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2012年8月4日星期六

[Anogenital dermatoses--allergic and irritative causative factors. Analysis of IVDK data and review of the literature].

[Anogenital dermatoses--allergic and irritative causative factors. Analysis of IVDK data and review of the literature].

J Dtsch Dermatol Ges. 2005 Dec;3(12):979-86

Authors: K�gler K, Brinkmeier T, Frosch PJ, Uter W

Abstract
BACKGROUND: Anogenital dermatoses (AGD) are common and often very distressing. Clinically it is often unclear if allergic contact dermatitis or irritant dermatitis is involved. In order to optimize therapy and prophylaxis, it is essential to identify relevant allergens or irritants.
PATIENTS AND METHODS: Data of the Information Network of Departments of Dermatology (IVDK, data center in G�ttingen) collected between 1999 and 2003 were analyzed. The anogenital area was involved in 1 168 patients with suspected allergic contact dermatitis. Clinical variables and patch test results were statistically compared with the remaining IVDK patch test population, the latter standardized for age and sex.
RESULTS: Allergic contact dermatitis had been suspected prior to patch testing in 39.5 %, while in 24.6 % this diagnosis was eventually confirmed. Irritant contact dermatitis was diagnosed in 11.8 %. Other diagnoses, included balanitis, lichen sclerosus et atrophicus and herpes genitalis. Positive reactions to cinchocaine (6.6 %), bufexamac (3.5 %) and benzocaine (2.4 %) were observed significantly more often among patients with anogenital dermatitis. Among those in whom co-factors were considered important (n = 422), wetness (38.4 %), occlusion (30.3 %), mechanical strain (4.7 %) and heat (3.6 %) were mentioned as irritation factors.
CONCLUSION: Because of the significantly higher frequency of sensitization to cinchocaine, benzocaine and bufexamac in patients with anogenital dermatitis, these ingredients should be used only with caution. According to the literature, ingredients of toiletries, cosmetics and contraceptives of any kind seem to cause allergic contact dermatitis rarely although there are several case reports. Comprehensive patch test including the standard series plus major sensitizers such as cinchocaine, benzocaine and bufexamac, and in particular patients' own skin care products, is recommended.

PMID: 16405714 [PubMed - indexed for MEDLINE]

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Contact allergy to bufexamac.

Contact allergy to bufexamac.

Contact Dermatitis. 1989 Apr;20(4):307-8

Authors: Perret CM, Happle R

PMID: 2752743 [PubMed - indexed for MEDLINE]

Bufexamac HDAC Inhibitors Bufexamac 2438-72-4 Bufexamac 1353882-38-8

Oral dosage form for modified release comprising a jak3 inhibitor

The invention essentially relates to oral dosage forms comprising a JAK3 inhibitor, preferably tasocitinib, suitable for modified release, and processes of preparing such oral dosage forms....

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Silk Film Acts As Vaccine Preservative

Technique could replace costly refrigeration for vaccine use in developing world

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2012年8月3日星期五

Simulations Peg Protein Folding

Molecular dynamics simulations are the first that replicate experimental thermodynamic and kinetic data on such a large protein

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Why Supermarket Tomatoes Taste Bland

Plant Biology: Because of a genetic mutation, commercial tomatoes sacrifice flavor for uniform color

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Use of bufexamac suppositories in rectal conditions.

Use of bufexamac suppositories in rectal conditions.

J Postgrad Med. 1975 Jul;21(3):131-4

Authors: Samsi AB

PMID: 1206602 [PubMed - indexed for MEDLINE]

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Sugar Scaffold Templates Blood Vessels

Bioengineering: 3-D-printed sugar lattices provide vascular network for lab-grown material

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2012年8月2日星期四

Bufexamac: a review of its pharmacological properties and therapeutic efficacy in inflammatory dermatoses.

Bufexamac: a review of its pharmacological properties and therapeutic efficacy in inflammatory dermatoses.

