The aim of this guideline was to find evidence on whether carrying out Doppler examinations and CTGs in low-risk cohorts of pregnant women improves outcomes.
First, a systematic search for ...guidelines was carried out. Identified guidelines were evaluated using the DELPHI instrument of the AWMF. Three guidelines were found to be suitable to evaluate CTG. Two DEGUM best practice guidelines were judged suitable to describe the methods. All studies on this issue were additionally analyzed using 8 PICO questions. A structured consensus of the participating professional societies was achieved using a nominal group process and a structured consensus conference moderated by an independent moderator.
No antepartum Doppler sonography examinations should be carried out in low-risk cohorts in the context of antenatal care. No antepartum CTG should be carried out in low-risk cohorts. NOTE: The guideline will be published simultaneously in the official journals of both professional societies (i. e.,
for the DGGG and
for the DEGUM).
Purpose
The aim of this guideline was to find evidence on whether carrying out Doppler examinations and CTGs in low-risk cohorts of pregnant women improves outcomes.
Methods
First, a systematic ...search for guidelines was carried out. Identified guidelines were evaluated using the DELPHI instrument of the AWMF. Three guidelines were found to be
suitable to evaluate CTG. Two DEGUM best practice guidelines were judged suitable to describe the methods. All studies on this issue were additionally analyzed using 8 PICO questions. A
structured consensus of the participating professional societies was achieved using a nominal group process and a structured consensus conference moderated by an independent moderator.
Recommendations
No antepartum Doppler sonography examinations should be carried out in low-risk cohorts in the context of antenatal care. No antepartum CTG should be carried out in
low-risk cohorts.
Note
The guideline will be published simultaneously in the official journals of both professional societies (i.e.,
Geburtshilfe und Frauenheilkunde
for the DGGG and
Ultraschall in der Medizin/European Journal of Ultrasound
for the DEGUM).
Abstract
Purpose The aim of this guideline was to find evidence on whether carrying out Doppler examinations and CTGs in low-risk cohorts of pregnant women improves outcomes.
Methods First, a ...systematic search for guidelines was carried out. Identified guidelines were evaluated using the DELPHI instrument of the AWMF. Three guidelines were found to be
suitable to evaluate CTG. Two DEGUM best practice guidelines were judged suitable to describe the methods. All studies on this issue were additionally analyzed using 8 PICO questions. A
structured consensus of the participating professional societies was achieved using a nominal group process and a structured consensus conference moderated by an independent moderator.
Recommendations No antepartum Doppler sonography examinations should be carried out in low-risk cohorts in the context of antenatal care. No antepartum CTG should be carried out in
low-risk cohorts.
Note The guideline will be published simultaneously in the official journals of both professional societies (i.e., Geburtshilfe und Frauenheilkunde for the DGGG and
Ultraschall in der Medizin/European Journal of Ultrasound for the DEGUM).
Zusammenfassung
Ziel Das Ziel dieser LL ist die Etablierung der Evidenz dafür, ob in einem Low-Risk-Schwangerschaftskollektiv die Durchführung des Dopplers oder CTGs das Outcome verbessert.
Methoden Es wurde zunächst eine systematische Suche nach Leitlinien durchgeführt. Die aufgefundenen Leitlinien wurden mithilfe des DELPHI-Instruments der AWMF bewertet. Es wurden 3
LL für eine Adaptation für das CTG als grundsätzlich geeignet befunden. Es wurden 2 DEGUM Best Practice Guidelines für die Methodenbeschreibung als grundsätzlich geeignet befunden.
Zusätzlich wurden alle Studien zur Fragestellung anhand von 8 PICO-Fragen untersucht. Die strukturierte Konsensfindung zwischen den Fachgesellschaften erfolgte im Rahmen eines nominalen
Gruppenprozesses und einer strukturierten Konsenskonferenz unter unabhängiger Moderation.
Empfehlungen Im Low-Risk-Kollektiv sollte keine antepartuale Doppler-Sonografie im Rahmen der Überwachung durchgeführt werden. Im Low-Risk-Kollektiv sollte kein antepartuales CTG
geschrieben werden.
Hinweis Die Leitlinie wird gleichzeitig in den offiziellen Zeitschriften beider Fachgesellschaften (d. h. Geburtshilfe und Frauenheilkunde für die DGGG und Ultraschall in der
Medizin/European Journal of Ultrasound für die DEGUM) veröffentlicht.
