Loading dose of Dexdor® and optimal sedation during oral and maxillofacial ambulatory surgery procedures: An observational study. / Dosis de carga de Dexdor® y nivel óptimo de sedación durante procedimientos de cirugía oral y maxilofacial en régimen ambulatorio: un estudio observacional.

INTRODUCTION: Dexdor® do not include the possibility of loading dose, which could increase time to achieve adequate sedation for ambulatory procedures. The objective of this study was to evaluate the effect of several loading dose of dexmedetomidine in the time to achieve and maintain an optimal level of sedation and its clinical hemodynamic repercussion. MATERIAL AND METHODS: The IRB approved this observational study for patients that underwent oral and maxillofacial ambulatory surgery under dexmedetomidine at the University of Navarra Clinic from February 2013 to November 2014. According to the loading dose the patients were grouped into 3 categories:<0.5, 0.5, and>0.5µg/kg. Optimal level of sedation was defined as bispectral index<85. Data were analyzed using survival analysis techniques. Vasoactive drugs requirements was evaluated using exact logistic regression. RESULTS: Eighty-one patients were evaluated. Hazard ratios for patients in 0.5 and >0.5µg/kg loading dose categories for achieving a bispectral index<85 were 1.5 (95% CI 0.9, 2.6) and 1.8 (95% CI 0.8, 3.9), respectively, compared with the lowest category. Five patients (6.2%) required atropine for bradycardia. Patients in the group>0.5µg/kg showed greater risk of requiring atropine compared with the group<0.5µg/kg (odds ratio 2.2; 95% CI 0.03, 183). CONCLUSION: Loading dose of dexmedetomidine>0.5µg/kg appears minimize the time to achieve and maintain an optimal level of sedation during the first 60min of procedure. Further investigation to elucidate the association between loading dose of dexmedetomidine and subsequent atropine requirements may be warranted.

A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human α4ß2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

Unconscious context-specific proportion congruency effect in a stroop-like task.

Cognitive control is a central topic of interest in psychology and cognitive neuroscience and has traditionally been associated with consciousness. However, recent research suggests that cognitive control may be unconscious in character. The main purpose of our study was to further explore this area of research focusing on the possibly unconscious nature of the conflict adaptation effect, specifically the context-specific proportion congruency effect (CSPCE), by using a masked Stroop-like task where the proportion of congruency was associated to various masks. We used electrophysiological measures to analyze the neural correlates of the CSPCE. Results showed evidence of an unconscious CSPCE in reaction times (RTs) and the N2 and P3 components. In addition, the P2 component evoked by both target and masks indicated that the proportion of congruency was processed earlier than the congruency between the color word and the ink color of the target. Taken together, our results provided evidence pointing to an unconscious CSPCE.

The insulin sensitizing effects of PPAR-γ agonist are associated to changes in adiponectin index and adiponectin receptors in Zucker fatty rats.

The adiponectin high molecular weight isoform (HMW-adp) and its relation with the other adiponectin isoforms (adiponectin index, S(A)), have been identified as essential for the adiponectin insulin sensitizing effects. The objective of this study is to gain further insight on the effect of the insulin sensitizing agents, PPAR-γ agonists, on the distribution of the adiponectin isoforms and the adiponectin receptors, adipoR1 and adipoR2 in an animal model of obesity and insulin resistance. To achieve the objective, Zucker fatty rats were treated with pioglitazone, rosiglitazone or placebo for six weeks. At the end of the treatment, total adiponectin, adiponectin isoforms and adiponectin receptors expression were measured. In order to see the possible relation with insulin sensitivity parameters, HOMA-IR, muscle insulin-stimulated glucose transport, muscle GLUT4 and plasma free fatty acids were also measured. The two glitazones improved insulin sensitivity and both muscle insulin-stimulated glucose transport and GLUT4 total content. Total plasma adiponectin and visceral fat HMW-adp were increased only by pioglitazone. On the other hand, both glitazones changed the distribution of adiponectin isoforms in plasma, leading to an increase in the S(A) of 21% by pioglitazone and 31% by rosiglitazone. Muscle adipoR1 expression was increased by both glitazones whereas liver adipoR2 expression was increased by rosiglitazone and tended to increase in the pioglitazone group. The insulin sensitizing action of glitazones is mediated, at least in part, by their effect on muscle insulin-stimulated glucose transport and by their direct influence on the adiponectin index and the adiponectin receptors expression.

A dedicated intravenous cannula for postoperative use effect on incidence and severity of phlebitis.

