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Rationale: The intravenous anesthetic propofol is known to induce positive mood effects during routine clinical use, suggesting it might be repurposed as an antidepressant, but also raising concerns about abuse potential. How propofol's acute effects vary by dose and with repeated infusions is unknown., Objectives: This exploratory analysis aimed to (1) compare the immediate mood effects of propofol administered at two different doses, (2) describe how those mood effects change with repeated infusions, and (3) evaluate whether acute mood improvement predicts later antidepressant response., Methods: Twenty-four adults with moderate-to-severe treatment-resistant depression were randomized into two dosing groups. Six low- or high-dose propofol infusions were administered under blinded conditions over a two-week period. Self-reported mood states were recorded before and after each infusion using the Positive and Negative Affect Schedule (PANAS-X). Abuse potential was evaluated with the Drug Effects Questionnaire (DEQ-5)., Results: At the first infusion, propofol induced acute improvements in PANAS-X Sadness, Fear, Joviality, and Serenity scales (p < 0.002), independent of dose. Over the series of six infusions, acute changes in Sadness, Fear, and Joviality, but not Serenity, diminished with infusion number (p < 0.002). The DEQ-5 "want more" rating decreased across infusions (p = 0.002). Changes in PANAS-X scales with the first infusion did not predict later improvement in depression severity (p > 0.05)., Conclusion: Cumulative changes in mood states observed with repeated infusions suggest that propofol engages adaptive mechanisms in mood circuitry. Subjective responses with repeated infusions do not indicate increasing potential for abuse in this patient population., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Nucleic acid assays are not typically deployable in point-of-care settings because they require costly and sophisticated equipment for the control of the reaction temperature and for the detection of the signal. Here we report an instrument-free assay for the accurate and multiplexed detection of nucleic acids at ambient temperature. The assay, which we named INSPECTR (for internal splint-pairing expression-cassette translation reaction), leverages the target-specific splinted ligation of DNA probes to generate expression cassettes that can be flexibly designed for the cell-free synthesis of reporter proteins, with enzymatic reporters allowing for a linear detection range spanning four orders of magnitude and peptide reporters (which can be mapped to unique targets) enabling highly multiplexed visual detection. We used INSPECTR to detect a panel of five respiratory viral targets in a single reaction via a lateral-flow readout and ~4,000 copies of viral RNA via additional ambient-temperature rolling circle amplification of the expression cassette. Leveraging synthetic biology to simplify workflows for nucleic acid diagnostics may facilitate their broader applicability at the point of care., (© 2023. The Author(s).)

Aim: The OPTIM1SE study observed long-term real-world outcomes of cetuximab-based infusional 5-fluorouracil (5-FU) regimens for first-line treatment of metastatic colorectal cancer (mCRC) across Asia-Pacific and Middle East regions, aiming to characterize their use, effectiveness, and safety in routine practice., Methods: OPTIM1SE was a prospective, open-label, observational study. Patients with untreated KRAS wild-type mCRC and distant metastases were treated per locally approved labels and monitored for 3 years via electronic medical records. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS)., Results: From November 19, 2013, to June 30, 2016, 520 patients were enrolled in 51 sites. Patients were mostly male (61.2%), with a mean age of 58.5 (±12.0) years; 420 patients received leucovorin, 5-FU, and irinotecan-based regimens and 94 received leucovorin, 5-FU, and oxaliplatin. The most common primary tumor site was the rectum (38.8%), with liver metastases (65.0%). ORR was 45.4% (95% CI, 41.1%-49.7%), including 26 patients (5.0%) with a complete response. Median PFS was 9.9 months (95% CI, 8.2-11.0); median OS (mOS) was 30.8 months (95% CI, 27.9-33.6). Higher mOS was associated with tumors of left compared with right-sided origin (hazard ratio, 0.69 [95% CI, 0.49-0.99]); higher ORR was also associated with liver metastases compared with all other metastases (55.4% vs. 40.2%). Adverse events were consistent with the known safety profile of cetuximab., Conclusion: Cetuximab-based 5-FU regimens were effective first-line treatments for mCRC in routine practice, particularly in patients with left-sided disease and liver metastases only., (© 2023 The Authors. Asia-Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

