Prevention of First-Episode Psychosis in People at Clinical High Risk: A Randomized Controlled, Multicentre Trial Comparing Cognitive-Behavioral Therapy and Clinical Management Plus Low-Dose Aripiprazole or Placebo (PREVENT).

BACKGROUND: There is limited knowledge of whether cognitive-behavioral therapy (CBT) or second-generation antipsychotics (SGAs) should be recommended as the first-line treatment in individuals at clinical high risk for psychosis (CHRp). HYPOTHESIS: To examine whether individual treatment arms are superior to placebo and whether CBT is non-inferior to SGAs in preventing psychosis over 12 months of treatment. STUDY DESIGN: PREVENT was a blinded, 3-armed, randomized controlled trial comparing CBT to clinical management plus aripiprazole (CM + ARI) or plus placebo (CM + PLC) at 11 CHRp services. The primary outcome was transition to psychosis at 12 months. Analyses were by intention-to-treat. STUDY RESULTS: Two hundred eighty CHRp individuals were randomized: 129 in CBT, 96 in CM + ARI, and 55 in CM + PLC. In week 52, 21 patients in CBT, 19 in CM + ARI, and 7 in CM + PLC had transitioned to psychosis, with no significant differences between treatment arms (P = .342). Psychopathology and psychosocial functioning levels improved in all treatment arms, with no significant differences. CONCLUSIONS: The analysis of the primary outcome transition to psychosis at 12 months and secondary outcomes symptoms and functioning did not demonstrate significant advantages of the active treatments over placebo. The conclusion is that within this trial, neither low-dose aripiprazole nor CBT offered additional benefits over clinical management and placebo.

Nonintubated Surfactant Application vs Conventional Therapy in Extremely Preterm Infants: A Randomized Clinical Trial.

IMPORTANCE: Treatment of respiratory distress syndrome in premature infants with continuous positive airway pressure (CPAP) preserves surfactant and keeps the lung open but is insufficient in severe surfactant deficiency. Traditional surfactant administration is related to short periods of positive pressure ventilation and implies the risk of lung injury. CPAP with surfactant but without any positive pressure ventilation may work synergistically. This randomized trial investigated a less invasive surfactant application protocol (LISA). OBJECTIVE: To test the hypothesis that LISA increases survival without bronchopulmonary dysplasia (BPD) at 36 weeks' gestational age in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: The Nonintubated Surfactant Application trial was a multicenter, randomized, clinical, parallel-group study conducted between April 15, 2009, and March 25, 2012, in 13 level III neonatal intensive care units in Germany. The final follow-up date was June 21, 2012. Participants included 211 of 558 eligible (37.8%) spontaneously breathing preterm infants born between 23.0 and 26.8 weeks' gestational age with signs of respiratory distress syndrome. In an intention-to-treat design, infants were randomly assigned to receive surfactant either via a thin endotracheal catheter during CPAP-assisted spontaneous breathing (intervention group) or after conventional endotracheal intubation during mechanical ventilation (control group). Analysis was conducted from September 6, 2012, to June 20, 2013. INTERVENTION: LISA via a thin catheter. MAIN OUTCOMES AND MEASURES: Survival without BPD at 36 weeks' gestational age. RESULTS: Of 211 infants who were randomized, 104 were randomized to the control group and 107 to the LISA group. Of the infants who received LISA, 72 (67.3%) survived without BPD compared with 61 (58.7%) of those in the control group. The reduction in absolute risk was 8.6% (95% CI, -5.0% to 21.9%; P = .20). Intervention group infants were less frequently intubated (80 infants [74.8%] vs 103 [99.0%]; P < .001) and required fewer days of mechanical ventilation. Significant reductions were seen in pneumothorax (5 of 105 intervention group infants [4.8%] vs 13 of 103 12.6%]; P = .04) and severe intraventricular hemorrhage (11 infants [10.3%] vs 23 [22.1%]; P = .02), and the combined survival without severe adverse events was increased in the intervention group (54 infants [50.5%] vs 37 [35.6%]; P = .02; absolute risk reduction, 14.9; 95% CI, 1.4 to 28.2). CONCLUSIONS AND RELEVANCE: LISA did not increase survival without BPD but was associated with increased survival without major complications. Because major complications are related to lifelong disabilities, LISA may be a promising therapy for extremely preterm infants. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN64011614.