Drugs. 1975;10(5-6):351-6

Authors: Brogden RN, Pinder RM, Sawyer PR, Speight TM, Avery GS

PMID: 1204506 [PubMed - indexed for MEDLINE]

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Fetal DNA Sequencing Opens Door

Baby?s DNA in mom?s plasma can be used for prenatal whole-genome sequencing and genetic screening

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Biocatalysis

As pharmaceutical manufacturers increasingly use enzymatic reactions in their processes, a robust business model still eludes biocatalysis companies

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[Erythema multiforme after topical administration of bufexamac (3 cases)].

[Erythema multiforme after topical administration of bufexamac (3 cases)].

Ann Dermatol Venereol. 1991;118(11):901-2

Authors: Poli F, Pouget F, Revuz J

PMID: 1789676 [PubMed - indexed for MEDLINE]

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Contact allergy to bufexamac.

Contact allergy to bufexamac.

Contact Dermatitis. 1989 Apr;20(4):307-8

Authors: Perret CM, Happle R

PMID: 2752743 [PubMed - indexed for MEDLINE]

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2012年8月1日星期三

C&EN Talks With Alan Kozikowski

A medicinal chemist who is skeptical of the need for and effectiveness of psychiatric drugs

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Method for treatment of inflammatory disease and disorder

The present disclosure provides a method, composition and kit for treatment of inflammatory disease and disorder using PKC isoform modulators. Exemplary modulators include inhibitors of PKC-alpha, PKC-epsilon and PKC-eta, as well as activators of PKC-delta....

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Implantable Hydrogels Release Drugs, One At A Time

Drug Delivery: Gels could help doctors trigger multistep healing

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Combinations comprising a protein kinase inhibitor being a pyrimidylaminobenzamide compound and a hsp90 inhibitor such as 17-aag

and a method for treating or preventing a proliferative disease using such a combination.

b) an HSP90 inhibitor,
a) a pyrimidylaminobenzamide compound; and

The invention provides a pharmaceutical combination comprising:...

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Solvent Viscosity Tunes DNA Folding

DNA completes folding into G-quadruplexes over months in a high-viscosity solvent, but over minutes in a low-viscosity one

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2012年7月31日星期二

Role of second-line systemic treatment post-docetaxel in metastatic castrate resistant prostate cancer- current strategies and future directions.

Role of second-line systemic treatment post-docetaxel in metastatic castrate resistant prostate cancer- current strategies and future directions.

Anticancer Agents Med Chem. 2011 Mar;11(3):296-306

Authors: Ansari J, Hussain SA, Alhasso A, Mahmood R, Ansari A, Glaholm J

Abstract
Treatment of metastatic castrate resistant prostate cancer (mCRPC) after progression on docetaxel chemotherapy is a challenging clinical scenario with limited availability of treatment options. Re-treatment with docetaxel, either as monotherapy or in combination with other cytotoxics or targeted agents has shown durable responses. However, most docetaxel re-treatment studies have been either retrospective or early phase non-randomised studies which have not formally assessed Quality of life or survival gain with re-treatment. Despite limited evidence for efficacy of mitoxantrone in the second-line, it continues to remain widely used, largely due to lack of available suitable alternatives. Cabazitaxel in combination with prednisolone is the only chemotherapy to have shown a significant survival benefit and receive approval by the U.S. Food and Drug Administration for patients with mCRPC previously treated with a docetaxel-based regimen. Abiraterone acetate has recently demonstrated a significant improvement in survival when compared to placebo in patients with docetaxel-treated mCRPC. This review aims to summarize the current evidence and discuss future strategies for treatment of mCRPC patients following failure of docetaxel chemotherapy.

PMID: 21426298 [PubMed - indexed for MEDLINE]

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A Novel Method for Determination of Drug Distribution in Rat Brain Tissue Sections by LC/MS/MS: Functional Tissue Microanalysis.

