Degeneracija aksona i esteraza povezana s neuropatskim djelovanjem organofosfornih spojeva - pregled

This brief review summarises recent observations which suggest a possible mechanism for organophosphateinduced delayed neuropathy (OPIDN). Neuropathy target esterase (NTE) has been shown to deacylate endoplasmic reticulum (ER) membrane phosphatidylcholine (PtdCho). Raised levels of PtdCho are present in the brains of swiss cheese/NTE mutant Drosophila together with abnormal membrane structures, axonal and dendritic degeneration and neural cell loss. Similar vacuolated pathology is found in the brains of mice with brain-specific deletion of the NTE gene and, in old age, these mice show clinical and histopathological features of neuropathy resembling those in wild-type mice chronically dosed with tri-ortho-cresylphosphate. It is suggested that OPIDN results from the loss of NTE’s phospholipase activity which in turn causes ER malfunction and perturbation of axonal transport and glial-axonal interactions.Ovim se kratkim pregledom razmatraju nedavna opažanja koja upućuju na mogući mehanizam odgođene neuropatije uzrokovane organofosfatima (engl. organophosphate-induced delayed neuropathy, krat. OPIDN). Za esterazu povezanu s neuropatskim djelovanjem organofosfornih spojeva (engl. neuropathy target esterase, krat. NTE) dokazano je da deacilira fosfatidilkolin (PtdCho) membrane endoplazmatskog retikuluma (ER). Povišene razine PtdCho prisutne su u mozgu swiss cheese/NTE mutanta mušice Drosophila uz abnormalne membranske strukture, degeneraciju aksona i dendrita te gubitak neurona. Slična je vakuolarna patologija zamijećena u mozgu miševa u kojih je obrisan NTE gen u mozgu te koji u starijoj dobi pokazuju kliničke i histopatološke znakove neuropatije koja je slična onoj u običnih miševa kronično tretiranih tri-ortho-krezilfosfatom. Odgođena neuropatija uzrokovana organofosfatima mogla bi biti posljedicom prestanka djelovanja fosfolipaze NTE, što potom uzrokuje zatajenje endoplazmatskog retikuluma i smetnje u prijenosu signala putem aksona te interakcije između glija i aksona

A Rotating-Tip-Based Mechanical Nano-Manufacturing Process: Nanomilling

We present a rotating-tip-based mechanical nanomanufacturing technique, referred to here as nanomilling. An atomic force microscopy (AFM) probe tip that is rotated at high speeds by out-of-phase motions of the axes of a three-axis piezoelectric actuator is used as the nanotool. By circumventing the high-compliance AFM beam and directly attaching the tip onto the piezoelectric actuator, a high-stiffness arrangement is realized. The feeding motions and depth prescription are provided by a nano-positioning stage. It is shown that nanomilling is capable of removing the material in the form of long curled chips, indicating shearing as the dominant material removal mechanism. Feature-size and shape control capabilities of the method are demonstrated

Vitamin D prevents endothelial progenitor cell dysfunction induced by sera from women with preeclampsia or conditioned media from hypoxic placenta

Context: Placenta-derived circulating factors contribute to the maternal endothelial dysfunction underlying preeclampsia. Endothelial colony forming cells (ECFC), a sub-population of endothelial progenitor cells (EPCs), are thought to be involved in vasculogenesis and endothelial repair. Low vitamin D concentrations are associated with an increased risk for preeclampsia. Objective: We hypothesized that the function of human fetal ECFCs in culture would be suppressed by exposure to preeclampsia-related factors-preeclampsia serum or hypoxic placental conditioned medium- in a fashion reversed by vitamin D. Design, Setting, Patients: ECFCs were isolated from cord blood of uncomplicated pregnancies and expanded in culture. Uncomplicated pregnancy villous placenta in explant culture were exposed to either 2% (hypoxic), 8% (normoxic) or 21% (hyperoxic) O2 for 48 h, after which the conditioned media (CM) was collected. Outcome Measures: ECFC tubule formation (Matrigel assay) and migration were examined in the presence of either maternal serum from preeclampsia cases or uncomplicated pregnancy controls, or pooled CM, in the presence or absence of 1,25(OH)2 vitamin D3. Results: 1,25(OH)2 vitamin D3 reversed the adverse effects of preeclampsia serum or CM from hypoxic placenta on ECFCs capillary-tube formation and migration. Silencing of VDR expression by VDR siRNA, VDR blockade, or VEGF pathway blockade reduced ECFC functional abilities. Effects of VDR or VEGF blockade were partially prevented by vitamin D. Conclusion: Vitamin D promotes the capillary-like tubule formation and migration of ECFCs in culture, minimizing the negative effects of exposure to preeclampsia-related factors. Further evaluation of the role of vitamin D in ECFC regulation and preeclampsia is warranted. © 2014 Brodowski et al