Induction of apoptosis and up-regulation of cellular proliferation in oral leukoplakia cell lines inside electric field.

OBJECTIVE: In dentistry, metallic alloys are used for dentures, restorative materials, and orthodontic devices. Electric voltages up to 950 mV may occur between different dental alloys in the oral cavity. This study aimed to investigate physiologic reactions of oral leukoplakia cells in vitro to electric fields. STUDY DESIGN: A human leukoplakia cell line (MSK-LEUK1), cultivated in keratinocyte growth medium (KGM-2) supplemented with growth factors in 5% CO(2) humidified air at 37°C, was exposed to electric field strength of 1-20 V/m for 24 hours in a custom-made pulse chamber. The cells were then analyzed for proliferation with the use of BrdU assay and for apoptosis with the use of TUNEL assay. Findings were assessed with the use of fluorescent microscopy. Ultrastructural changes were studied by transmission electron microscopy. RESULTS: Electric field strength of 1-10 V/m led to up-regulation of cell proliferation rate from 10.64% to 44.06% (P = .0001). The apoptotic index increased significantly (P = .0001) from 20.03% at 1 V/m to 46.56% at 10 V/m. Individual cell keratinization was seen in leukoplakia cells treated with 16 V/m. CONCLUSIONS: Oral galvanism induces subcellular changes in oral precancer cells in vitro that closely simulate some of the morphologic features of oral squamous cell carcinoma cells in vivo.

Remifentanil/midazolam versus fentanyl/midazolam for analgesia and sedation of mechanically ventilated neonates and young infants: a randomized controlled trial.

PURPOSE: Common opioids for analgesia and sedation of mechanically ventilated infants may tend to accumulate and cause prolonged sedation with an unpredictable extubation time. Remifentanil is a promising option due to its unique pharmacokinetic properties, which seem to be valid in adults as well as in infants. METHODS: In this double-blind, randomized, controlled trial mechanically ventilated neonates and young infants (<60 days) received either a remifentanil or fentanyl-based analgesia and sedation regimen with low dose midazolam. The primary endpoint of the trial was the extubation time following discontinuation of the opioid infusion. Secondary endpoints included efficacy and safety aspects. RESULTS: Between November 2006 and March 2010, we screened 431 mechanically ventilated infants for eligibility. The intention to treat group included 23 infants who were assigned to receive either remifentanil (n = 11) or fentanyl (n = 12). Although this was designed as a pilot study, median extubation time was significantly shorter in the remifentanil group (80.0 min, IQR = 15.0-165.0) compared to the fentanyl group (782.5 min, IQR = 250.8-1,875.0) (p = 0.005). Remifentanil and fentanyl provided comparable efficacy with more than two-thirds of the measurements indicating optimal analgesia and sedation (66.4 and 70.2 %, respectively; p = 0.743). Overall, both groups had good hemodynamic stability and a comparably low incidence of adverse events. CONCLUSIONS: As neonates and young infants have a decreased metabolism of common opioids like fentanyl and are more prone to respiratory depression, remifentanil could be the ideal opioid for analgesia and sedation of mechanically ventilated infants.

Rationale and baseline characteristics of PREVENT: a second-generation intervention trial in subjects at-risk (prodromal) of developing first-episode psychosis evaluating cognitive behavior therapy, aripiprazole, and placebo for the prevention of psychosis.

Antipsychotics, cognitive behavioral therapy (CBT), and omega-3-fatty acids have been found superior to control conditions as regards prevention of psychosis in people at-risk of first-episode psychosis. However, no large-scale trial evaluating the differential efficacy of CBT and antipsychotics has been performed yet. In PREVENT, we evaluate CBT, aripiprazole, and clinical management (CM) as well as placebo and CM for the prevention of psychosis in a randomized, double-blind, placebo-controlled trial with regard to the antipsychotic intervention and a randomized controlled trial with regard to the CBT intervention with blinded ratings. The hypotheses are first that CBT and aripiprazole and CM are superior to placebo and CM and second that CBT is not inferior to aripiprazole and CM combined. The primary outcome is transition to psychosis. By November 2010, 156 patients were recruited into the trial. The subjects were substantially functionally compromised (Social and Occupational Functioning Assessment Scale mean score 52.5) and 78.3% presented with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition axis I comorbid diagnosis. Prior to randomization, 51.5% of the participants preferred to be randomized into the CBT arm, whereas only 12.9% preferred pharmacological treatment. First, assessments of audiotaped treatment sessions confirmed the application of CBT-specific skills in the CBT condition and the absence of those in CM. The overall quality rating of the CBT techniques applied in the CBT condition was good. When the final results of the trial are available, PREVENT will substantially expand the current limited evidence base for best clinical practice in people at-risk (prodromal) of first-episode psychosis.

