De-regulation of the sonic hedgehog pathway in the InsGas mouse model of gastric carcinogenesis

This study investigated sonic hedgehog (Shh) signalling in gastric metaplasia in the insulin-gastrin (InsGas) hypergastrinaemic mouse +/- Helicobacter felis (H. felis) infection. Sonic hedgehog gene and protein expression was reduced in pre-metaplastic lesions from non-infected mice (90% gene reduction, P<0.01) compared to normal mucosa. Sonic hedgehog was reactivated in gastric metaplasia of H. felis-infected mice (3.5-fold increase, P<0.01) compared to pre-metaplastic lesions. Additionally, the Shh target gene, glioma-associated oncogene (Gli)-1, was significantly reduced in the gastric glands of InsGas mice (75% reduction, P<0.05) and reactivated with H. felis infection (P<0.05, base of glands, P<0.01 stroma of metaplastic glands). The ability of H. felis to activate the Shh pathway was investigated by measuring the effect of target cytokine, interleukin-8 (IL-8), on Shh expression in AGS and MGLVA1 cells, which was shown to induce Shh expression at physiological concentrations. H. felis induced the expression of NF-kappaB in inflammatory infiltrates in vivo, and the expression of the IL-8 mouse homologue, protein KC, in inflammatory infiltrates and metaplastic lesions. Sonic hedgehog pathway reactivation was paralleled with an increase in proliferation of metaplastic lesions (15.75 vs 4.39% in infected vs non-infected mice, respectively, P<0.001). Furthermore, Shh overexpression increased the growth rate of the gastric cancer cell line, AGS. The antiapoptotic protein, bcl-2, was expressed in the stroma of infected mice, along with a second Shh target gene, patched-1 (P=0.0001, stroma of metaplastic gland). This study provides evidence suggesting reactivation of Shh signalling from pre-metaplastic to advanced metaplastic lesions of the stomach and outlines the importance of the Shh pathway as a potential chemoprophylactic target for gastric carcinogenesis.     

The neuronal KCNQ channel opener retigabine inhibits locomotor activity and reduces forebrain excitatory responses to the psychostimulants cocaine, methylphenidate and phencyclidine

Many central stimulating drugs have a pronounced stimulatory effect on striatal and cortical activity which is associated to enhanced function of mesencephalic dopaminergic neurons. Mesencephalic KCNQ (also termed K_v7) potassium channels suppress the basal activity of dopaminergic neurons in the substantia nigra and ventral tegmental area. These regions have extensive dopaminergic projections to the striatum and cortex, and positive modulation of KCNQ channel function may therefore potentially reduce the reinforcing impact of central stimulating drugs. We studied the effects of the principal neuronal KCNQ channel opener, retigabine, in rats exposed acutely to cocaine, methylphenidate (dopamine reuptake inhibitors) or phencyclidine (PCP, a psychotomimetic NMDA receptor antagonist). Retigabine (≥ 1.0 mg/kg) inhibited cocaine, methylphenidate and PCP-stimulated locomotor activity. Also, retigabine reduced spontaneous locomotor activity. The inhibitory effect of retigabine on psychostimulant-induced locomotor activity was accompanied by a marked reduction in c-Fos expression, in particular the nucleus accumbens and primary motor cortex were responsive to retigabine pre-treatment. Notably, retigabine also reduced basal extracellular levels of striatal dopamine metabolites and partially prevented dopamine overflow in the striatum induced by dopamine reuptake blockade. In combination, these data suggest that retigabine reduces striatal and cortical excitability, thereby attenuating excitatory effects of central stimulating drugs in dopamine-rich areas of the rat forebrain. KCNQ channel openers may therefore be of potential relevance in the treatment of addiction states caused by abuse of psychostimulants.     