Conditional gene regulation in Drosophila through binary expression systems like the LexA-LexAop system provides a superb tool for investigating gene and tissue function. To increase the availability of defined LexA enhancer trap insertions, we present molecular, genetic, and tissue expression studies of 301 novel Stan-X LexA enhancer traps derived from mobilization of the index SX4 line. This includes insertions into distinct loci on the X, II, and III chromosomes that were not previously associated with enhancer traps or targeted LexA constructs, an insertion into ptc, and seventeen insertions into natural transposons. A subset of enhancer traps was expressed in CNS neurons known to produce and secrete insulin, an essential regulator of growth, development, and metabolism. Fly lines described here were generated and characterized through studies by students and teachers in an international network of genetics classes at public, independent high schools, and universities serving a diversity of students, including those underrepresented in science. Thus, a unique partnership between secondary schools and university-based programs has produced and characterized novel resources in Drosophila, establishing instructional paradigms devoted to unscripted experimental science., Competing Interests: Conflicts of interest statement The author(s) declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Burst suppression is a brain state consisting of high-amplitude electrical activity alternating with periods of quieter suppression that can be brought about by disease or by certain anesthetics. Although burst suppression has been studied for decades, few studies have investigated the diverse manifestations of this state within and between human subjects. As part of a clinical trial examining the antidepressant effects of propofol, we gathered burst suppression electroencephalographic (EEG) data from 114 propofol infusions across 21 human subjects with treatment-resistant depression. This data was examined with the objective of describing and quantifying electrical signal diversity. We observed three types of EEG burst activity: canonical broadband bursts (as frequently described in the literature), spindles (narrow-band oscillations reminiscent of sleep spindles), and a new feature that we call low-frequency bursts (LFBs), which are brief deflections of mainly sub-3-Hz power. These three features were distinct in both the time and frequency domains and their occurrence differed significantly across subjects, with some subjects showing many LFBs or spindles and others showing very few. Spectral-power makeup of each feature was also significantly different across subjects. In a subset of nine participants with high-density EEG recordings, we noted that each feature had a unique spatial pattern of amplitude and polarity when measured across the scalp. Finally, we observed that the Bispectral Index Monitor, a commonly used clinical EEG monitor, does not account for the diversity of EEG features when processing the burst suppression state. Overall, this study describes and quantifies variation in the burst suppression EEG state across subjects and repeated infusions of propofol. These findings have implications for the understanding of brain activity under anesthesia and for individualized dosing of anesthetic drugs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jones, Lybbert, Euler, Huang, Lunt, Richards, Jessop, Larson, Odell, Kuck, Tadler and Mickey.)

Study Design: Prospective randomized Food and Drug Administration investigational device exemption clinical trial., Objective: The purpose of the present study is to report the 1-year clinical and radiographic outcomes and safety profile of patients who underwent lumbar facet arthroplasty through implantation of the Total Posterior Spine System (TOPS) device., Summary of Background Data: Lumbar facet arthroplasty is one proposed method of dynamic stabilization to treat grade-1 spondylolisthesis with stenosis; however, there are currently no Food and Drug Administration-approved devices for facet arthroplasty., Methods: Standard demographic information was collected for each patient. Radiographic parameters and patient-reported outcome measures were assessed preoperatively and at regular postoperative intervals. Complication and reoperation data were also collected for each patient., Results: At the time of this study, 153 patients had undergone implantation of the TOPS device. The mean surgical time was 187.8 minutes and the mean estimated blood loss was 205.7cc. The mean length of hospital stay was 3.0 days. Mean Oswestry Disability Index, Visual Analog Score leg and back, and Zurich Claudication Questionnaire scores improved significantly at all postoperative time points ( P >0.001). There were no clinically significant changes in radiographic parameters, and all operative segments remained mobile at 1-year follow-up. Postoperative complications occurred in 11 patients out of the 153 patients (7.2%) who underwent implantation of the TOPS device. Nine patients (5.9%) underwent a total of 13 reoperations, 1 (0.6%) of which was for device-related failure owing to bilateral L5 pedicle screw loosening., Conclusions: Lumbar facet arthroplasty with the TOPS device demonstrated a statistically significant improvement in all patient-reported outcome measures and the ability to maintain motion at the index level while limiting sagittal translation with a low complication rate., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Patients with neurogenic urinary incontinence due to an incompetent outlet may be offered bladder neck reconstruction, but the quest for the perfect surgical-outlet procedure continues. Our aim was to characterize continence and complications after modified Mitchell urethral lengthening/bladder neck reconstruction (MMBNR) with sling and to introduce a modification of exposure that facilitates subsequent steps of MMBNR., Methods: A single-institution, retrospective cohort study of patients who underwent primary MMBNR between May 2011 and July 2019 was performed. Data on demographics, urodynamic testing, operative details, unanticipated events, continence, bladder changes, and additional procedures were collected. A 2013 modification that permits identification of the incompetent bladder neck prior to urethral unroofing was applied to the last 17 patients. The trigone and bladder neck are exposed via an oblique low anterolateral incision on the bladder. Ureteral reimplantation is not routinely performed. Focal incision of the endopelvic fascia after posterior plate creation limits breadth of blunt dissection for sling placement. Descriptive statistics were utilized., Results: A total of 25 patients (13 females) had MMBNR with sling at a median age of 10 years [interquartile range (IQR) 8-11]. Bladder augmentation was performed concurrently in 14/25 (56%) patients. At a median of 5.0 (IQR 3.9-7.5) years follow-up after MMBNR, 9/11 (82%) without bladder augmentation and 13/14 (93%) with bladder augmentation had no leakage per urethra during the day without further continence procedures. Of the three patients with persistent incontinence, two achieved continence with bladder wall Botox injection (overall continence 24/25, 96%). New and recurrent vesicoureteral reflux was noted in five patients and one patient, respectively. Two patients required subsequent bladder augmentation for pressures and one other will likely require it. None have required bladder neck closure or revision., Conclusion: MMBNR with sling provides promising continence per urethra in neurogenic bladder with low need for secondary continence procedures. Ongoing modifications may achieve elusive total continence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bowen, Cheng, Hirsch, Huang, Meyer, Rosoklija, Chu and Yerkes.)