In vitro measurements of flow using multislice computed tomography (MSCT).

To examine in vitro whether an assessment of flow in normal and obstructed vessels is essentially possible using modern multislice CT-scanners. An experimental model allowed known stenoses to be perfused at defined flow rates. Aorta and coronary arteries were simulated by silicone tubes. A pulsatile pump was used to perfuse water through the system with intermittent injection of a bolus of radio-opaque contrast agent. CT-measurements were carried out with slice orientation perpendicular to the tubes. 50-90% concentric stenoses were examined 5 times at 4 different stenosis slice distances. A mathematical algorithm calculated the temporal density changes within a ROI in the tube cross-sections. Quantitative assessment of the data simultaneously acquired with the 16-slice system for the "coronary" and "aortal" time-density curves showed that the model allowed for exclusion of a ≥ 80% stenosis grade with a 99% probability when the slopes of the density increase quotient was > 0.79; a stenosis grade of ≥ 90% could be excluded when the slopes of the density increase quotient was > 0.52. A Quotient > 0.94 for "peak density" was associated with a 99% probability of a stenosis grade ≥ 70%. The 64-slice system allowed stenosis grades of ≥ 80% to be discriminated from lower grades. The general feasibility of the in vitro approach was verified in an in vivo model. The spatial, contrast and temporal resolution of CT scanners with at least 16 detector rows enables qualitative and semiquantitative assessment of stenotic changes in flow.

Image quality of digital direct flat-panel mammography versus an indirect small-field CCD technique using a high-contrast phantom.

OBJECTIVE: To compare the detection of microcalcifications on mammograms of an anthropomorphic breast phantom acquired by a direct digital flat-panel detector mammography system (FPM) versus a stereotactic breast biopsy system utilizing CCD (charge-coupled device) technology with either a 1024 or 512 acquisition matrix (1024 CCD and 512 CCD). MATERIALS AND METHODS: Randomly distributed silica beads (diameter 100-1400 µm) and anthropomorphic scatter bodies were applied to 48 transparent films. The test specimens were radiographed on a direct digital FPM and by the indirect 1024 CCD and 512 CCD techniques. Four radiologists rated the monitor-displayed images independently of each other in random order. RESULTS: The rate of correct positive readings for the "number of detectable microcalcifications" for silica beads of 100-199 µm in diameter was 54.2%, 50.0% and 45.8% by FPM, 1024 CCD and 512 CCD, respectively. The inter-rater variability was most pronounced for silica beads of 100-199 µm in diameter. The greatest agreement with the gold standard was observed for beads >400 µm in diameter across all methods. CONCLUSION: Stereotactic spot images taken by 1024 matrix CCD technique are diagnostically equivalent to direct digital flat-panel mammograms for visualizing simulated microcalcifications >400 µm in diameter.

Meta-analysis for the effect of medical therapy vs. placebo on recovery of idiopathic sudden hearing loss.

OBJECTIVES: To estimate the effect of recovery of idiopathic sudden hearing loss under placebo (first aim) and under medical therapy (second aim). STUDY DESIGN: Systematic review and meta-analysis. METHODS: A total of 1,674 studies published between January 1974 and April 2009 were found following suggestions in the Cochrane Handbook for Systematic Reviews. After filtering by criteria of Cochrane Collaboration, four trials remained for continuous and two for dichotomous data. RESULTS: Using Review Manager, weighted mean difference as well as standardized mean effect of hearing recovery were calculated and pooled. The values for weighted mean difference of hearing gain in dB were 0.79, 95% confidence interval (CI) (-2.04-3.61) and for standardized mean effect 0.06, 95% CI (-0.13-0.24), respectively, which computationally favors active treatment, but statistically is not significantly different from no effect (0 dB). This was in accordance to the comparison of descriptive means between recovery under placebo with 14.3 dB and active treatment with 15.8 dB hearing gain. Treatment effect of dichotomous data (hearing gain vs. no hearing gain) suggested a statistically significant better outcome for active treatment; the odds ratio (OR) [fixed] is 2.18 (1.06-4.46). CONCLUSIONS: In five different statistical analysis methods used, treatment effect of medical therapy was slightly better than recovery under placebo in which spontaneous recovery could be assumed, but no significant effect was detected. Against the background of recovery under placebo of 14.3 dB vs. 15.8 dB hearing gain of active treatment as averages of all measured frequencies, recovery under placebo seems not to have worse outcome than recovery under medical therapy.