A Novel Method for Determination of Drug Distribution in Rat Brain Tissue Sections by LC/MS/MS: Functional Tissue Microanalysis.

Curr Top Med Chem. 2012 Jun 1;12(11):1243-9

Authors: Masucci JA, Mahan AD, Kwasnoski JD, Caldwell GW

Abstract
Determination of drug distribution in brain and other tissues is important in pharmaceutical research. Tissue drug levels need to be determined routinely as they are usually diagnostic for both efficacy and toxicity. Determination of tissue levels in small organ subregions is frequently performed due to important functional considerations. These measurements have traditionally been very tedious requiring extensive dissection and specimen pooling to achieve detection of analytes of interest. Direct and indirect methods utilizing mass spectrometry have been reported for detection of analytes in tissue specimens. Typically, these require very specialized MS or sampling equipment and are only partially successful due to analyte response. We have developed a novel approach for quantitation of tissue sections called Functional Tissue Microanalysis (FTM) in which small circular samples are removed from subregions of interest, extracted and analyzed by conventional LC/MS/MS utilizing electrospray ionization. This allows direct measurement of regional concentrations without dissection and homogenization of tissue specimens as many subregions can be sampled from a single mounted section. Utilization of the FTM approach for analysis of both sagittal and coronal rat brain sections is shown for quantitation of raclopride and rimonabant. Reproducibility of this approach and comparison to conventional methods is reported.

PMID: 22571786 [PubMed - in process]

Rimonabant SR14171 Rimonabant 168273-06-1

Ibipinabant attenuates ?-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight.

Ibipinabant attenuates ?-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight.

Diabetes Obes Metab. 2012 Jun;14(6):555-64

Authors: Rohrbach K, Thomas MA, Glick S, Fung EN, Wang V, Watson L, Gregory P, Antel J, Pelleymounter MA

Abstract
AIM: To test the antidiabetic efficacy of ibipinabant, this new cannabinoid receptor 1 (CB1) antagonist was compared with food-restriction-induced weight loss, rosiglitazone (4 mg/kg) and rimonabant (3 and 10 mg/kg), using parameters of glycaemic control in male Zucker diabetic fatty (ZDF) rats.
METHODS: Body weight, food and water intake, fasted and non-fasted glucose and insulin, glucose tolerance and glycosylated haemoglobin (HbA1c) were all assessed over the course of the 9-week study. Pancreatic insulin content and islet area were also evaluated.
RESULTS: At the end of the study, vehicle-treated ZDF rats were severely hyperglycaemic and showed signs of ?-cell decline, including dramatic reductions in unfasted insulin levels. Ibipinanbant (10 mg/kg) reduced the following relative to vehicle controls: fasting glucose (-61%), glucose excursion area under the curve (AUC) in an oral glucose tolerance test (OGTT, -44%) and HbA1c (-50%). Furthermore, non-fasting insulin, islet area and islet insulin content were all increased (71, 40 and 76%, respectively) relative to vehicle controls by the end of the study. All of these effects were similar to those of rimonabant and rosiglitazone, where ibipinabant was slightly more effective than rimonabant at the lowest dose and somewhat less effective than rosiglitazone at all doses. These antidiabetic effects appear independent of weight loss because none of the parameters above were consistently improved by the comparable weight loss induced by food restriction.
CONCLUSIONS: Ibipinabant may have weight loss-independent antidiabetic effects and may have the potential to attenuate ?-cell loss in a model of progressive ?-cell dysfunction.

PMID: 22268426 [PubMed - indexed for MEDLINE]

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Quantification of irinotecan, SN38, and SN38G in human and porcine plasma by ultra high-performance liquid chromatography-tandem mass spectrometry and its application to hepatic chemoembolization.

Quantification of irinotecan, SN38, and SN38G in human and porcine plasma by ultra high-performance liquid chromatography-tandem mass spectrometry and its application to hepatic chemoembolization.