Dexmedetomidine for the treatment of postanesthesia shivering in children

BACKGROUND: Shivering is a common postanesthesia adverse event with multiple etiologies and multiple suggested prophylactic and abortive treatment regimens. Dexmedetomidine, a centrally acting alpha(2)-adrenergic agonist, has been used as a sedative agent and is known to reduce the shivering threshold. We hypothesized that children with postanesthesia shivering would reduce shivering behavior following a single bolus dose of dexmedetomidine. METHODS: Dexmedetomidine was administered in a prospective, open-label fashion. The anesthesia management was uniform consisting of maintenance inhaled anesthesia (sevoflurane) and the intraoperative administration of fentanyl (1-2 microg.kg(-1)) plus a regional anesthetic technique (either a neuraxial or peripheral block) for postoperative analgesia. Criteria for treatment included: (i) shivering, (ii) successful extubation, and (iii) no other complaint/indication of pain. All children who met the criteria were treated with a single intravenous bolus dose of dexmedetomidine (0.5 microg.kg(-1)) over 3-5 min. Following the completion of drug administration, shivering activity was recorded every minute (up to 10 min) with any adverse effects or complaints. The efficacy of shivering reduction at 5 min in this cohort is compared with previous reports from the literature of the efficacy of clonidine and meperidine. RESULTS: Twenty-four children ranging in age from 7 to 16 years (11.5 +/- 2.5 years) were treated. All children had a cessation of shivering behavior within 5 min following the completion of dexmedetomidine administration. The onset of effect was 3.5 +/- 0.9 min. No adverse effects were observed. No shivering behavior recurred. CONCLUSIONS: This study demonstrates the efficacy of dexmedetomidine in the treatment of postanesthesia shivering.     

Tension chylothorax in two pediatric patients

Although the accumulation of gas is the most common cause of an expanding interpleural space, the presence of other structures or substances (hydrothorax, gastrothorax, hemothorax, urohemothorax, pyothorax, and chylothorax) under pressure may be sufficient to cause hemodynamic and respiratory compromise. We present two pediatric patients that developed hemodynamic and respiratory effects secondary to a chylothorax. The first patient presented in respiratory distress and cardiovascular collapse 4 weeks after a Fontan procedure. Placement of a chest tube resulted in the release of chyle under pressure and prompt resolution of hemodynamic and respiratory symptoms. The second patient was a 2100 g neonate who developed a chylothorax during an episode of sepsis following gastroschisis repair. On two separate occasions, the development of the chylothorax was associated with tachycardia, oliguria, and increased requirements during mechanical ventilation. Chest tube placement resulted in the release of chyle under pressure and resolution of the symptoms. These two cases demonstrate that chylothorax like pneumothorax can have deleterious effects on hemodynamic and respiratory function.     

Continuous SvO2 measurement in infants undergoing congenital heart surgery--first clinical experiences with a new fiberoptic probe

BACKGROUND: SvO2-guided therapy, using fiberoptic oximetric catheters can help to improve the outcome after complex congenital heart surgery especially in infants undergoing the Stage 1-Norwood-Procedure. So far, fiberoptic catheters have to be placed transthoracically by the surgeon into the vena cava or the pulmonary artery putting the infant at an additional risk of bleeding at the time of catheter removal. METHODS: We used a new percutaneously applicable fiberoptic probe for continuous monitoring of central venous saturation in three infants undergoing modifications of the Stage 1-Norwood-Procedure (reconstruction of the aortic arch), two in combination with a bidirectional cavopulmonary connection (Glenn shunt), the third with reconstruction of the pulmonary arteries (biventricular repair). The approved clinical monitoring system consisted of a small (2 F) fiberoptic probe and a bed-side-monitor. The probe was inserted via the routine central venous access for such a case. RESULTS: Continuous SvO2 measurement is feasible in infants using the CeVOX system in combination with routine central venous access, and the advantages of continuous monitoring are discussed. CONCLUSIONS: We believe that compared with transthoracically inserted oximetric catheter, the presented percutaneous technique avoids additional risks at the time of catheter removal (i.e. bleeding) and has become part of our standard management.     