Oral administration (gavage) of a second-generation probiotic, Lactobacillus reuteri (L. reuteri), that releases interleukin-22 (LR-IL-22) at 24 h after total-body irradiation (TBI) mitigates damage to the intestine. We determined that LR-IL-22 also mitigates partial-body irradiation (PBI) and whole-abdomen irradiation (WAI). Irradiation can be an effective treatment for ovarian cancer, but its use is limited by intestinal toxicity. Strategies to mitigate toxicity are important and can revitalize this modality to treat ovarian cancer. In the present studies, we evaluated whether LR-IL-22 facilitates fractionated WAI in female C57BL/6 mice with disseminated ovarian cancer given a single fraction of either 15.75 Gy or 19.75 Gy or 4 daily fractions of 6 Gy or 6.5 Gy. Mice receiving single or multiple administrations of LR-IL-22 during WAI showed improved intestinal barrier integrity (P = 0.0167), reduced levels of radiation-induced intestinal cytokines including KC/CXCL1 (P = 0.002) and IFN-γ (P = 0.0024), and reduced levels of plasma, Eotaxin/CCL11 (P = 0.0088). LR-IL-22 significantly preserved the numbers of Lgr5+GFP+ intestinal stem cells (P = 0.0010) and improved survival (P < 0.0343). Female C57BL/6MUC-1 mice with widespread abdominal syngeneic 2F8cis ovarian cancer that received LR-IL-22 during 6.5 Gy WAI in 4 fractions had reduced tumor burden, less intestinal toxicity, and improved 30-day survival. Furthermore, LR-IL-22 facilitated WAI when added to Paclitaxel and Carboplatin chemotherapy and further increased survival. Oral administration (gavage) of LR-IL-22 is a potentially valuable intestinal radioprotector, which can facilitate therapeutic WAI for widespread intra-abdominal ovarian cancer., (©2022 by Radiation Research Society. All rights of reproduction in any form reserved.)

