difference was present after dose 3 for Pk or Tr levels. Overall, 98% of Pk and 95% of Tr levels were within the acceptable prophylaxis range. No VTE events were noted. There were no major and 3 minor bleeding events through dose 5. Conclusions: FP dosed at an extended interval regimen of 2.5 mg q48h for VTE prophylaxis in ICU patients with renal failure results in satisfactory Pk and Tr levels. This dosing regimen appears pharmacologically sound, effective and safe in this patient population.

Fecal progesterone analysis for monitoring reproductive status in dairy goats

The present study was undertaken to evaluate the use of fecal progesterone (FP_4) concentration for early pregnancy diagnosis, estrus detection, and predicting the litter size and parturition date in dairy goats. Fecal samples were collected from 17 hand-mated goats 3 times a week for 22-23 weeks, beginning on the day of mating. The levels of FP_4 were determined by enzyme-linked immunosorbent assay (ELISA). Significant positive correlations were found between the levels of serum P_4 and FP_4 (r = 0.8787, n = 13). Pregnancy diagnosis was performed at 2 months postmating with transabdominal ultrasonography and confirmed upon birth of the offspring. The results indicated a significant difference in the mean FP_4 concentration obtained during days 19 and 20 postmating between the pregnant and nonpregnant does (2492.4 ± 239.1 vs. 577.0 ± 112.9 ng/g, P < 0.05). A significant drop in the FP_4 concentration was noted 3 days prior to the detected day of estrus (P < 0.05). The mean weekly FP_4 profile obtained in this study showed a progressive increase from week 7 to 14 until a plateau was reached between weeks 15 and 21, and then a rapid decline began 5 to 6 days prepartum, with a significant drop 1-2 days prepartum (from 3884.3 ± 576.0 to 1205.0 ± 339.0 ng/g, P < 0.05). No significant correlation was observed between the FP_4 concentration and the number of kids born. In conclusion, the measurement of FP_4 concentration could potentially be an alternative method for early pregnancy diagnosis, prediction of estrus, and parturition in dairy goats.

Reproductive characteristics of wild female Phayre's leaf monkeys

Understanding female reproductive characteristics is important for assessing fertility, interpreting female behavior, and designing appropriate conservation and captive management plans. In primate species lacking morphological signs of receptivity, such as most colobines, determination of reproductive parameters depends on the analysis of reproductive hormones. Here, we use fecal hormone analysis to characterize cycle patterns (N=6 females) and gestation length (N=7 females) in a group of wild Phayre's leaf monkeys (Trachypithecus phayrei crepusculus) in Phu Khieo Wildlife Sanctuary, Thailand. We found that both fecal estrogen (fE) and progestin (fP) levels showed clear biological patterns indicative of ovulation and conception. However, because fP patterns were inadequate in determining the end of the luteal phase, we used fE rather than fP patterns to delineate menstrual cycle parameters. We found a mean cycle length of 28.4 days (N=10), with follicular and luteal phases of 15.4 (N=10) and 12.5 days (N=14), respectively. On average, females underwent 3.57 (N=7) cycles until conception. Average gestation length was 205.3 days (N=7), with fE levels increasing over the course of pregnancy. Overall, the reproductive characteristics found for Phayre's leaf monkeys were consistent with results for other colobine species, suggesting that fecal hormone monitoring, particularly for fE metabolites, can provide useful reproductive information for this species.

Phytochemicals and reproductive function in wild female Phayre's leaf monkeys (Trachypithecus phayrei crepusculus)

Female reproduction is known to be influenced by food availability and its impact on energetic status. However, emerging evidence suggests that the phytochemical content of food may also be an important factor. Here, we investigated this hypothesis, presenting 20months of data on fecal progestin (fP) patterns in wild female Phayre's leaf monkeys (Trachypithecus phayrei crepusculus). We examined whether (a) the availability of Vitex (a plant known to contain phytochemicals) might be linked to seasonal fP levels, (b) fP levels were associated with female reproductive performance, and (c) reproductive performance might also be linked with energetic status (as measured by physical condition). We collected fecal samples (N=2077) from 10 adult females to analyze estrogen (fE) and progestin (fP) metabolites, behavioral data from 7 cycling females to determine receptivity, and monthly data on Vitex availability and female physical condition. Seasonally elevated fP levels were found in all females, with higher levels when Vitex leaves and fruits were abundant. During the period of high progestins, females had longer cycle lengths and follicular phases, while receptive periods did not change. Nevertheless, when ovulations occurred, females were more likely to conceive. On the other hand, conceptions were also more likely when physical condition was improving, suggesting that the effects of phytochemicals and energetic status on reproduction may be difficult to separate. Although our results support the predicted effects of Vitex on endocrine and reproductive function, future studies with detailed feeding data and chemical analyses of plants are needed to confirm this finding.