Transcriptomic variation of pharmacogenes in multiple human tissues and lymphoblastoid cell lines.

Variation in the expression level and activity of genes involved in drug disposition and action ('pharmacogenes') can affect drug response and toxicity, especially when in tissues of pharmacological importance. Previous studies have relied primarily on microarrays to understand gene expression differences, or have focused on a single tissue or small number of samples. The goal of this study was to use RNA-sequencing (RNA-seq) to determine the expression levels and alternative splicing of 389 Pharmacogenomics Research Network pharmacogenes across four tissues (liver, kidney, heart and adipose) and lymphoblastoid cell lines, which are used widely in pharmacogenomics studies. Analysis of RNA-seq data from 139 different individuals across the 5 tissues (20-45 individuals per tissue type) revealed substantial variation in both expression levels and splicing across samples and tissue types. Comparison with GTEx data yielded a consistent picture. This in-depth exploration also revealed 183 splicing events in pharmacogenes that were previously not annotated. Overall, this study serves as a rich resource for the research community to inform biomarker and drug discovery and use.

Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).

Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients.

Murine TMJ loading causes increased proliferation and chondrocyte maturation.

The purpose of this study was to examine the effects of forced mouth opening on murine mandibular condylar head remodeling. We hypothesized that forced mouth opening would cause an anabolic response in the mandibular condylar cartilage. Six-week-old female C57BL/6 mice were divided into 3 groups: (1) control, (2) 0.25 N, and (3) 0.50 N of forced mouth opening. Gene expression, micro-CT, and proliferation were analyzed. 0.5 N of forced mouth opening caused a significant increase in mRNA expression of Pthrp, Sox9, and Collagen2a1, a significant increase in proliferation, and a significant increase in trabecular spacing in the subchondral bone, whereas 0.25 N of forced mouth opening did not cause any significant changes in any of the parameters examined. Forced mouth opening causes an increase in the expression of chondrocyte maturation markers and an increase in subchondral trabecular spacing.

Effects of anticholinergics on postoperative vomiting, recovery, and hospital stay in children undergoing tonsillectomy with or without adenoidectomy.

BACKGROUND: Nausea and vomiting are the most frequent problems after minor ambulatory surgical procedures. The agents used to induce and maintain anesthesia may modify the incidence of emesis. When neuromuscular blockade is antagonized with anticholinesterases, atropine or glycopyrrolate is used commonly to prevent bradycardia and excessive oral secretions. This study was designed to evaluate the effect of atropine and glycopyrrolate on postoperative vomiting in children. METHODS: Ninety-three patients undergoing tonsillectomy with or without adenoidectomy were studied. After inhalation induction of anesthesia with nitrous oxide, oxygen, and halothane, anesthesia was maintained with a nitrous oxide-oxygen mixture, halothane, morphine, and atracurium. Patients were randomized to receive, in a double-blinded manner, either 15 microg/kg atropine or 10 microg/kg glycopyrrolate with 60 microg/kg neostigmine to reverse neuromuscular blockade. Patient recovery, the incidence of postoperative emesis, antiemetic therapy, and the duration of postoperative hospital stay were assessed. RESULTS: There were no significant differences in age, gender, weight, or discharge time from the postanesthesia care unit or the hospital between the groups. Twenty-four hours after operation, the incidence of vomiting in the atropine group (56%) was significantly less than in the glycopyrrolate group (81%; P<0.05). There was no significant difference between the atropine and glycopyrrolate groups in the number of patients who required antiemetics or additional analgesics. CONCLUSIONS: In children undergoing tonsillectomy with or without adenoidectomy, reversal of neuromuscular blockade with atropine and neostigmine is associated with a lesser incidence of postoperative emesis compared with glycopyrrolate and neostigmine.

Use of esmolol to control bleeding and heart rate during electroconvulsive therapy in a patient with an intracranial aneurysm.