Background and Aim: The portal pressure gradient (PPG) is a useful predictor of portal hypertension (PH) related complications. We previously showed the feasibility and safety of endoscopic ultrasound guided PPG measurement (EUS-PPG). Now EUS-guided liver biopsy (EUS-bx) has been shown to be a safe and effective alternative to percutaneous or Interventional Radiology-guided liver biopsy for the diagnosis of chronic liver disease (CLD). We aimed to evaluate the correlation between PPG and clinical markers of PH, and assess the feasibility and safety of concomitant, single session EUS-PPG and EUS-bx., Methods: This was a retrospective study of patients undergoing EUS-PPG for CLD at a single tertiary endoscopy center between February 2014 and March 2020. EUS-PPG was performed using a 25-gauge needle and compact manometer. Data analysis was performed with SAS version 9.4., Results: Eighty-three patients underwent EUS-PPG with 100% technical success. The mean PPG was 7.06 mmHg (SD 6.09, range 0-27.3). PPG was higher in patients with (vs without) clinical features of cirrhosis (9.46 vs 3.61 mmHg, P < 0.0001), esophageal or gastric varices (13.88 vs 4.34 mmHg, P < 0.0001), and thrombocytopenia (9.25 vs 4.71 mmHg, P = 0.0022). In the 71 patients (85.5%) who underwent EUS-bx, 70 (98.6%) specimens were deemed adequate by the pathologist for histologic diagnosis. There were no early or late major adverse events., Conclusion: EUS-PPG correlates well with clinical markers of PH. EUS-bx can be performed safely during the same session as EUS-PPG, providing a comprehensive endoscopic evaluation of the patient with CLD., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Anterior inferior cerebellar artery (AICA) aneurysms are rare, less than 1%-2% of all intracranial aneurysms. Aneurysms of the distal AICA are even less common and can present with hearing loss and facial paralysis because of their relationship with the internal auditory canal (IAC). A 65-year-old male was followed for fluctuating left facial weakness and left-sided hearing loss for over a year. Serial magnetic resonance imaging (MRI) scans showed a mass near the left IAC, thought to be a vestibular schwannoma. Just prior to his next clinic visit, the patient deteriorated suddenly from a subarachnoid hemorrhage. Cerebral angiography revealed a 5.5 mm saccular aneurysm at the distal left AICA, which was clip ligated via a translabyrinthine (TL) approach. The patient had a good functional outcome (modified Rankin Scale [mRS] 1) after 30 days despite persistent left facial weakness. Stable obliteration of the aneurysm was demonstrated by cerebral angiography postoperatively. Distal AICA aneurysms are rare and can have a similar presentation to tumors in the cerebellar pontine angle. Because of the unique anatomy of the distal AICA, open clip ligation via a TL approach is an effective method to secure these aneurysms., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Liang et al.)

