Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma.

PRDM1/BLIMP-1, a master regulator of plasma-cell differentiation, is frequently inactivated in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) patients. Little is known about its genetic aberrations and relevant clinical implications. A large series of patients with de novo DLBCL was effectively evaluated for PRDM1/BLIMP-1 deletion, mutation, and protein expression. BLIMP-1 expression was frequently associated with the ABC phenotype and plasmablastic morphologic subtype of DLBCL, yet 63% of the ABC-DLBCL patients were negative for BLIMP-1 protein expression. In these patients, loss of BLIMP-1 was associated with Myc overexpression and decreased expression of p53 pathway molecules. In addition, homozygous PRDM1 deletions and PRDM1 mutations within exons 1 and 2, which encode for domains crucial for transcriptional repression, were found to show a poor prognostic impact in patients with ABC-DLBCL but not in those with germinal center B-cell-like DLBCL (GCB-DLBCL). Gene expression profiling revealed that loss of PRDM1/BLIMP-1 expression correlated with a decreased plasma-cell differentiation signature and upregulation of genes involved in B-cell receptor signaling and tumor-cell proliferation. In conclusion, these results provide novel clinical and biological insight into the tumor-suppressive role of PRDM1/BLIMP-1 in ABC-DLBCL patients and suggest that loss of PRDM1/BLIMP-1 function contributes to the overall poor prognosis of ABC-DLBCL patients.

Aging- and photoaging-dependent changes of enzymic and nonenzymic antioxidants in the epidermis and dermis of human skin in vivo.

This is a comprehensive study of the changes in major antioxidant enzymes and antioxidant molecules during intrinsic aging and photoaging processes in the epidermis and dermis of human skin in vivo. We show that the activities of superoxide dismutase and glutathione peroxidase are not changed during these processes in human skin in vivo. Interestingly, the activity of catalase was significantly increased in the epidermis of photoaged (163%) and naturally aged (118%) skin (n = 9), but it was significantly lower in the dermis of photoaged (67% of the young skin level) and naturally aged (55%) skin compared with young (n = 7) skin. The activity of glutathione reductase was significantly higher (121%) in naturally aged epidermis. The concentration of alpha-tocopherol was significantly lower in the epidermis of photoaged (56% of young skin level) and aged (61%) skin, but this was not found to be the case in the dermis. Ascorbic acid levels were lower in both epidermis (69% and 61%) and dermis (63% and 70%) of photoaged and naturally aged skin, respectively. Gluta thione concentrations were also lower. Uric acid did not show any significant changes. Our results suggest that the components of the antioxidant defense system in human skin are probably regulated in a complex manner during the intrinsic aging and photoaging processes.

Continuous infusion epidural analgesia with lidocaine: efficacy and influence during the second stage of labor.

A randomized double-blind study evaluated the analgesic efficacy and influence of maintaining a continuous epidural infusion of 0.75% lidocaine during the second stage of labor in nulliparous women. When the cervix was 8 cm or more dilated, unidentified study solution was substituted for the known 0.75% lidocaine solution and continued until delivery. The study solution for 26 patients was 0.75% lidocaine; 27 subjects received saline. During the first stage of labor, 88% of women in the lidocaine group and 81% of women in the saline group had analgesia of excellent or good quality, a nonsignificant difference. During the second stage, there was a tendency (not statistically significant) toward improved analgesia quality in the lidocaine patients, but there was no significant difference in the frequency of perineal anesthesia (23% lidocaine, 7% saline). There was no difference between the groups in the duration of the second stage of labor (73 +/- 63 versus 76 +/- 48 minutes). Operative delivery frequency was similar (31 and 37%), as were umbilical cord blood acid-base values. It is concluded that maintenance of the continuous epidural infusion of 0.75% lidocaine did not prolong the second stage of labor, but it also did not significantly differ from saline in quality of second stage analgesia or frequency of perineal anesthesia.

Epidural hydromorphone for postcesarean analgesia.

The efficacy of epidurally administered hydromorphone for postcesarean analgesia was evaluated in a prospective, randomized, double-blind study. Patients in group H (N = 26) received 1.0 mg of hydromorphone in preservative-free saline (total volume = 10 mL), administered epidurally. Patients in group B (N = 26) received 10 mL of 0.25% bupivacaine, administered epidurally. Both groups subsequently received intramuscular injections of hydromorphone as needed. There were significant differences between the two groups in pain score, patient assessment of analgesia quality, time to first analgesic intervention, and total dosage of hydromorphone during the first 24 hours. Nausea/vomiting and pruritus occurred more frequently in group H. No patient had a respiratory rate less than or equal to 10. There were no statistically significant differences between groups in mean times to first ambulation, first void, first passage of flatus, or hospital discharge.