Interspinous implants (X Stop, Wallis, Diam) for the treatment of LSS: is there a correlation between radiological parameters and clinical outcome?

Neurogenic intermittent claudication, caused by lumbar spinal stenosis (LSS), usually occurs after the age of 50 and is one of the most common degenerative spinal diseases in the elderly. Among patients over the age of 65 with LSS, open decompression is the most frequently performed spinal operation. The recently introduced interspinous spacers are a new alternative under discussion. In this retrospective study, we reviewed medical records and radiographs of patients with LSS and NIC treated from June 2003 to June 2007. All included patients (n = 129) were treated with interspinous implants (X Stop Wallis, or Diam). Evaluations of pain, using a visual analog scale (VAS), and radiographic signs, using two-plane X-rays of the lumbar spine, were performed preoperatively (preop), postoperatively (postop) and after discharge (FU 2-3). Gender ratio (m:w) was 1.1:1. Mean age of the patients was 60.8 +/- 16.3 years. Foraminal height, foraminal width, foraminal cross-sectional area, intervertebral angle, as well as anterior and posterior disc height changed significantly (P < 0.0001) after implantation of the interspinous device. Postoperatively, symptom relief (VAS) was significant (P < 0.0001). The X Stop implant improved (in some cases significantly) the radiographic parameters of foraminal height, width, and cross-sectional area, more than the Diam and Wallis implants; however, there was no significant difference among the three regarding symptom relief. FU 1 was on average 202.3 +/- 231.9 and FU 2 527.2 +/- 377.0 days postoperatively. During FU, the radiological improvements seemed to revert toward initial values. Pain (VAS) did not increase despite this "loss of correction." There was no correlation between age and symptom improvement. There was only very weak correlation between the magnitude of radiographic improvement and the extent of pain relief (VAS). The interspinous implant did not worsen low-grade spondylolisthesis. Provided there is a strict indication and fusion is not required, implantation of an interspinous spacer is a good alternative to treat LSS. The interspinous implant offers significant, longlasting symptom control, even if initially significant radiological changes seem to revert toward the initial values ("loss of correction").

Long-term outcome and prognostic factors in early-stage nodal low-grade non-hodgkin's lymphomas treated with radiation therapy.

PURPOSE: Retrospective analysis of therapy results in patients with stage I-II and limited stage III nodal low-grade non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: The present retrospective study covers 65 patients treated between 1988 and 2006 at the Department of Radiation Oncology, University of Cologne, Germany. 50 patients were treated with radiotherapy alone (EF [extended field]: n = 35, IF/REG [involved field/regional field]: n = 9, TNI/TLI [total nodal/total lymphatic]: n = 6), 15 patients additionally received chemotherapy. Median age was 58 years. 58 patients presented with centroblastic-centrocytic or follicular lymphomas, seven patients had centrocytic lymphomas. Apart from overall and relapse-free survival, relapse patterns were examined and the impacts of patient characteristics and therapy modalities were analyzed. RESULTS: After a median follow-up of 9.1 years, overall 5-year and 10-year survival was 86% and 55%, relapse-free survival was 55% and 37%, respectively. Relapses occurred in 28 patients during the observation period. Overall survival was favorably influenced by low patient age (p = 0.037), centroblastic-centrocytic/follicular histology (p = 0.006), and early disease stage (p = 0.045). Favorable prognostic factors for relapse-free survival were low patient age (p = 0.035) and centroblastic-centrocytic/follicular histology (p = 0.001). CONCLUSION: Radiotherapy of early-stage low-grade NHL is a curative therapy option, particularly in younger patients and patients with follicular histology. Relapse analysis confirmed the benefits of total nodal or total lymphatic irradiation, although the small number of patients needs to be considered.

Image quality of digital direct flat-panel mammography versus an analog screen-film technique using a low-contrast phantom.