Nuclear radiation and radioactive fallouts resulting from a nuclear weapon detonation or reactor accidents could result in injuries affecting multiple sensitive organs, defined as acute radiation syndrome (ARS). Rapid and early estimation of injuries to sensitive organs using markers of radiation response is critical for identifying individuals who could potentially exhibit ARS; however, there are currently no biodosimetry assays approved for human use. We developed a sensitive microRNA (miRNA)-based blood test for radiation dose reconstruction with ±0.5 Gy resolution at critical dose range. Radiation dose-dependent changes in miR-150-5p in blood were internally normalized by a miRNA, miR-23a-3p , that was nonresponsive to radiation. miR-23a-3p was not highly expressed in blood cells but was abundant in circulation and was released primarily from the lung. Our assay showed the capability for dose estimation within hours to 1 week after exposure using a drop of blood from mice. We tested this biodosimetry assay for estimation of absorbed ionizing radiation dose in mice of varying ages and after exposure to both improvised nuclear device (IND)-spectrum neutrons and gamma rays. Leukemia specimens from patients exposed to fractionated radiation showed depletion of miR-150-5p in blood. We bridged the exposure of these patients to fractionated radiation by comparing responses after fractionated versus single acute exposure in mice. Although validation in nonhuman primates is needed, this proof-of-concept study suggests the potential utility of this assay in radiation disaster management and clinical applications., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objectives: To demonstrate the clinical feasibility of an articulated laparoscopic needle driver to assist in the performance of laparoscopic partial nephrectomy (LPN). Previous studies have demonstrated under-utilization of minimally invasive techniques for patients undergoing partial nephrectomy (PN)., Methods: Consecutive patients with renal masses amenable to PN underwent LPN with an articulating laparoscopic needle driver. A consecutive cohort of patients who previously underwent robot assisted laparoscopic PN (RALPN) was selected as a comparison cohort. Preoperative, perioperative, and postoperative variables were retrospectively collected., Results: A total of 20 patients underwent PN with 10 patients assigned to each of the LPN and RALPN cohorts. Median R.E.N.A.L. nephrometry scores assigned to the LPN and RALPN cohorts were 7 and 6 respectively (P= .31). Median warm ischemia time for patients in the LPN and RALPN groups was 25.5 and 18.5 minutes respectively (P= .36). Median estimated blood loss for LPN and RALPN was 200 and 50 mL (P= .03). Median operative time for LPN and RALPN was 203 and 194 minutes respectively (P= .76). Median Length of stay after LPN and RALPN was similar (3.0 vs 2.5 nights, P= .26). Following LPN, 3 patients required blood transfusion as compared to 2 patients in the RALPN cohort (P= .61)., Conclusion: Our initial results demonstrated the clinical safety and feasibility of a new surgical device for performing LPN. Patients who underwent LPN with a novel articulating needle driver demonstrated equivalent results to RALPN across several key outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Mitral valve prolapse (MVP) is a common valve condition and has been associated with sudden cardiac death. Premature ventricular contractions (PVCs) from the papillary muscles (PMs) may play a role as triggers for ventricular fibrillation (VF) in these patients., Objectives: To characterize the electrophysiological substrate and outcomes of catheter ablation in patients with MVP and PM PVCs., Methods: Of 597 patients undergoing ablation of ventricular arrhythmias during the period 2012-2015, we identified 25 patients with MVP and PVCs mapped to the PMs (64% female). PVC-triggered VF was the presentation in 4 patients and a fifth patient died suddenly during follow-up. The left ventricle ejection fraction (LVEF) was 50.5% ± 11.8% and PVC burden was 24.4% ± 13.1%. A cardiac magnetic resonance imaging was performed in nine cases and areas of late gadolinium enhancement were found in four of them. A detailed LV voltage map was performed in 11 patients, three of which exhibited bipolar voltage abnormalities. Complete PVC elimination was achieved in 19 (76%) patients and a significant reduction in PVC burden was observed in two (8%). In patients in which the ablation was successful, the PVC burden decreased from 20.4% ± 10.8% to 6.3% ± 9.5% (P = 0.001). In 5/6 patients with depressed LVEF and successful ablation, the LV function improved postablation. No significant differences were identified between patients with and without VF., Conclusions: PM PVCs are a source of VF in patients with MVP and can induce PVC-mediated cardiomyopathy that reverses after PVC suppression. Catheter ablation is highly successful with more than 80% PVC elimination or burden reduction., (© 2019 Wiley Periodicals, Inc.)

Glioblastoma multiform (GBM) is the most common malignant brain tumor characterized by poor prognosis, increased invasiveness, and high relapse rates. The relative survival estimates are quite low in spite of the standard treatment for GBM in recent years. Now, it has been gradually accepted that the amount of tumor mass removed correlates with longer survival rates. Although new technique advances allowing intraoperative analysis of tumor and normal brain tissue and functional paradigms based on stimulation techniques to map eloquent areas have been used for GBM resection, visual identification of tumor margins still remains a challenge for neurosurgeons. This article attempts to review and summarize the evolution of surgical resection for glioblastomas., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

Objectives: Stress urinary incontinence in women is a common problem that significantly impacts quality of life. Periurethral injection of urethral bulking agents (UBAs) is a simple, noninvasive, and cost-effective treatment. However, complications associated with UBA are often underappreciated. Objective of this review was to get a complete overview of all published complications of UBA., Methods: An extensive search of the scientific literature was conducted to quantitatively summarize the complications and their treatments of 8 UBAs. A total of 117 articles (original articles and case reports) were included in the final analysis. Complication incidence, treatment incidence, and follow-up time were extracted when mentioned. Statistical analysis of complication incidence of each UBA was calculated if possible., Results: A total of 2095 complications in 6462 treated patients were reported in 79 studies. Sixty-seven (3%) were considered serious implying operative correction (Clavien grade III); of these, 46 (69%) required incision and drainage, and 21 (31%) required a more invasive procedure. In 38 case reports and small case series, 49 patients were treated for 110 complications. Of these 110 complications, 41 (37%) can be classified as Clavien grade III., Conclusions: This extensive review shows that various UBAs have different complication rates, with certain UBAs being more prone to serious complications. Based on available publications, most UBAs have a good safety profile, with low complication rates. However, although the majority of UBA complications are transient and require no or noninvasive treatment, serious complications may require invasive intervention and treatment.

