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Simple effective tools to monitor the long treatment of tuberculosis (TB) are lacking. Easily measured host derived biomarkers have been identified but need to be validated in larger studies and different population groups. Here we investigate the early response in IP-10 levels (between day 0 and day 7 of TB therapy) to identify bacteriological status at diagnosis among 127 HIV-infected patients starting TB treatment. All participants were then classified as responding or not responding to treatment blindly using a previously described IP-10 kinetic algorithm. There were 77 bacteriologically confirmed cases and 41 Xpert MTB/RIF® and culture negative cases. Most participants had a measurable decline in IP-10 during the first 7 days of therapy. Bacteriologically confirmed cases were more likely to have high IP-10 levels at D0 and had a steeper decline than clinically diagnosed cases (mean decline difference 2231 pg/dl, 95% CI: 897-3566, p = 0.0013). Bacteriologically confirmed cases were more likely to have a measurable decline in IP-10 at day 7 than clinically diagnosed cases (48/77 (62.3%) vs 13/41 (31.7%), p < 0.001). This study confirms the association between a decrease in IP-10 levels during the first week of treatment and a bacteriological confirmation at diagnosis in a large cohort of HIV positive patients.

Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone produced by gastrointestinal tract in response to food ingestion. GLP-1 plays a very important role in the glucose homeostasis by stimulating glucose-dependent insulin secretion, inhibiting glucagon secretion, inhibiting gastric emptying, reducing appetite and food intake. Because of these actions, the GLP-1 peptide-mimetic exenatide is one of the most promising new medicines for the treatment of type 2 diabetes. In vivo treatments with GLP-1 or exenatide prevent neo-intima layer formation in response to endothelial damage and atherosclerotic lesion formation in aortic tissue. Whether GLP-1 modulates vascular smooth muscle cell (VSMC) migration and proliferation by controlling mitochondrial dynamics is unknown. In this report, we showed that GLP-1 increased mitochondrial fusion and activity in a PKA-dependent manner in the VSMC cell line A7r5. GLP-1 induced a Ser-637 phosphorylation in the mitochondrial fission protein Drp1, and decreased Drp1 mitochondrial localization. GLP-1 inhibited PDGF-BB-induced VSMC migration and proliferation, actions inhibited by overexpressing wild type Drp1 and mimicked by the Drp1 inhibitor Mdivi-1 and by overexpressing dominant negative Drp1. These results show that GLP-1 stimulates mitochondrial fusion, increases mitochondrial activity and decreases PDGF-BB-induced VSMC dedifferentiation by a PKA/Drp1 signaling pathway. Our data suggest that GLP-1 inhibits vascular remodeling through a mitochondrial dynamics-dependent mechanism., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The vascular endothelium plays an essential role in the control of the blood flow. Pharmacological agents like quinone (menadione) at various doses modulate this process in a variety of ways. In this study, Q7 , a 2-phenylamino-1,4-naphthoquinone derivative, significantly increased oxidative stress and induced vascular dysfunction at concentrations that were not cytotoxic to endothelial or vascular smooth muscle cells. Q7 reduced nitric oxide (NO) levels and endothelial vasodilation to acetylcholine in rat aorta. It also blunted the calcium release from intracellular stores by increasing the phenylephrine-induced vasoconstriction when CaCl 2 was added to a calcium-free medium but did not affect the influx of calcium from extracellular space. Q7 increased the vasoconstriction to BaCl 2 (10 -3  M), an inward rectifying K + channels blocker, and blocked the vasodilation to KCl (10 -2  M) in aortic rings precontracted with BaCl 2 . This was recovered with sodium nitroprusside (10 -8  M), a NO donor. In conclusion, Q7 induced vasoconstriction was through a modulation of cellular mechanisms involving calcium fluxes through K + channels, and oxidative stress induced endothelium damage. These findings contribute to the characterization of new quinone derivatives with low cytotoxicity able to pharmacologically modulate vasodilation.

Differentiation and dedifferentiation of vascular smooth muscle cells (VSMCs) are essential processes of vascular development. VSMC have biosynthetic, proliferative, and contractile roles in the vessel wall. Alterations in the differentiated state of the VSMC play a critical role in the pathogenesis of a variety of cardiovascular diseases, including atherosclerosis, hypertension, and vascular stenosis. This review provides an overview of the current state of knowledge of molecular mechanisms involved in the control of VSMC proliferation, with particular focus on mitochondrial metabolism. Mitochondrial activity can be controlled by regulating mitochondrial dynamics, i.e., mitochondrial fusion and fission, and by regulating mitochondrial calcium handling through the interaction with the endoplasmic reticulum (ER). Alterations in both VSMC proliferation and mitochondrial function can be triggered by dysregulation of mitofusin-2, a small GTPase associated with mitochondrial fusion and mitochondrial-ER interaction. Several lines of evidence highlight the relevance of mitochondrial metabolism in the control of VSMC proliferation, indicating a new area to be explored in the treatment of vascular diseases.

The sciatic nerve (SN) is easily blocked under ultrasound guidance by identifying either the SN common trunk or its two components: the tibial nerve (TN) and the common peroneal nerve (CPN). The authors investigate whether there are anatomical differences between newborns and adults. The SN, TN and CPN of both lower extremities in 24 (11 neonatal and 13 adults) formolized cadavers were dissected. Distances were measured from the origin of the SN (passing under the piriformis muscle) to its division into TN and CPN, and from there to the popliteal crease. The sciatic/thigh coefficient (proportion relating SN length to thigh length) and the variation coefficient for the SN were calculated. The distance from the popliteal crease to the SN division was significantly shorter in neonates than in adults (1.04 ± 0.9 cm vs. 5.6 ± 5.1 cm, P = 0.0003). In addition, the neonatal SN divided at a proportionally more distal position in the thigh than it did in adults (86 ± 13 vs. 74 ± 15%, P = 0.0059). However, the coefficient of variation between the SN-division distances was not statistically different in infants and adults (12.8 vs. 18.2%, P = 0.4345). The variations in the point of SN division seen in the adult SN are already seen in the neonatal period, but in newborns the SN divided in a more distal position in relation to the thigh than in adults, so this finding of anatomical variability in neonates suggests that ultrasound guidance can be useful when performing a SN block in these small patients., (© 2013 Anatomical Society.)

Background: The bioequivalence of different formulations of a same pharmaceutical product must be tested empirically., Aim: To evaluate the relative bioavailability for an oralformulation of mycophenolate mofetil (MMF) (Linfonex™) compared to the reference formulation (Cellcept™) to determine the bioequivalence between both formulations., Material and Methods: A randomized, crossover, double-blind trial in 22 healthy male volunteers, who received a single oral dose of 1000 mg of Linfonex and Cellcept with a washout period of 10 days. Plasma levels of the drug were determined by high performance liquid chr ornatography. Plasma concentrations were plotted and maximum concentration, area under the plasma concentration versus time between 0 and 12 hours after administration and área under plasma concentration curve versus time after administration between 0 and infinity, were calculated for both products., Results: The active compound, mycophenolic acid, was similarly absorbed in both formulations. No statistically significant differences were found in calculated pharmacokinetic parameters between both formulations., Conclusions: Linfonex™ 500 mg is bioequivalent to Cellcept™ 500 mg.

Introduction: Airway management in patients with middle third facial skeleton fractures is a challenge for anesthesiologists and surgeons, given that the natural routes for intubation--the nose and mouth--are both compromised by trauma. In this setting, the airway can only be accessed by tracheotomy. Tracheotomy, however, is an invasive technique that should be reserved for cases in which it is absolutely necessary., Objectives: To establish the utility of submental intubation as an alternative to tracheotomy in patients with middle third facial skeletal fractures., Patients and Methods: We reviewed the cases of the 15 patients intubated with the aforementioned technique between 1996 and 2002 in Hospital Universitario La Paz in Madrid, Spain. We describe the surgical technique and postoperative course recorded for those patients., Results: The courses of surgery and postoperative recovery were without complications. All extubations were uneventful and no patient required a tracheotomy., Conclusions: Submental intubation is a simple, useful technique for managing the airway of patients with middle third facial skeletal fractures. The technique has few complications.

Purpose: To compare the epidural administration of fentanyl (1 microg/mL) combined with lidocaine 0.4% to preservative-free morphine for postoperative analgesia and side effects in children undergoing major orthopedic surgery., Methods: In a prospective, double-blind study, 30 children, ASA I-II, 2-16-yr-old, were randomly allocated to receive immediately after surgery either epidural F-L (epidural infusion at a rate of 0.1-0.35 mL/kg/hr of 1 microg/mL of fentanyl and lidocaine 0.4%) or epidural M (bolus of 20 microg/kg of morphine in 0.5 mL/kg saline every eight hours). Both groups received 40 mg/kg of iv metamizol (dipyrone) every six hours. In the F-L Group, blood samples were taken on the second and third postoperative day to determine total lidocaine concentrations. Adequacy of analgesia using adapted pediatric pain scales (0-10 score) and side-effects were assessed every eight hours postoperatively., Results: Resting pain scores were under 4, 95% of the time in the F-L Group and 87% of the time in the M Group (Chi square=4.674, P <0.05). The frequency of complications was very similar in both groups. The F-L Group total plasma lidocaine concentrations were directly related to the dose received, and below the toxic range in all patients., Conclusions: Postoperative epidural fentanyl with lidocaine infusion provides slightly better analgesia than conventional bolus administration of epidural morphine. Side-effects or risk of systemic toxicity were not augmented by the addition of lidocaine to epidural opioids.