J Pharm Biomed Anal. 2012 Mar 25;62:140-8

Authors: Chen X, Peer CJ, Alfaro R, Tian T, Spencer SD, Figg WD

Abstract
An analytical method was developed and validated for the quantitative determination of irinotecan, its active metabolite SN38, and glucuronidated SN38 (SN38-G) in both porcine and human plasma. Calibration curves were linear within the concentration range of 0.5-100 ng/mL for SN38 and SN38-G, and 5-1000 ng/mL for irinotecan. Sample pretreatment involved solid-phase extraction of 0.1 mL aliquots of plasma. Irinotecan, SN38, SN38-G, and the internal standards, irinotecan-d10, tolbutamide, and camptothecin, respectively, were separated on a Waters ACQUITY UPLC BEH RP18 column (2. 1mm � 50 mm, 1.7 ?m), using a mobile phase composed of methanol and 0.1% formic acid. Accuracy of quality control samples in human plasma ranged from 98.5 to 110.3%, 99.5 to 101.7% and 96.2 to 98.9% for irinotecan, SN38, and SN38-G, respectively. Precision of the three analytes in the same order ranged from 0.8 to 2.8%, 2.4 to 5.7%, and 2.4 to 2.8%. All three analytes proved stable in plasma through four freeze/thaw cycles, as well as through 6h in whole blood at room temperature. The method was likewise validated in porcine plasma with comparable accuracies and precisions also within the generally acceptable range. The validated method was applied to both preclinical and clinical trials involving hepatic chemoembolization of irinotecan drug-eluting beads to study the pharmacokinetics of the three analytes.

PMID: 22305081 [PubMed - indexed for MEDLINE]

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Polysaccharide peptides from Coriolus versicolor competitively inhibit model cytochrome P450 enzyme probe substrates metabolism in human liver microsomes.

Polysaccharide peptides from Coriolus versicolor competitively inhibit model cytochrome P450 enzyme probe substrates metabolism in human liver microsomes.

Phytomedicine. 2012 Mar 15;19(5):457-63

Authors: Yeung JH, Or PM

Abstract
Polysaccharide peptide (PSP), isolated from COV-1 strain of Coriolus versicolor, is commonly used as an adjunct in cancer chemotherapy or health supplement in China. Previous studies have shown that PSP decreased antipyrine clearance and inhibited rat CYP2C11-mediated tolbutamide 4-hydroxylation and in human CYP2C9. In this study, the effects of the water extractable fraction of PSP on the metabolism of model CYP1A2, CYP2D6, CYP2E1 and CYP3A4 probe substrates were investigated in pooled human liver microsomes. PSP (1.25-20?M) dose-dependently decreased CYP1A2-mediated metabolism of phenacetin to paracetamol (IC(50) 19.7?M) and CYP3A4-mediated metabolism of testosterone to 6?-hydroxytestosterone (IC(20) 7.06?M). Enzyme kinetics studies showed the inhibition of CYP1A2 activity was competitive and concentration-dependent (K(i)=18.4?M). Inhibition of testosterone to 6?-hydroxytestosterone was also competitive and concentration-dependent (K(i)=31.8?M). Metabolism of dextromethorphan to dextrorphan (CYP2D6-mediated) and chlorzoxazone to 6-hydroxychlorzoxazone (CYP2E1-mediated) was only minimally inhibited by PSP, with IC(20) values at 15.6?M and 11.9?M, respectively. This study demonstrated that PSP competitively inhibited the CYP1A2- and CYP3A4-mediated metabolism of model probe substrates in human liver microsomes in vitro. The relatively high K(i) values for CYP1A2 and CYP3A4 would suggest a low potential for PSP to cause herb-drug interaction related to these CYP isoforms.

PMID: 22305191 [PubMed - in process]

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2012年7月30日星期一

Cannabinoid facilitation of behavioral and biochemical hedonic taste responses.

Cannabinoid facilitation of behavioral and biochemical hedonic taste responses.