Thrombocytopenia or chronic depletion of platelets in blood, could create life-threatening conditions in patients who receive aggressive systemic radiation and chemotherapy. Currently there are no approved agents for the rapid treatment of thrombocytopenia. In the present study, we demonstrate that administration of Orientin, a glycosidic flavonoid or dietary administration of Orientin containing Tulsi (Holy Basil) leaves, results in a significant increase in circulating platelets in a clinically relevant mouse model. No noticeable effects were observed on red blood cells, white blood cells or other hematologic parameters in treated animals indicating that Orientin specificity enhances platelet formation. The gene expression and immunophenotyping of bone marrow revealed that Orientin stimulates megakaryopoiesis specific transcriptional program. A significant increase in colony formation in bone marrow cells from Orientin pretreated mice further complemented the effect of Orientin on progenitor cells. The ex-vivo differentiation of irradiated human peripheral blood CD34 + stem cells demonstrated stimulatory effects of Orientin on megakaryocyte erythrocyte progenitors (MEP). The results show that Orientin, a non-toxic readily available natural product can counter platelet imbalances. Thrombocytopenia also develop as a consequence of multiple hematologic malignancies and side effects of treatments. Dietary supplementation of Orientin containing phytochemicals could be effective as countermeasures and viable therapeutics.

Ureterocutaneous fistulas are rare, often iatrogenic complications. We present a case of a 60 year old woman suffering a ureterocutaneous fistula in association with an infected vascular graft. Percutaneous diversion of urinary fluid with a nephrostomy tube is an acceptable form of management.

Background: The subcutaneous implantable cardioverter defibrillator (S-ICD) is a novel implanted defibrillator for the prevention of sudden cardiac death that avoids intravascular access. Use of this device is limited by its inability to provide backup pacing. Combined use of the S-ICD with a permanent pacemaker may be the optimal choice in certain situations though experience with the use of both devices together remains limited., Methods: We reviewed our single-center experience with the S-ICD from March 2011 to November 2015. Four patients with concomitant use of the S-ICD and a permanent pacemaker were identified. Clinical indication for device therapy, operative details, and subsequent follow-up was reviewed. During implantation, S-ICD sensing of paced morphologies was evaluated at maximal voltage output. After S-ICD implant, if feasible, the upper rate was adjusted to ≤50% of the S-ICD tachycardia zone to minimize risk of inappropriate shocks., Results: After a mean follow-up of over 1 year, no adverse events occurred, including no inappropriate shock, lead malfunction, or device infection. One patient had a total of eight appropriate shocks, while another individual had no inappropriate shocks despite having a unipolar pacing lead., Conclusions: In unique situations, combined use of the S-ICD and a permanent pacemaker may be preferable to alternative options. In our experience, this approach was successful in varying conditions including complex congenital heart disease, recurrent device infection, and limited vascular access., (© 2016 Wiley Periodicals, Inc.)

Objective: To evaluate the efficacy and safety of tapentadol immediate-release (IR) for treating acute pain following orthopedic bunionectomy surgery in a Taiwanese population., Methods: This was a phase 3, randomized, double-blind, placebo-controlled, parallel-group bridging study in which Taiwanese patients (N = 60) with moderate-to-severe pain following bunionectomy were randomized (1:1:1) to receive tapentadol IR 50 or 75 mg or placebo orally every 4-6 hours over a 72 hour period. The primary endpoint was the sum of pain intensity difference over 48 hours (SPID48), analyzed using analysis of variance., Results: Out of 60 patients randomized (mainly women [96.7%]; median age 44 years), 41 (68.3%) completed the treatment. Mean SPID48 values were significantly higher for tapentadol IR (p ≤ 0.006: 50 mg, p ≤ 0.004: 75 mg) compared with placebo. Between-group differences in LS means of SPID48 (vs. placebo) were tapentadol IR 50 mg: 105.6 (95% CI: 32.0; 179.2); tapentadol IR 75 mg: 126.6 (95% CI: 49.5; 203.7). Secondary endpoints including SPID at 12, 24, and 72 hours, time to first use of rescue medication, cumulative distribution of responder rates, total pain relief and sum of total pain relief and sum of pain intensity difference at 12, 24, 48, and 72 hours, and patient global impression of change showed numerically better results supporting that tapentadol IR (50 and 75 mg) was more efficacious than placebo in relieving acute pain. The most frequent treatment emergent adverse events reported in ≥ 10% patients in either group were dizziness, nausea, and vomiting. A limitation of this study may possibly include more controlled patient monitoring through 4-6 hour dosing intervals, which reflects optimal conditions and thus may not approximate real-world clinical practice. However, all treatment groups would be equally affected by such bias of frequent monitoring, if any, since it was a randomized and double-blind study., Conclusions: Tapentadol IR treatment significantly relieved acute postoperative pain and was well tolerated in a Taiwanese population. ClinicalTrials.gov identifier: NCT01813890.