Electroconvulsive therapy (ECT) is a commonly used treatment modality for patients with major affective disorders that are unresponsive to pharmacological therapy. While ECT has been shown to be a very safe treatment, it is associated with transient hemodynamic alterations, including hypertension, which are associated with an increased risk of rupture of an intracranial aneurysm. We describe our use of the ultrashort acting beta-blocker, esmolol, for blood-pressure control in a woman with known cerebral aneurysmal disease who required ECT for treatment of recurrent major depression.

Penile block timing for postoperative analgesia of hypospadias repair in children.

PURPOSE: It has been well established that a dorsal penile nerve block immediately after surgery decreases postoperative pain in children undergoing hypospadias repair. However, to our knowledge the efficacy of a penile block immediately before versus immediately after surgery for postoperative pain control has not been previously studied in such children. MATERIALS AND METHODS: We evaluated 98 healthy boys 6 months to 12 years old undergoing hypospadias repair. General anesthesia was induced and maintained in a standard fashion. Patients were randomly assigned to receive a penile block with the same total dose of bupivacaine at the completion of surgery, before the incision or before and at the completion of surgery. No other analgesic was administered intraoperatively. Pain was assessed using a modified objective pain-discomfort scale at 15 minutes, and 3, 12 and 24 hours after surgery. The number of doses of acetaminophen required to control postoperative pain was also recorded. RESULTS: Pain scores were defined in a range of 0-no pain to 6-greatest pain. During recovery median pain scores in the 30, 36 and 32 boys who received a penile block after, before, and before and after surgery were 3, 1.5 and 0 at 15 minutes; 2.5, 1 and 0 at 3 hours; 3, 2 and 0 at 12 hours; and 1, 0 and 0 at 24 hours, respectively. There was no difference in acetaminophen doses required 15 minutes and 3 hours postoperatively in the 3 groups. By 12 hours after surgery the number of acetaminophen doses required for pain control was significantly lower in the before and after, and before groups than in the after group. By 24 hours boys in the before and after group required significantly fewer doses of analgesics than those in the after and before groups. There was no statistically significant difference between the after and before groups. CONCLUSIONS: Two penile blocks performed at the beginning and conclusion of hypospadias repair, respectively, provide better postoperative pain control than 1 penile block done before or after surgery (p < 0.05). These patients require less analgesic than those who receive a penile block only before or only after surgery.

Primary fibrinolysis during supraceliac aortic clamping.

PURPOSE: An increased incidence of bleeding complications has been observed after supraceliac aortic clamping (SCC). This study was performed to identify possible hemostatic abnormalities that contribute to this problem. METHODS: A prospective cohort study over a 3-month period was performed by comparing hemostatic parameters in 10 consecutive patients who required elective SCC with those of eight concurrent randomly selected control subjects who required infrarenal clamping (IRC) for abdominal aortic reconstruction. Measures of coagulation, fibrinolysis, platelet function, temperature, hemodilution, and hepatic function were performed at selected times before, during, and after operation. RESULTS: Aneurysm size, fibrinogen, D-dimers, prothrombin, partial thromboplastin time, platelet counts, bleeding times, hemodilution, and temperature were comparable in both groups. Patients in the SCC group, however, consistently developed a primary fibrinolytic state within 20 minutes after supraceliac clamping, reflected by significantly decreased euglobulin clot lysis times (ECLT; p < 0.0001), elevated tissue plasminogen activator (t-PA) levels (p < 0.0006), elevated t-PA-to-plasminogen activator inhibitor-1 ratios (p < 0.0001), and reduced alpha 2-antiplasmin levels (p < 0.002). SCC produced hepatocellular injury documented by elevations in both aspartate transaminase (p < 0.0001) and lactate dehydrogenase (p < 0.009). CONCLUSIONS: SCC rapidly induces a primary fibrinolytic state manifested by increased circulating t-PA, reduced alpha 2-antiplasmin, and increased fibrinolytic activator-to-inhibitor ratios. These effects may be a result of hepatic hypoperfusion caused by SCC leading to insufficient clearance of t-PA. Antifibrinolytic agents may be of benefit if bleeding develops after aortic procedures that require supraceliac clamping.

Unsuspected subglottic stenosis in a two-year-old.

Unsuspected subglottic stenosis was encountered in the operating room in a 23-month-old girl who had been diagnosed having Vater syndrome without the component of tracheooesophageal fistula. Her scheduled elective thumb reconstruction was postponed until tracheal reconstruction was performed. A rational approach to handle this situation is described.

The hyperventilation of cirrhosis: progesterone and estradiol effects.

Progesterone and estradiol are metabolized in the liver and are elevated in patients with cirrhosis. Progesterone stimulates ventilation by activating progesterone receptors in the central nervous system; estradiol may facilitate progesterone's actions by increasing progesterone receptors. This study evaluated whether progesterone and estradiol contribute to the respiratory alkalosis common in cirrhotic patients. Arterial blood gases and progesterone and estradiol levels were obtained in 50 patients with cirrhosis. Multiple linear regression revealed a statistically significant correlation between PaCO2 and progesterone and estradiol (r = .54, P < .05). Patients with severe hyperventilation (PaCO2 < or = 30 mm Hg) had statistically higher levels of progesterone and estradiol than did patients with mild hyperventilation (30 < PaCO2 < or = 35) or normal ventilation (PaCO2 > 35) (P < .05). Although the progesterone levels were two orders of magnitude lower than those associated with hyperventilation in pregnant patients, the increased ventilatory effect may be because of the altered blood-brain barrier (BBB) present in cirrhotic patients. Progesterone and estradiol appear to contribute to the hyperventilation in cirrhotic patients.

Comparison of end-tidal and arterial carbon dioxide in infants using laryngeal mask airway and endotracheal tube.

The laryngeal mask airway (LMA) has become a popular tool for airway management in selected adult and pediatric patients undergoing routine surgical procedures. The relationship between end-tidal and arterial carbon dioxide during controlled ventilation via the LMA in infants under 10 kg has not been reported. After induction of general anesthesia, the LMA was placed in 12 healthy infants and mechanical ventilation initiated. After maintaining steady-state level of end-tidal carbon dioxide (minimum 5 min), an arterial blood sample was obtained and end-tidal carbon dioxide level noted. The laryngeal mask was then removed, the trachea intubated, and mechanical ventilation resumed with initial ventilatory variables. After reaching a steady-state level of end-tidal carbon dioxide, a second arterial sample was obtained and end-tidal carbon dioxide level noted. The mean end-tidal carbon dioxide and arterial partial pressure of carbon dioxide obtained during ventilation were 42.2 +/- 7.9 and 47.1 +/- 11.0 (LMA) and 37.4 +/- 4.6 and 42.6 +/- 6.7 (endotracheal tube), respectively. Analysis of differences between partial pressure of carbon dioxide and end-tidal carbon dioxide using the Bland and Altman method revealed bias+/-precision of 4.9 +/- 3.9 and 5.3 +/- 3.2 with ventilation via the laryngeal mask and endotracheal tube. Our data indicate that, while ventilating infants under 10 kg with LMA, end-tidal carbon dioxide is an accurate indicator of arterial partial pressure of carbon dioxide.

Effect of methohexitone and propofol with or without alfentanil on seizure duration and recovery in electroconvulsive therapy.

We have studied the effects of methohexitone and propofol with and without alfentanil on seizure duration and recovery in this observer-blinded, prospective, randomized, crossover study involving 24 patients undergoing electroconvulsive therapy (ECT). Each patient had four treatment sessions, and received the following four i.v. regimens in random order: methohexitone 0.75 mg kg-1, methohexitone 0.50 mg kg-1 and alfentanil 10 micrograms kg-1, propofol 0.75 mg kg-1, propofol 0.50 mg kg-1 and alfentanil 10 micrograms kg-1. Additional methohexitone or propofol was given as needed in 10-20-mg increments until loss of consciousness. Suxamethonium 1.0 mg kg-1 i.v. was given for muscular paralysis. Mean motor and EEG seizure durations were longer with methohexitone-alfentanil (44.7 (SD 15.0) and 70.5 (29.7) s) than with methohexitone (37.6 (12.6) and 52.6 (15.3) s) and similarly, seizures were longer with propofol-alfentanil (36.8 (15.2) and 54.5 (20.9) s) than with propofol alone (27.2 (11.9) and 39.2 (3.9) s). Seizures were longest with methohexitone-alfentanil and shortest with propofol. Recovery time was statistically shorter in patients receiving propofol compared with methohexitone-alfentanil and methohexitone alone. Alfentanil with a reduced dose of methohexitone or propofol provided unconsciousness and increased seizure duration in patients undergoing ECT. We conclude that the combination of methohexitone with alfentanil is a good regimen for ECT, especially for patients with short seizure duration.

Subarachnoid sufentanil versus lidocaine spinal anesthesia for extracorporeal shock wave lithotripsy.

BACKGROUND AND OBJECTIVES: Anesthetic techniques that reduce the time required for postoperative care can significantly reduce the cost of procedures. This study was designed to discover whether the use of subarachnoid sufentanil for extracorporeal shock wave lithotripsy (ESWL) would enable patients to be discharged more rapidly following surgery as compared with subarachnoid lidocaine, while providing equivalent efficacy. METHODS: Thirty-nine patients undergoing 40 ESWLs were randomized to receive either 12.5 microg of sufentanil or 75 mg of lidocaine by the subarachnoid route. The need for additional analgesia, incidence of adverse effects, and time to discharge were recorded and compared. RESULTS: Patients receiving sufentanil were discharged 52 minutes sooner than patients receiving lidocaine (166 +/- 77 vs 218 +/- 46 minutes, respectively, P < .05). Analyzed separately, women receiving sufentanil were discharged earlier than those receiving lidocaine (120 +/- 55 vs 208 +/- 42 minutes, P < .01). There was no significant difference in discharge times between men in each group. Patients in the sufentanil group had more pruritus and less change in blood pressure than patients in the lidocaine group. There was no significant difference in the incidence of other adverse effects or in the use of additional analgesia or sedation. CONCLUSIONS: Subarachnoid sufentanil provides acceptable analgesia for ESWL and offers the advantages of more rapid discharge for female patients and better hemodynamic stability as compared with lidocaine spinal anesthesia.

Unexpected neurologic deficit following spinal anesthesia.

BACKGROUND AND OBJECTIVES: A case of unexpected neurologic deficit of the left lower extremity following a successful spinal block is reported. METHODS: A spinal block was performed in a 45-year-old woman with a 25-gauge Whitaker needle at the L3-L4 interspace. After establishing flow of clear cerebrospinal fluid, 1.6 mL of 0.75% bupivacaine was injected into the subarachnoid space. The patient had a good motor and sensory block (level T4), and she underwent uneventful extracorporeal shock wave lithotripsy of a right kidney stone. After satisfactory recovery in the postanesthesia care unit, she was transferred to the ambulatory surgical center for further recovery and discharge home. RESULTS: About 11 hours after administration of the spinal anesthetic and recovery from the spinal block, the patient complained of not being able to move her left leg. Neurologic examination revealed motor loss and hyperesthesia to touch, vibration, pressure, and temperature from her groin to toes in the left leg only. The remainder of the neurologic examination was normal. A nuclear magnetic resonance scan of the spine revealed no abnormality. Neurologic and psychiatric consultations were sought, and the patient was diagnosed to have a conversion disorder. She responded to psychological intervention and returned to her previous state of health in 2 weeks. CONCLUSIONS: Neurologic deficit following spinal or epidural block should be investigated completely and appropriate consultations sought. Psychiatric disorder may be a rare cause of neurologic deficit after successful regional anesthesia and should be made part of a complete workup.