The ability of Arabidopsis thaliana to successfully prevent colonization by Phytophthora infestans, the causal agent of late blight disease of potato (Solanum tuberosum), depends on multilayered ...defense responses. To address the role of surfacelocalized secondary metabolites for entry control, droplets of a P. infestans zoospore suspension, incubated on Arabidopsis leaves, were subjected to untargeted metabolite profiling. The hydroxycinnamic acid amide coumaroylagmatine was among the metabolites secreted into the inoculum. In vitro assays revealed an inhibitory activity of coumaroylagmatine on P. infestans spore germination. Mutant analyses suggested a requirement of the p-coumaroyl-CoA:agmatine N4-p-coumaroyl transferase ACT for the biosynthesis and of the MATE transporter DTX18 for the extracellular accumulation of coumaroylagmatine. The host plant potato is not able to efficiently secrete coumaroylagmatine. This inability is overcome in transgenic potato plants expressing the two Arabidopsis genes ACT and DTX18. These plants secrete agmatine and putrescine conjugates to high levels, indicating that DTX18 is a hydroxycinnamic acid amide transporter with a distinct specificity. The export of hydroxycinnamic acid amides correlates with a decreased ability of P. infestans spores to germinate, suggesting a contribution of secreted antimicrobial compounds to pathogen defense at the leaf surface.
The reactions of tBu2P–P=P(tBu2)CH2Li at low temperature with dichlorophosphanes RPCl2 (R = Ph, Me, NEt2, tBu) lead to “P‐7‐chains” as primary products wherein two ylidic moieties are linked by a ...CH2–PR–CH2 unit. However, if R = tBu the long chain is only a by‐product in addition to tBu2P–P=P(tBu2)Me. The thermal decomposition of “P‐7‐chains” as monitored by 31P NMR spectroscopy results in tBu2P–CH2–PR–CH2–PtBu2 (“P‐3‐chains”) and the phosphanylphosphanylidene {tBu2P–P} which is observed as its cyclic trimer or tetramer. In the reactions of tBu(Me3Si)P–P=P(tBu2)CH2Li with RPCl2 the corresponding “P‐7‐chains” and the P4CH2‐rings are formed. The substituent R strongly determines the ratio of chain to ring as well as the thermal stability of the products. The solid‐state structures of one representative of both “P‐7‐chains”, and of the oxidized derivative of the P4CH2‐ring with R = tBu were determined by single‐crystal X‐ray diffraction analysis.
New neutral “P7‐chains” with two ylidic moieties linked by a CH2–P(R)–CH2 unit have been synthesized. The thermal decomposition was followed by 31P NMR spectroscopy.
Tissue inhibitor of metalloproteinases-1 (TIMP-1) plays a crucial role in the pathogenesis of hepatic fibrosis and thus may represent an important therapeutic target in the design of anti-fibrotic ...strategies for chronic liver disease. We present an innovative therapy based on the assignment of inactivated enzymes acting as scavengers for TIMP-1. Hepatic fibrosis was induced in BALB/c mice by repetitive intraperitoneal CCl₄ injection. The animals were treated with proteolytic inactive matrix metalloproteinase-9 mutants (E402Q, H401A, E402H/H411E) using adenovirus-mediated gene transfer. Application of these MMP-9 mutants inhibited fibrogenesis, which was indicated by decreasing portal and periportal accumulation of collagen. Total hydroxyproline of liver tissue, the morphometric stage of fibrosis as well as mRNA expression of marker proteins for hepatic fibrosis in livers of E402Q- and H401A-treated mice were significantly reduced. MMP-9 mutants suppressed transdifferentiation of hepatic stellate cells to the myofibroblast like phenotype in vitro and in vivo. Moreover, adenoviral application of the mutants MMP-9-H401A and -E402Q led to increased apoptosis of activated hepatic stellate cells, thought to be the main promoters of hepatic fibrosis. Application of MMP-9 mutants as TIMP-1 scavengers may provide a new therapeutic strategy for hepatic fibrosis.--Roderfeld, M., Weiskirchen, R., Wagner, S., Berres, M.-L., Henkel, C., Grötzinger, J., Gressner, A. M., Matern, S., Roeb, E. Inhibition of hepatic fibrogenesis by matrix metalloproteinase-9 mutants in mice.
Background & aims:
Multidrug resistance-associated protein 2 (MRP2), a transporter of organic anions in hepatocytes, renal epithelial cells, and enterocytes, is differentially regulated in liver and ...kidney during cholestasis, but little is known about its regulation in the intestine.