Systemic absorption and cardiovascular effects of phenylephrine eyedrops.

We studied 24 patients undergoing vitreoretinal surgery to compare the systemic absorption and cardiovascular effects of 2.5% aqueous and 10% viscous ophthalmic solutions of phenylephrine hydrochloride. Plasma levels measured in patients receiving two drops of 10% viscous solution were consistently higher ten, 20, and 60 minutes after instillation (P less than .02). Although the mean systolic and diastolic blood pressure was generally higher with the 10% viscous solution, the difference was not statistically significant. Blood pressure was high in several isolated cases. Because maximum plasma levels are achieved within ten to 20 minutes after topical instillation, phenylephrine eyedrops should be administered under close observation so that if an adverse reaction occurs it can be readily treated.

Computer-assisted fluoroscopic targeting system for pedicle screw insertion.

OBJECTIVE: Biplanar fluoroscopic imaging linked to a computer-driven mechanical end-effector is under development as a targeting system for spinal surgery. This technology has the potential to enhance standard intraoperative fluoroscopic information for localization of the pedicle entry point and trajectory, and it may be an effective alternative to the computed tomography-based image-guided system (IGS) in pedicle screw placement. A preclinical study to assess the accuracy and time efficiency of this system versus a conventional IGS was conducted. METHODS: Pedicle screw placement was performed in six cadavers from T1 to S1 levels using the ViewPoint IGS (Picker International, Inc., Cleveland, OH) on one side versus the Fluorotactic guidance system (Z-Kat, Inc., Miami, FL) on the other side. Of 216 possible pedicles, 208 were instrumented; 8 pedicle diameters were too small or were not adequately imaged. Postinsertion, each pedicle was assessed for the presence and location of cortical perforation using computed tomographic scanning and direct visualization. RESULTS: The number of successful screw placements was 89 (87.3%) of 102 for IGS and 87 (82.1 %) of 106 for the Fluorotactic guidance system, respectively. The mean time to register and operate on one level using the Fluorotactic guidance system was 14:34 minutes (minutes:seconds), compared with 6:50 minutes using the IGS. The average fluoroscope time was 4.6 seconds per pedicle. CONCLUSION: Our data indicate that this first-generation fluoroscopy-based targeting system can significantly assist the surgeon in pedicle screw placement. The overall accuracy is comparable to an IGS, especially in the region of T9-L5. A second-generation system with a faster end-effector and user-friendly interface should significantly reduce the operating and fluoroscope time.

Low frequency jet ventilation for tracheal resection.

Low frequency jet ventilation was used successfully for maintaining normal ventilation during tracheal resection for stenosis. Following resection of the stenosis around the endotracheal tube, the tube was withdrawn and the proximal end of a sterile double lumen nasogastric tube with the distal end removed passed over the ether screen. The larger lumen was connected to a Saunders jet apparatus and the smaller to a CO2 analyzer. With the distal end held in the lumen of the distal tracheal stump, jet ventilation was initiated at a rate of 20/min at a pressure sufficient to obtain adequate chest rise and fall. Adequate CO2 removal was verified by monitoring the expired level and blood gases. We obtained normal arterial and end tidal gas tensions by this method which allowed the surgeon complete freedom to anastomose the posterior and lateral tracheal walls.

Nitrous oxide and human state-dependent memory.

State-dependent effects of nitrous oxide on human memory were examined by administering serial and paired-associate learning tasks to subjects receiving 20 and 30% nitrous oxide or placebo. Nitrous oxide in 30% concentration impaired learning of both tasks. In addition, it produced an atypical form of asymmetric state-dependent memory; subjects who learned while receiving placebo and recalled while receiving nitrous oxide displayed the worst recall.

Conscious sedation for procedures under local or topical anesthesia.

For many surgical procedures in otolaryngology general anesthesia is not required, but it is difficult to block completely all noxious sensations with local or topical anesthesia. Intravenously administered antianxiety and analgesic drugs can make the procedure more tolerable for the patient. A technique of conscious sedation based upon titrating diazepam to specific eye signs and fentanyl to specific end points is described. Safety is maintained by ensuring that the patient is always in verbal contact with the surgeon. The rationale for administering the sedative before the narcotic is presented along with the treatment of side effects and untoward responses to the drugs.

