Erythropoietin (EPO) increases myelin gene expression in CG4 oligodendrocyte cells through the classical EPO receptor

Erythropoietin (EPO) has protective effects in neurodegenerative and neuroinflammatory diseases, including in animal models of multiple sclerosis, where EPO decreases disease severity. EPO also promotes neurogenesis and is protective in models of toxic demyelination. In this study, we asked whether EPO could promote neurorepair by also inducing remyelination. In addition, we investigated whether the effect of EPO could be mediated by the classical erythropoietic EPO receptor (EPOR), since it is still questioned if EPOR is functional in non-hematopoietic cells. Using CG4 cells, a line of rat oligodendrocyte precursor cells, we found that EPO increases the expression of myelin genes (myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP)). EPO had no effect in wild-type CG4 cells, which do not express EPOR, whereas it increased MOG and MBP expression in cells engineered to overexpress EPOR (CG4-EPOR). This was reflected in a marked increase in MOG protein levels, as detected by western blot. In these cells, EPO induced by 10-fold the early growth response gene 2 (Egr2), which is required for peripheral myelination. However, Egr2 silencing with a siRNA did not reverse the effect of EPO, indicating that EPO acts through other pathways. In conclusion, EPO induces the expression of myelin genes in oligodendrocytes and this effect requires the presence of EPOR. This study demonstrates that EPOR can mediate neuroreparative effects

Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock

The present study was designed to define the potential ofchlorpromazine (CPZ) as a protective agent against lipopolysaccharide (LPS) toxicity in comparison with glucocorticoids, and to obtain initial correlations with its effects on the levels of tumor necrosis factor (TNF), a pivotal mediator of endotoxic shock. It was found that CPZ protects mice, normal or adrenalectomized, and guinea pigs against lethality of LPS, and inhibited TNF serum levels, like dexamethasone (DEX), a well-known inhibitor ofTNF synthesis. CPZ protected against LPS lethality when administered 30 minutes (min) before, simultaneously, or up to 10 min after LPS and was ineffective when given 30 min after LPS, paralleling the inhibitory effect on TNF production. In another experimental model, where mice were sensitized to LPS toxicity by actinomycin D, CPZ significantly inhibited LPS lethality and hepatotoxicity, whereas under these conditions DEX was inactive. These experiments indicate that CPZ has a protective action in both glucocorticoid-sensitive and -resistant models of endotoxic shock

Inhibitor binding mode and allosteric regulation of Na+-glucose symporters.

Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 in complex with inhibitors by combining computational and functional studies. Inhibitors bind with the sugar moiety in the sugar pocket and the aglycon tail in the extracellular vestibule. The binding poses corroborate mutagenesis studies and suggest a partial closure of the outer gate upon binding. The models also reveal a putative Na+ binding site in hSGLT1 whose disruption reduces the transport stoichiometry to the value observed in hSGLT2 and increases inhibition by aglycon tails. Our work demonstrates that subtype selectivity arises from Na+-regulated outer gate closure and a variable region in extracellular loop EL5

Transumbilical versus transvaginal retrieval of surgical specimens at laparoscopy: a randomized trial.

Objective We sought to compare transumbilical (TU) and transvaginal (TV) route for retrieval of surgical specimens at laparoscopy. Study design Women scheduled for a laparoscopic resection of an adnexal mass were randomized to have their surgical specimen removed either through a posterior colpotomy (n = 34) or the umbilical port site (n = 32). Group allocation was concealed from patients and bedside clinicians. The primary outcome was postoperative incisional pain assessed by a 10-cm visual analog scale at 1, 3, and 24 hours after surgery. Results TV retrieval caused less postoperative pain than TU specimen extraction at each time point (visual analog scale score at 1 hour: 2.6 \ub1 2.9 vs 1.2 \ub1 2.0, P = .03; at 3 hours: 2.4 \ub1 2.0 vs 1.4 \ub1 2.0, P = .02; and at 24 hours: 1.1 \ub1 1.5 vs 0.5 \ub1 1.4, P = .02). A higher proportion of women in the TU group than in the TV group indicated the umbilicus as the most painful area at 1 and 3 hours postoperatively. Two months after surgery, the participants scored similarly as to their overall satisfaction, cosmetic outcome, and dyspareunia upon resumption of intercourse. Conclusion A TV approach for specimen removal after laparoscopic resection of adnexal masses offers the advantage of less postoperative pain than TU retrieva

Oral healthcare access and adequacy in alternative long-term care facilities

This study was undertaken to determine practices and perceived barriers to access related to oral health by surveying administrators in Michigan alternative long-term care facilities (ALTCF). A 24-item questionnaire was mailed to all 2,275 Michigan ALTCF serving residents aged 60+. Facility response rate was 22% (n = 508). Eleven percent of facilities had a written dental care plan; 18% stated a dentist examined new residents; and 19% of facilities had an agreement with a dentist to come to the facility, with 52% of those being for emergency care only. The greatest perceived barriers were willingness of general and specialty dentists to treat residents at the nursing facility and/or private offices as well as financial concerns. Substantial barriers to care were uniformly perceived.Oral health policies and practices within Michigan ALTCF vary, as measured by resources, attitudes, and the availability of professional care. There is limited involvement by dental professionals in creating policy and providing consultation and service.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79086/1/j.1754-4505.2010.00132.x.pd

Ductus venosus blood flow velocity characteristics of fetuses with single umbilical artery

Objectives: Sonographic Doppler evaluation of the fetal ductus venosus has been proved to be useful in the evaluation of fetal cardiac function. The aim of this study was to investigate the ductus venosus blood flow profile in fetuses with single umbilical artery and to correlate it with the umbilical cord morphology. Methods: Fetuses at > 20 weeks' gestation with single umbilical artery who were otherwise healthy were consecutively enrolled into the study. The sonographic examination included evaluation of the following Doppler parameters: umbilical artery resistance index, maximum blood flow velocity of the ductus venosus during ventricular systole (S-peak) and atrial contraction (A-wave), ductus venosus time-averaged maximum velocity (TAMXV), and pulsatility index for veins (PIV). The cross-sectional area of the umbilical cord and its vessels were measured in all cases. The Doppler and morphometric values obtained were plotted on reference ranges. Results: A total of 88 fetuses with single umbilical artery were scanned during the study period. Of these 52 met the inclusion criteria. The S-peak velocity, A-wave velocity, and TAMXV were below the 5th centile for gestational age in 57.7%, 59.6%, and 57.7% of cases, respectively. The PIV was within the normal range in 80.1% of cases. The umbilical vein cross-sectional area of fetuses with single umbilical artery was above the 95th centile for gestational age in 34.6% cases. Conclusions: The ductus venosus blood flow pattern is different in fetuses with single umbilical artery from that in those with a three-vessel cord. This difference may be caused in part by the particular morphology of umbilical cords with a single artery. Copyright © 2003 ISUOG. Published by John Wiley & Sons, Ltd

Carrageenan-induced acute inflammation in the mouse air pouch synovial model. Role of tumour necrosis factor

We used the mouse air pouch model of inflammation to study the interaction between cytokines, prostaglandin E2 (PGE2) and cell migration during the various phases of acute local inflammation induced by carrageenan. In serum, the levels of interleukin 1 (IL-1), interleukin 6 (IL-6), tumour necrosis factor (TNF), serum amiloid-A (SAA) and Fe++ were never different from controls, indicating that no systemic inflammatory changes were induced. Locally the exudate volume and the number of leukocytes recruited into the pouch increased progressively until 7 days after carrageenan. The same was true for PGE2 production. We could not measure IL-1 but the production of IL-6 and TNF reached a maximum after 5-24 h then quickly decreased. Anti-TNF antibodies inhibited cell migration by 50% 24 h after treatment. Pretreatment with interleukin 10 (IL-10) inhibited TNF production almost completely and cell migration by 60%. Carrageenan-induced inflammation was modulated by anti-inflammatory drugs. Pretreatment with dexamethasone (DEX) or indomethacin (INDO) inhibited cell migration and reduced the concentration of TNF in the exudate. Production of PGE2 or vascular permeability did not correlate with the number of cells in the pouch. Local TNF seems to play an important role in this model, particularly for leukocyte migration in the first phase of the inflammatory process. In conclusion, the air pouch seems to be a good model for studying the regulation of the early events of local inflammation, particularly the role of cytokines and cell migration

Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions

Polymeric micelles, i.e. aggregation colloids formed in solution by self-assembling of amphiphilic polymers, represent an innovative tool to overcome several issues related to drug administration, from the low water-solubility to the poor drug permeability across biological barriers. With respect to other nanocarriers, polymeric micelles generally display smaller size, easier preparation and sterilization processes, and good solubilization properties, unfortunately associated with a lower stability in biological fluids and a more complicated characterization. Particularly challenging is the study of their interaction with the biological environment, essential to predict the real in vivo behavior after administration. In this review, after a general presentation on micelles features and properties, different characterization techniques are discussed, from the ones used for the determination of micelles basic characteristics (critical micellar concentration, size, surface charge, morphology) to the more complex approaches used to figure out micelles kinetic stability, drug release and behavior in the presence of biological substrates (fluids, cells and tissues). The techniques presented (such as dynamic light scattering, AFM, cryo-TEM, X-ray scattering, FRET, symmetrical flow field-flow fractionation (AF4) and density ultracentrifugation), each one with their own advantages and limitations, can be combined to achieve a deeper comprehension of polymeric micelles in vivo behavior. The set-up and validation of adequate methods for micelles description represent the essential starting point for their development and clinical success