Neuropharmacology. 2012 Jul;63(1):161-8

Authors: De Luca MA, Solinas M, Bimpisidis Z, Goldberg SR, Di Chiara G

Abstract
Cannabinoid receptor agonists are known to stimulate feeding in humans and animals and this effect is thought to be related to an increase in food palatability. On the other hand, highly palatable food stimulates dopamine (DA) transmission in the shell of the nucleus accumbens (NAc) and this effect undergoes one trial habituation. In order to investigate the relationship between the affective properties of tastes and the response of NAc shell DA we studied the effect of delta-9-tetrahydrocannabinol (THC) on behavioral taste reactivity to intraoral infusion of appetitive (sucrose solutions) and aversive (quinine and saturated NaCl solutions) tastes and on the response of in�vivo DA transmission in the NAc shell to intraoral sucrose. Rats were implanted with intraoral cannulae and the effect of systemic administration of THC on the behavioral reactions to intraoral infusion of sucrose and of quinine or saturated NaCl solutions were scored. THC increased the hedonic reactions to sucrose but did not affect the aversive reactions to quinine and NaCl. The effects of THC were completely blocked by the CB1 receptor inverse agonist/antagonist rimonabant given at doses that do not affect taste reactivity to sucrose. In rats implanted with microdialysis probes and with intraoral cannulae, THC, made sucrose effective in raising dialysate DA in the shell of the NAc. As in the case of highly palatable food (Fonzies, sweet chocolate), the stimulatory effect of sucrose on shell DA under THC underwent one trial habituation. Altogether, these findings demonstrate that stimulation of CB1 receptors specifically increases the palatability of hedonic taste without affecting that of aversive tastes. Consistent with the ability of THC to increase sucrose palatability is the observation that under THC pretreatment sucrose acquires the ability to induce a release of DA in the shell of the NAc and this property undergoes adaptation after repeated exposure to the taste (habituation). This article is part of a Special Issue entitled 'Central Control of Food Intake'.

PMID: 22063718 [PubMed - in process]

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Low dose aspirin prevents duodenoesophageal reflux induced mucosal changes in�wistar rat esophagus by MAP kinase mediated pathways.

Low dose aspirin prevents duodenoesophageal reflux induced mucosal changes in�wistar rat esophagus by MAP kinase mediated pathways.

Int J Surg. 2012;10(2):73-9

Authors: Selvan B, Ramachandran A, Korula A, Amirtharaj GJ, Kettimuthu K, Nair S, Nair A, Samuel P, Mathew G