The evaluation of concussed athletes, including testing to determine if and when they may return to play, has become an important task of athletic trainers and team physicians. Currently, concussion protocols are in place, which depend largely upon assessments based upon neurocognitive testing (NCT). The authors have evaluated the use of a biomarker of brain trauma, marinobufagenin (MBG), and compared its application in concussed athletes with the performance of NTC. We found a disparity between these two testing procedures. In this communication, the findings of these comparative data are presented. We noted that athletes whose NCT evaluations had returned to baseline and who were allowed to again participate in play then showed a recurrence of elevated urinary MBG excretion. These observations raise concern as to the processes currently in effect with regard to the decision as to returning athletes to the full activity. They suggest a need for further evaluation.

Differential diagnosis between intramedullary tumors and tumor-like lesions (TLL) in the cervicomedullary junction region and cervical spinal cord is important, sometimes clinical dilemma on conventional MR imaging and empirical treatment. We evaluated advanced MR diffusion tensor imaging (DTI) and perfusion weighted imaging (PWI) in 25 patients, including 12 with intramedullary tumors and 13 with TLL in the cervicomedullary junction region and cervical spinal cord. We found that mean fractional anisotropy value of tumors was significantly lower than the value found in TLL, and the mean trace apparent diffusion coefficient and peak height values of tumors were significantly higher (P < 0.05). The receiver operating characteristic curve analysis showed that peak height was better than any of the other imaging parameters, with a sensitivity of 90.9% and specificity of 80% using a cutoff value of 4.523 to differentiate between tumors and TLL. In conclusion, the MR DTI and PWI could be useful in differentiating between intramedullary tumors and TLL in the cervicomedullary junction region and cervical spinal cord.

We report the formation of solid-state nanopores using a scanning helium ion microscope. The fabrication process offers the advantage of high sample throughput along with fine control over nanopore dimensions, producing single pores with diameters below 4 nm. Electronic noise associated with ion transport through the resultant pores is found to be comparable with levels measured on devices made with the established technique of transmission electron microscope milling. We demonstrate the utility of our nanopores for biomolecular analysis by measuring the passage of double-strand DNA.

Human recombinant activated factor-VII (rFVIIa) has been used successfully in the treatment of spontaneous intracerebral hemorrhage. In addition, there is increasing interest in its use to treat uncontrolled bleeding of other origins, including trauma. The aim of this study was to evaluate the safety and potential effectiveness of rFVIIa to mitigate bleeding using a clinically relevant model of traumatic brain injury (TBI) in the pig. A double injury model was chosen consisting of (1) an expanding cerebral contusion induced by the application of negative pressure to the exposed cortical surface and (2) a rapid rotational acceleration of the head to induce diffuse axonal injury (DAI). Injuries were performed on 10 anesthetized pigs. Five minutes after injury, 720 microg/kg rFVIIa (n=5) or vehicle control (n=5) was administered intravenously. Magnetic resonance imaging (MRI) studies were performed within 30 min and at 3 days post-TBI to determine the temporal expansion of the cerebral contusion. Euthanasia and histopathologic analysis were performed at day 3. This included observations for hippocampal neuronal degeneration, axonal pathology and microclot formation. The expansion of contusion volume over the 3 days post-injury period was reduced significantly in animals treated with rFVIIa compared to vehicle controls. Surprisingly, immunohistochemical analysis demonstrated that the number of dead/dying hippocampal neurons and axonal pathology was reduced substantially by rFVIIa treatment compared to vehicle. In addition, there was no difference in the extent of microthrombi between groups. rFVIIa treatment after TBI in the pig reduced expansion of hemorrhagic cerebral contusion volume without exacerbating the severity of microclot formation. Finally, rFVIIa treatment provided a surprising neuroprotective effect by reducing hippocampal neuron degeneration as well as the extent of DAI.