A prospective, randomised, controlled clinical study was performed to compare the incidence and severity of postoperative peripheral venous thrombophlebitis associated with a single intravenous cannula used for both intra-operative and postoperative purposes, and two cannulae, one used intra-operatively and the other postoperatively. Sixty American Society of Anaesthesiologists (ASA) physical status I or II patients aged 18-65 years undergoing elective surgery were studied. The technique of cannula insertion was standardised. After surgery, the cannulation sites were examined daily by a blinded investigator for the presence and severity of thrombophlebitis using the Baxter Scale. The two groups were similar in terms of age, gender, weight, type and duration of surgical procedures, and drugs and fluids administered both intra-operatively and postoperatively. The proportion of patients that developed phlebitis was significantly less in the two cannulae group (26.1%) than in the single cannula group (63.3%) (p < 0.0001). The severity of phlebitis was greater in the single cannula group than in the two cannulae group. These results indicate that the use of a dedicated cannula for postoperative use decreases the incidence and severity of postoperative, peripheral, cannula-related phlebitis.

[General intubation anesthesia in primates for experimental otoneurologic surgery]. / Anestesia general intubada en primates para cirugía otoneurológica experimental.

INTRODUCTION: We report our experience in anaesthetic and surgical management of primates (M. fascicularis) in an experimental otoneurosurgical procedure. MATERIAL & METHODS: The VIII cranial nerve was bilaterally sectioned in a translabyrinthine approach in 21 adult primates. In 14 animals subsequently, a prototype of auditory brainstem implant was placed unilateraly within the brain stem for surface stimulation of cochlear nuclei. Premedication consisted in an intramuscular mixture of ketamine, midazolam and atropine. Surgical procedure was performed under intubated general anaesthesia, after propofol (1.5 mg/kg) administration and maintained with nitrous oxide and halotane. RESULTS: The mixture of ketamine, midazolam and atropine produced a deep anaesthesia in 4 +/- 1.7 minutes, permitting safe animal handling. Atraumatic nasotracheal intubation without muscle relaxing agents was easily achieved in all animals. Anaesthesia was adequately maintained with nitrous oxide and halotane. Animals did not present any relevant incidents during surgery, and were extubated 10 +/- 2.5 minutes after cessation of gas administration. Post-operatively, no relevant surgical complications occurred. CONCLUSIONS: We report an anaesthetic technique that provides an optimal restrain and anaesthesia for experimental otoneurosurgical procedures with primates. This technique offers a quick recovery and avoids the use of muscular relaxing agents for intubation, and thus could be safely used in other kind of surgical procedures.

[A superior vena cava syndrome due to a surgical retractor]. / Síndrome de vena cava superior por retractor quirúrgico.

A 56-year-old male diagnosed of epidermoid carcinoma of the right lung (T4 N0 M0, stage IIIb) is described. He had earlier received chemotherapy and radiotherapy and was scheduled for removal of the right lung. During surgery the need to resect tumor infiltration of the right atrium became evident. During weaning from by-pass sudden deterioration of hemodynamics occurred with poor response to volume and inotropic drugs. Superior vena cava syndrome due to traction of the innominate trunk from a surgical retractor was diagnosed; the crisis resolved when the retractor was withdrawn. We discuss the pathophysiology of this clinical picture and relevant intraoperative aspects.

Cyclin E-cdk2 activation is associated with cell cycle arrest and inhibition of DNA replication induced by the thymidylate synthase inhibitor Tomudex.