Abstract
BACKGROUND: Investigations of molecular mechanisms behind the progression of neoplastic changes in the esophagus have uncovered the role of the COX & 5-Lox pathways. Human squamous esophageal mucosa produces relatively large amounts of eicosanoids in the presence of inflammation. Laboratory and epidemiological data suggest that aspirin and non-steroidal anti-inflammatory drugs may be chemo preventive through their inhibitory effect on COX25, 10. Cell culture studies have shown that the members of the mitogen activated protein (MAP) kinase family plays an important role in the development of bile acid-induced carcinogenesis. Differences in MAPK pathways activated by bile exposure were also noted in esophageal squamous cell lines and biopsies from patients with GERD. The protective role of aspirin and its molecular mechanism is not well understood.
AIMS: 1. The effect of duodenal reflux on esophageal mucosa. 2. The role of aspirin in preventing duodenal reflux induced esophageal mucosa changes. 3. If it is proven to be preventive, the mechanism of its action. A duodenal reflux rat animal model was used by an end- to-side esophago duodenostomy.
METHODS: Total of 56 rats was included. 3 were "Naive control" animals which did not undergo the surgical procedure. The remaining animals were divided into two groups: Surgery alone (experimental) and Surgery + aspirin [therapy group], esophagoduodenostomy. At 40 weeks, the rats were euthanized and appropriate esophageal samples were analysed for histopathology and p38 & ERK MAP kinases, VEGF, protease activity and caspase 3 activities.
RESULTS: The presence of gross mucosal nodularity was seen in 21 and 10 rats of the experimental and therapy group respectively (p = 0.03; Table 1). Reflux-associated changes such as basal cell hyperplasia were more common in the experimental group, however this association did not reach statistical significance (p = 0.15; Table 1). Epithelial hyperplasia was seen more in the experimental group, which was prevented by aspirin [p < 0.01]. Papillomatosis, as shown in Fig. 4 was more common in the experimental group (p = 0.02). Activation of p38 & ERK MAP kinases was prevented in aspirin group (p < 0.05, CI -1.796--0.014). Examination of protease activity by zymographic analysis of the esophageal samples revealed a number of gelatinolytic bands in 50% rats of the experimental group, not observed in the therapy group. No significant changes were seen in Caspase 3 [Normal areas -99.74 & nodular areas - 100.34 percent of controls] or VEGF [mean 0.64, sd � 0.76 Vs 0.69 � 0.96] activity.
CONCLUSIONS: Our data demonstrated that low dose aspirin reduced the incidence of duodenoesophageal reflux induced histological changes in the esophagus by preventing activation of proliferative & anti-apoptotic MAP kinases such as p38 & ER as well as protease activity. Though Barretts' changes and adenocarcinoma have not developed, it could explain the role of duodenoesophageal reflux in the development of different histological but potential premalignant lesions and molecular level changes which are prevented by low dose aspirin.

PMID: 22197650 [PubMed - indexed for MEDLINE]

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Does hormone therapy, tibolone or raloxifene modify VEGF expression in cervical epithelial cells?

Does hormone therapy, tibolone or raloxifene modify VEGF expression in cervical epithelial cells?

Climacteric. 2012 Apr;15(2):181-5

Authors: Sioulas VD, Politi E, Rizos D, Augoulea A, Kyroudi A, Sergentanis TN, Panoulis C, Aravantinos L, Creatsa M, Lambrinoudaki I

Abstract
AIM: Vascular endothelial growth factor (VEGF) seems to be a critical molecule in cervical carcinogenesis. We aimed to investigate the possible associations between hormonal factors and VEGF expression in cervical epithelial cells from postmenopausal women.
METHOD: A total of 105 healthy postmenopausal women (aged 45-68 years old) attending a university menopause clinic were enrolled in this cross-sectional study. Pap smears were derived from current users of 17?-estradiol 1 mg + norethisterone acetate 0.5 mg (n = 28), tibolone 2.5 mg (n = 23), raloxifene HCl 60 mg (n = 21) and women not receiving treatment (n = 33). VEGF immunostaining was evaluated in squamous, glandular and metaplastic cells, using a semiquantitative method (rating scale: 0-3).
RESULTS: Concerning endogenous hormones, higher ?4-androstenedione levels were associated with more intense VEGF immunostaining in glandular (p = 0.041) and metaplastic cells (p = 0.004). Hormone therapy and raloxifene did not induce any changes in VEGF immunoreactivity in the examined cells. In contrast, tibolone administration was accompanied by diminished VEGF presence in metaplastic cells (p = 0.016 vs. controls).
CONCLUSION: Our findings may in part reflect the molecular processes contributing to the safe profile of hormone therapy, tibolone and raloxifene in cervical carcinogenesis.

PMID: 22066937 [PubMed - indexed for MEDLINE]

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2012年7月29日星期日

Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis.

Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis.