OBJECTIVE: The objective of our study was to compare the detectability and distinguishability of simulated soft-tissue opacities of 50 variants of an anthropomorphic breast phantom in mammograms acquired with a digital direct flat-panel detector versus an analog system; we also compared the image settings "analog film," "digital film," and "digital monitor." MATERIALS AND METHODS: The studies were performed on digital (Lorad Selenia) and analog (Mammomat 3) mammography systems. Four hundred fifty silicone cubes devised with different randomly distributed columns, holes, or both columns and holes (diameter, 3-7 mm; height, 0.5-4.0 mm) were used as test bodies. One experimental series was performed with a silicone scatter body and one with a silicone and an anthropomorphic ground-meat scatter body. All x-rays were obtained at identical settings and exposures. Four radiologists rated the films and monitor-displayed images independently of each other in randomized order on a standardized electronic questionnaire. RESULTS: The digital monitor technique generally scored better than digital film viewing and analog readings. The McNemar test for multiple paired comparisons mostly yielded a p value of < 0.0005. The smallest volume category counted as the most valid test scenario for all raters, where the percentage of correct positive findings ranged between 30% and 58% (analog technique), 43% and 68% (digital film viewing), and 55% and 66% (monitor viewing). The corresponding accuracy rates were 77-93%, 75-95%, and 81-85%, respectively, with kappa values of 0.2-0.5 (analog) and 0.3-0.6 (digital) for comparing the gold standard with raters' evaluations. CONCLUSION: Digital flat-panel mammography is superior to the analog screen-film method for the detection of simulated opacities.

Early surfactant in spontaneously breathing with nCPAP in ELBW infants--a single centre four year experience.

OBJECTIVE: To evaluate whether the experience with a method to administer surfactant during spontaneous breathing with nasal continuous positive airway pressure (nCPAP) as primary respiratory support in infants with respiratory distress syndrome (RDS) influences the frequency of its use and affects the outcome of patients. METHODS: All inborn extremely low birthweight (ELBW) infants treated after introduction of the method were retrospectively studied (n=196). The entire observational period was divided into four periods (periods 1-4) and compared with a control period (period 0) (n=51). Primary respiratory support, demographics, prenatal risks and outcomes were compared. RESULTS: There were no changes in demographics or prenatal risks over time. The choice of nCPAP as initial airway management significantly increased from 69% to 91% and for nCPAP with surfactant from 75% to 86%. The rate of nCPAP failure decreased from 46% to 25%. Survival increased significantly between periods 0 and 1 from 76% to 90% and survival without bronchopulmonary dysplasia (BPD) rose from 65% to 80%. No changes in nonpulmonary outcomes were observed. CONCLUSION: The success of nCPAP increased with increasing use of nCPAP with surfactant. Simultaneously, mortality decreased without deterioration of other outcomes indicating that the use of surfactant in spontaneous breathing with nCPAP could be beneficial.

Prospective volumetric analysis of gallbladders in critically ill newborns: the impact of nutrition.

BACKGROUND: Neonatal reference values of gallbladder size have been assessed in healthy newborns with enteral feeding regimen. Their applicability to critically ill patients under total parenteral nutrition (TPN) remains to be questioned. OBJECTIVE: Our aim was to evaluate the impact of short-term TPN versus enteral nutrition (EN), gender and birth weight on neonatal gallbladder volume. METHOD: A prospective pilot study was initiated with a single sonographic investigator blinded towards feeding regimen. In total, 61 neonates (33 males, 28 females) were consecutively enrolled on the intensive care unit; 31 newborns were examined both under TPN and bolus EN (breast milk/formula). Patients with malformations of the biliary tract were excluded. Prior to ultrasound examinations, a minimum fasting period of 2 h was maintained. Sonographic measurements of gallbladder length, depth and width were performed to calculate gallbladder volume using the ellipsoid formula. RESULTS: Neonatal gallbladder volume differed significantly between TPN and EN (p < 0.001). Using TPN, range of gallbladder length, width and volume exceeded reference values. Birth weight was weakly correlated with gallbladder volume (correlation index 0.3776, p = 0.01). We found no gender-related differences. CONCLUSIONS: Neonatal gallbladder volume under TPN was significantly larger compared to EN. Using TPN, gallbladder dimensions exceeded reference values without causing clinical complications. The benign course of gallbladder enlargement required no specific medication or surgical treatment.

Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer.