Circulating TRAIL Shows a Significant Post-Partum Decline Associated to Stressful Conditions

Background: Since circulating levels of TNF-related apoptosis inducing ligand (TRAIL) may be important in the physiopathology of pregnancy, we tested the hypothesis that TRAIL levels change at delivery in response to stressful conditions. Methods/Principal Findings: We conducted a longitudinal study in a cohort of 73 women examined at week 12, week 16, delivery and in the corresponding cord blood (CB). Serum TRAIL was assessed in relationship with maternal characteristics and to biochemical parameters. TRAIL did not vary between 12 (67.6627.6 pg/ml, means6SD) and 16 (64.0616.2 pg/ml) weeks ’ gestation, while displaying a significant decline after partum (49.3626.4 pg/ml). Using a cut-off decline.20 pg/ml between week 12 and delivery, the subset of women with the higher decline of circulating TRAIL (41.7%) showed the following characteristics: i) nullipara, ii) higher age, iii) operational vaginal delivery or urgent CS, iv) did not receive analgesia during labor, v) induced labor. CB TRAIL was significantly higher (131.6652 pg/ml) with respect to the corresponding maternal TRAIL, and the variables significantly associated with the first quartile of CB TRAIL (,90 pg/ml) were higher prepregnancy BMI, induction of labor and fetal distress. With respect to the biochemical parameters, maternal TRAIL at delivery showed an inverse correlation with C-reactive protein (CRP), total cortisol, glycemia and insulin at bivariate analysis, but only with CRP at multivariate analysis

Glycerol treatment as recovery procedure for cryopreserved human skin allografts positive for bacteria and fungi

Human donor skin allografts are suitable and much used temporary biological (burn) wound dressings. They prepare the excised wound bed for final autografting and form an excellent substrate for revascularisation and for the formation of granulation tissue. Two preservation methods, glycerol preservation and cryopreservation, are commonly used by tissue banks for the long-term storage of skin grafts. The burn surgeons of the Queen Astrid Military Hospital preferentially use partly viable cryopreserved skin allografts. After mandatory 14-day bacterial and mycological culture, however, approximately 15% of the cryopreserved skin allografts cannot be released from quarantine because of positive culture. To maximize the use of our scarce and precious donor skin, we developed a glycerolisation-based recovery method for these culture positive cryopreserved allografts. The inactivation and preservation method, described in this paper, allowed for an efficient inactivation of the colonising bacteria and fungi, with the exception of spore-formers, and did not influence the structural and functional aspects of the skin allografts

Caffeine Reduces 11β-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Trophoblast Cells through the Adenosine A2B Receptor

Maternal caffeine consumption is associated with reduced fetal growth, but the underlying molecular mechanisms are unknown. Since there is evidence that decreased placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is linked to fetal growth restriction, we hypothesized that caffeine may inhibit fetal growth partly through down regulating placental 11β-HSD2. As a first step in examining this hypothesis, we studied the effects of caffeine on placental 11β-HSD2 activity and expression using our established primary human trophoblast cells as an in vitro model system. Given that maternal serum concentrations of paraxanthine (the primary metabolite of caffeine) were greater in women who gave birth to small-for-gestational age infants than to appropriately grown infants, we also studied the effects of paraxanthine. Our main findings were: (1) both caffeine and paraxanthine decreased placental 11β-HSD2 activity, protein and mRNA in a concentration-dependent manner; (2) this inhibitory effect was mediated by the adenosine A2B receptor, since siRNA-mediated knockdown of this receptor prevented caffeine- and paraxanthine-induced inhibition of placental 11β-HSD2; and (3) forskolin (an activator of adenyl cyclase and a known stimulator of 11β-HSD2) abrogated the inhibitory effects of both caffeine and paraxanthine, which provides evidence for a functional link between exposure to caffeine and paraxanthine, decreased intracellular levels of cAMP and reduced placental 11β-HSD2. Taken together, these findings reveal that placental 11β-HSD2 is a novel molecular target through which caffeine may adversely affect fetal growth. They also uncover a previously unappreciated role for the adenosine A2B receptor signaling in regulating placental 11β-HSD2, and consequently fetal development