Tomudex (ZD1694) is a specific antifolate-based thymidylate synthase inhibitor active in a variety of solid tumor malignancies. Studies were carried out in vitro to evaluate downstream molecular alterations induced as a consequence of the potent and sustained inhibition of thymidylate synthase by Tomudex. Twenty-four hours following the initial 2-h treatment with Tomudex, human A253 head and neck squamous carcinoma cells, not expressing p53 and p21(WAF1), were accumulated with DNA content characteristic of early S phase of the cell cycle with a concomitant reduction of cells in G1 and G2/M phases. The changes in cyclin and cdk protein expression and their kinase activities were examined in control and drug-treated A253 cells. Tomudex treatment resulted in the decrease in p27(kip1) expression, with an increase in cyclin E and cdk2 protein expression and kinase activities 24 h after a 2-h exposure. Although cyclin A protein expression was markedly increased, cyclin A kinase activity was only slightly increased. Cyclin D1, cyclin B, cdk4, and cdc2 protein expression and kinase activities remain constant. Lack of activation of cyclin A- and B-cdc2 was associated with a reduced proportion of cells in G2/M phases. Increased cyclin E-cdk2 protein expression was accompanied by the inhibition of DNA synthesis, with a decrease in E2F-1 expression. These results propose that cyclin E-cdk2 kinase can negatively regulate DNA replication. The studies with dThyd rescue from cyclin E-cdk2 protein overexpression and growth inhibition by Tomudex indicate that increased cyclin E-cdk2 protein expression is associated with effective inhibition of thymidylate synthase and resultant dNTP pool imbalance. Provision of dThyd more than 24 h after exposure to Tomudex allowed cells to replicate DNA for a single cycle back to G1, but did not prevent the profound growth-inhibitory effect manifested in the following 5 days. Tomudex treatment resulted in a time-dependent induction of the megabase DNA fragments, followed by secondary 50- to 300-kb DNA fragmentation. The 50- to 300-kb DNA fragmentation may be derived from the inhibition of DNA synthesis associated with cyclin E-cdk2 activation. These results suggest that the megabase DNA fragmentation is induced as a consequence of inhibition of thymidylate synthase by Tomudex and kilobase DNA fragmentation may correlate with the reduction of p27(kip1) expression and the increase in cyclin E and cdk2 kinase activities. Activation of cyclin E and cdk2 kinases allows cells to transit from G1 to S phase accompanied by the inhibition of DNA synthesis. The changes in cell cycle regulatory proteins associated with growth inhibition and DNA damage by Tomudex are not p53 dependent.

[Efficacy of 0.1 mg of subarachnoid morphine combined with bupivacaine on postoperative analgesia in total hip arthroplasty]. / Eficacia de 0,1 mg de morfina subaracnoidea asociada a la bupivacaína sobre la analgesia postoperatoria en la artroplastia total de cadera.

OBJECTIVES: To analyze the analgesic efficacy, safety and side effects of subarachnoid morphine (0.1 mg) with bupivacaine in patients undergoing total hip arthroplasty. PATIENTS AND METHODS: Thirty patients scheduled for total hip replacement under spinal anesthesia with bupivacaine were randomly assigned to two groups according to whether local anesthetic with 0.1 mg subarachnoid morphine was also provided or not (group M [n = 15] and group S n = 15[, respectively). Top-up analgesia with morphine was available through a patient-controlled device. Postoperative pain was assessed on a visual analogue scale (VAS) and consumption of intravenous morphine in the first 48 hours after surgery was recorded. RESULTS: VAS scores (mean +/- SD) were significantly lower in the first six hours in group M, but no differences between the two groups were observed thereafter. Total consumption of morphine at 48 hours was much lower in group M (6.80 +/- 7.74 mg) than in group S (31.38 +/- 13.17 mg). The incidence of nausea was high in both groups (46%). Slight pruritus affected 26.6% of patients in group M. Urinary retention necessitating temporary placement of a catheter was observed only in group M, where the incidence was 35.7%. No cases of respiratory depression occurred. Drowsiness was observed in 26.6% of patients in group S in comparison with 6.6% in group M. CONCLUSIONS: Combining 0.1 mg morphine and bupivacaine for total spinal anesthesia during hip arthroplasty significantly decreased the consumption of intravenous morphine during the first 48 hours after surgery. No respiratory depression occurred and the only side effects were urinary retention and mild pruritus and drowsiness.

Repeated transient neurological symptoms after spinal anaesthesia with hyperbaric 5% lidocaine.

We report a case of repeated delayed pain after cystoscopy under spinal lidocaine anaesthesia, which may be caused by transient radicular irritation. The possible aetiology of the symptoms is discussed.

[Common variable immunodeficiency associated with autoimmune thrombocytopenia: anesthetic management]. / Inmunodeficiencia variable común asociada a trombopenia autoinmune: manejo anestésico.

A 44-year-old man diagnosed of common variable immunodeficiency associated with thrombopenia due to autoimmunity required anesthesia for anal fissure repair and hemorrhoidectomy. Hemostatic complications developed after surgery, with extreme thrombopenia (1,000 platelets/pl) and analytical changes that necessitated administration of six units of platelets from apheresis, as well as immunoglobulins, antifibrinolytic agents (e-aminocaproic acid) and granulocytic colony stimulating factors. Anesthesia for such patients is reviewed, with emphasis on careful management of the airways, preparation of sufficient material for surgery (rapid transfusion equipment, large caliber intravenous catheters, sterile material) and orientation of anesthetic technique toward general anesthesia through a laryngeal mask.