Molecular prognostic indicators for oropharyngeal squamous cell carcinoma (OSCC), including HPV-DNA detection, epidermal growth factor receptor (EGFR) and p16 expression, have been suggested in the literature, but none of these are currently used in clinical practice. To compare these predictors, 106 newly diagnosed OSCC for the presence of HPV-DNA and expression of p16 and EGFR were analyzed. The 5-year disease-free survival (DFS) and overall survival (OS) were calculated in relation to these markers and a multivariate Cox analysis was performed. Twenty-eight percent of the cases contained oncogenic HPV-DNA and 30% were positive for p16. The p16 expression was highly correlated with the presence of HPV-DNA (p < 0.001). Univariate analysis of the 5-year DFS revealed a significantly better outcome for patients with p16-positive tumors (84% vs. 49%, p = 0.009). EGFR-negative tumors showed a tendency toward a better prognosis in DFS (74% vs. 47%, p = 0.084) and OS (70% vs. 45%, p = 0.100). Remarkable and highly significant was the combination of p16 and EGFR expression status, leading to 5-year DFS of 93% for p16+/EGFR- tumors vs. 39% for p16-/EGFR+ tumors (p = 0.003) and to a 5-year OS of 79% vs. 38%, respectively (p = 0.010). In multivariate analysis p16 remained a highly significant prognostic marker for DFS (p = 0.030) showing a 7.5-fold increased risk for relapse in patients with p16-negative tumors. Our data indicate that p16 expression is the most reliable prognostic marker for OSCC and further might be a surrogate marker for HPV-positive OSCC. HPV+/p16+ tumors tended to have decreased EGFR expression, but using both immunohistological markers has significant prognostic implications.

Image quality of digital direct flat-panel mammography versus an analog screen-film technique using a phantom model.

OBJECTIVE: The objective of our study was to compare the detection and distinguishability of microcalcifications on mammograms obtained with a digital direct flat-panel detector versus an analog system using an anthropomorphic breast phantom. MATERIALS AND METHODS: Studies were performed with a digital mammography system (Selenia) and an analog mammography system (Mammomat 3). Sixty-five transparent films were used as test specimens. Randomly distributed round and heterogeneous silicate particles (diameter, 100-1,400 microm) and an anthropomorphic scatter body were applied to the films. All radiographs were taken at identical settings and exposures. Six radiologists rated the films and monitor-displayed images independently of each other in random order on a standardized electronic questionnaire. RESULTS: Interpretations based on monitor reading produced superior results over those based on digital image reading and analog film reading. In 41.1% (95% CI, 38.7-43.5%) of all the monitor readings, 20.2% (18.2-22.2%) of all digital images, and 19.6% (17.6-21.6%) of all analog films, the number of detectable microcalcifications agreed with the gold standard method. The diameter of visible microcalcifications was interpreted correctly in 35.6% (33.2-38.0%) of monitor readings, 19.0% (17.1-21.0%) of digital images, and 21.0% (18.9-23.0%) of analog films; and microcalcification shape was interpreted correctly in 53.8% (51.4-56.3%) of monitor readings, 28.2% (26.0-30.4%) of digital images, and 28.3% (26.0-30.5%) of analog films. Microcalcification number and size were underestimated more frequently than overestimated. Regardless of display medium, accuracy increased proportionately with the diameter of the simulated microcalcifications for all evaluation variables. CONCLUSION: Digital flat-panel mammography is superior to the analog screen-film method for the detection and morphologic characterization of microcalcifications larger than 200 microm in diameter when the display medium is a monitor.

Prospective sonographic evaluation of fentanyl side effects on the neonatal gallbladder.