Methylisothiazolinone (MIT) is a biocide widely used in industrial and cosmetic products with potential as a neurotoxicant. We previously reported that short acute exposures to relatively high concentrations of MIT (100 microM) lead to widespread and selective neuronal death in vitro. To evaluate the biological properties of chronic exposures to MIT, freshly dissociated rat cortical neurons were continuously exposed to low concentrations (0.1-3 microM) of the biocide in serum-containing media. Although we observed minimal effects on cell viability, MIT induced a dramatic inhibition of neurite outgrowth. Immunoblotting and immunoprecipitation experiments revealed that focal adhesion kinase (FAK) phosphorylation was primarily affected by the MIT treatment. The phosphorylation level at tyrosines 576 and 861 of FAK was significantly decreased and likely contributed to the overall reduction of tyrosine phosphorylation of this protein. MIT inhibited Src family kinases (SFKs) in cell-free assays and led to the physical dissociation of FAK from the signaling complexes that it normally forms with c-Src and Fyn in developing neurons. High-density neuronal cultures were then employed to increase cell-to-cell contact. This approach resulted in an overall enhancement of SFKs and FAK phosphorylation and could overcome the deficits induced by MIT. This study suggests that a disruption of FAK-SFK complexes due to SFK inhibition leads to FAK dysfunction, with detrimental effects to immature neurons. Prolonged exposure to low levels of MIT and related compounds may have damaging consequences to the developing nervous system.

This retrospective case analysis investigated the epidemiology of eyelid tumors in a subtropical area. The study assessed the proportion of all eyelid tumors that were malignancies, the accuracy of diagnosis, and surgical results. We retrospectively collected all cases of eyelid tumors in the Department of Ophthalmology, Kaohsiung Medical University, Taiwan, between January 1994 and December 1998. Among the 144 cases collected, about half of the tumors were located in the upper eyelids and the other half in the lower eyelids. Nearly 50% of cases underwent tumor resection with eyelid reconstruction. When followed up to April 1999, 97% of patients were satisfied with the surgical results. There were 18 cases (12.5%) of malignant tumors, including 14 basal cell carcinomas, three sebaceous carcinomas, and one squamous cell carcinoma. Before surgery, two malignancies were presumed to be benign tumors while another two were thought to be different malignant tumors. The benign tumors included 38 nevi, 15 squamous papillomas, 13 cysts, 11 verrucae, 10 seborrheic keratoses, four hemangiomas, and others. All tumors that were thought to be malignancies were treated using complete resection with margin monitoring by frozen section. At the end of follow-up, no recurrence was noted. More than 10% of cases of eyelid tumors in this subtropical teaching hospital were malignant. All surgeons should be alert to this phenomenon when they operate on an eyelid tumor. The best policy is to send all specimens for pathologic examination.

Electromagnetic fields have been used to augment the healing of fractures because of its ability to increase new bone formation. The mechanism of how electromagnetic fields can promote new bone formation is unknown, although the interaction of electromagnetic fields with components of the plasma membrane of cells has been hypothesized to occur in bone cells. Gap junctions occur among bone forming cells, the osteoblasts, and have been hypothesized to play a role in new bone formation. Thus it was investigated whether extremely low-frequency (ELF) magnetic fields alter gap junction intercellular communication in the pre-osteoblastic model, MC3T3-E1, and the well-differentiated osteoblastic model, ROS 17/2.8. ELF magnetic field exposure systems were designed to be used for an inverted microscope stage and for a tissue culture incubator. Using these systems, it was found that magnetic fields over a frequency range from 30 to 120 Hz and field intensities up to 12.5 G dose dependently decreased gap junction intercellular communication in MC3T3-E1 cells during their proliferative phase of development. The total amount of connexin 43 protein and the distribution of connexin 43 gap junction protein between cytoplasmic and plasma membrane pools were unaltered by treatment with ELF magnetic fields. Cytosolic calcium ([Ca(2+)](i)) which can inhibit gap junction communication, was not altered by magnetic field exposure. Identical exposure conditions did not affect gap junction communication in the ROS 17/2.8 cell line and when MC3T3-E1 cells were more differentiated. Thus ELF magnetic fields may affect only less differentiated or pre-osteoblasts and not fully differentiated osteoblasts. Consequently, electromagnetic fields may aid in the repair of bone by effects exerted only on osteoprogenitor or pre-osteoblasts., (Copyright 2002 Wiley-Liss, Inc.)