Methods:
We investigated duodenal protein expression of MRP2 in male Sprague-Dawley rats with bile duct ligation (BDL) or biliary diversion as well as in 20 cholestatic patients with biliary obstruction.
Results:
In biliary obstruction, but not biliary depletion, intestinal Mrp2 protein mass was reduced to 9.3% ± 5.5% of controls and mRNA to 40.5% ± 20.8% of controls after 7 days. Binding of RXRα:RARα heterodimers to the Mrp2 promoter element was significantly reduced in BDL rats. Cytokine blockade identified IL-1β as the responsible inducer of Mrp2 down-regulation. In humans with obstructive cholestasis, intestinal MRP2 protein expression was reduced to 27.3% ± 20.3% of control patients; this reduction correlated with the duration of cholestasis and was reversible after reconstitution of bile flow by stenting of the common bile duct. However, no significant differences in MRP2 mRNA levels were detected by RT-PCR in humans. Intestinal protein expression of P-glycoprotein, breast cancer resistance protein (BCRP), and MRP3 was unchanged. In BDL rats, oral bioavailability of the Mrp2 substrate and food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo4,5-bpyridine (PhIP) was elevated 2.5 times compared with sham-operated rats.
Conclusions:
Cholestasis promotes down-regulation of MRP2 expression in the duodenum of rats and humans. Selective down-regulation during cholestasis might be the consequence of species-specific transcriptional and posttranscriptional mechanisms and contributes to higher bioavailability of a food-derived carcinogen.
Matrix metalloproteinases (MMPs) are involved in the remodeling processes of the extracellular matrix and the basement membrane. Most MMPs are composed of a regulatory, a catalytic, and a hemopexin ...subunit. In many tumors the expression of MMP-9 correlates with local tumor growth, invasion, and metastasis. To analyze the role of the hemopexin domain in these processes, the MMP-9 hemopexin domain (MMP-9-PEX) was expressed as a glutathioneS-transferase fusion protein in Escherichia coli. After proteolytic cleavage, the isolated PEX domain was purified by size exclusion chromatography. In a zymography assay, MMP-9-PEX was able to inhibit MMP-9 activity. The association and dissociation rates for the interaction of MMP-9-PEX with gelatin were determined by plasmon resonance. From the measured rate constants, the dissociation constant was calculated to be Kd = 2,4 × 10−8m, demonstrating a high affinity between MMP-9-PEX and gelatin. In Boyden chamber experiments the recombinant MMP-9-PEX was able to inhibit the invasion of melanoma cells secreting high amounts of MMP-9 in a dose-dependent manner. These data demonstrate for the first time that the hemopexin domain of MMP-9 has a high affinity binding site for gelatin, and the particular recombinant domain is able to block MMP-9 activity and tumor cell invasion. Because MMP-9 plays an important role in metastasis, this antagonistic effect may be utilized to design MMP inhibition-based cancer therapy.
MMP-7, a member of the matrix metalloproteinase family, is believed to play a significant role in the growth and proliferation of colon cancer cells. The aim of this study was to evaluate MMP-7 gene ...expression in comparison with MMP-1, MMP-3, and MMP-13 in patients with resectable rectal and colon cancer by a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR).
Biopsy samples of tumor ( n=30) and distant normal mucosa ( n=30) from 30 patients were obtained intraoperation. Messenger (m)RNA was extracted from all of the tissue samples and reverse transcribed to double-stranded cDNA. Semi-quantitative RT-PCR was performed to study the MMP gene expression in both the tumor and normal mucosal specimens. MMP mRNA values were expressed relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for each sample.
In all 30 cases an increase in MMP-7 mRNA expression was detected in the cancerous tissue ( p=0.00004). In 21 out of 30 cases an increase in MMP-13 mRNA ( p=0.023) and in 22 out of 30 cases an increase in MMP-3 mRNA ( p=0.075) was detected in the cancerous tissue. In contrast, there was no significant change in the MMP-1 expression of normal and cancerous mucosal specimens in either colon or rectal carcinomas. There were no significant differences between rectum and colon carcinomas.
Taking into account our earlier studies, we conclude that most cases of colorectal carcinogenesis are characterized by enhanced expression of MMP-7, -13, -3 and the gelatinases, whereas MMP-1-expression is very inconsistent and not overexpressed in many cases. MMP-7 inhibition as well as inhibition of MMP-13 and MMP-3 may be a useful preventive or therapeutic adjunct in colorectal cancer.
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