OBJECTIVE: In an effort to minimise the stress and pain of mechanically ventilated neonates, the application of opioids has increased markedly. Abdominal adverse effects of opioid analgesics are constipation and increased pressure in the biliary system. Our aim was to evaluate the impact of continuous intravenous infusion of fentanyl on the volume of the neonatal gallbladder and to assess potential gastrointestinal side effects. METHODS: We prospectively matched pairs of 40 mechanically ventilated neonates (28-42 gestational weeks) under total parenteral nutrition and midazolam sedation. One group (20 patients) received continuous fentanyl infusions (dose 0.5-2 microg kg(-1) h(-1)) the other group (20 patients) served as controls. Sonographic measurements of gallbladder length, depth and width were performed to calculate gallbladder volume using the ellipsoid method. Repeated ultrasound images, date of meconium release and serum bilirubin levels were documented. RESULTS: Fentanyl application was not associated with gallbladder sludge/stones, gallbladder hydrops, hyperbilirubinemia or prolonged meconium release. Neonatal gallbladder length, width and volume did not differ significantly (data expressed as mean, standard deviation, median, interquartile range: length (cm) 3.16+/-0.68, 3.3, 0.675 vs 3.06+/-0.62, 3.3, 1.1; P=0.645; width (cm) 1.02+/-0.23, 1.0, 0.28 vs 0.89+/-0.27, 0.9, 0.38, P=0.12; volume (cm(3)) 1.52+/-0.67, 1.7, 0.86 vs 1.22+/-0.77, 1.09, 1.19, P=0.20). CONCLUSION: In our study fentanyl caused no major complications in the biliary system and intestine of ventilated preterm and term neonates. Sonographic investigations of the gallbladder under fentanyl treatment may be dispensable. Further investigations are required to assess adverse gastrointestinal effects.

Intensity of androgen and epidermal growth factor receptor immunoreactivity in samples of radical prostatectomy as prognostic indicator: correlation with clinical data of long-term observations.

PURPOSE: We analyzed the potential prognostic significance of the immunohistochemical expression of androgen and growth factor receptors determined in prostatectomy specimens of patients with prostate cancer. MATERIALS AND METHODS: A cohort of 211 patients with locally confined prostate cancer treated with radical prostatectomy with or without antiandrogen pretreatment between January 1, 1990 and August 31, 1996 was observed prospectively. Prostatectomy samples were processed immunohistochemically to visualize androgen and growth factor receptors, of which immunoreaction intensity was scored relative to that of positive control tissue. Clinical postoperative data were processed using the Kaplan-Meier method, log rank test, and univariate and multivariate explorative Cox modeling to evaluate the contribution to overall and relapse-free survival. RESULTS: There were statistical dependencies between the androgen receptor and epidermal growth factor receptor staining indexes. Following data stratification according to the epidermal growth factor receptor staining index the prognosis associated with a low androgen receptor staining index was worse than that with a higher androgen receptor staining index. Cox regression analysis for relapse-free survival confirmed that the risk factors low androgen receptor and increased epidermal growth factor receptor staining were associated with significantly increased relative risk. Univariate Kaplan-Meier analysis showed that patients with grade 3 carcinoma had a worse prognosis than those with better differentiated carcinoma, whereas antiandrogen pretreatment had no influence on overall survival or relapse-free survival. CONCLUSIONS: Using a multivariate proportional hazards regression model for data on a cohort of 211 patients with 68 showing relapse/progress or death from disease a low intensity of androgen receptor staining indicated a poor prognosis.

The effect of mitomycin C in reducing epidural fibrosis after lumbar laminectomy in rats.

OBJECT: Extensive epidural fibrosis after lumbar spine surgery might be an important underlying cause of failed-back syndrome. Based on previously obtained data, the effect of mitomycin C (MMC) in a concentration of 0.1 mg/ml on spinal epidural fibrosis in a rat laminectomy model was investigated in a large series. METHODS: Eighty adult Wistar rats underwent lumbar laminectomy. In 40 rats, MMC in a concentration of 0.1 mg/ml was locally applied to the laminectomy sites. No similar treatment was performed in the other 40 rats. At intervals from one to 12 weeks after laminectomy, both macroscopic and histological evaluations were performed. For radiological investigation, 10 rats underwent magnetic resonance (MR) imaging at 6 weeks postoperatively. Furthermore, the concentration of MMC in cerebrospinal fluid (CSF) and serum was determined 12 hours postoperatively in seven rats. Due to ease of absorption, high levels of MMC were rapidly detectable in serum, whereas the values obtained from the CSF were markedly lower. In the majority of MMC-treated laminectomy sites, epidural scarring was significantly reduced and dural adhesions were absent, in comparison with control sites (p < 0.001), as confirmed by MR images. Accordingly, the macroscopic dissection of epidural fibrous tissue to reexpose the dura mater was performed more easily and without severe bleeding in these rats. The healing of skin and the lumbar fascia was not affected, and dural leakage was not observed. All control sites showed dense epidural fibrosis with marked dural adherence. CONCLUSIONS: In this experimental model, it was shown that locally applied MMC in a concentration of 0.1 mg/ml effectively reduces epidural fibrosis and dural adherence without side effects in rats that underwent lumbar laminectomy.