BJOG. 2012 Jun;119(7):778-87

Authors: Kleinrouweler CE, Wiegerinck MM, Ris-Stalpers C, Bossuyt PM, van der Post JA, von Dadelszen P, Mol BW, Pajkrt E, EBM CONNECT Collaboration

Abstract
BACKGROUND: Biomarkers have been proposed for identification of women at increased risk of developing pre-eclampsia.
OBJECTIVES: To investigate the capacity of circulating placental growth factor (PlGF), vascular endothelial growth factor (VEGF), soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin (sENG) to predict pre-eclampsia.
SEARCH STRATEGY: Medline and Embase through October 2010 and reference lists of reviews, without constraints.
SELECTION CRITERIA: We included original publications on testing of PlGF, VEGF, sFLT1 and sENG in serum or plasma of pregnant women at <30 weeks of gestation and before clinical onset of pre-eclampsia.
DATA COLLECTION AND ANALYSIS: Two reviewers independently identified eligible studies, extracted descriptive and test accuracy data and assessed methodological quality. Summary estimates of discriminatory performance were obtained.
MAIN RESULTS: We included 34 studies. Concentrations of PlGF (27 studies) and VEGF (three studies) were lower in women who developed pre-eclampsia: standardised mean differences (SMD) -0.56 (95% CI -0.77 to -0.35) and -1.25 (95% CI -2.73 to 0.23). Concentrations of sFLT1 (19 studies) and sENG (ten studies) were higher: SMD 0.48 (95% CI 0.21-0.75) and SMD 0.54 (95% CI 0.24-0.84). The summary diagnostic odds ratios were: PlGF 9.0 (95% CI 5.6-14.5), sFLT1 6.6 (95% CI 3.1-13.7), sENG 4.2 (95% CI 2.4-7.2), which correspond to sensitivities of 32%, 26% and 18%, respectively, for a 5% false-positive rate.
AUTHOR'S CONCLUSIONS: PlGF, sFLT1 and sENG showed modest but significantly different concentrations before 30 weeks of gestation in women who developed pre-eclampsia. Test accuracies of all four markers, however, are too poor for accurate prediction of pre-eclampsia in clinical practice.

PMID: 22433027 [PubMed - indexed for MEDLINE]

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Bevacizumab-associated fistula formation in postoperative colorectal cancer patients.

Bevacizumab-associated fistula formation in postoperative colorectal cancer patients.

J Am Coll Surg. 2012 Apr;214(4):582-8; discussion 588-90

Authors: Ganapathi AM, Westmoreland T, Tyler D, Mantyh CR

Abstract
BACKGROUND: Adjuvant chemotherapy regimens for metastatic colorectal cancer (CRC) routinely include bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF). We have identified a correlation between bevacizumab and fistula formation after resection of advanced CRC.
STUDY DESIGN: Patients undergoing treatment with bevacizumab for metastatic CRC after 2005 were identified and reviewed. Of 222 consecutive patients, 9 patients treated with bevacizumab subsequently developed fistulas. These patients' charts were reviewed with attention to diagnosis, timing of operation relative to bevacizumab therapy, location of fistula, and fistula treatment.
RESULTS: Of the 9 identified patients (9 of 222, 4.1%), 6 had rectal cancer, 2 had colon cancer, and 1 had synchronous CRC. Fistulas were most commonly anal or perineal (6 of 9, 66.7%) and colovesicular (3 of 9, 33%). On average, bevacizumab was initiated 23.6 months after the initial operation; complications occurred 3.9 months after starting bevacizumab. Nearly uniformly, cessation of bevacizumab led to fistula healing; however, 3 patients (33%) required fecal diversion.
CONCLUSIONS: Bevacizumab is the most common antiangiogenesis agent used for treatment of metastatic CRC. Previous adverse events associated with bevacizumab treatment include venous thromboembolism, poor wound healing, and spontaneous bowel perforation. In this report, late postoperative development of fistulas occurred relatively soon after initiation of bevacizumab and usually spontaneously resolved with cessation of bevacizumab treatment. Based on the timing of fistula development relative to operation and initiation of bevacizumab, fistulas are likely secondary to bevacizumab therapy rather than postsurgical complications. Bevacizumab-induced fistulas occur in a small, but significant proportion of CRC patients and must be recognized early.

PMID: 22321523 [PubMed - indexed for MEDLINE]

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