Rapid sequence intubation without a neuromuscular blocking agent in a 14-year-old female patient with myasthenia gravis

The anesthesia care of a 14-year-old female patient with an acute exacerbation of myasthenia gravis (MG) and a full stomach who required emergency surgery for placement of a hemodialysis catheter is described. A nonventilated rapid sequence induction was successful with the use of propofol, lidocaine, remifentanil, cricoid pressure and no neuromuscular blocking agent. Although the use of combinations of i.v. anesthetic agents have been suggested for tracheal intubation without the need for neuromuscular blocking agents, none of these techniques has been advocated for rapid sequence intubation. We review existing literature on the topic of tracheal intubation using remifentanil and propofol without a neuromuscular blocking agent and on the topic of tracheal intubation of patients with MG using i.v. anesthesia and no neuromuscular blocking agents.     

Prognostic relevance of capsular involvement and collecting system invasion in stage I and II renal cell carcinoma

OBJECTIVE: To define the prognostic relevance of capsular involvement (invasion with no penetration) and collecting-system invasion in patients with stage I (pT1N0M0) and stage II (pT2N0M0) renal cell carcinoma (RCC), by evaluating the outcome of patients treated with nephrectomy. PATIENTS AND METHODS: In all, 519 patients from a kidney cancer database treated with nephrectomy for stage I and II RCC between 1985 and 2005 were assessed retrospectively. The primary endpoint was recurrence-free survival time. The prognostic relevance of capsular involvement and collecting-system invasion were examined using univariate and multivariate survival analysis. RESULTS: Capsular involvement and collecting-system invasion were evident in 112 (21.6%) and 39 (7.5%) patients, respectively. Capsular involvement was associated with higher Fuhrman grades and larger tumours. The incidence of collecting-system invasion was higher in patients with microvascular invasion. The median follow-up was 49 months. In univariate analysis, patients with capsular involvement and collecting-system invasion had a worse prognosis than patients without (P = 0.007 and <0.001, respectively). In multivariate analysis, capsular involvement (hazard ratio 1.84, P = 0.036) and collecting-system invasion (3.78, P < 0.001) were independent prognostic factors of recurrence-free survival. Interestingly, there was no survival difference between patients with capsular involvement in stage I/II and patients with invasion of perinephric tissue (pT3aN0M0). CONCLUSIONS: These findings suggest that capsular involvement and collecting-system invasion are poor prognostic findings in stage I and II RCC. They should both be considered when planning the follow-up. A revised pT3a stage including patients with capsular involvement could improve its prognostic validity.     

Regional Gas Exchange and Cellular Metabolic Activity in Ventilator-induced Lung Injury

Background: Alveolar overdistension and repetitive derecruitment-recruitment contribute to ventilator-induced lung injury (VILI). The authors investigated (1) whether inflammatory cell activation due to VILI was assessable by positron emission tomography and (2) whether cell activation due to dynamic overdistension alone was detectable when other manifestations of VILI were not yet evident.

Methods: The authors assessed cellular metabolic activity with [18F]fluorodeoxyglucose and regional gas exchange with [13N]nitrogen. In 12 sheep, the left ("test") lung was overdistended with end-inspiratory pressure of 50 cm H2O for 90 min, while end-expiratory derecruitment of this lung was either promoted with end-expiratory pressure of -10 cm H2O in 6 of these sheep (negative end-expiratory pressure [NEEP] group) or prevented with +10 cm H2O in the other 6 (positive end-expiratory pressure [PEEP] group) to isolate the effect of overdistension. The right ("control") lung was protected from VILI.

Results: Aeration decreased and shunt fraction increased in the test lung of the NEEP group. [18F]fluorodeoxyglucose uptake of this lung was higher than that of the control lung and of the test lung of the PEEP group, and correlated with neutrophil count. When normalized by tissue fraction to account for increased aeration of the test lung in the PEEP group, [18F]fluorodeoxyglucose uptake was elevated also in this group, despite the fact that gas exchange had not yet deteriorated after 90 min of overdistension alone.