The role of mitomycin C in reducing recurrence of epidural fibrosis after repeated operation in a laminectomy model in rats.

OBJECT: Extensive peridural fibrosis after lumbar spine surgery may contribute to poor outcome and recurrent symptoms leading to repeated operation. Secondary procedures are considerably hampered by the presence of scar tissue. Moreover, after excision of the peridural scar, the fibrous tissue may recur, leading to unsuccessful surgical outcome. Mitomycin C (MMC), an alkylating antibiotic substance isolated from Streptomyces caespitosus, potentially suppresses fibroblast proliferation after surgical intervention. The authors investigated the effect of MMC on the reformation of epidural fibrosis in a laminectomy model in rats. METHODS: Twenty-four Wistar rats underwent a repeated lumbar laminectomy 3 months after the first operation. In 12 rats, MMC in a concentration of 1 mg/ml was locally applied to the laminectomy site. No treatment was performed in the control group of the other 12 rats. All rats underwent clinical evaluation. Mobility ratings and any evidence of neurological deficit were recorded. Twelve weeks after the second operation, the animals were killed for histological examination. The extent of epidural fibrosis and dural adherence was evaluated. All MMC-treated animals showed reduced epidural scarring, compared with the control group. In nine MMC-treated rats (75%), dural adhesions were moderate. In contrast, all control sites showed dense epidural fibrosis with marked dural adherence. No side effects of the treatment were observed. CONCLUSIONS: In this experimental study, MMC in a concentration of 1 mg/ml locally applied significantly reduced recurrence of epidural fibrosis and dural adhesions without any side effects after repeated spinal surgery in a laminectomy model in rats.

Incidence of postradioiodine immunogenic hyperthyroidism/Graves' disease in relation to a temporary increase in thyrotropin receptor antibodies after radioiodine therapy for autonomous thyroid disease.

BACKGROUND: The aim of the study was to analyze retrospectively the incidence of postradioiodine immunogenic hyperthyroidism/Graves' disease in relation to a temporary increase in TSH-receptor antibodies without overt hyperthyroidism after radioiodine therapy for autonomous thyroid disease. PATIENTS AND METHODS: Between May 2000 and May 2003 all patients (n = 1,357) who had undergone radioiodine therapy for autonomous thyroid disease were retrospectively analyzed for development of postradioiodine immunogenic hyperthyroidism. On pretreatment evaluation 565 of 1,357 patients (41.6%) had unifocal autonomous thyroid disease (UFA), 693 of 1,357 patients (51.1%) had multifocal autonomous thyroid disease (MFA), and 99 of 1,357 patients (7.3%) had diffuse thyroid disease (DISS). Free triiodothyronine (FT(3)), free thyroxine (FT(4)), thyrotropin (TSH), and thyroid antibodies were measured. Ultrasound examinations and thyroid scintigraphy were performed before and after radioiodine therapy. A sensitive assay with the human TSH receptor as antigen was chosen for measurement of the TSH receptor antibody and the study was limited to analysis of data obtained since introduction of this assay. RESULTS: Fifteen of 1,357 patients (1.1%) (UFA, 8/565 = 1.4%; MFA, 6/693 = 0.9%; DISS 1/99 = 1.0%) developed postradioiodine hyperthyroidism between 1 and 13 months after radioiodine therapy with clinically overt hyperthyroidism and an elevation of TSH receptor antibodies. Patients with elevated thyroid peroxidase (TPO) antibodies before radioiodine therapy had an almost 10-fold (6/57 patients =10.5%) higher risk of developing postradioiodine immunogenic hyperthyroidism. Thirteen of 999 patients (1.3%) with antibody measurements after radioiodine therapy (UFA, 2/421 = 0.5%; MFA, 9/494 = 1.8%, DISS, 2/84 = 2.4%) had increased levels of TSH receptor antibodies and, to some extent, TPO antibodies without development of clinically overt hyperthyroidism. CONCLUSIONS: There is an estimated 1.1% risk of developing postradioiodine immunogenic hyperthyroidism/Graves' disease in patients undergoing radioiodine therapy for autonomous thyroid disease and this increases approximately 10-fold when TPO antibody levels are elevated before radioiodine therapy. Furthermore, there is an estimated 1.3% risk of a temporary increase of TSH receptor antibodies after radioiodine therapy for autonomous thyroid disease without development of clinically overt hyperthyroidism.