Is management of anesthesia in achondroplastic dwarfs really a challenge?

STUDY OBJECTIVE: To review our eight-year anesthetic experience with achondroplastic patients. DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: 15 achondroplastic patients who underwent 53 surgical procedures of orthopedic surgery between 1987 and 1994. INTERVENTIONS: Anesthetic technique, drugs, number of incidents, and complications in the intraoperative and postoperative period were recorded. MEASUREMENTS AND MAIN RESULTS: Adequate premedication before the transfer to the operating room was very useful to reduce anxiety and increase cooperation. Inhalation induction was well tolerated and allowed easy peripheral venous cannulation. Only one patient presented difficulties during intubation (on two occasions). In the other patients, we found small difficulties only during ventilation with a face mask, which was easily corrected by modifying the position of the patient and/or inserting an oropharyngeal airway. No adverse effect was identified for any particular anesthetic drug or technique used. CONCLUSIONS: Although the characteristic deformities of achondroplastic patients can impede the management of anesthesia, in our study we found no special difficulties. Airway complications did not occur. Thus, no specific optimal anesthetic regimen can be recommended.

p53 and WAF1 are induced and Rb protein is hypophosphorylated during cell growth inhibition by the thymidylate synthase inhibitor ZD1694 (Tomudex).

In a previous study, we found that treatment of HCT-8 cells with ZD1694, a specific antifolate-based thymidylate synthase inhibitor, resulted in DNA fragmentation. In this study, we have demonstrated the dose- and time-dependent induction of DNA fragmentation accompanied by elevation of p53 and WAF1 protein expression by ZD1694. WAF1 mRNA showed a time-dependent increase, whereas p53 mRNA was not found to be significantly overexpressed. The initial increase in WAF1 mRNA was detected at 4 hr, but increased WAF1 protein expression was detected 8-24 hr after a 2-hr exposure. The amount of total and hypophosphorylated pRb seems to be rising greatly after ZD1694 exposure. The effects of ZD1694 on the expression of E2F1 and formation of the E2F1-Rb complex were investigated after a 2-hr drug exposure (IC90). The results showed a time-dependent decrease in E2F1 mRNA and protein expression; an increase in the abundance of the E2F-Rb complex could be demonstrated beginning 4 hr after drug exposure by a gel shift assay. Kinetic analysis showed increased availability of hypophosphorylated pRb for inhibition of E2F, which could indirectly result from WAF1-induced inhibition cyclin-dependent kinase activity. Whereas thymidylate synthase inhibition by ZD1694 was rapid in onset and maintained for at least 24 hr after drug treatment, drug-induced cellular growth inhibition was significant 24 hr after drug exposure. The increased abundance of hypophosphorylated pRb and binding to transcription factor E2F-1 is consistent with ZD1694-induced cell growth inhibition in HCT-8 cells. Therefore, the observed effect on downstream events after effective inhibition of thymidylate synthase may offer the critical determinants of response to ZD1694.

Four days' continuous infusion of cisplatin-5-fluorouracil and short daily infusion of high-dose leucovorin as induction chemotherapy for locally advanced head and neck cancer.

Cisplatin-fluorouracil (PF) is the most frequently used combination as induction chemotherapy (CT) for the treatment of locally advanced squamous cell head and neck cancer. This study was designed to evaluate the role of leucovorin (L) in the modulation of the therapeutic activity of PF continuously infused for 4 days. Between June 1990 and June 1992, stage III and IV previously untreated patients received PFL induction chemotherapy followed by surgery, radiotherapy, or both. The chemotherapy consisted of P 25 mg/m2, F 1000 mg/m2 both continuously infused for 4 days and L 250 mg/m2 infused for 2 hours before each daily infusion of PF. PFL was administered every 3 weeks for 4 cycles. The overall response rate at the completion of PFL was 91%, with 54% CR and 37% PR. Locoregional treatment was performed on 68 patients, 11 (16%) underwent surgery, 20 (29%) surgery plus radiotherapy, and 37 (54%) radiotherapy. Complete response status after both induction and locoregional therapy was 71%. Biopsies of the primary tumor or definitive resection specimens immediately after PFL therapy were available in 25 patients in CR. Pathological CR was found in 11 (44%). With a maximum follow-up of 44 months, the overall survival rate is 51% and the median survival has not been reached. PFL is highly active as induction chemotherapy. A randomized comparison between PF and PFL is necessary to define the place of leucovorin modulation in the treatment of head and neck cancer.