Development of an electrohydraulic total artificial heart at the National Cardiovascular Center, Osaka, Japan.

The authors have been developing an electrohydraulic total artificial heart with a basic concept placing the blood pumps and an electrohydraulic energy converter separately, in the thorax and the abdominal region, respectively, to minimize anatomic constraints. Major problems of the system were a high energy consumption of 56 W at 6 L/min output and an insufficient maximum output of 6.7 L/min. The energy converter was redesigned to overcome these problems. A three phase, 4 pole brushless DC motor, which has maximum efficiency of 79% at a motor rotation of 2500 rpm with a load of 0.1 Nm, was developed for the new energy converter. Flow-channel design of the regenerative oil pump was optimized, which resulted in increasing the maximum flow rate at one directional motor rotation from 18 to 29 L/min. In vitro performance of the electrohydraulic total artificial heart was evaluated in a mock circulation with physiologic pressure conditions. Maximum output was increased to 10.7 L/min at a pump rate of 120 bpm and energy consumption of the motor at 6 L/min output was reduced to 18 W. Based upon these favorable results, the system is now being assembled for chronic animal implantation.

Analysis of the interventricular pressure waveform in the moving-actuator total artificial heart.

Right and left filling pressures are important parameters in the automatic control of a total artificial heart (TAH) within normal physiologic ranges. Our TAH is composed of a moving actuator, right and left ventricles, and an interventricular space (IVS) enclosed by a semirigid housing. During operation of the TAH, the IVS volume is changed dynamically by the difference between the ejection volume of one ventricle and the inflow volume of the other. We measured the interventricular pressure (IVP) waveform by using a pressure sensor and analyzed the relationship between the IVP and the preload condition. From in vitro and in vivo experiments, we found that the measured filling pressures were linearly related to the negative peak value of the IVP. Additionally, we found that we could use the time interval from actuator start to the positive peak value of the IVP (outflow valve opening) as a useful parameter to estimate the blood filling volume of the diastole ventricle.

Development of a precise controller for an electrohydraulic total artificial heart. Improvement of the motor's dynamic response.

In an electrohydraulic total artificial heart developed at the National Cardiovascular Center (Osaka, Japan), two blood pumps are pushed alternatively by means of the bidirectional motion of a brushless DC motor for pump systole and diastole. Improvement in the dynamic response of the motor is very important to obtain better pump performance; this was accomplished by using power electronic simulation. For the motor to have the desired dynamic response, it must be commutated properly and the damping ratio (zeta), which represents transient characteristics of the motor, must lie between 0.4 and 0.8. Consequently, all satisfactory specifications with respect to power consumption must be obtained. Based on the simulated results, the design criteria were determined and the precise controller designed to reduce torque ripple and motor vibration, and determine motor stop time at every direction change. In in vitro tests, evaluation of the controller and dynamic response of the motor was justified in terms of zeta, power consumption, and motor stop time. The results indicated that the power consumption of the controller and the input power of the motor were decreased by 1.2 and 2.5 W at zeta = 0.6, respectively, compared to the previous system. An acceptable dynamic response of the motor, necessary for the reduction of torque ripple and motor vibration, was obtained between zeta = 0.5 and zeta = 0.7, with an increase in system efficiency from 10% to 12%. The motor stop time required for stable motor reoperation was determined to be over 10 msec, for a savings in power consumption of approximately 1.5 W. Therefore, the improved dynamic response of the motor can contribute to the stability and reliability of the pump.

Skin is the frequent site for involvement of peripheral T-cell and natural killer cell lymphomas in Korea.

We have studied the clinicopathological features of 19 Korean cases of peripheral T-cell and natural killer (NK) cell lymphomas, not including mycosis fungoides. Primary cutaneous involvement was demonstrated in eight of these 19 cases, and we recognized four clinicopathologic subtypes among these eight patients: nasal type NK/T cell lymphoma, three cases; primary cutaneous CD30 positive anaplastic large cell lymphoma, two cases; subcutaneous panniculitis-like T-cell lymphoma, one case; lymphoma with hydroa vacciniforme-like cutaneous lesions, two cases. We did not, however, encounter any cases of HTLV-associated adult T-cell lymphoma/leukemia, which is common in Taiwan and Japan. EBV-associated lymphoma is the most prominent type of peripheral T-cell and NK cell neoplasm involving the skin in Korea.

Effect of intravenous administration of Ringer's lactate on maternal capillary blood glucose before elective cesarean section.

Capillary blood glucose concentrations were determined before and after intravenous infusion of 20 mL/kg of Ringer's lactate (RL) in 35 women scheduled for elective cesarean section. Mean (+/- SD) capillary blood glucose concentrations before and after infusion of RL were 84.7 +/- 13.2 and 89.0 +/- 16.5 mg/dL, respectively (P = NS). No parturient had a glucose level less than 60 mg/dL before or after infusion of RL. There were no instances of neonatal hypoglycemia. We conclude that large volumes of RL without dextrose may be rapidly infused into healthy pregnant women undergoing elective cesarean section without risk of dilutional hypoglycemia in the mother or neonate.

A new automatic cardiac output control algorithm for moving actuator total artificial heart by motor current waveform analysis.

A new automatic cardiac output control algorithm for an implantable electromechanical total artificial heart (TAH) was developed based on the analysis of motor current waveform without using any transducer. The basic control requirements of an artificial heart can be described in terms of three features: preload sensitivity, afterload insensitivity, and balanced ventricular output. In previous studies, transducers were used to acquire information on the hemodynamic states for automatic cardiac output control. However, such a control system has reliability problems with the sensors. We proposed a novel sensorless automatic cardiac output control algorithm (ACOCA) providing adequate cardiac output to the time-varying physiological demand without causing right atrial collapse, which is one of the critical problems in an active filling device. In vitro tests were performed on a mock circulatory system to assess the performance of the developed algorithm and the results show that the new algorithm satisfied the basic control requirements of the cardiac output response.

Neuromuscular and cardiovascular effects of mivacurium chloride (BW B109OU) during nitrous oxide-narcotic, nitrous oxide-halothane and nitrous oxide-isoflurane anesthesia in surgical patients.

One hundred seventeen adult surgical patients were studied to compare neuromuscular and cardiovascular effects of mivacurium chloride during nitrous oxide-narcotic (BAL, n = 45) nitrous oxide-halothane (HAL, n = 27) and nitrous oxide-isoflurane (ISF, n = 45) anesthesia. Anesthesia was maintained with nitrous oxide (60%-70%) and oxygen (30%-40%) with end-tidal concentrations of halothane or isoflurane to yield a total MAC of approximately 1.25, or with supplemental fentanyl and thiopental as clinically indicated. Twitch response of the adductor pollicis muscle was elicited by supramaximal square wave pulses of 0.2 msec duration at a frequency of 0.15 Hz (Grass S44 stimulator) to the ulnar nerve and quantitated by a Grass FT10 transducer. Nine patients in each of the HAL and ISF groups received one of four doses of mivacurium (0.03, 0.05, 0.10 or 0.15 mg/kg). Ninety patients in the balanced anesthesia group received one of seven doses of mivacurium (0.03, 0.04, 0.05, 0.08, 0.15, 0.20, 0.25 mg/kg). The ED50, ED75 and ED95 of mivacurium in each group were estimated from linear regression plots of log dose versus probit of maximum percentage depression of twitch height. The ED50, ED75 and ED95 for halothane and isoflurane are 0.040, 0.053 and 0.081 and 0.037, 0.043 and 0.053, respectively. The ED50, ED75, and ED95 for the balanced group are 0.039, 0.050, and 0.073 mg/kg respectively. There was no significant difference between the slopes of the HAL and BAL inhalation anesthetic dose-response curves. The slope of the ISF group was significantly than the slope of the BAL group. Intercepts of the HAL and BAL curves were not different. The isoflurane curve's intercept was significantly less than the other groups' intercepts, lying above the halothane curve, but below the BAL curve. For the 0.05 mg/kg dose, maximum block was greater in the ISF group (89.1 +/- 2.7%, n = 9) than in the HAL (70.3 +/- 7.6%, n = 9) or BAL (67.7 +/- 6.4%, n = 9) groups. At higher doses of mivacurium, isoflurane produces a greater potentiation of neuromuscular block than halothane or balanced anesthesia. There were no significant cardiovascular changes seen in any group following mivacurium doses up to 0.15 mg/kg (approximately 2xED95).

The MLL recombinome of acute leukemias in 2013.

Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (≈ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.

Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study.

Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development-namely germinal center B-cell like and activated B-cell like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1 and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B cells. Cutoffs for each marker were obtained using receiver-operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1 and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy.